•  Take frequent short rest breaks (559)

•  Spend time in low-stimulation environment (198)

•  Rest (572)

•  Personal development (e.g. learn to say 'no', care less about opinion others, letting go of shoulds and musts, acceptance, become more relaxed and balanced) (450)

•  Wheelchair (66)

•  Ignore people who think ME/CFIDS is not real (363)

•  Low-Dose Naltrexone (LDN) (89)

•  Avoid biotoxins (82)

•  Complete stillness & quiet (154)

•  Diet changes (509)

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•  Adequate rest (49)

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•  Go to bed early and sleep longer (448)

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AMPLIGEN

DESCRIPTION. Ampligen (poly I:poly C12U) is a mismatched double-stranded RNA (ribonucleic acid) with immodulatory and antiviral properties. Because Ampligen has not yet been approved by the Food and Drug Administration (FDA), its use to date has been experimental.

BACKGROUND. In the early 1980s, a molecule called Poly(I)-Poly(C) was discovered to inhibit tumor growth and stimulate interferon production. As a result, it was used in a number of cancer trials. However, it was found that the substance made patients quite ill with serious side effects. While Poly(I)-Poly(C) was extremely toxic, the toxicity decreased significantly when the structure of the RNA was altered. Fortunately, the effectiveness of the new substance (Ampligen) was not diminished, despite the change in structure.

In 1987 Ampligen was used experimentally in a small group of patients with AIDS (acquired immunodeficiency syndrome). The positive results of this trial seemed to confirm the claim that Ampligen works by enhancing natural killer cell function and influencing the 2-5A synthetase pathway. This pathway is vital in the defense against viral infections. According to Dr. Robert Suhadolnick of Temple University in Philadelphia, there are defects in key components in the antiviral system in some CFS/ME patients, the most notable of which are low latent 2-5A synthetase and upregulated RNase (ribonuclease) L activity (Journal of Interferon and Cytokine Research, 1997). Ampligen is thought to correct both of these defects.

USES IN CFS/ME. In August 1988, Dr. Daniel Peterson, a pioneer in CFS/ME treatment, was the first physician to use Ampligen on an extremely ill patient with CFS/ME. Because of the severity of the patient's illness, Dr. Peterson was able to obtain permission from the FDA to use Ampligen under compassionate care status. The results were impressive and encouraging. One year into therapy the patient had recovered near-normal function in some areas and demonstrated a 46-point increase in IQ. This justified the next pilot study by Dr. Peterson, as well as several other formal studies conducted independently.

At the 1990 CFIDS Conference in Charlotte, North Carolina, and at the Cambridge Symposium, Dr. Peterson reported positive results after treating 15 patients with Ampligen. At the end of 24 weeks, most of the patients demonstrated increased performance status (using Karnofsky scores) and exercise tolerance (as measured by treadmill testing). Cognitive improvement was demonstrated by improved memory and increased IQ scores. No significant toxicity was reported. Ampligen's antiviral properties were confirmed by evidence that human herpesvirus 6 (HHV-6) reactivation was absent after treatment and abnormal components of the 2-5A pathway returned to normal range. It is of interest that of the two or three patients who did not respond to Ampligen therapy, the only significant pretreatment difference was measurable differences in 2-5A synthetase pathways.

The encouraging results of Dr. Peterson's study paved the way for a larger FDA-approved double-blind study in 1991 involving 92 patients in four U.S. cities. Again the results were encouraging. Many of the participants had been severely disabled before treatment and required assistance for simple daily activities. More than half of those in the study who received Ampligen demonstrated improvement and many were able to carry out daily activities with minimal assistance.

A study in Brussels, Belgium, presented at the 1996 American Association for Chronic Fatigue Syndrome (AACFS) Conference, to evaluate the safety and efficacy of intravenously administered Ampligen also showed encouraging results. Eleven patients with myalgic encephalomyelitis (ME) were given intravenous Ampligen twice a week for 24 weeks. The Belgian physicians reported that at the end of 24 weeks, all 11 experienced some improvement. In addition, no adverse effects to treatment were noted. These positive results paved the way for expanded trials. It was hoped that with an expansion of clinical trials to Canada and Belgium, and Ampligen's subsequent approval for Canada's Emergency Drug Release Program, that the drug would soon be approved for use in the U.S.

Unfortunately, since 1996 little progress has been made in obtaining FDA approval of the drug. A seemingly endless series of lawsuits, missed deadlines and administrative setbacks effectively quashed the widespread support the drug had enjoyed in the 90s. To cap the matter, in 2009, after the completion of Phase III of Ampligen's drug trials, the FDA refused to grant Ampligen “new drug,” status which, in effect, relegated Ampligen once more to clinical trials.

PROTOCOL. Because this drug is still, after more than twenty years, in the trial phase, treatment protocols are still evolving. Ampligen is quite fragile, which makes administration difficult (it must be given intravenously). Two intravenous injections a week of 400 mg are given over a 6- to 12-month period, though some doctors recommend a course of treatment up to 18 months for more severely ill patients. Longer courses of treatment seem to produce longer lasting results.

PROS. No other drug has received more attention from the CFS/ME community than Ampligen. But even in the wake of delays, reversals and lawsuits, many doctors still defend Ampligen as the most effective drug for those patients who have acute viral onset, persistent herpesvirus infections, depressed natural killer cell function, and 2-5A synthesase/RNase L up-regulation. For those who have been bedridden for years, who are confined to wheelchairs, and whose lives have lost all semblance of normality,Ampligen may be a godsend, and the frustration of those who have experienced a return to a functional life during Ampligen trials, only to have it taken away again at the end of the trial, is more than justified.

Dr. Kenny DeMeirleir claims that close to 80% of his patients reported “complete clinical recovery” after taking an extended course of treatment. Patients report improvement in overall function, energy levels, cognitive performance, and some have been able to return to work. Dr. Lapp, who has been using Ampligen since 1998, reports significant improvement in 50% of his severely ill patients. It is important to note that while few doctors claim that Ampligen works for the majority of their patients, it seems to have a very positive effect on a subset of those who are the most seriously ill, and that, in and of itself, provides a good reason for Hemispherx to pursue Ampligen's final approval.

CONS. Although test results are encouraging, it is important to note that Ampligen is not a surefire cure. The percentage of patients who demonstrate substantial improvement with the drug has yet to be determined. Side effects are common. Although Hermispherx maintains that Ampligen is generally well tolerated, patients have reported diarrhea, constipation, flushing, temporary vision loss, muscle aches, depression, loss of libido, dizziness, chills, fever, malaise, anxiety, and loss of energy.

Dr. Peterson reported at the 1990 CFIDS Conference that some patients experienced an interferon-like reaction, with headaches, myalgias, and, rarely, hair loss. A puzzling effect noted by Dr. Paul Cheney was that although patients report overall lessening of symptoms, particularly cognitive symptoms, they do not necessarily equate this lessening of severity to “feeling good” (CFIDS Chronicle, Physicians Forum, 1991). Side effects usually subside after several months, but that may be too long for many patients to endure.

AVAILABILITY AND COST. As of 2011, Ampligen is available only at Dr. Lapp's Hunter-Hopkins clinic in Charlotte, NC, and Dr. Peterson’s Lake Tahoe clinic under an open-label trial. (An open-label trial is one in which all patients receive, and pay for, the drug.) Dr. Bateman’s Fatigue Consultation Clinic in Salt Lake City and Dr. Enlander's clinic in New York have also begun to seek recruits for an open-label trial. Hemispherx is planning to add several other sites around the U.S., as well as sites in Mexico and Argentina. In July 2012, Hemispherx announced that it had submitted a new drug application to ANMAT (Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica), the agency responsible for the national regulation of drugs, foods and medical technology in Argentina, under the ANMAT's Orphan Drug regulations.

Ampligen is quite expensive. A single infusion costs $150. At two infusions a week, that amounts to $1200 per month. Additional costs, such as medical visits, lab work and the administration of the infusions, can amount to $1000 a month. Altogether, one year of treatment will cost over $24,000. Patients must pay for the cost of the treatment because Ampligen is available on a cost recovery basis only. Some insurers will reimburse for administration costs and lab work, which can save roughly $12,000 a year. Medicare does not cover any expenses for investigational therapies.

MORE INFORMATION

The Hunter-Hopkins Center's report from the 9th Hemispherx Biopharma investigators meeting. Quite technical but very thorough: http://www.drlapp.net/meLetterMar2011.htm

NIH webpage on clinical trials. Shows current status of Ampligen trials. http://www.clinicaltrials.gov/ct2/show/NCT00215813?term=00215813&rank=1

Informative thread on patients' experiences with Ampligen. http://forums.phoenixrising.me/showthread.php?12999-Ampligen-Experiences

Dr. Lapp's Ampligen protocol: http://www.drlapp.net/ampligen.htm

Hemispherx Biopharma's page on Ampligen. http://www.hemispherx.net/content/rnd/drug_candidates.htm

A fascinating blog written by a New Zealand journalist who moved to the U.S. to participate in an open-label Ampligen trial: http://ampligen-treatment.blogspot.com/

San Francisco Ampligen trial (with prices): http://phoenixrising.me/forums/showthread.php?12305-Ampligen-Treatment-Study-(AMP-511)-starting-in-San-Francisco-Bay-Area

ProHealth's history of Ampligen: http://aboutmecfs.org.violet.arvixe.com/Trt/AmpHist.aspx

Cort Johnson's up-to-date news on the status of Ampligen: http://phoenixrising.me/archives/8819?utm_source=newsletter+subscribers&utm_campaign=9dd3ad21ce-April_Newsletter4_28_2012&utm_medium=email

ANTIBIOTICS

DESCRIPTION. Antibiotics (derived from the Greek anti meaning 'against', and bios meaning 'life') are substances that either kill microbes or inhibit their growth.

BACKGROUND. As with so many monumental discoveries, antibiotics are the result of a mistake. In 1928, Alexander Fleming, a brilliant (but messy) Scottish biologist, was investigating the properties of the bacterium staphylococcus. He had left his samples piled up on a bench before going away on holiday. When he returned, he discovered that one of the petri dishes had been invaded by mold, and that the bacteria that had come into contact with the mold had died. After overcoming his initial annoyance, Fleming realized that he had stumbled across a remarkable substance. He named it penicillin.

Since Fleming's remarkable discovery, antibiotics have become an integral feature of modern medicine. Their ability to kill bacteria and protozoa has saved millions of lives worldwide, making them one of the medical miracles of our time. However, Fleming noted that when antibiotics were used at too low a dose, or for too little time, the bacteria would become resistant. With the passage of time, it turned out that bacteria become resistant even with the proper administration of antibiotics. (Any microbe will adapt to a changing environment, producing, in the end, a stronger version.) This has led to the development of ever-stronger antibiotics, which, inevitably, have produced “super bugs” – bacteria which are resistant to all antibiotic therapy.

Basically, antibiotics kill bacteria by inducing oxidative stress. This is the same mechanism through which many parts of the immune system kill bacteria. Given the fact that bacteria are living organisms, it should not come as a surprise that bacteria utilize many of the same mechanisms to protect themselves from oxidative stress as do other cells. A recent study led by Evgeny Nudler, a professor of biochemistry at New York University, showed that nitric oxide (NO) produced by bacteria neutralizes many antibacterial compounds. By using NO's ability to destroy attackers, bacteria cleverly employ the body's own defense mechanisms to ward off the effects of antibiotics.

USES IN CFS/ME. The idea that CFS/ME is caused by a “bug” is not a new one. As early as the 1930s it was thought that CFS/ME (then called “atypical polio”) was caused by an enterovirus. The close association with Epstein-Barr virus (EBV) and other endemic viruses, as well as well-documented high levels of viral markers in CFS/ME patients, has led researchers to conclude that the illness is caused by a virus. However, a small, but significant, number of researchers has proposed the active involvement of bacteria in the development of CFS/ME.

One of the first researchers to propose a causal role for bacteria was Garth Nicolson. Nicolson found that both CFS/ME and Gulf War Syndrome (GWS) patients were infected with mycoplasma. (Mycoplasma are bacteria that lack a cell wall, and are thus impervious to many antibiotics). Nicolson proposed that ongoing mycoplasma infections were responsible for many immunological anomalies associated with both CFS/ME and GWS. He successfully treated GWS and CFS/ME patients with long courses of different antibiotics to eradicate mycoplasma infections. In a subsequent study, Nicolson found that many patients diagnosed with CFS/ME were subsequently diagnosed with Lyme Disease, which is caused by a rickettsial bacterium.

Several fascinating studies have indicated a causative role for rickettsial and chlamydial bacterial infections in CFS/ME. Phillipe Bottero, a French doctor practicing in Paris, found that all of his CFS patients tested positive for bacterial infections. An impressive 78.5% of Bottero's 98 CFS patients improved significantly after treatment with antibiotics. (His article is in Chronic Fatigue Syndrome: Critical Reviews and Clinical Advances). A smaller second group, composed of patients diagnosed with ADHD, schizophrenia and autism also showed a similar rate of improvement. Bottero proposed that due to the long survival of rickettsial infections in vascular linings, the resulting vasculitis could produce many of the symptoms common in CFS/ME.

Cecile Jadin, a Belgian surgeon, also found strong correlations between rickettsial infections and patients diagnosed with CFS/ME. Jadin reversed symptoms in five hundred patients previously diagnosed with CFS, FM, MS, depression, heart disease, and psychosis with a simple course of tetracycline.

In 2009 Frykholm found that ninety days of treatment with antibiotics, combined with vitamin B injections, cured one of his CFS/ME patients. When two patients with long-standing and incapacitating CFS/ME came to his clinic in 2007 he treated them both with antibiotics. After sixty days the first showed excellent improvement which continued on follow-up one year later, whereas the second, who also took antibiotics for sixty days, showed a significant improvement. While studies of this kind may ultimately raise more questions about the process of diagnosis than to etiology, it is nonetheless interesting to consider the role that bacterial infections play in perpetuating, if not causing, CFS/ME.

In the 1990s, Luther Lindner, a pathologist at Texas A&M, believed he had found the elusive agent that was the cause of CFS/ME, as well as other autoimmune diseases. While examining the blood of an MS patient, he found a novel bacterium. Lindner then identified the bacterium in the blood of patients with CFS/ME. Though the prospect of having discovered a potential cure for the illnesses was exciting, Lindner was cautious in his treatment recommendations. For while he noted good short-term response in CFS/ME patients, he also noted that the new strain was highly resistant to antibiotic treatment. Lindner cautioned against the use of antibiotic regimens without monitoring the number of organisms present. Paradoxically, he also found that “antibiotics can actually stimulate bacterial growth and make the patient worse.” He added that this can usually be predicted by sensitivity testing. Indeed, Lindner's theories may be borne out by the significant number of CFS/ME patients who report having taken long courses of antibiotics before falling ill.

An entirely different role for antibiotics as a CFS/ME treatment was explored by Vermeulen and Scholte. In their retrospective study of 99 CFS/ME patients, 58 patients reported a decrease in symptoms after taking azithromycin. All of the responding patients had low levels of acetylcarnitine. The authors concluded that “the efficacy of azithromycin in the responsive patients could be explained by the modulating effect on a chronic primed state of the immune cells of the brain, or the activated peripheral immune system. Their lower acetylcarnitine levels may reflect a decreased antioxidant defense and/or an increased consumption of acetylcarnitine caused by oxidative stress.” In short, the azithromycin was functioning as an immune system modulator in these cases, rather than as a bactericide.

PROTOCOL. Most CFS/ME physicians prescribe antibiotics when there is a clear indication of a bacterial infection. However, there are some protocols that involve low-dose antibiotics as part of an overall treatment strategy. The Marshall Protocol uses pulsed low-dose antibiotics to treat CFS/ME even in the absence of an active bacterial infection.

Dr. Teitelbaum also uses antibiotics to treat hidden infections. These are indicated if the patient has chronic lung congestion, low fever, recurrent scalp sores, a history of a bad reaction to other antibiotics, transient improvement with antibiotics, vertigo, and severe night sweats. In these instances, Dr. Teitelbaum assumes the presence of a bacterial infection that may be difficult to detect (e.g., Lyme, mycoplasma, chlamydia) and recommends a long course of antibiotics. Dr. Nicolson's course of antibiotic treatment can last as long as two years.

PROS AND CONS. CFS/ME patients report that antibiotics of various kinds can both exacerbate and improve symptoms. Common side effects include nausea, “brain fog”, and GI disturbances. Most CFS/ME patients find that they do better “pulsing” with low-dose antibiotics, and that longer courses of treatment are either ineffective or cause relapse. Some report that after initial “miraculous” improvement, they became much worse. A small number of patients have reported dramatic improvement.

FURTHER READING

“Study explains bacteria's resistance to antibiotics.” AFP Sept 13, 2009. http://www.google.com/hostednews/afp/article/ALeqM5jbBIAufNyKV0owj4rc08LmSA5GKg

Technical article explaining the mechanisms of antibiotics http://www.bu.edu/abl/files/nrm_kohanski.pdf

Garth Nicolson's article on the role of bacterial infections in CFS/ME and Gulf War Syndrome. http://www.immed.org/illness/fatigue_illness_research.html

Garth Nicolson's antibiotic protocols http://www.newtreatments.org/doc/Mycoplasma/12

Good summary of Nicolson's theories and protocols http://www.rense.com/general7/microplasm.htm

Doris Jones proposes that antibiotics may be the cause of CFS/ME. http://www.prohealth.com/fibromyalgia/blog/boardDetail.cfm?id=1015520&b1=CHWEBO

Ringing in ears caused by minocycline http://forums.phoenixrising.me/showthread.php?9291-Minocyclin

Article on Luther Linder's research: http://ottem.org/ccca/news/newsletters/vol16-1.htm

Luther Lindner's explanation of why antibiotics might potentially make CFS/ME worse. http://www.thisisms.com/forum/antibiotics-f28/topic572.html

Marshall Protocol and pulsed, low-dose antibiotics http://mpkb.org/home/protocol/mp_antibiotics

Dr. Teitelbaum on the use of antibiotics in CFS/ME http://www.endfatigue.com/health_articles_f-n_2/Infections-treating_hidden_antibiotic_cfs_fm.html

RESEARCH

Frykholm BO. “On the question of infectious aetiologies for multiple sclerosis, schizophrenia and the chronic fatigue syndrome and their treatment with antibiotics.” Med Hypotheses. 2009 Jun;72(6):736-9. http://www.ncbi.nlm.nih.gov/pubmed/19269110 (Abstract)

Nicolson, Garth L, Nancy L. Nicolson, and Joerg Haier. “Chronic Fatigue Syndrome Patients Subsequently Diagnosed with Lyme Disease Borrelia burgdorferi:

Evidence for Mycoplasma species Co-Infection.” Journal of Chronic Fatigue Syndrome. 2008; 14(4): 5-17. http://www.lymepa.org/Chronic%20Fatigue%20Syndrome%20patients%20subsequently%20diagnosed%20with%20Lyme%20disease%20and%20coinfections.pdf

Vermeulen RC, Scholte HR. “Azithromycin in chronic fatigue syndrome (CFS), an analysis of clinical data.” J Transl Med. 2006 Aug 15;4:34. http://www.ncbi.nlm.nih.gov/pubmed/16911783(Abstract)

PATIENT REVIEWS

CFS/ME patient reviews of doxycycline: http://www.revolutionhealth.com/drugs-treatments/rating/doryx-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Zithromax: http://www.revolutionhealth.com/drugs-treatments/rating/zithromax-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Biaxin: http://www.revolutionhealth.com/drugs-treatments/rating/biaxin-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of minocycline: http://www.revolutionhealth.com/drugs-treatments/rating/minocin-for-chronic-fatigue-syndrome-cfs-cfids-me

BOOK

Patarca Montero, Roberto and Kenny De Meirleir. Chronic Fatigue Syndrome: Critical Reviews and Clinical Advances. Informa Healthcare; 1st edition (October 30, 2000).

ANTICONVULSANTS

Gabapentin (Trade name:Neurontin), Gabitril, Lyrica (pregabalin)

Anticonvulsants are used to treat seizure disorders (epilepsy). More recently, they have been used to treat neuropathic pain, anxiety and insomnia. The most commonly prescribed anticonvulsants for CFS/ME are Neurontin (generic: gabapentin), Gabitril, and Lyrica (pregabalin).

FURTHER READING

Maija Haavisto's website: http://maija-haavisto.suite101.com/anticonvulsants-cfsme-and-fm-a65954

Good overview of the use of anticonvulsants for CFS/ME and FM.

GABAPENTIN (NEURONTIN)

DESCRIPTION: Gabapentin (trade name: Neurontin) is a GABA (gamma aminobutyric acid) analogue used to treat epilepsy.

BACKGROUND. GABA is the chief inhibitory neurotransmitter in the nervous system. Basically, nerves have only two responses to stimuli—either they fire, or they don't. The role of GABA in the nervous system is to prevent neurons from firing, essentially turning them off. As the nervous system depends on a balance of chemicals that promote firing (excitatory neurotransmitters) and those that don't (inhibitory neurotransmitters), GABA serves an essential regulatory function. Without GABA too many neurons would fire at once, resulting in seizures.

Neurontin was originally approved by the FDA for the treatment of epilepsy. However, since its approval, it has been marketed for many off-label uses, including pain, headaches, alcohol and cocaine withdrawal, hiccups, restless leg syndrome, hot flashes and fibromyalgia. In 2004, in one of the biggest lawsuits in pharmaceutical history, Pfizer, the manufacturer of Neurontin, was sued for fraud based on its marketing of the drug for many of these off-label purposes. A second lawsuit claimed that Pfizer engaged in "outright deception of the biomedical community, and suppression of scientific truth." However costly for Pfizer, lawsuits for off-label uses have not prevented doctors from continuing to prescribe Neurontin for insomnia, pain, anxiety disorders, and diabetes.

USES IN CFS/ME. Dr. Jay Goldstein (now retired) was one of the early proponents of Neurontin as a CFS/ME treatment. His theory was that the brain needed to be “reset” in CFS/ME patients, and to accomplish that goal, he used Neurontin. Dr. Seastrunk, a psychiatrist in Texas, believed that Neurontin helped minimize focal brain injury in CFS/ME and FMS patients. Dr. Cheney has also included Neurontin in his treatment protocol, believing that it exerts a protective effect on the brain.

In 2007, research supported by the National Institutes of Health's National Institute of Arthritis and Musculoskeletal and Skin Diseases showed that gabapentin can be an effective treatment for fibromyalgia. In a randomized, double-blind trial of 150 patients with FM, researchers found that patients taking daily doses of 1,200 to 2,400 mg of gabapentin experienced significantly less pain than those taking placebo.

PROTOCOL. Dr. Goldstein recommended a total daily dose of 5,000 mg (if lower doses were not beneficial). However, he first tested his patients with only 100-800 mg for possible reactions. Dr. Seastrunk recommended starting with small doses and increasing to 3,200 mg a day, taken throughout the day. Dr. Cheney's protocol started at 300 mg, taken three times a day. Dr. Teitelbaum recommends beginning with 100-300 mg at night, and slowly increasing up to 300-900 mg taken three times a day.

PROS AND CONS. CFS/ME patients report that gabapentin helps with pain and insomnia. However, because gabapentin reduces neuronal firing, it can also produce dizziness, tingling, “brain fog,” and a “drunk” feeling. One of the reported side effects is an increase in bladder pain among people with interstitial cystitis. When going off gabapentin, slowly decreasing the dose rather than stopping all at once is advised.

AVAILABILITY AND COST. Gabapentin (generic) is available at any pharmacy. It requires a prescription. A 100-tablet bottle (100 mg) costs from $24 to $32. Insurance usually covers.

FURTHER READING

Good description of the different function that GABA plays in the nervous system. http://www.denvernaturopathic.com/news/GABA.html

National CFS/ME foundation's report on Neurontin: http://www.ncf-net.org/forum/neurontin98.htm

“Neurontin and Brain Injury Treatment.” Dr. Seastrunk's views on Neurontin: http://www.ncf-net.org/forum/neurontin98.htm

“Researchers explore many uses for Neurontin; no CFS/ME trials planned.” CFIDS Chronicle, March-April 1999 http://www.cfids.org/archives/1999/1999-2-article04.asp

“Gabapentin Shown Effective for Fibromyalgia Pain.” http://members.boardhost.com/WellnessTrain/msg/1188292455.html

RESEARCH

Foldvary-Schaefer N, De Leon Sanchez I, Karafa M, Mascha E, Dinner D, Morris HH. “Gabapentin increases slow-wave sleep in normal adults.” Epilepsia. 2002 Dec;43(12):1493-7. http://www.ncbi.nlm.nih.gov/pubmed/12460250 (Abstract)

Kesselheim AS, Darby D, Studdert DM, Glynn R, Levin R and Avorn J. “False claims act prosecution did not deter off-label drug use in the case of neurontin.” Health Aff (Millwood). 2011 Dec;30(12):2318-27. http://www.ncbi.nlm.nih.gov/pubmed/22147859 (Abstract)

PATIENT REVIEWS

A woman with interstitial cystitis recounts her experience with Neurontin: http://www.ic-network.com/iclifestyles/may03.html

CFS/ME patient reviews of Neurontin: http://www.revolutionhealth.com/drugs-treatments/rating/neurontin-for-chronic-fatigue-syndrome-cfs-cfids-me

GABITRIL

DESCRIPTION. Gabitril (generic: tiagabine) is a selective GABA reuptake inhibitor used to treat seizure disorders.

BACKGROUND. Gabitril was first developed in 1988 by the Danish pharmaceutical company, Novo Nordisk. Currently, it is approved by the FDA for the treatment of partial seizures, although doctors prescribe it for treating panic disorder and neuropathic pain (including fibromyalgia). Gabitril is also used in combination with antidepressants and benzodiazepines for treating anxiety.

PROTOCOL. Dr. Goldstein considers Gabitril to be safe and effective at low doses. He cautions that if the dose is increased too rapidly, patients may become delirious or manic.

PROS AND CONS. Some patients report that Gabitril is a “wonder drug” for treating insomnia. Patients also report a reduction in pain and fatigue. Other patients report either no effect at all, or excessive sedation. The most frequently reported side effects of Gabitril are sedation, increase in “brain fog,” and gastric upset, and, in doses over 8 mg, tingling (paresthesia) in the hands. Gabitril can induce seizures in those without previous seizure disorder, particularly in people taking other GABA enhancers.

AVAILABILITY AND COST. Gabitril is available with a prescription at pharmacies. It is quite expensive. A 30-tablet bottle (2 mg) costs roughly $170. Insurance usually covers the cost.

PATIENT REVIEWS

CFS/ME patient reviews of Gabitril: http://www.revolutionhealth.com/drugs-treatments/rating/gabitril-for-chronic-fatigue-syndrome-cfs-cfids-me

LYRICA

DESCRIPTION. Lyrica (pregabalin, pronounced “pruh-GA-buh-lin”) is an anticonvulsant used to treat neuropathic pain and partial seizures.

BACKGROUND. Lyrica was designed by Richard Silverman, a medicinal chemist at Northwestern University, as a stronger version of gabapentin. Aside from its anti-seizure effects, it is used for post-herpetic neuralgia (shingles), and diabetic peripheral neuropathy. Pfizer has also claimed that Lyrica is useful for treating anxiety. Although Pfizer was later sued for making that claim, Lyrica has been approved in Europe for treating generalized anxiety disorder. In 2010, sales reached $3,063 million. Lyrica was the first medication approved by the FDA for the treatment of fibromyalgia.

USES IN CFS/ME. Lyrica is used mainly as a sleep aid and for pain. While most doctors feel that it is no more effective than gabapentin, the decreased risk of habituation makes it an attractive alternative.

In a study published in the journal Pediatrics in 2009, Drs. Felicia B. Axelrod and Dena Berlin successfully treated a small group of children suffering from daily dysautonomic crises with Lyrica. Dysautonomic crises are severe upsets to the sympathetic nervous system, which are characterized primarily by profound nausea and retching, as well as flushing, tachycardia, and excessive production of gastric and pulmonary mucus. After measuring the effects of Lyrica, Axelrod and Berlin found that 53% of the patients experienced a greater than 50% reduction in crises.

While this was a small study, it is highly significant for the CFS/ME community. Dysautonomia is found in 96% of the CFS/ME population, and while not all experience dysautonomic crises, those who do may find relief with Lyrica.

PROTOCOL. Physicians start patients with a low dose of Lyrica and increase it gradually. Therapeutic effects appear after one week. Dr. Teitelbaum recommends 50-250 mg a night as a sleep aid.

PROS AND CONS. In many respects, Lyrica is similar to benzodiazepines (minor tranquilizers). But, unlike benzodiazepines, effects do not decrease over time. Lyrica does not disrupt sleep cycles, and produces less cognitive impairment than benzodiazepines. It also has a low potential for dependence. Patient reviews of Lyrica are mixed. Some patients have found that it helps enormously with fatigue, while other report it increases fatigue. Most patients report that it helps them more with pain than any other symptom. Side effects include jitters, dizziness, and nausea.

AVAILABILITY AND COST. Lyrica is available at any pharmacy with a prescription. It costs roughly $3 a pill. Insurance usually covers the cost.

FURTHER READING

Axelrod, Felicia B., and Dena Berlin. “Pregabalin: A New Approach to Treatment of the Dysautonomic Crisis.” Pediatrics 2009;124;74. http://pediatrics.aappublications.org/content/124/2/743.full.pdf

PATIENT REVIEWS

CFS/ME patient reviews of Lyrica: http://www.revolutionhealth.com/drugs-treatments/rating/lyrica-for-chronic-fatigue-syndrome-cfs-cfids-me

ANTIDEPRESSANT DRUGS

CAUTION: The FDA has instituted a “black box” label warning for antidepressants, indicating that antidepressants may increase the risk of suicidal thinking and behavior in some children and adolescents. A black-box warning is the most serious type of warning in prescription drug labeling.

DESCRIPTION. Antidepressant drugs are a class of pharmaceutical products that influence neurochemicals in the brain.

BACKGROUND. The National Institute of Mental Health estimates that one in five adults can expect to experience at least one episode of mood disorder in the course of a lifetime. Although antidepressants were developed to treat mood disorders such as anxiety and depression, clinicians have found that the symptoms of many chronic illnesses seem to respond to antidepressant therapy. Antidepressants have been used to treat chronic pain syndromes, migraine headaches, irritable bowel syndrome, bladder and urinary problems, and bulimia. Antidepressants are currently the third most prescribed drug in the U.S. According to the CDC, one in ten Americans over the age of twelve is currently taking an antidepressant.

The first antidepressants, monoamine oxidase inhibitors (MAOIs), were discovered by accident in the 1950s, when doctors in a Swiss tuberculosis clinic noticed euphoria in patients treated with an MAOI called iproniazid. By the late 1950s, MAOIs were developed to treat depression and severe panic disorder. This class of drug operates by inhibiting the action of monoamine oxidase, the enzyme that breaks down epinephrine (adrenaline), norepinephrine (noradrenaline), serotonin, and other monoamines.

In the late 1960s, a more targeted drug, the tricyclic antidepressant, was introduced. The tricyclics (TCAs) were originally developed from antihistamines, and like MAOIs induced heightened mood in patients. Tricyclics operate by increasing the amounts of serotonin and/or norepinephrine in the brain. However, the tricyclics produced several side effects, so in the late 1980s, a new neurochemical modulator, Prozac (fluoxetine), was approved by the Food and Drug Administration (FDA). Prozac is one of the family of drugs known as selective serotonin reuptake inhibitors (SSRIs). These act directly on a brain cell's ability to reabsorb serotonin, a neurotransmitter involved in many neurological functions, including sleep, digestion, blood flow, and, of major importance, mood elevation.

Unfortunately, the SSRIs produced sexual dysfunction, so in 1994 yet another class of antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), was developed by Wyeth. It was thought that by acting on two neurotransmitters the SNRIs would avoid the major side effects of the SSRIs, as well as helping with chronic pain.

USES IN CFS/ME. Antidepressants are perhaps the most widely prescribed pharmaceuticals for CFS/ME. Patients often are dismayed and concerned when their physicians suggest an antidepressant. It appears they are being diagnosed with depression, which, although sometimes a symptom of CFS/ME, is clearly not the underlying cause. Nonetheless, low-dose antidepressants have a place in the treatment of a number of CFS/ME symptoms.

Most CFS/ME patients have low amounts of serotonin and dopamine, two neurochemicals which have profound effects on sleep, cognitive function, and digestion. As a consequence, antidepressants have proven helpful in improving sleep, energy levels, and cognitive function. In addition, SSRIs, SNRIs and tricyclics have been shown to have anti-inflammatory and immunomodulatory effects. A secondary, though significant, effect of antidepressants is to increase blood volume by reducing urinary output. Pain and fatigue often increase urinary volume, which in turn can lead to reduced blood pressure and blood volume, along with a loss of metabolites. Antidepressants can improve kidney function, leading to improved metabolism and a reduction of overall fatigue.

Although there are various antidepressants to choose from, not all patients with CFS/ME respond well to these medications. Often CFS/ME patients with sensitivities to medications cannot tolerate any antidepressant, even in the smallest doses. In a survey of patients with chemical sensitivities conducted by a DePaul University research team, more than 50% of respondents reported negative effects of antidepressants.

Dr. Fred Friedberg, author of Coping With Chronic Fatigue Syndrome: Nine Things You Can Do, also found that a substantial proportion (about one-third) of 249 patients with CFS/ME reacted negatively to antidepressants. This finding is borne out by a treatment survey conducted in 2010 by the ME Association in which 30%-38% of respondents reported that antidepressants, of all classes, made them feel worse.

It is crucial for physicians and patients to remember that CFS/ME patients usually require much lower doses of these medications than other patients, and therefore the dose prescribed should be one tenth or less (depending on the sensitivity of the patient) of the standard dose. In his book, The Doctor's Guide to Chronic Fatigue Syndrome, Dr. David Bell, pediatric CFS/ME specialist, states that giving patients with CFS/ME a standard dose of antidepressants can virtually serve as a diagnostic test for the illness – most patients are immobilized by it.

That being said, antidepressants do provide some degree of symptomatic relief for many patients. It is important, however, to be attentive to side effects, which frequently mimic the symptoms of the illness itself. Excessive fatigue and drowsiness, headaches, nausea, diminished libido, insomnia, and agitation can either be due to the effects of the drug or to the CFS, so it is important to be observant and monitor the dosage carefully.

FURTHER READING

“Using Antidepressants to Treat Chronic Fatigue Syndrome.” Dr. Charles Lapp. CFIDS Chronicle, Summer 2001. http://www.cfids.org/archives/2001rr/2001-rr3-article01.asp

Dr. Lapp's treatment protocols for antidepressants. Contains a useful chart. http://www.cfids.org/archives/2001rr/2001-rr3-article01.asp?view=printhttp://www.prohealth.com/library/showarticle.cfm?libid=8801

Interesting thread on antidepressants used for gut problems. http://phoenixrising.me/forums/showthread.php?6321-Thoughts-on-the-methylation-treatment-for-CFS/page5

Lists antidepressants, side effects, brand names by country, “things your doctor won't tell you.” http://www.crazymeds.us/pmwiki/pmwiki.php/Main/HomePage

BOOK

Dr. Cheney recommends patients and physicians read the book Prozac Backlash: Overcoming the Dangers of Prozac, Zoloft, Paxil and Other Antidepressants by Joseph Glenmullen, M.D., a psychiatrist at the Harvard Medical School

TRICYCLIC ANTIDEPRESSANTS

CAUTION: Tricyclic antidepressants increase the amount of norepinephrine in the brain. They cannot be given in conjunction with MAOIs because of the risk of producing dangerously high blood pressure. The National Institutes of Health (NIH) does not recommend tricyclics for children or teens.

DOXEPIN

Brand: Sinequan, Silenor, Adapin

USES IN CFS/ME. Doxepin, one of the most commonly used medications in the treatment of CFS/ME, is of major benefit in treating sleep disturbance. In a study conducted by Weber et al, 3 – 6 mg of doxepin administered before bed improved total sleep time without causing next-day sedation. Krystal et al found that as little as 1 – 3 mg of doxepin increased slow wave sleep (stage 3 and 4) in elderly patients. It is believed that doxepin may help correct the slow-wave sleep deficit found in both CFS/ME and fibromyalgia. Improvement in sleep often brings an increase in energy levels and reduction in the pain associated with CFS/ME and fibromyalgia. Many patients with CFS/ME also report improvement in allergies as a result of doxepin's potent histamine-blocking properties. In this regard, Dr. Cheney believes that doxepin at low doses may function as an immune modulator. By softening immune system activation, doxepin can relieve sore throats, swollen glands and congestion.

PROTOCOL. Low doses (2 to 10 mg) of doxepin, taken 1 to 2 hours before bedtime, are usually prescribed to treat CFS/ME symptoms. Liquid formulations allow for even smaller doses. Because CFS/ME patients can be very sensitive to doxepin, Dr. Cheney recommends starting at two drops of liquid doxepin (10mg/cc) on the tongue, increasing up to 10 drops (5mg or ½ cc). Liquid doxepin can mixed into four ounces of water or juice.

PROS. Most patients report improved quality of sleep, better endurance, and energy. While some patients experience daytime sedation during the first few days, this problem usually resolves rapidly. Benefits are often noted fairly quickly, within a few days.

CONS. Side effects include weight gain, constipation, and dry mouth. Too high a dose can result in nightmares. Many patients with CFS/ME report excessive sedation or a drugged feeling and therefore cannot tolerate treatment. Paradoxically, some feel depressed after taking the drug (but not before).

AVAILABILITY AND COST. Liquid doxepin costs about $17 for a 120 cc bottle. (If you are taking two drops on the tongue, 120 ccs will last a very long time). Both pill and liquid forms are available by prescription in generic and brand-name formulations. Insurance usually covers.

FURTHER READING

Good review of sleep studies with low-dose doxepin http://brainposts.blogspot.com/2011/01/low-dose-doxepin-for-insomnia-treatment.html

AMITRIPTYLINE

Brand: Elavil, Vanatrip, Endep (Australia; Canada; New Zealand; South Africa); Domical (United Kingdom)

USES IN CFS/ME. Amitriptyline is beneficial for treating pain, sleep disturbance, headaches, and gastrointestinal problems and may be recommended if doxepin produces excessive sedation. In addition, amitriptyline is often helpful in treating interstitial cystitis, a disorder that affects many women with CFS/ME. Interstitial cystitis symptoms that may respond to amitriptyline are frequent urination, and bladder and pelvic pain. Dr. Alan Wein, a urologist who specializes in treating interstitial cystitis, has noted that amitriptyline is effective for nearly 50% of his patients, probably because of its antihistamine properties.

PROTOCOL. Dosage varies, but generally 10 mg or less nightly is prescribed. Dr. Myhill starts at 5 mg to minimize side effects. Some patients report better results with amitriptyline by “pulsing” the medication (taking it every third or fourth night).

PROS. Benefits are noted quickly. The most frequent benefits reported by people with CFS/ME are improved sleep and reduced pain.

CONS. The side effects of amitriptyline are similar to those of doxepin, although exacerbation of muscle weakness in CFS/ME seems to be more common with amitriptyline than with other antidepressants. Some patients have had to discontinue the drug because of weight gain, dry mouth, and palpitations. Dr. Lapp notes that while amitriptyline may help patients improve sleep, it can reduce deep sleep, which impairs its effectiveness over the long term. There is some evidence that amitriptyline may cause CoQ10 deficiency, resulting in oxidative stress and altering the function of mitochondria. In a 2011 study, Bautista-Ferrufino et al recommend supplementation with CoQ10 during treatment with amitriptyline.

AVAILABILITY AND COST. Amitriptyline is available by prescription and is inexpensive. The generic drug costs about $10 for a 30-day supply. Insurance usually covers.

FURTHER READING

Good summary of the uses of Elavil for CFS/ME: http://phoenixrising.me/?page_id=4710

PATIENT REVIEWS

CFS/ME patients' reviews of Elavil: http://www.everydayhealth.com/drugs/elavil-for-chronic-fatigue-syndrome-cfs-cfids-me/review?page=2

RESEARCH

Bautista-Ferrufino, María Rosa, Mario D. Cordero, José Antonio Sánchez-Alcázar, Matilde Illanes, Ana Fernández-Rodríguez, Plácido Navas, Manuel de Miguel. “Amitriptyline induces coenzyme Q deficiency and oxidative damage in mouse lung and liver.” Toxicology Letters. Volume 204, Issue 1, 4 July 2011, Pages 32-37. http://www.sciencedirect.com/science/article/pii/S0378427411001342 (Abstract)

NORTRIPTYLINE, DESIPRIMINE, IMIPRAMINE, CLOMIPRAMINE, TRIMIPRAMINE

Generic: Nortriptyline Brand: Pamelor, Sensoval, Aventyl , Allegron, Noritren, Nortrilen

Generic: Desipramine Brand: Norpramin, Pertofrane

Generic: Imipramine Brand: Tofranil

Generic: Trimipramine Brand: Sermontil

Generic: Clomipramine Brand: Anafranil

USES IN CFS/ME. Nortriptyline, desipramine and imipramine are second-generation tricyclic antidepressants which primarily block the reuptake of norepinephrine, and, to a lesser degree, serotonin. All three are used in patients with CFS/ME, though not as frequently as first-generation tricyclics. They are helpful in treating fatigue, pain, sleep disturbance, and anxiety. Their main side effects are similar to those of other tricyclic antidepressants: dry mouth, constipation, and weight gain (due to increased appetite). Although the second-generation tricyclics are often prescribed for sleep, they often interfere with sleep onset. Other side effects experienced by people with CFS/ME include shakiness, agitation and nausea.

Clomipramine and trimipramine, both of which were first developed in the 1960s, are in wider use in Europe than in the U.S. Like the other tricyclics, their mode of action is to block the uptake of serotonin and norepinephrine.

AVAILABILITY AND COST. Prices for second-generation tricyclics vary. Nortriptyline (generic) can be purchased for as low as $10 for a 30-day supply. Desipramine is slightly more expensive, ranging from $15 - $30 for a 30-day supply, while imipramine can be purchased for less than $10 for a 30-day supply. Insurance usually covers.

PATIENT REVIEWS

CFS/ME patient reviews of Pamelor: http://www.revolutionhealth.com/drugs-treatments/rating/pamelor-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of trimipramine: http://www.revolutionhealth.com/drugs-treatments/rating/surmontil-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of clomipramine: http://www.revolutionhealth.com/drugs-treatments/rating/anafranil-for-chronic-fatigue-syndrome-cfs-cfids-me

FURTHER READING

General information on trimipramine: http://en.wikipedia.org/wiki/Trimipramine

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

CAUTION: SSRIs must not be taken within 14 days of discontinuing MAOIs. The NIH recommends against giving SSRIs to children or teens.

FLUOXETINE

Brand: Prozac, Sarafem, Rapiflux, Selfemra, Lovan (Australia), Oxactin (United Kingdom), Fluctin (Germany).

BACKGROUND. Fluoxetine (Prozac), the first SSRI to be approved in the late 1980s, differs from earlier antidepressants in that its mode of action is more specific. It works directly on altering the level and action of serotonin only (the tricyclic antidepressants inhibit uptake of norepinephrine as well). The SSRIs are often prescribed in place of tricyclic antidepressants because they have fewer side effects. Unlike other antidepressants, SSRIs do not cause sedation. In fact, fluoxetine can often act as a stimulant to increase energy. Nor does it cause the dry mouth, palpitations, and dry cough that are common with tricyclic drugs.

USES IN CFS/ME. Dr. Nancy Klimas, CFS/ME specialist and immunologist at the University of Miami, has studied the effect of SSRIs on the immune system. At the 1990 CFIDS conference in Charlotte, North Carolina, Dr. Klimas reported that more than half of 25 CFS patients given fluoxetine for three months showed moderate to marked improvement. Improvements in the number of natural killer cells seem to indicate that fluoxetine (and other serotonin-influencing drugs) may have a modulating effect on the immune system. However, in spite of these encouraging reports, no subsequent study has shown that fluoxetine has a greater effect than placebo on CFS/ME patients.

PROTOCOL. When used in CFS/ME, fluoxetine is generally given in considerably smaller dosage (2 to 10 mg, taken in the morning) than the standard dose used to treat depression.

PROS. Fluoxetine is effective in treating the fatigue of CFS/ME, the hallmark symptom of the syndrome. Other symptoms that may respond to treatment are pain, cognitive dysfunction, and sometimes excessive sleep. The drug is also helpful in treating the physiological depression that may accompany CFS/ME as a result of metabolic changes, as well as the secondary depression that stems from the devastating experience of having a chronic, debilitating illness. An additional benefit is that, unlike the tricyclic antidepressants, fluoxetine does not cause weight gain.

Fluoxetine has been shown to have a significant effect on patients with FM. In 2002, Arnold et al conducted a randomized, double-blind study, which showed improvement in pain, fatigue and depression in fibromyalgia patients. A similar study conducted in 1996 by Goldenberg et al found that the combination of fluoxetine and amitriptyline produced improvements in pain, sleep, and global well-being. (In Handbook of Primary Care Psychology, by Leonard J. Haas)

CONS. A number of people with CFS/ME are unable to tolerate the side effects of fluoxetine and have stressed emphatically that they will never try it again. Reports of anxiety, agitation, and even excessive sedation (a paradoxical reaction not unusual in CFS/ME patients) are common. In some cases the side effects of fluoxetine are profound, producing dissociation, flatness of affect and loss of a sense of self.

Because fluoxetine acts as a stimulant, people who have difficulty sleeping almost universally report worsening of insomnia. In addition, many clinicians advise their patients who have been taking MAOIs to allow a longer than usual interval (up to 5 weeks) before taking fluoxetine. This drug's long half-life may also require a longer interval after discontinuation before starting new antidepressant treatments. A double-blind study conducted by Dr. J.H. Vercoulen of the University Hospital of Nijmegen in The Netherlands concluded that fluoxetine (20 mg/day) had no beneficial effect on fatigue or any other symptoms of CFS (Lancet, 1996). Dr. Cheney has strongly advised against long-term use of fluoxetine, citing possible permanent disruption of serotonergic pathways.

AVAILABILITY AND COST. Fluoxetine is available in liquid to allow smaller doses. The cost can be as low as $4 a month for generic. Insurance usually covers the cost. Not recommended for patients with diabetes.

PATIENT REVIEWS

CFS/ME patient reviews of Prozac: http://www.revolutionhealth.com/drugs-treatments/rating/prozac-for-chronic-fatigue-syndrome-cfs-cfids-me

REFERENCES

Haas, Leonard J, ed. Handbook of Primary Care Psychology. Oxford University Press, USA, 2004.

Vercoulen J et al. “Randomized, double-blind, placebo-controlled study of fluoxetine in chronic fatigue syndrome.” Lancet. 1996; 347: 858-61 and 1770-2.

SERTRALINE, PAROXETINE

Generic: Sertraline Brand: Zoloft, Lustral (Britain, Ireland, Israel)

Generic: Paroxetine Brand: Paxil, Pexeva, Seroxat (Britain), Aropax (Australia, New Zealand)

USES IN CFS/ME. Sertraline (Zoloft) and paroxetine (Paxil) are two newer drugs that are similar to fluoxetine, but because they are associated with fewer side effects may be more easily tolerated. Both drugs have a shorter half-life than fluoxetine does. Both have been used to treat CFS/ME for treating symptoms such as fatigue, cognitive dysfunction, mood swings, pain, sleep disorders, and immune dysfunction.

PROS AND CONS. As with other SSRIs, patient experiences vary widely. Some patients report an increase in energy and relief from pain, while others report nausea, loss of appetite, a “floating feeling,” and hormonal complications. Withdrawal symptoms of paroxetine may be intense, producing flu-like symptoms, nausea, irritability, anxiety, and crying jags. A few patients have mentioned that they felt as bad while taking these drugs as they did with other antidepressants, reminding us that many patients cannot tolerate any form of antidepressant. For these patients, alternative treatments have been suggested, including vitamins, amino acids, herbs, and other complementary therapies.

PATIENT REVIEWS

CFS/ME patient reviews of Zoloft: http://www.revolutionhealth.com/drugs-treatments/rating/zoloft-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Paxil: http://www.revolutionhealth.com/drugs-treatments/rating/paxil-for-chronic-fatigue-syndrome-cfs-cfids-me

CITALOPRAM

Brand: Celexa; Cipromil (Britain, Australia)

USES IN CFS/ME. Celexa is sometimes prescribed for POTS (postural orthostatic tachycardia syndrome), so those patients with syncope (fainting), NMH (neurally mediated hypotension), and related disorders may benefit from Celexa. It is not as frequently prescribed for CFS/ME as other antidepressants, due to numerous side effects.

PROS AND CONS. Some patients report a lessening of symptoms, particularly those associated with PMS. Others report severe migraines, nose bleeds, insomnia, nightmares, and confusion. Sexual dysfunction is a common side effect. Patients should start at a very low dose.

PATIENT REVIEWS

CFS/ME patient reviews of Celexa: http://www.revolutionhealth.com/drugs-treatments/rating/celexa-for-chronic-fatigue-syndrome-cfs-cfids-me

EXCITALOPRAM

Brand: Lexapro, Cipralex, Seroplex, Lexamil, Lexam, Entact

Excitalopram is an SSRI noted for its high selectivity of serotonin. It is reputed to be a more potent antidepressant than its “parent,” citalopram. Excitalopram has had a history of controversy since its introduction in the 1990s, and has generated a number of lawsuits. Nonetheless, excitalopram is one of the SSRIs that has been used for CFS/ME, though not as widely as other antidepressants.

PATIENT REVIEWS

CFS/ME patient reviews of Lexapro: http://www.google.com/search?rlz=1C1GGGE_enUS379US379&aq=f&gcx=w&sourceid=chrome&ie=UTF-8&q=lexapro

MONOAMINE OXIDASE INHIBITORS (MAOIs)

CAUTION: Foods and medications containing a high amount of tyrosine (fermented foods, wine, cheese, pickles, decongestants) can interact with MAOIs, producing sharply elevated blood pressure and increasing the risk of stroke.

PHENALZINE, TRANYLCYPROMINE

Generic: Phenalzine Brand: Nardil, Nardelzine

Generic: Tranylcypromine Brand: Parnate, Jatrosom

USES IN CFS/ME. MAOIs are used much less frequently than other antidepressants to treat CFS/ME. The side effects associated with phenalzine (Nardil ) and tranylcypromine (Parnate) can be severe. An additional drawback is the dietary restrictions that accompany MAOI use. Foods that contain the amino acid tyramine (aged cheese, yogurt, wine, avocado, among many others) must be avoided to prevent severe hypertensive crisis. Because these foods are so common, patients may find compliance difficult. While some patients with CFS/ME have found MAOIs effective, others have reported agitation and insomnia. One patient believed an MAOI may have contributed to a prolonged relapse, producing even greater neurological and cognitive problems than she had experienced previously.

AVAILABILITY. MAOIs are available from any pharmacy with a doctor's prescription. Most major insurance carriers do not cover MAOIs for the treatment of CFS/ME.

OTHER ANTIDEPRESSANTS

BUPROPION

Brand: Wellbutrin, Aplenzin, Budeprion, Buproban, Zyban

CAUTION: Bupropion should not be taken by patients with a history of seizures.

USES IN CFS/ME. Bupropion is an atypical antidepressant frequently used to treat the fatigue associated with CFS/ME. Bupropion is the first antidepressant to increase dopamine, a neurotransmitter often found to be low in CFS/ME patients. Bupropion is believed to be both a norepinephrine and dopamine reuptake inhibitor.

PROS. Physicians who specialize in the treatment of CFS/ME have prescribed bupropion when SSRIs have failed, and find it of benefit in improving energy and controlling mood. In some patients, bupropion does not produce the unpleasant side effects noted with other antidepressants. The drug may be taken alone or with other tricyclic antidepressants to improve sleep. Patients have reported increased energy, alleviation of depression, increase in concentration, and better sleep.

CONS. Bupropion is short acting, much like stimulants (e.g., Ritalin). Because bupropion raises dopamine, it is more habit-forming than other antidepressants. Side effects can be similar to those of SSRIs (jitters, anxiety, insomnia). Many patients find that bupropion, like CNS stimulants, provides only a short burst of energy, followed by a crash. Even patients who feel that bupropion has provided significant relief for cognitive symptoms have reported “cyclic thoughts” (like having a song stuck in your head). Patients have also reported headaches, nightmares, shakiness, rapid heartbeat, weight gain, and stomach irritation. The biggest drawback to the use of bupropion is the risk of seizures. Bupropion is not recommended for patients who are sensitive to stimulants, or who have a history of seizures or heart problems.

PROTOCOL. The standard initial prescribed dose is 75 mg daily. CFS/ME patients may wish to start with a third of the standard dose to check for tolerance.

AVAILABILITY AND COST. Bupropion is available at any pharmacy with a prescription. A one-month supply costs from $10-$24. It can be ordered online with a prescription. Insurance usually covers.

PATIENT REVIEWS

CFS/ME patient reviews of Wellbutrin: http://www.revolutionhealth.com/drugs-treatments/rating/wellbutrin-for-chronic-fatigue-syndrome-cfs-cfids-me

TRAZODONE

Brand: Desyrel, Oleptro, Trialodine (Deprax in Spain, Molipaxin in Britain, Thombran in Europe, Trazorel in Canada )

USES IN CFS/ME. Among the most sedating antidepressants, Desyrel is often used to treat insomnia. Desyrel stimulates deep sleep (stage 3 and stage 4) and is particularly helpful for those who wake up too early. It is not, however, as helpful as many of the other antidepressants in treating anxiety and depression in CFS/ME. Some patients report improved sleep with a low dose of Desyrel, but experience severe orthostatic hypotension with higher doses. Desyrel has fewer anticholinergic side effects than tricyclics, but patients still report dry eyes and mouth, and constipation. The most commonly reported side effects include nausea, excessive sedation, nightmares, dizziness, and unrefreshing sleep. Morning grogginess (“hangover”) is common.

PROTOCOL. The prescribed dose in CFS/ME is generally 25 to 50 mg at bedtime. Dr. Bell recommends 25 mg taken ½ hour to two hours before bed.

AVAILABILITY AND COST. A 30-day supply of the generic drug (25mg) costs about $7.

VENLAFAXINE

Brand: Effexor

USES IN CFS/ME. When it was approved for commercial use, Effexor (venlafaxine) received a remarkable amount of publicity and was touted as a newer and better Prozac. Effexor is chemically unrelated to the other antidepressants and has a unique mode of action, blocking serotonin, norepinephrine, and dopamine reuptake. However, effects of the drug in CFS/ME have been less than dramatic. Many patients report that Effexor worsens anxiety, and, paradoxically, depression. Withdrawal symptoms can be severe, including dizziness, nausea and headaches. Dr. Jay Goldstein commented that, while Effexor may have been marketed as "the best thing since sliced bread," his experience taught him to view it simply as another alternative treatment, rather than the most effective antidepressant (CFIDS Chronicle, Physicians Forum, Fall 1993). Dr. Goldstein reported nausea and hypertension as possible side effects.

AVAILABILITY AND COST. The generic is available at pharmacies and online regardless of dosage at roughly $10 for a 30-day supply (prices vary).

PATIENT REVIEWS

CFS/ME patient reviews of Effexor: http://www.revolutionhealth.com/drugs-treatments/rating/effexor-for-chronic-fatigue-syndrome-cfs-cfids-me

DULOXETINE

Brand: Cymbalta; Yentreve and Ariclaim (Europe)

USES IN CFS/ME. Cymbalta, one of three medications currently approved for the treatment of fibromyalgia. is a serotonin-norepinephrine reuptake inhibitor (SNRI) primarily prescribed for pain. Although Cymbalta is often prescribed by rheumatologists for their patients with fibromyalgia, most CFS/ME doctors prefer tricyclics or SSRIs over Cymbalta.

PROS and CONS. Many CFS/ME patients report that Cymbalta makes them restless and anxious. But patients who have had success with other stimulants may find that Cymbalta improves energy and mood. Because of its short half-life, discontinuation symptoms can be quite severe, including depression, irritability, agitation, sensory disturbances, dizziness, headache, insomnia, and seizures.

PROTOCOL. Doctors recommend beginning at a low dose (20 mg) and then gradually increasing as needed. Cymbalta can be pulsed (taken every second or third day).

AVAILABILITY AND COST. Cymbalta is available at any pharmacy with a prescription. A month's supply of the generic at 20 mg costs roughly $28.

PATIENT REVIEWS

CFS/ME patient reviews of Cymbalta: http://www.revolutionhealth.com/drugs-treatments/rating/cymbalta-for-chronic-fatigue-syndrome-cfs-cfids-me

MIRTAZAPINE

Brand: Remeron; Avanza, Axit (Australia); Zispin SolTab (Britain and Ireland); Norset (France); Remergil (Germany)

BACKGROUND. Remeron is a tetracyclic antidepressant, one of the few drugs that falls into the class of noradrenergic and specific serotonergic antagonists (NaSSAs). The NaSSAs act by inhibiting adrenergic and serotonin receptors. Remeron is dispensed orally in a tablet that dissolves on the tongue.

PROS AND CONS. The most common side effect of Remeron is weight gain, but as with tricyclics, CFS/ME patients may also experience blurred vision, dry mouth, constipation, dizziness and sedation. Many patients report sugar cravings. On the positive side, some patients report that Remeron has helped improve sleep. Dr. Lapp prescribes Remeron when there has been significant weight loss coupled with insomnia.

AVAILABILITY AND COST. Remeron is available at most pharmacies. A month's supply of 15 mg of the brand version costs roughly $25.

PATIENT REVIEWS

CFS/ME patient reviews of Remeron: http://www.revolutionhealth.com/drugs-treatments/rating/remeron-for-chronic-fatigue-syndrome-cfs-cfids-me

ANTIFUNGAL AGENTS

Nystatin, Diflucan, Nizoral, Sporanox

DESCRIPTION. Antifungal drugs are used to treat Candida albicans and other fungal infections.

NYSTATIN

BACKGROUND. In the 1940s, two scientists found a bacterium in soil that inhibited the growth of molds. They discovered that the bacterium binds to ergosterol, a major component of the cell membrane of the fungus. When the bacterium was sufficient concentrations, it formed pores in the membrane that produced leakage and eventually led to the death of the fungus. They named the substance “nystatin,” after New York State, where it was discovered. The drug was patented in the 1950s, and for the next twenty years nystatin was primarily used in suppositories to treat vaginitis. It was popularized in the early 1980s, when studies by several clinicians chronicled the successful treatment of chronic candidiasis (yeast infection) with nystatin.

USES IN CFS/ME. Because candidiasis is a condition that produces extreme fatigue, depression, muscle pain, concentration problems, along with other symptoms which are common in CFS/ME, many CFS/ME patients turned to antifungal regimens in the 1980s. Although some physicians consider candidiasis controversial and without scientific basis, many CFS/ME clinicians use nystatin and other antifungal agents to treat Candida overgrowth. Dr. Murray Susser and Dr. Michael Rosenbaum, among other physicians, used antifungal medications when symptoms of Candida infection were present, especially when accompanied by a medical history of antibiotic or steroid use that may have contributed to Candida overgrowth. As an additional aid to determining whether an antifungal regimen might be helpful, a number of physicians use stool tests to measure Candida.

PROTOCOL. Many CFS/ME physicians suggest using the powdered form of nystatin, citing that it works better than the pill form and is more pure (free of dyes

or additives). The target dose is ¼ teaspoon, four times a day. A much lower dose (1/16 tsp once a day) should be used initially to prevent die-off reactions.

Dr. Teitelbaum recommends a target dose of two tablets three times a day (500,000 units), starting with one tablet a day and increasing by one tablet a day until you are up to the target dose for five to eight months. He recommends that if nausea occurs the dose be reduced to two tablets a day, or replaced by nystatin powder mixed in water. In Chronic Fatigue Syndrome and the Yeast Connection, Dr. William Crook notes that flushing, fever, and agitation may indicate that the dose is too high. Indications that the dose is too small include excessive fatigue, cold, and achiness.

PROS. Nystatin is considered safe when taken in oral or topical form. As nystatin is not absorbed through the gut, side effects from the drug are minimal. A surprisingly large number of patients report that nystatin (in combination with dietary changes and nutritional supplements as part of Candida control) has helped improve symptoms of CFS/ME. Patients often report increased energy, improved immune function, and better overall health after taking nystatin. Some symptoms (e.g., thrush, gastrointestinal complaints) respond quickly to treatment, but it can take weeks or months before overall improvement is observed.

CONS. While a number of patients note steady improvement over time, others experience no benefit after long trials of nystatin, and still others are not able to tolerate the drug at all. It is important to note that with all antifungal medications the phenomenon of "die-off" may be the actual cause of side effects; that is, as the antifungal medication kills the yeast cells, the dead cells secrete toxins into the body and symptoms may worsen initially. Symptoms of die-off include increased fatigue, muscle aches, and headaches, as well as diarrhea, nausea, upset stomach and vomiting. It can be difficult to differentiate between symptoms that could be due to die-off, intolerance for the drug, or perhaps simply a "bad day."

AVAILABILITY AND COST. Nystatin is available over the counter in suppository form to treat vaginitis and is widely available in creams for topical use. It is available in pill, tablet, liquid, lozenge, and powder form by prescription at most pharmacies. The powder comes in 15-, 30-, and 60-gram bottles. Hi-Tech Pharmacal Co, Inc. Amityville, NY 11701 and Paddock Laboratories, Inc. Minneapolis, MN 55427 are the two companies that currently produce nystatin powder. The powder is quite expensive at over $100 for a 30-gram bottle. Nystatin, in all forms, is usually covered by insurance.

DIFLUCAN

BACKGROUND. Diflucan (fluconazole), an antifungal introduced in the United States in 1990, is extremely valuable in treating the life-threatening Candida infections that sometimes occur in immunocompromised patients, such as those with AIDS or advanced cancer.

Diflucan differs from nystatin in that it is absorbed through the intestinal wall and traverses the bloodstream, thereby penetrating anywhere excessive yeast

colonization is found. Therefore, in theory at least, Diflucan may be more beneficial than nystatin to treat pervasive yeast infections.

USES IN CFS/ME. Many clinicians have found Diflucan beneficial for treating CFS/ME symptoms. A respected CFS/ME specialist, Dr. Carol Jessop, has used antifungal therapies when patients have symptoms suggestive of Candida overgrowth. She has stated that although other agents may be of benefit, Diflucan was her treatment of choice. Dr. Jessop found that because Diflucan penetrates the central nervous system, her patients experienced improvement in cognitive problems. This was not the case with nystatin or Nizoral. On the other hand, Dr. Jay Goldstein, who used Diflucan chiefly to treat gastric disturbances, reported only limited success (CFIDS Chronicle, Physician's Forum, Spring 1991).

PROTOCOL. Dr. Teitelbaum prescribes 200 mg for 6-12 weeks. If die-off symptoms appear, he recommends dropping the dose to 25 mg a day for 3 to 14 days.

PROS AND CONS. Diflucan is usually well tolerated. The principal side effects are nausea and other gastrointestinal complaints. Diflucan works very quickly, which means patients will see results almost immediately. For some patients this means an immediate improvement—for others, immediate side effects.

AVAILABILITY AND COST. Diflucan is available by prescription. The generic (fluconazole) costs roughly $1 a tablet. Insurance plans usually cover the cost (if your insurance does not include Diflucan, you may qualify for a compassionate low-cost supply; contact Pfizer, Inc., 866-706-2400 or, for an application form and more information go to: http://www.pfizerhelpfulanswers.com/pages/misc/Default.aspx

PATIENT REVIEWS

CFS/ME patient reviews of Diflucan: http://www.revolutionhealth.com/drugs-treatments/rating/diflucan-for-chronic-fatigue-syndrome-cfs-cfids-me

NIZORAL

Nizoral (ketoconazole) is somewhat similar to Diflucan but is used less frequently because of its serious side effects, including liver toxicity and endocrine system disturbances. Nizoral can also lower adrenal hormone levels. Although the drug is effective and inexpensive, many physicians are cautious about prescribing it. Patients taking Nizoral generally undergo blood tests, including a liver profile, every thirty days. Nizoral is available by prescription. A 30-day supply generally costs about $85. It is usually covered by insurance.

SPORANOX

USES IN CFS/ME. Like Diflucan and Nizoral, Sporanox is used to treat Candida overgrowth. Because it is less toxic to the liver, it is safer than Nizoral. Dr. Teitelbaum has observed that yeast that is resistant to Diflucan is usually resistant to Sporanox. The drug is generally well tolerated. The most common side effects are transient nausea and headache. As with Diflucan, Sporanox can cause liver inflammation. Dr. Teitelbaum recommends taking lipoic acid as a liver protector when taking either drug.

PROTOCOL: Doses range from 100 to 200 mg/day.

AVAILABILITY AND COST: Sporanox is available at most pharmacies. The cost of a month's supply of 100 mg tablets is roughly $450 brand, $250 for generic (itraconazole). Because the drug is expensive, it is advisable to check with your insurance carrier to see if it is covered.

PATIENT REVIEWS

CFS/ME patient reviews of Sporanox: http://www.revolutionhealth.com/drugs-treatments/rating/itraconazole-for-chronic-fatigue-syndrome-cfs-cfids-me

SEE: Candida

ANTIHISTAMINES

Benadryl, Claritin, Allegra, Zyrtec, Chlor-Trimeton, Atarax and Vistaril, Dramamine

DESCRIPTION. Antihistamines are a class of drugs that compete with histamine for cell receptor sites on effector cells, thereby blocking the effects of histamine.

BACKGROUND. Antihistamines have been used for many years to treat allergies and allergic reactions. Some antihistamines are also used to treat motion sickness and mild Parkinson's disease.

USES IN CFS/ME. Because many patients with CFS/ME have allergies (usually preceding but often developing after the onset of CFS/ME), antihistamines are often prescribed for relief of seasonal allergies. But in addition to allergies, patients with CFS/ME often develop an intolerance to histamine itself. (For this reason, anesthesiologist Patrick Glass recommends that CFS/ME patients avoid anesthetics containing histamine releasers, such as sodium pentothal, during surgery. For more tips on anesthesia see: http://www.squidoo.com/anesthesia-with-CFS)

Histamine is found in a number of foods, particularly fermented foods, and additives. Because histamine is a vasodilator, reactions to these foods and additives can mimic true allergies, producing flushing, lowered blood pressure, headache and palpitations. Aside from treating allergies, antihistamines are also of benefit in treating many other symptoms of CFS/ME, including insomnia, bladder problems (interstitial cystitis), anxiety, and muscle pain. Benefits are noted rapidly, usually within 24 hours.

BENADRYL (diphenhydramine)

USES IN CFS/ME. Benadryl is useful for treating hives, seasonal allergies, upper airway congestion, and severe allergic reactions (anaphylactic shock). The drug is very sedating and can be used as a sleep aid for CFS/ME-related insomnia if taken at bedtime. Like other antihistamines, Benadryl is not addictive, and thus may offer a good alternative to habit-forming sleeping pills. However, as Dr. David Bell points out in The Doctor's Guide to Chronic Fatigue Syndrome, Benadryl can lose effectiveness with continuous use for longer than a few weeks and therefore may be better used only occasionally.

Some patients note that, although Benadryl ensures a good night's sleep, rotating it with a benzodiazepine prevents developing a tolerance to either drug (see Benzodiazepines). Although Benadryl is generally well tolerated, adverse reactions – notably agitation and tachycardia – have been reported. If you are taking other medications, it is important to check with your physician before trying Benadryl, especially if you are prone to heartbeat irregularities.

AVAILABILITY AND COST. Benadryl is inexpensive, costing less than $7 per bottle or package. It is also available as a dye-free pill and in liquid form, which may be of benefit to CFS/ME patients with chemical sensitivities. Benadryl can be purchased without a prescription.

CLARITIN (loratadine)

USES IN CFS/ME. Claritin is a second-generation antihistamine useful in the treatment of seasonal allergy symptoms, such as runny nose, sneezing, itching, and watery eyes. Because it is very similar in structure to the tricyclic antidepressants, it may cause similar side effects (urinary retention, blurred vision, dry mouth, GI disturbances). In spite of being described as a “non-sedating” antihistamine, Claritin does produce drowsiness. Some patients have reported that they feel “zombie-like” after taking Claritin. Others report that Claritin has brought great relief from hay fever symptoms without adverse effects.

AVAILABILITY AND COST. Prescription strength Claritin is available over the counter at pharmacies supermarkets. A package of 24 gels costs roughly $20.

PATIENT REVIEWS

CFS/ME patient reviews of Claritin: http://www.revolutionhealth.com/drugs-treatments/rating/claritin-for-chronic-fatigue-syndrome-cfs-cfids-me

ALLEGRA (fexofenadine)

Fexofenadine is a second-generation antihistamine that does not readily cross the blood-brain barrier, and so causes less drowsiness than first-generation antihistamines (such as Benadryl). Like other antihistamines, it works by antagonizing the H1 receptor. As Allegra is non-sedating, it is recommended for patients who suffer from allergies, and who also have hypersomnia. Allegra comes in a tablet and as a liquid. Allegra works better if it is not taken with fruit juices such as orange, grapefruit, or apple juice. It is available over-the-counter at pharmacies and supermarkets. A package of 15 tablets costs roughly $7.

ZYRTEC (cetirizine)

Zyrtec is a second-generation antihistamine that crosses the blood-brain barrier only slightly, thereby reducing its sedating effects. In 2008 it was the highest grossing non-food product in the U.S., generating sales in excess of $300 million. Unlike other antihistamines, Zyrtec is only taken once a day, preferably at the same time. Paradoxically, Zyrtec D's (decongestant) stimulating effect may help insomnia. One CFS/ME patient reported that after suffering from frequent panic micro-arousals on a nightly basis, taking Zyrtec D actually helped her stay asleep. The Zyrtec elevated her metabolic rate, preventing the sudden release of adrenaline that was preventing her from getting into a deep sleep.

AVAILABILITY AND COST. Zyrtec is available at pharmacies and supermarkets. A package of 30 tablets costs roughly $20.

CHLOR-TRIMETON (chlorpheniramine maleate)

Chlorpheniramine is a first-generation antihistamine with relatively weak sedative effects. Chlorpheniramine is normally used to treat allergies, however, it also functions as a serotonin and norepinephrine reuptake inhibitor (SNRI). One patient with long-term CFS/ME reported that a dose of 2 mg of Chlor-Trimeton improved her sleep and she felt less miserable in the day. “There was less aching, less fatigue, a little more mental clarity.” After the drug effect reached a plateau, she increased the dose and noticed that all her symptoms improved, not just sleep disturbances (CFIDS Chronicle, Winter 1994).

AVAILABILITY AND COST. Chlor-Trimeton is available over the counter. It is relatively inexpensive at less than $8 for 24 tablets.

ATARAX, VISTARIL (hydroxyzine)

BACKGROUND. Hydroxyzine is an older first-generation antihistamine used for allergies, motion sickness, nausea and mild anxiety. Although it has sedative effects, it is not addictive, nor does it produce the side effects common to tranquilizers and anxiolytics. Hydroxyzine is frequently used in conjunction with opioid pain killers to increase the effectiveness of the drugs without increasing toxicity.

USES IN CFS/ME. Hydroxyzine has a wide range of uses in treating CFS/ME symptoms, including anxiety, pain and interstitial cystitis. Dr. Paul Cheney prescribes Vistaril to treat muscle pain (CFIDS Chronicle, Spring 1995).

Two physicians who specialize in treating interstitial cystitis, Dr. Grannum Sant and Dr. Theoharis Theoharides of Tufts University, have published several papers detailing the effectiveness of hydroxyzine. Dr. Theoharides noted that several patients given hydroxyzine experienced improvement in urinary frequency and bladder pain. He theorizes that this drug may inhibit secretion of mast cells, a type of cell involved in allergic reactions that may be responsible for many symptoms in interstitial cystitis. Dr. Theoharides states that hydroxyzine is unique in that other antihistamines do not seem to be effective in treating interstitial cystitis (Seminars in Urology, 1991). Symptoms often recur after discontinuation of the drug. However, the success rate is high and the risks low, compared with more invasive therapies for interstitial cystitis.

PROS AND CONS. Although Vistaril is often prescribed for anxiety, it can paradoxically cause panic and anxiety attacks. Some patients report that Vistaril “knocks them out,” which may be beneficial for people with insomnia.

PROTOCOL. The initial dosage is 25 mg a day, which can be slowly increased to 100 mg. Daytime sedation, the most common side effect, generally disappears in a few days. Hydroxyzine is fast-acting, with results seen within 30 minutes. When used for anxiety, its effectiveness is generally limited to a few months. Hydroxyzine is not recommended for the elderly.

AVAILABILITY AND COST. Atarax and Vistaril are available by prescription, in brand-name or generic formulations. The generic form of these drugs is inexpensive. Thirty tablets of 25 mg generic drug cost about $12.

DRAMAMINE (meclizine)

Meclizine is a first generation antihistamine very similar to hydroxyzine. It is used primarily to treat vertigo, dizziness, and motion sickness. In CFS/ME, it is frequently prescribed to treat vertigo as well as balance problems, nausea, motion sickness, and Meniere's disease. Dramamine is safe to use. The most common side effect is excessive sedation. DiVertigo, a natural herbal alternative to Dramamine can also be purchased at pharmacies, as well as health food stores. DiVertigo is a liquid blend of lavender peppermint, frankincense, chamomile, myrrh and ylang-ylang, which is rubbed behind the ear rather than swallowed.

AVAILABILITY AND COST. Over-the-counter Dramamine costs roughly $15 for 36 tablets. In-house pharmacy brands are considerably less expensive. DiVertigo costs roughly $20.

SEE: Allergies, Sleep Disturbances, Urinary Problems

REFERENCE

Theoharides TC, Sant GR. “Bladder mast cell activation in interstitial cystitis.” Semin Urol. 1991 May;9(2):74-87. http://www.ncbi.nlm.nih.gov/pubmed/1853017 (Abstract)

ANTIVIRAL AGENTS

Acyclovir, Famvir, Amantadine, Valacyclovir, Valganciclovir

DESCRIPTION. Antiviral agents are a group of drugs used to inhibit the replication of viruses.

USES IN CFS/ME. Most CFS/ME physicians in the United States adhere to the theory that CFS/ME is caused by a virus. Although the causal virus has not yet been identified, reactivated latent viral infections are not only quite common in CFS/ME patients, but highly problematic, as the reactivated viruses produce many of the symptoms characteristic of the illness. As a consequence, antivirals have a long track record in treating CFS/ME. Most CFS/ME doctors have incorporated antivirals of one kind or another into their protocols, particularly for patients with either high viral titers, or who have had a viral onset of the illness.

Dr. Guyer, Director of The Advanced Medical Center in Indianapolis, Indiana, uses antivirals for patients with viral onset of CFS/ME, that is, those patients who initially had mononucleosis, or “flu,” from which they never recovered. Dr. Guyer reports that these patients typically have lab findings of depressed natural killer cells, hormone deficiencies, elevated RNase L levels, and elevated antibodies to Human Herpesvirus 6 (HHV-6), cytomegalovirus (CMV), Epstein-Barr virus (EBV) and other viruses.

Several doctors have reported success with antiviral treatments for a subset of their patients. Dr. Lerner, an infectious disease specialist who has been investigating and treating CFS/ME for more than 20 years, found that long-term antiviral therapy was very effective for his patients with high viral titers, sometimes providing these patients with nearly full recovery.

ACYCLOVIR

BACKGROUND. In the early 1980s, acyclovir (Zovirax) was hailed as one of the first drugs to be proven effective against genital herpes. Although later shown to be not as universally helpful as researchers first thought, acyclovir does relieve the severity, duration, and frequency of outbreaks for many patients with genital herpes. Acyclovir is not a cure for the infection because it does not kill the virus but merely inhibits its ability to replicate. In addition to treating herpes simplex, which causes genital herpes, acyclovir has been used with some success to treat other types of herpesvirus infections, such as chickenpox (varicella zoster virus), shingles (herpes zoster), cytomegalovirus (CMV), and infectious mononucleosis (Epstein-Barr virus), among others.

USES IN CFS/ME. In the mid-1980s, Epstein-Barr virus was thought to be the cause of the illness now known as CFS/ME. Because Epstein-Barr virus is one of the herpesviruses, it was logical for acyclovir to be used to treat cases of what was then called chronic Epstein-Barr virus or chronic mononucleosis. At that time, physicians using acyclovir noted symptomatic improvement in many of their patients. However, the first formal study was not completed until 1988, when Dr. Steven Straus of the National Institutes of Health (NIH) headed a double-blind, placebo-controlled study to determine the effectiveness of acyclovir against CFS/ME. Dr. Straus' results revealed no difference between the placebo group and patients given acyclovir (New England Journal of Medicine, 1988).

Notwithstanding these inconclusive results, many physicians familiar with CFS/ME continue to prescribe acyclovir, citing both their success rate and the flawed methods of the Straus study as justifications. Dr. Charles Lapp, for example, reported “remarkable results with this medication.” Dr. Guyer, Director of The Advanced Medical Center in Indianapolis, Indiana, recommends acyclovir for patients with viral onset of CFS/ME (after mononucleosis or other viral infection), especially in the presence of high titers of herpesvirus, recurrent shingles, or other clinical evidence of viral infection (CFIDS Chronicle, Spring 1991).

PROTOCOL. The oral form is most commonly recommended because intravenous injections carry some risk of toxicity. Daily doses range from 800 to 4000 mg divided throughout the day. Topical creams or ointment can be applied directly to the skin to treat surface blisters and other lesions. Despite the associated risks, patients with acute infections may require intravenous administration. Because resistance can develop, 30- to 60-day intervals between courses of therapy are recommended to ensure continued effectiveness.

PROS AND CONS. Acyclovir, while not a cure for CFS/ME, may lessen the viral load in patients with CFS/ME who demonstrate a lot of viral activity (high titers of herpesvirus, recurrent flu-like symptoms, shingles). A number of patients with CFS/ME have reported success with acyclovir in controlling shingles and eliminating chronic sore throat.

In their book, CFIDS: An Owner's Manual, Barbara Brooks and Nancy Smith reported success with acyclovir, claiming it to be the most important component of their respective treatments. Positive results are far from universal, however. An equal number of patients with CFS/ME report little or no benefit, even after months of trial. For those who do receive some benefit, the results are generally short-lived. Many patients must take the drug daily to see any result at all. Acyclovir, although usually well tolerated, produces frequent side effects, notably light-headedness, nausea, and headache. Patients with kidney disease should not take acyclovir.

AVAILABILITY AND COST. Oral acyclovir is available by prescription. Oral acyclovir can be purchased for as little as $30 a month (200 mg tablets). Insurance plans usually cover the cost.

PATIENT REVIEWS

CFS/ME patient reviews of Zovirax: http://www.revolutionhealth.com/drugs-treatments/rating/zovirax-for-chronic-fatigue-syndrome-cfs-cfids-me

REFERENCES

Physician's Forum. CFIDS Chronicle, Vol 1, Issue 1, March 1991.

Straus, Steven, Dale, JK, Tobi, M, et al. “Acyclovir Treatment of the Chronic Fatigue Syndrome.” New England Journal of Medicine. 26:1692-1698,1988.

FAMVIR

Famvir (famcyclovir) is an oral antiviral used for herpesviruses, particularly herpesviruses 6 and 7, two viruses that play an important role in CFS/ME. Technically, Famvir is a prodrug; that is, a substance that is converted into an active drug once in the body. Famvir functions the same as Zovirax, but with fewer side effects. There is some indication that it may be more effective, as well.

Currently, only a few CFS/ME clinicians prescribe Famvir, so not much information is available as to its effectiveness in treating CFS/ME. Dr. Guyer has observed the patients who experience milder symptoms of shorter duration, accompanied by elevated levels of IgG to EBV, seem to do well with Famvir.

AVAILABILITY AND COST. Famvir is available by prescription. This drug is quite expensive. A one -month supply can cost as much as $700, depending on the dosage.

REFERENCE

“Dale Guyer, M.D., on Treating Chronic Fatigue Syndrome & Fibromyalgia: 'Covering the Bases & Peeling Back the Layers of the Onion.'” ProHealth.com. June 13, 2006 http://www.prohealth.com/library/showarticle.cfm?libid=9761

AMANTADINE

Amantadine (Symmetrel) is prescribed for viral infections (type A influenza virus) and Parkinson's disease. It acts by blocking the penetration of cell membranes by the infectious material from viruses. As an antiviral agent, it is of no benefit unless administered at the onset of infection. In patients with CFS/ME who cannot tolerate flu shots, amantadine might be a good alternative, especially for those patients susceptible to frequent episodes of influenza. In CFS/ME, its most common use is not as an antiviral agent but as a stimulant. It is used to treat fatigue and lethargy in mild cases. Common side effects include insomnia, confusion, headaches, and dizziness. Amantadine interacts with antidepressants and antihistamines. Some patients with CFS/ME cannot tolerate this drug so the initial dose should be small.

AVAILABILITY AND COST. Amantadine is available by prescription. A one-month supply of the generic amantadine costs approximately $12.

PATIENT REVIEWS

CFS/ME patient reviews of amantadine: http://www.revolutionhealth.com/drugs-treatments/rating/symmetrel-for-chronic-fatigue-syndrome-cfs-cfids-me

VALACYCLOVIR (Valtrex)

DESCRIPTION. Valacyclovir is an oral pro-drug that converts to acyclovir once ingested. It is more bioavailable than acyclovir and is therefore more effective.

BACKGROUND. Valtrex is marketed for herpes simplex, but in 2009 Hoshino et al found that it also reduced the replication of EBV. They concluded that latent EBV (Epstein-Barr virus) might be completely eradicated by Valtrex if reinfection did not occur.

USES IN CFS/ME. A 2007 study by Dr. Lerner of CFS/ME patients with EBV reactivation found that Valtrex resulted in both increased physical functioning and improved heart functioning (reduced sinus tachycardia, decreased abnormal cardiac wall movements) as well as reducing EBV antibody levels. By the end of the 36-month trial many patients were able to resume normal activities. Patients with both EBV and CMV infections did not improve.

PROTOCOL. Valtrex is prescribed at 2000 mg/day, and then reduced. Patients can expect to take it for over a year.

PROS AND CONS. Valtrex may be very effective for patients with high herpesvirus and EBV titers alone. It is less effective against HHV-6 than Valcyte.

AVAILABILITY AND COST. Valtrex is available with a prescription from most pharmacies. It is expensive. A one-month supply can cost upwards of $350.

PATIENT REVIEWS

CFS/ME patient reviews of Valtrex: http://www.revolutionhealth.com/drugs-treatments/rating/valtrex-for-chronic-fatigue-syndrome-cfs-cfids-me

VALGANCYCLOVIR (Valcyte)

DESCRIPTION: Valcyte is an antiviral drug approved for treating cytomegalovirus (CMV) infections. Valcyte is a prodrug, converting quickly to ganciclovir after oral administration.

USES IN CFS/ME. In 2001 and 2002, Lerner et al conducted small trials of Valcyte which showed that the drug reduced EBV titers and significantly improved the symptoms of a subset of patients. In 2007 Dr. Jose Montoya of Stanford Hospital Infectious Disease Clinic, conducted a double blinded placebo controlled clinical trial to determine whether CFS/ME patients with elevated antibody titers for HHV-6 and EBV would benefit from valganciclovir treatment. The trial enrollment was small (30 patients), however the study indicated that patients on Valcyte experienced significant cognitive improvement.

Valcyte is one of the newer antivirals, so there is not yet a lot of feedback on its success rate in the CFS/ME population. The Holtorf Medical Group in Torrance, California, has used Valcyte since 2003 for treating CFS/ME, and has found it to be effective in patients with “flu-like symptoms or having symptoms that started with a flu-like illness; elevated IgG or EA against Epstein bar virus, cytomegalovirus and/or HHV-6; low natural killer cell activity; high RNAse-L activity; high ACE (>35); coagulation activation; high tumor necrosis factor (TNF); low melanocyte stimulation hormone (MSH); high interleukin-6 (IL-6); low WBC; increased 1-25 vitamin D/25 vitamin D ratio and/or elevated or decreased total IgA, IgM or IgG levels.” In the absence of similar testing, it would be difficult to evaluate which patient sub-group would best benefit from Valcyte.

PROS AND CONS. Patients who have taken Valcyte for several months have reported significant side effects, including muscle weakness, flu-like symptoms and joint pain in spite of a dramatic decline in viral titers. Nearly all patients feel significantly worse for the first two to four weeks. Valcyte is prohibitively expensive. A one-month supply costs between $1500 and $2000.

SEE: In Search of a Cause

FURTHER READING

Summary of Valtrex studies: http://aboutmecfs.org.violet.arvixe.com/Trt/TrtValtrex.aspx

Summary of Dr. Lerner's antiviral research and treatment of CFS/ME patients. http://aboutmecfs.org.violet.arvixe.com/Int/Lerner.aspx

Dr. Guyer discusses his antiviral protocol: http://www.prohealth.com/library/showarticle.cfm?libid=13222

RESEARCH

Lerner, A Martin, Safedin Beqaj, James T Fitzgerald, Ken Gill, Carol Gill, James Edington. “Subset- directed antiviral treatment of 142 herpesvirus patients with chronic fatigue syndrome.” Dovepress Journal: May 2010 Volume 2010:2 Pages 47 – 57

ARTESUNATE (Hepasunate)

DESCRIPTION. Artesunate is a semi-synthetic anti-malarial drug derived from artemisia annua (wormwood).

BACKGROUND. While artemisia has been used for centuries as an herbal anti-parasitic, it wasn't until the 1960s that Chinese scientists developed an artemisinin drug to combat malaria. Since then, artesunate and other artemisia-based drugs have been used worldwide to combat malaria. However, it was not until 2007 that the FDA approved artesunate for the treatment of severe malaria in the United States. The action of artesunate is still unclear, but it is thought to kill the parasite by destroying its mitochondrial membrane.

USES IN CFS/ME. Recent cell studies indicate that artesunate significantly reduces viral protein production in HHV-6 infected cells. An in vitro study in 2005 confirmed that artesunate also significantly reduces cytomegalovirus (CMV) replication in cells. Because so many CFS/ME patients test positive for HHV-6 and CMV reactivation, artesunate may provide a means to control, if not eliminate, the symptoms associated with the proliferation of the viruses. Although this drug is experimental, some doctors are using it to treat CFS/ME, with positive results. Dr. Cheney has observed a reduction in viral titers, and a cessation of diastolic heart dysfunction.

PROTOCOL. Dr. Cheney puts his patients on 50 mg of Hepasunate (the form of artesunate available for online purchase) three days a week (empty ½ capsule under the tongue, hold for a minute, swish, and spit), and wormwood elixir 4 days a week (½ tsp in water, swish and spit).

PROS AND CONS. This supplement is highly experimental for CFS/ME, which means that few doctors use it, and, as a consequence, patients who take it independently may not be monitored for side effects, toxicity, or drug interactions.

As one might expect, reports from patients who have tried artesunate are mixed. Some report a significant reduction in fatigue and flu-like symptoms. Others report dizziness, diarrhea and malaise. There is no way of determining from these reports whether the side effects (or improvements) are due to the dosage, brand or, perhaps, completely independent factors. This is a “use at your own risk” medication, so you are advised to exercise caution and go slowly. The twice a week swish and spit method is the gentlest way to introduce artesunate.

AVAILABILITY AND COST. Hepasunate (the brand Dr. Cheney uses) can be purchased online for $50 for a bottle of 50 capsules. Before trying artesunate, please read the following Phoenix Rising forum discussing the experiences of patients who have followed Dr. Cheney's artesunate protocol. It contains details of the experiences of patients who have taken artesunate, as well as links to useful articles.

FURTHER READING

CFS/ME patient forum on artesunate: http://forums.phoenixrising.me/showthread.php?601-Artesunate-Cheney-dosage-and-benefits

This thread provides detailed information about side effects, dosage, and efficacy.

Supplier of Hepasunate in the U.S.: http://www.hepalin.com/hepasunate50.htm

Efferth, Thomas, Marta R. Romero, Dana G. Wolf, Thomas Stamminger, Jose J. G. Marin, and Manfred Marschall. “The Antiviral Activities of Artemisinin and Artesunate.” Clin Infect Dis. (2008) 47 (6):804-811. http://cid.oxfordjournals.org/content/47/6/804.long

This is an excellent article on the history, mechanisms and effects of artesunate.

RESEARCH

Auerochs S, Korn K, Marschall M. “A reporter system for Epstein-Barr virus (EBV) lytic replication: anti-EBV activity of the broad anti-herpesviral drug artesunate.” J Virol Methods. 2011 May;173(2):334-9. Epub 2011 Mar 17. http://www.ncbi.nlm.nih.gov/pubmed/21396962

Chou S, Marousek G, Auerochs S, Stamminger T, Milbradt J, Marschall M. “The unique antiviral activity of artesunate is broadly effective against human cytomegaloviruses including therapy-resistant mutants.” Antiviral Res. 2011 Nov;92(2):364-8. http://www.ncbi.nlm.nih.gov/pubmed/21843554

Efferth T, Kaina B. “Toxicity of the antimalarial artemisinin and its derivatives.” Crit Rev Toxicol. 2010 May;40(5):405-21. http://www.ncbi.nlm.nih.gov/pubmed/20158370

Gordi T, Lepist EI. “Artemisinin derivatives: toxic for laboratory animals, safe for humans?” Toxicol Lett. 2004 Mar 1;147(2):99-107.

Milbradt J, Auerochs S, Korn K, Marschall M. “Sensitivity of human herpesvirus 6 and other human herpesviruses to the broad-spectrum antiinfective drug artesunate.” J Clin Virol. 2009 Sep;46(1):24-8. http://www.ncbi.nlm.nih.gov/pubmed/19501020

BENZODIAZEPINES

Klonopin (clonazepam), Valium (diazepam), Xanax (alprazolam)

DESCRIPTION. Benzodiazepines are central nervous system depressants. They are classed as minor tranquilizers. Benzodiazepines comprise a very large group of drugs, with over 30 distinct formulations, and nearly 100 brand names.

BACKGROUND. The benzodiazepines are a group of drugs used to treat anxiety, skeletal muscle spasm, insomnia, and panic. Their calming effect is produced by a general slowing of the central nervous system. Within a decade of their introduction on the market, they had become one of the most frequently prescribed medications in the United States and, by the late 1980s, more than 10% of the U.S. population had taken some form of tranquilizer.

Although the benzodiazepines do not pose as many problems as the major tranquilizers, they also produce tolerance and dependence. Benzodiazepines can be classified into two main groups, depending on their half-life (how long it takes to clear half the drug from the body). In general, the shorter acting benzodiazepines (with a half-life of 4 to 20 hours) are more habit forming than those with a longer half-life (24 to 72 hours). In cases where dependence develops, doses should be tapered off slowly to avert withdrawal symptoms (anxiety, jitters, insomnia, confusion, sweating, heart palpitations, and depression).

USES IN CFS/ME. The benzodiazepines are frequently prescribed, often in combination with a small dose of antidepressant, to treat insomnia. The logic behind prescribing both drugs is that one gets you to sleep and the other keeps you asleep. The majority of CFS/ME physicians also recommend some form of benzodiazepine for patients with panic disorder or agitation due to upregulation of the sympathetic nervous system.

It is important to note that benzodiazepines are usually prescribed in small doses to treat CFS/ME. Normal doses of these drugs can produce paradoxical reactions, creating the very symptoms the drug is supposed to control. Even tiny doses can produce adverse reactions in patients hypersensitive to chemicals and drugs. It may be worthwhile to do a toothpick test (crush the pill and take only what clings to the end of a moistened toothpick) before embarking on a full program.

KLONOPIN (in Canada, Rivotril) (clonazepam)

BACKGROUND. Klonopin (clonazepam) acts directly on the limbic system, thalamus, and hypothalamus to produce anticonvulsant effects. It has been used since the late 1970s to control seizures. Klonopin is easily absorbed through the digestive tract and has a half-life of 24 to 72 hours. Effects are noticeable within 20 minutes and can last for 12 hours.

USES IN CFS/ME. Klonopin is the most widely recommended benzodiazepine for patients with CFS/ME. Dr. Cheney, a long-time proponent of the benefits of Klonopin, prescribes it to protect the brain against what he calls “excitatory neurotoxicity.” Most CFS/ME patients have excess amounts of neuroexcitatory neurotransmitters in their nervous systems, resulting in a brain which is overstimulated. The “tired and wired” feeling CFS/ME patients so often describe is the result of this excess stimulation. Because Klonopin is so long-acting, it serves to down regulate the nervous system. Klonopin is also beneficial for treating insomnia, especially if taken in conjunction with Sinequan. A number of patients have reported that Klonopin helps improve cognitive symptoms, particularly poor concentration and “brain fog.” Some patients also report that Klonopin helps alleviate flu-like achiness.

PROTOCOL. The dose recommended to treat CFS/ME-related insomnia is low, generally 0.5 to 1 mg taken before bedtime for insomnia. Dr. Cheney also recommends daytime doses of a quarter of a tablet to increase energy and concentration.

PROS AND CONS. The side effects of Klonopin are mild, especially compared to those of some of the other benzodiazepines. Some patients with CFS/ME, however, experience sedation, excessive thirst, depression, and gastrointestinal upset even with small doses. Like all benzodiazepines, it loses its efficacy over time. If taken for longer than a month, Klonopin should not be discontinued suddenly. On the positive side, Klonopin appears to be well tolerated by many patients with CFS/ME. Patients report that the generic form is less effective than brand.

AVAILABILITY AND COST. Klonopin is available by prescription. A 30-day supply of the generic drug (clonazepam, 0.5 mg) costs about $2. The cost is usually covered by insurance (but check for time limitations).

PATIENT REVIEWS

CFS/ME patient reviews of Klonopin: http://www.revolutionhealth.com/drugs-treatments/rating/klonopin-for-chronic-fatigue-syndrome-cfs-cfids-me

VALIUM

BACKGROUND. Valium (diazepam) was introduced in the United States in 1963. It acts by depressing the area of the central nervous system that controls the emotions (limbic system). It is also used as an anticonvulsant in patients with epileptic seizures and to relieve skeletal muscle spasms. Side effects from long-term use can include depression, drowsiness, lethargy, fainting, slurred speech, tremor, blurred or double vision, gastrointestinal disorders, nausea, and respiratory depression. It has a half-life of 20 to 50 hours. Onset occurs within 30 minutes to an hour, with peak action in 1 to 2 hours.

USES IN CFS/ME. Valium is less frequently recommended than Klonopin, nevertheless some people have found it to be very effective. In most cases, Valium is used for insomnia. It is taken just before bed. As with Klonopin, it should be taken at the lowest possible dose. If side effects or tolerance develop, Valium should be eliminated by slowly tapering off the dose.

AVAILABILITY AND COST. Valium is available by prescription. A one-month supply (30 tablets) of the generic drug at the lowest dose (2 mg) costs about $15.

XANAX

BACKGROUND. Xanax (alprazolam) was introduced in 1982 to treat anxiety, muscle spasms, and insomnia. It is also widely prescribed to treat panic attacks, agitated depression, and phobias. Xanax is more rapidly metabolized and eliminated than other benzodiazepines and causes less “hangover.” It has a half-life of 12 to 15 hours, rapid onset (about 15 minutes), and its peak action occurs within 1 to 2 hours.

USES IN CFS/ME. Because Xanax acts so quickly, it is usually recommended to treat panic and anxiety attacks. It is not often prescribed for persistent insomnia, although it may be recommended on a short-term basis. As with other benzodiazepines, Xanax should be taken at the lowest possible dose. It is not recommended as a daily medication, but only as needed to alleviate the effects of panic or anxiety due to overactive nervous system responses. It is highly addictive.

AVAILABILITY AND COST. Xanax is available by prescription. It is inexpensive; a supply of 30 tablets of the generic drug (alprazolam) at the lowest dose (0.25 mg) costs about $7.

SEE: Cognitive and Emotional Symptoms, Sleep Disorders

PATIENT REVIEWS

CFS/ME patient reviews of Xanax: http://www.revolutionhealth.com/drugs-treatments/rating/xanax-for-chronic-fatigue-syndrome-cfs-cfids-me

BETA BLOCKERS

Propanolol (Inderol), Atenolol (Tenormin), Labetalol (Normodyne), Nebivolol (Bystolic)

DESCRIPTION. Beta blockers slow heart activity by interfering with adrenal hormones.

BACKGROUND. Beta blockers are used primarily to treat angina and high blood pressure, and to control irregular heartbeat in damaged hearts. They can also be used to prevent migraine headaches, control ocular fluid pressure, and reduce anxiety. Beta blockers work by occupying the specific receptors in the heart, airways, and blood vessels (beta1 and beta2 adrenergic receptors) designed to receive the stimulating neurohormone, norepinephrine. By preventing the action of norepinephrine, beta blockers reduce the force and rate of heartbeats and prevent dilation of blood vessels surrounding the brain and of the airways leading to the lungs. The action of most beta blockers makes them useful for treating neurally mediated hypotension (NMH), an abnormal reflex interaction between the heart and brain. Patients with NMH experience sudden drops in blood pressure, leaving them feeling faint and weak. Beta blockers are used to help maintain constant blood pressure in NMH.

USES IN CFS/ME. According to Dr. Lapp, various forms of dysautonomia (including NMH), postural orthostatic tachycardia syndrome (POTS), and other forms of orthostatic intolerance occur in 96% of CFS/ME patients. Researchers of the Northern CFS/ME Clinical Network and Newcastle University found that POTS is three times more likely to occur in CFS/ME patients than in the general population. And researchers at Johns Hopkins University have published findings that seem to demonstrate a link between CFS/ME and NMH. Beta blockers have been prescribed to treat to treat low blood pressure common in CFS/ME, NMH and POTS as well as idiosyncratic heart problems (palpitations, mitral valve prolapse, and rapid or irregular heartbeat) and, in some circumstances, anxiety and headaches.

PROTOCOL. The beta blockers usually recommended for NMH are propranolol and atenolol (Tenormin). CFS/ME doctors recommend a very low dose. Beta blockers are normally prescribed as part of a program that includes increased intake of dietary salt and Florinef (fludrocortisone), a steroid drug (see Florinef). Beta blockers should not be taken with any food, drug, or other medication that contains caffeine or alcohol because the combination may increase heart rate or blood pressure. Dr. Light proposes that low-dose Nordyne, a combined alpha and beta adrenergic antagonist used to treat high blood pressure, might be of benefit for patients who don't respond to propanolol.

PROS. In 1995 a Johns Hopkins University study led by Issam Bou-Holaigah and Peter Rowe created quite a stir in the CFS/ME community (Journal of the American Medical Association, 1995). Of the 22 patients with CFS/ME and NMH treated in this study, nine reported full recovery and seven noted some improvement on beta blockers. (However, it should be noted that not all of these patients received beta blockers; some were given only Florinef.) These initial results were encouraging. Reports from CFS patients have since been mixed, but some claim substantial improvement from beta blockers.

CONS. Symptoms of CFS/ME do not always respond favorably to beta blockers. Some patients report little or no effect. A little over 50% report that symptoms actually get worse. Moreover, long-term and severe cases have not shown substantial improvement using this regimen. Beta blockers can cause the very symptoms they are supposed to alleviate: orthostatic hypotension (the feeling of fainting on standing), fatigue, dizziness, light-headedness, depression, and headaches.

Other common side effects include drowsiness, decreased sex drive, nervousness, depression, nightmares, upset stomach, constipation, and diarrhea. An additional consideration for those who have taken beta blockers for a long period of time is that the drug should not be discontinued suddenly but should be tapered off gradually over several weeks to avert irregularities in heart rate. People with poor circulation in the arms and legs, a frequent problem in CFS/ME, are also cautioned not to take beta blockers because these drugs make the problem worse. Beta blockers may also lower melatonin levels in the body, which may lead to insomnia. Those with mast cell disorders should not take beta blockers.

AVAILABILITY AND COST. Beta blockers are available by prescription. The cost ranges from $4 a month for the older beta blockers to $10 a month for the newer ones. Beta blockers are usually covered by insurance.

FURTHER READING

Dr. Lapp on orthostatic intolerance: http://www.cfids.org/about-cfids/diagnostic-testing.asp

CFIDS Association of America's review of medications used to treat orthostatic intolerance. http://www.cfids.org/cfidslink/2009/070104.asp

Survey of CFS/ME patients using beta blockers: http://www.cfidsresearch.com/2011/02/22/beta-blockers/

PATIENT REVIEWS

A patient's experience with atenolol: http://www.revolutionhealth.com/drugs-treatments/rating/tenormin-for-chronic-fatigue-syndrome-cfs-cfids-me

RESEARCH

Bou-Holaigah, Issam, Rowe, Peter C, Ran, Jean, and Calkins, Hugh. “The Relationship Between Neurally Mediated Hypotension and the Chronic Fatigue Syndrome.” Journal of the American Medical Association. 274(12):961-967,1995. http://www.ncbi.nlm.nih.gov/pubmed/7674527 (Abstract)

Raj, Satish MS, Bonnie Black, RN, Italo Biaggioni MD, Sachin Y. Paranjape, Maricelle Ramirez, William D. Dupont, PhD, David Robertson, MD. “Propranolol Decreases Tachycardia and Improves Symptoms in the Postural Tachycardia Syndrome: Less is More.” Circulation. 2009; 120: 725-734. http://circ.ahajournals.org/content/120/9/725.full

CALCIUM CHANNEL BLOCKERS

Nicardipine, Nimodipine, Nifedipine, Verapamil

DESCRIPTION. Calcium channel blockers inhibit the transmembrane influx of calcium ions into cardiac and smooth muscle.

BACKGROUND. Calcium channel blockers work by preventing calcium ions from entering smooth muscle cells. Calcium is especially important for the functioning of these cells and specialized cells in the heart. When calcium levels are lowered, the result is a relaxation of blood vessels, allowing an increased supply of blood and oxygen to the heart while decreasing its work load. As a consequence of their effect on blood vessels, calcium channel blockers are useful in treating cardiovascular disorders, such as angina (chest pain) and coronary artery disease, and to lower blood pressure. These drugs also may improve exercise capacity and subsequently reduce the need for surgery in patients with cardiac problems.

USES IN CFS/ME. At the 1990 CFIDS conference in Los Angeles, Dr. Ismael Mena presented evidence of cerebral dysfunction in patients with CFS/ME. Using neurological spectroscopic scanning techniques, Dr. Mena reported that 71% of CFS/ME patients have low blood flow (hypoperfusion) in the temporal lobe of the brain. He further reported that after treatment with calcium channel blockers, some of these patients exhibited clinically improved cerebral blood flow (CFIDS Chronicle, Spring/Summer 1990).

A number of CFS/ME clinicians have noted improvement in cognitive function in patients given calcium channel blockers. Cardene also is helpful in treating migraine-type headaches. Dr. Jay Goldstein also observed improvements in cognitive function and energy level in patients given calcium channel blockers. He also noted increased exercise tolerance, decreased tender point sensitivity, and alleviation of panic disorder with nimodipine.

In October 1994, Dr. Robert Keller, Medical Director of the Center for Special Immunology in Miami, reported improvement of symptoms in 25 patients with CFS/ME after treatment with the calcium channel blocker verapamil. Within one month of finding the optimal dose of verapamil, patients reported improvement in fatigue, memory, and myalgia. Dr. Keller also reported a decrease in the number of activated T cells, demonstrating that calcium channel blockers may have some immunomodulatory properties.

In 2000, Chauduri et al correlated the symptoms of CFS/ME, particularly fluctuating fatigue, with abnormal ion channel function. This finding appears to have been borne out by an interesting double-blind study carried out by Dr. Weibe, in which a patient reported dramatic declines in fatigue, sleep disturbance, pain and mental “fog” after being given nimodipine as opposed to placebo.

PROTOCOL. The most commonly prescribed calcium channel blockers in patients with CFS/ME are nimodipine, nicardipine, and verapamil. Doses must be individualized for each patient, but generally are quite low.

 Nimodipine 30 mg, 2 or 3 times daily

 Nicardipine 20 mg, 2 or 3 times daily

Verapamil 120 to 240 mg, taken nightly

PROS. Symptomatic relief can be obtained quickly with calcium channel blockers; therefore a trial is often worthwhile in many cases, even in the absence of a single-photon emission computed tomography (SPECT) scan. Improved cognitive function, fewer headaches, increased energy, and decreased muscle spasms have all been reported with use of these drugs.

CONS. Although calcium channel blockers can be effective for some of the more problematic CFS/ME symptoms (e.g., cognitive dysfunction), side effects can be a problem. The most common are lowered blood pressure (which can be serious if blood pressure is already low), severe pressure headaches, dizziness, gastrointestinal problems (diarrhea, constipation), and weakness. In addition, hypertensive effects can be exaggerated by concomitant use of other drugs that affect blood pressure, such as beta blockers. Tagamet (cimetidine) also increases the effects of calcium channel blockers. The use of calcium channel blockers requires close supervision by a physician due to their effects on blood pressure. Most CFS/ME doctors do not include calcium channel blockers in their protocols, except for patients who have high blood pressure. Not recommended for people with a history of kidney problems.

AVAILABILITY AND COST. Calcium channel blockers are available by prescription. Nimodipine is expensive, costing between $1.75 and $5.00 a pill. Nicardipine and verapamil are much less expensive, about $10 - $15 for 30 tablets. Insurance usually covers.

FURTHER READING

A detailed discussion by Cort Johnson of the role ion channels play in CFS. http://aboutmecfs.org.violet.arvixe.com/Rsrch/NeurologicalChannelopathy.aspx

Weibe, E. “Managing Chronic Fatigue Syndrome: Two Case Reports.” Can Fam Physician.1996 November;42: 2214–2217. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2146911/?page=1

RESEARCH

Chaudhuri, A., W.S. Watson, J. Pearn and P.O. Behan. “The Symptoms of Chronic Fatigue Syndrome are Related to Abnormal Ion Channel Function.” Med Hypotheses. 2000 Jan;54(1):59-63. http://www.ncbi.nlm.nih.gov/pubmed/10790725 (Abstract)

CENTRAL NERVOUS SYSTEM STIMULANTS

Ritalin, Dexedrine, Lonamin, Provigil, Strattera

DESCRIPTION. Central nervous system (CNS) stimulants are a class of drugs that, much like the amphetamines, speed CNS responses by releasing stored norepinephrine from nerve terminals in the brain.

BACKGROUND. CNS stimulants have played an important role in human history. The cultivation of chocolate, which contains small amounts of caffeine (a xanthine alkaloid) goes back to 1100 B.C. Chocolate's reputation as an aphrodisiac is, no doubt, partially due to its stimulating effects. Tea, which contains about 3% caffeine, has been under cultivation since the 10th century B.C. Coffee, which is approximately 1.2% caffeine, has been consumed as a stimulant since the 13th century. In fact, coffee was so stimulating that it was banned under Charles II, who blamed the drink for inciting the people to sedition. (Pope Clement VIII also banned coffee until it was revealed that he himself was a major importer of the “devil's drink,” whereupon he immediately baptized the brew, making it safe to drink.)

In the 19th and early 20th century, cocaine, another CNS stimulant, was used to treat depression. Sigmund Freud, an early proponent of the curative powers of cocaine, recommended cocaine as a cure for depression, sexual impotence, and as an anesthetic. Amphetamines, first synthesized in 1887, were used for asthma, and in the 1940s became widely used for weight loss. By the 1960s CNS stimulants were prescribed as treatments for a variety of disorders, including hyperactivity, depression, and attention deficit disorder (ADD). In 2004 the FDA approved the stimulant modafinil (Provigil) for the treatment of narcolepsy.

USES IN CFS/ME. CNS stimulants are generally used to increase energy and cognitive function. The drug most commonly recommended for CFS/ME patients is Ritalin (methylphenidate), although Dexedrine (dextroamphetamine) is also sometimes prescribed. Lonamin (phentermine), a mild CNS stimulant that activates dopamine in the brain, is sometimes recommended in CFS/ME patients with hypersomnia or significant cognitive impairment. The mild stimulation induced by a low dose of any of these drugs can often dispel feelings of lethargy and “brain fog” and, because effects are so immediate, they can act as a quick fix in an emergency.

While there is great appeal in seeing immediate improvement in energy levels and cognitive function, most CFS/ME clinicians prescribe these drugs with caution. Dr. Cheney believes that the disabling fatigue of CFS/ME may be a protective mechanism. Therefore, creating energy artificially may in the long run cause relapse and may even exacerbate the disease process.

PROTOCOL. Dosage varies according to the individual needs of the patient, as determined by a physician. Patients with CFS/ME, however, are advised to start with the smallest dosage to avert the negative effects of overstimulation. Dexedrine, for example, is prescribed at the lower than usual dose of 5 to 10 mg. Lonamin dosage varies between 15 and 30 mg (taken in the morning).

For the subset of CFS/ME patients with fibromyalgia, Dr. Bateman recommends Adderall, starting with the lowest dosage and working up to 5-20 mg. two to three times a day. Dr. Bateman also uses Provigil (modafinil) 50-400 mg (long-acting) as well as Wellbutrin, a stimulant antidepressant.

 Dr. Lapp recommends using low doses of CNS stimulants such as Ritalin, Adderall or Provigil for fatigue. Dr. Lapp has found that “Provigil not only improves fatigue, but also somnolence, mental clarity, attention deficits, and depression."

 Surprisingly, while Dr. Teitelbaum advises that CFS/ME patients steer clear of coffee, he recommends 10-30 mg of Ritalin taken three times a day up to a maximum of 60 mg/day. Dr. Teitelbaum observes that “the medications ritalin and dexedrine can be very helpful at lower doses in those with chronic fatigue syndrome, as they help stabilize the low blood pressure and the low dopamine levels found in chronic fatigue syndrome.”

Dr. Rowe recommends that ME/CFS patients with orthostatic intolerance take low doses of vasoconstrictor medications, including Ritalin and Dexedrine to treat blood pooling. He recommends 5 mg in the morning repeated, if necessary, four hours later.

PROS. It appears that the less ill the patient the better the response. The boost received from these drugs may enable patients with mild symptoms to work full-time or part-time. Most people use CNS stimulants on an "as needed" basis to provide extra energy on particularly long or important days. Many patients report a lessening of “brain fog” as well as increased focus and stamina. Doses for these patients have been very small.

CONS. Whereas CNS stimulants have been effective in some patients, they are of modest to little benefit for most. Stimulants, while appearing to provide more energy, tax the system. As a consequence, they are beneficial only if the system is strong to begin with. A number of patients report feeling much worse while taking stimulants. The most common side effects are anxiety, excitation, insomnia, gastrointestinal problems, dizziness, headache, palpitations, dry throat, appetite loss, chest pain, and hypertension. Patients also report that Ritalin causes anxiety and paranoia. With nearly all CNS stimulants, patients report rebound fatigue after the drug wears off.

As with other medications that affect the CNS, some patients experience a paradoxical reaction of extreme fatigue and weakness. Drug interactions are numerous, including antidepressants (especially MAOIs), anticonvulsants, and caffeine. As with MAOIs, foods high in tyramine should be avoided (see Urinary Tract Problems). CNS stimulants are contraindicated in patients with cardiovascular disease or hyperthyroidism.

AVAILABILITY AND COST. CNS stimulants are available by prescription, either as brand name or generic drug. Most of the older varieties are fairly inexpensive. Ritalin, for example, costs about $25 a month. Provigil, a newer drug, costs upwards of $250 a month. Insurance usually reimburses the cost.

FURTHER READING

Dr. Bateman's protocol, including stimulants: http://www.offerutah.org/cfsmetreatment.htm

Drs. Bateman, Natelson, and Lapp discuss CNS stimulant protocols for fibromyalgia and CFS/ME. http://www.fmnetnews.com/articles-hot.php

Summary of CNS stimulants used for CFS/ME patients: http://phoenixrising.me/?page_id=2299

Summary of Provigil's use in CFS/ME: http://phoenixrising.me/?page_id=4803

Summary of dexedrine's use in CFS/ME: http://phoenixrising.me/?page_id=4762

Effects of caffeine and CNS stimulants on patients with CFS/ME. Observations on use of CNS stimulants by Drs. Teitelbaum and Papernik: http://www.everydayhealth.com/chronic-fatigue-syndrome/relief-with-caffeine.aspx

PATIENT REVIEWS

CFS/ME patient ratings of Adderall: http://www.revolutionhealth.com/drugs-treatments/rating/adderall-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of dexedrine: http://www.revolutionhealth.com/drugs-treatments/rating/dexedrine-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of methylphenidate (Ritalin and Concerta). http://www.revolutionhealth.com/drugs-treatments/rating/methylphenidate-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of phentermine: http://www.revolutionhealth.com/drugs-treatments/rating/phentermine-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Provigil: http://www.revolutionhealth.com/drugs-treatments/rating/provigil-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Strattera: http://www.revolutionhealth.com/drugs-treatments/rating/pamelor-for-chronic-fatigue-syndrome-cfs-cfids-me

CYTOTEC (misoprostol)

CAUTION: Do not take Cytotec during pregnancy.

DESCRIPTION. Cytotec (misoprostol) is a synthetic prostaglandin analogue that replaces depleted gastric prostaglandins.

BACKGROUND. Cytotec is routinely used to prevent gastric ulcers in elderly or debilitated patients who are receiving nonsteroidal anti-inflammatory drug (NSAID) therapy. In these patients, the actions of natural prostaglandins (hormone-like substances that regulate inflammation, blood vessel dilation, and a host of other physiological responses) are blocked.

USES IN CFS/ME. Cytotec is primarily recommended for patients who are taking non-steroidal anti-inflammatory drugs (NSAIDs). Cytotec not only protects the stomach lining from the damaging effects of pain killers, it also appears to protect the small intestines. Dr. Leo Galland believes the drug can prevent “leaky gut,” a condition in which the small intestine becomes overly permeable, thereby leading to food sensitivities and allergies. Cytotec is also used to treat Interstitial Cystitis (IC), a condition experienced by many people with CFS/ME. In 1998 Kelly et al found that 24 out of 25 patients with IC improved after receiving misoprostol, with minimal side effects.

PROTOCOL. Physicians recommend taking four 100 mcg tablets a day (one with each of three meals and one before bedtime). When reducing dosage, the bedtime dose should be the last tablet eliminated.

PROS AND CONS. Patients who have taken Cytotec to treat the symptoms of IC describe it as a “miracle.” Many patients who have tried Cytotec for food sensitivities report an increase in the number of foods they can tolerate and a decrease in related gastrointestinal symptoms. Patients with severe food intolerance have noted sustained improvement even after eventually discontinuing Cytotec. Cytotec has relatively few side effects. The most common side effects are diarrhea, flatulence, nausea, headache, and, rarely, vaginal bleeding. If side effects last longer than a week or are severe, the dosage should be lowered. Cytotec is contraindicated in pregnant women, because it may induce miscarriage.

AVAILABILITY AND COST. 100 pills of the generic cost between $30 and $55. Cytotec is available by prescription, and the cost is covered by most insurance plans. Uninsured patients may meet the manufacturer's criteria for its "Patients in Need" program and qualify for a free supply (contact Searle, 5200 Old Orchard Rd., Skokie, IL 60077; 800-542-2526).

FURTHER READING

A general review of the therapeutic uses of misoprostol. http://www.ncbi.nlm.nih.gov/pubmed/11191738

RESEARCH

Kelly JD, Young MR, Johnston SR, Keane PF. “Clinical response to an oral prostaglandin analogue in patients with interstitial cystitis.” Eur Urol. 1998;34(1):53-6. http://www.ncbi.nlm.nih.gov/pubmed/9676414 (Abstract)

DIAMOX

DESCRIPTION. Diamox (acetazolamide) is a carbonic anhydrase inhibitor.

BACKGROUND. Diamox was introduced in 1953 as a diuretic. Because it reduces intraocular pressure, it is used to treat glaucoma. Diamox can also be used to treat edema, high-altitude sickness, and as an anticonvulsant. Diamox blocks the action of carbonic anhydrase, an enzyme that helps form hydrogen and bicarbonate ions from carbon dioxide and water. It promotes excretion of sodium, potassium, water, and bicarbonate. By blocking carbonic anhydrase in the central nervous system and increasing carbon dioxide tension, Diamox also helps decrease abnormal neuronal discharge that may lead to convulsions. Because Diamox lowers blood pH, and encourages respiration, it has been prescribed to help with sleep apnea as well. Other uses include absence seizures, periodic paralysis and congestive heart failure.

USES IN CFS/ME. Dr. Cheney has found Diamox very useful to treat pressure-type headaches in CFS/ME patients. He also found that it helped balance problems, and, over time, improved neurocognitive function, as it increases blood flow to the brain. Patients taking Diamox often report increased energy.

PROTOCOL. Diamox usually is prescribed at 250 mg to be taken two or three times a day. The Academy of Medicine of New Jersey recommends 500 mg of Diamox prior to bedtime to lower cerebral spinal blood pressure in patients with headaches. In A Doctor's Guide to Chronic Fatigue Syndrome, Dr. Bell advises starting Diamox at very low doses. He recommends using this drug with caution and discontinuing if side effects should appear. Because Diamox is a diuretic, potassium supplementation or potassium-rich foods (bananas and apricots) may be necessary. Diamox can be taken with food to lessen the chance of nausea or stomach irritation.

PROS AND CONS. For severe, hard-to-treat headaches, Diamox can be a real boon. It is also one of the few drugs that can actively help with cognitive impairment. Diamox acts within a couple of weeks; therefore, a long trial is not necessary. On the negative side, it can create metabolic acidosis, weakness, skin tingling, loss of appetite, and near-sightedness; may cause allergic reactions in people allergic to sulfa drugs; and may activate gout or cause syndromes similar to lupus if taken for extended periods. Diamox can increase the effects of tricyclic antidepressants. Not recommended for patients with kidney stones.

AVAILABILITY AND COST. Diamox is available by prescription only. It is inexpensive. A one-month supply costs roughly $10. Insurance usually covers.

SEE: Headaches

FURTHER READING

The Academy of Medicine of New Jersey's 2002 manual on treating CFS/ME. http://www.njcfsa.org/Manual.pdf

The 1995 Cheney lectures. http://homepage.mac.com/doctormark/Medical/CFS/CFSpapers/cheneylecturescfs.html

EPOGEN (PROCRIT)

DESCRIPTION. Epogen is human erythropoietin, a glycoprotein that controls red blood cell production in bone marrow.

BACKGROUND. Epogen has been approved for treating anemia caused by kidney failure or chemotherapy, and after certain types of surgery in order to decrease the need for blood transfusions. Epogen has also been used to treat orthostatic hypotension, a condition in which blood pressure drops upon standing, causing light-headedness, dizziness or fainting.

USES IN CFS/ME. Dr. Hugh Calkins, a cardiologist at Johns Hopkins, has observed that CFS/ME is closely associated with neurally-mediated hypotension (NMH). He found that 90% of CFS/ME patients have some form of NMH. This observation was independently confirmed by Dr. David Streeten who discovered that among two groups of patients with orthostatic intolerance (OI), one had an abnormally low volume of red blood cells, and another had low plasma circulation. As it turned out, both of these were people with CFS/ME. Dr. Streeten treated these patients using protocols and medications for OI, including Florinef, beta-blockers and epogen to raise standing blood pressure. It wasn't until he was contacted by Dr. Bell, whose CFS/ME patients were exhibiting the same symptoms, that Dr. Streeten realized he had successfully treated a group of CFS/ME patients. Since that time, most doctors in the CFS/ME community have incorporated NMH treatments into their protocols.

In an important study conducted at the University of Miami, Hurwitz et al observed that 60-70% of CFS/ME patients show below normal red blood cell volume. The authors concluded that “the findings indicate that lower cardiac volume levels, displayed primarily by subjects with severe CFS, were not linked to diminished cardiac contractility levels, but were probably a consequence of a co-morbid hypovolaemic condition.” This study was significant because it proved that diminished blood volume was pervasive among CFS/ME patients. Unfortunately, while Procrit increased red blood cell volume, fatigue and exercise intolerance did not improve in the treated group.

PROTOCOL. Very few CFS/ME doctors use Procrit. Dr. Shoemaker treats his patients with 8,000 units of Procrit twice a week for five doses and then decreases the dosage to 4,000 to 6,000 every three to five days. This rather intensive protocol has not gone without criticism from doctors who point out that the “off label” use of Procrit for non-anemic patients is risky.

PROS AND CONS. Procrit is by no means a proven treatment for the correction of low blood volume in CFS/ME. In fact, even weeks after correcting low red blood cell volume in CFS/ME patients, Hurwitz et al noted that there was no corresponding reduction in symptoms. Procrit includes a boxed warning that “ESAs [Erythropoiesis-Stimulating Agents ] increase the risk of death, myocardial infarction, stroke and thrombosis.” Needless to say, CFS/ME patients should give careful thought to the possible risks before embarking on a protocol that includes Procrit.

FURTHER READING

Safety update from the makers of Procrit: http://www.procrit.com/

CFS/ME Forum review of treatments for NMH in CFS/ME: http://www.ncf-net.org/forum/orthostatic98.htm

Fall 2002 CFIDS Chronicle Q&A with Dr. Hurwitz about Procrit. http://www.cfids.org/archives/2002/2002-4-article01.asp

RESEARCH

Hurwitz, Barry E., Virginia T. Coryell, Meela Parker, Pedro Martin, Arthur LaPerriere, Nancy G. Klimas, George N. Sfakianakis and Martin S. Bilsker. “Chronic fatigue syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function.” Clinical Science (2010) 118, (125–135) (Printed in Great Britain) http://www.clinsci.org/cs/118/cs1180125.htm

FLEXERIL

DESCRIPTION. Flexeril (cyclobenzaprine) is a muscle relaxant used to treat pain and skeletal muscle spasms.

BACKGROUND. Flexeril is closely related to tricyclic antidepressants such as Elavil and Tofranil. The drug works by blocking nervous system impulses from the spinal cord to skeletal muscle. Researchers are not entirely sure how Flexeril specifically blocks pain impulses. Some claim that the drug's tricyclic properties (blocking the uptake of serotonin and norepinephrine) exert direct analgesic effects. Other studies seem to indicate that the inhibition of serotonergic pathways alone are responsible for a decreased firing of motor neurons.

USES IN CFS/ME. Flexeril is a commonly prescribed medication that can be extremely beneficial in treating the fibromyalgia component of CFS/ME. Because it is sedating, it is also used to treat insomnia.

PROTOCOL. For muscle pain, 10 mg one to three times a day is recommended. To treat insomnia, Dr. Teitelbaum recommends 10 mg at bedtime. Patients who are sensitive to medications may wish to start with 5 mg or lower.

PROS AND CONS. Flexeril is an older drug with a good safety record and minimal side effects. The most common side effects are excess sedation the next day (a “sleep hangover”) and dry mouth. Both CFS/ME and fibromyalgia patients report that Flexeril is most useful for episodes of muscle spasms or back pain. Most patients who are intolerant to other sleep medications report that it relieves insomnia. Flexeril is not addictive, but, as is the case with many sleeping pills, it tends to lose its effectiveness over time. Because of its anticholinergic effects, Flexeril is contraindicated in patients who have taken an MAOI within 14 days, have a history of heart arrhythmias, or are taking other anticholinergic drugs (such as antihistamines).

AVAILABILITY AND COST. Flexeril is available by prescription, in generic or brand-name formulations. The drug is inexpensive. A one-month supply of the generic costs as little as $7 and is covered by most insurance policies.

SEE: Pain, Sleep Disorders

PATIENT REVIEWS

CFS/ME patient reviews of Flexeril: http://www.revolutionhealth.com/drugs-treatments/rating/flexeril-for-chronic-fatigue-syndrome-cfs-cfids-me

FLORINEF

DESCRIPTION. Florinef (fludrocortisone) is a synthetic corticosteroid.

BACKGROUND. Florinef is primarily used to treat patients with Addison's disease, a condition in which the adrenal glands do not produce sufficient adrenal steroids. Florinef is also a first-line treatment for orthostatic intolerance; it helps the body retain salt which otherwise would be passed in the urine. Because it has mineralocorticoid activity, its effects are limited to regulation of electrolyte and water balance. Like other corticosteroids, Florinef will raise blood sugar levels.

USES IN CFS/ME. Florinef received considerable attention as a CFS/ME medication as the direct result of a highly publicized Johns Hopkins study of neurally mediated hypotension (NMH). In NMH, sudden decreases in blood pressure leads to fainting (syncope), light-headedness, trouble concentrating, and dizziness. As nearly all of the CFS/ME patients in the Johns Hopkins study tested positive for NMH, researchers have been hopeful about treatments that would address this particular symptom. Florinef, because of its ability to increase sodium retention, helps to raise blood pressure. In so doing, many symptoms associated with decreased blood pressure can be relieved.

PROTOCOL. Most physicians currently working with CFS/ME patients recommend starting at a low dose to avert any possible drug reactions. Prior to taking Florinef, Dr. Rowe recommends increasing salt and fluid intake, then beginning with ¼ tablet. He increases the dose by ¼ tablet every 4 to 7 days until a final dose of one tablet (0.1 mg) is reached. If there are no significant side effects, he recommends increasing to a maximum of 1½-2 tablets a day. Dr. Bell has observed that Florinef seems to work best on younger patients. One patient noted that Florinef must be taken exactly every 24 hours or symptoms return; thus a rigid schedule is advised once the medication is started.

Because Florinef causes the body to excrete more than the usual amount of potassium, a potassium supplement is advised. In addition, plenty of fluids should be consumed while taking this medication. The side effects of headache or stomach ache can be lessened when Florinef is taken with a full glass of water. The small amount of lactose in Florinef may cause some discomfort to those who are lactose intolerant or allergic to milk protein.

PROS AND CONS. Although Florinef has been highly touted as an overall CFS/ME treatment, CFS/ME specialists have pointed out that the success rate is not high with this drug. Two randomized control studies conducted in 1998 and 2000 failed to show any improvement in a group of adult CFS/ME patients. In 2001 Rowe et al found that mono-treatment with Florinef fared no better than placebo in a group of 100 CFS/ME patients. Dr. Myhill has listed Florinef as one of the treatments “not worth trying.” She noted that Florinef produced nothing but swollen ankles in her patients.

Florinef can produce serious side effects, the most common of which are high blood pressure and depression. Florinef can also deplete the body of electrolytes (potassium, calcium and magnesium). Common side effects include difficulty sleeping, light-headedness, headache, appetite changes, nausea, increased sweating, and nervousness. Because of these side effects, some doctors recommend starting with licorice, which can mimic the action of steroids, but is a more gentle treatment.

Before embarking on a course of treatment with Florinef or its substitutes, patients are advised to undergo thorough testing to confirm NMH. Because these drugs affect blood pressure, treatment must be closely supervised by a physician.

AVAILABILITY AND COST. Florinef is available by prescription. A 30-day supply of 0.1 mg tablets costs about $14.

SEE: Cardiac and Cardiovascular Symptoms; Herbs (licorice).

FURTHER READING

Cort Johnson's excellent review of Florinef. http://aboutmecfs.org.violet.arvixe.com/Trt/TrtFlorinef.aspx

The Outs and Ins of OI. Excellent article by Kimberly McCleary on OI in CFS/ME. Includes treatments: http://www.research1st.com/2011/06/19/the-outs-and-ins-of-oi/

PATIENT REVIEWS

Review of Florinef by an Australian with CFS/ME who has tried (and reviewed) many treatments. http://livingwithchronicfatiguesyndrome.wordpress.com/2010/07/27/fludrocortisone-for-cfs/

CFS/ME patient reviews of Florinef: http://www.revolutionhealth.com/drugs-treatments/rating/fludrocortisone-for-chronic-fatigue-syndrome-cfs-cfids-me

RESEARCH

Peterson PK, Pheley A, Schroeppel J, Schenck C, Marshall P, Kind A, Haugland JM, Lambrecht LJ, Swan S and Goldsmith S. “A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome.” Arch Intern Med. 1998 Apr 27;158(8):908-14. http://www.ncbi.nlm.nih.gov/pubmed/9570178 (Abstract)

Rowe PC, Calkins H, DeBusk K, McKenzie R, Anand R, Sharma G, Cuccherini BA, Soto N, Hohman P,Snader S, Lucas KE, Wolff M, Straus SE. “Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial.” JAMA. 2001 Jan 3;285(1):52-9. http://www.ncbi.nlm.nih.gov/pubmed/11150109 (Abstract)

GAMMA GLOBULIN

DESCRIPTION. Gamma globulin is a class of blood plasma proteins that contain antibodies.

BACKGROUND. Gamma globulin, or immunoglobulin, is a blood product pooled from many donors and processed so that it contains a high concentration of immunoglobulin G (IgG) and other antibodies that mitigate against and prevent certain diseases. Gamma globulin has been in use for more than 40 years to prevent hepatitis, particularly in health care workers, as a prophylactic during epidemics of measles and rubella, as an immune modulator in Kawasaki syndrome and in myasthenia gravis (a disease that affects the muscles).

USES IN CFS/ME. Although it has fallen out of favor in recent years, gamma globulin was one of the earliest CFS/ME treatments. The rationale behind the use of gamma globulin is twofold. First, it was reasoned that if CFS/ME were caused by a virus, particularly a common virus that most of the general public had been exposed to (such as Epstein-Barr virus), gamma globulin would contain certain antibodies to fight the virus.

Second, certain patients with CFS/ME had demonstrated deficiency of IgG subclasses and it was proposed that gamma globulin could correct this deficiency. While gamma globulin has sometimes been helpful in treating CFS/ME, it is not easy to determine why. It seems that patients who demonstrate IgG deficiency do not always respond better to gamma globulin therapy than do those without IgG deficiency. Several studies, both controlled and open, have been completed in the United States and other countries with inconclusive results.

In 1986 Dr. James Oleske and colleagues from the New Jersey School of Medicine in Newark conducted an open trial of 12 patients with chronic Epstein-Barr virus infection (CFS/ME) with IgG or IgG subclass deficiency. These patients underwent intravenous gamma globulin therapy for one year. Symptoms improved in eight and showed no improvement in four, but did not worsen in any patients.

Also in 1986, Dr. Richard DuBois of Atlanta, Georgia, reported the results of a double-blind controlled study of patients with chronic mononucleosis syndrome (CFS/ME) treated with intramuscular gamma globulin. Symptoms in 52% of the patients who received gamma globulin improved after treatment.

In 1988 Dr. Phillip Peterson of the University of Minnesota headed a double-blind controlled trial of intravenous gamma globulin in 30 patients with CFS/ME. Patients received an infusion of gamma globulin every month for 6 months. Of these 30 patients, 12 (40%) had low IgG concentrations and 29 (9%) had a viral onset. Given the immunological deficiencies, a presumed viral component, and a severely affected group of patients, the results fell short of expectations. No significant difference was demonstrated between the placebo and drug responses.

In 1991 Dr. Denis Wakefield of Sydney, Australia, concluded a study of 49 patients with CFS/ME enrolled in a double-blind placebo-controlled study of intravenous gamma globulin. Twenty-three patients received gamma globulin infusions over 90 days, with encouraging results. Symptoms in 10 patients improved. In addition, several immune parameters tested showed improvement after treatment. Some side effects were reported, but they may have been due to the high dose of gamma globulin. Dr. Wakefield and his colleagues reported interest in undertaking a larger trial with a lower dose of gamma globulin.

In 1997 Australian pediatrician Dr. K.S. Rowe published the results of a study of 70 adolescents (ages 12 to 18 years) with chronic fatigue syndrome who received intravenous gamma globulin therapy. After three months of treatment, significant improvement was noted, but there were some side effects.

In 2001 Dr. Rowe's long-term study of pediatric patients who were followed for seven years also showed that patients experienced significant improvement. Unfortunately, there has been little research after 2001 into the potential benefits gamma globulin.

PROTOCOL. Intravenous gamma globulin may be infused once a month for six months or longer. Intramuscular (IM) gamma globulin can be injected once or twice a week for six weeks, after which the patient is reassessed. Dr. Paul Cheney has noted that IM gamma globulin is not as effective as intravenous administration (CFIDS Chronicle, Spring 1995).

PROS. Many leading clinicians continue to use gamma globulin therapy, with varying degrees of success. Gamma globulin is not usually a first-line treatment and is often used after other therapies have been attempted. Dr. Cheney has found gamma globulin particularly useful in helping reduce the frequency of upper respiratory tract infections in some patients. Dr. Murray Susser and Dr. Michael Rosenbaum, authors of Solving the Puzzle of Chronic Fatigue Syndrome, state that, although CFS/ME requires an integrative approach, if they had to choose the single most effective treatment, it would be gamma globulin. A number of more severely ill patients note improvement of almost all symptoms – notably, cognition, energy, and mood.

CONS. A significant number of patients note little or no benefit. Side effects include headaches, dizziness, and nausea, particularly if the dose is high or the rate of infusion is too fast. A number of patients with CFS/ME have expressed concern about the safety of gamma globulin, inasmuch as it is a blood product. Most physicians believe it is safe because, to date, there is no record of anyone contracting human immunodeficiency virus (HIV) from gamma globulin therapy. However, in early 1994 there were reports in newspapers concerning batches of gamma globulin overseas that were contaminated with hepatitis C virus.

In May 1994 a new manufacturing process for intravenous gamma globulin was developed that inactivates any viral contaminants. Gamma globulin therapy is now considered safe. Nevertheless, it is important to carefully discuss the risks and benefits with a physician.

AVAILABILITY AND COST. Gamma globulin is obtained through a physician and is usually administered in the office. Intravenous infusions are costly and can run as much as $3000 a month. Some insurance companies reimburse the cost if the claim carefully documents specific immune dysfunction such as IgG subclass deficiency or hypogammaglobulinemia. Intramuscular gamma globulin is much less costly, generally around $50 a vial.

RESEARCH

Rowe KS. “Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents.” J Psychiatr Res. 1997 Jan-Feb;31(1):133-47. http://www.ncbi.nlm.nih.gov/pubmed/9201655 (Abstract)

Rowe, Katherine S. MBBS, MD, MPH, Dip Ed (Lond), FRACP. “Five-Year Follow-Up of Young People with Chronic Fatigue Syndrome Following the Double Blind Randomised Controlled Intravenous Gammaglobulin Trial.” Journal of Chronic Fatigue Syndrome (The Haworth Medical Press, an imprint of The Haworth Press, Inc.) Vol. 5, No. 3/4, 1999. http://www.co-cure.org/infores6.htm

GcMAF

DESCRIPTION. GcMAF is a naturally occurring substance in the human body which destroys pathogens by activating macrophages. The acronym stands for Gc (a vitamin D binding protein) Macrophage Activating Factor.

BACKGROUND. In the early 1990s, Dr. Nobuto Yamamoto, director of the Division of Molecular Immunology and Immunotherapy at the Socrates Institute for Therapeutic Immunology in Philadelphia, Pennsylvania, discovered a substance that inhibited tumor production in mice. Throughout the 1990s Dr. Yamamoto continued his research, expanding it to cases of cancer in humans. But it wasn't until 2008 that Dr. Yamamoto published his groundbreaking study on breast cancer. In this study, weekly injections of GcMAF were given to 16 breast cancer patients. Within three months the tumors were eradicated, with no recurrence over the next four years.

Subsequent studies with GcMAF used for colorectal and prostate cancer yielded similar results. In all cases the tumors disappeared with no recurrence. The rationale behind the success of GcMAF is that when the naturally occurring Gc protein is destroyed by cancer cells (more specifically by an enzyme called nagalase) it hamstrings the immune system's ability to make sufficient tumor-destroying macrophages. The result is an immunosuppressed state which allows the cancer to spread. Injecting GcMAF into cancer patients restores the compromised immune system, which then successfully combats the cancer.

The implications for other immune compromised patients are enormous. In 2009 Dr. Yamamoto published a study demonstrating that after fewer than 18 weekly administrations of GcMAF, HIV infection was also completely eradicated. According to the study, "no recurrence occurred and their healthy CD + cell counts were maintained for 7 years."

USES IN CFS/ME. Given the spectacular results of the Yamamoto studies one would have expected to have seen front-page spreads in the New York Times. However, apart from Reuters, the news agencies barely took notice. As of today, no clinics in the U.S. are using GcMAF as a treatment for cancer. Several prominent CFS/ME physicians, however, have begun using GcMAF for patients who test high in nagalase.

Dr. Kenny De Meirleir treated 108 of his CFS/ME patients with weekly administration of GcMAF. This group of patients showed high amounts of nagalase, which Dr. De Meirleir notes can be produced by intestinal bacterial infections as well as herpes and retroviral infections. (Dr. Chia also points out that nagalase can be elevated as a result of enteroviral infections, which produce small intestinal bacterial overgrowth (SIBO) leading to subsequent immune system dysregulation.) After an average of 15 weeks of treatment, 68 of the 108 patients reported significant improvement in fatigue, sleep, pain, cognitive impairment, orthostatic intolerance, and digestive disturbances. (See below for a link to Dr. De Meirleir's presentation.)

Because GcMAF causes an increase in immune system activation, Dr. De Meirleir recommends starting with a very low dose of GcMAF. Some CFS/ME patients have undiagnosed infections which could lead to Immune Reconstitution Inflammatory Syndrome (IRIS). Once the immune system is stimulated, symptoms due to co-infections can worsen. Of Dr. De Meirleir's 108-patient cohort, 20-30% of them experienced IRIS.

Dr. Cheney has also begun to treat patients with GcMAF, as well as with a natural yogurt probiotic MAF (MAF 314) developed by Professors Ruggiero and Pacini in Italy. GcMAF demonstrated a response rate of 79% (15 out of 19 patients), which is similar to Dr. De Meirleir's results. The oral MAF 314 demonstrated a response rate of 76% over a period of only 28 days.

PROTOCOL: There are several protocols currently in use. Most CFS physicians begin with 0.20 - 0.25 ml via injection (IM) weekly. Dr. Cheney starts his severely ill patients at a much lower dose administered sublingually, then gradually increases the dose. Typically, the full course of treatment is 8-20 weeks. In order to be effective, GcMAF requires adequate levels of vitamin D. Patients should be tested for vitamin D levels prior to beginning treatment. (Optimal ranges fall between 42 and 60). Patients should also be tested for nagalase levels before treatment and on a monthly basis after beginning GcMAF.

Physicians may recommend concurrent antiviral treatment with Nexavir if the viral load is high. Artesunate may also be prescribed, as well as adjunctive supplementation with B vitamins.

Anti-inflammatory drugs, such as corticosteroids (prednisolone, prednisone, etc.) and NSAIDs (ibuprofen, aspirin, etc.) should be avoided while taking GcMAF as these will interfere with the treatment. Morphine analogs (oxycodone, tramadol, etc.), beta blockers, and cytotoxic medications (Sendoxan, Vepesid, Taxol, etc.) should be avoided. Aspartame and carrageenan, two food additives, can also block GcMAF.

GcMAF is contraidicated for patients with MS.

PROS AND CONS. GcMAF is an experimental drug, which means not much is known about its effects on the CFS/ME population other than the few studies performed by Drs. De MeirLeir and Cheney. As with other medications, patients report a wide range of responses, from feeling significantly worse to an almost miraculous recovery of strength and energy. Frequently, a patient will notice improvement over the first six weeks, and then experience a decline. This may be due to exhaustion of vitamin D reserves. For this reason, continuing supplementation with vitamin D may be advised.

AVAILABILITY AND COST. Drs. Cheney, Enlander and De Meirleir are currently using GcMAF with their CFS/ME patients. The price for 2.2 ml of GcMAF (about 8 doses at .25 per dose) is roughly $1000 ($800 euros). Because of the risk of IRIS, it is not recommended that CFS/ME patients take GcMAF without the supervision of a knowledgeable physician. MAF 314 can be obtained from Dr. Cheney's clinic for $3500. Dr. Enlander is currently developing a less expensive form of probiotic MAF (MAF 378) in New York. The test for nagalase levels can be ordered by physicians from Health Diagnostics. It costs $65. GcMAF must be refrigerated

TESTING

Health Diagnostics and Research Institute (formerly Vitamin Diagnostics, Inc.)

South Amboy Medical Center

540 Bordentown Ave., Suite 2300

South Amboy, New Jersey 08879

Telephone: (732) 721-1234

Fax: (732) 525-3288

Testing for nagalase.

SUPPLIERS

GcMAF

Clos de Balade 21

1140 Evere

Brussels

Belgium

Website: http://www.gcmaf.eu/info/

BGLI Bio Group Laboratories

Tel: 31-3576-00-176 (GMT+2) (Netherlands)

Website: http://www.bgli.nl/ (There is a contact form on the site)

FURTHER READING

Dr. Kenny De Meirleir's talk on GcMAF and its use in treating CFS/ME: http://cfspatientadvocate.blogspot.com/2011/11/mt-sinai-mecfs-conference-de-meirleir.html

Dr. Cheney's GcMAF studies: http://www.cheneyclinic.com/gcmaf-studies-presented-at-iacfsme-meetings-in-ottawa/833

Excellent information on GcMAF, including where to find clinics in Europe that use GcMAF, patient forums, and purchasing information: http://www.gcmaf.eu/info/

European lab that offers testing for nagalase: http://www.europeanlaboratory.nl/

Phoenix Rising forum threads on GcMAF discussing Kenny De Meirleir's use of GcMAF, where to purchase, and how to obtain testing for nagalase: http://forums.phoenixrising.me/showthread.php?6019-GcMAF-for-XMRV-Gc-protein-derived-macrophage-activating-factor-anyone-taking-it/page116

and

http://forums.phoenixrising.me/showthread.php?6019-GcMAF-for-XMRV-Gc-protein-derived-macrophage-activating-factor-anyone-taking-it/page117

Patient thread on MAF 314: http://phoenixrising.me/forums/showthread.php?14838-MAF-314

"Who Responds to GcMAF." Very technical discussion of gene types http://www.cfscentral.com/2011/01/who-responds-to-drug-gcmaf.html

Good article about cancer and GcMAF by Bill Sardi http://www.thenhf.com/article.php?id=633

Another good follow-up article by Bill Sardi: http://www.thenhf.com/article.php?id=771

Cancer and GcMAF: http://www.center4cancer.com/glyco-protein.php

Professor Ruggiero's website on GcMAF and MAF 314 http://www.marcoruggiero.org/pdf/Oct%2022.pdf

“Compassionate Use Treatment of CFS with GHP (GcMAF)” Dr. Paul Cheney, Sept. 2011. http://www.gcmaf.nl/documents/research/Compassionate%20use%20Treatment%20of%20CFS%20with%20GHP%20(%20GcMAF%20).pdf

Dr. Cheney's pilot study of GcMAF.

PATIENT EXPERIENCES

A Cheney patient blog about her experience with GcMAF. This blog is very detailed, with information about dosage, testing and patient responses. http://nopostergirl.com/2011/04/16/the-post-appointment-post/

Cheney patient blog on GcMAF http://blogwormwood.blogspot.com/2011/05/gcmaf.html

RESEARCH

Yamamoto N, Suyama H, Yamamoto N, Ushijima N. “Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF).” Int J Cancer. 2008 Jan 15;122(2):461-7. http://www.ncbi.nlm.nih.gov/pubmed/17935130 (Abstract)

Yamamoto N, Suyama H, Koga Y. “Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF.” Cancer Immunol Immunother. 2008 Jul;57(7):1007-16. http://www.ncbi.nlm.nih.gov/pubmed/18058096 (Abstract)

Yamamoto N, Suyama H, Yamamoto N, “Immunotherapy for Prostate Cancer with Gc Protein-Derived Macrophage-Activating Factor, GcMAF.” Transl Oncol. 2008 Jul;1(2):65-72. http://www.ncbi.nlm.nih.gov/pubmed/18633461 (Abstract)

Yamamoto N, Ushijima N, Koga Y. “Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF).” J Med Virol. 2009 Jan;81(1):16-26. http://www.ncbi.nlm.nih.gov/pubmed/19031451 (Abstract)

GUAIFENESIN

DESCRIPTION. Guaifenesin is an expectorant that helps clear mucus from congested passageways by increasing production of respiratory tract fluids. It is the primary active ingredient in many cough syrups.

USES IN CFS/ME. Dr. Paul St. Armand, an endocrinologist at the University of California at Los Angeles, first began working with patients with fibromyalgia in the 1960s. From his observations, Dr. St. Armand speculated that patients with fibromyalgia and CFS/ME might have an inherited metabolic defect that causes faulty excretion of phosphates. According to Dr. St. Armand, if phosphate accumulates in the mitochondria of cells, then the production of adenosine triphosphate (ATP) is impaired, leading to a loss of cellular energy. The accumulation of phosphates also leads to increased calcium within the cells, possibly creating the tender points so commonly seen in fibromyalgia. It appeared to Dr. St. Armand that this defect in phosphate excretion could account for the symptoms of fibromyalgia and CFS/ME.

In support of his theory, Dr. St. Armand observed that gout medications, which increase excretion of both uric acid and phosphate, produced positive results in FM patients, although they did have serious side effects if used long term. To Dr. St. Armand's delight another medication, guaifenesin, produced the same results, without the side effects.

PROTOCOL. For people with CFS/ME, guaifenesin LA (long acting) is usually prescribed. It can be purchased in pill form, without added antihistamines or decongestants. Dr. St. Armand recommends an initial dosage of 300 mg of pure guaifenesin twice a day. If that proves ineffective, the dosage is increased to 600 mg twice a day. About 30% of his patients may require higher doses. Dr. St. Armand claims that two months of treatment reverses a year of illness, which should provide a baseline for calculating how long the medication may be needed – for example, a person who has been ill for four years will need eight months of treatment.

Dr. St. Armand cautions that for guaifenesin to be effective, salicylate must not be used (salicylate or salicylic acid ingredients are in Pepto-Bismol, Ben-Gay, Myoflex Creme, aspirin, Alka-Seltzer, cosmetics, plant-containing shampoos and conditioners, plant-derived vitamins, and herbal remedies). Dr. St. Armand also recommends that patients take a calcium and magnesium supplement with meals to block absorption of phosphates in food.

PROS. No controlled studies have been performed to confirm or disprove the effectiveness of guaifenesin in treating symptoms of CFS/ME, so commentaries on this drug are anecdotal. One patient with long-term CFS/ME reported dramatic symptomatic improvement with guaifenesin (Mass CFS/ME Update, Summer 1996). She began taking guaifenesin in 1994 to treat a stubborn bout of bronchitis and was surprised to note a number of other symptoms began improving. After several months she noticed she was beginning to have clusters of "good days" and that her pain was "almost nonexistent." She also noted improvements in cognitive function, energy, and vision.

CONS. Although few side effects are directly attributable to guaifenesin, most CFS/ME patients report that their symptoms initially worsen while their systems are being “cleaned out.” Often a patient may feel much worse for the first two to four months of treatment (some even longer), the most common side effect being severe pain. Dr. St. Armand warns that this treatment "takes confidence and strength" because results may not be seen for several months. He also warns that patients with both fibromyalgia and hypoglycemia will not notice any improvement with guaifenesin treatment unless the hypoglycemia is corrected (see Hypoglycemia for dietary and other recommendations). Although Dr. St. Armand believes the long-term benefits are worthwhile for patients with fibromyalgia, many patients with CFS/ME may be justifiably wary of risking relapse.

Patients interested in trying guaifenesin should also note that although Dr. St. Armand claims significant improvement among his patients, studies have not replicated his results. A double-blind controlled study conducted at the Oregon Health Sciences University by Dr. Robert M. Bennett and Dr. Sharon Clark found no difference between the guaifenesin and placebo groups after a year of treatment. Neither did they find an increase in urinary excretion of phosphates, which seems to undercut the basis for guaifenesin's theoretical mode of action. In addition, muscle studies by Muhammad Yunus, M.D., of University of Illinois College of Medicine, and Dr. Robert Simms have shown that calcium phosphate deposits have never been a problem in fibromyalgia. Currently, none of the major CFS/ME clinics or doctors include guaifenesin in their protocols.

AVAILABILITY AND COST. Guaifenesin is available through online distributors. ProHealth sells a 100-pill bottle of fast-acting guaifenesin (400 mg) for $15.79. The long-acting variety costs about $50.00 a bottle.

BOOKS AND ARTICLES

St. Armand, Paul and Claudia Craig Marek. What Your Doctor May Not Tell You About Fibromyalgia: The Revolutionary Treatment That Can Reverse the Disease. Wellness Central. 2006.

St. Armand, R. Paul M.D. “Chronic Fatigue and Fibromyalgia: One Disease, Two Names.” 1999. http://www.fibromyalgiatreatment.com/Research_TwoNames.htm

FURTHER INFORMATION

Guaifenesin protocol. Includes a list of doctors and practitioners http://fibromyalgiatreatment.com/

The Fibromyalgia Network's consumer alert on guaifenesin http://www.fmnetnews.com/resources-alert-product6.php

Guaifenesin support group. Last updated in 2007: http://www.psha-inc.com/guai-support/sf/FAQ-GuaiProductTroubleshooter.htm

PATIENT REVIEWS

CFS/ME patient reviews of guaifenesin: http://www.revolutionhealth.com/drugs-treatments/rating/mucinex-for-chronic-fatigue-syndrome-cfs-cfids-me?page=2&view=treatment

H2 BLOCKERS - TAGAMET AND ZANTAC

DESCRIPTION. Tagamet (cimetidine) and Zantac (ranitidine) are histamine H2 receptor antagonists that inhibit acid secretion in the stomach.

BACKGROUND. Before the Food and Drug Administration (FDA) approval of Tagamet in 1977, the pain resulting from duodenal ulcers was nearly impossible to treat with standard medications. While not a cure, Tagamet is thought to allow ulcers to heal by blocking acid secreted by the stomach in response to histamine. Millions of patients now take Tagamet and Zantac (approved in 1983) and a substantial number have obtained significant relief from pain. Tagamet, Zantac, and two other approved H2 blockers, Axid (nizatidine) and Pepcid (famotidine), are also prescribed to treat heartburn and gastritis.

In the early 1980s, Dr. Jay Goldstein used Tagamet to treat infectious mononucleosis (confirmed by monospot test, enlarged spleen, and other clinical findings consistent with the diagnosis) in a college student. The symptoms resolved within 24 hours. Dr. Goldstein's rationale for treatment was based on the fact that Epstein-Barr virus, which causes mononucleosis, is a herpesvirus and, in most herpes infections, there is an increased number of T suppressor cells. It had been recently demonstrated that T suppressor cells had H2 receptors on their surfaces, and it was thought that the cells were activated by histamine. Dr. Goldstein theorized that perhaps the T suppressor cells could be inactivated by Tagamet, an H2 blocker. His theory appears to have validity, as Dr. Goldstein reported positive results in 90% of cases of mononucleosis treated with Tagamet. He has received positive feedback from physicians around the United States who have replicated his results (CFIDS Chronicle, 1988 Compendium).

In 1990 Ashir Kumar, a researcher at Michigan State University, supported Dr. Goldstein's findings with his own research. In several studies, he found that cimetidine (Tagamet) enhanced immune function. “Patients who received cimetidine were shown to exhibit enhanced cell-mediated immunity as evaluated by increased response to skin-test antigens, restoration of sensitivity following development of acquired tolerance, and increased responses of lymphocytes to mitogen stimulation. Patients also demonstrated that patients with herpes zoster and herpes simplex who were given cimetidine may have benefited therapeutically from the drug.”

In an interesting corollary to its other uses, some urologists prescribe H2 blockers for interstitial cystitis when other medications are not tolerated.

USES IN CFS/ME. In 1985 Dr. Goldstein began to see his first cases of what was then called chronic Epstein-Barr virus infection (now CFS/ME). Using the same logic that he used to treat mononucleosis, Dr. Goldstein gave his patients Tagamet and Zantac. He found over the course of years that at least 20% of patients with CFS/ME responded favorably to treatment with H2 blockers. Although the cause of CFS/ME remains undetermined, it is known that in CFS/ME there is activation of T suppressor cells, probably due to viral activity. It is believed that H2 blockers have a modulatory effect on the immune system in that they probably inhibit overproduction of lymphokines responsible for some of the flu-like symptoms of CFS/ME.

Several leading CFS/ME clinicians, including Dr. Charles Lapp, use H2 blockers to treat gastrointestinal symptoms as well as for immune system modulation. Dr. Murray Susser and Dr. Michael Rosenbaum used H2 blockers to treat immune system dysfunction.

PROTOCOL. Most patients take only low doses of these H2 blockers (even a sliver of a pill can be effective, according to Dr. Goldstein). Others are able to tolerate the standard prescribed dose for ulcers: Tagamet 300 to 400 mg, one or more tablets per day; Zantac 75 to 300 mg/day.

PROS. H2 blockers work rapidly, and results can often be seen in less than two weeks, thereby making a trial worthwhile. Many patients have reported a variety of benefits. CFS/ME patients with allergies feel much better overall after taking Zantac. Some have found significant relief from digestive disturbances. Not surprisingly, given the effects that H2 blockers have on the immune system, people with CFS/ME also report that Tagamet gives them more energy and lessens the weak, achy feeling of CFS/ME.

CONS. Dr. Goldstein has noted that some patients feel nervous and agitated while taking Tagamet. Other clinicians believe H2 blockers cause depression (a less common side effect according to the Physicians’ Desk Reference). Because Tagamet may interact with and increase blood concentrations of many drugs, some of which are commonly prescribed in CFS/ME (e.g., antidepressants and benzodiazepines), it is important to advise your physician of all medications you are taking. Zantac may be prescribed more frequently than Tagamet to treat symptoms of CFS/ME, because it interacts with fewer medications and may pose less risk for side effects. Both Tagamet and Zantac will either aggravate pre-existing hypochloridia, or cause it. High levels of Zantac are known to cause an unusual condition in men which produces breast enlargement (gynecomastia).

AVAILABILITY AND COST. Tagamet and Zantac are available by prescription and over the counter at any pharmacy. Over-the-counter Tagamet HB 200 and Zantac 75 mg are available for between $10 and $15.

FURTHER READING

Kumar A. “Cimetidine: an immunomodulator.” Department of Pediatrics and Human Development, Michigan State University, East Lansing 48824. DICP 1990 Mar;24(3):289-95. http://www.ncbi.nlm.nih.gov/pubmed/2138376 (Abstract)

Overview of immunological effects of H2 blockers. http://www.lef.org/magazine/mag2001/mar2001_report_tagamet_1.html

Thread discussing histamine blockers in CFS/ME patients, including Zantac and Tagamet. http://forums.phoenixrising.me/showthread.php?2077-Tagamet-(cimetidine)-for-CFS/ME-(worked-for-me)/page2

Article discussing gynecomastia after excess Tagamet. http://gerd.emedtv.com/cimetidine/cimetidine-and-gynecomastia.html

HORMONES

Growth Hormone, Testosterone, Thyroid Hormones

Hormones are chemical messengers that are released from glands in the endocrine system. Because hormones can be released directly into the bloodstream, they affect nearly every function in the body. Hormones are responsible for stimulating growth, regulating the immune system, initiating “fight or flight” responses, sexual maturation and reproduction, hunger, thirst, mood swings, metabolic regulation, and maintaining homeostasis. A deficiency or dysregulation of hormone production will produce profound effects on the body.

Endocrine system disturbances are common, if not universal, among CFS/ME patients. As a consequence, hormone production is also affected. Unfortunately, hormones are usually released in spurts, and their effects, while widespread, are not constant. This makes hormone regulation through medical intervention problematic. A steady dose of hormones may, in fact, worsen symptoms. That being said, patients who consistently test low in certain hormones may benefit greatly from supplementation with bio-identical or synthetic hormones. Because of their widespread effects on the body, hormone treatments should always be monitored by a physician.

FURTHER READING

“Endocrine Causes of Chronic Fatigue: A Review of Symptoms, Treatments.” CFIDS Chronicle, Spring 2003. http://www.cfids.org/archives/2003/2003-2-article02.asp

This is a good summary of various endocrine disturbances that can cause fatigue.

GROWTH HORMONE

DESCRIPTION. Growth Hormone (GH) is a peptide hormone produced in the pituitary gland.

BACKGROUND. Growth Hormone is primarily responsible for increasing height in children, although it has a number of other functions as well, including increasing protein synthesis, stimulating the growth of internal organs, maintaining pancreatic islets, and stimulating the immune system. Medically, it is prescribed for children with growth failure stemming from GH deficiency.

In rare cases, adults will develop GH deficiency. Usually, this is caused by structural problems in the pituitary gland (tumors), although unexplained disruptions in hormone production can also occur. When a physician suspects GH deficiency, he or she will test for the presence of IGF-1 in the body to determine if GH levels are low. (GH secretion leads to IGF-1 production.) As most GH is secreted during deep sleep, patients may be kept overnight to measure GH levels.

Because GH builds muscle mass, strengthens bones and increases energy, it has become a popular, if dubious, supplement for athletes, who use it to improve performance. Too much GH can result in acromegaly, or gigantism. Due to its reputed anti-aging effects, GH has also been promoted as a “fountain of youth,” which has no doubt spurred the increase of off-shore manufacturers.

USES IN CFS/ME. Disturbances in the HPA (hypothalamus-pituitary-adrenal) axis have been well-documented in CFS/ME patients. One of the earliest studies to show that GH is affected by HPA axis dysfunction was conducted by Allain et al in 1997. The research team found that people with CFS/ME showed abnormalities of the GH-IGF (insulin growth factor) axis. A subsequent study by Moorkens et al, using a larger cohort, found that CFS/ME patients showed significant impairment of GH response during insulin-induced hypoglycemia, as well as a low nocturnal GH secretion. A number of studies have also shown low GH secretion among fibromyalgia patients. (See Holtorf article below for an excellent summary of relevant research.)

The causes of GH deficiency in CFS/ME and FM patients are various. Disruptions in the HPA axis will certainly contribute to lower production of GH. It has also been speculated that because GH is secreted during stage 3 and 4 sleep, widespread insomnia in these two groups, and the subsequent reduction of deep sleep, may be a contributory factor.

PROTOCOL. The synthetic equivalent of GH, Somatropin, is administered through injection. The standard dose is 0.2 mg three times a week. Dr. Cheney uses a much lower dose with his patients, as little as 0.2 mg once a week. He notes that higher doses cause “crashes.”

PROS AND CONS. Like most hormone treatments, the effects of Somatropin are felt throughout the body, which means it should be used with caution. Because GH upregulates the immune system, this could potentially aggravate symptoms in people with CFS/ME. Those for whom Somatropin has been of benefit report a dramatic increase in energy, as well as the additional benefit of “beautiful skin.”

AVAILABILITY AND COST. Somatropin is available by prescription only (although there is a large black market of suppliers). Somatropin is highly regulated, and difficult to obtain without a confirmation of deficiency. A single 5 mg vial costs $1500. Unfortunately, there is no substitute for GH. Taking natural GH precursors (arginine, ornithine, lysine, glutamine, GABA) is ineffective.

FURTHER READING

Good general information on Somatropin: http://www.somatropin.net/

Dr. Holtorf's excellent article on HPA axis dysfunction and GH in CFS/ME and FM. (Scroll down to find it.): http://www.holtorfmed.com/index.php?section=downloads&file_id=57

Excellent article about GH deficiency in FM http://www.myalgia.com/growth_hormone_deficiency_in_fib.htm

Dr. Cheney discusses the role of GH in CFS/ME. Includes treatment protocols http://www.dfwcfids.org/medical/advances.html

Interesting patient discussion of GH: http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=999131

PATIENT REVIEWS

Patient review of somatropin: http://www.revolutionhealth.com/drugs-treatments/rating/somatropin-for-chronic-fatigue-syndrome-cfs-cfids-me

RESEARCH

Allain TJ, Bearn JA, Coskeran P, Jones J, Checkley A, Butler J, Wessely S, Miell JP. “Changes in growth hormone, insulin, insulinlike growth factors (IGFs), and IGF-binding protein-1 in chronic fatigue syndrome.” Biological Psychiatry. 1997 Mar 1;41(5):567-73. http://www.ncbi.nlm.nih.gov/pubmed/9046989 (Abstract)

Moorkens G, Berwaerts J, Wynants H, Abs R. “Characterization of pituitary function with emphasis on GH secretion in the chronic fatigue syndrome.” Clin Endocrinol (Oxf.) 2000 Jul;53(1):99-106. http://www.ncbi.nlm.nih.gov/pubmed/10931086 (Abstract)

TESTOSTERONE

DESCRIPTION. Testosterone is the principal male hormone. It is produced in the testes.

BACKGROUND. Testosterone is the hormone responsible for the development of primary male sexual characteristics (sex organs), as well as secondary characteristics such as growth of body hair, increase in bone and muscle mass, and deepening of the voice. Testosterone promotes energy and a sense of well-being, and helps regulate the HPA axis. Women also produce testosterone, although at only a tenth of male levels. Low-dose testosterone is sometimes recommended for women at risk of osteoporosis.

As men age, their production of testosterone decreases. While this is a natural process, some men experience an abrupt or dramatic decline, sometimes brought about by disease processes. This abrupt decline has been dubbed "male menopause" (although gradual declines are often referred to as "male menopause" as well). The medical community has mixed views on male menopause. Some doctors offer hormone replacement therapy, just as they do their female patients, while others view male menopause as a myth.

USES IN CFS/ME. As with other hormone deficiencies, low levels of testosterone are fairly common in CFS/ME patients. In men, this will be felt as a loss of libido, as well as a decrease in muscle strength, depression, anxiety, and bladder problems – all of which are symptoms common among CFS/ME patients of both sexes. As testosterone has such wide-ranging effects on the body, doctors should prescribe testosterone only after blood tests confirm low levels.

PROS AND CONS. Men who have taken testosterone report an increase in energy. Some men experience "teenage problems" (acne).

AVAILABILITY AND COST. Testosterone is available as an injection, gel or patch. Of the three modes of delivery, the gel (Androgel) is the least problematic. (Patches can fall off, and injections require a doctor.) Androgel is applied to the arms. It dries quickly, and leaves no residue. A 30-day supply of Androgel costs about $100, so check to see if your insurance will cover the cost.

FURTHER READING

Article about male menopause: http://men.webmd.com/guide/male-menopause

Good summary of male menopause and CFS/ME http://www.prohealth.com/library/showarticle.cfm?libid=8114

PATIENT REVIEWS

CFS/ME patient reviews of testosterone: http://www.revolutionhealth.com/drugs-treatments/rating/testosterone-for-chronic-fatigue-syndrome-cfs-cfids-me

THYROID HORMONES

CAUTION: Taking an initial high dose of T3 can lead to heart attack.

DESCRIPTION. Thyroid hormones are tyrosine-based hormones produced in the thyroid, a butterfly-shaped gland in the neck.

BACKGROUND. Thyroid hormones regulate metabolism and, as a consequence, can act on nearly every cell in the body. They increase basal metabolic rate, regulate long bone growth (along with growth hormone), and increase the body's sensitivity to adrenaline and noradrenaline. Thyroid hormones also regulate protein, fat, and carbohydrate metabolism. They stimulate the metabolism of vitamins, which means thyroid hormones regulate how much energy is available to cells. There are two primary thyroid hormones, T4 (thyroxine) and T3 (triiodothyonine). T4 is first converted in the body to T3, which is two to three times more potent than T4, and then to T2 and T1. All four are essential for the basic functioning of the human body.

USES IN CFS/ME. Fatigue is one of the hallmark symptoms of low thyroid function, therefore it is not surprising that CFS/ME patients are often suspected of having hypothyroidism. Other hypothyroid symptoms, such as low body temperature, cold intolerance, depression, hair loss, and weight gain are also quite common among CFS/ME patients, indicating that low thyroid function could be the root of many CFS/ME symptoms.

According to Dr. Teitelbaum, low thyroid function is one of the most underdiagnosed conditions in America. The reason many doctors miss the diagnosis, even in the presence of "text book" symptoms, is that testing is inadequate. Up until a few years ago the gold standard for testing the thyroid was to measure TSH levels (thyroid stimulating hormone). TSH, the hormone which stimulates the thyroid to release hormones, is produced in the pituitary gland, which means that as long as a patient has a normally functioning pituitary, the TSH results will be within normal range – regardless of how faulty his or her thyroid may be.

When clinicians realized the TSH test was inadequate, they began to use free T3 and T4 levels to determine low thyroid function, but those tests, like the previous one, missed many patients with low thyroid function, including Hashimoto's disease patients, whose thyroids are being attacked by their own immune systems, as well as nearly everyone with HPA axis dysfunction (e.g., fibromyalgia and CFS/ME patients).

This lack of sensitivity in testing has led some CFS/ME physicians to prescribe thyroid hormone supplementation to their patients even in the absence of abnormal test results.

PROTOCOL. Thyroid hormones come in two forms, synthetic and natural. T4 (Synthroid, levothyroxine) and T3 (Cytomel) are both synthetic. (T4 helps with lethargy and T3 helps with cognitive problems, "brain fog," and mental focus.) Armour Thyroid is a natural glandular which contains all four thyroid hormones (T1, T2, T3, and T4). Nature-Throid, another natural glandular, contains T3 and T4.

How patients respond to thyroid hormone therapy is highly individualized. Some do well on synthetic formulations, others do better with natural glandulars. (Although, it should be noted that Hashimoto's disease patients tend to respond better to synthetic formulations.) People with primary hypothyroidism need to take both T3 and T4, as their thyroids will not make the conversion.

Dr. Myhill advises that CFS/ME patients have their thyroid hormones checked often while on medication. Too high a dose can lead to thyrotoxicosis, a dangerous condition in which the patient experiences sweating, fever, heart palpitations, and, potentially, heart attack. Patients starting thyroid hormone therapy should always begin with the lowest possible dose.

PROS AND CONS. There is no doubt that patients with concomitant hypothyroidism experience an overall improvement with the administration of thyroid hormones. Patients report a cessation of fatigue, improvements in mood, stamina and strength, normalization of weight, and hair regrowth. Patients whose thyroid levels are normal also experience improvement in energy levels after taking thyroid hormones. However, in similar fashion to CNS stimulants, the improvement is often followed by a crash. The main drawback of taking thyroid hormone is that once hormone replacement has begun, the thyroid ceases making its own hormones. For people taking long-term thyroid hormones, discontinuation may not be possible.

FURTHER READING

Dr. Teitelbaum's recommendations for thyroid supplementation http://www.endfatigue.com/health_articles_d-e/Diet-thyroid_hormone_deficiency.html

Mary Shomon's discussion of low thyroid function in CFS/ME http://thyroid.about.com/cs/fibromyalgiacfs/a/cfsfibrothyroid.htm

Good general information about thyroid testing and CFS/ME: http://blog.nutri-living.com/?p=405

Dr. Myhill's discussion of underactive thyroid in CFS/ME http://www.drmyhill.co.uk/wiki/Hypothyroidism_-_A_Common_Hormonal_Problem_in_CFS

James Burton's article about thyroid hormone deficiencies in CFS/ME patients http://www.prohealth.com/library/showarticle.cfm?libid=10827

PATIENT REVIEWS

CFS/ME patient ratings of Cytomel: http://www.revolutionhealth.com/drugs-treatments/rating/cytomel-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Synthroid: http://www.revolutionhealth.com/drugs-treatments/rating/synthroid-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Armour thyroid: http://www.revolutionhealth.com/drugs-treatments/rating/armour-thyroid-for-chronic-fatigue-syndrome-cfs-cfids-me

HYDROCORTISONE/CORTEF

DESCRIPTION. Hydrocortisone is the pharmaceutical name for cortisol, a glucocorticoid hormone excreted by the adrenal cortex in response to stress, inflammation, and low blood sugar levels.

BACKGROUND. Cortisol is produced in the outer layer of the adrenal gland, known as the adrenal cortex. The release of cortisol is controlled by the hypothalamus, which secretes corticotropin-releasing hormone (CRH) to the pituitary gland, which in turn releases adrenocorticotropic hormone (ACTH). ACTH is carried by the bloodstream to the adrenal glands, where cortisol is then released.

Cortisol has numerous effects on body functions, including reduction of inflammation, maintenance of sodium and potassium balance, and regulation of blood sugar. Cortisol also has profound effects on protein and carbohydrate metabolism. Because cortisol can suppress the immune system (specifically the proliferation on T cells), hydrocortisone is used medically to treat inflammatory conditions such as rheumatoid arthritis, lupus, and allergies.

USES IN CFS/ME. Whether hydrocortisone should be used to treat CFS/ME is a topic of much debate among CFS/ME clinicians. Studies performed by Dr. Mark Demitrack and colleagues showing endocrine system deficiency along the hypothalamic-pituitary-adrenal axis (HPA axis) seem to indicate that there is a chronic adrenal insufficiency in patients with CFS/ME (Journal of Clinical Endocrinology and Metabolism, 1991). The low levels of cortisol found in some CFS/ME patients, combined with increased or new inflammatory responses, such as allergies, irritable bowel syndrome, and rheumatic conditions, also seem to point to the use of cortisol as a potentially effective treatment.

Several studies have confirmed that treatment with low-dose hydrocortisone increases energy levels and stamina in CFS/ME patients. In 1999 Cleare et al found that in a group of 32 CFS/ME patients treated with 5-10 mg of cortisol daily for a month, energy levels were significantly improved. In a subsequent study published in 2001, Cleare also found that low-dose cortisol restored normal adrenal responses to CRH in CFS/ME patients.

A number of prominent CFS/ME doctors include low-dose hydrocortisone as part of their CFS/ME protocols. In a 2008 study of 500 patients, Dr. Holtorf found that 5-15 mg a day of time-release hydrocortisone resulted in an overall improvement in 94% of his patients. Moreover, Dr. Holtorf states that “physiologic [low] doses of cortisol have been shown to improve cellular and hormonal immunity, including natural killer cell activity” both of which are problems with CFS/ME patients.

However, not all clinicians agree that treatment with hydrocortisone is beneficial. Cortisol can be an immune system suppressant and, in cases in which the immune system is already compromised, its effects could be disastrous. Clinicians who are critical of hydrocortisone's usefulness as a CFS/ME treatment point out that glucocorticoids are best used as a short-term treatment for severe allergic reactions. Long-term use may exacerbate the disease process.

PROTOCOL. Hydrocortisone (cortisone, cortisol) may be given as a single injection to treat severe allergic response or in acute cases of CFS/ME when immediate intervention is required. It may also be administered in pill form (Cortef) in low doses (5 to 15 mg) on a daily basis.

PROS. Many patients report a significant increase in energy and stamina from hydrocortisone. For some patients hydrocortisone makes the difference between having to lie in bed all day and being able to get up, which can make all the difference in the world for the severely ill. Single ("pulse") administrations of cortisol can be lifesaving for patients with severe allergic reactions or acute-onset CFS/ME.

CONS. Cortisol is a naturally occurring chemical. However, its use on a long-term basis, carries significant risks. When the body registers the presence of hydrocortisone, the adrenal glands decrease production. Although proponents of low-dose hydrocortisone claim that the risks are minimal, when taken over a long period of time the adrenal glands may fail to produce glucocorticoids altogether, making the patient entirely dependent on a drug source for this essential hormone.

In addition to the risk of dependency, the dosage must not be excessive or Cushing's syndrome may eventually develop, with tendencies for obesity, hypertension, osteoporosis, and mental disturbances. Side effects of even small doses of cortisol include headache, gastrointestinal disturbances, insomnia, and weakness. Hydrocortisone is strongly contraindicated for people with fungal infections.

AVAILABILITY AND COST. Hydrocortisone is available by prescription, in generic and brand-name formulations. The cost of brand (Cortef) or generic is similar, ranging from $15 to $30 a month, depending on the dosage. It is usually covered by insurance.

BOOKS

Jeffries, William. Safe Uses of Cortisol. Charles C Thomas Pub Ltd , 3rd edition. 2004. (Originally published in 1970, this is the “bible” for physicians who prescribe hydrocortisone for CFS/ME and FM.)

FURTHER INFORMATION

Excellent discussion of low-dose hydrocortisone by a CFS/ME patient detailing the dosage and effects: http://www.revolutionhealth.com/groups/me-chronic-fatigue-syndrome-support/discussions/topic/c433312d-35c5-41b1-a2b2-7be3aecc6987

Pro-health's patient thread on low-dose hydrocortisone http://www.prohealth.com/fibromyalgia/blog/boardDetail.cfm?id=1058069&b1=CHWEBO#1058069/

A review of the literature concerning low-dose hydrocortisone treatment in CFS/ME and FM: http://www.endfatigue.com/health_articles_f-n/Hormones-adrenal_problems_in_cfs.html

Discussion of low-dose hydrocortisone in CFS/ME http://enotes.tripod.com/fatigue2.htm

Dr. Teitelbaum's excellent review of HPA axis dysfunction and low-dose hydrocortisone treatment in CFS/ME patients: http://www.endfatigue.com/health_articles_f-n/Hormones-adrenal_problems_in_cfs.html

Dr. Holtorf's review of HPA axis dysfunction and study of 500 patients receiving low-dose hydrocortisone: http://www.holtorfmed.com/dr-pdf/Diagnosis%20Treatment%20CFS%20FM.pdf

Dr. Baschetti discusses the benefits of low-dose cortisol and makes a comparison of 36 shared features between Addison's disease and CFS/ME http://jcem.endojournals.org/content/84/6/2263-a.full

PATIENT REVIEWS

CFS/ME patient reviews of Cortef (hydrocortisone) http://www.revolutionhealth.com/drugs-treatments/rating/cortef-for-chronic-fatigue-syndrome-cfs-cfids-me

RESEARCH

Cleare AJ, Heap E, Malhi GS, Wessely S, O'Keane V, Miell J. “Low-dose hydrocortisone in chronic fatigue syndrome: a randomised crossover trial.”

Lancet 1999 Feb 6;353(9151):455-8. http://www.ncbi.nlm.nih.gov/pubmed/9989716 (Abstract)

Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, O'Keane V. “Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome, and the effects of low-dose hydrocortisone therapy.” J Clin Endocrinol Metab. 2001 Aug;86(8):3545-54. http://jcem.endojournals.org/content/86/8/3545.full

Demitrack, Mark A, Dale, Janet K, Straus, Stephen E, Laue, Louisa, Listwak, Sam J, Dreusi, Markus JP, Chrousos, George P, and Gold, Philip W. “Evidence for Impaired Activation of the Hypothalamic-Pituitary-Adrenal Axis in Patients With Chronic Fatigue Syndrome.” Journal of Clinical Endocrinology and Metabolism. 73:1224-1234,1991.

HYPNOTICS

Ambien, Lunesta, Rozerem, Xyrem

Sleep disturbance is found in 100% of people with CFS/ME. This can manifest itself in either too much sleep (hypersomnia) or, more commonly, in poor, unrefreshing sleep. As sleep deprivation tends to worsen all other symptoms, nearly every CFS/ME physician includes an arsenal of insomnia treatments, both pharmaceutical and natural, in their protocols.

AMBIEN (zolpidem)

Ambien (generic: zolpidem) is a hypnotic that potentiates gamma aminobutyric acid (GABA) in the brain. It works very quickly (15 minutes) and has a short half-life. It is most effective for sleep initiation problems, rather than sleep maintenance. Because tolerance is easily developed, a low dose (10 mg) used intermittently for not more than twelve weeks is recommended. Common side effects are sedation, rebound insomnia, GERD, and impaired psychomotor and cognitive function the following day. While some CFS/ME patients report that Ambien gives them a good night's sleep, others report rapid heartbeat, a “trippy” feeling (hallucinations), and a general worsening of CFS/ME symptoms. Because Ambien has been associated with several deaths, (including actor Heath Ledger), it is under review in the U.S. In Australia, Zolpidem (brand: Stilnox) contains a “black box” warning.

PATIENT REVIEWS

CFS/ME patient reviews of Ambien: http://www.revolutionhealth.com/drugs-treatments/rating/ambien-for-chronic-fatigue-syndrome-cfs-cfids-me

LUNESTA (aszopiclone)

Lunesta (aszopiclone) is a short-acting sedative hypnotic used for the treatment of primary insomnia. It acts as a GABA agonist, stimulating GABA action in the brain. It is rapidly absorbed, with levels peaking at one to three hours after ingestion.

There has been considerable controversy surrounding Lunesta. In an article published in the New England Journal of Medicine in 2009, Drs. Lisa Schwartz and Steven Woloshin examined the manufacturer's clinical trials and found that Lunesta only improved sleep onset by 15 minutes as compared to placebo. Sleep duration was increased by 37 minutes. The authors concluded that “FDA approval does not mean that a drug works well; it means only that the agency deemed its benefits to outweigh its harms.”

PROTOCOL. The recommended dose is 2 mg–3 mg for adults (roughly equivalent to 10 mg of Valium). Lunesta is not available in Europe.

FURTHER READING

Schwartz, M Lisa M..D., and Steven Woloshin, M.D. “Lost in Transmission — FDA Drug Information That Never Reaches Clinicians.” N Engl J Med 2009; 361:1717-1720. October 29, 2009. http://www.nejm.org/doi/full/10.1056/NEJMp0907708

ROZEREM

Unlike most other sleep medications, Rozerem (Ramelteon) does not bind to GABA receptors. Instead it binds to melatonin receptors. Like melatonin, it is used to treat delayed sleep onset. There are no published studies indicating whether Rozerem is more effective than melatonin (which has the advantage of being much less expensive and widely available over-the-counter in the U.S. and Canada).

Like Lunesta, Rozerem came under the scrutiny of Drs. Lisa Schwartz and Steven Woloshin, who found that clinical trials revealed no subjective improvements in total sleep time, sleep quality, or the time it took to fall asleep. Outpatient trials confirmed that people didn't notice much benefit from Rozerem. Nor did it improve the ability to fall back asleep after waking, number of awakenings, total sleep time, or sleep quality.

FURTHER READING

CFS/ME patient reviews of Rozerem: http://www.revolutionhealth.com/drugs-treatments/rating/rozerem-for-chronic-fatigue-syndrome-cfs-cfids-me

XYREM

BACKGROUND. Xyrem (sodium oxybate) – also known as the “date rape drug,” or GHB – is a central nervous system depressant. Chemically, Xyrem is the equivalent of gamma hydroxobutyric acid (GHB), a naturally occurring substance found in the central nervous system. While Xyrem is widely (and illegally) available as a street drug, its use for medical purposes is highly restricted. To date, the only approved use of Xyrem is for narcolepsy, a rare condition in which people suddenly fall asleep during the day. In 2010 the makers of Xyrem, Jazz Pharmaceuticals, submitted a New Drug Approval to the FDA for fibromyalgia. Approval was denied. Xyrem is currently listed as an “orphan drug” (a drug used for rare conditions).

USES IN CFS/ME. Xyrem has gained some popularity among CFS/ME physicians for treating the intractable insomnia experienced by many CFS/ME patients. CFS/ME doctors who use Xyrem include Dr. Enlander and Dr. Klimas. Because of its potential for illegal use, physicians and patients who wish to use Xyrem must be registered with Jazz Pharmaceuticals. Registration includes a precise set of instructions for how to take Xyrem. These include not getting up after ingestion and using the bathroom before ingestion. Side effects include nausea, dizziness, headache, vomiting, sleepiness, and bed-wetting (for those who did not use the bathroom first).

PROS AND CONS. Given the popularity of Xyrem as a party drug, there is an unusual amount of data available about dosage and safety. In the general population, it is well-tolerated, safe, and quite definitely effective. Some CFS/ME patients have reported that Xyrem is a “godsend,” providing them with their first deep, refreshing sleep in years. The adverse reactions most commonly reported are nausea and headaches.

SEE: Sleep Disorders

PATIENT REVIEWS

Detailed patient experiences with Xyrem: http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=809597

CFS/ME patient reviews of Xyrem: http://www.revolutionhealth.com/drugs-treatments/rating/xyrem-for-chronic-fatigue-syndrome-cfs-cfids-me

MIDODRINE (Amatine, Proamatine)

DESCRIPTION. Midodrine is an anti-hypotensive agent, that is, it causes an increase in blood pressure. It is classed as an alpha-agonist.

BACKGROUND. Midodrine was developed to treat orthostatic hypotension, a form of orthostatic intolerance (OI) in which a person's blood pressure drops upon standing. The most common cause of orthostatic hypotension is diabetes mellitis. The drug works by acting on alpha-adrenergic receptors in arteries and veins, producing an increase in vascular tone. Unlike beta-blockers, midodrine does not affect cardiac beta-adrenergic receptors. Nor does it cross the blood-brain barrier, which means it has little effect on the central nervous system.

Several studies have proven the efficacy of midodrine in patients with orthostatic hypotension. In 1997 Low et al found that in a group of 171 patients there was significant improvement in standing blood pressure, as compared to placebo. Side effects, including urinary retention, goose bumps, itching, and a feeling of "pins and needles," were minimal. In 2011 Chen et al found that midodrine was more effective than conventional therapies in 53 children with Postural Orthostatic Tachycardia Syndrome (POTS). Midodrine has also been recommended as a treatment for vasovagal syndrome (fainting), spinal cord injuries, and dysautonomia caused by Parkinson's disease.

Currently, the status of midodrine in the U.S. is unclear. After being approved and marketed, the FDA withdrew its approval of midodrine because the manufacturer had failed to complete required studies confirming its safety. Later the FDA agreed to keep it on the market as an “orphan drug” provided that the manufacturer (Shire) completed standard testing.

USES IN CFS/ME. Dysautonomia, including OI and POTS, is so common in CFS/ME that many physicians find the conditions to be virtually synonymous. In fact, Naschitz JE et al found that specific responses to a tilt table test can be used to accurately diagnose CFS/ME. A recent study in 2009 by a group of researchers at Newcastle University in England confirmed that people with CFS/ME not only have lower blood pressure but abnormal diurnal blood pressure regulation. They found that the greater the dysregulation in diurnal blood pressure, the greater the fatigue. The researchers recommended midodrine as a possible treatment. A number of CFS/ME physicians have used midodrine to treat OI in their patients, including Dr. Klimas, Dr. Rowe, and Dr. Chia.

PROTOCOL. Dr. Hugh Calkins, a cardiologist at Johns Hopkins University, recommends starting midodrine at 2.5 mg taken three times a day. Dr. Klimas suggests taking midodrine before meals. Regular blood pressure monitoring is advised. Because it lowers blood pressure, midodrine should not be taken before bed.

PROS. People with CFS/ME report an increase in stamina, a decrease in dizziness and light-headedness, and an improvement in their ability to stand for periods of time. Some report an overall improvement in symptoms. Midodrine does not pass through the blood-brain barrier, which is advantageous for patients with drug sensitivities.

CONS. Midodrine is used for patients with consistently low blood pressure. However, patients in a double-blind study also experienced a significant number of adverse effects (Journal of the American Medical Association, 1997). Nausea and headache appear to be the two most common side effects of midodrine. Chills, goose bumps, tingling, and frequent urination have also been reported. Some patients experience a sudden rise in blood pressure that feels “stroke-like.” Paradoxically, some patients experience a “crash” a few hours after taking midodrine, in which their blood pressure falls dramatically. Midodrine cannot be taken by anyone with a heart condition, hypertension or kidney disease.

AVAILABILITY AND COST. Midodrine is available from pharmacies. A bottle of 90 pills at the lowest dosage costs roughly $60.

SEE: Cardiac and Cardiovascular Symptoms

FURTHER READING

Good summary of how midodrine is used in CFS/ME. http://aboutmecfs.org.violet.arvixe.com/Trt/TrtMidodrine.aspx

“Tilt-Test Formula: A Diagnostic Marker for CFS?” CFIDS Chronicle. Spring 2003. http://www.cfids.org/archives/2003rr/2003-rr1-article02.asp

CFS/ME doctors discuss treatments for OI: http://www.co-cure.org/experts.htm

PATIENT REVIEWS

Patient reviews of midodrine: http://www.revolutionhealth.com/drugs-treatments/rating/proamatine-for-chronic-fatigue-syndrome-cfs-cfids-me?rid=13060

RESEARCH

Chen L, Wang L, Sun J, Qin J, Tang C, Jin H, Du J. “Midodrine hydrochloride is effective in the treatment of children with postural orthostatic tachycardia syndrome.” Circ J. 2011 Apr;75(4):927-31. http://www.ncbi.nlm.nih.gov/pubmed/21301135 (Abstract)

Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. “Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group.” JAMA. 1997 Apr 2;277(13):1046-51. http://www.ncbi.nlm.nih.gov/pubmed/9091692 (Abstract)

Newton JL, Sheth A, Shin J, Pairman J, Wilton K, Burt JA, Jones DE. “Lower ambulatory blood pressure in chronic fatigue syndrome.” Psychosom Med. 2009 Apr;71(3):361-5. http://www.ncbi.nlm.nih.gov/pubmed/19297309 (Abstract)

NALTREXONE

DESCRIPTION. Naltrexone (Depade or ReVia) is an opioid antagonist. Naltrexone binds to opioid receptors in the nervous system, blocking the effects of narcotics.

BACKGROUND. Naltrexone was first synthesized in 1963 by a small pharmaceutical company in Long Island. Because of its limited application, there was virtually no interest in the drug until 1971 when the Federal government stepped in and endorsed the use of naltrexone for the treatment of heroin addiction. After ten years of trials with narcotics, the drug was determined to be useful for alcoholism. In 1995 naltrexone (ReVia) was formally approved by the FDA for the treatment of alcoholism. Derivatives of naltrexone have been also been used to treat smoking addiction.

While the Federal government was pursuing the use of naltrexone for narcotics addictions, Dr. Ian S. Zagon, Professor of Neuroscience and Anatomy at Pennsylvania State University, discovered that, in contrast to normal doses of naltrexone (50 mg), low dose naltrexone (LDN) blocked the growth of certain cancer tumors. Dr. Zagon's studies drew considerable attention from the scientific community, and researchers began to investigate other possible medical applications of LDN. In 1985 Dr. Bihari, director of the Division of Alcoholism and Drug Dependence, SUNY/Health Science Center at Brooklyn, New York, began to prescribe LDN to AIDS patients, and in the 1990s he successfully used LDN to treat multiple sclerosis. In the decade following Dr. Bihari's success with LDN, researchers found that LDN was also successful in treating Crohn's disease, rheumatoid arthritis, celiac disease, lupus and other autoimmune disorders.

Theories explaining the mechanism of LDN are still evolving. It is believed that low doses of naltrexone act to stimulate endorphins by temporarily blocking opioid receptor sites. (Endorphins are naturally occurring substances present in high concentrations during various illnesses, including viral and autoimmune disease.) Simply stated, when low dose naltrexone blocks opioid receptors for a few hours, the body produces more endorphins to compensate for the temporary lull. One particular endorphin, Opioid Growth Factor (OGF), is an important immune system regulator. When LDN blocks the receptor site for OGF, the body responds by producing more OGF, which, in turn, acts to regulate the immune system.

LDN also appears to block pain receptors along the spine. In 2009 Drs. Sean Mackey and Jarred Younger of Stanford University completed a successful trial of LDN in ten patients with fibromyalgia. The researchers found that low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug. Side effects were minor. They concluded that “low-dose naltrexone may be an effective, highly tolerable, and inexpensive treatment for fibromyalgia.”

USES IN CFS/ME. CFS/ME clinicians have expressed interest in naltrexone, especially in light of findings regarding naltrexone's effect on the immune system. Dr. Susan Levine, a well-known CFS/ME expert affiliated with Mt. Sinai Hospital, New York, explains the rationale for the use and success of naltrexone. "Naltrexone can act to counteract some of the negative effects of excess stimulation by endorphins, such as diminished immune function, and may help to improve cognition and listlessness" (CFIDS Chronicle, January/February 1989). One study by Dr. Levine provided encouraging results. Cognitive symptoms improved in six of ten CFS/ME patients treated with 5 mg naltrexone. No clinically significant side effects were observed.

Despite numerous studies on the immunological benefits of naltrexone, relatively few CFS/ME doctors have included LDN as part of their protocols. Dr. Klimas prescribes LDN to boost immune system responses and for pain. Dr. Enlander prescribes LDN, but remains “neutral” as to its benefits.

PROTOCOL. LDN dosage ranges from 3-5 mg. Patients who have taken LDN for several months report that it is better to start with half the lowest recommended dose (1.5 mg) and slowly work up to 3 mg a day. LDN is generally taken before bed, but may be taken during the day if sleep is disturbed.

PROS AND CONS. A number of patients have reported dramatic improvement in flu-like symptoms, energy, sleep and concentration. Some even claim that LDN has cured them of all their symptoms. Side effects are fairly mild and are usually transient: nausea, headaches, weakness, unusually vivid dreams and fatigue. Naltrexone seems to work best with patients who have had a viral onset, or who have significant flu-like symptoms (sore throat, low fever). Because naltrexone is an opioid antagonist, it cannot be taken with any narcotic pain medication, or with corticosteroids.

AVAILABILITY AND COST. LDN is available by prescription through compounding pharmacies. The cost is approximately $40 for a 30-day supply. Irmat Pharmacy in Manhattan supplies 30 capsules of 4.5mg LDN for $38. Insurance coverage may vary, so check with your carrier.

SEE: Pain

FURTHER READING

Very thorough review of the history and current uses of LDN written by Maija Haavisto. Also included are the patient's own experience with LDN http://www.fiikus.net/?ldn

Phoenix Rising discussion of LDN for CFS/ME patients. Includes explanation of how the drug works: http://aboutmecfs.org.violet.arvixe.com/Trt/LDN.aspx

Biography of Dr. Zagon and general information: http://www.ldnscience.org/ldn-researchers/119

Where to find LDN http://www.lowdosenaltrexone.org/index.htm#What_diseases_has_it_been_useful_for

General information about LDN: http://www.lowdosenaltrexone.org/index.htm

Yahoo group for low dose naltrexone http://health.groups.yahoo.com/group/lowdosenaltrexone/

PATIENT REVIEWS

CFS/ME patient reviews of naltrexone: http://www.revolutionhealth.com/drugs-treatments/rating/naltrexone-for-chronic-fatigue-syndrome-cfs-cfids-me

A patient's experience with naltrexone: http://livewithcfs.blogspot.com/2008/04/low-dose-naltrexone-treatment-for-cfs.html

Detailed information on how LDN affected the immune system of a CFS/ME patient over a two-year period. This blog is well worth reading: http://www.users.on.net/~julian.robinson/cfs/naltrexone.htm

RESEARCH

Younger J, Mackey S. “Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study.” Pain Med. 2009 May-Jun;10(4):663-72. http://www.ncbi.nlm.nih.gov/pubmed/19453963 (Abstract)

NEXAVIR (formerly Kutapressin)

DESCRIPTION. Nexavir is a peptide and amino acid solution derived from porcine (pig) liver.

BACKGROUND. In the late 1920s, it was discovered that liver helped patients with acne vulgaris. As a result of this observation, attempts were made to isolate the active factor from liver. Not until the 1940s was a specially purified liver fraction isolated. Subsequent refinements in the isolation of the active material led to the development of what was then called Kutapressin, a biological (as opposed to synthetic) medication which had anti-inflammatory properties. Over the following decade, Kutapressin was used to treat a variety of dermatological conditions, including poison ivy, hives, eczema, and severe sunburn. According to Dr. Thomas Steinbach, Kutapressin was used decades ago to treat neurasthenia, a condition that bore a remarkable resemblance to CFS/ME.

USES IN CFS/ME. Kutapressin's value as a CFS/ME treatment did not become generally known until Dr. Thomas Steinbach and Dr. William Hermann used Kutapressin successfully in the early 1980s to treat shingles and what was then referred to as Epstein-Barr virus reactivation (CFIDS Chronicle, Summer 1990). Dr. Steinbach had observed that Kutapressin's antiviral and anti-inflammatory properties made it an effective treatment for infectious mononucleosis. Because of Kutapressin's excellent safety record and the positive results in treating Epstein-Barr virus infection, they conducted an informal unblinded study of some 270 patients with CFS/ME.

The results were impressive. Of the study participants, 75% showed improvement, and in some cases marked improvement, after only 40 injections of Kutapressin. Even more promising was that many of these patients had been ill with CFS/ME for more than five years.

The study riveted the attention of CFS/ME clinicians, because no drug treatment to date had produced such impressive results. A second study published by Dr. Steinbach and Dr. Hermann demonstrated the same impressive results (presented at the International CFIDS Conference, Albany, N.Y., 1992). Of the 130 patients who participated in the second study, 85% reported notable or marked reduction of symptoms while receiving Kutapressin injections. Of 111 patients who reported significant reductions in symptoms, 103 noted results within six months of treatment. As a result of these studies, many CFS/ME clinicians began to incorporate Kutapressin in their treatment plans, particularly when there was evidence of viral activity (high titers of human herpesvirus 6 and high interferon levels).

Some researchers have theorized that Kutapressin must have had both antiviral and immunomodulatory properties to simultaneously curtail viral reactivation and the characteristic immune system upregulation typical in CFS/ME. Kutapressin's role in suppressing viral activity is fairly well documented. A study published by Dr. D.V. Ablashi and colleagues proved that Kutapressin was a potent inhibitor of herpesvirus 6 in vitro without causing cell damage (In Vivo, 1994). A later study conducted in 1996 by Dr. E. Rosenfeld and colleagues found that Kutapressin was also effective against Epstein-Barr virus (In Vivo, 1996). However, its role in immunomodulation remains speculative. Dr. Steinbach and Dr. Hermann postulated that Kutapressin may have acted to mediate the action of lymphokines, the immune system chemicals that are thought responsible for many of the symptoms characteristic of CFS/ME.

On the heels of these promising studies, the ownership of Kutapressin changed hands. The distributor, Schwartz Pharma, sold Kutapressin, along with its client list, to Nexco Pharma, a Texas-based company. The product was renamed Nexavir, and while patients and doctors were assured that it was identical to the original formulation, this turned out not to be the case. Nexavir contains preservatives as well as tyrosine, an amino acid to which many CFS/ME patients are sensitive. This prompted some doctors to switch to Hepapressin, a bovine liver alternative. According to Dr. Steinbach, Hepapressin is not nearly effective as the original formulation of Kutapressin (personal communication).

PROTOCOL. The original protocol developed by Dr. Steinbach and Dr. Hermann consisted of a daily intramuscular injection of 2 ml of Kutapressin for 25 days followed by 2 ml injections every other day for 25 days, followed by 2 ml injections three times a week for several months. This is the protocol currently followed for Nexavir.

When he was still using Kutapressin, Dr. Cheney prescribed lower doses (1 ml) working up to 4 ml daily for six months. A 23-gauge 1-inch-long needle is recommended for deep intramuscular injection.

Many doctors who include Nexavir in their protocols (or its counterpart, Hepapressin), combine it with other medications. Dr. Enlander combines Hepapressin with magnesium, B12, folic acid and minerals. Dr. De Meirleir combines Nexavir with B12. In Dr. De Meirleir's experience with this combination, 50% of patients are pain free within three months, and sleep often normalizes within three days.

PROS. Most patients who have benefited from it note an immediate cessation of sore throats, a reduction in flu-like feelings, pain, and fatigue, and improvement in energy level. Many others have reported decreased duration and severity of episodes of flu, increased energy and stamina, and a feeling of overall improvement with Nexavir. Although Nexavir is considered safe, it does produce a few minor side effects initially, but these usually pass quickly after the first few injections are given. In most patients, side effects subside within the first 20 days of treatment.

CONS. Nexavir, although effective for some patients, is not universally helpful. A small number of patients may even feel worse, particularly those who are sensitive to tyrosine. Nexavir can involve a lot of time and money, with little gain. To that end, patients often do not continue with it for the full six months if they have noted no results after three or four months. People with allergies to pork and women who are pregnant should not take Nexavir.

AVAILABILITY` AND COST. Nexavir is available by prescription only. It costs about $145 per 20 ml vial (10 injections). A full six-month course of treatment can cost upwards of $2,000. Some insurance companies cover the cost. However, many companies consider Nexavir an experimental drug for off-label usage and will not cover the cost.

FURTHER READING

Detailed information about Nexavir http://livingwithchronicfatiguesyndrome.wordpress.com/2010/10/25/nexavir-kutapressin-for-cfs/

Dr. Steinbach's groundbreaking 1996 study of Kutapressin in CFS/ME treatment: http://www.me-cvs.nl/index.php?pageid=3423

Nice run-down of various CFS/ME doctors' Nexavir protocols: http://esme-eu.com/antivirals/nexavir-kutapressin-for-me-cfs-article447-135.html

RESEARCH

Ablashi DV, Berneman ZN, Lawyer C, Kramarsky B, Ferguson DM, Komaroff AL. “Antiviral activity in vitro of Kutapressin against human herpesvirus-6.” In Vivo. 1994 Jul-Aug;8(4):581-6. http://www.ncbi.nlm.nih.gov/pubmed/7893985 (Abstract)

Rosenfeld E, Salimi B, O'Gorman MR, Lawyer C, Katz BZ. “Potential in vitro activity of Kutapressin against Epstein-Barr virus.” In Vivo.1996 May-Jun;10(3):313-8. http://www.ncbi.nlm.nih.gov/pubmed/8797033 (Abstract)

NITROGLYCERIN

DESCRIPTION. Nitroglycerin is a nitrate commonly used to relieve angina.

BACKGROUND. Nitroglycerin is one of the oldest drugs in continual use, having been used for more than 100 years to treat angina pectoris, a condition in which a spasm of the coronary arteries causes oxygen loss (ischemia) to the heart. It is a vasodilator; that is, it causes relaxation of the blood vessels. This in turn increases the supply of blood and oxygen to meet the needs of the heart.

USES IN CFS/ME. Nitroglycerin has been used primarily to treat fibromyalgia-type pain in people with CFS/ME, although it has other uses as well. At the 1992 CFIDS conference in Albany, New York, Dr. Jay Goldstein reported that nitroglycerin not only relieved pain but often helped alleviate many other symptoms associated with low blood flow (hypoperfusion) in the brain. After initiating nitroglycerin treatment, Dr. Goldstein's patients reported a decrease in headaches, sore throat, irritable bowel-type symptoms, anxiety, and depression. They also noted increased energy and improved cognition. A point of great interest regarding nitroglycerin as a CFS/ME treatment is that some patients with concurrent multiple chemical sensitivities report improvement in symptoms.

Aside from Dr. Goldstein, very few doctors have investigated the effects of nitroglycerin on CFS/ME patients. In contrast, a number of doctors and researchers have pursued the possible benefits of nitroglycerin for those who suffer from fibromyalgia. A 2011 study by Cho et al found that in fibromyalgia patients, blood flow was restricted due to endothelial dysfunction (an imbalance between vasodilation and vasoconstriction in the inner lining of blood vessels). Nitroglycerin could potentially correct that problem.

Dr. Mark Reed, a podiatrist, prescribed nitroglycerin patches for use on the ankles of a patient with severe foot pain due to fibromyalgia. The patient reported a cessation of pain, and a return of normal skin color on her feet. The only side effect was headache, which was relieved by cutting the patches into 1/8” segments. It is possible, given its vasodilating properties, that topical nitroglycerin can be used to alleviate localized ischemic pain in other areas of the body as well.

PROTOCOL. Because nitroglycerin affects the heart, it is best to determine a specific dose with your physician (individual requirements vary). Dr. Goldstein prescribed sublingual nitroglycerin, generally 0.04 mg (more information on Dr. Goldstein's protocol can be obtained by reading Dr. Goldstein's book, Chronic Fatigue Syndrome: The Limbic Hypothesis).

PROS AND CONS. In marked contrast to other CFS/ME medications, nitroglycerin acts very quickly. Improvement in symptoms can be noted within minutes, making the drug easy to evaluate. Benefits can be global; energy, pain, cognitive function, and mood may improve significantly. However, side effects are common.

The most frequent problems are reduced blood pressure, fainting, dizziness, and headache. For this reason, nitroglycerin is usually administered while the patient is sitting. Patients with migraine headaches should not take this drug because it will worsen the condition. An additional drawback to nitroglycerin is that it loses its effectiveness over time. Dr. Goldstein states, "The most vexing problem in my use of nitroglycerin has been the development of tolerance, which is sometimes extremely rapid, occurring even after the first dose" (CFIDS Chronicle, Summer 1993).

Concurrent use of any drug that lowers blood pressure or alcohol will exaggerate the hypotensive effect of nitroglycerin. Because it is a vasodilator, patients with syncope or hypotension should avoid nitroglycerin.

AVAILABILITY AND COST. Nitroglycerin is available by prescription, in pill or patch formulation. It can be purchased as a generic drug or any of more than two dozen brand-name drugs. Nitroglycerin is inexpensive; 100 sublingual pills cost less than $30. The price of 10 patches is around $10. Insurance usually covers the cost.

FURTHER READING

Interesting article about the pain-relieving effects of nitroglycerin patches for peripheral neuropathy in a patient with FM: http://www.fmaware.org/News2fa26.html?news_iv_ctrl=-1&page=NewsArticle&id=9359

“Nitroglycerin: A Potential Mediator for Hypoperfusion in CFS.” Jay Goldstein. http://www.me-cvs.nl/index.php?pageid=3022&printlink=true&highlight=cfs

RESEARCH

Cho KI, Lee JH, Kim SM, Lee HG, Kim TI. “Assessment of endothelial function in patients with fibromyalgia--cardiac ultrasound study.” Clin Rheumatol. 2011 May;30(5):647-54. http://www.ncbi.nlm.nih.gov/pubmed/20957400 (Abstract)

OXYTOCIN (Pitocin, Syntocinon)

DESCRIPTION. Oxytocin is a hormone produced in the posterior lobe of the pituitary gland. It acts as a neuromodulator.

BACKGROUND. Oxytocin is a pituitary hormone that stimulates uterine muscle contraction and sensitizes nerves. It also controls microcirculation in the brain. Oxytocin is naturally produced in large quantities during childbirth, lactation, in response to certain stressors (hypoglycemia, exercise, hypothermia), and during sexual intercourse. Its most common medical use has been as an aid in stimulating contractions during labor. Oxytocin is also used to control postpartum uterine bleeding. The neurotransmitter dopamine stimulates oxytocin production.

Oxytocin is sometimes referred to as the “love” hormone. It produces feelings of calmness, trust and bonding while reducing anxiety and fear, all of which are important emotions to feel while caring for an infant. Oxytocin also has myriad other effects on the body. It reduces blood pressure and cortisol levels, improves pancreas and bowel function, and, of primary importance to CFS/ME patients, facilitates microcirculation in the brain. Catecholamines (adrenaline, noradrenaline) inhibit the release of oxytocin.

USES IN CFS/ME. CFS/ME clinician Dr. Jorge Flechas suggested that patients with CFS/ME might well have a deficiency in oxytocin (CFIDS Chronicle, Spring 1995). Dr. Flechas based his theory on the fact that CFS/ME patients have lower levels of two other hormones, corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), which are coexpressed with oxytocin in the same region of the brain. He pointed out that many of the symptoms of CFS/ME (pain, loss of libido, sleep disturbances, low exercise tolerance, circulatory problems, and metabolic disorders) could be generated by oxytocin deficiency.

Several CFS/ME clinicians, including Dr. Flechas, Dr. Cheney and Dr. Jay Goldstein, have used oxytocin to treat CFS/ME symptoms. They have reported increased stamina, decreased pain, and improved cognitive function in those patients who have used it. In his book, Betrayal by the Brain, Dr. Goldstein also noted a decrease in fibromyalgia pain, anxiety, depression, and perhaps even food allergies.

Dr. Cheney has observed dramatic improvement in fatigue, pain, and short-term memory in his CFS/ME patients, which he attributes oxytocin's effects on microcirculation in the brain and deep tissues. Dr. Lapp also notes that oxytocin increases blood flow to the eyes, brain and muscles in CFS/ME patients:

“You think more clearly and you see more clearly. It can be remarkable. I can give the patient a shot of oxytocin in the hip and five minutes later they will say, "I haven’t seen this clearly, I haven’t felt this well in months." It doesn’t work for everybody, but when it does, it is quite miraculous and can be a long-term therapy.”

Interestingly, several CFS/ME doctors have observed that when their patients become pregnant, their CFS/ME symptoms abate. Many attribute this improvement to an increase in oxytocin.

PROTOCOL. Oxytocin may be administered orally, sublingually, or as an intramuscular injection (IM). Dr. Cheney has used sublingual oxytocin at 10 units up to three times a day. Dr. Teitelbaum recommends 10 units IM for patients in whom a deficiency is suspected (those with pallor and cold extremities). According to Dr. Teitelbaum, effects will begin within 45 minutes to an hour. He prescribes injections daily or on an “as needed” basis. Some specialists note the benefits of oxytocin after a single injection, while others believe it takes several injections to determine if oxytocin will have a positive effect.

Dr. Cheney has used a sublingual form of oxytocin at 10 to 20 units up to three times per day. Sublingual oxytocin has the advantage of being able to spit it out if a negative reaction occurs.

PROS AND CONS. Oxytocin has so many functions in regulating primary systems in the body that it may provide, as Dr. Lapp says, nearly “miraculous” results. But, it doesn't work for everybody. Because oxytocin is a hormone which can influence nearly every system in the body, side effects can be serious: nausea, irregular heartbeat, changes in blood pressure, convulsions, headache, weight gain, dizziness, difficulty breathing, and mental disturbances. Any side effects should be reported to your physician. Pregnant women should not take oxytocin.

AVAILABILITY AND COST. Oral oxytocin (Pitocin, Syntocinon) is available by prescription only. Injectable oxytocin can be expensive, $50 for 10 ml. Nasal spray is less expensive. Belmar Pharmacy has also made available both a sublingual and oral form of oxytocin which may reduce the risk of side effects.

SUPPLIER

Belmar Pharmacy

Website: http://www.belmarpharmacy.com/oxytocin.htm

FURTHER READING

Dr. Lapp's 1997 presentation on treatments, including oxytocin http://www.prohealth.com/library/showarticle.cfm?id=2926&t=CFS/ME_FM

Detailed discussion of oxytocin, primarily as it relates to FM http://findarticles.com/p/articles/mi_m0FDL/is_3_14/ai_n27448236/

Very thorough explanation of the various functions of oxytocin by Dr. Jorge Flechas http://cypress.he.net/~bigmacnc/drflechas/abstract1.html

How oxytocin is used for fibromyalgia and chronic pain http://sacfs.asn.au/news/2011/01/01_25_oxytocin_may_offer_benefits_in_treatment_of_chronic_pain.htm

PATIENT REVIEWS

Blog of one patient's unsuccessful treatment with oxytocin http://livingwithchronicfatiguesyndrome.wordpress.com/2010/07/05/oxytocin-for-cfs/

PAIN RELIEVERS (ANALGESICS)

Aspirin, NSAIDs, Tylenol, Aleve, Ultram, Narcotics

NOTE: Most analgesics are available over the counter, but it is still important to discuss dosage and side effects with your physician, especially if any of these medications are taken regularly.

DESCRIPTION. Analgesics are agents that diminish pain.

BACKGROUND. Analgesics, or pain killers, work by blocking the body's production of hormones that send pain messages to the brain (prostaglandins) or by occupying the sites that receive those messages. The two general types of analgesics are non-narcotics, which block chemical production, and narcotics, which block reception in the brain. Non-narcotic pain killers include aspirin and other salicylates, acetaminophen (Tylenol), naproxen (Aleve) and nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin). Narcotic pain killers include the opiates and opioids, such as codeine, Darvon or Wygesic (propoxyphene), Demerol (meperidine), and morphine. Because narcotics are habit-forming, they are used on a short-term basis only. A number of prescription analgesics contain a combination of non-narcotic and narcotic pain killers. The most common combinations contain codeine and acetaminophen or aspirin. These drugs are used when pain persists or is not relieved by other non-narcotic or narcotic drugs.

ASPIRIN

DESCRIPTION. Aspirin is a salicylate, a group of drugs with many medicinal uses, including reduction of fever and inflammation, as well as exhibiting mild antibiotic properties. Aspirin blocks pain by inhibiting the enzyme cyclooxygenase (COX-1), which helps the body produce inflammation-causing prostaglandins. The main active ingredient in aspirin is acetylsalicylic acid, a chemical that was first derived from willow bark.

Aside from blocking pain, aspirin has a number of physiological mechanisms. It has been shown to prevent glutamate toxicity in the brain. Glutamate is a neuroexcitatory neurotransmitter which is frequently high in CFS/ME patients. Aspirin also reduces ATP storage pools, which increases bleeding time; increases extracellular adenosine, which is associated with short-term energy increase; and lowers inducible nitric oxide synthase activity (NO mediates vasodilation in blood vessels).

USES IN CFS/ME. Aspirin is recommended for those CFS/ME patients with continual or severe joint and muscle pain. In his book, The Doctor's Guide to Chronic Fatigue Syndrome, Dr. David Bell notes that aspirin is beneficial for CFS/ME patients with "prominent joint and muscle pain, headache, lymph node pain and general aching, and is less effective in patients with prominent fatigue, nausea, and neurologic symptoms."

PROTOCOL. Aspirin can be taken as needed to prevent or treat pain. Dr. Bell suggests that some patients with intractable pain may benefit from daily use of aspirin. To avoid stomach upset, aspirin should be taken with food. As with other drugs, it is best to begin with a small dose to assess tolerance.

PROS. For many patients, aspirin is an inexpensive, reliable analgesic. Some patients report an increase of energy after taking aspirin, probably due to the temporary increase of adenosine.

CONS. Although aspirin is generally regarded as safe, frequent use can lead to a number of side effects, including tinnitus (ringing in the ears), nausea, and heartburn. If aspirin is taken on a regular basis, an anti-ulcer medication (such as Cytotec, Zantac or Tagamet) may also be recommended to protect the lining of the stomach. Patients with a history of ulcers, gastroesophageal reflux, or other gastrointestinal problems should avoid aspirin. Some nutritionists recommend that patients with food sensitivities avoid salicylates. Aspirin should not be given to children because it can cause Reye's syndrome.

AVAILABILITY AND COST. Aspirin is available over the counter at any pharmacy and most supermarkets. It is quite inexpensive, often less than $5 for a bottle of 300 tablets. Check the label carefully because some aspirin brands contain other potentially irritating ingredients, such as caffeine.

RESEARCH

Crisanti P, Leon A, Lim DM, Omri B. “Aspirin prevention of NMDA-induced neuronal death by direct protein kinase Czeta inhibition.” J Neurochem. 2005 Jun;93(6):1587-93. http://www.ncbi.nlm.nih.gov/pubmed/15935075?dopt=Abstract (Abstract)

Czyz M, Watala C. [Aspirin--the prodigious panacea? Molecular mechanisms of the action of acetylsalicylic acid in the organism]. Postepy Hig Med Dosw (Online). 2005 Mar 23;59:105-15. http://www.ncbi.nlm.nih.gov/pubmed/15928593 (Abstract)

PATIENT REVIEWS

A CFS/ME patient's review of Bayer aspirin http://www.revolutionhealth.com/drugs-treatments/rating/bayer-aspirin-for-chronic-fatigue-syndrome-cfs-cfids-me

NSAIDs

Ibuprofen (Advil, Motrin), Naproxen (Aleve), Nabumetone (Relafen), Celecoxib (Celebrex), Meloxicam (Mobic), diclofenac (Arthrotec)

DESCRIPTION. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting prostaglandin production by blocking both COX-1 and COX-2. Like aspirin, they reduce inflammation, pain, and fever. Unlike aspirin, which is cleared from the body quickly, NSAIDs have a long half-life and thus require less frequent administration. Their lower dosage leads to fewer side effects. There is also a class of strictly COX-2 inhibitors, of which Celebrex is the most common. These produce greater risks of side effects and should not be taken with other NSAIDs.

USES IN CFS/ME. NSAIDs are recommended to treat recurring pain in muscles and joints. Many patients with CFS/ME who have chronic acute pain prefer ibuprofen (Advil, Motrin) over other pain medications.

PROTOCOL. NSAIDs are generally taken as needed. Patients should start with a small dose to assess tolerance.

PROS. Some CFS/ME patients report that taking ibuprofen gives them an extra “boost.” Because NSAIDs actively work to reduce inflammation, they may work better on joint pain and stiffness than other analgesics.

CONS. Because all NSAIDs can produce gastrointestinal problems, caution must be exercised. Buffered or enteric-coated drugs help protect the stomach lining. The medication should always be taken with food. Finally, patients should be alert for signs of gastrointestinal distress (heartburn, reflux, pain). NSAIDs raise blood pressure, so patients with a history of hypertension should avoid taking them. NSAIDs are also contraindicated for patients with a history of kidney problems.

AVAILABILITY AND COST. NSAIDs are available over the counter. The most common is ibuprofen (Advil, Motrin). A bottle of 50 tablets of Advil (200 mg) costs around $5.00. Prescription NSAIDs include Clinoril, Feldene, and Tolectin. Intramuscular Toradol may be prescribed for severe pain. NSAIDs are generally more expensive than aspirin or acetaminophen.

PATIENT REVIEWS

CFS/ME patient reviews of Advil: http://www.revolutionhealth.com/drugs-treatments/rating/advil-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Aleve: http://www.revolutionhealth.com/drugs-treatments/rating/aleve-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Arthrotec: http://www.revolutionhealth.com/drugs-treatments/rating/arthrotec-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Celebrex: http://www.revolutionhealth.com/drugs-treatments/rating/celebrex-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Mobic: http://www.revolutionhealth.com/drugs-treatments/rating/mobic-for-chronic-fatigue-syndrome-cfs-cfids-me

CFS/ME patient reviews of Naproxen: http://www.revolutionhealth.com/drugs-treatments/rating/naprosyn-for-chronic-fatigue-syndrome-cfs-cfids-me

ACETAMINOPHEN (Tylenol)

CAUTION: In January 2011, the FDA limited the use of acetaminophen-opioid combinations due to the risk of liver failure. These include hydrocodone with acetaminophen (Vicodin, Lortab), and oxycodone with acetaminophen (Tylox, Percocet).

USES IN CFS/ME. In contrast to NSAIDs, which work by inhibiting signals to the nervous system, acetaminophen (Tylenol) acts in the brain, where it blocks the perception of pain. As a consequence, acetaminophen is not of particular benefit in treating joint or muscle pain due to inflammation. Its primary uses in CFS/ME are to relieve headache and generalized achiness, and to reduce fevers.

PROS. Acetaminophen does not cause stomach irritation, as do aspirin and other NSAIDs. However, a number of patients with CFS/ME find they can tolerate only low or infrequent doses.

CONS. A serious problem associated with acetaminophen is that high doses can lead to liver damage—as can any dose of this drug taken with alcohol. Acetaminophen also interacts in a similar fashion with opioids (narcotics). If signs of liver malfunction develop (jaundice or pain under the right side of the rib cage), acetaminophen should be discontinued immediately.

AVAILABILITY AND COST. Acetaminophen is available over the counter in brand-name and generic formulations. It is inexpensive. A bottle of 24 capsules costs less than $6.00.

FURTHER READING

Study linking acetaminophen to liver failure: http://www.masscfids.org/resource-library/3-research/61-increasing-number-of-fatal-acute-liver-failure-cases-linked-to-the-popular-painkiller-acetaminophen-tylenol

PATIENT REVIEWS

CFS/ME patient reviews of Tylenol: http://www.revolutionhealth.com/drugs-treatments/rating/tylenol-for-chronic-fatigue-syndrome-cfs-cfids-me

ULTRAM

DESCRIPTION. Ultram (tramadol) is a centrally acting synthetic opioid analgesic used for severe pain.

BACKGROUND. Tramadol was developed in the 1970s by the German company Grunenthal GmbH. Somewhat like narcotics, it is an opioid agonist, releasing serotonin and inhibiting the uptake of norepinephrine. Because tramadol is structurally similar to Effexor, it has been proposed as a treatment for mood disorders, phobias and anxiety, although physicians have not endorsed it for these uses.

USES IN CFS/ME. Ultram has been prescribed to treat muscle and fibromyalgia-type pain that has been resistant to other medications.

PROS. Some patients report that Ultram is the most effective medication for pain and that it also helps relieve insomnia and fatigue. Ultram acts quickly and does not seem to produce as many side effects as other pain medications.

CONS. Ultram is addictive. Withdrawal symptoms from extended use are more severe than for other opioids, and last for a longer period of time. This drug is contraindicated in patients with seizure disorders and those taking monoamine oxidase inhibitors (MAOIs) or other antidepressants.

AVAILABILITY AND COST. Tramadol is available by prescription. The generic is relatively inexpensive. Thirty tablets costs around $20.

PATIENT REVIEWS

CFS/ME patient reviews of Ultram: http://www.revolutionhealth.com/drugs-treatments/rating/ultram-for-chronic-fatigue-syndrome-cfs-cfids-me

NARCOTICS

USES IN CFS/ME. The subset of CFS/ME patients with severe, burning, intractable pain that does not respond to other treatments may need stronger medications. In these cases, narcotics may be recommended. Although effective, narcotics are addictive and therefore should be used only when other pain treatments have failed to alleviate pain.

PROS. Narcotics offer immediate and sometimes total relief from certain types of pain. Some CFS/ME patients with fibromyalgia report that a single injection of Demerol may relieve pain for up to 6 months. The reasons for this are not clear, but for some patients breaking the cycle of pain reception in the brain seems to have long-term benefits.

CONS. Narcotics can be used only infrequently and in small doses because the risk of addiction is high. The most common side effects are drowsiness, mood changes, and constipation. Codeine also causes stomach upset. The higher the dose, the more serious the side effects. High doses, for example, may cause breathing problems; therefore, patients with a history of respiratory problems should exercise caution or avoid narcotics entirely.

FURTHER READING

CFIDS Association of America's list of commonly used analgesics and side effects http://www.cfids.org/resources/analgesic.asp

FDA limits use of acetaminophen-opioid combinations: http://www.fightingfatigue.org/?p=8933

PENTOXIFYLLINE (Trental)

DESCRIPTION. Pentoxifylline (Trental) is a hemorrheologic agent derived from xanthine. A number of stimulants, including caffeine, are derived from xanthine.

BACKGROUND. Pentoxifylline improves capillary blood flow by increasing the flexibility of red blood cells and lowering blood viscosity. This double action enables blood cells to squeeze through tiny capillaries with greater ease. Traditionally, pentoxifylline is used to treat vascular diseases, especially those that inhibit blood flow. Pentoxifylline is also used to treat the nausea and headaches associated with altitude sickness.

USES IN CFS/ME. Some clinicians have recommended pentoxifylline in CFS/ME to increase blood flow to the brain. Single-photon emission computed tomography (SPECT) scans consistently reveal lowered blood flow in patients with CFS/ME. In theory, pentoxifylline should resolve that problem.

Pentoxifylline may also address another blood problem common to CFS/ME. Dr. L.O. Simpson, a pathologist from the University of Otago Medical School in

Dunedin, New Zealand, discovered that patients with CFS/ME have irregularly shaped red blood cells, which makes it more difficult for blood cells to pass through capillaries. Dr. Simpson believes the decreased cerebral blood flow in CFS/ME is the consequence of abnormally shaped blood cells. Many of the symptoms of inadequate blood supply such as light-headedness, vertigo, and cognitive problems might be alleviated if blood flow is increased.

Apart from pentoxifylline's well-known effects on blood flow, it also has broad antiviral activity. A study conducted in 1993 by a team of Russian scientists found that trental [pentoxifylline] was an “effective broad spectrum virus inhibitor.” Pentoxifylline also has the ability to inhibit proinflammatory cytokines, which have been shown to be upregulated in CFS/ME patients.

PROTOCOL. The usual recommended dose for vascular problems is 400 mg three times a day, with meals. Patients with CFS/ME should begin with a lower dose (400 mg once a day) to assess sensitivity.

PROS AND CONS. CFS/ME patients who have benefited from pentoxifylline report dramatic improvement in cognitive function as well as a reduction in flu-like symptoms (sore throats, swollen glands, and malaise). Pentoxifylline should not be used by those who cannot tolerate stimulants. (Xanthine, from which pentoxifylline is derived, is closely related to caffeine.) Pentoxifylline is contraindicated in patients with peptic ulcers and those at risk for hemorrhage. The most commonly reported side effects are nausea, headache and flushing.

AVAILABILITY AND COST. Pentoxifylline is available by prescription. It is not expensive. Ninety tablets can cost as little as $20.

FURTHER READING

A very thorough discussion of one patient's experiences with pentoxifylline. http://livingwithchronicfatiguesyndrome.wordpress.com/2011/09/05/pentoxifylline-for-me/

An excellent CFS Report on Les Simpson, blood flow and fatigue in CFS. http://www.cfidsreport.com/Articles/researchers/lessimpson.htm

RESEARCH

Amvros'eva TV, Votiakov VI, Andreeva OT, Vladyko GV, Nikolaeva SN, Orlova SV, Azarova IA, Zgirovskaia AA. “New properties of trental as an inhibitor of viral activity with a wide range of activity.” Vopr Virusol. 1993 Sep-Dec;38(5):230-3. http://www.ncbi.nlm.nih.gov/pubmed/8284924 (Abstract)

PLAQUENIL

DESCRIPTION. Plaquenil (hydroxychloroquine) is an antimalarial drug. Chemically, it is classed as a 4-aminoquinoline compound.

BACKGROUND. Hydroxychloroquine is one of a number of drugs that have been used for many years in the treatment of malaria. It has also been used to treat a number of autoimmune and inflammatory disorders, including systemic lupus, rheumatoid arthritis, and Sjögren's Syndrome. Hydroxychloroquine reduces the activation of dendritic cells, thus mitigating the inflammatory process.

USES IN CFS/ME. Hydroxychloroquine (Plaquenil) is prescribed to CFS and FMS patients if they have a high ANA level plus symptoms of Sjögren's syndrome, lupus, or other autoimmune diseases. Patients starting hydroxychloroquine therapy should have an ophthalmology exam every six months to monitor for retina toxicity.

PROTOCOL. As very few doctors use Plaquenil for CFS/ME, there is no protocol.

PROS AND CONS. Some patients report a decrease in pain and insomnia. The drawbacks, however, do not justify the benefits, which may be obtained through other less risky medications. As with all chloroquine medications, there are numerous serious side effects. People of African descent can develop severe anemia. In children, Plaquenil can be fatal.

Plaquenil diffuses rapidly into adipose (fatty) tissues, which are found abundantly in the nervous system and eyes. Permanent eye damage (retinal and corneal), including blindness, has been reported. Some patients experience psychosis (hearing voices, delusions, hallucinations, disorientation). The 4-aminoquinoline compounds are very rapidly and completely absorbed after ingestion, which means accidental overdoses, even at low doses, can occur. Toxic symptoms can occur within 30 minutes. These consist of headache, drowsiness, visual disturbances, cardiovascular collapse, and convulsions, followed by sudden and early respiratory and cardiac arrest (death).

AVAILABILITY AND COST. Plaquenil is available by prescription only.

FURTHER READING

Patient thread on Plaquenil: http://forums.phoenixrising.me/showthread.php?3171-Plaquenil-hydroxychloroquine

PATIENT REVIEWS

One patient's review of Plaquenil: http://www.revolutionhealth.com/drugs-treatments/rating/hydroxychloroquine-for-chronic-fatigue-syndrome-cfs-cfids-me

PYRIDOSTIGMINE (Mestinon)

DESCRIPTION. Pyridostigmine (brand: Mestinon) is an acetylcholinesterase inhibitor. Pyridostigmine is poorly absorbed in the gut and does not cross the blood-brain barrier.

BACKGROUND. Pyridostigmine works by preventing the breakdown of acetylcholine (ACh) in nervous system synapses. This leads to an increase in acetylcholine, a neurotransmitter widely found in both the peripheral and central nervous systems. Acting as both an excitatory and inhibitory neurotransmitter, acetylcholine performs a variety of functions. Within the skeletal muscular system it contracts muscle, allowing for movement. It slows the heart, and promotes REM sleep. In the central nervous system, ACh is closely associated with learning, attention, and short-term memory.

Pyridostigmine is mainly prescribed for myasthenia gravis, an autoimmune condition in which acetylcholine is blocked, leading to profound muscle weakness. In spite of the fact that it does not cross the blood-brain barrier, pyridostigmine is also used to enhance memory in people with Alzheimer's disease. Pyridostigmine has been administered as a treatment for the paralysis caused by organophosphate pesticide poisoning. In a similar vein, the military administered pyridostigmine as a prophylactic to soldiers during the Gulf War to block potential exposure to Soman, a nerve gas which acts on acetylcholine in much the same manner as organophosphate pesticides. Recently, pyridostigmine has been used to treat orthostatic intolerance.

USES IN CFS/ME. In his book, Betrayal by the Brain, Dr. Jay Goldstein proposed that pyridostigmine can be used in CFS/ME with much the same results as in patients with myasthenia gravis: the alleviation of muscle weakness. Surprisingly, Dr. Goldstein found that even though pyridostigmine does not cross the blood-brain barrier it increased mental clarity in his CFS/ME patients. He noted that because pyridostigmine helps increase the secretion of growth hormone (GH), it might be of benefit to CFS/ME patients, who tend to have low levels of GH.

In 2003 a group of Japanese researchers published a study in which low-dose pyridostigmine was administered to three CFS/ME patients with dysautonomia and positive Epstein-Barr virus (EBV) titers. In all three cases, a one-month course of pyridostigmine relieved fatigue and muscle weakness. The authors speculated that EBV infection induces antibodies, which, through an inhibition of calcium influx at motor terminals, reduces acetylcholine release and causes muscle weakness and cholinergic autonomic dysfunction. The authors concluded that their case studies “strongly suggest therapy using a small dose (10 mg per day) of oral pyridostigmine in patients with CFS who have had more than a 40% amplitude increase in response to the RNS [repetitive nerve stimulation] test, positive anti-VCA IgG of EBV and mild impairment of autonomic functions.”

Based on findings that pyridostigmine increases growth hormone, a 2008 study of fibromyalgia patients in Portland, Oregon was conducted comparing exercise, diet and treatment with pyridostigmine. While the researchers did not find that either pyridostigmine alone or pyridostigmine plus exercise produced an improvement in most FM symptoms, they did find that pyridostigmine improved anxiety and sleep. The authors speculated that pyridostigmine may have improved vagal tone, thus alleviating sleep and anxiety symptoms.

PROS AND CONS. CFS/ME patients report a decrease in fatigue and post-exertional malaise. However, there are many side effects if taken at normal recommended doses. Common side effects include increased saliva, increased sweating, increased urination, watery eyes, stomach upset, stomach pain, nausea, warmth, tingling, and diarrhea.

AVAILABILITY AND COST. Pyridostigmine is available at most pharmacies with a prescription. A 30-day supply of generic 60 mg tablets costs about $20. Insurance usually covers the cost.

PATIENT REVIEWS

FM patient reviews of Mestinon (pyridostigmine): http://www.revolutionhealth.com/drugs-treatments/rating/mestinon-for-fibromyalgia-syndrome-fms

RESEARCH

Arvat E, Cappa M, Casanueva FF, Dieguez C, Ghigo E, Nicolosi M, Valcavi R, Zini M. “Pyridostigmine potentiates growth hormone (GH)-releasing hormone-induced GH release in both men and women.” J Clin Endocrinol Metab. 1993 Feb;76(2):374-7. http://www.ncbi.nlm.nih.gov/pubmed/8432781 (Abstract)

Jones KD, Burckhardt CS, Deodhar AA, Perrin NA, Hanson GC, Bennett RM. “A six-month randomized controlled trial of exercise and pyridostigmine in the treatment of fibromyalgia.” Arthritis Rheum. 2008 Feb;58(2):612-22. http://www.ncbi.nlm.nih.gov/pubmed/18240245 (Abstract)

Kawamura, Yasuo, Mikihiro Kihara, Kazuhiro Nishimoto, Mayumi Taki. “Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports.” Pathophysiology 9 (2003) 189-194. http://www.cfids-cab.org/cfs-inform/Coicfs/kawamura.etal03.pdf

QUESTRAN (cholestyramine)

DESCRIPTION. Questran (cholestyramine) is a bile sequestrant; it attaches to bile in the intestines and removes it.

BACKGROUND. Bile is produced in the liver. When it is released via the gall bladder into the small intestine, it serves to break down fats. Bile is then reabsorbed by the ileum (the portion of the small intestine where it joins the large intestine). In some situations, such as GI surgery or Crohn's disease, the bile is not properly reabsorbed, resulting in a watery green diarrhea. Questran helps bind bile acids, reducing diarrhea. Questran's binding action is useful for the pruritus (itching) experienced by people with liver failure, and for reducing high levels of cholesterol in the bloodstream. Questran also binds to mold toxins, and is used by some alternative doctors to treat “sick building syndrome.”

USES IN CFS/ME. The idea that CFS/ME patients suffer from neurotoxicity and oxidative stress is not a new one. Normally, CFS/ME physicians treat their patients with a combination of antioxidants (for oxidative stress) and nervous system down regulators, such as Klonopin (for neurotoxicity). However, it was Dr. Shoemaker's treatment of oxidative stress in mold toxicity, chronic Lyme and other bacterial infections with Questran that led to its use in CFS/ME.

PROTOCOL. The normal recommended dose of Questran is one packet (4 oz) of powder mixed into a beverage and drunk slowly. Dr. Cheney recommends that CFS/ME patients start with as little as ¼ teaspoon at bedtime. Be sure to drink plenty of water during the day as Questran is very constipating. Because Questran absorbs everything in your intestinal tract, you should not take Questran within an hour of taking other medications.

PROS AND CONS. Nothing will stop diarrhea faster than Questran, which is a boon to people who experience diarrhea often. Questran is a medication with a good safety record and with few side effects. However, it is a stomach irritant. Because it binds to bile and fats, it not only can cause constipation, but can lead to deficiencies in fat-soluble vitamins. Questran contains sugar, which is not recommended for CFS/ME patients. Questran “Light” contains aspartame, which is also not recommended. Notwithstanding these drawbacks, some CFS/ME patients swear by it.

AVAILABILITY AND COST. Questran is quite expensive, but if you buy generic cholestyramine powder the price drops considerably. (A single dose of brand costs about $2, whereas generic costs roughly 40 cents.) Insurance usually covers.

FURTHER READING

Basic drug information about Questran: http://www.drugs.com/pro/questran.html

Summary of Dr. Cheney's protocol: http://www.dfwcfids.org/medical/cheney.html

Dr. Teitelbaum's recommendations for how best to take Questran: http://www.endfatigue.com/tools-support/Neurotoxins-Information-Sheet.html

CFS/ME patient reviews of Questran: http://www.revolutionhealth.com/drugs-treatments/rating/questran-for-chronic-fatigue-syndrome-cfs-cfids-me

RITUXIMAB

DESCRIPTION. Rituximab (trade names: Rituxan, MabThera) is a monoclonal antibody which acts against the protein CD20. Rituximab was first approved by the FDA in 1997 for the treatment of non-Hodgkin's lymphoma.

BACKGROUND. All cells have receptors on their surfaces which allow molecules to attach themselves and cause metabolic changes within the cell. One of these receptors, primarily found on the surface of B cells, is called CD20. Molecules that attach to CD20 can affect the growth and development of tumor cells, and, sometimes, cause the production of new tumor cells. Tests confirming the expression of CD20 antigens are important in diagnosing B-cell lymphomas and leukemia.

Rituximab was developed using cloning and recombinant DNA technology from human and murine (mice or rat) genes. It is believed that rituximab destroys tumors by attaching to the CD20 receptor on B cells, causing the tumor cells to disintegrate. In some non-Hodgkin's B-cell lymphomas, rituximab prevents the production of more tumor cells.

Rituximab is also used in the treatment of autoimmune disorders, such as rheumatoid arthritis and Wegener's granulomatosis. In these cases, rituximab works by temporarily depleting the total number of B cells, which are important in promoting inflammation. Rich Van Konynenburg has proposed that this is the reason rituximab may work for CFS/ME patients – by reducing B cells, rituximab reduces inflammation.

USES IN CFS/ME. The effect of rituximab on CFS/ME patients was discovered by accident. Two Norwegian doctors, Øystein Fluge and Olav Mella of Haukeland University Hospital, noticed that after treating a CFS/ME patient for Hodgkin's lymphoma with rituximab, she recovered from CFS/ME. This led the doctors to initiate a small study of rituximab on CFS/ME patients.

Three CFS/ME patients were given rituximab in an open-label trial (that is, the patients knew they were receiving the drug). All three patients experienced significant improvement; two of them responded within six weeks and the third had a delayed response, occurring six months after treatment. The positive effects lasted for between 16 and 44 weeks. After relapse, the patients were administered another dose of rituximab, with the same positive results. The investigators hypothesized that B cells of the immune system might play a significant role in CFS, at least for a subset of patients, and that “CFS may be amenable to therapeutic interventions aimed at modifying B-cell number and function.”

The positive results of this, as well as a second open-label trial, led Drs. Fluge and Mella to conduct a larger study with a more rigorous design to test the effects of the drug. In 2009 they initiated a double-blind, placebo-controlled phase trial with 30 CFS/ME patients. As in the earlier open-label studies, the responses to rituximab were significant. Sustained overall improvements were noted in 67% of the patients (as opposed to 13% of the control group). Four of the rituximab patients showed improvement past the study period. The authors concluded that the delayed responses starting from 2–7 months after rituximab treatment, in spite of rapid B-cell depletion, “suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses.”

The result of this study not only generated headlines all over the world, but prompted an unprecedented apology from the Norwegian Directorate of Health. In a televised announcement, Deputy Director Bjørn Guldvog stated: "I think that we have not cared for people with ME to a great enough extent. I think it is correct to say that we have not established proper health care services for these people, and I regret that."

FURTHER READING

“Rituximab Trial Shows Promise.” Kimberly McCleary. CFIDS Association of America. http://www.research1st.com/2011/10/19/rituximab-trial/

ABC article on rituximab study: http://abcnews.go.com/Health/Wellness/chronic-fatigue-syndrome-study-supports-autoimmune-disease-theory/story?id=14801908

“Norwegian research breakthrough can solve CFS mystery.” English translation of first Norwegian news article on Rituximab: http://www.tv2.no/nyheter/innenriks/english-version-norwegian-research-breakthrough-can-solve-cfsmystery-3615631.html

“Will rituximab be a viable treatment option for ME/CFS.” A thoughtful, clear analysis of the possible role of rituximab as a treatment for CFS/ME. http://www.masscfids.org/resource-library/9/351

Cort Johnson's review of rituximab, including an interview with Dr. Olav Mella: http://esme-eu.com/treatment/a-drug-for-me-cfs-the-rituximab-story-article468-110.html

Apology from the Norwegian Directorate of Health. http://www.euro-me.org/news-Q42011-003.htm

List of rituximab clinical trials. http://www.clinicaltrials.gov/ct2/results?term=rituximab

Dr. Jamie-Deckhoff-Jones' fascinating blog. Scroll down for her explanation of how rituximab works in CFS/ME, as well as her personal critique. Both are quite good. http://treatingxmrv.blogspot.com/2011/10/rituximab-big-guns-for-mecfs.html

RESEARCH

Fluge, Øystein, Olav Mella. “Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: a preliminary case series.” BMC Neurol. 2009 Jul 1;9:28 http://www.ncbi.nlm.nih.gov/pubmed/19566965 (Abstract)

Fluge, Øystein, Ove Brulan, Kristin Risa, Anette Storstein, Einar K. Kristoffersen, Dipak Sapkota, Halvor Næss, Olav Dahl, Harald Nyland, Olav Mella. “Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study.” http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0026358

Vandermeer's critique of Fluge et al double-blind study.

http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c&root=info%3Adoi%2F10.1371%2Fannotation%2F43f3e6a8-cf7d-4438-8b97-b21b9c31bf5c

Fluge and Mella's response to Vandermeer's critique. (This is well worth reading, as it lays the foundation for CFS/ME as an autoimmune disease.) http://niceguidelines.blogspot.com/2011/10/dr-oystein-fluge-and-professor-olav.html

TRANSFER FACTOR

DESCRIPTION. Transfer factor, an extract from peripheral blood lymphocytes (white blood cells) of a healthy donor, facilitates the transfer of T cell-mediated immunity from one person to another.

BACKGROUND. Transfer factor has been used for more than 40 years to transfer immunity from a presumably healthy donor to a recipient. It has been used to treat viral, parasitic, and bacterial infections. Distinctive types of transfer factor may be used, depending on the condition being treated. Nonspecific transfer factor from a pool of healthy donors may be used for immune system modulation. Disease-specific transfer factor is used to treat a specific virus or infection, such as herpesviruses or human immunodeficiency virus (HIV). In addition, donor-specific or dedicated donor transfer factor can be obtained from a relative or other household member.

USES IN CFS/ME. Transfer factor, at least in theory, would appear to be valuable as a primary therapy in CFS/ME. Because the cause of CFS/ME is still unknown, it has been difficult to find a universally effective treatment. Transfer factor is considered adaptogenic; that is, it can boost a deficient immune system or, conversely, can down regulate the immune system in certain autoimmune conditions. This makes it an ideal immunomodulator in CFS/ME. However, as the following data reveal, reports of the efficacy of transfer factor have been inconclusive.

At the May 1994 CFIDS conference in Dublin, Ireland, information was presented regarding a study of 20 patients with CFS treated with oral transfer factor by Dr. Giancarlo Pizza and colleagues from Bologna, Italy. Of the 20 patients, improvement was noted in 12 and remission was observed in two. There were no significant side effects. This oral form of transfer factor was specific for Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, and herpes simplex virus.

Dr. Perry Orens of Great Neck, New York, reported a positive experience with transfer factor (CFIDS Chronicle, Fall 1993). With Dr. Hugh Fudenberg, a leading international expert on transfer factor, Dr. Orens used injectable, donor-specific transfer factor to treat symptoms of CFS in nine patients. The results were complete remission in two patients, marked improvement in two, partial improvement in two, and no improvement in three.

In 1991 Dr. Denis Wakefield of Australia reported the results of an extensive double-blind study of transfer factor. Of 90 patients with CFS, 46 received the transfer factor and 44 received a placebo. Twenty-five patients received specific transfer factor donated by a family member and 21 received transfer factor from an unrelated donor (a healthy control). Follow-up three months later showed no difference in quality of life, immunological assessment, or activity levels. It was concluded that neither specific nor nonspecific transfer factor were of benefit. It is important to note that the treatment consisted of only eight injections, given over the course of a month. It is possible that the short duration of treatment affected the outcome.

At the 2003 AACFS Conference held in Chantilly, Virginia, Dr. Brewer presented the results of a study in which 28 CFS patients were given a transfer factor (TF) preparation derived from bovine colostrum that has activity against HHV-6. Ten CFS patients (controls) received a similar TF preparation derived from bovine colostrum, except that it was devoid of any specific activity for HHV-6. Following the administration of the HHV-6 transfer factor preparation, improvements were noted in symptom scores in 68% and NK function in 75% of patients studied, as compared to 0% for both symptom score and NK function in the control group taking the TF preparation without HHV-6.

PROTOCOL. Transfer factor may be given in oral or injectable form. It may take at least six months before improvement is noted.

PROS AND CONS. Because transfer factor has not been widely tested as a treatment for CFS/ME, it is difficult to assess its efficacy. It is worth noting that when transfer factor is effective, the results are global, with significant improvement of symptoms.

In his book, The Type I/Type 2 Allergy Relief Program, Dr. Alan Levin wrote of his extensive experience with transfer factor. After using it to treat severe allergic conditions in more than 300 patients, he reported a 68% success rate, with miraculous results in some patients. However, he pointed out some serious side effects, including heart or muscle malfunction, temporary or permanent brain damage, and aggravated vasculitis, and recommended that transfer factor should probably be used only in patients with incapacitating symptoms.

Other physicians have not shared Dr. Levin's success rate and a number of CFS/ME patients have reported not only lack of improvement but even a worsening of allergic-type symptoms, even after lengthy treatments with transfer factor. In fact, treatment surveys conducted by De Paul University and independent researchers have shown that about a third of those who try transfer factor consider it "harmful." Side effects of treatment may vary. Dr. Pizza notes that fatigue, sore throat, fever, and headache may occur within the first few days of treatment, but these resolve quickly. These side effects might be the result of immune system activation in response to transfer factor.

Few CFS/ME doctors currently use transfer factor, so it is difficult to assess its usefulness as a treatment. Dr. Cheney has used transfer factor, but to our knowledge, there are no other CFS/ME protocols that include transfer factor.

AVAILABILITY AND COST. Oral transfer factor is available through a number of online sources. ProHealth sells Transfer Factor Essentials for $40 a bottle. Chisolm Biological Laboratory's ImmunFactor formulations cost $140 for a bottle of 30 gel caps.

FURTHER READING

Sloan Kettering's excellent review of transfer factor: http://www.mskcc.org/cancer-care/herb/transfer-factor

Patient thread discussing transfer factor: http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=1374195

MORE INFORMATION

Ordering information for transfer factor multi-immune: http://www.forresthealth.com/_search.php?page=1&q=transfer+factor&x=0&y=0

Ordering information for Chisolm Labs transfer factor: http://www.forresthealth.com/chisolm-biological-laboratories/

RESEARCH

Brewer, Joseph. “Administration of Transfer Factor for Human Herpesvirus 6 (HHV-6) in Patients with Chronic Fatigue Syndrome and HHV-6 Viremia.” HHV6 News. http://hhv6.blogspot.com/2005/07/joseph-brewer-on-hhv-6-transfer-factor.html

De Vinci, C, Levine, PH, Pizza, G, Fudenberg, HH, Orens, P, Pearson, G, Viza, D. “Lessons from a pilot study of transfer factor in chronic fatigue syndrome.” Biotherapy. 1996;9(1-3):87-90. http://www.ncbi.nlm.nih.gov/pubmed/8993764 (Abstract)

CHAPTER 5: NUTRITIONAL SUPPLEMENTS AND BOTANICALS

INTRODUCTION

This section encompasses nutritional supplements, botanicals (herbs), and compounds that are naturally found in the body. Although some of these are also classed as pharmaceuticals, nearly everything in this section can be purchased without a prescription. (The exception is injectables.) We have not included each and every supplement that is available on the market, but have limited our selection to those for which there is relevant medical research, or which are in common use either by CFS/ME clinicians or by CFS/ME patients themselves.

Nutritional supplements are an essential component of any CFS/ME treatment protocol. Research has shown that people with CFS/ME are routinely deficient in many important nutrients (notably zinc, magnesium, and carnitine). These deficiencies, in and of themselves, can decrease the degree to which the body can absorb and make use of other nutrients. Even when there are no clinical nutritional deficiencies, the physiological demands of a chronic illness make it necessary to provide additional nutritional support – especially in light of the numerous GI problems prevalent in the CFS/ME population, which may lead to malabsorption. For these reasons, and because most CFS/ME doctors recommend supplements, this section attempts to be as inclusive as possible.

There is a method to taking nutritional supplements. As with pharmaceuticals, supplements should initially be taken in very small doses to test for sensitivity. Even if a supplement consists of something “natural” there is nothing natural about taking it in concentrated doses. Your body reacts to these as it would to any chemical. For that reason, it is wise to take supplements with food, unless instructed otherwise.

“Take with food” means eat a little first, then take the supplement, then eat some more. By sandwiching the supplement within a meal, you lower the risk of reactions, as the supplement is processed along with food. Sandwiching supplements also reduces the risk of heartburn. When a supplement is taken with water only it floats to the top of the stomach, where it can easily flow back into the esophagus, causing irritation.

New supplements should be taken one at a time. That is, don't start several supplements at once, even if they act synergistically. Take the new supplement for three or four days before introducing another. This allows you to evaluate the supplements for possible negative reactions or sensitivities.

Supplements can be quite expensive and are not usually covered by health insurance. But purchasing the cheapest brand is not always the wisest course to take. There is a wide range in quality when it comes to nutritional supplements. Some of the cheapest brands may not even contain the ingredients on the label. It is best to stick to well-known brands and to purchase from reputable suppliers. (See Appendix D: Mail Order Suppliers.) Purchasing online, rather than from retail outlets can cut the cost of expensive supplements in half. Whenever possible, we have included recommendations in each entry.

Most online suppliers include product label information on their websites, but for those who wish to compare the product labels of a supplement made by different manufacturers, or check into recalls or FDA notices for specific supplements, there are several helpful websites that will provide this information:

 The Dietary Supplements Labels Database. This is a very useful website that allows searches for product labels by manufacturer and by product. From the website: “The Dietary Supplements Labels Database offers information about label ingredients in more than 6,000 selected brands of dietary supplements. It enables users to compare label ingredients in different brands. Information is also provided on the "structure/function" claims made by manufacturers.” http://dietarysupplements.nlm.nih.gov/dietary/index.jsp

 Natural Products Foundation. The NPF keeps an excellent database of supplements, as well as the medical conditions they are used for. From the website: “The Dietary Supplement Information Bureau™ (DSIB™) was founded in 2001 to promote the responsible use of vitamins, minerals, herbs and specialty supplements. In June 2008 DSIB became part of the Natural Products Foundation, a not-for-profit organization whose mission is to promote and facilitate research and education related to natural products for the benefit of consumers and industry.” http://www.naturalproductsinfo.org/

 Consumer Healthcare Products Association. The CHPA website provides a search for government warnings and decisions regarding most OTC medications and supplements. From the website: “The Consumer Healthcare Products Association (CHPA), founded in 1881, is a member-based association representing the leading manufacturers and distributors of nonprescription, over-the-counter (OTC) medicines and dietary supplements.” http://www.chpa-info.org/

FURTHER READING

Dowson, David, MD. “Nutrition Toxicity and ME/CFS.” http://www.annhilltrust.org/nutrition-toxicity-and-me.html

5-HTP

DESCRIPTION. 5-Hydroxytryphophan (5-HTP) is a naturally occurring amino acid which serves as a precursor to the neurotransmitter serotonin.

BACKGROUND. 5-HTP is a precursor as well as a metabolic intermediate in the synthesis of serotonin and melatonin from tryptophan. Through the action of vitamin B6, 5-HTP is converted in the liver and nervous system to 5-HP (serotonin). Most commercially marketed 5-HTP is derived from the seeds of the Griffonia simplicifolia. a woody climbing shrub native to West Africa.

Serotonin is the most abundant neurotransmitter in the human body. In the brain it plays a crucial role in sleep, mood, learning, memory and appetite. However, the vast majority of serotonin, 90%, is produced in the lining of the intestines, which has led Dr. Michael Gershon, chairman of the department of anatomy and cell biology at Columbia University, to refer to the gut as the “second brain.” This eponym is apt, for today gastroenterologists routinely prescribe serotonin enhancers for treating GI motility problems.

USES IN CFS/ME. Several studies have shown that 5-HTP is an effective overall treatment for fibromyalgia. For people with CFS/ME, 5-HTP is most often used as a sleep aid.

PROTOCOL. Dr. Rodger Murphree, a chiropractor and nutritionist who has been treating CFS/ME for over 15 years, recommends taking 5-HTP 30 minutes before bed, on an empty stomach, with four ounces of juice. Start with 100 mg, then go to 150 and then to 200. Don’t go above 300 mg. It may take several nights to take effect. If it doesn’t work in two weeks, Dr. Murphree suggests stopping and switching to melatonin. According to Dr. Murphree, patients who stay on 5-HTP for more than three months should take a broad-based amino acid supplement to balance out the other neurotransmitters.

PROS AND CONS. 5-HTP, like many antidepressants, can cause strange, vivid dreams. These dreams usually diminish over time. Excessively high serotonin levels can cause insomnia, hyperactivity, headache, and increased heart rate. CFS/ME patients who have a negative reaction to 5-HTP should either lower the dose or stop.

AVAILABILITY AND COST. 5 HTP is sold in most health food stores and by online distributors. A bottle of 60 tablets can cost as little as $8.00.

CAUTION: High doses of 5-HTP can cause serotonin syndrome, a condition in which serotonin is raised to dangerous levels. Taking 5-HTP with serotonin-enhancing pharmaceuticals such as triptans (for migraines), antidepressants, Demerol, Robitussin, and Ultram can also lead to serotonin syndrome.

FURTHER READING

Good summary of 5-HTP as a CFS/ME treatment: http://www.immunesupport.com/98wtr002.htm

Discussion of 5-HTP as a CFS/ME treatment: http://aboutmecfs.org.violet.arvixe.com/Trt/5-HTP.aspx

Dr. Teitelbaum on 5-HTP and other natural sleep aids: http://www.healthy.net/scr/Column.aspx?Id=647

General information on 5-HTP: http://www.herbwisdom.com/herb-5-htp.html

PATIENT REVIEWS

CFS/ME patient reviews of 5-HTP: http://www.revolutionhealth.com/drugs-treatments/rating/5-htp-5-hydroxytryptophan-for-chronic-fatigue-syndrome-cfs-cfids-me

RESEARCH

Caruso I, Sarzi Puttini P, Cazzola M, Azzolini V. “Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome.” J Int Med Res. 1990 May-Jun;18(3):201-9. http://www.ncbi.nlm.nih.gov/pubmed/2193835 (Abstract)

Sarzi Puttini P, Caruso I, “Primary fibromyalgia syndrome and 5-hydroxy-L-tryptophan: a 90-day open study.” J Int Med Res.1992 Apr;20(2):182-9. http://www.ncbi.nlm.nih.gov/pubmed/1521674 (Abstract)

ALPHA KETOGLUTARATE

DESCRIPTION. Alpha ketoglutarate (AKG) is an ionic form of alpha ketoglutarate acid, an intermediate in the tricarboxylic cycle (Krebs cycle, or citric acid cycle).

BACKGROUND. Alpha ketoglutarate (AKG) fulfills a vital role in the metabolism and utilization of carbohydrates, proteins, and long-chain fatty acids. Its best known function is as a component of a number of energy-producing cycles at the cellular level. The first of these, the Krebs cycle, breaks down and transforms citric acid through a series of enzyme-controlled reactions to produce adenosine triphosphate (ATP), a crucial energy source for many cell processes. AKG, as an early intermediate in the Krebs cycle, forms the basis for all further transformations. It is also required for catabolism of many amino acids, another process that generates energy.

Another important function of AKG involves the formation of nonessential amino acids (amino acids that are biosynthesized in the body), notably glutamate and, through its action, proline, alanine, aspartic acid, and asparagine. AKG is also one of the most important transporters of cellular nitrogen, combining with nitrogen in the cell to prevent an overload of ammonia in the body.

USES IN CFS/ME. AKG is used as a short-term energy enhancer and for Krebs cycle support in patients with CFS/ME. Because of its essential role in energy production and carbohydrate metabolism, it may be useful as a general CFS/ME treatment as well. AKG is also beneficial for the intestines. Many people with CFS/ME suffer from digestive problems, including food sensitivities, dysbiosis, slow transit time, small intestine bacterial overgrowth (SIBO) and a host of other disorders. AKG is converted in the intestines into glutamate, which regulates gastric emptying and provides an environment for healthy gut flora. AKG also prevents damage to the mucosal lining of the intestines by inhibiting oxidative stress.

PROTOCOL. The suggested dosage of AKG is one or two 300 mg capsules per day, which can be taken with meals. Because of its location in the Krebs cycle, alpha ketoglutarate is generally more effective if taken with other Krebs cycle supports such as vitamin C, B vitamins, essential fatty acids (evening primrose oil, borage oil, or fish oil), magnesium, nutritional supplements, and NAC (N-acetyl-L-cysteine).

PROS. Because alpha ketoglutarate is not a stimulant but works through natural metabolic pathways, it is a relatively risk-free source of energy. People who take alpha ketoglutarate usually do not "crash" afterward. It has no reported side effects at recommended doses. Patients with low levels of AKG (as confirmed by an Organic Acids Test) have noted significant improvement in energy levels with alpha ketoglutarate supplementation.

CONS. Results tend to be less dramatic than those obtained with CoQ10, which may make this product less attractive to those who want a greater boost. Among its many function, AKG leads to production of nitric oxide (NO), which Dr. Pall has implicated in many CFS/ME symptoms. He has recommended that NO should be down regulated in people with CFS/ME. Because AKG is normally combined with excitatory amino acids, it can cause insomnia.

AVAILABILITY AND COST. Pure AKG is difficult to find. Most suppliers combine AKG with an amino acid, such as arginine or glutamine. Douglas Labs sells a 90-tablet bottle of AKG (300 mg) combined with vitamin B6, calcium and phosphorus for $18.

FURTHER READING

Benefits of AKG and its functions in the Krebs cycle: http://www.ei-resource.org/articles/general-environmental-health-articles/influencing-your-krebs-cycle/

A detailed description of Krebs cycle intermediaries, including AKG. Very technical. http://www.nutritionreview.org/library/krebs.php

RESEARCH

Hou Y, Wang L, Ding B, Liu Y, Zhu H, Liu J, Li Y, Kang P, Yin Y, Wu G. “Alpha-Ketoglutarate and intestinal function.” Front Biosci. 2011 Jan 1;16:1186-96. http://www.ncbi.nlm.nih.gov/pubmed/21196226 (Abstract)

ALPHA LIPOIC ACID

DESCRIPTION. Alpha lipoic acid, or lipoic acid, is a an organic compound derived from caprylic acid. It is both fat and water soluble.

BACKGROUND. Alpha lipoic acid (ALA) has been referred to as the “mother” of all antioxidants. This well-deserved epithet is due to the fact that not only does it act as a potent free radical scavenger, it can transform an oxidant into an antioxidant. Notably, when glutathione is oxidized, ALA can transform it back into its reduced form, thus increasing the pool of glutathione.

ALA is produced throughout the body through the biosynthesis of fatty acids. Although it is found in many foods (especially organ meats, yeast extract and leafy green vegetables), alpha lipoic acid is not readily available through dietary sources. As a consequence, all alpha lipoic acid supplements must be synthesized.

Alpha lipoic acid has been studied for its effects on many disease states, including treatment for cardiovascular disease, prevention of migraines, preventing organ dysfunction, slowing the progression of Alzheimer's disease, reducing inflammation, and the treatment of chronic diseases involving oxidative stress. A study conducted in 1999 by Kishi et al found that the reduced glucose uptake in diabetes was completely reversed with alpha lipoic acid, which not only corrected the deficit, but improved the peripheral neuropathy found in diabetics.

A detailed proposal submitted to the National Cancer Institute by the Chemical Selection Working Group (see below) indicates that ALA may work best when combined with acetyl L-carnitine. Acetyl-L-carnitine facilitates the movement of fatty acids into the mitochondria for energy and is also used to generate acetyl coenzyme A, while ALA is involved in mitochondrial ATP production and can recycle other antioxidants. The authors propose that the combination of acetyl L-carnitine and ALA may have significant synergistic effects – increasing energy and reducing oxidative stress.

USES IN CFS/ME. A number of CFS/ME clinicians and researchers, notably Martin Pall and Dr. Myhill, have pointed out that oxidative stress is a primary component in the cascade of CFS/ME symptoms. Oxidative stress can affect every system in the body, and has particularly deleterious effects on oxygen transport systems (blood). ALA has been shown to improve the integrity of red blood cells (which are often abnormal in CFS/ME patients) leading to elevated glutathione levels. Glutathione, one of the body's most potent antioxidants, is often diminished in CFS/ME patients.

PROTOCOL. The “R” form is the most bioavailable and stable form of alpha lipoic acid. (The “S” form deteriorates rapidly.) There is no set protocol for ALA. CFS/ME patients who have tried ALA recommend beginning at the lowest dose (100 mg) to avoid detox symptoms (headache, “hungover” feeling).

PROS. ALA has no documented side effects at low doses. Many people have noted an increase in energy, muscle strength, and mental alertness, particularly when taken with acetyl-L carnitine.

CONS. Too high a dose can cause insomnia and stomach upset. ALA lowers blood sugar, which may pose a problem for people with hypoglycemia. There is one study that suggests that ALA competes with biotin (vitamin B7) in rats, but the results have not been confirmed in humans. Those who take large quantities of lipoic acid may wish to independently supplement with biotin.

AVAILABILITY AND COST. ALA is widely available in health food stores and through online distributors. It is not expensive. A 60-capsule bottle of R-ALA (100 mg) can cost less than $10.

FURTHER READING

This article questions the necessity of supplementing lipoic acid with biotin. http://www.geronova.com/content/lipoic-acid-biotin

RESEARCH

Kishi, Yutaka, James D. Schmelzer, Jeffrey K. Yao, Paula J. Zollman, Kim K. Nickander, Hans J. Tritschler, and Phillip A. Low. “ a-Lipoic Acid: Effect on Glucose Uptake, Sorbitol P a t h w a y, and Energy Metabolism in Experimental Diabetic Neuropathy.” Diabetes, VOL. 48, October 1999 http://diabetes.diabetesjournals.org/content/48/10/2045.full.pdf

Mirjana M, Jelena A, Aleksandra U, Svetlana D, Nevena G, Jelena M, Goran P, Melita V. “Alpha-lipoic acid preserves the structural and functional integrity of

red blood cells by adjusting the redox disturbance and decreasing O-GlcNAc modifications of antioxidant enzymes and heat shock proteins in diabetic rats.” Eur J Nutr. 2011 Nov 18. http://www.ncbi.nlm.nih.gov/pubmed/22094580 (Abstract)

“Acetyl-L-Carnitine/a-Lipoic Acid Supplements.” This is a proposal prepared for the National Cancer Institute by the Chemical Selection Working Group (CSWG) on behalf of Technical Resources International, Inc. It contains a thorough and exhaustive account of the mechanisms of alpha lipoic acid. http://ntp.niehs.nih.gov/ntp/htdocs/chem_background/exsumpdf/carnliposupp.pdf

AMINO ACIDS

Carnitine, Glutamine, Lysine, Taurine

DESCRIPTION. Amino acids are nitrogen-containing chemical units (amines) that, bound together, make up protein.

BACKGROUND. The amino acids, in various combinations, form the hundreds of types of proteins present in every living organism. These proteins are essential for nearly all processes that induce cell growth and repair, as well as for continued maintenance of every body tissue, organ, and structure within the body. Amino acids link together to form tens of thousands of proteins and enzymes, each of which has a specific function. They can also perform as individual units. Single amino acids can act as neurotransmitters or as precursors to neurotransmitters in the central nervous system. Therefore, not only are they responsible for providing and maintaining the very substances of which we are made, but also for the communications system that enables us to plan, dream, think, feel, and direct our every action.

There are 20 primary amino acids. About 80% are produced in the liver and the remaining 20% must be obtained from food. Whether an amino acid can be produced within the body is what distinguishes the essential from nonessential amino acids. The essential amino acids (those which must be obtained from food sources) are arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Nonessential amino acids (those which can be produced within the body) include alanine, glutamine, asparagine, glycine, proline, and serine. Given the countless functions that amino acids perform, a protein shortage or congenital defect in amino acid synthesis can lead to problems that involve every system in the body.

Amino acids occur in two isomers: L and D. The L isomer is the form most commonly found in nutritional supplements.

USES IN CFS/ME. Specific amino acids, both essential and nonessential, have been recommended as treatments by a number of CFS/ME clinicians. Their applications include mediation of hyperactive nervous system responses, repair of leaky gut and other intestinal disturbances, and regulation of the fundamental CFS/ME metabolic dysfunction that results in loss of cellular energy.

A number of researchers have documented imbalances in amino acid ratios among people with CFS/ME. In an article published in 1994, Dr. Alexander Bralley and Dr. Richard Lord noted that people with CFS/ME commonly have deficiencies in tryptophan, phenylalanine, taurine, isoleucine, and leucine. They also found lower than normal amounts of arginine, methionine, lysine, threonine, and valine in a smaller number of CFS/ME patients. It is significant that the most common deficiencies found by Drs. Bralley and Lord are of phenylalanine and tryptophan because these two amino acids are precursors to the catecholamines and serotonin, neurotransmitters that are closely involved with sleep function, stress responses, and regulation of pain and mood.

Dr. Scott Rigden has also noted that many of his patients with metabolic abnormalities have an imbalance in amino acid ratios. The implication is that, for these patients, amino acids may be either synthesized or utilized at a slower rate or appear in such disequilibrium that they no longer function together with full efficiency – perhaps giving a clue to the origins of the collagen formation problems and enzyme disturbances common in many patients with CFS/ME.

An extensive study published in 2005 by Jones et al compared organic acids in people with CFS/ME, major depression, and rheumatoid arthritis. The researchers found lower levels of taurine, GABA, histidine and tyrosine in the group with CFS/ME. The researchers also found low levels of histidine in plasma from rheumatoid arthritis patients, leading the team to speculate that a similar etiology might be involved for the two illnesses (i.e. inflammation).

A more recent study by Niblett et al confirms specific deficiencies in CFS/ME patients of asparagine, phenylalanine, leucine, isoleucine, valine, and the organic acid, succinic acid, as well as increases in 3-methylhistidine (an amino acid associated with protein loss) and tyrosine. The authors concluded that “urinary excretion and blood parameters data supported the hypothesis that alterations in physiologic homeostasis exist in CFS patients.”

In 2012 a team of Australian researchers identified low levels of glutamine and ornithine, along with other metabolites that participate in the urea cycle, in a group of CFS/ME patients. (CFS/ME patients are consistently low in uric acid.) The researchers suggested that a specific disturbance of amino acid and nitrogen metabolism was implicated in CFS/ME which might potentially serve as a biomarker.

Amino acid supplementation has received particular attention as a treatment for CFS/ME from nutritionists. Using an amino acid analyzer to measure specific imbalances, Drs. Bralley and Lord tailored a supplement to correct amino acid deficiencies. In a study of 25 CFS/ME patients, they found that correcting specific amino acid imbalances resulted in 50% to 100% improvement in symptoms (Journal of Applied Nutrition, 1994). The greatest effect was noted in energy levels. Two patients who had had CFS/ME symptoms for 15 years experienced dramatic improvement. Patients also reported improvement in cognitive function and elimination of "brain fog."

It should be noted that single amino acids taken as dietary supplements may not be well tolerated by patients with serious metabolic disturbances. Also note that tyrosine, an amino acid often found to be deficient in CFS/ME patients, is seldom recommended. Tyrosine is a dopamine precursor which triggers symptoms in patients with inflammatory disorders such as migraine, interstitial cystitis, and rosacea. Dr. Bell has observed that in CFS/ME patients, dopamine precursors make the majority of CFS/ME patients feel much worse.

FURTHER READING

Bralley J., Alexander and Richard S. Lord. “Treatment of Chronic Fatigue Syndrome with Specific Amino Acid Supplementation.” Journal of Applied Nutrition, Vol 46, No 3, 1994. http://www.metametrix.com/files/learning-center/articles/Chronic-Fatigue-Amino-Acids.pdf

Dr. Michael Rosenberg's amino acid protocols for treating CFS/ME. http://www.prohealth.com/library/showarticle.cfm?id=4337&t=CFS/ME_FM

RESEARCH

Armstrong, Christopher W., Neil R. McGregor, John R. Sheedy, Ian Buttfield, Henry L. Butt, Paul R. Gooley. “NMR metabolic profiling of serum identifies amino acid disturbances in Chronic Fatigue Syndrome.” Clinica Chimica Acta. Available online 21 June 2012. http://www.sciencedirect.com/science/article/pii/S0009898112003270

Jones, Mark G., Elizabeth Cooper, Saira Amjad, Stewart C. Goodwin, Jeffrey L. Barron, Ronald A. Chalmers. “Urinary and plasma organic acids and amino acids in chronic fatigue syndrome.” Clin Chim Acta. 2005 Nov;361(1-2):150-8. http://www.cfids-cab.org/cfs-inform/Hypotheses/jones.etal.05.pdf

Niblett SH, King KE, Dunstan RH, Clifton-Bligh P, Hoskin LA, Roberts TK, Fulcher GR, McGregor NR, Dunsmore JC, Butt HL, Klineberg I, Rothkirch TB. “Hematologic and urinary excretion anomalies in patients with chronic fatigue syndrome.” Exp Biol Med (Maywood). 2007 Sep;232(8):1041-9. http://www.ncbi.nlm.nih.gov/pubmed/17720950 (Abstract)

CARNITINE

DESCRIPTION. Carnitine (L-carnitine) is one of the methyl group donors. It is crucial for the transport of long-chain fatty acids into the mitochondria of cells, providing energy to skeletal and heart muscle. Carnitine also aids in reducing toxic buildup of organic acids which are a natural byproduct of cell metabolism. Carnitine deficiency produces fatigue, muscle weakness, malaise, exercise intolerance, heartbeat abnormalities, and tissue acidosis. Carnitine deficiency can result from congenital metabolic defects as well as the administration of antibiotics containing pivalic acid (e.g., Pondocillin).

USES IN CFS/ME. Japanese researchers have shown that CFS/ME patients have a deficiency in intracellular levels of acylcarnitine. They found no deficiency in serum levels of free carnitine, however, indicating the deficiency is not the result of lack of carnitine in the system but of its derivative, acylcarnitine. Acylcarnitine deficiency can be expected to produce not only the fatigue and weakness characteristic of interruption in mitochondrial processes but also the malaise typical of autointoxication. Dr. Hiroko Kuratsune and colleagues discovered that in their sample group of 38 CFS/ME patients, low levels of acylcarnitine covaried with the severity of the illness (Clinical Infectious Diseases, 1994). As symptoms improved, so did acylcarnitine levels. In a study comparing amantadine and carnitine, Dr. Audrius Plioplys and Dr. Sigita Plioplys found "statistically significant clinical improvement" after eight weeks of treatment with L-carnitine (Neuropsychobiology, 1997).

A subsequent study in 2004 by Okada et al, found secondary proof for acetyl-carnitine deficiency in CFS/ME patients. Using MRI imaging, they found that there was a reduction in gray matter in the prefrontal cortex of CFS/ME patients as compared to controls. The researchers concluded that their results were “consistent with previous reports of an abnormal distribution of acetyl-L-carnitine uptake, which is one of the biochemical markers of chronic fatigue syndrome, in the prefrontal cortex. Thus, the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue.”

In a recent study conducted in 2011, researchers from the University of South Australia compared L-carnitine levels of 44 CFS/ME patients to 49 controls. They found that levels of acylcarnitine was 30-40% lower in CFS/ME patients. The authors hypothesized that the administration of omega-3 fatty acids in combination with L-carnitine would improve chronic fatigue syndrome symptomology.

PROTOCOL. Carnitine can be taken in liquid or pill form as an over-the-counter nutritional supplement. As a food supplement, the general recommended dosage is 1000 mg/day taken with a meal. The liquid is often better tolerated than the pill form although patients with chemical sensitivities should note that the liquid may also contain artificial flavors, colors, preservatives (methylparaben), and sucrose.

Dr. Teitelbaum has observed that in his experience acetyl-L-carnitine is much more effective that L-carnitine. This is due to the fact that acetyl-L-carnitine crosses the blood-brain barrier, as opposed to L-carnitine, which is too rapidly excreted by the kidneys to be adequately utilized by the brain. Dr. Teitelbaum recommends taking 500 mg of pure acetyl-L-carnitine 2-3 times a day. In low doses, acetyl-L-carnitine can mimic the effects of pyridostigmine and galantamine, increasing the availability of acetylcholine in both the peripheral and central nervous systems.

Because carnitine interferes with thyroid hormone production, thyroid levels (free T3 and T4, as well as TSH) should be taken before beginning supplementation. Even if thyroid hormone levels fall within the normal range, carnitine should not be taken for more than a month. Signs of thyroid suppression are dry skin, low energy level, weight gain, excessive sleep, and hormonal disturbances.

PROS. L-Carnitine as a food supplement is widely available. Patients have reported increased muscle function, decreased weakness, and overall improved stamina and well-being after a few weeks of carnitine supplementation. In some cases, the benefits remain even after finishing the course of treatment.

CONS. Carnitine is not recommended for patients with low thyroid function, as it interferes with thyroid hormones. Excess amounts of carnitine can cause diarrhea and stomach upset, so start with low doses.

AVAILABILITY AND COST. A 12 oz bottle of the liquid nutritional supplement Mega L -Carnitine (Twin Labs) can be purchased online at Vitacost for $10. At the recommended dosage of 1 tablespoon a day, the bottle will last for 1 month. A 30-capsule bottle of acetyl-L-carnitine costs around $18. (There are many brands. Check Vitacost for a cost comparison.)

FURTHER READING

Dr. Teitelbaum's carnitine protocol: http://www.endfatigue.com/health_articles_c/CFS_FM-acetyl-l-carnitine_for_cfs.html

RESEARCH

Benvenga S, Amato A, Calvani M, Trimarchi F. “Effects of carnitine on thyroid hormone action.” Ann NY Acad Sci. 2004 Nov;1033:158-67. http://www.ncbi.nlm.nih.gov/pubmed/15591013 (Abstract)

Colucci S, Mori G, Vaira S, Brunetti G, Greco G, Mancini L, Simone GM, Sardelli F, Koverech A, Zallone A, Grano M. “L-carnitine and isovaleryl L-carnitine fumarate positively affect human osteoblast proliferation and differentiation in vitro.” Calcif Tissue Int. 2005 Jun;76(6):458-65. http://www.ncbi.nlm.nih.gov/pubmed/15906015 (Abstract)

Eder K, Felgner J, Becker K, Kluge H. “Free and total carnitine concentrations in pig plasma after oral ingestion of various L-carnitine compounds.” Int J Vitam Nutr Res. 2005 Jan;75(1):3-9. http://www.ncbi.nlm.nih.gov/pubmed/15830915 (Abstract)

Ho JY, Kraemer WJ, Volek JS, Fragala MS, Thomas GA, Dunn-Lewis C, Coday M. Häkkinen K, Maresh CM. “L-Carnitine l-tartrate supplementation favorably affects biochemical markers of recovery from physical exertion in middle-aged men and women.” Metabolism. 2010 Aug;59(8):1190-9. http://www.ncbi.nlm.nih.gov/pubmed/20045157 (Abstract)

Holme, Elisabeth, Carl-Eric Jacobson, Ingalill Nordin, Joachim Greter, Sven Lindstedt, Bengt Kristiansson, Ulf Jodal. “Carnitine Deficiency Induced by Pivampicilin and Pivmecillinam Therapy.” The Lancet. Volume 334, Issue 8661, Pages 469 - 473, 26 August 1989. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(89)92086-2/abstract (Abstract)

Kuratsune H, Yamaguti K, Takahashi M, Misaki H, Tagawa S, Kitani T. “Acylcarnitine deficiency in chronic fatigue syndrome.” Clin Infect Dis. 1994 Jan;18 Suppl 1:S62-7. http://www.ncbi.nlm.nih.gov/pubmed/8148455 (Abstract)

Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N. “Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome.” BMC Neurol. 2004 Oct 4;4(1):14. http://www.ncbi.nlm.nih.gov/pubmed/15461817 (Abstract)

Patano N, Mancini L, Settanni MP, Strippoli M, Brunetti G, Greco G, Tamma R, Vergari R, Sardelli F, Koverech A, Colucci S, Zallone A, Grano M. “L-carnitine fumarate and isovaleryl-L: -carnitine fumarate accelerate the recovery of bone volume/total volume ratio after experimentally induced osteoporosis in pregnant mice.” Calcif Tissue Int. 2008 Mar;82(3):221-8. http://www.ncbi.nlm.nih.gov/pubmed/18265928 (Abstract)

Plioplys AV, Plioplys S. “Amantadine and L-carnitine treatment of Chronic Fatigue Syndrome.” Neuropsychobiology. 1997;35(1):16-23. http://www.ncbi.nlm.nih.gov/pubmed/9018019 (Abstract)

Reuter SE, Evans AM. “Long-chain acylcarnitine deficiency in patients with chronic fatigue syndrome. Potential involvement of altered carnitinepalmitoyltransferase-I activity.” J Intern Med. 2011 Jul;270(1):76-84. http://www.ncbi.nlm.nih.gov/pubmed/21205027 (Abstract)

Spiering BA, Kraemer WJ, Vingren JL, Hatfield DL, Fragala MS, Ho JY, Maresh CM, Anderson JM, Volek JS. “Responses of criterion variables to different supplemental doses of L-carnitine L-tartrate.” Journal of Strength and Conditioning Research. 2007 Feb;21(1):259-64. http://www.ncbi.nlm.nih.gov/pubmed/17313301 (Abstract)

Vermeulen RC, Scholte HR. “Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome.” Psychosom Med. 2004 Mar-Apr;66(2):276-82. http://www.ncbi.nlm.nih.gov/pubmed/15039515 (Abstract)

GLUTAMINE

DESCRIPTION. Glutamine is the most abundant nonessential amino acid in the body. It is a precursor to glutathione.

BACKGROUND. Glutamine plays an important role in many biological functions, including protein synthesis, providing cellular energy, and as a non-toxic transporter of ammonia in the bloodstream. When converted to glutamic acid, it acts as an excitatory neurotransmitter in the brain.

In the intestinal tract, glutamine strengthens the gut's function as an immune barrier by supporting the production of secretory immunoglobulin A (sIgA), which helps maintain the structure, metabolism, and function of the mucosal lining of the intestines. Glutamine can help heal injured gut mucosa after surgery and, in a high percentage (92%) of patients, completely heals ulcer damage. Glutamine is an important detoxifying agent for ammonia, a neurotoxin and one of the toxic by-products of protein metabolism. It is used to treat sugar craving, fatigue, ADHD, peptic ulcers, and personality disorders. Dietary sources of glutamine include beef, chicken, fish, eggs, milk, dairy products, wheat, cabbage, beets, beans, and spinach.

USES IN CFS/ME. Because it is so important in gastrointestinal growth and function, glutamine is primarily used to treat leaky gut. Clinicians recommend taking 1000 mg of glutamine daily on an empty stomach, divided into equal doses (Patients with many sensitivities may want to test a very small amount of this amino acid before taking the full dose.)

PROS. A number of CFS/ME patients have noted improvement in gut function and increased food tolerance with this treatment as well as a decrease in “brain fog.” Side effects from this amino acid are relatively rare (but see below).

CONS. L-glutamine can cause gastrointestinal symptoms such as nausea and diarrhea. In patients with small intestinal bacterial overgrowth (SIBO) glutamine may actually worsen symptoms. Because glutamine is an excitatory neurotransmitter it may cause insomnia in individuals who do not tolerate stimulants. People who are sensitive to MSG should not take glutamine.

AVAILABILITY AND COST. Glutamine is available at health food stores and online in both powder and pill form. It is inexpensive. A 100-tablet bottle can cost as little as $6. Glutamine is also available from some compounding pharmacies as enteric coated tablets which are formulated to bypass the stomach and increase bioavailability.

RESEARCH

Blachier, François, Claire Boutry, Cécile Bos, Daniel Tomé. “Metabolism and functions of L-glutamate in the epithelial cells of the small and large intestines.” Am J Clin Nutr September 2009 vol. 90 no. 3 814S-821S. http://www.ajcn.org/content/90/3/814S.abstract

LYSINE

DESCRIPTION. Lysine is an essential amino acid. (It cannot be synthesized in the body.)

BACKGROUND. Lysine is needed for bone growth in children and to maintain nitrogen balance in adults. It also aids in the production of antibodies, hormones, and enzymes as well as helping in collagen formation, muscle building, and tissue repair. Lysine deficiency can result in hair loss, anemia, bloodshot eyes, loss of energy, and irritability. Food sources of lysine include meat, eggs, legumes and milk.

USES IN CFS/ME. Lysine is recommended chiefly because of its ability to inhibit reproduction of herpesviruses (herpes simplex virus, varicella zoster virus, human herpesvirus 6, and Epstein-Barr virus), which require arginine in order to reproduce. Lysine's structure is similar enough to arginine, however, that herpesviruses can be fooled into using lysine instead. Since the virus cannot use lysine for replication, the virus loses its ability to reproduce, effectively halting the spread of the infection. Some CFS/ME doctors recommend lysine to treat frequent outbreaks of cold sores (herpes simplex) or shingles (herpes zoster).

PROTOCOL. Dr. Charles Lapp recommends 1000 to 2000 mg of lysine, taken daily with meals. Foods high in arginine, such as chocolate, nuts, raisins, whole wheat, cereal, and brown rice, should be avoided.

PROS. Lysine appears to be a safe, effective treatment for cold sores.

CONS. Side effects of lysine can include dizziness, sweating, nausea, appetite loss, and difficulty swallowing. Lysine should be discontinued if these symptoms develop.

AVAILABILITY AND COST. Lysine is available in most health food stores and can be purchased inexpensively. Most brands retail for less than $10 for a 100-capsule bottle (500 mg).

RESEARCH

Griffith RS, Walsh DE, Myrmel KH, Thompson RW, Behforooz A. “Success of L-lysine therapy in frequently recurrent herpes simplex infection. Treatment and prophylaxis.” Dermatologica 1987;175(4):183-90. http://www.ncbi.nlm.nih.gov/pubmed/3115841 (Abstract)

TAURINE

DESCRIPTION. Although taurine is usually classified as an amino acid, it is actually an organic acid, which is an organic compound with acidic properties but without a carboxyl group.

BACKGROUND. Taurine acts as a building block for all other amino acids and consequently is present in every cell in the body. It is a prime component of bile (thus aiding in fat digestion and vitamin absorption) and is found in high concentrations in heart muscle, skeletal muscle, white blood cells, and the central nervous system (CNS). Anxiety, hyperactivity, and poor brain function are related to taurine deficiency. Taurine can be synthesized in the body from cysteine, with the aid of vitamin B6.

Taurine is unusual in that it not only functions as a neurotransmitter, but as a potent antioxidant. When taurine interacts with the oxidant hypochlorous acid it forms taurine monochloramine, which inhibits the transcription iNOS gene as well as the expression of COX-2 protein, both of which are primary sources of inflammation. Taurine lowers NF-kappaB activity, which helps inhibit another important inflammatory pathway. It also acts to reduce intracellular calcium levels, thus lowering the production of nitric oxide. In its role as a neuromodulator, taurine stimulates the synthesis of GABA, the primary inhibitory neurotransmitter. It also stimulates glycine receptors, leading to a down regulation of excitatory NMDA receptors. (Glycine is also used in the biosynthesis of hemoglobin, which is very important in the maintenance of red blood cell integrity and oxygen transport.)

USES IN CFS/ME. Dr. Majid Ali, author of The Canary and Chronic Fatigue, makes extensive use of taurine as an antioxidant and has reported excellent results in treating fatigue and chronic constipation. Dr. Cheney has observed that taurine may also be of benefit in treating hyperactive nervous system responses. CFS/ME patients have been shown to have high amounts of glutamate in the brain, which increases neuroexcitatory responses. Because taurine slows CNS impulses, it may help relieve symptoms such as insomnia, anxiety, and restlessness, especially when taken in conjunction with magnesium. Taurine is transported easily across the blood-brain barrier, allowing taurine supplements to work in the brain.

PROTOCOL. Dr. Ali recommends a dosage of 250 mg/day, along with magnesium and potassium. Dr. Cheney recommends ½ cc of injectable magnesium (250 mg) accompanied by ½ cc injectable taurine.

PROS AND CONS. Taurine has very few side effects, however, excess doses can cause GI upset (yellow diarrhea, gas, pale stools).

AVAILABILITY AND COST. Taurine can be purchased in most health food and vitamin stores and costs less than $10 a bottle. Powdered forms can be purchased, for those who prefer to titrate dosage.

FURTHER READING

Very thorough discussion of the role of taurine: http://me-cfsmethylation.com/viewtopic.php?f=3&t=149

RESEARCH

El Idrissi A , Trenkner E. “Taurine as a modulator of excitatory and inhibitory neurotransmission.” Neurochem Res. 2004 Jan;29(1):189-97. http://www.ncbi.nlm.nih.gov/pubmed/14992278 (Abstract)

Liu, Y, Tonna-DeMasi, M, Park, E, Schuller-Levis, G, Quinn, MR. "Taurine chloramine inhibits production of nitric oxide and prostaglandin E2 in activated C6 glioma cells by suppressing inducible nitric oxide synthase and cyclooxygenase-2 expression. "Brain Res. Mol. Brain Res. 59,189-195. http://www.sciencedirect.com/science/article/pii/S0169328X98001454

Nakagawa K, Kuriyama K. “Effect of taurine on alteration in adrenal functions induced by stress.” Jap. J. Pharmacol. 1975 Dec;25(6):737-46. http://www.ncbi.nlm.nih.gov/pubmed/6814 (Abstract)

Park E, Jia J, Quinn MR, Schuller- Levis G. “Taurine chloramine inhibits lymphocyte proliferation and decreases cytokine production in activated human leukocytes.” Clin Immunol. 2002 Feb;102(2):179-84. http://www.ncbi.nlm.nih.gov/pubmed/11846460 (Abstract)

ANTIOXIDANTS

DESCRIPTION. Antioxidants are a group of vitamins, minerals, and enzymes that help protect cells from free radical damage.

BACKGROUND. Antioxidants have long been used as preservatives because of their ability to retard the oxidation that causes oils to become rancid. However, they have garnered increased attention over the past few years for their medical value. The same process that allows them to prevent oils from becoming rancid also protects the body from damage caused by free radicals. Free radicals are atoms or groups of atoms that have lost an electron. These molecules containing unpaired electrons are highly unstable and can easily pick up other elements, causing volatile reactions. When large numbers of free radicals are formed, whether from exposure to radiation, toxic chemicals or rancid oils, or because of prolonged illness and immune activation, significant damage can result. When dangerously high levels of free radicals are present, they can cause changes in protein structure. The body may identify the altered proteins as foreign elements and launch an immune system attack.

The body has its own defenses against excess free radical formation. The three most potent antioxidants produced in the body are superoxide dismutase (SOD), CoQ10, and glutathione peroxidase. However, the group of biochemicals known as antioxidants are also found abundantly in nature in the form of vitamins, minerals, and enzymes. Among the most widely used antioxidants are vitamins A, C, and E, alpha lipoic acid (ALA), gamma-linoleic acid (GLA), the amino acid cysteine, glutathione, taurine, the mineral selenium, CoQ10, and the bioflavonoids in pycnogenol, milk thistle, and gingko.

Antioxidants operate in concert to prevent free radical damage. A single antioxidant, once it has neutralized the free radical, can itself cause cell damage. The action of other antioxidants is necessary to return antioxidants to their reduced state, in which they can continue to scavenge free radicals. Therefore, antioxidants should be taken in combination rather than single forms. An article in the New England Journal of Medicine reports that heavy smokers in Finland who took very high doses of the antioxidant beta carotene had a higher rate of lung cancer than those taking a placebo (CFIDS Chronicle, Spring 1995). However, when beta carotene was combined with vitamin E, this was not the case.

Due to the potential of antioxidants to mitigate the more damaging effects of chronic illnesses (including cancer and diabetes) research on antioxidants is rapidly evolving. In 2004 Rezk et al proposed a new class of antioxidants based on the mechanism of vitamin E. In a study comparing the activities of different forms of vitamin E, the researchers discovered that vitamin E phosphate prevented the transfer of free radicals by forming a detergent barrier.

USES IN CFS/ME. Several studies have confirmed oxidative damage in CFS/ME patients. In 2000 a team of Italian researchers investigating the source of muscle pain found oxidative damage to DNA and lipids (fats) in the muscle tissue of CFS/ME patients. They also found significant differences in the composition of muscle membranes as compared to controls and patients with FM. The researchers concluded that their data “support an organic origin of CFS, in which muscle suffers oxidative damage.”

Patients with CFS/ME who experience depression also show evidence of free radical formation. In a 2001 study conducted by Maes et al, glutathione peroxidase levels were found to correlate with depressed mood and autonomic symptoms. The lower the glutathione levels, the greater the depression. The researchers recommended supplementation with glutathione, NAC and selenium.

Two studies conducted independently in 2000 and 2005 found that oxidative stress in CFS/ME patients could be measured through blood samples. In Australia, Richards et al measured methemoglobin in CFS/ME patients and controls.

Methemoglobin (pronounced “met-hemoglobin”) is an altered form of hemoglobin that does not bind well to oxygen, limiting the blood's ability to carry oxygen to tissues and organs. The formation of methemoglobin can be caused by various health problems and is a sign of oxidative stress. The study found that in CFS/ME patients, symptoms such as sleep disturbance, pain, and fatigue correlated with methemoglobin levels. They concluded that their data suggested that “oxidative stress due to excess free radical formation is a contributor to the pathology of CFS and was associated with symptom presentation.”

A second study by Kennedy et al. investigated free radical damage in CFS/ME symptoms using the “gold standard” of oxidative stress: isoprostanes. Isoprostanes are prostaglandin-like compounds which are formed after free radicals catalyze essential fatty acids. They have long been recognized as an accurate predictor of oxidative stress. Kennedy et al found that in CFS/ME patients, raised levels of isoprostanes correlated with post-exertional malaise. They postulated that in CFS/ME the excessive free radical formation could be due to persistent viral infection, to inflammation, or to metabolic abnormalities in mitochondria and lipids.

Antioxidants fall into many classes. The most commonly recommended antioxidants for CFS/ME patients are:

 Vitamins: A, C, E

 Vitamin co-factors: CoQ10

 Minerals: Manganese, selenium, zinc

 Hormones: Melatonin

 Flavonoids: Quercetin, pycnogenol, grape seed extract, Ecklonia cava

 Phenols: Silymarin

 Plant sources: Capsaicin, bilberry

 Enzymes: SOD

 Various Others: N-acetyl cysteine, alpha lipoic acid, essential fatty acids, glutathione, taurine

PROTOCOL. Most, if not all, CFS/ME doctors have included some form of antioxidant therapy into their protocols. Usually they recommend a broad-spectrum approach, as opposed to single-supplement therapy, accompanied in many cases by bioflavonoids such as pycnogenol (which is a potent antioxidant), grape seed extract, or “super foods” such as blue-green algae. Vitamin E, because it is the only fat-soluble antioxidant, is particularly good in combination with other antioxidants.

 Martin Pall, one of the leading researchers of oxidative stress in CFS/ME, recommends vitamin C, flavonoids, Ecklonia cava extract, B12, CoQ10, vitamin E, lipoic acid, as well as a host of other antioxidants to combat free radical damage.

 Dr. Cheney recommends daily doses of 2000-4000 mg vitamin C, 400-800 IU of Vitamin E, 200 mg of CoQ10, 100-300 mg of lipoic acid, omega-6 and omega-3 essential fatty acids and flavonoids. He stresses that because high doses of antioxidants can increase oxidative stress, flavonoids should be taken to mitigate potential free radical damage stemming from excessive antioxidant activity.

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 Dr. Myhill recommends 300 mg of CoQ10 daily for three months, then reduced to 100 mg daily, 250 mg of glutathione daily together with 20 mcg of selenium as well as minerals to help produce the powerful free radical scavenger, superoxide dismutase. (Please see below for her discussion of antioxidants.)

FURTHER READING

Dr. Myhill's excellent discussion of antioxidants: http://drmyhill.co.uk/wiki/Antioxidants

Logan, Alan C. and Cathy Wong. “Chronic Fatigue Syndrome: Oxidative Stress and Dietary Modifications.” Altern Med Rev 2001;6 (5): 450-459. http://www.altmedrev.com/publications/6/5/450.pdf

This article contains an excellent summary of research concerning oxidative stress in CFS/ME as well as a proposed list of antioxidant treatments.

Martin Pall's supplement list: http://esme-eu.com/supplements/supplements-in-me-cfs-by-prof-martin-pall-article276-139.html

Dr. Cheney's talk on CFS/ME treatments, including antioxidants: http://www.me-cfs.info/cheneyII3.pdf

RESEARCH

Fulle S, Mecocci P, Fan G, Vecchiet I, Vecchini A, Racciotti D, Cherubini A, Pizzigallo E, Vecchiet L, Senin U, Beal MF. “Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome.” Free Radic Biol Med. 2000 Dec 15;29(12):1252-9. http://www.ncbi.nlm.nih.gov/pubmed/11118815 (Abstract)

Kennedy, Gwen, Vance A. Spence, Margaret McLaren, Alexander Hill, Christine Underwood, Jill J.F. Belch. “Blood parameters indicative of oxidative stress are associated with symptom expression in chronic fatigue syndrome.” Free Radical Biology & Medicine 39 (2005) 584 – 58. http://www.cfids-cab.org/rc/Kennedy.pdf

Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. “Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis /chronic fatigue syndrome: another pathway that may be associated with coronary artery disease and neuroprogression in depression.” Neuro Endocrinology letters. 2011;32(2):133-40. http://www.ncbi.nlm.nih.gov/pubmed/21552194 (Abstract)

Miwa K, Fujita M. “Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome.” Heart Vessels. 2010 Jul;25(4):319-23. http://www.ncbi.nlm.nih.gov/pubmed/20676841 (Abstract)

Rezk BM, Haenen GR, Van Der Vijgh WJ, Bast A. “The extraordinary antioxidant activity of vitamin E phosphate.” Biochim Biophys Acta. 2004 Jul 5;1683(1-3):16-21. http://www.ncbi.nlm.nih.gov/pubmed/15238215 (Abstract)

Richards RS, Roberts TK, McGregor NR, Dunstan RH, Butt HL. “Blood parameters indicative of oxidative stress are associated with symptom expression in chronic

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fatigue syndrome.” Redox Rep. 2000;5(1):35-41. http://www.ncbi.nlm.nih.gov/pubmed/10905542 (Abstract)

Saransaari, P, Oja S. “Nitric oxide is involved in taurine release in the mouse brainstem under normal and ischemic conditions.” Amino Acids. 2008 Apr;34(3):429-36 http://www.ncbi.nlm.nih.gov/pubmed/17665274 (Abstract)

BETAINE HCl

DESCRIPTION. Betaine HCl is a synthesized chemical compound consisting of betaine, a methyl group donor, and hydrochloride, a salt.

BACKGROUND. Betaine is a vitamin-like substance that was originally derived from beets. For many years Betaine HCl was added to over-the-counter digestive aids, until in 1993 the FDA determined that it has not been proven “generally safe and effective.” At that point Betaine HCl began to be sold as a separate supplement.

Betaine HCl is still marketed as a digestive aid, particularly for the treatment of hypochloridia, a condition in which the stomach does not produce enough acid. Hypochloridia can occur after taking stomach acid suppressors (antacids, proton pump inhibitors), through H. Pylori infections (which interfere with stomach acid production), as well as any disease process that causes inflammation in the stomach lining. Stomach acid is often low in the elderly.

Lack of stomach acid can lead to the phenomenon known as “dumping,” in which the stomach's contents (chyme) are released into the small intestines before having been adequately broken down. The ability of the small intestines to further break down the chyme can result in poor absorption of nutrients, leading to deficiency states, particularly of minerals, which require acid to be absorbed. One of the most common symptoms of hypochloridia is reflux, which is frequently misdiagnosed as excess acid.

The most reliable test to determine hypochloridia is the Heidelberg Capsule test. The capsule contains a high frequency transmitter attached to a string. When the capsule is swallowed and drawn back up the esophagus, it gives an instant pH reading.

USES IN CFS/ME. A number of clinicians have proposed that low levels of stomach acid are responsible for many of the GI symptoms found in CFS/ME patients. Dr. Cheney routinely recommends Betaine HCl as a supplement to correct hypochloridia and prevent dumping. Dr. Myhill also maintains that people with CFS/ME chronically suffer from low levels of stomach acid.

PROTOCOL. Dr. Cheney recommends starting with a capsule (or ½ capsule) with meals. Paradoxically, too low a dose may actually increase reflux, as there still isn't enough stomach acid to trigger the opening of the sphincter that releases chyme into the intestines. The food that then returns through the esophagus contains not only normally occurring stomach acid, but the additional Betaine HCl as well. According to Dr. Cheney, increasing the dose will actually reduce reflux.

PROS AND CONS. Although Betaine HCl does not contain hydrochloric acid (the HCl, in this case, is a salt), some people report improved digestion. The

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supplement does have mild acidifying properties, which is perhaps why people report having to take so many capsules with their meals (up to seven). It is quite possible that many of its benefits may actually come from the betaine, which acts as a liver support.

AVAILABILITY AND COST. Betaine HCl is easily available from health food stores and from online suppliers. It is inexpensive. Vitacost markets a 100-capsule bottle of Twinlab's Betaine HCl for about $7.

FURTHER READING

Dr. Sara Myhill's excellent discussion of hypochloridia: http://www.drmyhill.co.uk/wiki/Hypochlorhydria_-_lack_of_stomach_acid_-_can_cause_lots_of_problems

Basic information about Betaine HCl: http://www.encyclopedia.com/doc/1G2-3435100086.html

A good explanation of the Heidelberg capsule test and hypochloridia. http://www.antiagingwellnesscenter.com/phcapsule.shtml

Dr. Paul Cheney on dumping, hypochloridia, and Betaine HCl supplementation. http://www.prohealth.com/library/showarticle.cfm?libid=8037

BIOFLAVONOIDS

Grape seed extract, Pycnogenol, Quercetin

DESCRIPTION. Bioflavonoids are glycosides (sugars) derived from citrus, paprika, and other plants, which serve to protect capillaries. Although formerly known as "vitamin P," bioflavonoids are not vitamins.

BACKGROUND. Bioflavonoids were first extracted from paprika in 1936 by a scientist who claimed that the substance had a greater effect than vitamin C in reducing capillary bleeding. It was later shown that the substance, or rather substances, helped maintain capillary strength by inhibiting permeability of the walls (rather than maintaining the actual structure, as does vitamin C). This may be because bioflavonoids inhibit oxidation of epinephrine (adrenaline), the hormone directly responsible for capillary wall integrity. Bioflavonoids enhance absorption of vitamin C and, when taken together, can help protect and preserve capillaries, increase circulation, prevent cataracts, and produce a mild antibacterial effect. Flavonoids have anti-allergic, anti-inflammatory and anti-microbial effects.

Dietary sources include buckwheat, black currants, peppers, and the white part of citrus peel. There are many bioflavonoids available for purchase through health food stores and online vitamin suppliers.

Bioflavonoids are rapidly absorbed in the system, and almost as rapidly excreted through the kidneys. Peak blood levels occur roughly two hours after ingestion, which means that to be effective, they should be taken throughout the day.

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USES IN CFS/ME. Bioflavonoids are poorly absorbed, so for better utilization its best to take several. The most active intracellular free radical scavengers are lycopene, a carotenoid found in red fruits (except strawberries) and lutein, found in green leafy vegetables. Dr. Pall recommends FlaviNOx, which is a combination of standardized bioflavonoids derived from herbs (gingko, bilberry, milk thistle, grape seed extract, decaffeinated green tea extract, cranberry and hawthorn). The combination of antioxidants in FlaviNOx is designed to scavenge peroxynitrite and superoxide, two highly damaging free radicals.

AVAILABILITY AND COST. A 90-capsule bottle of FlaviNOx (Allergy Research Group) costs roughly $35.

GRAPE SEED EXTRACT

DESCRIPTION. Grape seed extract is a polyphenolic compound derived from grape seeds.

BACKGROUND. Grape seeds contain polyphenols, procyanidins, and proanthocyanidins, which are antioxidants many times more powerful than vitamin C or E. Grape seed extract is reported to be a potent peroxynitrite scavenger, and therefore can protect the cells from intracellular damage. The effects of polyphenols are far-reaching, including the inhibition of skin cancer, reduction of inflammation, neuroprotective action, improvement of cerebral circulation, acceleration of wound healing, modulation of intestinal flora, repairing leaky gut, and immune system regulation.

USES IN CFS/ME. Grape seed extract is often used as a less expensive alternative to pycnogenol. Patients report that it helps with pain.

PROTOCOL. One 100 mg tablet taken with food.

AVAILABILITY AND COST. Grape seed extract is widely available in health food stores and through online distributors. A bottle of 120 capsules can cost as little as $13. Grape seed extract is frequently combined with other bioflavonoids, such as green tea and resveratrol (found in grape skin) to increase its antioxidant effects.

FURTHER READING

Sloan Kettering's review of the mechanisms of grape seed extract. Includes a list of studies. http://www.mskcc.org/cancer-care/herb/grape-seed

RESEARCH

Afaq F, Katiyar SK. “Polyphenols: Skin Photoprotection and Inhibition of Photocarcinogenesis.” Mini Rev Med Chem. 2011 Oct 28. http://www.ncbi.nlm.nih.gov/pubmed/22070679 (Abstract)

Lin, B. “Polyphenols and Neuroprotection against Ischemia and Neurodegeneration.” Mini Rev Med Chem. 2011 Oct 28 http://www.ncbi.nlm.nih.gov/pubmed/22070681 (Abstract)

Vendrame S, Guglielmetti S, Riso P, Arioli S, Klimis-Zacas D, Porrini M. “Six-week consumption of a wild blueberry powder drink increases bifidobacteria in the

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human gut.” J Agric Food Chem. 2011 Nov 7. http://www.ncbi.nlm.nih.gov/pubmed/22060186 (Abstract)

PYCNOGENOL

DESCRIPTION. Pycnogenol (proanthocyanadin) is a bioflavonoid antioxidant derived from the bark of the French maritime pine tree.

BACKGROUND. Pycnogenol is a potent free radical scavenger. Studies have shown that, as an antioxidant, pycnogenol is up to 50 times more effective than other antioxidants to clear free radicals created from chemical sources (air pollution and food additives). It is 20 times more effective than vitamin C in scavenging superoxide, hydroxyl, and peroxide radicals. Pycnogenol is reported to enhance immune system function, increase energy, promote healing, and reduce allergic reactions. It is particularly effective in the brain.

USES IN CFS/ME. Pycnogenol has not been widely investigated for use in CFS/ME patients although it has been researched for other virally induced diseases. Some patients who have used pycnogenol report small increases in mental and physical energy and better resistance to bacterial and viral infections as well as stress.

PROTOCOL. The recommended dosage is 50 mg a day, taken with food. Some CFS/ME patients report that pycnogenol is more effective on an empty stomach.

AVAILABILITY AND COST. Pycnogenol can be purchased from health food stores and vitamin catalogs. Twinlab markets a 60-capsule bottle of pycnogenol (50 mg) for $25 through Vitacost.

FURTHER READING

Sloan Kettering's excellent summary of the mechanisms of pycnogenol. Contains a list of research studies: http://www.mskcc.org/cancer-care/herb/pine-bark-extract

Iravani S., and B. Zolfaghari. “Pharmaceutical and nutraceutical effects of Pinus pinaster bark extract.” PhD. Res Pharm Sci. 2011 Jan-Jun;6(1): 1–11. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203267/

A thorough review of all research articles investigating pycnogenol.

RESEARCH

Feng WY, Tanaka R, Inagaki Y, Saitoh Y, Chang MO, Amet T, Yamamoto N, Yamaoka S, Yoshinaka Y. “Pycnogenol, a procyanidin-rich extract from French maritime pine, inhibits intracellular replication of HIV-1 as well as its binding to host cells.” Jpn J Infect Dis. 2008 Jul;61(4):279-85. http://www.ncbi.nlm.nih.gov/pubmed/18653969 (Abstract)

QUERCETIN

BACKGROUND. Quercetin, a flavonol, is chiefly used to treat asthma and allergies. Quercetin has properties similar to that of the antihistamine disodium cromoglycate (found in Gastrocrom and Nasalcrom). It can inhibit mast cell

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production and block histamine release, two functions that together can curb many allergic responses. In its antioxidant function, quercetin decreases the synthesis of pro-inflammatory leukotrienes, and inhibits free radical production and lipid peroxidation.

Quercetin is reported to help relieve muscle pain, particularly along the upper back and shoulders. It is commonly found in many food sources: green tea, apples, red onions, red grapes, citrus fruits, tomato, broccoli, leafy green vegetables, cranberries and raspberries, among others.

USES IN CFS/ME: An interesting study conducted in 2009 by Davis et al found that quercetin increased the genesis of mitochondria in mice, significantly improving exercise tolerance. The reason this study is important is that it was done in vivo. (Most studies on antioxidants are performed in test tubes.) As exercise intolerance is the hallmark symptom of CFS/ME, quercetin may play an important role in improving physical stamina among people with CFS/ME.

PROTOCOL. Because it is so poorly absorbed, quercetin needs to be taken with bromelain, an enzyme found in pineapple. Dr. James Balch, author of Prescription for Nutritional Healing, recommends 1000 to 2000 mg one to three times a day to prevent or lessen the severity of asthma attacks and allergies. CFS/ME patients are advised to start with much smaller doses, 200-1200 mg a day.

PROS AND CONS. Quercetin is the most widely used bioflavonoid among patients with CFS/ME. A number of allergy-prone patients with CFS/ME have noted that allergy symptoms subside with quercetin. For patients with many allergies, this may provide overall improvement because allergy symptoms can cause systemic problems. Some patients with interstitial cystitis have noted an improvement in symptoms after taking quercetin. The primary side effect is that high doses may cause diarrhea.

AVAILABILITY AND COST. Quercetin (with bromelain) is available from health food stores and online vitamin catalogs. A three-month supply may cost as little as $8. ProHealth markets a 100-tablet bottle of a quercetin-bromelain combination (also containing vitamin C and magnesium) for about $15.

FURTHER READING

Davis JM, Murphy EA, Carmichael MD, Davis B. “Quercetin increases brain and muscle mitochondrial biogenesis and exercise tolerance.” Am J Physiol Regul Integr Comp Physiol. 2009 Apr;296(4):R1071-7. http://www.ncbi.nlm.nih.gov/pubmed/19211721 (Abstract)

Park HH, Lee S, Son HY, Park SB, Kim MS, Choi EJ, Singh TS, Ha JH, Lee MG, Kim JE, Hyun MC, Kwon TK, Kim YH, Kim SH. “Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells.” Arch Pharm Res. 2008 Oct;31(10):1303-11. http://www.ncbi.nlm.nih.gov/pubmed/18958421 (Abstract)

Pearce FL, Befus AD, Bienenstock J. “Mucosal mast cells. III. Effect of quercetin and other flavonoids on antigen-induced histamine secretion from rat intestinal

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mast cells.” J Allergy Clin Immunol. 1984 Jun;73(6):819-23. http://www.ncbi.nlm.nih.gov/pubmed/6202731 (Abstract)

Shaik YB, Castellani ML, Perrella A, Conti F, Salini V, Tete S, Madhappan B, Vecchiet J, De Lutiis MA,Caraffa A, Cerulli G. “Role of quercetin (a natural herbal compound) in allergy and inflammation.” J Biol Regul Homeost Agents. 2006 Jul-Dec;20(3-4):47-52. http://www.ncbi.nlm.nih.gov/pubmed/18187018 (Abstract)

BUTYRIC ACID (BUTYRATE)

DESCRIPTION. Butyrates (butanoic, or butyric acid) are short-chain saturated fatty acids found naturally in the human intestine and in butter fat.

BACKGROUND. Short-chain fatty acids (volatile fatty acids) are produced in the colon as natural by-products of the bacterial fermentation of fiber. These fatty acids provide an energy source for the mucosal cells of the lining of the colon, enabling them to check the proliferation and establishment of pathogens (such as salmonella and Candida) and allowing greater absorption of magnesium and vitamin K. Deficiency of these fatty acids results in malabsorption, diarrhea, and, over the long term, colitis.

Of the three fatty acids found in all mammals – butyrate, acetate, and propionate – butyrate is the preferred energy substrate. It stimulates the normal proliferation of mucous cells, enabling greater efficiency of all colonic functions. Butyrates have been used successfully to treat Candida overgrowth (yeast infection), cancer, ulcerative colitis, and nonspecific inflammatory conditions of the colon. It is one of the treatments recommended for leaky gut and for alleviating food sensitivities.

USES IN CFS/ME. A significant number of people with CFS/ME suffer from gastrointestinal problems. According to Dr. Cheney, 90% of his CFS/ME patients have small intestinal bacterial overgrowth (SIBO), a condition in which bacteria from the large intestine migrate into the small intestines, interfering with fat and carbohydrate metabolism and causing a spate of GI symptoms. Rao et al found that 50% of CFS/ME patients meet the criteria for irritable bowel syndrome (IBS), a gut motility disorder. Butyrates, because they provide a substrate for beneficial intestinal flora, can be used in conjunction with probiotics to help restore gut mucosa damaged by SIBO as well as maintaining gut motility.

Although butyrates are primarily recommended for treating digestive disorders, it may also have a positive effect on some neurological problems associated with CFS/ME. Dr. Cheney proposes that an imbalance in the actions of the neuroexcitatory chemical NMDA (N-methyl-D-aspartate) and the neuroinhibitor GABA (gamma amino butyric acid) may lead to many of the troubling neurological symptoms experienced by patients with CFS/ME (insomnia, intolerance of sensory stimuli, seizure-like activity, pain) (CFIDS Chronicle, Spring 1995).

For many patients, down regulation of the NMDA receptors, accomplished with small doses of Klonopin (clonazepam), magnesium, Nimotop (nimodipine), melatonin, or calcium channel blockers, leads to general improvement of all

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symptoms. Butyrate, because it forms a component of GABA, may also rectify some of this neurochemical imbalance by increasing the amount of neuroinhibitory action in the brain.

PROTOCOL. Butyrate is usually taken orally. The suggested dose is one or two capsules with each meal. It smells awful, so you may want to store it in the refrigerator.

PROS AND CONS. Butyrate is inexpensive, safe, and does not require a prescription.

AVAILABILITY AND COST. ButyrEn tablets, marketed by Allergy Research Group, are hypoallergenic, containing no yeast, wheat, corn, soy, dairy products, or artificial colors or resins. The tablets are buffered with calcium and magnesium. ButyrEn is available from online distributors and some specialized vitamin stores. One bottle of 100 capsules costs as little $9 on amazon. PureFormulas markets a 90-capsule bottle of Cal-Mag Butyrate made by Ecological Formulas for $10.50. Shipping is free.

FURTHER READING

Life Extension is a bit pricier than other suppliers, but their website contains a very thorough description of the mechanisms of butyric acid. http://www.lifeextensionvitamins.com/bualregr.html

RESEARCH

Rao, A Venket, Alison C Bested, Tracey M Beaulne, Martin A Katzman, Christina Iorio, John M Berardi and Alan C Logan. “A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome.” Gut Pathogens 2009, 1:6. http://www.gutpathogens.com/content/1/1/6

CHOLINE

DEFINITION. Choline is an amine (a nitrogen-containing compound) similar in function to B vitamins.

BACKGROUND. Choline is an essential nutrient, which means it cannot be synthesized by the body and must be obtained through food sources. Foods high in choline include egg yolk, liver, fatty meats, nuts and brown rice.

Choline performs three vital biological functions: 1) It is an important component of phosphatidylcholine, which forms cell walls and supports cellular function; 2) Choline serves as a precursor to acetylcholine, the neurotransmitter responsible for memory formation and muscle movement; 3) Choline is an important methyl donor, supporting the methylation cycle through its metabolite, trimethylglycine (betaine).

A deficiency in choline can lead to liver damage (“fatty liver”) and a reduction in kidney function. Lack of choline in the diet can also cause infertility, growth impairment, bone abnormalities, and hypertension. Because choline plays such an important role in nervous system development, a deficiency in early life can lead to

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neurological deficits. Vegans and athletes are particularly prone to choline deficiency.

USES IN CFS/ME. Because choline serves as a marker for certain types of brain damage, it is one of the compounds that is measured in magnetic resonance (MR) spectroscopy. For example, high amounts of choline accompanied by low amounts of creatine and N-acetyl aspartate (NAA) are indicative of stroke (cerebral ischemia and hypoxia). MR spectroscopy can also be used to monitor changes in tumors, stroke, epilepsy, metabolic disorders, infections, and neurodegenerative diseases.

In 2004 Chaudhuri and Behan used MR spectroscopy to assess brain chemistry in CFS/ME patients. They found that in CFS/ME patients, choline levels in the occipital cortex and basal ganglia were raised, but NAA and creatine were normal. The researchers concluded that in the absence of NAA and with no structural abnormalities, the increase in choline was probably due to increased phospholipase activity (the enzyme that breaks down the phospholipids that make up cell walls) rather than to inflammation. They theorized that viral activity could possibly contribute to the increased choline, as many viruses increase the activity of phospholipase.

While Chaudhuri and Behan concluded that inflammation in the brain was not indicated by their test results, further research indicates otherwise. Martin Pall has suggested that activation of NMDA receptors (due to oxidative stress) provides the missing inflammatory pathway that Chaudhuri and Behan were unable to identify. In fact, an increase in choline can be an early signal of an inflammatory process, even in the absence of NAA. The mechanism which induces release of choline was identified by Gasull et al as an inhibition of phosphatidylcholine synthesis rather than phospholipase degradation. The researchers found that the increase in extracellular choline was induced by NMDA receptor activation, which ties in with Martin Pall's theory. In addition, Gasull's group found that early choline release was directly related to excitotoxic cell death caused by glutamine.

PROTOCOL. Given the important role of choline in neuronal protection from oxidative stress, as well as the fact that it is a component of acetylcholine, choline comprises a valuable addition to any CFS/ME treatment plan. Dr. Cheney recommends taking 50 mg of choline bitartrate a day. Dr. Teitelbaum recommends the same dose, accompanied by vitamin C.

High doses (10 to 16 grams/day) of choline are not recommended. Side effects from excessive intake of choline have been associated with a fishy body odor, vomiting, salivation, and increased sweating. (The fishy body odor results from excretion of trimethylamine, a metabolite of choline.) Taking large doses of choline in the form of phosphatidylcholine (lecithin) does not generally result in fishy body odor. However, lecithin is not usually well-tolerated by CFS/ME patients.

AVAILABILITY AND COST. Choline bitartrate supplements are not widely available, so most people decide to purchase lecithin powder, which is inexpensive and easy to find. PureFormulas.com markets a bottle of 100 choline bitartrate capsules (235 mg) for roughly $10. Purebulk.com sells a 100-gram container of

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choline bitartrate powder for $4.25. The powder may be a more viable option for most people as it allows for titration. Many B vitamin formulations contain choline, so check labels. It may be worthwhile to purchase a good-quality B-complex supplement that includes choline, as this will give you the proper balance of B vitamins as well.

FURTHER READING

This Oregon University site provides excellent information about choline. http://lpi.oregonstate.edu/infocenter/othernuts/choline/

“What are Choline and Inositol?” (Good overview): http://www.livestrong.com/article/326852-what-are-choline-inositol/

“Choline on the Brain? A Guide to Choline in Chronic Fatigue Syndrome.” Cort Johnson. Aug, 2005. http://aboutmecfs.org.violet.arvixe.com/Rsrch/CholineBrain.aspx

Ray Sahelian's sensible advise on choline: http://www.raysahelian.com/cdp.html

“Fundamentals of MR Spectroscopy.” John R. Hesselink. (A nice summary of MR spectroscopy.) http://spinwarp.ucsd.edu/neuroweb/Text/mrs-TXT.htm

RESEARCH

Chaudhuri, A., P.O. Behan. “In vivo magnetic resonance spectroscopy in chronic fatigue syndrome.” Prostaglandins, Leukotrienes and Essential Fatty Acids 71 (2004) 181–183. http://www.cfids-cab.org/cfs-inform/MitochondrialATP/chaudhuri.behan04.pdf

Chaudhuri A, Condon BR, Gow JW, Brennan D, Hadley DM. “Proton magnetic resonance spectroscopy of basal ganglia in chronic fatigue syndrome.” Neuroreport. 2003 Feb 10;14(2):225-8. http://www.cfids-cab.org/cfs-inform/Brainscans/chaudhuri.etal03.pdf

Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM. “Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study.” JAMA. 1995 Sep 20;274(11):902-7. http://www.nutrasal.com/library/pdfs/21.pdf

Doležal, Vladimír, Stanislav Tuček. “Activation of muscarinic receptors stimulates the release of choline from brain slices.” Biochem Biophys Res Commun. 1984 May 16;120(3):1002-7. http://www.ncbi.nlm.nih.gov/pubmed/6732780 (Abstract)

Gasull, Teresa, Nuria DeGregorio-Rocasolano, Agustin Zapata and Ramon Trullas. “Choline Release and Inhibition of Phosphatidylcholine Synthesis Precede Excitotoxic Neuronal Death but Not Neurotoxicity Induced by Serum Deprivation.” First Published on March 28, 2000. The Journal of Biological Chemistry, 275,18350-18357. http://www.jbc.org/content/275/24/18350.full

COQ10 (UBIQUINONE, UBIQUINOL)

DESCRIPTION. CoQ10 (ubiquinone) is a fat-soluble coenzyme found in the mitochondria of most mammal cells.

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BACKGROUND. CoQ10 was first discovered by R.A. Morton, a biochemist who gave it the name ubiquinone after its ubiquitous presence in nearly all living things. "Co" stands for coenzyme (a vitamin-like substance), "Q" for quinone (the group of organic chemicals to which CoQ belongs), and "10" for the number of isoprene units that characterize the particular coenzyme found in animal cells.

CoQ10 is vital for electron transport, the intracellular function that ultimately provides the energy necessary to sustain life. CoQ10 is also a powerful antioxidant and is important in immune system function. The Japanese have successfully used CoQ10 to treat gum disease, heart disease, and high blood pressure, and to enhance the effectiveness of the immune system. Research performed in Japan and elsewhere indicates that CoQ10 can be of benefit in treating allergies (owing to its ability to block the effects of histamine), asthma, candidiasis, obesity, diabetes, mental function diseases such as Alzheimer's disease, and can slow the aging process (CoQ10 levels decline with age).

High amounts of CoQ10 occur naturally in fatty saltwater fish, especially mackerel, salmon, and sardines.

USES IN CFS/ME. CoQ10 is one of the most frequently used supplements for the treatment of CFS/ME-related fatigue because of its importance in the production of adenosine triphosphate (ATP), the cellular source of energy. In addition to reducing fatigue, CoQ10 may alleviate muscle weakness and pain. It is also one of the few supplements that seems to reduce cognitive dysfunction. Its role as a free radical scavenger may lead to improvement in immune responses in patients with CFS/ME. Although its effects as a natural antihistamine have not yet been specifically explored in CFS/ME, patients with allergies may benefit from CoQ10.

There is also evidence that CoQ10 is deficient in CFS/ME patients. In 2009 Maes et al measured plasma CoQ10 in 58 CFS/ME patients. Compared to normal controls, the CFS/ME group had values significantly below the lowest recorded levels of the control group. Patients with very low levels of CoQ10 suffered significantly more from concentration and memory disturbances. The researchers concluded that lowered levels of CoQ10 play a role in the pathophysiology of ME/CFS and that “symptoms, such as fatigue, and autonomic and neurocognitive symptoms may be caused by CoQ10 depletion.” Their results suggested that patients with CFS/ME would benefit from CoQ10 supplementation in order to normalize the low CoQ10 syndrome.

PROTOCOL. Nearly all CFS/ME physicians recommend supplementation with CoQ10. CoQ10 can be taken in a single dose or divided into two doses taken at different times during the day. There is evidence that dividing the dose is more effective than taking it all at once. The normal recommended dose is between 30 and 200 mg/day. Dr. Lapp and Dr. Klimas recommend 120 mg a day. Sublingual CoQ10, reputedly more effective against cognitive dysfunction, may be taken at higher doses. Oral CoQ10, although primarily absorbed by the digestive tract and liver, is also effective for some patients. The oral dosage varies, but is usually 25 to 50 mg/day. It may take up to eight weeks to see effects from oral CoQ10. Because

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CoQ10 is fat-soluble, it should be taken with a meal that contains some kind of fat or oil.

PROS. Taken at lower doses, CoQ10 is a supplement with very few side effects. Patients report improvements in energy, stamina, light-headedness, and syncope (fainting). Dr. Lapp reports that half of his patients see improvement after taking CoQ10. A significant number of patients, particularly those with fibromyalgia, find that CoQ10 increases their energy over the course of the day.

CONS. Some patients report that CoQ10, while giving them an initial energy boost, also increases insomnia and causes jitters. Some people report, paradoxically, that CoQ10 produces exhaustion, although this effect may be more common in the acutely ill than in those with stable symptoms. CoQ10 lowers blood sugar levels, which may be problematic for patients with hypoglycemia. High doses can cause flu-like symptoms.

AVAILABILITY AND COST. CoQ10 can be purchased at most health food stores and from online distributors. There is a mind-boggling array of CoQ10 products. High-grade brands are preferred. (CoQ10 deteriorates rapidly when exposed to heat and light.) Because CoQ10 is fat-soluble, it should be purchased as a softgel (not capsule), preferably with a natural preservative (such as vitamin E).

Sublingual CoQ10 can be purchased from online sources without a prescription. Intensive Nutrition, Inc. markets a sustained-release sublingual CoQ10 for $25 (80 mg, 30 count). Source Naturals sells sublingual CoQ10 for $14 (30 mg, 120 count).

CoQ10 is also available by prescription as a gel. Unlike other forms of CoQ10, the gel is water soluble, and bypasses the GI tract completely. The gel is more easily absorbed that oral forms, so less CoQ10 needs to be taken. CoQ10 gel has been given orphan status by the FDA for treating mitochondrial dysfunction. (Orphan status means that a drug has been approved for the treatment of rare disorders.)

A more easily absorbed form of CoQ10, ubiquinol, is currently being marketed in the U.S. CoQ10 is converted in the body to ubiquinol, which is the active form of the enzyme, and therefore, more potent. Not only is ubiquinol more easily absorbed, it is longer acting than ubiquinone. Ubiquinol can be purchased from health food stores and online distributors. Vitacost sells a wide variety of ubiquinol products, ranging in cost from $8 to $74. (Read the labels carefully to confirm that the product contains pure ubiquinol.) Olympian Labs sells a bottle of 60 ubiquinol softgels (50 mg) with relatively few additives for $27.62.

Oral CoQ10 is not usually covered by insurance, as it is classed as a supplement.

FURTHER READING

Excellent summary of CoQ10 in CFS/ME: http://phoenixrising.me/?page_id=4759

An interesting and useful site containing a discussion of ubiquinol, a comparison of ubiquinol to CoQ10, links and research: http://ubiquinol.org/what-is-ubiquinol

Website of the International CoQ10 Association: http://www.icqa.org/ICQA/home.html

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Ray Sahelian's informative site. Effects of CoQ10, studies and FAQs. http://www.raysahelian.com/coq10.html

Compounding pharmacies that make CoQ10 troches: http://www.mitoaction.org/blog/coq-10-update

Information on CoQ10 gel: http://www.epic4health.com/noname.html

PATIENT REVIEWS

Patient reviews of CoQ10: http://www.revolutionhealth.com/drugs-treatments/rating/coenzyme-q10-coq10-for-chronic-fatigue-syndrome-cfs-cfids-me?sort=recent

RESEARCH

Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. “Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder.” Neuro Endocrinol Lett. 2009;30(4):470-6. http://www.ncbi.nlm.nih.gov/pubmed/20010505 (Abstract)

D-RIBOSE

DESCRIPTION. D-Ribose is a water-soluble simple sugar that is an important component of nucleic acids, vitamin B2, and various coenzymes.

BACKGROUND. Ribose was first identified in 1891 by Emil Fischer, a German chemist and recipient of the Nobel Prize in Chemistry. Fischer's primary work concerned sugars and the identification of their various functions. Ribose is an extremely important sugar in that it comprises the backbone of RNA, one of the three major macromolecules essential to all forms of life. Ribose is also a component of ATP, NADH and several other compounds that control the metabolism of carbohydrates, proteins, and fat.

USES IN CFS/ME. Mitochondrial defects that lead to low production of ATP, the principal source of cellular energy, have been thoroughly documented in people with CFS/ME. Low levels of ATP are responsible for the hallmark symptoms of CFS/ME, exercise intolerance and fatigue. However, direct supplementation with ATP seems to have no effect on either fatigue or stamina. This is due to the fact that ATP has a molecular weight of more than 500, which means that it is nearly impossible to absorb. Therefore, the mitochondrial defects leading to low ATP production must be addressed at a lower level in the metabolic chain.

The body makes ATP through the Krebs cycle, in which various enzymes convert citric acid into ATP. These enzymes are often deficient in people with CFS/ME, resulting in a lower production of ATP. The body can also make ATP from glucose, but the process involves first converting glucose into lactic acid, which then accumulates in the muscles, causing the familiar “burn” of over-exertion. This is also a longer and less efficient process than the Krebs cycle. D-Ribose cuts the time

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required to produce ATP because the body can quickly convert D-Ribose into ATP without converting it first into lactic acid.

In a 2006 pilot study, Teitelbaum et al found that in 36 CFS/FM patients, 66% experienced improvement in energy, pain, sleep, mental clarity and overall well-being after treatment with D-Ribose. The average improvement in energy was 45%, while the global improvement was 30%. The researchers concluded that D-Ribose “significantly reduced symptoms in patients suffering from fibromyalgia and chronic fatigue syndrome.”

Apart from its uses in CFS/ME, D-Ribose is among the most popular nutritional supplements to have been recently patented. In 2010, Bioenergy Inc, the company which markets Corvalen (the brand recommended by Dr. Teitelbaum), achieved its highest revenue earnings in the history of the company.

PROTOCOL. The serving size recommended by Jarrow is 2 grams (½ tsp/one scoop) up to three times a day. Dr. Teitelbaum recommends 5000 mg (5 grams) of D-Ribose three times a day for two to three weeks, then twice a day. Dr. Myhill also recommends 15 grams a day. Interestingly, she notes that the effects of D-Ribose can be enhanced by caffeine. She notes that D-Ribose has a short half-life, which is why it must be taken in small doses throughout the day. D-Ribose should be taken with food.

While initial doses of 15 grams are recommended by Drs. Teitelbaum and Myhill, it should be remembered that many CFS/ME patients are sensitive to supplements. Dr. Cheney has observed that fully one-third of his patients cannot tolerate D-Ribose. To test for sensitivities, an initial small dose (1 to 2 grams a day) is recommended.

PROS. D-Ribose appears to be generally well tolerated by people with CFS/ME. Patients usually notice improvement in energy levels within two or three days, although one patient commented that “within an hour, it was like a super thick fog bank had dissipated.” D-Ribose works particularly well with brain fog, daytime sleepiness and hypersomnia.

CONS. Some patients report that D-Ribose makes them sleepy, and that it saps them of energy. Those who take high doses (15 grams a day) have reported diarrhea, nausea, and headache. Because D-Ribose is derived from corn, those with corn allergies may not be able to tolerate this supplement. Although D-Ribose does not have the same properties as table sugar, it can be converted back to glucose, which may have an adverse effect on patients with Candida, as well as those with blood sugar problems. D-Ribose supplementation is not advised for diabetics. Nor is it recommended for those with gout, as it causes an increase in uric acid levels (which are usually low in people with CFS/ME).

AVAILABILITY AND COST. D-Ribose is widely available in health food stores and from online suppliers. Costs range from $10 to $75, depending on the brand. Corvalen, the brand Dr. Teitelbaum prefers, sells for roughly $30 for a 280-gram container (56 servings, or roughly an 18-day supply at three scoops a day). Vitacost markets a 100-gram bottle made by Jarrow for about $10 (45 scoops).

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FURTHER READING

Dr. Teitelbaum addresses questions about D-Ribose: http://www.endfatigue.com/web-newsletters/Newsletter_3_questions_d-ribose.html

Dr. Teitelbaum explains the functions and benefits of D-Ribose. http://www.endfatigue.com/health_articles_d-e/D-ribose-powerful_body_energizer.html

Teitelbaum JE, JA St. Cyr, C Johnson. “The Use of D-Ribose in Chronic Fatigue Syndrome and Fibromyalgia: A Pilot Study” J Alternative and Complementary Medicine2006;12(9):857-862. http://www.fibroandfatigue.com/files/d-ribose.pdf

Dr. Lapp's list of supplements, including D-Ribose: http://www.prohealth.com/library/showarticle.cfm?libid=16109

Myhill, Sarah, Norman E. Booth, and John McLaren-Howard. “Chronic fatigue syndrome and mitochondrial dysfunction.” Int J Clin Exp Med.2009;2(1): 1–16. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

(This is a very long paper. You may want to jump to the following site.)

A summary of the information in the previous paper: http://www.drmyhill.co.uk/wiki/CFS_-_The_Central_Cause:_Mitochondrial_Failure

Creatine and D-Ribose studies: http://www.vrp.com/energizers/mitochondrial-restoration-part-iii-d-ribose-and-creatine-increase-mitochondrial-energy-production

A patient's encouraging report of her experiences with D-Ribose. http://www.healingwell.com/community/default.aspx?f=15&m=1253136

DIGESTIVE ENZYMES

DESCRIPTION. Gastrointestinal enzymes are secreted in the GI tract for the purpose of breaking down large food molecules into smaller molecules that are more easily absorbed.

BACKGROUND. Digestive enzymes are secreted in the mouth by salivary glands, in the stomach, in the pancreas and throughout the small intestine. Enzymes are classed into groups according to their function: proteases split proteins into amino acids, lipases split fat into fatty acids and glycerol, carbohydrases split sugars and carbohydrates into glucose, and nucleases split nucleic acids into nucleotides, which form RNA and DNA. Nucleotides also potentiate the production of ATP.

The mouth is where the digestive process is initiated. Enzymes which are released by salivary glands include lingual lipase, to start the digestion of fats; and amylase, which starts the conversion of carbohydrates into glucose; as well as immune system chemicals such as IgA to battle bacterial toxins, and R-factor which helps with the absorption of B12.

The main enzyme produced in the stomach is pepsin, which breaks down proteins. There are a number of other gastric secretions in the stomach which aid the process of breaking down food, the most important of which are hydrochloric

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acid (HCl ), which activates pepsin and destroys bacteria; intrinsic factor, which aids in the absorption of B12 by protecting it from HCl ; and gastrin, the hormone which stimulates the stomach lining to produce HCl and intrinsic factor.

The pancreas produces trypsin, which further breaks down proteins into amino acids; pancreatic lipase, which breaks down fats; pancreatic amylase, which further breaks down carbohydrates into glucose; protease, for breaking down proteins; and several nucleases.

The small intestines, among many other chemicals, produce sucrase, to break down sugars; lactase, to break down lactose in milk; and maltase, which breaks maltose down into glucose.

USES IN CFS/ME. Given the broad range of GI disturbances in CFS/ME patients, as well as the importance of the GI tract in maintaining both nutritional health and immune system functioning, digestive enzymes can play a critical role in treatment. Dr. Cheney believes enzyme supplementation is essential for all CFS/ME patients.

PROTOCOL. Dr. Cheney recommends one or two tablets of Ultrazyme (made by Douglas Labs). Ultrazyme provides a broad spectrum of enzymes, including lipase, amylase, protease, ox bile extract, cellulase, pepsin and L-lysine. Dr. Myhill recommends Polyzyme Forte, a broad-spectrum enzyme supplement made by BioCare (available the U.K.). Enzymes are sensitive to temperature extremes. They should be taken with warm water or food. Enzymes are activated by moisture, so make sure you keep the tablets dry.

PROS. Many patients swear by enzymes, claiming that they help eradicate digestion problems as well as many food sensitivities.

CONS. Enzymes can be hard on the stomach. For those who are prone to reflux, or heartburn, enzymes may exacerbate these problems. Stomach problems can be mitigated by taking enzymes with food (rather than on an empty stomach).

AVAILABILITY AND COST. Enzymatic supplements are readily available at any health food store and from online suppliers. A 60-tablet bottle of Ultrazyme (Douglas Labs) sells for around $15 on amazon.com. Enzymatic supplements can also be purchased in powder form. Plant-based enzymes, which are not degraded by stomach acid, should always be purchased.

FURTHER READING

Dr. Cheney discusses gut dysbiosis and CFS/ME symptoms: http://www.cheneyclinic.com/gut-dysbiosis-modulates-significant-cfs-symptoms/247

Dr. Cheney discusses Betaine HCl and the function of enzymes. (Written by Carol Sieverling) http://www.prohealth.com/library/showarticle.cfm?libid=8037

Lots of articles about enzymes: http://www.enzymestuff.com/

DHEA

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NOTE: Not all CFS/ME patients have low levels of DHEA. Before embarking on a course of DHEA, make sure to have your DHEA level tested.

DEFINITION. DHEA (dehydroepiandrosterone) is a naturally occurring adrenal hormone.

BACKGROUND. DHEA, a hormone produced in the adrenal cortex, generates the sex hormones estrogen and testosterone. It is the most common hormone in the blood and is found in greatest concentrations in the brain. Perhaps because DHEA levels decrease with age, it has been called "the fountain of youth." A substantial body of research has provided evidence that DHEA may help the elderly by strengthening bones and muscles, decreasing joint pain, and improving sleep and mood. In addition to influencing hormone production, DHEA has several effects on immune system function, not the least of which is the regulation of lymphokine production.

A study conducted in 1993 by researchers at the University of Tennessee showed that DHEA decreases the amount of circulating interleukin-6 (a potent bone resorber and pro-inflammatory cytokine) and enhances the function of natural killer cells. Another study conducted in 1998 confirmed an inverse correlation between DHEA levels and IL-6 (as DHEA drops, IL-6 increases). DHEA has also been used to treat osteoporosis. A twelve-month study conducted in Canada confirmed that in post-menopausal women the application of DHEA in the form of 10% cream stimulated bone formation.

USES IN CFS/ME. Inspired by mounting evidence of adrenal cortical hypofunction in CFS/ME, clinicians have tested for blood levels of DHEA in CFS/ME patients. Some have discovered lower than normal levels. Based on these results, low doses of DHEA have been administered in hopes of raising immune function and normalizing the metabolic and endocrine disturbances that commonly accompany CFS/ME. It is believed that DHEA could also act as an antiviral agent because testosterone, a DHEA derivative, has demonstrable antiviral effects.

PROTOCOL. The usual dosage of DHEA is 25 to 100 mg/day, although a number of clinicians report good results with smaller doses. Dr. Majid Ali states that he frequently prescribes DHEA in doses of 50 mg taken on alternating days for up to several months. In contrast, Dr. James McCoy found that smaller doses (10 mg or less) are equally, if not more, effective than larger doses (CFIDS Chronicle, Fall 1993). He recommended starting at one tenth the normal dose to minimize the chance of negative reactions. Many patients with CFS/ME confirm that smaller doses (10 mg) work well for them.

PROS. Patients with CFS/ME have reported weight loss, increased energy, improved cognitive function, and better immune system responses with DHEA.

CONS. A number of patients have reported heart palpitations, jitters, and altered mental and emotional states. Female patients have experienced hair loss and acne. Dr. Paul Cheney points out that DHEA is often most beneficial in mild CFS/ME. He notes that even in cases where DHEA deficiency can be documented, administration of this hormone has caused severe relapse in some of his more profoundly ill patients (CFIDS Chronicle, Spring 1995).

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Researchers have noted side effects in older women given standard doses of DHEA (25-200 mg a day), including acne and hirsutism (facial hair growth). DHEA also lowers cortisol, an anti-inflammatory adrenal hormone responsible for raising blood sugar levels. It is important to remember that even though DHEA is a natural substance, it is still a powerful hormone. Hormones, because they are released directly into the bloodstream, produce profound metabolic effects, not all of which are intended. Like other steroid or hormone treatments, DHEA is not without some risk and must be approached with caution.

AVAILABILITY AND COST. DHEA can be purchased online and at most health food stores. It is inexpensive. Vitacost sells many brands for less than $10. Mexican wild yam products containing diosgenin should be avoided, as the body cannot convert diosgenin to DHEA.

Although DHEA is sold as a supplement in the U.S., it cannot be purchased in the U.K. and Canada without a prescription. South Dakota and Missouri prohibit the sale of DHEA. Those under the age of 18 cannot purchase DHEA without a prescription. Most bottles of DHEA contain the warning: “Not for women under the age of 35.”

One of the natural precursors to DHEA, pregnenolone, may be less risky than DHEA. Patients report increased energy, enhanced mental clarity, and general improvement after taking pregnenolone. The dosage is 10 mg every other day in patients younger than 50 years, and 20 mg every other day in patients over 50 years old. Pregnenolone can be purchased from online suppliers at roughly the same cost as DHEA. Pregnenolone carries the same warnings as DHEA.

FURTHER READING

Very thorough overview of DHEA. Many studies are cited. http://www.tidesoflife.com/dhea__basic_information.htm

Dr. Cheney on DHEA and other supplements (1995). http://www.immunesupport.com/news/95sum003.htm

Good article on the effects of DHEA on aging: http://www.anti-agingmd.com/dhea.html

PATIENT REVIEWS

CFS/ME patient reviews of DHEA: http://www.revolutionhealth.com/drugs-treatments/rating/dehydroepiandrosterone-for-chronic-fatigue-syndrome-cfs-cfids-me

RESEARCH

Casson PR, Andersen RN, Herrod HG, Stentz FB, Straughn AB, Abraham GE, Buster JE. “Oral dehydroepiandrosterone in physiologic doses modulate immune function in postmenopausal women.” Am J Obstet Gynecol. 1993 Dec;169(6):1536-9. http://www.ncbi.nlm.nih.gov/pubmed/8267058 (Abstract)

Labrie F, Diamond P, Cusan L, Gomez JL, Bélanger A, Candas B. "Effect of 12-Month Dehydroepiandrosterone Replacement Therapy on Bone, Vagina, and

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Endometrium in Postmenopausal Women." J Clin Endocrinol Metab. 1997 Oct;82(10):3498-505. http://jcem.endojournals.org/content/82/10/3498.short (Abstract)

ESSENTIAL FATTY ACIDS

Fish Oil, Flaxseed Oil, Evening Primrose Oil, Borage Seed Oil

DESCRIPTION. Essential fatty acids are fats (lipids) that are important in a number of physiological processes. They cannot be produced by the body and therefore must be obtained through dietary sources.

BACKGROUND. The two most important types of essential fatty acids are omega-3 and omega-6. Omega-3 fatty acids – alpha linolenic acid (ALA), docosahexanoic acid (DHA), and eicosapentaenoic (EPA) – are found in fish oil (especially cold water fish) and flaxseed oil. Omega-6 fatty acids (linoleic acid, LA) are found in many plant oils, including evening primrose oil, borage oil, and black currant oil.

Essential fatty acids are vital to a number of physiological processes, such as regulating cholesterol levels, keeping the skin moist and supple, and producing prostaglandins (hormone-like substances that affect a variety of body functions). Essential fatty acids are also indispensable in maintaining the structure and function of cell membranes. Most important, essential fatty acids, particularly those found in fish oil, can act as immune system modulators, enhancing immune system activity where needed, and inhibiting it when there is an upregulated immune response.

Several factors can affect fatty acid metabolism. Poor diet, stress, diabetes, excessive alcohol intake, radiation, and viral infections can disrupt the metabolism of essential fatty acids, making it difficult for the body to produce fatty acid metabolites in sufficient quantities. In such cases, supplementation may be necessary to prevent deficiency states. Supplementation with essential fatty acids has improved such diverse conditions as premenstrual syndrome (PMS), heart disease, rheumatoid arthritis, multiple sclerosis, hyperactivity in children, depression and mononucleosis.

USES IN CFS/ME. In 1987 Dr. Peter Behan, a professor of Clinical Neurology in Glasgow, Scotland, found that patients with CFS/ME have a disorder in fatty acid metabolism. Dr. Behan surmised that the disorder was the result of chronic viral infection much like mononucleosis, a prolonged illness that also produces abnormal serum fatty acid concentration. He conducted a double-blind trial using a fatty acid supplement (Efamol) containing both omega-3 and omega-6 fatty acids (Acta Neurologica Scandinavica, 1990). After 16 weeks of treatment, an astounding 85% of patients showed marked improvement, primarily in the areas of fatigue, dizziness, headaches, depression, and muscle pain.

In 1994, Gray and Martinovic hypothesized that the chronic immune system activation found in CFS/ME patients results in hyporesponsiveness of essential

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fatty acid metabolites, which produces a state in which even minor stressors can disturb homeostasis. They tested their hypothesis by administering dietary essential fatty acids to a group of CFS/ME patients. After three months, 90% of the patients treated showed signs of improvement.

While the results of Behan's and Gray's studies were encouraging, not all studies have confirmed that the administration of EFAs significantly improves CFS/ME symptoms. It wasn't until specific EFAs were tested that some light was shed on the effects of EFA supplementation in CFS/ME.

In 2003 Liu et al measured specific EFAs in the red blood cells of CFS/ME patients. The researchers found that both DHA and ARA (arachidonic acid) levels were low, indicating a state of oxidative stress. The authors concluded that because ratios of EFAs are essential in maintaining signal transduction, the disruption in EFA ratios might induce an impairment in both circulation and immune system function. The authors stated that recurrent sore throat, tender lymph nodes, muscle aches, arthralgia, and headaches might be due to disruption in EFA signaling.

Puri's 2004 study of eicosapentaenoic acid (EPA) showed that it was the omega-3 fatty acids that produced the greatest improvement in CFS/ME symptoms. Four patients with chronic, intractable CFS/ME were treated with high doses (approx 1500 mg a day) of an over-the-counter high eicosapentaenoic acid fatty acid supplement (Equazen, Ltd., London). All four patients showed improvement in symptoms within 12 weeks of treatment. They reported a lessening of “brain fog,” and an overall sense of well-being. The same patients when treated with a placebo did not note a similar improvement. While the cohort was small, the findings of this study were significant.

On the heels of this study, in 2005 Maes et al studied the ratios of fatty acids in CFS/ME patients. The researchers measured omega-6 and omega-3 fatty acid ratios in 22 CFS/ME patients and 12 controls. They found that CFS/ME patients, regardless of age or gender, had significantly higher levels of linoleic acid and arachidonic acid (omega-6) than controls. Both linoleic acid and arachidonic acid are implicated in the production of pro-inflammatory cytokines. They speculated that the low levels of circulating zinc found in CFS/ME patients (indicating an inflammatory response) might be due to the depletion of omega-3 fatty acids. The authors further hypothesized that the defects in T cell activation found in CFS/ME might also be attributed to a deficit in omega-3 fatty acids.

AVAILABILITY AND COST. EFAs are available at any health food store and through online suppliers. Many companies sell combinations of different EFAs for maximum effect. Because these are oils which are highly prone to rancidity, it is worth the price to buy a high quality product.

FURTHER READING

“The ABCs of EFAs.” CFIDS Chronicle, Summer 2008. http://www.cfids.org/cfidslink/2009/040107.pdf

Good summary of essential fatty acids, their function, and their role as a treatment for CFS/ME.

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RESEARCH

Gray JB, AM Martinovic. “Eicosanoids and essential fatty acid modulation in chronic disease and the chronic fatigue syndrome.” Medical Hypotheses; Vol 43, Issue 1, July 1994, Pages 31-42 http://www.ncbi.nlm.nih.gov/pubmed/7968718 (Abstract)

Liu, Zhandong, Dexin Wang, Qiming Xue, Jun Chen, Yongjie Li, Xiaoli Bai, and Liwen Chang. “Determination of Fatty Acid Levels in Erythrocyte Membranes of Patients with Chronic Fatigue Syndrome.” Nutritional Neuroscience, Volume 6 Number 6 (December 2003), pp. 389–392. http://www.cfids-cab.org/cfs-inform/Hypotheses/liu.etal03.pdf

Maes, Michael, Ivana Mihaylova and Jean-Claude Leunis. “In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc defects and defects in T cell activation.” Neuroendocrinology Letters; No 6, December, Vol 26, 2005. http://www.nel.edu/26-2005_6_pdf/NEL260605A22_Maes.pdf

Ninjs, Jo, and Kenny De Meirleir. “Letter to the Editor: Oxidative Stress Might Reduce Essential Fatty Acids in Erythrocyte Membranes of Chronic Fatigue Syndrome Patients.” Nutritional Neuroscience, Volume 7 Number 4 (August 2004), pp. 251–253 http://cfids-cab.org/cfs-inform/Hypotheses/nijs.demeirleir04.pdf

Puri BK. “The use of eicosapentaenoic acid in the treatment of chronic fatigue syndrome.” Prostaglandins Leukot Essent Fatty Acids. 2004 Apr;70(4):399-401. http://www.cfids-cab.org/cfs-inform/CFStreatment/puri04.pdf

FISH OILS

DESCRIPTION. The oil derived from deep-sea fish (sardines, mackerel, salmon, and herring) is the richest source of omega-3 fatty acids (DHA and EPA). Four ounces of salmon can contain as much as 3600 mg of omega-3 fatty acids. Fish oil capsules have been particularly helpful in treating fibromyalgia, often providing immediate relief from pain. Fish oil is so effective that some physicians suggest it in place of Advil (ibuprofen) for pain from inflammation. Because of its anti-inflammatory properties, fish oil can also be used to treat arthritis and colitis.

AVAILABILITY AND COST. High-quality brands of fish oils are available from Kyolic and Cardiovascular Research Ltd. Plain cod liver oil is not recommended because the amount needed to provide sufficient fatty acids might lead to an overdose of vitamin A. Fish oils can range in price from $5 to $15 for a month's supply, depending on the brand, and can be purchased in health food stores or through online vitamin catalogs. The usual dose is one to four capsules a day.

For those who experience stomach upset with fish oil, the enteric-coated version, Fisol (made by Nature's Way), may be preferred. The enteric coating allows the capsules to pass through the stomach, dissolving only once they reach the intestines. One capsule of Fisol provides 500 mg of omega-3 fatty acids. Vitacost sells a 180-capsule bottle of Fisol for $16.

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PATIENT REVIEWS

CFS/ME patient reviews of fish oil: http://www.revolutionhealth.com/drugs-treatments/rating/fish-oil-omega-3-epa-dha-fatty-acids-for-chronic-fatigue-syndrome-cfs-cfids-me

FLAXSEED OIL

DESCRIPTION. Flaxseed (linseed) is a good plant source of omega-3 fatty acids. It is also high in magnesium and zinc, two important factors in fatty acid metabolism, as well as B complex vitamins, protein, and potassium. Flaxseed oil is low in saturated fat and calories and contains no cholesterol. It has a delicious nutty flavor and can be added to salad dressings or sprinkled over vegetables.

Flaxseed is high in alpha-linoleic acid (ALA), which the body converts to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the two fatty acids found in fish oils. Some clinicians prefer flaxseed oil to fish oil because it is lower on the food chain and thus contains fewer fat-soluble contaminants. Fish oils, as opposed to vegetable oils, also contain large quantitites of vitamin A, which can be toxic in excessive amounts.

AVAILABILITY AND COST. Flaxseed oil can be purchased in health food stores and is inexpensive. NOW markets a 24-ounce bottle of organic flaxseed oil for $9. Flaxseed oil must be stored in the refrigerator to avoid rancidity. It should not be used for cooking. Gelcaps are also available.

PATIENT REVIEWS

CFS/ME patient ratings for flaxseed oil: http://www.revolutionhealth.com/drugs-treatments/rating/flax-seed-oil-omega-3-alpha-linolenic-acid-for-chronic-fatigue-syndrome-cfs-cfids-me

EVENING PRIMROSE OIL

DESCRIPTION. Evening primrose oil is one of the most popular and perhaps most effective of the omega-6 essential fatty acids. It comes from the evening primrose (Oenothera), a lovely yellow flower that grows wild along roadsides. The seeds contain large amounts of GLA (gamma-linoleic acid), a linoleic acid metabolite. Unlike other omega-6 fatty acids, GLA does not lead to increased production of pro-inflammatory cytokines, but has an anti-inflammatory effect. Evening primrose oil has been used to help alleviate the symptoms of premenstrual syndrome (PMS), menstrual cramps, and arthritis, often with dramatic results. It may even lessen the symptoms of endometriosis.

PROS AND CONS. Patients with CFS/ME have reported increased energy, improvements in skin disorders (eczema, acne, dry skin), and decreased mood swings. Side effects, although uncommon, include headache, nausea, mild intestinal discomfort, and, rarely, weight gain.

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AVAILABILITY AND COST. Evening primrose oil capsules are relatively inexpensive. A bottle of 60 softgels can be purchased for under $10 from online distributors.

PATIENT REVIEWS

CFS/ME patient ratings of evening primrose oil: http://www.revolutionhealth.com/drugs-treatments/rating/vitamin-c-ascorbic-acid-for-chronic-fatigue-syndrome-cfs-cfids-me

BORAGE SEED OIL

DESCRIPTION. Borage seed oil, made from the borage plant, contains the highest GLA content of any currently available seed oil, up to four times more than the GLA content of evening primrose oil. Patients who have gained little benefit from or cannot tolerate evening primrose oil because of food sensitivities often take borage oil with good results. The recommended dose is lower than for evening primrose oil, only one to three capsules a day. As with all EFAs, it is best to purchase products that are high quality. Pureformulas.com markets a bottle of 30 softgels made by Allergy Research Group for $14.

FOS (Fructooligosaccharides)

DESCRIPTION. FOS (Fructooligosaccharides) are natural sugars derived from fruits and vegetables.

BACKGROUND. FOS is produced from the degradation of inulin, or polyfructose. It is roughly half as sweet as sugar. FOS has achieved popularity as a “prebiotic,” something that provides a necessary substrate for lower intestinal flora, particularly bifidobacteria. FOS also helps increase the absorption of calcium and magnesium.

USES IN CFS/ME. FOS is primarily used in conjunction with probiotics to aid in the promotion of friendly gut bacteria.

Opinions about FOS are mixed in the CFS/ME community. Dr. Cheney, for example, is not a fan of FOS. In a 1999 talk about CFS/ME patients with leaky gut, he likened FOS to “throwing fertilizer on a patch of weeds.” By this, he is referring to the fact that FOS, like other prebiotics, will nourish harmful bacteria as well as friendly bacteria. In the presence of a bacterial infection in the gut or SIBO (small intestine bacterial overgrowth), prebiotics such as FOS will only make the condition worse. Dr. Myhill, on the other hand, recommends supplementation for FOS to help replenish friendly flora.

PROTOCOL. The normal dose is ¼ to 1 teaspoon of powder, taken 2 -3 times daily, in divided doses, with or between meals. FOS is sweet, so it can be used in place of sugar.

PROS AND CONS. There is not much patient feedback on FOS. In small amounts it does not cause side effects. If too much is taken, it can cause gas. Because FOS provides a substrate for all bacteria, it should not be taken in the presence of intestinal bacterial infections (such as C diff or SIBO).

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AVAILABILITY AND COST. FOS is available at health food stores and from online distributors. It can be purchased in capsules, tablets, or in a powder. Most health care practitioners recommend the powder, as it can be more easily titrated. PureFormulas.com markets a 100-gram container of FOS made by Pure Encapsulations for about $14. (At 1 teaspoon a day, a 100-gram container will last a month.) There are many probiotic/FOS combinations on the market.

GABA

DESCRIPTION. GABA (gamma aminobutyric acid) is the chief neuroinhibitory neurotransmitter in mammals. While GABA is commonly referred to as an amino acid, it is not incorporated into proteins.

BACKGROUND. Although GABA was first synthesized in the 19th century, it wasn't until 1950 that it was first discovered to be a central component of the nervous system of mammals. GABA is synthesized in the brain from glutamate, a neuroexcitatory neurotransmitter, through the enzyme L-glutamic acid decarboxylase in conjunction with the active form of vitamin B6. GABA's main function in the brain is to balance neuroexcitatory neurotransmitters by preventing nerves from excessive firing. There are many pharmaceuticals that act on GABA receptors, including anti-anxiety medications, anti-seizure medications, and pain medications. Valerian, skullcap, kava and L-theanine are supplements that act on GABA receptors.

USES IN CFS/ME. GABA has not been widely investigated in CFS/ME patients. Kowalski et al proposed that decreased activity of the enzymes which produce GABA may be the cause of several disorders, including CFS/ME. However, Murrough et al did not find any significant decrease in GABA itself among CFS/ME patients. In contradiction to Murrough's findings, McGregor et al found decreased beta-alanine (a GABA analogue) in CFS/ME patients, correlating with symptoms. However, Theodorsson et al found that while there was abnormal excretion of beta-alanine in CFS/ME patients, it did not correlate with symptoms. Notwithstanding this collection of contradictory evidence, it has long been proposed that people with CFS/ME suffer from neuroexcitatory states corresponding to an upregulated immune system.

Some CFS/ME doctors recommend GABA for their patients who experience anxiety and/or insomnia. Because GABA does not easily cross the blood-brain barrier, most physicians prefer to use pharmaceutical analogues such as Neurontin.

PROTOCOL. Dr. Rosenbaum recommends 500-1500 mg of GABA to his patients with insomnia.

PROS AND CONS. Given its inability to cross the blood-brain barrier, there is some doubt as to whether taking GABA supplements has any effect at all on the nervous system. But putting scientific skepticism aside, some patients report that it makes them jittery the day after using it for insomnia, which means it has some ability to affect the brain.

AVAILABILITY AND COST. GABA is sold in health food stores and from online suppliers. It is relatively inexpensive, and is available in pill, sublingual and

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powder form. The sublingual form is supposed to provide the greatest calming effect.

RESEARCH

Hannestad U, Theodorsson E, Evengård B. “Beta-Alanine and gamma-aminobutyric acid in chronic fatigue syndrome.” Clinica Chimica Acta. 2007 Feb;376(1-2):23-9. http://www.cfids-cab.org/cfs-inform/Hypotheses/hannestad.etal.06.txt

Kowalski A, Rebas E, Zylińska L. [Gamma-aminobutyric acid--metabolism and its disorders].Postepy Biochem. 2007;53(4):356-60. http://www.ncbi.nlm.nih.gov/pubmed/19024900 (Abstract)

McGregor NR, Dunstan RH, Zerbes M, Butt HL, Roberts TK, Klineberg IJ. “Preliminary determination of a molecular basis of chronic fatigue syndrome.” Biochem Mol Med. 1996 Apr;57(2):73-80. http://www.ncbi.nlm.nih.gov/pubmed/8733884 (Abstract)

Murrough JW, Mao X, Collins KA, Kelly C, Andrade G, Nestadt P, Levine SM, Mathew SJ, Shungu DC. “Increased ventricular lactate in chronic fatigue syndrome measured by 1H MRS imaging at 3.0 T. II: comparison with major depressive disorder.” NMR Biomed. 2010 Jul;23(6):643-50. http://www.ncbi.nlm.nih.gov/pubmed/20661876 (Abstract)

GALANTAMINE

DESCRIPTION. Galantamine is a selective acetylcholinesterase inhibitor.

BACKGROUND. Galantamine has been used for decades in Eastern Europe for various central nervous system disorders, including post-polio paralysis and myasthenia gravis. It was originally derived from the Galanthus Caucasicus (Caucasian snowdrop), whose nodding white blooms are among the first to appear in the spring. Recently, a synthetic compound, galantamine hydrobromide (brand name: Razadyne), was approved by the FDA as a treatment for Alzheimer's disease. Because galantamine increases acetylcholine, it has also been used to block the effects of nerve gas and organophosphate pesticides, which operate by blocking acetylcholine.

Chemically, galantamine reduces the action of acetylcholinesterase (AchE), the enzyme that breaks down acetylcholine. Galantamine also modulates nicotinic cholinergic receptors, which acts to increase the release of acetylcholine.

USES IN CFS/ME. The first study to test galantamine as a treatment for CFS/ME was conducted in 1996 by a team composed of Dr. Ernir Snorrason, Dr. Arni Geirsson and Dr. Kari Stefansson. Their hypothesis was that a dysfunction of the cholinergic system lay at the heart of CFS/ME. The researchers tested their hypothesis by administering galantamine hydrobromide to 39 CFS/ME patients.

The results were impressive; 43% reported an 50% improvement in fatigue, pain and sleep. The authors noted that the improvement was stable, and that none of the patients who had reported 50% improvement relapsed after the cessation of the trial. Most dramatic was the improvement in sleep. More than 60% of the patients who finished the study reported a 70% improvement of sleep disturbances.

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Given the striking results of this study, it is puzzling that there was so little follow-up. In 2009 Turan et al investigated the effects of galantamine on stress hormones in a group of CFS/ME patients. The study found that DHEAS/cortisol ratios normalized with galantamine treatment. But, while the findings confirmed a cholinergic deficit in CFS/ME, there have been no further treatment studies.

PROTOCOL. There is no protocol for galantamine. The Snorasson group used several different doses, but even at the lowest dose (5 mg) several patients developed severe nausea. High doses caused hallucinations, sweating, diarrhea, vomiting and confusion. Even though the side effects passed, Snorasson's group recommended starting with very low doses and close monitoring by a physician. They also recommended taking galantamine several hours before bed so as to reduce the risk of nightmares. Galantamine should be taken with choline.

AVAILABILITY AND COST. Galantamine is in the unusual class of medications that are both prescription drugs and supplements. (Even more confusing, nobody seems to know if there is a difference between the two.)

Galanta Mind, a blend of 4 mg galantamine hydrobromide, choline and B6 made by Life Enhancement, is available from such diverse sources as amazon.com, iHerb, and Sears. A 90-capsule bottle costs between $40 and $57, depending on the supplier. The manufacturer cautions that galantamine is for adults only. Instructions on the bottle read: “Start with one capsule each morning with breakfast for the first week. Add a second capsule with lunch, starting the second week. If desired, add another capsule to the breakfast serving the third week. Then, if desired, add another capsule to the lunch serving the fourth week, for a total of four capsules per day. If sensitivity occurs, reduce the amount used. If sensitivity continues, stop taking this supplement.”

FURTHER READING

“If Only Galantamine Could Talk.” Great summary of galantamine's fascinating history as well as its medicinal properties: http://www.life-enhancement.com/article_template.asp?ID=973

“Can Galantamine Help Chronic Fatigue?” Article on acetylcholine deficiency in CFS/ME patients. http://www.life-enhancement.com/article_template.asp?id=2224

Ray Sahelian discusses galantamine: http://www.raysahelian.com/galantamine.html

RESEARCH

Snorrason E, Geirsson A, Stefansson K. “Trial of a selective acetylcholinesterase inhibitor, galanthamine hydrobromide, in the treatment of chronic fatigue syndrome.” Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 35-54. http://www.hfme.org/researchmisc.htm (Scroll down for abstract.)

Spence VA, Khan F, Kennedy G, Abbot NC, Belch JJF. “Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome:

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a short review.” http://www.meresearch.org.uk/research/reviews/ach_review.html

Turan T, Izgi HB, Ozsoy S, Tanrıverdi F, Basturk M, Asdemir A, Beşirli A, Esel E, Sofuoglu S. “The effects of galantamine hydrobromide treatment on dehydroepiandrosterone sulfate and cortisol levels in patients with chronic fatigue syndrome.” Psychiatry Investig. 2009 Sep;6(3):204-10. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796068/

GLUCOSAMINE SULFATE

DESCRIPTION. Glucosamine sulfate is a mucopolysaccharide made up of the sugar glucose and the amino acid glutamine. It is the synthetic form of glucosamine, a naturally occurring amino acid compound found in the joints.

BACKGROUND. Glucosamine sulfate has been used for many years in Europe, Asia, and the Philippines to treat osteoarthritis. It appears to stimulate the synthesis of connective tissue and cartilage by aiding in the production of glucosaminoglycans and proteoglycans, the key building blocks of cartilage. Because glucosamine is also one of the main components of the synovial fluids that cushion joints and surrounding tissues, it has been used to treat degenerative joint diseases. It also may have anti-inflammatory properties, thereby lessening the need for anti-inflammatory pain medications.

USES IN CFS/ME. It is difficult to determine how useful glucosamine may be for people with CFS/ME. Its mode of action indicates that, in theory, it may be of benefit to patients with joint pain, fibromyalgia, or interstitial cystitis.

PROTOCOL. Dr. Jason Theodasakis, author of The Arthritis Cure, suggests taking glucosamine sulfate with chondroitin, another mucopolysaccharide, for maximum benefits. His daily dosage recommendations are based on patient weight:

 Less than 120 pounds: 1000 mg glucosamine sulfate plus 800 mg chondroitin

 120 to 200 pounds: 1500 mg glucosamine sulfate plus 1200 mg chondroitin

 200 pounds or more: 2000 mg glucosamine sulfate plus 1600 mg chondroitin

Other health care providers believe glucosamine sulfate is effective alone, although some recommend the addition of bromelain, an enzyme derived from pineapple, to help maximize its effects. Standard adult dosage as indicated by the manufacturer is one or two tablets three times a day. Health effects should be noticed within six to eight weeks. If no benefits are apparent by then, glucosamine sulfate should be discontinued.

PROS AND CONS. Glucosamine sulfate is generally considered safe and is well tolerated by most patients. However, some may be allergic to its source (usually crustacean shells). Patients taking blood thinners should consult with their physician before taking glucosamine sulfate because many of the mucopolysaccharides inhibit platelet formation.

AVAILABILITY AND COST. Glucosamine sulfate is available from health food stores and online distributors. A bottle of 120-tablets or capsules usually costs between $12 and $15. Glucosamine sulfate is also available in liquid form.

FURTHER READING

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Results of a comprehensive multi-center investigation of glucosamine chondroitin. http://nccam.nih.gov/research/results/gait/qa.htm

GLUTATHIONE

DESCRIPTION. Glutathione is a tripeptide composed of glycine, cysteine, and glutamic acid.

BACKGROUND. Glutathione is found in high concentrations in every tissue in the body. It is one of the three most powerful antioxidants and detoxification agents in the body, protecting tissues against damage from oxygen radicals such as hydrogen peroxide and superoxide. It also helps reduce injury caused by radiation, chemotherapy, heavy metals (mercury), and drugs (including cigarettes and alcohol). NAC (N-acetyl-L-cysteine), a precurser to glutathione, is an antidote to acetaminophen poisoning and helps deter the toxic effects of naphthalene, benzene, and anthracine. Low glutathione levels are associated with cataracts and muscle wasting diseases.

USES IN CFS/ME. A relationship between glutathione, muscle fatigue, low natural killer (NK) cell activity and CFS/ME was first proposed in 1997 by Droge and Holm, two scientists researching HIV in Heidelberg, Germany. Notably, Droge and Holm suggested cysteine supplementation as an adjunct to antiviral therapies to correct low glutathione. Expanding on their idea in 1999, two researchers at McGill University proposed that competition for glutathione between the immune system and skeletal muscles might be the cause of fatigue, muscle weakness, and pain in CFS/ME patients. More recently, Shungu et al found that glutathione levels were low in the cerebrospinal fluid of CFS/ME patients.

Dr. Patricia Salvato of Houston, Texas, reported in the CFIDS Chronicle (Jan/Feb 1998) that she had treated 276 CFS/ME patients with glutathione injections. Eighty-two percent of her patients experienced improvement in fatigue, 71 % reported improvement in memory and concentration, and 62% reported reduced pain. Natural killer cell function was also measured, with 187 people showing a two-fold increase. Some patients received the therapy for as long as 16 months. The only adverse side effects observed were palpitations in a few patients and a slight rash or itching around the site of injection.

Dr. Paul Cheney, who at one time stated that glutathione deficiency was universal among CFS/ME patients, has noted a striking improvement in his patients' symptoms, especially headache, within days of initiating glutathione treatment.

PROTOCOL. Because oral glutathione is poorly absorbed in the gut, Dr. Cheney recommends reduced glutathione (CFIDS Chronicle, Spring 1995). Initial doses are high, from 150 to 425 mg three times a day. After a short time, doses can be reduced to 75 to 150 mg three times a day and maintained at those levels. Glutathione can also be administered IV.

AVAILABILITY AND COST. There is no way of knowing how much, in any, glutathione is absorbed by mouth, so injectable forms are preferred. (These require a doctor.) Alternative forms of glutathione (suppositories and troches) may have

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greater absorption rates. A pack of 30 Zetpil glutathione suppositories are available through Forrest Health for $99. Glutathione troches are available through compounding pharmacies.

In part because glutathione is so difficult to administer effectively, a synthetic glutathione peroxidase mimic, ebselen, has been developed. Initial studies demonstrated that ebselen was effective in protecting against chemotherapy-induced hearing loss, renal injury and in recovery from stroke (if administered within 24 hours). Ebselen protects against manganese toxicity, inhibits Candida overgrowth, and performs a host of antioxidant activities. Ebselen has been licensed in the U.K. for treatment of ischemic stroke. It has not yet been approved by the FDA.

FURTHER READING

Rich Van Konynenburg's excellent review of glutathione, including protocols, dosages, suppliers. http://aboutmecfs.org.violet.arvixe.com/Trt/TrtGlutathioneBuild.aspx

Another excellent discussion by Rich Van Konynenburg proposing glutathione depletion as a cause of CFS/ME: http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=1287095

A list of articles about glutathione written by Rich Van Konynenburg. http://forums.phoenixrising.me/showthread.php?12927-Documents-by-Rich-Van-Konynenburg

An interesting, if somewhat convoluted, discussion of glutathione and its role in CFS/ME. http://user.xmission.com/~total/temple/Soapbox/Articles/glutathione.html

Ray Sahelian discusses glutathione's role in various disease processes. Some good research citations. http://www.raysahelian.com/glutathione.html

Glutathione suppositories: http://www.forresthealth.com/reduced-glutathione-suppositories-30-count.html

RESEARCH

Bounous G, Molson J. “Competition for glutathione precursors between the immune system and the skeletal muscle: pathogenesis of chronic fatigue syndrome.” Med Hypotheses 1999 Oct;53(4):347-9. http://www.ncbi.nlm.nih.gov/pubmed/10608272 (Abstract)

Droge W, and Holm E. “Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction.” FASEB J. (1997) 11:1077-1089. http://www.fasebj.org/content/11/13/1077

Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. “Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis / chronic fatigue syndrome: another pathway that may be associated with coronary artery disease and neuroprogression in depression.” Neuro Endocrinol Lett. 2011;32(2):133-40. http://www.ncbi.nlm.nih.gov/pubmed/21552194 (Abstract)

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Nakamura, Yoshimasa, Qing Feng, Takeshi Kumagai, Koji Torikai, Hajime Ohigashi, Toshihiko Osawa, Noriko Noguchi, Etsuo Niki, and Koji Uchida. “Ebselen, a Glutathione Peroxidase Mimetic Seleno-organic Compound, as a Multifunctional Antioxidant: Implication for Inflammation-Associated Carcinogensis.” The Journal of Biological Chemistry, January 25, 2002, 277, 2687-2694. http://www.jbc.org/content/277/4/2687 (Abstract)

Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, Medow MS, Natelson BH, Stewart JM, Mathew SJ. “Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology.” NMR Biomed. 2012 Jan 27. http://www.ncbi.nlm.nih.gov/pubmed/22281935 (Abstract)

HERBS

Aloe vera, Astragalus, Chamomile, Echinacea, Garlic, Ginger, Gingko, Ginseng, Goldenseal, Gotu kola, Kava, Licorice, Lomatium, Milk Thistle, St. John's Wort, Uva ursi, Valerian

DESCRIPTION. Medicinal herbs are plants taken orally as teas or tinctures, or applied topically as poultices in order to heal the body.

BACKGROUND. Plants have always been used as remedies, which makes herbal treatment the earliest form of medicine. (The earliest human graves contain remnants of medicinal flowers.) Even animals eat certain plants when they become ill. Throughout the ages, people have used herbal remedies for an assortment of problems and, until the nineteenth century, herbs were the treatment of choice for most common ailments. Herbs have such a long history they are regarded as folk remedies. The contemporary medical world, as a consequence, has largely excluded them from scientific investigations, with the exception of the Chinese, who take herbs quite seriously. The government of China has funded a considerable amount research to study the chemical components, action, and efficacy of a number of herbs.

USES IN CFS/ME. A large number of patients with CFS/ME symptoms use herbs regularly, either as herbal substitutes for pharmaceuticals or as adjuncts to other therapies. Although many find that a particular herb is helpful for a specific symptom, most report that herbs have limited value in treating CFS/ME over the long term. It should be noted, however, that patients who have tried Chinese herbs (usually on the recommendation of an acupuncturist) generally report a higher rate of success.

PROTOCOL. Although herbalists recommend blending herbs for maximum effect, patients with CFS/ME frequently have had poor responses to multiple-herb blends (with the notable exception of Chinese herbs). For CFS/ME symptoms, herbs are best taken singly in teas or tinctures. Teas are prepared according to the part of the plant used. One teaspoon of herb leaves is steeped in two cups of boiling water for 15 or 20 minutes or ½ teaspoon of herb root or bark is boiled in two cups of

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water. One to two cups of tea per day can be taken for up to two weeks. After that, the herb loses its potency. Tinctures are usually purchased from health food stores. Because they are quite strong, tinctures are usually taken a few drops at a time in water. For chronic symptoms, teas are advised. Short-term problems (flu, toothache, etc.) are best treated with tinctures.

Note: Most tinctures are prepared in an alcohol medium. People with CFS/ME are advised to "flash off" the alcohol by adding the tincture to scalding hot water.

PROS AND CONS. Herbs are inexpensive, safe, and readily available. However, it is always best to purchase them from a health food or specialty store. Culinary herbs from the grocery store are usually treated with chemical preservatives, seldom organic, and have little medicinal worth. The advantage of herbs for many people with drug and chemical sensitivities is that they can produce the desired therapeutic effects without as many side effects. This is not to say that negative reactions are not possible. People with bladder problems (interstitial cystitis), gastrointestinal symptoms, or migraine headaches may find that many herbs produce the same side effects as pharmaceuticals.

In general, patients with CFS/ME should avoid herbs classified as stimulants (ephedra, lomatium, and ginseng), because these can overtax the adrenal glands. Ephedra (ma huang), used to treat bronchial infections, is a powerful stimulant and can cause high blood pressure, palpitations, and even stroke. Ginseng and lomatium, although not as strong as ephedra, can produce similar reactions in the severely ill. Echinacea, because it is an immune system stimulant, might best be avoided by those with upregulated immune systems.

Some herbs such as goldenseal and St. John's Wort must be used with caution. St. John's Wort acts like a monoamine oxidase inhibitor (MAOI) and must be treated with the same care as the drug. (The newsletter of the Center for Specialized Immunology reported a serious reaction in a patient who took St. John's Wort concomitantly with an antidepressant.)

Chapparal and comfrey have caused liver problems in some people who took too high a dose. However, there are many other herbs that can provide temporary, safe relief from numerous CFS/ME symptoms. Those interested in pursuing herbal remedies should read about herbs before embarking on an herbal therapy program or should consult with an herbalist.

FURTHER READING

Dr. Teitelbaum's herb recommendations for CFS/ME patients. http://www.immunesupport.com/news/99spr012.htm

Nicely organized site about herbs. Herbs are listed alphabetically for easy access. http://www.herbwisdom.com/

BOOK

Castleman, Michael. The Healing Herbs. Emmaus, Pa.: Rodale Press, 1991

This is a well-organized introduction to herbs and their uses.

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ALOE VERA

Aloe vera is a succulent plant originating in Africa. Because it exudes a mucousy substance when cut, it has a long history as a topical treatment for minor burns. More recently, aloe juice has been promoted as an immune enhancer and as a treatment for cancer. Though research has not been able to substantiate these claims, aloe vera juice is recommended for people with a variety of immune system ailments.

While some people with CFS/ME have taken aloe and been pleased with the results, there are more negative than positive reviews. Although it is touted as a cure for IBS, aloe vera can cause diarrhea and intestinal irritation even in very small amounts.

FURTHER READING

General information about aloe vera: http://www.herbwisdom.com/herb-aloe-vera.html

CFS/ME patient reviews of aloe vera: http://www.revolutionhealth.com/drugs-treatments/rating/aloe-vera-aloe-barbadensis-for-chronic-fatigue-syndrome-cfs-cfids-me

ASTRAGALUS

Astragalus (Astragalus membranaceous) root has been popularized as an immune system modulator. It reputedly enhances immune system function when it is deficient and down regulates it when overactive. It is also thought to increase energy, stamina, and well-being and supports adrenal gland function. Some use it as a digestive aid. The effects of astragalus are not dramatic in most people, but some CFS/ME patients have noted increased energy after taking tincture of astragalus.

Recent research has shown that astragalus has measurable medicinal properties. A 2011 study by Cheng et al showed that astragalus may serve as a natural cholesterol-lowering agent. Astragalus has also been shown to enhance both humoral and cellular immune response (Th1 and Th2).

FURTHER READING

General information about astragalus http://www.immunesupport.com/news/98spr007.htm

More general information about astragalus: http://www.herbwisdom.com/herb-astragalus.html

RESEARCH

Cheng Y, Tang K, Wu S, Liu L, Qiang C, Lin X, Liu B. “Astragalus Polysaccharides Lowers Plasma Cholesterol through Mechanisms Distinct from Statins.” PLoS ONE. 2011;6(11):e27437. http://www.ncbi.nlm.nih.gov/pubmed/22110652 (Abstract)

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Du X, Chen X, Zhao B, Lv Y, Zhang H, Liu H, Chen Z, Chen Y, Zeng X. “Astragalus polysaccharides enhance the humoral and cellular immune responses of hepatitis B surface antigen vaccination through inhibiting the expression of transforming growth factor β and the frequency of regulatory T cells.” FEMS Immunol Med Microbiol. 2011 Nov;63(2):228-35 http://www.ncbi.nlm.nih.gov/pubmed/22077226

CHAMOMILE

Chamomile (Matricaria chamomila [German chamomile]; Anthemis nobilis [Roman chamomile]) is a member of the daisy family. It is currently one of the most popular herbs in the United States and is widely used as an herb tea, in shampoos and soaps, and in skin-care products. Chamomile has been known as a sedative and antifever medicine since ancient times and was used by Greek and Roman physicians to treat a variety of ailments.

Contemporary herbalists recommend chamomile to treat digestive problems and ulcers, to prevent the spread of infections, and to reduce inflammation. Because chamomile is an antispasmodic, it has also been used to lessen the severity of menstrual cramps. Perhaps the most interesting effect of this herb is its ability to stimulate the immune system. British researchers discovered that chamomile increases macrophages and B lymphocytes.

USES IN CFS/ME. Patients with CFS/ME have chamomile tea before bedtime to help with insomnia and to alleviate gastrointestinal symptoms. Simply inhaling the steam is enough to produce a calming effect. (The sedative effects of the tea may be due to apigenin, a flavonoid that binds to benzodiazepine receptors.) In general, the herb is well tolerated. Chamomile tea should not be boiled because boiling makes the tea bitter. Those allergic to ragweed should avoid this herb.

FURTHER READING

General information about chamomile: http://www.herbwisdom.com/herb-chamomile.html

ECHINACEA

The roots of the purple coneflower (Echinacea angustifolia, E. purpura) were used by Plains Indians as a cure for all kinds of infections. Although it has been relied on as a topical wound healer since Colonial times, echinacea's antibiotic properties have largely been unexplored until recently. Research conducted in Germany in the 1950s through the 1980s revealed that echinacea has broad antibiotic properties, much like penicillin, due to a substance (echinacein) that counteracts cell-penetrating enzymes. In this manner, echinacea works to strengthen individual cell defenses.

Echinacea also acts as an immune system stimulant. Echinacea boosts the macrophage's ability to destroy germs. It possesses antifungal as well as antibacterial properties. As an antiviral agent, echinacea has been used effectively to treat influenza and the common cold as well as to check herpesvirus infections.

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USES IN CFS/ME. People with CFS/ME often use echinacea at the first sign of a cold or flu to help lessen the severity of the illness, and some even report lessening of all symptoms after using this herb. Echinacea tinctures are more effective than pills or capsules. An alcohol-free tincture should be used, however, because alcohol dramatically lessens the potency of this herb. Dry echinacea root can be purchased in health food stores and boiled to make a tea.

PROTOCOL. Dr. Teitelbaum recommends 300 to 325 mg taken three times a day. He recommends that patients take a break from echinacea for one week each month, or it will stop working. He suggests echinacea may also improve adrenal function. Other practitioners recommend starting at lower doses (200 mg). Alcohol-free tinctures can be taken at 15 to 20 drops a day.

Dr. Cheney is not a fan of echinacea. He believes that the immune-activating properties of the herb may pose problems for CFS/ME patients with upregulated immune systems.

FURTHER READING

General information about echinacea: http://www.herbwisdom.com/herb-echinacea.html

CFS/ME patient reviews of echinacea: http://www.revolutionhealth.com/drugs-treatments/rating/echinacea-echinacea-spp-for-chronic-fatigue-syndrome-cfs-cfids-me

RESEARCH

See DM, Broumand N, Sahl L, Tilles JG. “In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients.” Immunopharmacology 1997 Jan;35(3):229-35. http://www.ncbi.nlm.nih.gov/pubmed/9043936 (Abstract)

GARLIC

Garlic (Allium sativum) has a long history as a medicinal plant. The earliest medicinal description of garlic dates from 3000 BC. Garlic was even found in the tomb of King Tut. It has been used to treat headache, insect bites, menstrual disorders, intestinal worms, tumors, and heart disease. Garlic is a powerful antibiotic and antiprotozoan agent. It kills intestinal parasites, destroys the bacterium that causes tuberculosis, and can be used against various fungi, including Candida albicans. Daily ingestion of as little as half a clove of garlic can lower cholesterol. Garlic also lowers blood pressure, which means it may have a negative effect on people with hypotension. Some people with CFS/ME tend to be sensitive to garlic in both its raw and cooked forms. Enteric, deodorized garlic pills can reduce intestinal upset. A commonly recommended brand of deodorized garlic in capsules, Kyolic, is widely available from health food stores.

FURTHER READING

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General information about garlic: http://www.herbwisdom.com/herb-garlic.html

CFS/ME patient reviews of garlic: http://www.revolutionhealth.com/drugs-treatments/rating/garlic-allium-sativum-for-chronic-fatigue-syndrome-cfs-cfids-me

GINGER

Ginger (Zingiber officinale) was used by the ancient Greeks as a digestive aid. It is still used as an antidote for motion sickness, nausea, and numerous digestive disturbances. It soothes smooth muscles, making it useful for alleviating menstrual cramps, as well. Ginger can be taken in capsule form or boiled to make tea. Ginger root is available from grocery or health food stores. Ginger powder, however, as found in the spice section of a grocery store, should not be used as a medication because it is usually irradiated. Excessive amounts may cause mild headache. Some people with CFS/ME find ginger difficult to tolerate.

USES IN CFS/ME. Dr. Teitelbaum is a ginger enthusiast. He recommends it for relief of muscle and joint pain, nausea, migraines, motion sickness, and for raising blood pressure (for those with hypotension). The most common use among people with CFS/ME is for nausea, a symptom which can be utterly debilitating if unchecked.

PROTOCOL. Ginger is a food, so it can be taken on an as-needed basis. It can be purchased as a whole root, grated and added to food, or boiled to make a tea. For those with less tolerance for ginger's strong flavor, candied ginger may be eaten (or simply held under the tongue) as an alternative. Dry encapsulations are also available, although these tend to be less effective.

PROS AND CONS. A small amount of ginger goes a long way. CFS/ME patients find it especially effective for nausea and dizziness. It has an almost immediate effect. Dry ginger capsules may cause heartburn.

AVAILABILITY AND COST. Fresh ginger and candied ginger are available in health food stores, supermarkets and Asian specialty markets. Dried, encapsulated ginger can be purchased at health food stores and from online distributors. A 180-capsule bottle of Nature's Way dry ginger costs about $5 from Vitacost.

FURTHER READING

CFS/ME patient reviews of ginger: http://www.revolutionhealth.com/drugs-treatments/rating/ginger-zingiber-officinale-for-chronic-fatigue-syndrome-cfs-cfids-me

GINGKO

Gingko (Gingko biloba) is the oldest species of tree on the planet. The Chinese have used its leaves for over 5000 years as an elixir to promote longevity. Studies have shown that gingko, by increasing blood flow to the brain, helps reduce the risk of stroke. It can also dramatically improve memory and reaction time. The neuroprotective effects of gingko are well documented. There is some evidence that

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gingko modulates serotonin and dopamine, and may have antidepressant-like effects. Gingko also acts as a potent antioxidant, reducing oxidative stress by simultaneously scavenging peroxynitrite, nitric oxide and superoxide. In Europe, gingko is used as a conventional drug for treating short-term memory loss, headache, tinnitus, anxiety, vertigo, and depression.

USES IN CFS/ME. Alan Logan and Cathy Wong, in their comprehensive assessment of non-drug treatments for CFS/ME, state that because ginkgo has specific effects on cerebral blood flow, it may be useful for CFS symptoms related to hypoperfusion in the brain. Many CFS/ME doctors have recommended gingko to their patients, including Dr. Cheney and Dr. Teitelbaum.

PROTOCOL. For maximum effectiveness, gingko biloba should be taken as an extract (not a tea). Extracts are available in either pill or liquid form. In pill form, Dr. Teitelbaum recommends a 50:1 extract standardized to have 24% Glycosides (this will be indicated on the label). A 60-mg capsule can be taken once a day. The standard dose of liquid extract is 20 drops, up to three times a day. It may take up to six weeks to take effect.

PROS. For some people, gingko has been a “lifesaver,” allowing them to process information again. Many CFS/ME patients have reported that gingko helps cognitive function, memory, and “brain fog.” Some report a decrease in migraines and headache, as well as increased circulation to the legs.

CONS. Although gingko is usually well tolerated, some patients with CFS/ME have reported increased fatigue. Excessive doses can cause irritability, restlessness, nausea, and diarrhea. Gingko has mild blood thinning properties, which means it cannot be taken in conjunction with pharmaceutical blood thinners (e.g., Coumadin).

FURTHER READING

General information about gingko: http://www.herbwisdom.com/herb-ginkgo-biloba.html

More general information about gingko: http://www.altnature.com/gallery/Ginkgo_Biloba.htm

CFS/ME patient reviews of gingko: http://www.revolutionhealth.com/drugs-treatments/rating/ginkgo-ginkgo-biloba-for-chronic-fatigue-syndrome-cfs-cfids-me

Logan, Alan C., and Cathy Wong. “Chronic Fatigue Syndrome: Oxidative Stress and Dietary Modifications.” http://www.thorne.com/altmedrev/.fulltext/6/5/450.pdf

RESEARCH

Bastianetto S, Ramassamy C, Doré S, Christen Y, Poirier J, Quirion R. “The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid.” Eur J Neurosci. 2000 Jun;12(6):1882-90. http://www.ncbi.nlm.nih.gov/pubmed/10886329 (Abstract)

Diamond BJ, Shiflett SC, Feiwel N, Matheis RJ, Noskin O, Richards JA, Schoenberger NE. “Ginkgo biloba extract: mechanisms and clinical indications.”

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Arch Phys Med Rehabil. 2000 May;81(5):668-78. http://www.ncbi.nlm.nih.gov/pubmed/10807109 (Abstract)

Ihl R., Bachinskaya N., Tribanek M., Hoerr R. and Napryeyenko O. for the GOTADAY Study Group. “Efficacy and Tolerability of a Once Daily Formulation of Ginkgo biloba Extract EGb 761® in Alzheimer's disease and Vascular Dementia: Results from a Randomised Controlled Trial.” Pharmacopsychiatry. 2011 Nov 15. http://www.ncbi.nlm.nih.gov/pubmed/22086747 (Abstract)

Rojas P, Serrano-García N, Medina-Campos ON, Pedraza-Chaverri J, Ogren SO, Rojas C. “Antidepressant-like effect of a Ginkgo biloba extract (EGb761) in the mouse forced swimming test: role of oxidative stress.” Neurochem Int. 2011 Oct;59(5):628-36. http://www.ncbi.nlm.nih.gov/pubmed/21672588 (Abstract)

Woelk H, Arnoldt KH, Kieser M, Hoerr R. “Ginkgo biloba special extract EGb 761 in generalized anxiety disorder and adjustment disorder with anxious mood: a randomized, double-blind, placebo-controlled trial.” J Psychiatr Res. 2007 Sep;41(6):472-80. http://www.ncbi.nlm.nih.gov/pubmed/16808927 (Abstract)

GINSENG

Ginseng (Panax schinseng,aka Chinese or Korean ginseng) is an ancient tonic and stimulant. It has been shown to possess anti-inflammatory, anti-diabetic, and antioxidant properties. Ginseng is frequently described as an “adaptogen,” which means it can have normalizing metabolic effects, especially when homeostasis is disrupted. Although it possesses enormous therapeutic potential for common ailments, ginseng is usually not recommended to patients with severe CFS/ME. Ginseng stimulates the adrenal glands and can increase production of interferon. Because most patients with CFS/ME have excessive interferon production as well as endocrine abnormalities, panax ginseng may increase symptoms.

Siberian ginseng (Eleutherococcus senticoccus), although it belongs to a different genus, has similar medicinal qualities to panax ginseng. (Though interestingly, Siberian ginseng appears to have the opposite effect of reducing inflammatory responses.) Siberian ginseng, marketed as Eleutherococcus Senticosus, is less expensive than panax ginseng and is often found in herbal ginseng formulations. (Check the label if you are looking for pure panax ginseng.)

Ginseng should not be used with estrogens or corticosteroids because of possible additive effects. It may affect the blood glucose levels of patients with diabetes mellitus.

RESEARCH

Gaffney BT, Hügel HM, Rich PA. “Panax ginseng and Eleutherococcus senticosus may exaggerate an already existing biphasic response to stress via inhibition of enzymes which limit the binding of stress hormones to their receptors.” Med Hypotheses. 2001 May;56(5):567-72. http://www.ncbi.nlm.nih.gov/pubmed/11388770 (Abstract)

Jung CH, Jung H, Shin YC, Park JH, Jun CY, Kim HM, Yim HS, Shin MG, Bae HS, Kim SH, Ko SG. “Eleutherococcus senticosus extract attenuates LPS-induced

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iNOS expression through the inhibition of Akt and JNK pathways in murine macrophage.” J Ethnopharmacol. 2007 Aug 15;113(1):183-7. http://www.ncbi.nlm.nih.gov/pubmed/17644291 (Abstract)

See DM, Broumand N, Sahl L, Tilles JG. “In vitro effects of echinacea and ginseng on natural killer and antibody-dependent cell cytotoxicity in healthy subjects and chronic fatigue syndrome or acquired immunodeficiency syndrome patients.” Immunopharmacology. 1997 Jan;35(3):229-35. http://www.ncbi.nlm.nih.gov/pubmed/9043936 (Abstract)

GOLDENSEAL

Goldenseal (Hydrastis canadensis) is a North American herb known best for its antibiotic properties. Berberine, a substance found in goldenseal, kills many of the bacteria that cause diarrhea, as well as the protozoa that cause amoebic dysentery and giardiasis. It has been used against cholera bacteria and as a treatment for throat, sinus, and topical bacterial infections. Research has shown that goldenseal is also effective against some viral infections. People with CFS/ME generally use goldenseal to treat sinusitis and canker sores. It should be used with caution, however. Excessive or lengthy (more than 10 days) treatment can lead to neurological disturbances and gastrointestinal upset. The safest way to take goldenseal is externally as a poultice or paste spread directly over the sinuses or other affected area. Goldenseal should not be used during pregnancy because it stimulates uterine contractions.

RESEARCH

Cecil CE, Davis JM, Cech NB, Laster SM. “Inhibition of H1N1 influenza A virus growth and induction of inflammatory mediators by the isoquinoline alkaloid berberine and extracts of goldenseal (Hydrastis canadensis).” Int Immunopharmacol. 2011 Nov;11(11):1706-14. http://www.ncbi.nlm.nih.gov/pubmed/21683808 (Abstract)

GOTU KOLA

Gotu kola (Centella asiatica; Hydrocotyle asiatica), also known as sheep rot, Indian pennywort, marsh penny, and water pennywort, was originally used in Sri Lanka as a promoter of longevity. It is a member of the Umbelliferae family, which also includes carrots, parsley, dill, and fennel. Despite the similarity in name, gotu kola is not related to the stimulant kola. In small amounts, gotu kola is taken as a tonic, and in larger amounts as a sedative. Gotu kola traditionally has been used in the treatment of leprosy, but it is also noted for its ability to promote blood circulation. Gotu kola has been used to increase memory and mental function by increasing circulation to the brain.

FURTHER READING

Shinomol G K, Muralidhara, Bharath M M. “Exploring the Role of "Brahmi" (Bocopa monnieri and Centella asiatica) in Brain Function and Therapy.”

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Recent Pat Endocr Metab Immune Drug Discov 2011 Jan;5 1:33-49. http://www.ncbi.nlm.nih.gov/pubmed/22074576 (Abstract)

KAVA

Kava, or kava-kava (Piper methysticum) is a plant native to the Pacific. Traditionally, it has been used in the South Pacific in drinks. The roots of the plants have a sedative effect, making it a popular treatment for anxiety.

There has been a considerable amount of controversy surrounding the medicinal use of kava in recent years. In 2001, researchers discovered an apparent link to kava and liver toxicity which led European, British and Canadian authorities to ban kava sales in 2002. However, further research indicated that the toxic compounds were located in the stem peelings and leaves, which are parts of the plant not traditionally consumed. (Only the roots are used in Pacific cultures.) A study published in 2003 by Whitton et al found that modern extraction methods, using acetone or ethanol, were responsible for kava toxicity.

Kava is used primarily as a sleep aid and as an anxiolytic. In 1997 Volz et al found that an extract of kava was just as efficacious as benzodiazepines or antidepressants in reducing anxiety, and with none of the side effects. There is also some evidence that kava may be useful in treating ADD, which might help reduce the need for stimulant medications in children.

PROTOCOL. The recommended dose of kava extract for insomnia is 70 – 200 mg taken an hour before bedtime. For daytime anxiety, 70 mg may be taken one to three times a day. Kava is not sedating when taken at moderate doses. To avoid stomach upset, it's best to take kava with a little food.

RESEARCH

Sarris J, Kean J, Schweitzer I, Lake J. “Complementary medicines (herbal and nutritional products) in the treatment of Attention Deficit Hyperactivity Disorder (ADHD): a systematic review of the evidence.” Complement Ther Med. 2011 Aug;19(4):216-27. http://www.ncbi.nlm.nih.gov/pubmed/21827936 (Abstract)

Teschke R, Sarris J, Schweitzer I. “Kava hepatotoxicity in traditional and modern use: The presumed Pacific kava paradox hypothesis revisited.” Br J Clin Pharmacol. 2011 Jul 29. http://www.ncbi.nlm.nih.gov/pubmed/21801196 (Abstract)

Volz HP, Kieser M. “Kava-kava extract WS 1490 versus placebo in anxiety disorders--a randomized placebo-controlled 25-week outpatient trial.” Pharmacopsychiatry 1997 Jan;30(1):1-5. http://www.ncbi.nlm.nih.gov/pubmed/9065962 (Abstract)

Whitton, Peter A., Andrew Lau, Alicia Salisbur, Julie Whitehousec, Christine S. Evans. “Kava lactones and the kava-kava controversy.” Phytochemistry, Volume 64, Issue 3, October 2003, Pages 673-679. http://www.sciencedirect.com/science/article/pii/S0031942203003819

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LICORICE

Licorice (Glycyrrhiza glabra) has long been known as one of nature's most potent healing herbs. It is a popular ingredient in many Chinese herbal remedies and has been used to treat cough, sore throat, ulcers, arthritis, herpes infections, and hepatitis. When combined with other herbs, licorice can increase their effectiveness.

USES IN CFS/ME. In CFS/ME, licorice is reputed to alleviate symptoms associated with adrenal insufficiency (intolerance to heat, cold, noise, and other stimuli, low blood pressure, faintness). Because the action of licorice's main active chemical, glycyrretinic acid (GA), resembles that of the adrenal hormone aldosterone, licorice helps the body retain salt (and water) and ultimately may help raise blood volume and pressure. Because low blood pressure is a problem for many patients with CFS/ME, licorice could prove beneficial, especially for those who are sensitive to the drugs normally recommended to correct low blood pressure. In addition, licorice raises serum cortisol levels (often low in CFS/ME patients) and stimulates natural killer cell activity.

PROTOCOL. Dr. Riccardo Baschetti has used licorice for patients with low or low-normal plasma levels of cortisol. He claimed that dramatic improvement in CFS/ME symptoms could be seen after taking licorice for just three days (New Zealand Medical Journal, 1995). Baschetti recommends 2.5 gm of licorice root a day, in extract or capsules dissolved in milk. (Milk enhances the aldosterone-like effects of the licorice.)

Dr. Peter D'Adamo, a naturopath who also uses licorice to treat symptoms of CFS/ME, suggests taking ¼ teaspoon (2 gm) of solid licorice extract one to three times a day. He recommends his patients take 500 mg of the amino acid methionine and 99 mg of potassium supplement three times a day along with the licorice to counteract any potassium and sodium imbalances.

A number of physicians have recommended licorice for NMH (neurally mediated hypotension). NMH is a common problem for patients with CFS/ME, affecting up to 90% of the CFS/ME population. Many people with CFS/ME are sensitive to Florinef, the medication normally prescribed for NMH. Dr. Calkins, a member of the team at Johns Hopkins Medical Center that performed the initial investigations on NMH in adolescents, stated that "medicinal licorice is a good alternative for those sensitive to Florinef."

Dr. Cheney also endorses licorice for treating NMH. Dr. Cheney has found that Florinef forces potassium depletion, which further depresses the HPA (hypothalamus-pituitary-adrenal) axis in CFS/ME patients. Licorice can accomplish the same results as Florinef, without the side effects. He recommends two licorice root tablets with glycerizzin two times a day. Dr. Cheney adds the caution, “Blood pressure must be monitored when taking licorice root!”

For optimal effect, licorice should be taken in the morning. (Cortisol levels in the body reach their peak at about 8AM.) It is important to note that licorice candies produced in the U.S. do not use licorice, but anise, as a flavoring. Doctors caution their patients to use pure licorice, not DGL. DGL (de-glycyrrhizinated

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licorice ), a form of licorice in which glycyrrhizin has been removed. Glycyrrhizin is removed in DGL to prevent hypertension, however, it is the ingredient in licorice that treats NMH.

PROS AND CONS. Patients who have taken licorice report increased energy levels and improvement in symptoms of hypoglycemia, though some have noticed that its effectiveness wanes after a few months. Because of its steroid-like qualities, and due to its ability to help retain sodium, it is important to monitor licorice intake. Too much licorice, especially without potassium supplementation, can cause serious side effects. If high blood pressure, headaches, lethargy, and water retention develop, the dosage should be decreased immediately. Patients taking drugs that could interact with licorice, such as heart medications, MAOIs, or diuretics, should consult with their physician before embarking on a licorice protocol.

AVAILABILITY AND COST. Solid licorice extract is marketed by Allergy Research Group. A 4-oz container (½ tsp = 3 grams) sells for $24 through PureFormulas.com (online). Douglas Labs sells a 60-capsule bottle of pure licorice (500 mg) for $16 (also through PureFormulas.com).

FURTHER READING

Good article on licorice: http://drholly.typepad.com/licorice/

Excellent summary of licorice as a treatment for CFS/ME: http://www.encognitive.com/node/15023

General information on licorice root: http://www.herbwisdom.com/herb-licorice-root.html

Ray Sahelian on licorice: http://www.raysahelian.com/licorice.html

Baschetti, R. “Chronic fatigue syndrome and liquorice” N Z Med J. 1995 Apr 26;108(998):156-7.

LOMATIUM

Lomatium is a North American herb reputed to have antiviral properties. It has been used to treat influenza, colds, and diseases such as measles. A number of patients who have tried lomatia extract have felt overstimulated. Some have experienced malaise, insomnia, and jitteriness after as little as one drop. Reports from the late 1980s stated that some CFS/ME patients have developed severe allergic reactions while taking this herb.

FURTHER READING

Literally everything you need to know about lomatium: http://www.naturalpedia.com/Lomatium.html

MILK THISTLE/SILYMARIN

Milk thistle (Silybum marianum), also referred to as silymarin, appears to have a remarkable effect on the liver. There is a great deal of research showing that active ingredient in silymarin, silybin, stimulates liver cells to regenerate and is effective in treating jaundice, hepatitis C, and cirrhosis. Silymarin increases the

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amount of liver glutathione, a tripeptide that activates liver enzymes. As a consequence, milk thistle helps protect the liver from toxins, including poisonous mushrooms, and various petrochemicals. In addition, silymarin has powerful antioxidant, anti-inflammatory, anti-cancer and cardioprotective properties. It also helps synthesize superoxide dismutase (SOD), an enzyme that increases mitochondrial function and can prevent oxidative stress both within and outside cell walls.

USES IN CFS/ME. Dr. Cheney has proposed that many people with CFS/ME have reduced liver function, and even subclinical hepatitis. For CFS/ME patients with mild liver dysfunction, milk thistle may provide some relief.

PROTOCOL. Milk thistle is poorly absorbed, so 150-300 mg a day is needed for basic liver support. Dr. Cheney recommends 150 mg silymarin/milk thistle taken twice a day. Siliphos, a more bioavailable form of silymarin, may be taken at lower doses. Some studies show that a silymarin-phosphatidylcholine complex may be absorbed more easily than regular standardized milk thistle. Phosphatidylcholine, a key element in cell membranes, helps silymarin attach easily to cell membranes, which may help in keeping toxins from getting inside liver cells.

PROS AND CONS. While milk thistle is generally well tolerated, common side effects are itching, indigestion and headache. Some patients have reported nausea and poor appetite on higher doses. People with allergies to plants in the aster family: daisies, artichokes, ragweed, chrysanthemums, marigolds, chamomile, yarrow, kiwi, and common thistle may also be allergic to milk thistle.

AVAILABILITY AND COST. Milk thistle, in liquid or capsule form, can be purchased at any health food store and through online vitamin suppliers. Standardized milk thistle extracts yielding 80% of the active ingredient in silymarin, silybin, are recommended. Jarrow, Metabolic Maintenance, Pure Encapsulations, and Douglas Labs all market standardized milk thistle. Prices range from $13 to $30 for a 100-capsule bottle. Siliphos is available from Vitacost and PureFormulas.com for roughly the same price.

FURTHER READING

Detailed information on silymarin: http://www.salamresearch.com/html/milk_thistle_product.html

Ray Sahelian on milk thistle. Includes dosage, research and medical uses. http://www.raysahelian.com/silymarin.html

RESEARCH

Chen IS, Chen YC, Chou CH, Chuang RF, Sheen LY, Chiu CH. “Hepatoprotection of silymarin against thioacetamide-induced chronic liver fibrosis.” J Sci Food Agric. 2011 Nov 18. http://www.ncbi.nlm.nih.gov/pubmed/22102319 (Abstract)

Kalantari H, Shahshahan Z, Hejazi SM, Ghafghazi T, Sebghatolahi V. “Effects of silybum marianum on patients with chronic hepatitis C.” J Res Med Sci. 2011 Mar;16(3):287-90. http://www.ncbi.nlm.nih.gov/pubmed/22091246 (Abstract)

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Rašković, A.; Stilinović, N.; Kolarović, J.; Vasović, V.; Vukmirović, S.; Mikov, M. “The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats.” Molecules. 2011 Oct 12;16(10):8601-13. http://www.mdpi.com/1420-3049/16/10/8601

ST. JOHN'S WORT

St. John's Wort (Hypericum perforatum), a plant with anti-inflammatory, antiseptic and mood lifting properties, has been documented as a remedy for roughly two thousand years. Currently, it is a well-established treatment for depression. In Germany, St. John's Wort is widely prescribed for children and teens with depression as a safe alternative to antidepressants. The Cochrane Collaboration, an organization that reviews trials of health care treatments, found that in 29 studies with over 5,400 depressed patients St. John's Wort fared better than placebo.

Like most herbs, St. John's Wort has the potential to treat a variety of health problems. In 2011 Mozaffari et al found that St. John's Wort was useful for treating IBS (irritable bowel syndrome), a bowel motility condition for which antidepressants are sometimes prescribed. Studies have shown that St. John's Wort increases mitochondrial function, reduces inflammation, and inhibits nerve firing in epilepsy.

PROS AND CONS. St. John's Wort is generally well tolerated. However, it cannot be taken in conjunction with other antidepressants. Like any pharmaceutical antidepressant, it cannot be taken within two weeks of treatment with MAOIs. St. John's Wort decreases the effectiveness of many drugs, including benzodiazepines, oral contraceptives, beta blockers, statins, antiretrovirals, and theophylline.

FURTHER READING

Good general information about St. John's Wort: http://www.herbwisdom.com/herb-st-johns-wort.html

Cochrane Collaboration's summary of research on St. John's Wort for depression. http://summaries.cochrane.org/CD000448/st.-johns-wort-for-treating-depression.

A CFS/ME patient's review of St. John's Wort: http://www.revolutionhealth.com/drugs-treatments/rating/st-johns-wort-hypericum-perforatum-for-chronic-fatigue-syndrome-cfs-cfids-me

RESEARCH

Huang N, Rizshsky L, Hauck C, Nikolau BJ, Murphy PA, Birt DF. “Identification of anti-inflammatory constituents in Hypericum perforatum and Hypericum gentianoides extracts using RAW 264.7 mouse macrophages.” Phytochemistry. 2011 Nov;72(16):2015-23. http://www.ncbi.nlm.nih.gov/pubmed/21855951 (Abstract)

Mozaffari S, Esmaily H, Rahimi R, Baeeri M, Sanei Y, Asadi-Shahmirzadi A, Salehi-Surmaghi MH, Abdollahi M. “Effects of Hypericum perforatum extract

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on rat irritable bowel syndrome.” Pharmacogn Mag. 2011 Jul;7(27):213-23. http://www.ncbi.nlm.nih.gov/pubmed/21969792 (Abstract)

Wang Y, Zhang Y, He J, Zhang H, Xiao L, Nazarali A, Zhang Z, Zhang D, Tan Q, Kong J, Li XM. “Hyperforin promotes mitochondrial function and development of oligodendrocytes.” J Neurochem. 2011 Nov;119(3):555-68. http://www.ncbi.nlm.nih.gov/pubmed/21848657 (Abstract)

Woelk H. “Comparison of St John's wort and imipramine for treating depression: randomised controlled trial.” BMJ. 2000 Sep 2;321(7260):536-9. http://www.ncbi.nlm.nih.gov/pubmed/10968813 (Abstract)

UVA URSI

A member of the Ericaceae family, uva ursi (Arctostaphylos uva-ursi) has been used for more than 100 years as a urinary tract antiseptic. Once in the urinary tract, the chemical (arbutin) found in uva ursi is transformed into an antiseptic agent, hydroquinone. This herb also contains diuretic chemicals (ursolic acid) and astringents. However, uva ursi is effective against urinary tract infections only if the urine is alkaline; therefore, citrus fruits (including tomatoes), vitamin C, and acidic foods should be avoided immediately before and after taking it.

Uva ursi is also used as an anti-Candida treatment and as an anti-bacterial.

PROS AND CONS. Some patients have reported “die-off” reactions from taking uva ursi.

VALERIAN

Valerian (Valeriana officionalis) has long been used as a tranquilizer, and for treating epilepsy, nervousness, anxiety, insomnia, headache, and intestinal cramps. During World War I, it was routinely taken to relieve the "overwrought nerves" brought on by artillery bombardment. Valerian is used extensively in Germany, where it is the active ingredient in more than 100 over-the-counter sleep aids. The active ingredients in valerian are chemicals known as valepotriates, which are found in highest concentrations in the roots of the plant.

CFS/ME physicians recommend valerian primarily as a sleep aid. It can be taken as a tea or in capsule form, but because of its odor, capsules are usually preferred. Valerian should be taken with a little milk or food to prevent stomach upset. Valerian is often combined with other herbal sleep aids, such as passionflower, hops, and skullcap.

FURTHER READING

Good summary of the uses of valerian: http://www.herbwisdom.com/herb-valerian.html

Several CFS/ME doctors discuss remedies for insomnia, including valerian. http://www.prohealth.com/library/showarticle.cfm?libid=8563

RESEARCH

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Dimpfel W, Suter A. “Sleep improving effects of a single dose administration of a valerian/hops fluid extract - a double blind, randomized, placebo-controlled sleep-EEG study in a parallel design using electrohypnograms.” Eur J Med Res. 2008 May 26;13(5):200-4. http://www.ncbi.nlm.nih.gov/pubmed/18559301 (Abstract)

Leathwood PD, Chauffard F, Heck E, Munoz-Box R. “Aqueous extract of valerian root (Valeriana officinalis L.) improves sleep quality in man.” Pharmacol Biochem Behav. 1982 Jul;17(1):65-71. http://www.ncbi.nlm.nih.gov/pubmed/7122669 (Abstract)

Taavoni S, Ekbatani N, Kashaniyan M, Haghani H. “Effect of valerian on sleep quality in postmenopausal women: a randomized placebo-controlled clinical trial.” Menopause. 2011 Sep;18(9):951-5. http://www.ncbi.nlm.nih.gov/pubmed/21775910 (Abstract)

HISTAME

DESCRIPTION. Histame is a dietary supplement containing the enzyme, diamine oxidase (DAO).

BACKGROUND. Diamine oxidase (also known as histaminase) is an enzyme found in large concentrations in the intestinal lining (mucosa) of all mammals. Its function is to break down histamine. Unlike antihistamines, Histame does not block histamine receptors, but acts directly on histamine itself.

In a study published in 1980, Luk et al found that after inducing damage to the intestines of rats, the amount of diamine oxidase was an accurate marker of intestinal integrity. The lower the amount of diamine oxidase, the greater the degree of damage. The researchers concluded that diamine oxidase was unique among intestinal mucosal enzymes in its ability to predict intestinal integrity.

In 2007 Maintz and Novak observed that people with low amounts of DAO can develop food sensitivities which symptomatically mimic food allergies (flushing, hypotension, diarrhea, headache, tachycardia, and itching). Although their symptoms match those of true allergies, these individuals do not test positive for IgE-mediated allergies. Low levels of circulating DAO prevent the breakdown of histamine in their intestines, causing allergic-type reactions, particularly to histamine-rich foods. Foods that are rich in histamine include all fermented and aged foods: cheese, alcohol, sauerkraut, canned fish (tuna, sardines), pizza, processed meats, as well as many fruits and chocolate. Nearly 100 drugs have been found to cause a decrease in DAO activity, including doxycycline, MAO inhibitors, cimetidine (Tagamet), and Verapamil (a calcium-channel blocker). DAO requires copper and Vitamins B2 and B6.

USES IN CFS/ME. Histamine intolerance is characteristic of CFS/ME patients. Aside from new allergies, many CFS/ME patients develop food sensitivities, as well as conditions such as migraines, rosacea and interstitial cystitis, which are provoked by tyrosine-rich foods. (Tyrosine is converted to tyramine, which is closely related to histamine.) Histame has been recommended by Dr. Kenny De Meirleir as part of treating gut dysbiosis in CFS/ME patients.

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PROTOCOL. The makers of Histame recommend taking one or two tablets within 15 minutes of consuming histamine-rich food. The capsules can be opened and the contents swallowed, if preferred.

AVAILABILITY. Histame can be purchased from a number of online sources. Prices range from $20-$40 for a bottle of 30 capsules.

FURTHER READING

Histame website: http://histame.com/

Patient thread on Histame: http://forums.phoenixrising.me/showthread.php?11967-90-cured-from-bed-bound-with-Histrelief-Histame-Daosin

Patient thread on histamine intolerance: http://forums.phoenixrising.me/archive/index.php/t-1804.html

Comprehensive list of histamine-rich foods: http://histame.com/histamine-rich-foods-substances

An interesting study about histamine fish poisoning: http://www.allergyclinic.co.nz/guides/63.html

RESEARCH

Luk, G D, T M Bayless, and S B Baylin Diamine oxidase (histaminase). “A circulating marker for rat intestinal mucosal maturation and integrity.” J Clin Invest. 1980 July; 66(1): 66–70. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC371506/

Maintz, Laura and Natalija Novak. “Histamine and histamine intolerance.” American Journal of Clinical Nutrition, Vol. 85, No. 5, 1185-1196, May 2007 http://www.ajcn.org/content/85/5/1185.full

In-depth medical study examining the effects of histamine on the gut, histamine intolerance, and the correlation of DAO levels with food intolerance.

INOSINE/ISOPRINOSINE

DESCRIPTION. Inosine is a purine ribonucleoside (a nitrogen-containing compound combined with D-ribose). Isoprinosine (brand: Imunovir) is its pharmaceutical equivalent (now largely replaced by inosine).

BACKGROUND. Inosine is a naturally occurring chemical in the body which leads to the production of uric acid, a potent free radical scavenger. As a basic component of cells, uric acid is involved in a number of physiological processes including carbohydrate metabolism, insulin regulation, and protein synthesis. Uric acid levels are low in all inflammatory diseases, including CFS/ME. Pharmaceutical forms of inosine (inosine pranobex, or isoprinosine) have been used as immune system modulators. Currently, inosine is being investigated as a possible treatment for Parkinson's disease.

As a supplement, inosine is primarily used to enhance athletic performance. Manufacturers claim that because inosine is a precursor to adenosine, it facilitates the production of ATP (adenosine triphosphate). As a consequence, inosine should theoretically increase energy and endurance. Although there does not appear to be

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any research to substantiate these claims, inosine is included in many sports supplements.

USES IN CFS/ME. Both Dr. Kenny De Meirleir and Dr. Cheney have largely replaced isoprinosine with inosine in their treatment protocols, under the assumption that the two are equivalent. Inosine, like its pharmaceutical counterpart, is supposed to modulate the immune system and act as an antiviral. However, inosine does not appear to possess the same antiviral properties as isoprinosine. The main function of inosine is as an antioxidant, which is linked to its ability to raise uric acid levels in the blood.

Dr. Klimas still uses isoprinosine (Imunovir) with her patients. The protocol is to alternate taking 3 and 6 pills daily, with weekends off, for three months. Over the next three months no Imunovir is taken. The physician decides how often to repeat this course of medication based on immune markers (as determined by blood tests).

PROTOCOL. The standard dosage of inosine is 500 mg three times a day for five days a week (allowing for weekend “drug holidays”). As always, CFS/ME patients are advised to start with low doses.

PROS AND CONS. Paradoxically, inosine seems to help with joint pain (gout is caused by an excess of uric acid, which is raised by inosine) and, to some degree, with energy. Although inosine functions as an antioxidant, the process of converting it to uric acid produces superoxide, a potent oxidant. Some patients report that inosine works fine for a while and then stops having an effect. Patients who were previously able to tolerate isoprinosine have reported headaches and insomnia while taking inosine.

AVAILABILITY AND COST. Inosine is a supplement, which means it can be purchased without a prescription at health food stores and from online distributors. Source Naturals markets a 120-tablet bottle of inosine (500 mg) for roughly $20. Imunovir is currently registered outside the United States for the treatment of acute and chronic viral infections, including herpes and measles. It can be obtained in Canada.

FURTHER READING

Basic information on isoprinosine, including sources. http://www.anapsid.org/cnd/drugs/isoprinosine.html

Manufacturer's description of Imunovir: http://www.rivexpharma.com/products_imunovir.html

CFS/ME patient thread discussing isoprinosine and inosine: http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=1396515

INOSITOL

DESCRIPTION. Inositol is a carbocyclic polyol (a sugar alcohol) which forms an essential component of cell membranes.

BACKGROUND. Inositol, like choline, is an important component of phospholipids, the fatty substances which surround all cells in the body. Also like

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choline, inositol helps with the transportation of fats, and prevents their accumulation in any one site (e.g., the liver). Because it is a key component of the myelin sheaths that surround nerves in the central nervous system, inositol performs a crucial role in maintaining the integrity of the nervous system.

Inositol also plays an important role in energy metabolism; its metabolites regulate bone mass and mediate amino acid signaling, acting as a “second messenger” for cell receptors. Inositol phosphates are important for a number of cellular functions, including cell growth, apoptosis (programmed cell death), cell migration, and cell differentiation. Inositol is found in the brain and nerves, muscles, bones, reproductive organs, stomach, kidney, spleen, liver and heart.

Because inositol is a second messenger of serotonin, it has been successfully used to treat several psychiatric conditions. (Second messengers are molecules that relay signals from neurotransmitters into the cell.) Medical uses of inositol include treatment of obsessive-compulsive disorder (OCD), anxiety, and depression. Inositol is also used for insomnia.

Inositol is produced in the gut in limited quantities by bacterial flora. Dietary sources include calf liver, cantaloupe, beans, dried beans, lentils, milk, nuts, oats, pork, rice, veal, wheat germ and whole-grain products.

PROTOCOL. Dr. Myhill recommends 500-2,000 mgs for low GABA activity. Dr. Teitelbaum recommends a slightly lower dose, 500-1,000 mgs a day. Maija Haavisto reports that 500 – 750 mg taken at bedtime improves insomnia.

PROS AND CONS. Inositol is safe and inexpensive. Some people report that they wake up at night with it. (This may be due to its SSRI-like effects.)

AVAILABILITY AND COST. Pure inositol (also known as myoinositol) can be purchased in powder form. PureFormulas.com markets a 250-gram container made by Pure Encapsulations for $35 (at 500 mg a day, this will last approximately a year and five months). Inositol frequently comes combined with choline. Twinlabs, NOW, Solgar and Source Naturals all market inositol/choline combinations (500 mg) at less than $10 a bottle. Inositol often is included in B complex supplements.

FURTHER READING

Ray Sahelian's informative page on inositol: http://www.raysahelian.com/inositol.html

Links to useful articles about inositol: http://www.livestrong.com/inositol/

A nice summary of the functions of inositol in the body: http://www.diagnose-me.com/treat/T47006.html

Treatment of obsessive-compulsive disorder, panic attacks, and depression with inositol. http://www.comprehensivepsychiatricresources.com/item.php?item_id=221&category_id=48

Maija Haavisto's excellent summary of treatments she has tried. Scroll down for inositol, or read them all: http://www.fiikus.net/?cfssupplements

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Very interesting and informative patient thread about the use of inositol in OCD and its relationship with histamine: http://www.stuckinadoorway.org/forums/archive/index.php?t-10476.html

RESEARCH

Gianfranco C, Vittorio U, Silvia B, Francesco D. “Myo-inositol in the treatment of premenstrual dysphoric disorder.” Hum Psychopharmacol. 2011 Oct;26(7):526-30. http://www.ncbi.nlm.nih.gov/pubmed/22031267 (Abstract)

MALIC ACID

DESCRIPTION. Malic acid, an intermediate in the Krebs cycle, aids in the production of adenosine triphosphate (ATP).

BACKGROUND. Malic acid is found primarily in apples and pears, as well as other fruits. It is used primarily as a flavor enhancer and to lend tartness to food products. Malic acid helps in the breakdown and utilization of fats and glucose in muscle tissue, even in low oxygen conditions, and plays an important role in the production of ATP.

USES IN CFS/ME. Because of the prominent role malic acid plays in the energy-producing Krebs cycle, a deficiency can lead to inadequate breakdown of glucose in muscle tissue, with resulting buildup of lactic acid and other toxins. Increased amounts of malic acid should relieve many of the symptoms associated with tissue acidosis (spasms, cramps, and burning pain). A number of CFS/ME physicians recommend malic acid combined with magnesium to treat fibromyalgia symptoms. Dr. Guy Abraham, Dr. J. E. Michalek, Dr. Jorge Flechas, and Dr. I. Jon Russell observed improvement in pain among CFS/ME patients taking Super Malic, a combination of 200 mg of malic acid and 50 mg of magnesium (Journal of Rheumatology, 1995). The researchers noted that low doses of Super Malic were not effective, and recommended six tablets a day for two months.

PROTOCOL. As with other supplements, physicians recommend starting with the lowest dose, one tablet daily taken with food and water, to check for possible sensitivities. The dosage can be increased gradually to between 6 and 12 tablets daily, depending on tolerance. If gastrointestinal problems develop, the dosage should be decreased. Although results may be experienced within a few days, most physicians recommend a trial of several months.

PROS. As a dietary supplement, malic acid is relatively risk free. People with CFS/ME report increased energy, less muscle pain and more stamina. One patient reported a complete cessation of leg spasms, allowing her to rest better. Surprisingly, a patient with kidney stones reported that they decreased after taking malic acid for ten days.

CONS. Some patients report nausea and stomach cramps (on 400 mg a day). Others find malic acid to be too stimulating, resulting in insomnia. The stimulating effects can be reduced by combining malic acid with magnesium.

AVAILABILITY AND COST. Malic acid is available from most health food and vitamin stores. Malic acid supplements are inexpensive. PureFormulas.com

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sells a bottle of 90 capsules (600 mg) made by Ecological Formulas for $12. Super Malic has been discontinued. However, various combinations of magnesium and malic acid are still available. Allergy Research Group markets a 120-tablet bottle of Magnesium Malate Forte (124 mg magnesium, 500 mg malic acid, with 10 mg B2) for roughly $20 (through PureFormulas.com).

FURTHER READING

Patient thread on malic acid: http://www.chronicfatiguetreatments.com/forums/vitamins-for-chronic-fatigue-f7/topic593.html

RESEARCH

Russell IJ, Michalek JE, Flechas JD, Abraham GE. Treatment of fibromyalgia syndrome with Super Malic: a randomized, double blind, placebo controlled, crossover pilot study.” J Rheumatol. 1995 May;22(5):953-8. http://www.ncbi.nlm.nih.gov/pubmed/8587088 (Abstract)

MELATONIN

DESCRIPTION. Melatonin is a hormone produced by the pineal gland.

BACKGROUND. Melatonin is a naturally occurring hormone produced in the pineal gland, the brain's "master gland." It is derived from serotonin, one of the brain's most important neurotransmitters. Serotonin, a neurochemical derived from the amino acid tryptophan, is converted by enzymes sensitive to the diurnal cycle of darkness and light into melatonin. Melatonin, because it is produced in the part of the brain that regulates diurnal rhythms, is essential for maintaining normal sleep patterns. Large amounts of melatonin are produced in children, which is one reason why young people sleep so much. As we age, melatonin levels decrease, making it more difficult for the elderly to sleep through the night.

Disruption of both melatonin and serotonin production has been implicated in seasonal affective disorder, the treatment of which involves increasing melatonin levels through exposure to full-spectrum light early in the day. Low melatonin and serotonin levels have also been implicated as contributing factors to depression. Currently, physicians are exploring the use of melatonin as an anti-aging factor. It is possible that supplementation with melatonin in the elderly may help correct the disturbed sleep, poor immune response, and diminished capacity for tissue repair typical of the aging process.

Melatonin may also help correct insomnia in the young. Studies released by the Massachusetts Institute of Technology showed that it took less than half the time for volunteers given melatonin to fall asleep than those given a placebo. Subjects given melatonin also tended to sleep about twice as long as those given placebo and woke without the “hangover” normally associated with sleeping pills. The results of this study are encouraging to those with sleep disorders. However, the effectiveness of melatonin depends on a number of other factors.

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Benita Middleton and her colleagues at the University of Surrey tested the effect of melatonin in conjunction with body temperature. They discovered that in subjects whose body temperature rose later in the day, melatonin had a negative effect on sleep, producing extremely fragmented sleeping and waking patterns. Although melatonin is produced in the pineal gland, it is regulated by a part of the hypothalamus, the suprachiasmatic nucleus, which acts as the body's “clock” by tracking the length of the day. The hypothalamus also controls body temperature, so it is not surprising that the body's internal clock is linked to core temperature. Middleton concluded that while melatonin plays an important role in circadian sleep cycles, the effects are highly individualized.

Melatonin also regulates the “gut clock.” About 400 times more melatonin is produced in the gut than in the brain. The reason for this vast production of melatonin is that digestion is regulated by circadian rhythms. Bile flow increases at night, as do other digestive secretions. Melatonin functions not only to set the circadian rhythms of the digestive system, but to harmonize them with immune and endocrine functions. When these rhythms are disrupted, digestive disturbances result.

It is known that people with severe insomnia are prone to irritable bowel syndrome (IBS), peptic ulcers, fatty liver, GERD, and dyspepsia. In an interesting study of the use of melatonin for treating IBS conducted by Lu et al in 2005, 88% of the patients reported significant improvement of their GI symptoms after 8 weeks of treatment with melatonin over placebo. Oddly enough, the patients experienced no difference in sleep between melatonin and placebo.

USES IN CFS/ME. Sleep disturbance is one of the primary symptoms of CFS/ME. Many patients experience persistent insomnia throughout the illness. Even after a full night's rest, patients with CFS/ME awaken tired. Many clinicians believe that treating the CFS/ME sleep disorder is of primary importance because it reduces the severity of many other symptoms. However, owing to the prevalence of drug and chemical sensitivities in the CFS/ME population, it is not always easy to find a safe, effective means of obtaining a good night's rest. Melatonin may offer an alternative.

In 2006 van Heukelom et al explored the use of melatonin on CFS/ME patients with Dim Light Melatonin Onset (DLMO) later than 11:30 PM. DLMO is when the body begins its own production of melatonin. In healthy people, it occurs roughly two hours before bedtime, provided the light is dim. Van Huekelom's group found that in people with CFS/ME the delayed onset of DLMO was rectified by administration of 5 mg of melatonin five hours before DLMO. After three months, fatigue, energy, and concentration were significantly improved. The researchers concluded that melatonin was an effective therapy for those CFS/ME patients with significantly delayed sleep onset.

Although many CFS/ME physicians use melatonin, there is no clear evidence from the literature that melatonin levels are actually deficient in CFS/ME patients. In a study of 13 adolescents with CFS/ME, Knook et al found that melatonin levels were actually higher in the CFS/ME group than in controls.

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There is a possible explanation for why some CFS/ME patients might be high in melatonin. Researchers have found that melatonin increases the release of cytokines, immune system chemicals that act as messengers to initiate various immune responses. In 1997 Garcia-Maurino et al found that melatonin increased the production of IL-2, IL-6 and gamma interferon, enhancing the effectiveness of Th1 (cellular) immunity (the type of immune function that combats viruses).

A previous study by Ben-Nathan et al found that injecting virus-infected mice with melatonin significantly reduced mortality rates. The implication for at least some people with CFS/ME is that the excess melatonin might be a response to reactivated viruses, providing a hormonal route to immune activation. In light of melatonin's role in enhancing cellular immunity, which is deficient in people with CFS/ME, this is an area which warrants further investigation, especially given the strong association between mono and CFS in teens.

PROTOCOL. Dr. Lapp uses melatonin with patients who have “phase shifted.” That is, they can't fall asleep until 1 or 2AM, and then sleep all day (indicating that the body's “clock” needs to be reset). He recommends starting with as little as 0.1 mg taken a half-hour before bedtime and increasing the dose until the desired effect is achieved. He also has observed that synthetic (not from animal sources) and sublingual forms of melatonin are safest and most effective (MEssenger, 1997). Dr. Lapp does not recommend melatonin for children younger than the late teens.

While product labels usually recommend one to two tablets (3 to 6 mg) taken before bedtime, studies at the Massachusetts Institute of Technology indicate 0.3 mg daily is sufficient to raise blood levels to normal. MIT researcher, Dr. Richard Wurtman, claims that serious side effects can be produced by taking standard doses, which can raise blood levels to more than 10 times the norm. Dr. Teitelbaum also agrees that the standard dose of 3 mg is too high. He recommends taking no more than 0.5 mg.

PROS. A number of CFS/ME patients have reported that melatonin has given them their best night's sleep in years. Melatonin works quickly. For people who become insomniacs while taking beta blockers, melatonin supplementation may provide considerable relief. (Beta blockers can deplete the body of melatonin.)

CONS. Melatonin can lose its effectiveness over time. After working beautifully for a few weeks or months, it can suddenly stop providing the desired results. Some people report paradoxical reactions, such as feeling more awake or experiencing partial or light sleep states. The reason melatonin works for some but not for others may have to do with individual biorhythms (see above). It is possible that patients with CFS/ME whose temperatures rise in the evening due to immune activation may not respond well to melatonin treatment.

Excessive doses of melatonin can cause jitters and headaches. Female patients may experience hormonal disturbances (early onset of periods). Interactions with antidepressant drugs such as Prozac, Elavil, or Zoloft and the pain medication, Ultram, have been reported. People taking antidepressants should

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discuss the risks and benefits of melatonin with their physicians. Preexisting depression as well as orthostatic intolerance may be worsened by melatonin.

AVAILABILITY AND COST. Although it is a hormone, melatonin is currently considered a nutritional supplement. Consequently, it can be purchased over the counter from most health food stores and vitamin catalogs. A 100-tablet bottle of melatonin (3mg) can cost less than $5. Those who wish to start with lower doses should order the liquid.

FURTHER READING

“Sleep and Snake Oil.” Rachel Preiser. Discover Magazine. March 1997. http://discovermagazine.com/1997/mar/sleepandsnakeoil1082

Cort Johnson's informative page about melatonin in CFS/ME. http://aboutmecfs.org.violet.arvixe.com/Trt/TrtMelatonin.aspx

Dr. Lapp on melatonin and other sleep medications. http://www.prohealth.com/library/showarticle.cfm?libid=8563

Melatonin safety assessment by the Mayo Clinic. http://www.mayoclinic.com/health/melatonin/NS_patient-melatonin/DSECTION=safety

CFS/ME patient forum on melatonin: http://forums.phoenixrising.me/archive/index.php/t-12516.html?s=8dd572918a1b8e25a023bda45d398c90

RESEARCH Ben-Nathan D, Maestroni GJ, Lustig S, Conti A. “Protective effects of melatonin in mice infected with encephalitis viruses.” Arch Virol. 1995;140(2):223-30. http://www.ncbi.nlm.nih.gov/pubmed/7710351 (Abstract)

Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. “A review of the multiple actions of melatonin on the immune system.” Endocrine. 2005 Jul;27(2):189-200. http://www.ncbi.nlm.nih.gov/pubmed/16217132 (Abstract)

Garcia-Maurino S, MG Gonzalez-Haba, JR Calvo, M Rafii-El-Idrissi, V Sanchez- Margalet, R Goberna and JM Guerrero. “Melatonin enhances IL-2, IL-6, and IFN-gamma production by human circulating CD4+ cells: a possible nuclear receptor-mediated mechanism involving T helper type 1 lymphocytes and monocytes.” The Journal of Immunology, Vol 159, Issue 2 574-581, 1997. http://www.jimmunol.org/content/159/2/574.abstract (Abstract) Guerrero JM, Reiter RJ. “Melatonin-immune system relationships.” Curr Top Med Chem. 2002 Feb;2(2):167-79. http://www.ncbi.nlm.nih.gov/pubmed/11899099 (Abstract) Knook L, Kavelaars A, Sinnema G, Kuis W, Heijnen CJ. “High nocturnal melatonin in adolescents with chronic fatigue syndrome.” J Clin Endocrinol Metab. 2000 Oct;85(10):3690-2. http://www.ncbi.nlm.nih.gov/pubmed/11061525 (Abstract) Konturek PC, Brzozowski T, Konturek SJ. “Gut clock: implication of circadian rhythms in the gastrointestinal tract.” J Physiol Pharmacol. 2011 Apr;62(2):139-50. http://www.ncbi.nlm.nih.gov/pubmed/21673361 (Abstract)

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http://www.jpp.krakow.pl/journal/archive/04_11/pdf/139_04_11_article.pdf (Full text) Lu WZ, Gwee KA, Moochalla S, Ho KY. “Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study.” Aliment Pharmacol Ther. 2005; 22: 927-934. http://www.ncbi.nlm.nih.gov/pubmed/16268966 (Abstract) Smits M G, Van Rooy R, Nagtegaal J E. “Influence of Melatonin on Quality of Life in Patients with Chronic Fatigue and Late Melatonin Onset.” J Chronic Fatigue Syndrome. 2002;10(3/4):25-32. 29. http://www.cfids-cab.org/cfs-inform/Melatonin/smits.etal02.pdf van Heukelom RO, Prins JB, Smits MG, Bleijenberg G. “Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome and late melatonin secretion.” Eur J Neurol. 2006 Jan;13(1):55-60. http://www.ncbi.nlm.nih.gov/pubmed/16420393 (Abstract) Williams G, Waterhouse J, Mugarza J, Minors D, Hayden K. “Therapy of circadian rhythm disorders in chronic fatigue syndrome: no symptomatic improvement with melatonin or phototherapy.” Eur J Clin Invest. 2002 Nov;32(11):831-7. http://www.ncbi.nlm.nih.gov/pubmed/12423324 (Abstract)

MINERALS

Calcium, Magnesium, Selenium, Colloidal Silver, Zinc

CALCIUM

BACKGROUND. Calcium is the most abundant mineral in the human body. A 150-pound adult's body contains about three pounds of calcium, 99% of which is found in the skeletal bones. The small portion of calcium found in soft tissues and body fluids is essential for maintaining a number of important biochemical functions, including regular heartbeat and transmission of nerve impulses. Calcium also prevents muscle cramps and is vital for the formation of healthy teeth and strong bones.

There are two main forms of calcium: inorganic and organic. The inorganic forms (sulfate, carbonate, and phosphate) are poorly absorbed. The organic forms (citrate, lactate, gluconate, orotate, aspartate, ascorbate and various chelates) are better absorbed. Once calcium is metabolized through the action of stomach acid, it passes into the small intestine where the ionized (liquified) calcium is absorbed into the bloodstream. Ionized calcium is the most important physiological component of calcium. In fact, because calcium is so easily bound to other compounds, blood measurements of total calcium are useless for determining the amount of calcium actually available in the body. Only ionized calcium gives an accurate picture as to how much calcium is actually available to maintain physiological functions.

USES IN CFS/ME. CFS/ME patients often take calcium at night to alleviate insomnia. It is also useful for treating muscle spasms. Those ingesting high amounts of protein or phosphorus may want to supplement their intake of dietary

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calcium because both protein and phosphorus increase calcium excretion from the body. Good natural sources of calcium are dairy products and green leafy vegetables.

PROTOCOL. Dr. Lapp recommends 1,000 mg to 1,500 mg daily. Calcium intake should not exceed 2500 mg a day. Calcium cannot be properly absorbed and assimilated unless vitamin D and trace minerals are present (chromium, boron, copper, iron, manganese, phosphorus, silicon, strontium, and zinc). It is important to supplement with these trace minerals while taking calcium, because calcium competes with other minerals for absorption in the intestines. It is also important to supplement with magnesium. (Magnesium prevents plaque buildup from unabsorbed calcium.)

Liquid ionic calcium is more easily absorbed and utilized than other forms of calcium. For example, only 10% of either calcium carbonate (Tums) or calcium citrate is absorbed. This means you get 100 mg of usable calcium for every 1,000 mg consumed. (You'd have to eat over 30 Tums to get 1000 mg of calcium.) Calcium lactate, found in milk, fares a little better at 33%. In contrast, calcium aspartate is 85% absorbed and calcium orotate is 90-95% absorbed. Ionic calcium is nearly 100% absorbed.

CFS/ME patients taking verapamil (a calcium channel blocker) to treat cognitive dysfunction need to be aware that calcium supplements may interfere with the effects of this medication. People with a history of kidney disease or kidney stones should not take calcium supplements, because the additional calcium may exacerbate the condition.

PROS AND CONS. Calcium is inexpensive and generally well tolerated. Calcium supplements can interfere with the absorption of both iron and zinc (but not magnesium), so if you are supplementing with either of these minerals, be sure to take them at least two hours after (or before) taking calcium.

AVAILABILITY AND COST. There is a wide variety of calcium supplements available at supermarkets, drug stores, health food stores, and from online distributors. Mineral Life sells an 8-oz bottle of liquid ionic calcium for $20 (60-day supply). Pure Essence markets Ionic Fizz (a blend of ionic trace minerals and vitamins) for $16 through Vitacost. Advanced Research markets a 100-tablet bottle of calcium orotate combined with magnesium for about $20 (through amazon.com). Advanced Research also markets a 100-tablet bottle of calcium aspartate for the very affordable price of $7.

FURTHER READING

Good overview of calcium, including rates of absorption for different calcium compounds. http://www.uswellnessmeats.com/Calcium_Myth_and_Facts.pdf

Brief interview with Dr. Spreen about the different forms of calcium and their bioavailability. http://www.alkalizeforhealth.net/Lcalcium.htm

Ionic calcium supplier: http://www.mineralifeonline.com/pd-calcium-8oz-60-day-supply.cfm

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“When Is It Appropriate to Order an Ionized Calcium?” Laura M. Calvi and David A. Bushinsky. JASN July 1, 2008 vol. 19 no. 71257-1260. http://jasn.asnjournals.org/content/19/7/1257.full

Good medical article about the importance of measuring ionic calcium in the bloodstream.

MAGNESIUM

BACKGROUND. Magnesium is one of the six major minerals classified as essential for the functioning of the human body. The average human body contains about 25 grams of magnesium salts, about half of which is stored in the bones and one-fourth in muscle. Only about 2% circulates freely in the blood. The rest is located within the cells. Blood levels of magnesium are controlled by the kidneys.

Magnesium is necessary for relaying nervous system impulses and for normal metabolism of calcium and potassium. Much like a vitamin, magnesium functions as a coenzyme, aiding in enzyme systems, storage and release of energy generated from carbohydrates, and synthesis of proteins and DNA. Magnesium deficiency can result in anorexia, nausea, learning disabilities, personality changes, weakness, exhaustion, and muscle pain.

According to the USDA, a staggering 68% of Americans do not consume the daily recommended intake for magnesium. In a forward-looking article written in 1990, Kubena et al outlined the effects of chronic marginal intakes of magnesium, including “abnormalities in reproduction, growth, and development and disorders of neuromuscular, cardiovascular, renal, and immune function.” In addition, the authors pointed out that problems related to the use of pharmacological agents or trace metals, such as aluminum (which has been implicated in the development of Alzheimer's disease), may be worsened with a low intake of magnesium. Dr. Pall has speculated that, given the likelihood that people with CFS/ME are marginally deficient in magnesium before falling ill, magnesium deficiency may contribute to the pathogenesis of the illness.

USES IN CFS/ME. Magnesium is an indispensable supplement for people with CFS/ME. Nearly every CFS/ME physician includes either injectable or oral magnesium as part of their protocol. In early 1991, I.M. Cox, M.J. Campbell, and D. Dowson published a preliminary study on magnesium levels in CFS/ME patients (Lancet, 1991). All 22 patients studied had reduced levels of serum magnesium.

They followed up their findings with a randomized clinical study in which 15 of the patients received intramuscular injections of magnesium sulfate every week for six weeks and 17 received a placebo. Of the 15 patients receiving magnesium, 12 reported improvement in symptoms. Although subsequent studies have not confirmed low serum levels of magnesium to be universal among CFS/ME patients, magnesium is still the most frequently recommended mineral supplement for patients with CFS/ME.

In his book, Explaining “Unexplained Illnesses,” Dr. Martin Pall presents a compelling argument implicating oxidative stress in the etiology of CFS/ME. An important part of the ongoing oxidative stress typical of multisystem illnesses like

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CFS/ME, FM and Gulf War Syndrome is the chronic excitability of NMDA receptors, which results in a hyperactive nervous system (along with cell damage, inflammation, and lowered production of ATP). Magnesium is one of the principal inhibitors of NMDA activity, which makes it a valuable treatment for any illness involving chronic oxidative stress.

Dr. Myhill believes that low magnesium levels in CFS/ME patients is a symptom of mitochondrial failure. When mitochondria fail, calcium leaks into cells and magnesium leaks out. According to Dr. Myhill, this leakage explains why it is useless to test serum levels of magnesium. As she puts it, “Serum levels are maintained at the expense of intracellular levels. If serum levels change this causes heart irregularities and so the body maintains serum levels at all cost. It will drain magnesium from inside cells and indeed from bone in order to achieve this.” Dr. Myhill's explanation not only accounts for why serum levels of magnesium are inconsistent in CFS/ME, but why magnesium supplementation is effective.

PROTOCOL. Magnesium can be administered orally or by injection. Because oral magnesium is difficult to absorb, the forms most frequently recommended are magnesium citrate and magnesium glycinate. Magnesium citrate will dissolve in water, which makes it more bioavailable than most other forms of magnesium. However, Dr. Cheney has observed that magnesium glycinate causes the least intestinal upset and is the most easily absorbed. The usual recommended dosage is 200 to 400 mg/day taken with food, although CFS/ME patients are cautioned to start with a smaller dose and increase it gradually. Intramuscular injections of 1 cc of magnesium sulfate (50%) or magnesium chloride can be administered once or twice a week. Because of magnesium's effect on heart function, the first injection should be performed in a physician's office.

PROS AND CONS. Most people who take magnesium, whether oral or injected, report increased stamina and energy. Many include better sleep as an additional benefit (most likely due to magnesium's muscle-relaxing effects). The main drawback of injected magnesium is that the injections are painful. The simultaneous administration of vitamin B12 or lidocaine helps relieve the pain of the injection. Because magnesium is a cathartic, high doses can cause diarrhea. In patients prone to gastrointestinal upset, a low dose is normally recommended.

AVAILABILITY AND COST. Oral magnesium is readily available from health food stores, online vitamin suppliers, and most drugstores. It is inexpensive. A bottle of 120 tablets of either magnesium glycinate or magnesium citrate (400 mg) costs $12 from Vitacost. Topical magnesium creams are also available. PureFormulas.com markets a 4-ounce jar of magnesium cream made by Kirkman for $16. (Or you can make your own cream using Epsom salts.) Magnesium can be purchased as a powder and mixed into a beverage for easier assimilation. Magnesium sulfate injections usually cost $16 to $20 per injection.

FURTHER READING

Excellent summary of magnesium's effects on the body from the Linus Pauling Institute. http://lpi.oregonstate.edu/infocenter/minerals/magnesium/

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Dr. Myhill discusses magnesium deficiency and treatment in CFS/ME patients. http://www.drmyhill.co.uk/wiki/Magnesium_-_treating_a_deficiency

USDA statistics on nutrient consumption by state and nationally. http://www.ars.usda.gov/Services/docs.htm?docid=11197

“Review and Hypothesis: Might Patients with the Chronic Fatigue Syndrome Have Latent Tetany of Magnesium Deficiency.” Mildred Seelig, MD, MPH http://www.mgwater.com/clmd.shtml

RESEARCH

Cox IM, Campbell MJ, Dowson D. “Red blood cell magnesium and chronic fatigue syndrome.” Lancet. 1991 Mar 30;337(8744):757-60. http://www.ncbi.nlm.nih.gov/pubmed/1672392 (Abstract)

Kubena KS, Durlach J. “Historical review of the effects of marginal intake of magnesium in chronic experimental magnesium deficiency.” Magnes Res.1990 Sep;3(3):219-26. http://www.ncbi.nlm.nih.gov/pubmed/2132753 (Abstract)

Lindberg JS, Zobitz MM, Poindexter JR, Pak CY. “Magnesium bioavailability from magnesium citrate and magnesium oxide.” J Am Coll Nutr. 1990 Feb;9(1):48-55. http://www.ncbi.nlm.nih.gov/pubmed/2407766 (Abstract)

Manuel y Keenoy, B, Moorkens, G, Vertommen, J, Noe, M, Neve, J, and De Leeuw, I. “Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium.” J Am Coll Nutr. 2000 Jun;19(3):374-82. http://www.ncbi.nlm.nih.gov/pubmed/10872900 (Abstract)

Seelig, Mildred MD, MPH. “Review and Hypothesis: Might Patients with the Chronic Fatigue Syndrome Have Latent Tetany of Magnesium Deficiency.” Journal of Chronic Fatigue Syndrome, Vol. 4(2) 1998 http://www.mgwater.com/clmd.shtml

SELENIUM

BACKGROUND. Selenium is a trace mineral found in the soil, and in foods such as lobster, tuna, shrimp, oysters, fish, brown rice, garlic, whole grains, sesame seeds, and mushrooms. Although it is needed in only small amounts, selenium performs an important role in kidney, spleen, pancreas and liver function, as well as in reproduction. In men, about half of the body's selenium is concentrated in the testes. Selenium forms a component of glutathione peroxidase, the body's most prolific antioxidant. Deficiencies in selenium can lead to infertility, arthritis, hypothyroidism (selenium is essential for making T3), loss of energy, immune system deficiency, and, in children, cardiac problems.

Apart from its many metabolic functions, selenium performs an important role in the functioning of the immune system. In a 1994 study performed at New York University, subjects who received a 200 mcg daily supplement of selenium for eight weeks showed an enhanced immune response to foreign antigens, including an increase natural killer cell activity. Research also indicates that selenium up-regulates IL-2 and increases activation of T helper cells. Selenium supplementation

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may also down regulate abnormally high levels of the inflammatory cytokines IL-8 and TNF alpha.

It is because of selenium's dual function as an antioxidant and as an immune system enhancer that attention has recently been drawn to its possible role in the creation of “superbugs,” such as the Ebola virus. In the mid-1990s two researchers, Melinda Beck, a virologist at the University of North Carolina, and Orville Levander, a nutritional chemist with the USDA, set about to investigate the effects of selenium deficiencies on mice infected with Coxsackie virus. They discovered that not only did the mice develop virally induced heart disease, but that the virus itself had mutated into a more virulent strain.

Subsequent studies by Beck and colleagues confirmed that a host deficient in selenium not only has a poor immune response, but also can influence the genetic makeup of the virus, producing a more deadly strain. In an enormously understated conclusion, the authors stated that “this latter finding markedly changes our concept of host-pathogen interactions and creates a new paradigm for the study of such phenomena.” For those who have suffered for decades from the long-term effects of viral infections, the implications of this study are ominous.

USES IN CFS/ME. In CFS/ME, selenium is used primarily as an antioxidant. Selenium helps form glutathione peroxidases (which eliminate peroxide oxidants in the cell), as well as acting as a peroxynitrite scavenger. Both of these properties make selenium an important adjunct in antioxidant therapy. Selenium's role in thyroid hormone production also make it an essential supplement for people suffering from borderline hypothyroidism (a common finding in CFS/ME, due to disturbances in the endocrine system). Selenium has been identified as a mood enhancer as well.

In an interesting study of the psychological impact of selenium, Benton observed that “the metabolism of selenium by the brain differs from other organs in that at times of deficiency the brain retains selenium to a greater extent.” Benton proposed that this preference indicates that selenium is important in psychological function, particularly mood. In his article, Benton cites five studies that have associated low selenium intake with poorer mood. These studies seem to bear out independent reports from CFS/ME patients who have successfully taken selenium in place of antidepressants.

PROTOCOL. Dr. Pall recommends selenium methionine as the best form of selenium. Unless there is a verified selenium deficiency, low doses are recommended (50 mcg).

PROS AND CONS. Selenium is toxic at high levels, and overdoses can cause numerous symptoms: hair loss, tooth decay, brittle nails, nausea, vomiting, poor appetite, metallic taste in the mouth, loss of feeling in the hands and feet, and changes in skin pigmentation. (A garlic smell on the breath is an indication of excessive selenium intake.) Selenium is often produced as a yeast, which is problematic for people with Candida overgrowth and mold allergies, so check the label carefully.

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AVAILABILITY AND COST. Selenium is widely available at health food stores and from online suppliers. PureFormulas.com markets a bottle of yeast-free seleno-methionine capsules (200 mcg) made by Douglas Labs for $26.40 (250 capsules). Capsules can be divided for a lower dose.

FURTHER READING

Detailed information about selenium from the Linus Pauling Institute.

http://lpi.oregonstate.edu/infocenter/minerals/selenium/

“Is Selenium Deficiency Behind Ebola, AIDS and Other Deadly Infections?” http://infonom.com.ar/task/html/selenium_deficiency_behind_tod.html

RESEARCH

Beck, Melinda A., Heather K. Nelson, Qing Shi, Peter Van Dael, Eduardo J. Schiffrin, Stephanie Blum, Denis Barclay, and Orville A. Levande. “Selenium deficiency increases the pathology of an influenza virus infection.” FASEB J. 2001 Jun;15(8):1481-3. http://www.fasebj.org/content/15/8/1481.full.pdf

Beck MA, Levander OA, Handy J. “Selenium deficiency and viral infection.” J Nutr. 2003 May;133(5 Suppl 1):1463S-7S. http://www.ncbi.nlm.nih.gov/pubmed/12730444 (Abstract)

Beck MA, Handy J, Levander OA. “Host nutritional status: the neglected virulence factor.” Trends Microbiol. 2004 Sep;12(9):417-23. http://www.ncbi.nlm.nih.gov/pubmed/15337163 (Abstract)

Benton D. “Selenium intake, mood and other aspects of psychological functioning.” Nutr Neurosci. 2002 Dec;5(6):363-74. http://www.ncbi.nlm.nih.gov/pubmed/12509066 (Abstract)

Kiremidjian-Schumacher L, Roy M, Wishe HI, Cohen MW, Stotzky G. “Supplementation with selenium and human immune cell functions. II. Effect on cytotoxic lymphocytes and natural killer cells.” Biol Trace Elem Res. 1994 Apr-May;41(1-2):115-27. http://www.ncbi.nlm.nih.gov/pubmed/7946899 (Abstract)

COLLOIDAL SILVER

NOTE: Some of the colloidal minerals distributed by multilevel marketers contain arsenic and lead, which are toxic even in small doses. Caution should be exercised. Read labels carefully!

DESCRIPTION. Colloidal silver solution is composed of ultrafine, non-soluble particles of silver suspended in a liquid medium such as water.

BACKGROUND. Colloidal silver has long been used as a germicide. In the early twentieth century, colloidal silver was used in place of antibiotics. Silver was used orally, intravenously, and intramuscularly (as an injection), as a throat gargle, and in eyedrops. Colloidal silver has been used to treat such varied maladies as tonsillitis, cystitis, ringworm, and dysentery. Over the course of this century,

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antibiotics have replaced silver as drugs of choice, although silver nitrate is still used to prevent eye infection in newborn infants.

USES IN CFS/ME. Some patients with CFS/ME report that colloidal silver helps control recurring infections, particularly in the mouth. Research has shown that colloidal silver may be of benefit in treating oral infections, sinusitis, sore throat, and canker sores.

PROTOCOL. Dosage varies, depending on the concentration of the product used.

PROS AND CONS. It appears that low doses of silver are fairly safe. However, argyria (grayish skin discoloration) may develop when excessive doses of silver are ingested. Because most studies evaluating the antimicrobial properties of silver are not conducted on people, patients are cautioned to exercise judgment before choosing silver over a medication whose mode of action and recommended dosage are better known.

AVAILABILITY AND COST. Colloidal silver may be purchased from most health food stores and online distributors. It costs $12 to $25 for a 4-oz bottle, depending on the brand. Some companies make a spray colloidal silver for oral use. Stick to reputable brands such as Source Naturals when purchasing.

RESEARCH

Damiani V, Di Carlo M, Grappasonni G, Di Domenico R, Dominici P. “Efficacy of a new medical device based on colloidal silver and carbossimetyl beta glucan in treatment of upper airways disease in children.” Minerva Peditr. 2011 Oct;63(5):347-54. http://www.ncbi.nlm.nih.gov/pubmed/21946445 (Abstract)

Eby DM, Luckarift HR, Johnson GR. “Hybrid antimicrobial enzyme and silver nanoparticle coatings for medical instruments.” ACS Appl Mater Interfaces. 2009 Jul;1(7):1553-60. http://www.ncbi.nlm.nih.gov/pubmed/20355960 (Abstract)

Khan SS, Mukherjee A, Chandrasekaran N. “Studies on interaction of colloidal silver nanoparticles (SNPs) with five different bacterial species.” Colloids Surf B Biointerfaces. 2011 Oct 1;87(1):129-38. http://www.ncbi.nlm.nih.gov/pubmed/21640562 (Abstract)

Lansdown AB. “Silver in health care: antimicrobial effects and safety in use.” Curr Probl Dermatol. 2006;33:17-34. http://www.ncbi.nlm.nih.gov/pubmed/16766878 (Abstract)

Monteiro DR, Gorup LF, Silva S, Negri M, de Camargo ER, Oliveira R, Barbosa DB, Henriques M. “Silver colloidal nanoparticles: antifungal effect against adhered cells and biofilms of Candida albicans and Candida glabrata.” Biofouling. 2011 Aug;27(7):711-9. http://www.ncbi.nlm.nih.gov/pubmed/2175619 2 (Abstract)

ZINC

BACKGROUND. Zinc is a remarkably versatile mineral. It plays an important role in the more than 70 enzyme systems that regulate most metabolic processes. It stimulates digestion, aids in extracting stores of vitamin A from the

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liver, helps maintain the mucous lining of the mouth, throat, stomach, and intestines, is vital for the normal growth of hair, skin, and nails, controls sexual maturation and fertility (zinc deficiency in men can lead to infertility), and aids in the healing of wounds. Zinc is necessary for the utilization of vitamin B6, a vitamin which is crucial for nervous system function. It also helps improve immune responses, although excessive intake of zinc (more than 50 mg) can suppress immune function. (High doses of zinc also deplete copper.)

USES IN CFS/ME. Many CFS/ME patients take zinc to help relieve sore throat and other viral symptoms. In a 2005 study published by Maes et al, 33 CFS/ME patients were examined for serum zinc deficiencies. The researchers found that serum levels of zinc were lower in CFS/ME patients than in controls. In addition, low serum zinc status was related to signs of inflammation and defects in early T cell activation pathways. Since zinc is a strong antioxidant, the results of this study support the findings that CFS is accompanied by increased oxidative stress. The researchers concluded that “the results of these reports suggest that some patients with CFS should be treated with specific antioxidants, including zinc supplements.”

PROTOCOL. The recommended daily allowance for zinc is 15 mg. The most bioavailable form is high-zinc yeast. This is a form of yeast that has a high zinc content. Unfortunately, it is not available in the U.S. (Lalmin Zn, a high-zinc yeast supplement using Saccharomyces cerevisiae, is produced in Denmark.) Zinc picolinate is well-absorbed, as is zinc citrate. Zinc carnosine, a combination of zinc and the amino acid carnosine, is reported to be well absorbed, as well as providing support for the mucosal lining of the stomach and gut.

AVAILABILITY AND COST. Zinc is available from health food stores, vitamin catalogs, and some drugstores. As with other mineral supplements, it is not expensive. A 100-tablet bottle of zinc picolinate (25 mg) made by Country Life costs less than $5 on Vitacost. Zinc should be taken with food to avoid stomach upset. Zinc is found naturally in pumpkin seeds, liver, egg yolks, and seafood (especially oysters).

FURTHER READING

Essential reading about zinc: http://ods.od.nih.gov/factsheets/Zinc-HealthProfessional/

Article discussing zinc bound in yeast: http://www.nutraingredients.com/Research/Zinc-bound-in-yeast-promotes-superior-bioavailability-claims-study

Interesting study of high-zinc yeast in rats: http://www.beta-glucan-info.com/pdf/Zinc_Bioavailability.pdf

RESEARCH

Maes, Michael, Ivana Mihaylova, Marcel De Ruyter. “Lower serum zinc in Chronic Fatigue Syndrome (CFS): Relationships to immune dysfunctions and relevance

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for the oxidative stress status in CFS.” Journal of Affective Disorders. 2006 Feb;90(2-3):141-7. http://cfids-cab.org/cfs-inform/Hypotheses/maes.etal05.pdf

Mahmood A , A J FitzGerald, T Marchbank, E Ntatsaki, D Murray, S Ghosh, and R J Playford. “Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes.” Gut. 2007 February; 56(2): 168–175. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1856764/

MONOLAURIN

DESCRIPTION. Monolaurin is a mono-ester formed from glycerol and lauric acid.

BACKGROUND. Monolaurin is a fatty acid found in human breast milk. Lauric acid, a closely related compound, is found in coconuts. It has broad anti-microbial properties. In in vitro studies, monolaurin was able to destroy several strains of bacteria. H. Pylori is particularly susceptible – which may be why coconut water is traditionally used as a treatment for dyspepsia in tropical countries.

Other in vitro studies have shown that monolaurin can kill viruses by destroying their lipid membrane. (Laurates are commonly found in soap.) Some of the viruses inactivated by these lipids are measles, herpes simplex, hepatitis C, and cytomegalovirus (CMV). A number of fungi, yeasts, and protozoa are also inactivated or killed by monolaurin. These include ringworm, Candida albicans, and the protozoan parasite Giardia lamblia. Among the many benefits of monolaurin is the fact that it can destroy harmful bacteria without affecting beneficial intestinal flora.

USES IN CFS/ME. Monolaurin is an antiviral, antifungal and anti-Candida treatment. It is used as a safe alternative to pharmaceutical antivirals and antifungals, which often have harmful side effects.

PROTOCOL. Physicians advise starting with very low doses (¼ scoop of Lauricidin) to prevent Herxheimer, or “die-off,” reactions. The makers of Lauricidin recommend starting with one pellet a day (approx 30 mg) in order to avoid Herxheimer reactions. Do not chew the pellets. (They taste like soap.) Monolaurin capsules can be taken with greater frequency. Dr. Teitelbaum recommends taking 9 capsules (300 mg) once a day on an empty stomach for 1 week, followed by 6 capsules once a day for 20 days. He recommends taking lysine 1500 mg twice a day while on monolaurin.

PROS AND CONS. Patients report that monolaurin helps ward off colds and flus. One patient wrote that at high doses (500 mg) it helped shingles. However, most patients report that monolaurin will cause “die off” (Herxheimer-like) reactions. Some fibromyalgia patients have reported an increase of pain on even very low doses of Lauricidin. Other side effects include acid reflux and a general “sick” feeling.

AVAILABILITY AND COST. Patients recommend purchasing pure monolaurin (Lauricidin). An 8-oz container of Lauricidin pellets can be purchased for around $30 on amazon.com. Ecological Formulas markets two monolaurin

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combinations (one with magnesium, and one with lysine) for roughly $13 for a 90-capsule bottle (through PureFormulas.com online).

FURTHER READING

A Review of Monolaurin and Lauric Acid. Shari Lieberman and Harry Preuss. http://www.easihealth.co.za/wordpress/wp-content/uploads/downloads/2011/02/trials/Monolaurin.pdf

Patient thread on monolaurin: http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=428991

Manufacturer's information on Lauricidin: http://lauricidin.com/tech_data/

RESEARCH

Preuss HG, Echard B, Enig M, Brook I, Elliott TB. “Minimum inhibitory concentrations of herbal essential oils and monolaurin for gram-positive and gram-negative bacteria.” Mol Cell Biochem. 2005 Apr;272(1-2):29-34.http://www.ncbi.nlm.nih.gov/pubmed/16010969 (Abstract)

Zhang H, Wei H, Cui Y, Zhao G, Feng F. “Antibacterial interactions of monolaurin with commonly used antimicrobials and food components.” Journal of Food Science. 2009 Sep;74(7):M418-21. http://www.ncbi.nlm.nih.gov/pubmed/19895490 (Abstract)

MUSHROOM EXTRACTS

LEM (shiitake), Maitake, Cordyceps

Mushroom extracts have become increasingly popular in recent years for their broad medicinal properties. Research has shown that mushroom extracts have anticancer, anti-diabetes, antibacterial, antifungal, and immune stimulating properties. Although many varieties of mushroom extracts are currently marketed for their medicinal effects, the two mushroom extracts most widely used for CFS/ME are the shiitake (LEM) and maitake.

In 2002 Dr. Peter R. Rothschild conducted a 120-day study to observe therapeutic responses to RM-10 (a combination of 10 mushroom extracts) for the reduction of symptoms in 33 CFS/ME patients. The researchers found that 60% of the participants reported a reduction of symptoms by 40%, with 33% totally asymptomatic by the end of the trial period. All participants reported some degree of improvement. Dr. Rothschild stated, "We had highly significant results with the multi-mushroom formula, brand named RM-10 [TM]. For affected patients, there was a remarkable percentage of remissions and a quite noticeable improvement in symptomology overall.”

FURTHER READING

Good general information about mushroom extracts. http://www.nammex.com/MedicinalMushroomBooks.html

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Report on RM-10 mushroom extract administered to CFS/ME patients. http://findarticles.com/p/articles/mi_m0ISW/is_2002_August-Sept/ai_90794449/

Description of RM-10: http://www.healthfoodemporium.com/garden-of-life/rm_10.html

SHIITAKE (LEM)

DESCRIPTION. LEM (Lentinus edodes mycelium) is an extract made from the immature shiitake mushroom.

BACKGROUND. Although shiitake mushrooms have long been used in the East for culinary purposes, they have recently gained attention for their medicinal value. Numerous studies, mostly conducted in Japan, have demonstrated that LEM increases immune system function by stimulating production of lymphocytes and macrophages, the immune system's defense against bacteria, viruses, and tumor cells. LEM may also interfere with the action of reverse transcriptase (an enzyme that aids in viral replication) and block cell receptor sites of viruses. Owing to these properties alone, LEM shows promise in treating cancer, diseases related to immune system dysfunction, and viral infections.

USES IN CFS/ME. Most patients with CFS/ME use LEM as a general treatment for lethargy, weakness, and exhaustion, three primary symptoms of CFS/ME. A number have reported improvement in stamina, energy, and strength, decreased diarrhea, and increased white blood cell count after taking LEM.

PROTOCOL. Shiitake extract is usually sold in liquid or tablet form. The suggested dose is 40 drops of liquid, taken twice daily. Up to eight tablets may be taken a day. As with other medications, patients with CFS/ME should start with smaller doses and gradually increase to the full dose.

PROS AND CONS. LEM is one of the few botanical products that affects CFS/ME as a whole. A number of patients report general improvement and lessening of some of their worst symptoms. LEM may provoke a severe allergic reaction in patients with allergies to mushrooms, molds, and other fungi. Those with recurring yeast infections, athlete's foot, or thrush should probably delay trying LEM until these problems are resolved.

AVAILABILITY AND COST. Shiitake extracts are widely available in health food stores and through internet suppliers. Vitacost sells a 2-oz bottle of pure shiitake extract made by Planetary Herbals for $12. Source Naturals markets a bottle of 40 tablets for about $15.

FURTHER READING

“Mushroom Extracts: Exciting News for Good Health.” Neenyah Ostrom's article on LEM and CFS/ME. http://www.immunesupport.com/news/93fal003txt.htm

Sloan Kettering's very thorough review of shiitake extract: http://www.mskcc.org/cancer-care/herb/shiitake-mushroom

MAITAKE EXTRACT

BACKGROUND. The maitake (Grifola frondosa) is a large mushroom that resembles Elizabethan neck ruffles. It grows in clusters at the base of oak trees in

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Japan and North America. Maitake mushrooms are used in Asian cuisine, and because of their size (up to 50 pounds) are known as the “king” of mushrooms. Maitake mushrooms are rich in nutrients, including B vitamins, magnesium, potassium, and calcium.

In the late 1980s an active constituent in maitake, a beta-glucan compound, was found to enhance immune activity. Studies have shown that whole maitake also has the ability to regulate blood sugar and blood pressure, as well as insulin, lipids and cholesterol. Recent research has shown that maitake also has antioxidant and anticancer properties.

USES IN CFS/ME. People with CFS/ME use maitake extract as an immune system stimulator, particularly of NK (natural killer) cells. (Low NK cell activity has been well documented among CFS/ME patients.)

PROTOCOL: Maitake capsules should be taken on an empty stomach. The standard dose for 300 mg capsules is one to three capsules taken twice daily.

AVAILABILITY AND COST. Iherb.com markets a full spectrum maitake extract made by Mushroom Science for $24 for a bottle of 90 capsules.

FURTHER READING

Extensive list of many maitake extracts: http://www.vitasprings.com/maitake.html

RESEARCH

Yeh JY, Hsieh LH, Wu KT, Tsai CF. “Antioxidant properties and antioxidant compounds of various extracts from the edible basidiomycete Grifola frondosa (Maitake).” Molecules. 2011 Apr 15;16(4):3197-211. http://www.ncbi.nlm.nih.gov/pubmed/21499220 (Abstract)

CORDYCEPS

BACKGROUND. Cordyceps is a fungus that grows on the larvae of the caterpillar, Hepialus armoricanus Oberthuer, found in China and Tibet. (Traditionally, the product contains both the fungus and its caterpillar host.) Cordyceps has been used in China to treat a wide range of conditions including fatigue, sexual dysfunction, and coughs. It is an adaptogen and immune stimulant.

Cordyceps has also been found to increase red blood cells, and to stimulate the production of testosterone (which is perhaps why it is used for sexual dysfunction). Research conducted primarily in China has also found cordyceps beneficial in increasing cellular oxygen absorption, protecting the liver, enhancing the immune system (by increasing natural killer cell activity), and improving shortness of breath and fatigue in patients suffering from chronic heart failure.

PROS AND CONS. CFS/ME patients have reported that cordyceps gives them a boost. It also reduces “air hunger” and increases stamina.

MORE INFORMATION

Sloan-Kettering's page on cordyceps: http://www.mskcc.org/cancer-care/herb/cordyceps

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“Dr Oz: Chronic Fatigue Syndrome, Cordyceps & D5 Ribose Sweetener.” http://www.drozfans.com/dr-ozs-advice/dr-oz-chronic-fatigue-syndrome-cordyceps-d5-ribose-sweetener/

“Cordyceps Chinensis.” Everything you could possibly want to know about Cordyceps. http://mdidea.com/products/herbextract/cordyceps/data06.html

“Mushroom remedy 'makes you fit' A Chinese mushroom improves the fitness of middle-aged and elderly people, research suggests.” http://news.bbc.co.uk/2/hi/health/3638543.stm

NAC (N-acetylcysteine )

DESCRIPTION. N-acetylcysteine (NAC) is a derivative of cysteine, an amino acid.

BACKGROUND. NAC acts as an antioxidant, and is a precursor to glutathione. Clinically, it has been used to treat acetaminophen (paracetamol in Britain) overdose. It has also been used to reduce the viscosity of mucus in pulmonary conditions such as pneumonia, bronchitis, emphysema and tuberculosis. NAC is commonly used in patients with renal impairment. It is being explored as a possible treatment for both schizophrenia and bipolar disorder. NAC's ability to counteract glutamate hyperactivity in the brain also make it a good candidate for treating obsessive-compulsive disorder. NAC is also a chelating agent for mercury, and can be used for mercury toxicity.

USES IN CFS/ME. NAC can inhibit muscle fatigue after exercise. Reid et al, in a 1994 study, showed that pre-treatment with NAC improved performance of muscles during exercise. They suggested that “oxidative stress plays a causal role in the fatigue process” and that NAC “may be useful clinically.”

Research on NAC has shown that it is effective in reducing depletion of glutathione. People with CFS/ME are demonstrably low on glutathione. However, direct supplementation with glutathione is problematic because glutathione is rapidly broken down in the gut. Taking glutathione precursors, such as NAC, allows the body to synthesize glutathione on its own.

PROTOCOL. Martin Pall has speculated that because NAC rapidly releases cysteine, it may cause neural excitotoxicity. He recommends using NAC at low doses.

PROS AND CONS. NAC is generally well tolerated. However, in those who are sensitive to stimulants, it can cause insomnia and headaches. NAC is contraindicated for people with kidney stones.

AVAILABILITY AND COST. NAC is available at health food stores and from online suppliers. It is inexpensive. A 60-capsule bottle of Carlson NAC (500 mg) costs about $8 (through Vitacost).

FURTHER READING

Kelly GS. “Clinical applications of N-acetylcysteine.” Altern Med Rev. 1998 Apr;3(2):114-27. http://www.ncbi.nlm.nih.gov/pubmed/9577247 (Abstract)

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Kerksicki, Chad and Darryn Willoughby. “The Antioxidant Role of Glutathione and N-Acetyl-Cysteine Supplements and Exercise-Induced Oxidative Stress.” Journal of the International Society of Sports Nutrition 2005, 2:38-44. http://www.jissn.com/content/2/2/38 (This is a review of research into glutathione and NAC in exercise-induced muscle fatigue.)

Reid MB, Stokić DS, Koch SM, Khawli FA, Leis AA. “N-acetylcysteine inhibits muscle fatigue in humans.” J. Clin. Invest. 1994 Dec;94(6):2468-74. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC330079/

NADH (ENADA)

DESCRIPTION. NADH is the reduced form of nicotinamide adenine dinucleotide (NAD), also called ubiquinone reductase. It is found in all living cells.

BACKGROUND. NADH was first discovered in the 1930s by an American scientist who observed that NADH played an essential role in the energy production of cells. It was not until more than 60 years had passed, however, that Dr. Georg Birkmayer, a biomedical researcher from Vienna, Austria, developed a stable oral form of NADH. Since then, a growing body of research has documented that NADH not only acts as a driving force in the production of cellular energy, but also is a potent antioxidant, is a key component of DNA repair and cellular regeneration, and stimulates the production of the neurotransmitters dopamine, noradrenaline, and serotonin. Ongoing research in the United States and abroad may help define the role of NADH in treating such degenerative neurological conditions as Alzheimer's disease and Parkinson's disease.

USES IN CFS/ME. NADH may be of great benefit in treating CFS/ME. When NAD is oxidized (NAD+) in the cell's mitochondria, energy is released. This energy is preserved in the form of adenosine triphosphate (ATP), a substance required by all energy-absorbing processes in the body.

Researchers have proposed that NADH may help correct the metabolic defect in CFS/ME that inhibits the production of ATP. Because low ATP production means less energy, clinicians believe NADH may alleviate CFS/ME-related exhaustion and may also improve cognitive function. The three neurotransmitters stimulated by NADH serve critical functions in the central nervous system: dopamine is important for short-term memory; noradrenaline contributes to alertness; and serotonin has a pronounced effect on mood and regulates sleep.

In 1999 Forsyth et al conducted a trial of NADH (as ENADA, a stable, bioavailable form of NADH) on 26 CFS/ME patients. Thirty-six percent of the CFS/ME patients taking NADH responded favorably, as opposed to 8% on placebo. No adverse effects were noted. In a longer term, open-label phase of the study, Birkmayer reports that “72% of the patients continued to report an improvement of their symptoms after six months of taking 10 mg ENADA daily. After approximately one year of taking ENADA the research doctors are reporting up to 81 percent of the patients continue to benefit from ENADA. These findings suggest that long-term ENADA therapy can lead to continued improvements, especially in energy and mental/ cognitive status.”

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While these results looked promising, there has been little follow-up on the initial trial with ENADA. Dr. Myhill lists ENADA as one of the CFS treatments “not worth trying” (along with graded exercise, CBT, and cold baths). As Dr. Myhill puts it, “It is the old story - single interventions are highly unlikely to result in worthwhile improvements because CFS is a complex problem - it is the combined approach that gets the results.”

PROTOCOL. Although Forsyth et al used 10 mg a day, the suggested starting dosage of NADH is 5 mg/day, (though some people report taking as much as 15 mg). The dosage is dependent on weight. Heavier people will need a higher dose to see an effect. NADH should be taken first thing in the morning on an empty stomach (about 20 minutes before your first meal).

Dr. Lapp recommends NADH in combination with acetyl-L-carnitine for his patients with severe “brain fog.” He observes that it can take three to six months to produce a response. Dr. Lapp recommends a dosage of 10 to 20 mg per day.

Patients note that sublingual NADH tablets are more effective than oral forms.

PROS AND CONS. Some patients report that NADH is moderately to mildly helpful, "making bad days somewhat less bad and good days somewhat better" (CFIDS Chronicle, Summer 1996). The majority of patients who take NADH note that it helps with cognitive symptoms more than fatigue.

AVAILABILITY AND COST. NADH is classified as a supplement and therefore does not require a prescription. Source Naturals sells a 60-tablet bottle of reduced Enada-NADH (5 mg) for $40 through Vitacost. PureFormulas.com sells a 30-tablet (10 mg) pack made by Physiologics for $38.50. Vitacost's own brand of sublingual NADH (10 mg) costs $20 for a packet of 30 tablets. A 30-tablet box of 5 mg ENADA costs $22.25 through the official ENADA website.

MORE INFORMATION

The official ENADA site, containing product and brand information: http://www.enada.com/

FURTHER READING

Dr. Birkmayer's review of ENADA, including summaries of trials, and recommended dosage. http://www.encognitive.com/node/5059

Patient thread on NADH. Includes references to several studies, responses and dosage. http://forums.phoenixrising.me/archive/index.php/t-5096.html

RESEARCH

Forsyth LM, Preuss HG, MacDowell AL, Chiazze L Jr, Birkmayer GD, Bellanti JA. “Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome.” Ann Allergy Asthma Immunol. 1999 Feb;82(2):185-91. http://www.ncbi.nlm.nih.gov/pubmed/10071523 (Abstract)

PROBIOTICS

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DESCRIPTION. Probiotic bacteria, primarily Lactobacillus acidophilus and Bifidobacterium bifidus, aid in many digestive processes and help maintain balance in the intestines.

BACKGROUND. Digestive tract bacteria (intestinal flora) have evolved within humans to aid in completing the breakdown and absorption of many foods. Without the thousands of "friendly" bacteria that inhabit the intestines, malnutrition would develop no matter how much food was eaten. These bacteria not only aid in digestion, but are responsible for manufacturing many nutrients that are essential to survival, such as the B vitamin complex. Some bacteria, such as bifidus, live in the large intestine; others, such as acidophilus, live in the small intestine.

As long as the intestinal flora are working well, a minimum of digestive problems can be expected. However, once the function of friendly flora is upset, harmful bacteria can proliferate, causing bloating, stomach upset, poor digestion, constipation, gas, and malabsorption problems. The most common sources of flora upset are recurrent use of antibiotics, oral contraceptives, aspirin, corticosteroids, poor diet, stress, and Candida infections. In these cases, it may be necessary to use a probiotic supplement to reestablish a healthy balance of intestinal flora.

A number of studies have shown that intestinal flora are effective for treating intestinal problems. In a review of probiotic treatments for diarrhea, Guandalini found that several strains of probiotics, including Lactobacillus GG, Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium ssp, Streptococcus ssp, and the yeast Saccharomyces boulardii, were effective in combating diarrhea due to antibiotics, C. difficile and viruses. Two strains, Lactobacillus GG and Saccharomyces boulardii were particularly effective. Researchers have also found probiotics helpful in treating irritable bowel syndrome and inflammatory bowel disease, suggesting a possible link between these two conditions.

USES IN CFS/ME. Patients with gastrointestinal symptoms or recurring yeast infections, or who regularly take antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, or cortisone are advised to use a probiotic supplement. Products that contain bifidus seem to help with leaky gut.

Generally, people with CFS/ME appear to suffer from a deficiency in friendly flora. According to a study by Butt et al in Australia, the colonic bacterial population in CFS/ME patients is deficient in Bifidobacterium and E. Coli. In contrast, the lactic acid bacteria, Enterococcus, is significantly higher – 28.7% of the total aerobic flora in CFS/ME patients – than in the healthy subjects (3-5%).

Remarkably, the researchers found that specific changes in gastrointestinal flora were associated with CFS/ME symptoms. A high enterococcal count positively correlated with neurological and cognitive functions: nervousness, memory loss, forgetfulness, confusion, and “mind going blank.” Similarly a high aerobe/anaerobe ratio significantly correlated with poor colonic functions, poor digestion, and malabsorption of the gastrointestinal tract. The implications of this study are that the composition of bacterial flora has a significant impact on both digestion and the nervous system, and that in people with CFS/ME the two are linked.

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In an interesting paper published in 2003, Logan et al proposed that probiotics might serve to enhance immune function in people with CFS/ME. The authors pointed out that people with CFS/ME have marked alterations in intestinal flora as well as oxidative stress. They state that “lactic acid bacteria (LAB) have the potential to influence the immune system in CFS patients by supporting . . . cellular immunity and may decrease allergies. In addition LAB are strong antioxidants, may improve EFA status, can enhance absorption of micronutrients by protecting the intestinal epithelial barrier.” The authors suggested that lactic acid bacteria might have a therapeutic role in the treatment of CFS/ME.

Probiotics may be useful for other reasons as well. Due to disruptions in the balance of neurotransmitters which are responsible for maintaining gut motility, people with CFS/ME often have motility problems. When motility is slowed, the bacteria from the large intestine can travel upward, where they colonize the small intestines. This leads to a condition known as SIBO (small intestinal bacterial overgrowth). Once established in the small intestines, the bacteria interfere with the breakdown of fats and carbohydrates. According to Dr. Cheney, a significant percent of the CFS/ME population suffers from SIBO. The standard treatment for SIBO is antibiotics, which, ironically, are also the primary cause of SIBO. Many gastroenterologists recommend treatment with probiotics, in particular Lactobacillus GG for SIBO in order to restore beneficial flora after antibiotic treatment.

PROTOCOL. Probiotics are sold in different forms. Each should be taken according to directions. Enteric-coated tablets, for example, need to be taken only once a day and can be taken with food, because the enteric coating protects the bacteria from being destroyed by stomach acids. Patients with altered intestinal flora as a result of taking antibiotics need to take a probiotic supplement for a least two weeks after finishing the treatment to repopulate the intestines. Single-strain varieties are reported to be more effective than multiple strains.

PROS. Most patients with CFS/ME who regularly take probiotics report easing of gastrointestinal symptoms (especially gas and bloating) and overall improvement in digestion. One of the main advantages of probiotics is that they can be taken daily for months, or even years, without causing any adverse effects or loss of benefits. They rarely cause side effects and are safe for children.

CONS. Probiotics are not without risk. There is some concern in the medical community about the safety of probiotic supplements (which is why it is important to purchase reputable brands). Probiotics should be used to caution in individuals with an abnormal gastrointestinal mucosal barrier (leaky gut), due to the risk of the bacteria penetrating the intestinal wall. Some people with CFS/ME who have been diagnosed with SIBO sometimes report experiencing flares and “brain fog” after taking probiotics, especially if the initial infection has not been eradicated.

AVAILABILITY AND COST. Many good brands of probiotic supplements can be purchased from health food stores and vitamin catalogs. Vitacost sells a package of 30 capsules of Culturelle (Acidophilus GG) for $15. Vitacost sells a 50-capsule bottle of Saccharomyces boulardii made by Allergy Research Group for about the same price.

Acidophilus can also be found in foods such as yogurt and kefir, although these are more effective at maintaining intestinal balance once it has been corrected. Foods such as miso and tofu can enhance bifidus growth, as can a number of vegetables that provide intestinal substrate (fructo-oligosaccharides (FOS) and inulin) in which the bacteria can flourish.

FURTHER READING

CFS/ME forum discussing some of the risks of probiotics. http://forums.phoenixrising.me/archive/index.php/t-8976.html

“Intestinal Flora.” Very good website with research and specific information on intestinal flora. http://www.probiotic.org/intestinal-flora.htm

"Probiotics in Clinical Practice: An Update." Good general information about the clinical use of probiotics: http://www.ecologyhealthcenter.net/node/839

“An Emerging Trend of High Dose Probiotic Use in Clinical Practice- A Brief Survey.” October 2011. http://www.pointinstitute.org/resources/Point+Inst.+High+Dose+Probiotics+Oct.+2011.pdf

Hibberd, Patricia L., Lisa E. Davidson. “Safety of probiotics.” http://chemistry-today.teknoscienze.com/pdf/HIBBERD%20AGRO4-08.pdf

Taylor C Wallace, Francisco Guarner, Karen Madsen, Michael D Cabana, Glenn Gibson, Eric Hentges, Mary Ellen Sanders. “Human gut microbiota and its relationship to health and disease.” Nutrition Reviews, Volume 69, Issue 7, pages 392–403, July 2011. http://onlinelibrary.wiley.com/doi/10.1111/j.1753-4887.2011.00402.x/full

RESEARCH

Butt H. L., Dunstan R. H., McGregor N. R., Roberts T. K. “Bacterial colonosis in patients with persistent fatigue.” Proceedings of the AHMF International Clinical and Scientific Conference; 2001 Dec 1–2; Sydney, Australia. http://www.ahmf.org/01access/01butt.html

Gibson GR, Beatty ER, Wang X, Cummings JH. “Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin.” Gastroenterology. 1995 Apr;108(4):975-82. http://www.ncbi.nlm.nih.gov/pubmed/7698613 (Abstract)

Guandalini S. “Probiotics for prevention and treatment of diarrhea.” J Clin Gastroenterol. 2011 Nov;45 Suppl:S149-53. http://www.ncbi.nlm.nih.gov/pubmed/21992955 (Abstract)

Logan, Alan C., A. Venket Rao, Dinaz Irani. “Chronic fatigue syndrome: lactic acid bacteria may be of therapeutic value.” Medical Hypotheses (2003) 60(6), 915–92. http://www.cfids-cab.org/cfs-inform/Hypotheses/logan.etal03.pdf

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Ku WH, Lau DCY, Huen KF. “Probiotics Provoked D-lactic Acidosis in Short Bowel Syndrome: Case Report and Literature Review.” HK J Paediatr (New Series) 2006;11:246-254. http://hkjpaed.org/details.asp?id=577&show=1234

PIRACETAM (Nootropil, Lucetam)

DESCRIPTION. Piracetam is a derivative of GABA (gamma-aminobutyricacid), the brain's primary neuroinhibitory amino acid.

BACKGROUND. Piracetam is a nootropic, or “smart drug.” It has been used for a wide range of neurological impairments, including seizures, dementia, focal lesions in the brain, and concussions. There is also evidence that it can enhance cognitive performance among the healthy. In a study by Dimond and Brouwers, administration of piracetam for 14 days improved verbal memory in a group of college students. Piracetam appears to work not just by acting on cholinergic receptors, but by decreasing the viscosity of blood, which, in turn, enhances the delivery of oxygen to the brain.

USES IN CFS/ME. Piracetam is used more widely in Europe than in the U.S., where the FDA has determined that because it is not a vitamin, mineral, amino acid, herb, botanical, or other dietary substance, it is therefore not a supplement. Nor is it approved as a drug, which puts piracetam in the odd category (along with galantamine) of having no clinical status. As a consequence, there has not been a great deal of research done on piracetam for CFS/ME.

There is, however, a small but significant body of research that seems to indicate that piracetam would be appropriate for the treatment of cognitive impairment in CFS/ME patients. In one such study, researchers in Brazil found that piracetam protected the hippocampus (the part of the brain associated with the formation of new memories) during alcohol withdrawal. It has been widely noted that CFS/ME patients have difficulty forming new memories, which is crucial to learning.

Of even greater interest to CFS/ME patients is a study conducted in 2002 by Gabryel et al, in which piracetam was shown to protect the brain against hypoxic injury. Not only did the drug prevent cell damage, it stimulated mitochondrial function, increasing intracellular ATP. Given the growing body of evidence that people with CFS/ME not only experience lowered oxygenation of brain tissues, but loss of brain matter, this finding could point the way to effective treatment.

PROTOCOL. Dr. Teitelbaum recommends 1200 mg twice a day for 2 weeks, and then 2400 mg twice a day for 2 weeks to treat brain fog. He recommends that piracetam be taken with hydergine, a dopamine-stimulating nootropic. CFS/ME patients may wish to start with the recommended dosage, which is 400-800 mg a day. Those with insomnia and sensitivities to stimulants should begin at an even lower dose – 50 mg.

PROS AND CONS. There are very few reported side effects, but large doses can cause headache, restlessness and insomnia. Patients report good effects at very low doses (50 mg a day). Effects are similar to caffeine – a feeling of alertness, greater focus, and “being awake.”

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AVAILABILITY AND COST. Piracetam is available online. Amazon.com sells 60-capsule bottle of piracetam (800 mg) for $23.42. This amounts to roughly $1 for 2 grams. If the product works for you, bulk purchase is much less expensive.

FURTHER READING

“Living With Chronic Fatigue Syndrome” blog entry on piracetam. http://livingwithchronicfatiguesyndrome.wordpress.com/2011/04/04/piracetam-for-mecfs/

Patient experiences with piracetam http://forums.phoenixrising.me/archive/index.php/t-9408.html

RESEARCH

Brandão F., M.M. Paula-Barbosa, A. Cadete-Leite. “Piracetam impedes hippocampal neuronal loss during withdrawal after chronic alcohol intake.” Alcohol, Volume 12, Issue 3, May–June 1995, 279–288. http://www.ncbi.nlm.nih.gov/pubmed/7639963 (Abstract)

Dimond SJ, Brouwers EM. "Increase in the power of human memory in normal man through the use of drugs." Psychopharmacology. 1976 49 (3): 307–9. https://www.ncbi.nlm.nih.gov/pubmed/826948 (Abstract)

Gabryel B, Adamek M, Pudełko A, Małecki A, Trzeciak HI. "Piracetam and vinpocetine exert cytoprotective activity and prevent apoptosis of astrocytes in vitro in hypoxia and reoxygenation". Neurotoxicology 2002, 23 (1): 19–31. https://www.ncbi.nlm.nih.gov/pubmed/12164545

Waegemans T, Wilsher CR, Danniau A, Ferris SH, Kurz A, Winblad B. "Clinical efficacy of piracetam in cognitive impairment: a meta-analysis." Dementia and geriatric cognitive disorders. (2002)13 (4): 217–24. https://www.ncbi.nlm.nih.gov/pubmed/12006732 (Abstract)

Winblad, B. "Piracetam: a review of pharmacological properties and clinical uses." CNS Drug Reviews (2005)11 (2): 169–82. www.ncbi.nlm.nih.gov/pubmed/16007238 (Abstract)

ROYAL JELLY

DESCRIPTION. Royal jelly is a thick, milky substance secreted by young nurse honeybees to nourish the young larvae in a colony, especially the queen larvae.

BACKGROUND. Royal jelly is one of nature's most potent foods. It is rich in B vitamins (especially pantothenic acid), biotin, folic acid, and inositol. It also contains vitamins A, C, D, and E, seven minerals, 18 amino acids, fatty acids, enzymes and hormones, and is the only natural source of acetylcholine, the neurotransmitter that aids in memory. Health-enhancing properties attributed to royal jelly range from reducing cholesterol levels to healing skin disorders.

In 2011 a group of researchers found that royal jelly exerted a protective effect on the liver and kidneys of rats which had been given cisplatin, a cytotoxic agent used for chemotherapy. The beneficial effects of royal jelly were attributed to

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a reduction of oxidative stress and apoptosis (cell death). Oxidative stress and increased cell apoptosis are commonly found in CFS/ME patients. Further research has indicated that royal jelly may be effective in reducing inflammation.

USES IN CFS/ME. Although CFS/ME doctors do not routinely prescribe royal jelly, it has been used by CFS/ME patients for decades. Royal jelly is a natural source of acetylcholine, a neurotransmitter some researchers believe is deficient in CFS/ME, which may be why it is effective in reducing muscle weakness some patients. Its anti-inflammatory properties make it well suited to mitigating pain. Royal jelly also provides an easily tolerated form of B vitamins. Many patients with CFS/ME who need B vitamins cannot tolerate yeast-based vitamin B products.

Steve Wilkinson, author of Chronic Fatigue Syndrome: A Natural Healing Guide, claims that royal jelly can help provide increased stamina and energy, greater mental alertness, and relief from muscle problems. He states that in his case the improvement in muscle pain was "dramatic" after just a few weeks of taking royal jelly.

In a pilot study conducted in England with ME patients, approximately 40 of the participants noted an improvement in energy and stamina. Twelve patients reported a decrease in muscle and joint pain. Another forty noted a decrease in depression. Eighty of the 109 participants said that royal jelly was beneficial.

PROTOCOL. Y&S Eco Bee Farms recommends taking ¼ teaspoon of royal jelly once or twice daily on an empty stomach, followed by a small amount of chilled water. Royal jelly can be taken for months. Some patients need two to three months before its benefits can be felt. Pure royal jelly (not mixed with honey) requires refrigeration because it spoils easily. Royal jelly should not be mixed into or consumed with anything hot.

PROS. Royal jelly is a safe, inexpensive supplement that provides some necessary nutrients, as well as acting as immune modulator. As the only natural source of acetylcholine (ACh), it is one of the safer treatments for the ACh deficiency posited in CFS/ME patients.

CONS. Allergic reactions to royal jelly are not unknown. Patients with a history of pollen allergies should be cautious in using royal jelly. Patients with allergies should be sure the royal jelly has not been mixed with other products (ginseng, bee pollen, honey) to avoid possible allergic reactions to these additives.

AVAILABILITY AND COST. Pure royal jelly is available as a thick liquid or in capsules. Ebeehoney.com sells a 2 oz jar of pure royal jelly for $13. (Shipped with an ice pack.) Because royal jelly loses its potency when improperly handled or processed, it may be worthwhile to buy the purest form available. The refrigerated section of health food stores usually contains the most potent royal jelly products.

FURTHER READING

A pilot study of Irena Royal Jelly conducted on 109 ME patients: http://www.irenesteinrj.com/files/ME%20REPORT.pdf

Suppliers of Y&S pure royal jelly: http://www.yahwehsaliveandwell.com/ysroyaljelly.html

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Online site for purchasing pure royal jelly: http://www.ebeehoney.com/royaljelly.html

RESEARCH

Harada S, Moriyama T, Tanaka A. [Two cases of royal jelly allergy provoked the symptoms at the time of their first intake]. Arerugi. 2011 Jun;60(6):708-13. http://www.ncbi.nlm.nih.gov/pubmed/21709438 (Abstract)

Karadeniz A, Simsek N, Karakus E, Yildirim S, Kara A, Can I, Kisa F, Emre H, Turkeli M. “Royal jelly modulates oxidative stress and apoptosis in liver and kidneys of rats treated with cisplatin.” Oxid Med Cell Longev. 2011;2011:981793. http://www.ncbi.nlm.nih.gov/pubmed/21904651 (Abstract)

Kohno K, Okamoto I, Sano O, Arai N, Iwaki K, Ikeda M, Kurimoto M. “Royal jelly inhibits the production of proinflammatory cytokines by activated macrophages.” Biosci Biotechnol Biochem. 2004 Jan;68(1):138-45. http://www.ncbi.nlm.nih.gov/pubmed/14745176 (Abstract)

Yanagita M, Kojima Y, Mori K, Yamada S, Murakami S. “Osteoinductive and anti-inflammatory effect of royal jelly on periodontal ligament cells.” Biomedical Research. 2011;32(4):285-91. http://www.ncbi.nlm.nih.gov/pubmed/21878736 (Abstract)

SAMBUCOL

DESCRIPTION. Sambucol is an extract made from the fruit of the European black elder tree (Sambucus nigra L), a member of the Adoxaceae family.

BACKGROUND. Black elderberry berries have long been used in Europe to make jams, jellies, soft drinks, and aromatic wines. In addition to its pleasant taste, elderberry is valued as a rich source of B vitamins and bioflavonoids, as well as minerals such as calcium and phosphorus. Medicinal use of black elderberry has been documented as early as the fifth century BC, when the ancient Greeks described it as a remedy for colds, flu, and upper respiratory tract infections. In the mid-1980s, researchers found that two of the active ingredients in elderberry inhibited the replication of the influenza virus by preventing the virus from entering cells.

In a continuation of that research, in 1992 a group of Israeli scientists and physicians formulated a black elderberry syrup that acted successfully against the influenza virus in a laboratory setting. Soon afterward, a double-blind, placebo-controlled study was conducted in patients with influenza in southern Israel. The results of that study indicated that black elderberry effectively reduced the duration and severity of influenza infections. Flu symptoms (fever, cough, and muscle pain) significantly improved in 20% of the patients within 24 hours, compared with 8% of the control group. Within three days, more than 90% of the patients were symptom free, compared with six or more days for the control group.

In 2011 a group of researchers from the Institute of Medical Biology in Germany found that standardized extract of elderberry inhibited viral replication of influenza A and influenza B. They also found that the extract possessed

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antimicrobial activity against both gram-positive and gram-negative bacteria in liquid cultures. Another group of researchers in Austria found that a fraction of elderberry produced broad anti-inflammatory effects and supported “the traditional use of extracts and preparations of Sambucus ebulus L., rich in ursolic acid, for the treatment of chronically inflammatory processes.” Results of further studies have also shown that elderberry extract can act against herpes virus and Epstein-Barr virus.

USES IN CFS/ME. The fact that Sambucol has such a wide range of antiviral effects may make it particularly useful for the many patients with CFS/ME who have frequent colds and flu. It may also be valuable for those who demonstrate reactivation of Epstein-Barr virus and other latent viruses, the effects of which can lead to many of the symptoms typical of CFS/ME. Many CFS/ME patients taking Sambucol have noted overall improvement (Mass CFS/ME Update, Fall 1995).

PROTOCOL. The recommended dosage of Sambucol syrup is 4 tablespoons daily in adults and 1 tablespoon daily in children younger than 12 years. Patients with CFS/ME should probably start with a smaller dose to check for tolerance. Sambucol should be taken on a full stomach. Dairy products should be avoided for 30 minutes before and after to avoid stomach upset. The manufacturers recommend refrigeration after opening.

PROS. Sambucol is an all-natural product, which is an advantage for patients with chemical and drug sensitivities. There are no reported side effects or contraindications associated with its use. Those who have tried it claim that it hastens recovery from flu and colds, and lessens general malaise. Sambucol is also safe for children, which is good news for parents of children with CFS/ME, because so few effective pediatric medications are currently available.

CONS. Some patients report allergy-type reactions (congestion, headache, dizziness) to elderberry. As fresh elderberry leaves and bark are poisonous (but not the berries), always purchase processed elderberry extracts with high flavonoid content from a reputable company. Do not make your own tea.

AVAILABILITY AND COST. Sambucol is currently marketed in the United States, Europe, Israel, and South Africa through health food stores and drugstores. The liquid extract contains glucose and honey for sweetening and raspberry extract to enhance flavor. If a glucose-free product is desired, Sambucol is available in lozenge form and as a liquid sweetened with sorbitol. Vitacost sells 4 oz bottle of liquid Sambucol for between $10 and $15. Lozenges in packs of thirty cost about $7. Prices at retail outlets are generally considerably higher.

FURTHER READING

Complete information about the composition, effects and clinical research of elderberry extract. http://www.drugs.com/npp/elderberry.html

RESEARCH

Konlee, M. “A new triple combination therapy.” Posit Health News. 1998 Fall;(No 17):12-4. http://www.ncbi.nlm.nih.gov/pubmed/11366542 (Abstract)

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Krawitz C, Mraheil MA, Stein M, Imirzalioglu C, Domann E, Plechka S, Hain T. “Inhibitory activity of a standardized elderberry liquid extract against clinically-relevant human respiratory bacterial pathogens and influenza A and B viruses.” BMC Complement Altern Med. 2011 Feb 25; 11:16. http://www.ncbi.nlm.nih.gov/pubmed/21352539 (Abstract)

Schwaiger S, Zeller I, Pölzelbauer P, Frotschnig S, Laufer G, Messner B, Pieri V, Stuppner H, Bernhard D. “Identification and pharmacological characterization of the anti-inflammatory principal of the leaves of dwarf elder (Sambucus ebulus L.).” J Ethnopharmacol. 2011 Jan 27;133(2):704-9. http://www.ncbi.nlm.nih.gov/pubmed/21040770 (Abstract)

Zakay-Rones Z, E Thom, T Wollan, and L Wadstein. “Randomized Study of the Efficacy of and Safety of Oral Elderberry Extract in the Treatment of Influenza A and B Virus Infections.” The Journal of International Medical Research. 2004; 32: 132-140. http://www.jimronline.net/content/full/2004/47/0445.pdf

SAMe

DESCRIPTION. SAMe (S-Adenosyl methionine), is a primary methyl group donor that is involved in the synthesis of neurotransmitters.

BACKGROUND. SAMe (pronounced “Sammy”) was first discovered in Italy in 1952. It is a cornerstone in the methylation cycle, which is the biochemical process through which amino acids are transformed into neurotransmitters. (SAMe's contribution of its methyl group (CH2) is what converts an amino acid into a neurotransmitter.) It should not come as a surprise that SAMe plays a key role in mood, nervous system regulation, and maintaining energy levels, since all of these are regulated by neurotransmitters.

The first studies of SAMe's use in depression were conducted in Italy in the 1970s. Because SAMe is a primary methyl group donor, the authors concluded that depression could be linked to the methylation cycle. Since that time, there have been dozens of studies confirming the efficacy of SAMe in treating depression.

USES IN CFS/ME: Rich Van Konynenburg has proposed that in CFS/ME there is a partial block of the methylation cycle. This would cause a depletion of ATP, as well as reductions in neurotransmitters, detoxing agents such as glutathione, and impairment of normal immune system function. Because SAMe is a vital component of the methylation cycle, Dr. Myhill recommends it as an all-round support.

PROTOCOL. SAMe should be taken on an empty stomach. Low doses, ranging from 50 to 100 mg/day are recommended. (Ray Sahelian advises taking half of a tablet, and storing the rest for the next day.) Because SAMe can produce insomnia, it is best taken in the morning. SAMe is highly unstable, and should be stored in a cool, dry place to prevent deterioration. SAMe should be taken with vitamin B6, B12 and folic acid as adjuncts.

PROS AND CONS. SAMe appears to have few side effects. But as with any product that affects the central nervous system (even indirectly), care should be exercised. While most people feel an immediate improvement in mood and focus,

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some sensitive individuals can experience side effects typical of stimulants (jitters, insomnia, headache, anxiety). SAMe raises levels of all neurotransmitters, so it is difficult to predict how any individual person may respond.

AVAILABILITY AND COST. SAMe is available in health food stores and from online suppliers. A package of 20 foil-wrapped enteric-coated tablets (200 mg) costs $10 through Vitacost.

SEE: Van Konynenburg/Yasko Methylation Protocol

FURTHER READING

Ray Sahelian on SAMe: http://www.raysahelian.com/sam-e.html

Dr. Myhill discusses the methylation cycle: http://drmyhill.co.uk/wiki/CFS_-_The_Methylation_Cycle

RESEARCH

Kagan BL, Sultzer DL, Rosenlicht N, Gerner RH. “Oral S-adenosylmethionine in depression: a randomized, double-blind, placebo-controlled trial.” Am J Psychiatry. 1990 May;147(5):591-5. http://www.ncbi.nlm.nih.gov/pubmed/2183633 (Abstract)

Mischoulon, David and Maurizio Fava. “Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence.” Am J Clin Nutr. 2002;76(suppl):1158S–61S. http://www.ajcn.org/content/76/5/1158S.full.pdf

VITAMINS

Vitamin A, Beta-Carotene, Vitamin B12, Vitamin B6, Vitamin B Complex, Vitamin C, Vitamin D, Vitamin E and Tocotrienols

DESCRIPTION. Vitamins are organic (carbon-containing) substances needed in tiny amounts to promote biochemical reactions within living cells.

BACKGROUND. Vitamins, as independent biochemical agents, were discovered around the turn of the century when an English biochemist proposed that diseases such as rickets and scurvy were most likely caused by a lack of "accessory food factors" in the diet. After observing that these diseases could be corrected by adding certain foods (whole rice, which is high in vitamin B, to cure rickets; and oranges, an easy source of vitamin C, to cure scurvy), scientists began to search for chemical compounds in these foods that could produce such extensive changes in the body. When these accessory food factors were finally isolated in food, the name "vita-mine" was proposed (from the Latin vita, necessary for life, and amine, a chemical substance containing nitrogen). Later, when it was discovered that not all vitamins were amines, the final "e" was dropped.

There are thirteen known vitamins, all of which act as catalysts, or more specifically, coenzymes; that is, they initiate or speed chemical reactions in cells while remaining unchanged themselves. They accomplish their task mainly by

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combining with a protein-containing apoenzyme (vitamins contain no protein) to form a complete enzyme. The completed enzyme performs the role of biochemical catalyst, enabling most of the body's vital cell functions to occur in an orderly and efficient manner. Without vitamins, many essential cell functions would cease, resulting in any number of vitamin deficiency-related diseases and problems. Most vitamins must be obtained from food because the body rarely manufactures them in adequate amounts (vitamin K is the exception).

USES IN CFS/ME. Most CFS/ME physicians and clinicians include vitamin supplementation as a part of a general treatment protocol. The reasons vitamin supplementation is considered such a central part of CFS/ME treatment are threefold. First, the ill body consumes vitamins much faster than the healthy body. Patients, particularly those with long-term illnesses, need vitamins in amounts that exceed those which can be derived from food, especially when (as in CFS/ME) the illness causes certain metabolic defects.

Second, at least 50% of patients with CFS/ME have absorption problems (leaky gut, low stomach acid production, or other gastrointestinal difficulties). When food is improperly digested, vitamins are not extracted efficiently, necessitating some kind of supplementation.

Third, as has been pointed out by a number of researchers, the particular nature of CFS/ME immune system activation prevents some vitamins from working properly. The excess cytokine production that blocks vitamin C function, for example, is justification enough for supplementation.

The most frequently recommended vitamin supplements are vitamin C and B12, but general wide-spectrum supplements are also important. Benefits of vitamin supplementation generally are not apparent for several weeks, but some undernourished patients notice significant effects within a few hours. Many CFS/ME patients report an overall improvement in vitality, energy level, and stamina with vitamin supplementation. Few report any adverse effects (and these are usually remedied by switching brands).

AVAILABILITY AND COST. Vitamins are easily obtained from supermarkets, health food stores, pharmacies, and online suppliers. Vitacost markets a good multi-vitamin/mineral supplement made by Carlson for $8.50 (90 gelcaps).

Care should be taken to purchase high-grade vitamins because the excessive heat and poor handling to which low-grade vitamin products are exposed often cause fat-soluble vitamins to become rancid and can considerably reduce the efficacy of water-soluble vitamins. Excess filler also makes some cheaper vitamins difficult to dissolve. (A good test for vitamin tablets is to place one in a small glass of lemon juice. If it doesn't dissolve in the lemon juice, it won't dissolve in your stomach.) With the exception of vitamin E, synthetic vitamin preparations are as effective as natural vitamins.

In addition to a wide-spectrum vitamin supplement, many CFS/ME physicians recommend taking extra amounts of specific vitamins for the purposes of

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providing added antioxidant protection, for immune system enhancement, or to compensate for the functional deficits common to the illness.

FURTHER READING

General information about vitamins (and other) supplements for CFS/ME patients. http://www.cfids.org/archives/2004/2004-1-article04.asp