Archive for the ‘CFS treatments’ Category


I must preface this blog entry with an apology for my lack of blog posts of late. This is attributable to my ME/CFS prohibiting me from using the computer for any meaningful length of time. I am unsure whether this is the result of natural ME/CFS progression, a consequence of one the treatments I am trialling or some combination of the two. Not being able to use the computer for more than several minutes at a time has meant that I have been unable to criticise the recently published PACE trial or follow ME/CFS or XMRV related happenings in any detail.

                                                                                                                                                                                                                                                                              I will attempt to document the ME/CFS treatments I have been taking during 2011 and include a status report pertaining to their effectiveness/side effects on me. Under normal circumstances I would like to write an examination of each treatment individually including studies, mechanisms of action, dose etc however I plan to keep this blog entry brief and I will instead provide links to exterior sources containing more plentiful information about each treatment.

                                                                                                                                                                                                                                                                          The Treatments

Cordyceps Sinensis: Cordyceps Sinensis are a hybrid caterpillar fungus that are often utilised in Chinese medicine. I became aware of this treatment as the result of viewing a documentary titled ‘Tibetan El Dorado.’

Information about Cordyceps Sinensis in general can be found here:


Cordyceps Sinenis possible usefulness and mechanisms as a treatment for ME/CFS can be found here: http://www.cfs-healing.info/database.htm (scroll down to ‘Cordyceps’)

                                                                                                                                                                                                                                                                        My Experience: I took Cordyceps Sinensis for several months and didn’t notice any beneficial effects or significant side effects. On two separate occasions I attempted to increase my consumption dose from 1 tablet (525mgs) to 2 or 3 tablets. I experienced an exacerbation of my ME/CFS symptoms during these attempted dose increases however I believed this to be a spurious similarity (it also didn’t resemble a Herxheimer reaction.) Side effects are apparently rare as a direct consequence of Cordyceps Sinensis consumption. I have now stopped taking this treatment.

                                                                                                                                                                                                                                                            Obtaining genuine Cordyceps Sinensis in western countries can be problematic however I eventually managed to find a large American company that cultivates Cordyceps Sinensis indoors. I don’t like to advertise companies or specific brands so if anyone wants to try this treatment and cannot find an appropriate supplier of Cordyceps, please leave a comment and I will email you a link to the homepage of the company I used.

                                                                                                                                                                                                                                                                       Kefir: Kefir is a fermented milk drink that some ME/CFS patients use for impaired gastrointestinal or immune systems and/or nasal symptoms.

Some information about Kefir and its relation to ME/CFS can be found here: http://forums.phoenix-cfs.org/showthread.php?1137-Kefir-KCLM-Research-Interview

                                                                                                                                                                                                                                                                           My Experience: I consumed both goats milk and water based Kefir products several times a day for approximately 5 weeks. My Mum obtained the Kefir from a fellow ME/CFS patient and she also grew the substances.  I didn’t notice any positive or negative effects while taking the Kefir.

                                                                                                                                                                                                                                                         Hawthorn: Hawthorns are a group of shrubs and trees that belong to the rose family. Hawthorn supplements have many potential effects on ME/CFS patients that centre on enhancing the heart’s abilities.

An excellent post describing Hawthorn and its relation to ME/CFS can be found here:  http://www.prohealth.com/me-cfs/blog/boardDetail.cfm?id=1013873 (the second post down- by Forebearance.)

                                                                                                                                                                                                                                                                        My Experience: I have been taking Hawthorn leaves and flower extract in capsule form for over 2 months now. The reasoning behind me trialling this treatment arose after reading that Dr. Cheney often recommends Hawthorn as an adjunctive treatment to Nexavir (which I am also taking.) Prior to starting Hawthorn, my resting pulse rate was between 76-80 beats per minute. My resting pulse rate is now 60 beats per minute (most likely as a direct result of the Hawthorn.) Prior to becoming ill, in my athletics days, my resting pulse was in the fourties. I am very pleased with my new, lower heart rate, especially considering that I am virtually bedbound. I haven’t noticed any other effects from taking the Hawthorn- no other positive effects, no side effects and no secondary positive effects from having a lower resting pulse rate (i.e. not noticeably improved peripheral circulation.) I am continuing to take Hawthorn at a dose of 500mg twice a day. 

                                                                                                                                                                                                                                                            Nexavir:  Over four months ago I wrote a blog entry about Nexavir that can be found here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/10/25/nexavir-kutapressin-for-cfs/ Nexavir is an injectable porcine liver extract that has had promising results in CFS studies.

                                                                                                                                                                                                                                                                        My Experience:  After four months of daily Nexavir injections, I am still yet to notice any vivid positive effects. Conversely I have also not experienced any negative effects. I plan to continue the Nexavir injections until I complete the 6 month course. Yesterday I began to pulse the Nexavir dose.

                                                                                                                                                                                                                                                        Melatonin: Melatonin is a naturally occurring hormone compound that has many possible mechanisms of action against ME/CFS. It is most widely used in ME/CFS patients to aid in the obtainment of quality sleep.

More information about Melatonin and its relation to ME/CFS can be found here: http://aboutmecfs.org/Trt/TrtMelatonin.aspx

                                                                                                                                                                                                                                                                         My Experience: I have found that my optimum dose of Melatonin is 0.6mgs (this dosage number varies among patients and is generally determined through the process of trial and error.) I find this dose doesn’t keep me drowsy throughout the day however slightly aids the deepness in which I sleep. I have taking Melatonin for approximately 4 weeks and plan to continue with this treatment.

                                                                                                                                                                                                                                                                  Immunoprop, Catapult and Immunoplus: Dr. Enlander uses these treatments as synergistic treatments to Hepapressin injections.

                                                                                                                                                                                                                                                                        My Experience: I took each of these treatments simultaneously for 3 months and did not notice any positive or negative effects.

                                                                                                                                                                                                                                                    Magnesium injections

A study found here: http://www.ncbi.nlm.nih.gov/pubmed/1672392 and titled ‘Red blood cell magnesium and chronic fatigue syndrome’ found low red blood cell magnesium levels in CFS patients. After intramuscular magnesium sulphate injections weekly for 6 weeks, 12 of the 15 CFS patients given magnesium benefited from the treatment. This contrasted 3 out of the 17 CFS patients given a placebo noting a symptomatic improvement.

                                                                                                                                                                                                                                                                 Despite this second study: http://www.ncbi.nlm.nih.gov/pubmed/11155461 being performed on Fibromyalgia patients, it demonstrates that plasma levels of magnesium are normal in such patients however their intracellular magnesium levels were low and potentially to blame for their muscular hypertonus.

                                                                                                                                                                                                                                                                         The purpose of using intramuscular injections of magnesium sulphate is that a large portion of CFS patients cannot intracellularly absorb magnesium when taken orally. IM magnesium shouldn’t be prescribed to patients with kidney problems. This website emphasizes that IM magnesium side effects are unlikely: http://www.medicinenet.com/magnesium_sulfate-injection/article.htm

                                                                                                                                                                                                                                                                         My Experience: I had 2.47g per 5ml of magnesium, injected intramuscularly, weekly for 4 weeks. The actual injections can be quite painful however the pain can be reduced by warming the magnesium sulphate to room temperature, adding B12 and/or using lidocaine. The magnesium injection does sting at the delivery site however I found that each magnesium injection was less painful that the last. I also took calcium (to avoid a mineral imbalance), B1 as recommended by Dr. Myhill (for its synergistic effects) and continued with oral magnesium. I didn’t notice any negative or positive effects as a result of the magnesium injections. 

                                                                                                                                                                                                                                                                Myers’ cocktails: Myers’ cocktails are an intravenously delivered nutrient therapy that contain a range of vitamins and minerals.

An 18 page document describing everything there is to know about Myers’ Cocktails can be found here 

                                                                                                                                                                                                                                                                        My Experience: I had weekly Myers’ cocktails for 3 weeks. During the infusions, I experienced a flushed face and felt relaxed. Following the infusion I felt sleepy. These are all standard symptoms as a result of Myers’ cocktails. Each morning after the Myers’ cocktail I felt slightly refreshed however this feeling was transient.  My Myers’ cocktails contained the standard ingredients including 15grams of vitamin C as well as zinc. Dr. Majid Ali has found that 15grams of vitamin C delivered intravenously can mend the abnormal shapes of ME/CFS patient’s red blood cells and hence improve blood flow. I didn’t notice any side effects or positive effects from the Myers’ cocktails.


Despite some of these treatments having excellent efficacy in CFS studies and when prescribed by ME/CFS specialists, I didn’t experience any beneficial effects despite a reduced resting heart rate as a consequence of taking Hawthorn. I have many further treatments planned and I will again update readers of this blog with the future effects of these therapies.




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This list documents what I believe are some of the most effective CFS treatments based on studies, anecdotal reports and/or mechanisms of action. This list is ranked from 1 to 10 with 1 being a potential treatment for broad Oxford Criteria CFS and 10 being a possible treatment for Canadian Consensus Criteria ME/CFS. The increasing numbers of this list correlate with more stringent CFS criteria. Another way of interpreting the rankings on this list involves possible prioritisations of treatments. In other words, it is unlikely one would take treatments 9 or 10 if they hadn’t yet tried the first few treatments. 

                                                                                                                                                                                                                                           This list purposefully contains treatments that are low in side effects however some CFS patients may experience side effects as a result of some of the treatments. I have also tried to provide some basic information about each treatment. Thorough information (dosage, side effects, contraindications etc) about each treatment is available elsewhere on the internet.

                                                                                                                                                                                                                                             1.       Energy Revitalizing System: This formula contains over 50 minerals, vitamins and nutrients aimed at providing energy to the consumer. As opposed to taking in excess of 30 tablets per day, Energy Revitalizing System provides this equivalence in one formula. It contains a range of B-vitamins, the equitable contents of a multi-vitamin tablet and many amino acids. The amino acids include 500mg servings of L-Serine, an amino acid that Dr. Buttfield believes at doses increasing from 500mg to 2g should help 60% of CFS patients significantly. I believe that Energy Revitalizing System contains a combination of potentially helpful treatments. It is worth noting that despite the array of amino acids in this formula, L-Carnitine is not included. L-Carnitine has been shown to benefit some CFS patients according to several studies.


2.       D-Ribose: D-Ribose may help the mitochondria keep the body’s cells supplied with energy. Dr. Myhill is an advocate of D-Ribose treatment as part of her mitochondrial treatments.  A pilot study was performed in which 5grams of D-Ribose was consumed three times per day by 41 CFS and Fibromyalgia patients. 66% of patients experienced significant improvement while taking the D-Ribose. I won’t provide a critique of the cohort selection or study itself here however one must maintain a degree of scepticism pertaining to the study results.   


3.       Vitamin B12 Injections: Cyanocobalamin and Hydroxocobalamin are the two B12 forms utilised by CFS specialists. Intramuscular B12 injections generally involve a 1000mcg-5000mcg dose administered 1-5 days per week for a total of 15-30 injections. Despite having normal B12 levels as determined by a blood test, CFS patients often have low B12 levels in their brains. High B12 injectable doses are a method of ensuring that adequate levels of B12 cross the blood-brain barrier. B12 is also a scavenger of nitric oxide, a compound that may contribute to some patients CFS symptoms. A poll detailed that 50%-80% of Dr. Lapp’s CFS patients improved to some degree as a result of vitamin B12 injections. Some CFS patients that don’t respond to vitamin B12 injections will respond to folic or folinic acid.


4.       Magnesium Injections: The standard procedure for magnesium injections involves magnesium sulphate (which requires a prescription) being administered intramuscularly 1gm/2mls weekly for 10 weeks. Approximately 70% of Dr. Myhill’s CFS patients improve based on this protocol. Oral thiamine may help the magnesium be absorbed by patient’s cells and a calcium supplement may aid avoidance of a mineral imbalance. Many CFS specialists believe that despite CFS patients having normal blood levels of magnesium, patients have low intracellular magnesium levels.


 5.       Inosine: Inosine is the active ingredient in the prescription medication ‘inosine pranobex.’ Inosine is available online without a prescription. A small study on Inosine’s prescription cousin, inosine pranobex found that it benefitted 6 out of 10 CFS patients after 28 weeks. Dr. Larry Sharp has labelled inosine pranobex “One of the safest, most cost effective and helpful drugs at our disposal.” It is an antiviral and immunomodulator. Dr. De Meirleir believes that the nutritional supplement inosine is as effective as the prescription version, inosine pranobex.


6.       Oxymatrine: Oxymatrine is an antiviral derived from the Sophora plant. It is commonly used to treat Hepatitis B and is sometimes used in China as an anti-cancer drug. It is most effective in those CFS patients with an enterovirus. Dr. Chia performed a study that found that 52% of CFS patients’ illness improved after taking oxymatrine. This was in comparison to 2% of the placebo group improving. Dr. Chia has given the herb to over 350 CFS patients and has concluded that 52% show some degree of improvement. Due to concerns over the purity of some brands of oxymatrine, Dr. Chia produced his own form called Equilibrant. This product can be ordered online and contains oxymatrine in tandem with various immune modulators. I have written some more information about oxymatrine here: https://livingwithchronicfatiguesyndrome.wordpress.com/2009/11/03/oxymatrine/


7.       Artesunate: Artesunate is an antiviral that is often used to treat malaria. Studies have shown that is has the ability to reduce herpes virus levels. Artesunate can also inhibit HIV. During August 2009, Dr. Cheney, the leading advocate of Artesunate as a treatment for CFS, found that Artesunate may inhibit XMRV via NK Kappa B inhibition. Wormwood is often used as an adjunctive therapy to Artesunate.  Using Artesunate, Dr. Cheney has doubled his amount of CFS cures and 75% of his patients show some level of improvement due to this treatment. I have written about an Artesunate dosing structure here: https://livingwithchronicfatiguesyndrome.wordpress.com/2009/08/25/antiviral-and-immunomodulator-cfs-treatment-i-am-trying/


8.       Low Dose Naltrexone: Low Dose Naltrexone (LDN) is a prescription drug that blocks the opioid receptors for a short period of time. This causes the body to create more opioids. These opioids are useful for several reasons including blocking pain, creating endorphins and having an effect on the immune system. A pilot study found that Fibromyalgia patients experienced a 30% reduction in pain and fatigue as a consequence of taking LDN. Dr Bihari has found that approximately 50% of CFS patients are helped by LDN. A study found that “individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone.” I have written more extensively about LDN here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/02/26/low-dose-naltrexone-for-cfs/


9.       Nexavir: Nexavir (Kutapressin) is a porcine liver extract that inhibits HHV-6 and EBV in vitro, is antiviral, anti-inflammatory and an immunomodulator. A 1990 study determined that 96% of CFS patients receiving more than 40 Kutapressin injections reached remission or near remission status. A 1994 study deemed that 85% of CFS patients went into remission or came close to remission after receiving 95 Kutapressin injections. 67% of Dr. Enlander’s CFS patients have improved as a result of Hepapressin injections (a similar agent to Nexavir) with adjunctive other treatments. Approximately 70% of Dr. De Meirleir’s CFS patients have improved as a consequence of taking Nexavir. Nexavir is very expensive, requires a prescription and injections as its delivery method. I have written more information about Nexavir here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/10/25/nexavir-kutapressin-for-cfs/


10.   GcMAF: Gc protein Macrophage Activating Factor is a glycoprotein. Its mechanism of action involves activating the immune system’s macrophages which act in a similar manner to the scavengers in Pacman and eat up the various viruses, infections and other harmful compounds in our body. GcMAF has achieved successful results in the treatment of certain cancers and the eradication (below detectable levels) of HIV. It is now being used by Dr. Cheney and Dr. De Meirleir to treat XMRV positive patients. Dr. Dr Meirleir has preliminary data that shows that XMRV does not grow in culture after Nexavir plus GcMAF administration. There have been many anecdotal reports of XMRV positive CFS patients improving as a result of taking GcMAF. European studies will soon be published demonstrating the effectiveness of GcMAF in treating CFS patients. Blood tests may be able to determine whether individual patients will likely respond to GcMAF treatment. More information about GcMAF and XMRV/CFS can be found here: http://forums.aboutmecfs.org/showthread.php?6019-GcMAF-for-XMRV-Gc-protein-derived-macrophage-activating-factor-anyone-taking-it



Despite purposefully compiling this list to document potentially effective CFS treatments that lack side effects, some of these treatments will be contraindicated in some CFS patients and some patients will experience side effects. I am not a doctor and patients should consult with their healthcare professional before undertaking any treatment regime. It is also worth noting that I have tried every treatment on this list except magnesium injections (which I hope to try imminently) and GcMAF which I hope to take in the future. Despite taking the other eight treatments at some stage during my ME/CFS, somewhat ironically my ‘favourite CFS treatments’ haven’t improved my ME/CFS. Some other treatments that aren’t included on this list however are also potentially helpful to some CFS patients include (ranked in a similar order to the main list); essential fatty acids, coenzyme Q10, NADH, probiotics, intravenous vitamin C, Myers’ cocktails and intravenous saline. In a future blog entry, I may compile an equitable list of strictly prescription CFS treatments that have a higher chance of side effects however are also potentially effective for CFS.


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                                                                                                                                                                                                                                                  I discussed using Fucoidan for CFS in a blog entry here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/09/14/fucoidan-for-cfs/

                                                                                                                                                                                                                                    Fucoidan is a sulfated polysaccharide that is found in various types of brown seaweeds. I have now completed the Fucoidan treatment.

                                                                                                                                                                                                                                                 I took Fucoidan for 9 weeks at the high dose of 1000mg per day. Studies have shown that this daily dose of Fucoidan can be effective against osteoarthritis.

                                                                                                                                                                                                                                                 I did not experience any improvement in CFS symptoms while taking Fucoidan. Conversely, I did not experience any side effects while undertaking the Fucoidan treatment.

                                                                                                                                                                                                                                          There have been in excess of 850 studies performed on Fucoidan and in my last blog entry about this treatment, I detailed some of the impressive properties of Fucoidan. Despite the studied potential benefits resultant from Fucoidan consumption, I am not overly surprised that Fucoidan had no effect on my CFS symptoms. In my last blog entry about this treatment, I stated that “I do not consider Fucoidan to be a serious CFS treatment and am hence only taking it on the side, next to more conventional and prescription CFS treatments.”


Fucoidan is often advertised as a panacea for many illnesses. This claim is often justified by the plethora of studies performed on Fucoidan that have discerned a range of medicinal properties. When these studies are examined closer, it becomes evident that the majority of these are in vitro or in vivo (mice) studies. Fucoidan had no effect on my CFS symptoms however this was not an unexpected outcome.



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                                                                                                                                                                                                                                       What is Nexavir?

During the 1940s, a product called Kutapressin was licensed to treat acne, cold sores, herpes viruses and other inflammatory viruses. In 1983, Kutapressin was trialled on ME/CFS patients. A company called Schwarz Pharma produced Kutapressin until several years ago when this product was discontinued.  A separate company called Nexco Pharma recently reintroduced this same product with a virtually identical composition to Kutapressin under the brand name ‘Nexavir.’ The terms Kutapressin and Nexavir will be used interchangeably in this article.

                                                                                                                                                                                                                                    Nexavir is a porcine liver extract that is the residual product from the process of vitamin B12 extraction. It is composed of peptides and amino acids.


                                                                                                                                                                                                                                   Nexavir Studies

Nexavir has been around for almost 70 years however few studies have been performed on it. I will examine the Nexavir studies relevant to ME/CFS. The first such study was a 1996 study titled ‘Potential in vitro activity of Kutapressin against Epstein-Barr virus.’ The abstract of this study can be found here: http://www.ncbi.nlm.nih.gov/pubmed/8797033 This study determined that Kutapressin can inhibit Epstein-Barr virus in vitro.

                                                                                                                                                                                                                                            The second study to assess the efficacy of Kutapressin was published in 1994 and titled ‘Antiviral activity in vitro of Kutapressin against human herpesvirus-6.’ The abstract of this study can be found here: http://www.ncbi.nlm.nih.gov/pubmed/7893985 This study concluded that Kutapressin has potent and previously unexpected antiviral effects. HHV-6 replication was inhibited in vitro by greater than 90%.

                                                                                                                                                                                                                                                A study was published in the 1990 spring CFIDS Chronicle titled ‘The Treatment of CFIDS with Kutapressin.’ This study can be found here: http://www.me-cvs.nl/index.php?pageid=3423&printlink=true&highlight=cfs This study was not peer reviewed and didn’t contain a control group or placebo treatment. Inclusion in this study required patients to fulfil the Holmes et al. criteria with symptoms present for at least four months. Many secondary tests were performed on this cohort to exclude CFS-related conditions. A large portion of those included in this study (59%) had abnormal EBV-EA IgG titer levels. 80% of this study cohort had CFS for greater than 1 year while 18% of the cohort had CFS for a duration exceeding 6 years.

                                                                                                                                                                                                                                           2ml of Kutapressin was administered daily for ten days followed by three times a week. Out of the 270 study participants, 96% of those receiving more than 40 injections reached remission or near remission status (with few residual symptoms.) 71% of patients receiving 11-40 injections reached remission or near remission status (with few residual symptoms.) This positive correlation of number of injections to treatment efficacy was realised post hoc by the study authors hence not all participants had more than 40 injections. High EBV-EA IgG titer levels were the main biomarker indicating a success of Kutapressin treatment, although patients with normal EBV-EA IgG levels also improved with Kutapressin.

                                                                                                                                                                                                                                            The final study that I will examine is titled ‘Subjective Reduction in Symptoms of Chronic Fatigue Syndrome Following Long-Term Treatment with a Porcine Liver Extract: A Phase 1 Trial.’ Some details of this study can be found here: http://www.ncf-net.org/library/kutreat.html This 1994 study was led by the same two study authors as the previously mentioned 1990 study. Consequentially, the same Holmes criteria were used to select participants and a greater than four months CFS duration was a prerequisite for patient inclusion. There was no control group or placebo treatment in this study. The 130 CFS patients in this study were administered 2ml injections of Kutapressin daily for 25 days, then every second day for 50 days followed by three times a week for 105 days. In total, the participants had 95 injections over a period of 180 days. Of the 180 CFS patients, following Kutapressin treatment 43% reached remission status while 42% reached near remission status (with few residual symptoms.) The authors concluded that Kutapressin subjectively decreased the clinical symptoms of the majority of CFS patients.


Nexavir’s Possible Mechanisms of Action on ME/CFS Patients

Nexavir may improve ME/CFS symptoms because it:

  • Inhibits EBV
  • Inhibit HHV-6
  • Is anti-inflammatory
  • Is antiviral
  • Is an immunomodulator (Nexavir may help shift the immune system away from Th2 dominance.)
  • Enhances blood flow in the brain (as measured by a SPECT scan.) This increased rate of blood flow may be a consequence of the Bradykinin effect which involves dilation of the blood vessels.



Side Effects

Nexavir has been used to treat a variety of conditions for almost 70 years and is widely regarded as safe. Some physicians that are reluctant to prescribe antivirals such as Valtrex and Famvir due to possible side effects instead prescribe Nexavir as a safer alternative.  

                                                                                                                                                                                                                                            The 1990 study titled ‘The Treatment of CFIDS with Kutapressin’ contained 270 CFS patients and involved the administration of 8,900 injections of Kutapressin. This study only noted one adverse reaction to Kutapressin in which the patient believed that they had new symptoms and observed a deterioration of functioning immediately following injections.

                                                                                                                                                                                                                                            The 1994 study titled ‘Subjective Reduction in Symptoms of Chronic Fatigue Syndrome Following Long-Term Treatment with a Porcine Liver Extract: A Phase 1 Trial’ also examined the side effects of Kutapressin injections. Out of the 130 CFS patients, only 21 had minor side effects. Out of the 21 patients experiencing mild side effects, 16 reached a remission or near remission of their CFS.

                                                                                                                                                                                                                                        Nexavir is contraindicated in those with an intolerance or hypersensitivity to liver or pork products. Nexavir contains tyramine and therefore cannot be used by patients taking MAO inhibitors. The tyramine may also cause migraines in a small portion of patients. Nexavir also contains phenol which may cause an allergic reaction in some users. Like with all injections; rashes, swelling, pain and stinging may occur at the injection site. Anecdotal reports online indicate that many users of Nexavir experience bruising at the injection site and therefore must vary the specific injection location.


ME/CFS specialists’ opinions on Nexavir

I will now present what an eclectic range of ME/CFS specialists’ thoughts are regarding Nexavir as an ME/CFS treatment. I have attempted to gather the most up-to-date viewpoints of these specialists however due to the perpetually evolving nature of ME/CFS treatments, some of these opinions may now be outdated.

                                                                                                                                                                                                                                              Dr. De Meirleir

Dr. De Meirleir performed a study involving the administration of Nexavir or a placebo to ME/CFS patients. 63% of those ME/CFS patients in the treatment group responded to Nexavir while only 17% of those ME/CFS patients in the placebo group responded. Dr. De Meirleir finds that approximately 50% of his patients are pain free after 2-3 months of Nexavir injections. His patients generally experience a normalisation of sleep within 3 days of commencing Nexavir. Approximately 70% of Dr. De Meirleir’s patients experience a 20+ point increase (based on the Karnovsky scale) as a consequence of taking Nexavir


Dr. Cheney

Dr Cheney formerly recommended Kutapressin as a treatment for ME/CFS. He stated that it is analogous to a weaker form of Ampligen. In the past Dr Cheney used Kutapressin/Nexavir injections however at some staged preferred using the gel form of Nexavir. He has also stated that his patients generally experience a 20-80% improvement as a consequence of taking Nexavir gel and secondary treatments.  ‘ECHO terrain maps’ now mainly influence Dr Cheney’s ME/CFS protocol and he has consequentially stopped prescribing Nexavir. He now uses his own mix of five cell signalling factors instead of Nexavir. These are; porcine brain, bison liver, bison heart, bison kidney and bison pancreas.


                                                                                                                                                                                                                                               Dr. Enlander

Dr. Enlander used Kutapressin for approximately 12 years until Schwarz Pharma ceased producing it. He then originally tried Nexavir on his patients however due to the preservatives within Nexavir, he trialled his patients on Hepapressin. Hepapressin is similar to Nexavir however it is an Argentinean bovine liver extract, as opposed to porcine liver extract. Dr. Enlander recommends that his patients take other substances in tandem with Hepapressin to increase its effectiveness. 67% of his patients have shown an improvement as a consequence of weekly Hepapressin injections in combination with other treatments. Recently, Dr. Enlander commenced a study alongside Dr. De Meirleir that examined alternative ways to administer Nexavir/Hepapressin.


Dr Teitelbaum

Dr. Teitelbaum has noticed a dramatic improvement in some of his CFS patients as a consequence of taking Nexavir regularly. He has found that those patients who took Nexavir three times a week didn’t gain much benefit as daily injections are a necessity. Dr. Teitelbaum has also observed that some of his patients’ CFS symptoms returned after discontinuing Nexavir.


Dr. Lapp

Dr. Lapp provided almost every ME/CFS patient that made an appointment with him, the opportunity to try Kutapressin. He has labelled it as a “wonderful alternative.” Dr. Lapp has stated that Nexavir was handmade for CFS patients with the main arguments against taking it being the cost and the necessary frequency of the ‘painful’ injections.  


 Combining Nexavir with Other Treatments

Many specialists combine Nexavir with other treatments to either increase the efficacy of Nexavir itself or through the means of multiple treatments increasing the chances of a successful treatment.

  • Dr. De Meirleir often uses Nexavir in combination with vitamin B12 injections. He recommends 10mgs of B12 (either methylcobalamin or hydroxocobalamin) be administered twice a week.
  • Dr. Enlander combines Hepapressin injections with injectable; magnesium sulphate, folic acid, B12, calphosan, glutathione and trace elements.  
  • Dr. Cheney (who no longer recommends Nexavir) formerly found combining Nexavir gel with Hawthorn leaf and flower an effective treatment.
  • Some anecdotal reports indicate that combining Nexavir with other, more traditional prescription antivirals may increase the efficacy of Nexavir or one of the other antivirals.


How to take Nexavir?

Nexavir is to be administered by either subcutaneous or intramuscular injection. Different ME/CFS specialists have various protocols regarding dosage and frequency of Nexavir injection however the most commonly recommended dosage is 2ml administered daily. Some patients may experience a herxheimer type reaction on a 2ml starting dose hence it may be wise to work up to a 2ml dose. Dr Cheney (when he prescribed Nexavir) recommended that the dose be varied between 1 and 4 cc a day. Nexavir should be taken for at least 6 months to determine whether it may be an effective treatment.


Other Details

A prescription is required to purchase the injectable form of Nexavir. The only company that manufactures Nexavir is a Texan company called Nexco Pharma. A Texas pharmacy called Village Compounding produces Nexavir compounded as a transdermal gel. A prescription is also required for this Nexavir gel. Nexavir should not be confused with ‘Nexavar,’ a drug that treats certain cancers.


Negatives of taking Nexavir

The main negative of taking Nexavir is the cost. At 2ml a day (the standard dose), Nexavir will cost approximately US$450 a month. As the minimum recommended treatment period of Nexavir is 6 months (barring side effects), the total cost of a Nexavir trial is approximately US $2,700. This is not including the cost of shipping, syringes or needles.  Some insurance companies may partially cover the cost of Nexavir.

                                                                                                                                                                                                                                  Another negative of taking Nexavir involves the cumbersome daily injections. These have been described by some Nexavir uses as “painful.” The final potential negative of using Nexavir as an ME/CFS treatment involves the possible side effects (mentioned in an earlier section.) While the likelihood of experiencing these side effects seems to be minimal, the possibility exists.


My Nexavir Protocol

I will begin Nexavir injections in the coming week. I will start at a 2ml daily dose and keep this dose static for 1-2 months. Depending on whether Nexavir has any effect on my ME/CFS symptoms, I may then begin to pulse the Nexavir dose. I may also attempt to combine Nexavir with other treatments to increase its efficacy. I will update this blog to detail any effects Nexavir has on my illness.



Nexavir/Kutapressin boast some of the most successful study results of CFS treatments. Although the heterogeneity of CFS  makes transposing CFS study results often problematic. The efficacy of Nexavir in tandem with the low possibility of side effects makes Nexavir (or one of its related derivatives) one of the primary ME/CFS treatments utilised by a multitude of specialists.

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I discussed the use of Fludrocortisone as a CFS treatment in a blog entry found here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/07/27/fludrocortisone-for-cfs/   I have now been on Fludrocortisone for 2 ½ months. I have been taking 0.1mg of Fludrocortisone twice a day.

                                                                                                                                                                                                                                          The Effects Fludrocortisone has had on me

Fludrocortisone has had one minor positive effect on me- My ‘crashing’ has become less severe. The word ‘crashing’ is often interchanged haphazardly with the term ‘post-exertional malaise.’ In a previous blog entry I discussed the misnomer that is ‘post-exertional malaise’ and how the term ‘crashing’ is a more appropriate, albeit slang description of this ME/CFS symptomatic phenomenon.  This blog entry can be found here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/07/18/how-to-gain-relief-from-%E2%80%98post-exertional-malaise%E2%80%99/

                                                                                                                                                                                                                                               In the above blog entry, I also detailed my limits as:

  1. “Not being able to be out of my bed for more than an hour a day.
  2. Not being able to talk too much. It takes a lot of energy for me to talk and I can only say about 200 words in an entire day. This is equivalent to you reading about 2 paragraphs out loud and then not being able to speak for the rest of the day
  3. Not being able to walk very far. My limit is 100metres (or about 1 minute.) Some days my limit is less as I may go to my letterbox and back and then ‘crash.’
  4. I cannot tolerate much stimulus.
  5. My ability to cope with stress is impaired, so I purposely try as hard as possible to avoid conflict around the house.
  6. I am not able to think too much. For instance if I played a game of chess I would definitely ‘crash.’
  7. I’m unable to leave my house for long. If I have been driven away from my house and spend 30 minutes in the car before returning to my house, I will ‘crash.’”

                                                                                                                                                                                                                                        Since taking Fludrocortisone, these limits have remained static however the intensity of the ‘crash,’ consequential of exceeding these limits has been reduced. Within the same ‘Post-exertional malaise’ blog entry, I described the severity of my ‘crashing.’ I wrote that 

This concept of crashing is difficult to convey to someone who hasn’t experienced it. As my CFS has progressed from mild to moderate to severe, the severity of my crashing has also increased proportionally. If I go outside just one of the limits mentioned above I will crash. For me at the moment crashing involves lying in bed for up to 2 weeks. I feel like I am a vegetable and am unable to role onto my back. I lie on my side and every few minutes spit mucus into a bin. I am unable to talk at all as my body has been draining of the little energy I had. The pain of crashing is like no pain I have ever experienced before. Prior to CFS I had only moaned in pain on 2 or 3 separate occasions when I was ill. When I crash I moan in pain for days on end and my body just feels like it’s begging for mercy. My cognitive abilities are also severely affected when I crash and if I was asked what 2+2 equals, I wouldn’t be able to tell you as my mind shuts down. This crashing lasts from several days to several weeks if I go outside just one of the limits mentioned above in the above ‘limits’ paragraph.”

                                                                                                                                                                                                                       Fludrocortisone has reduced the severity of my ‘crashing’ by approximately 15%.  When I reach a ‘crashed’ state, I will now be in slightly less pain than prior to my Fludrocortisone treatment. My ‘crashed’ state will now also be of a slightly shorter duration (on average) than pre Fludrocortisone treatment.

                                                                                                                                                                                                                                             The remainder of my symptoms have remained unaffected by Fludrocortisone. Despite this, I am pleased that one of my most severe and debilitating symptoms, ‘crashing’ has reduced in intensity and length. This reduction is minor and I am still in a quasi-vegetable like state for several days when I have ‘crashed.’

                                                                                                                                                                                                                                               In a blog post  prior to my Fludrocortisone treatment protocol, I speculated that Fludrocortisone may have an effect on me due to “Liquorice helping me when I am in a crashed state (and) liquorice root having a similar mechanism of action as Fludrocortisone.” When I took liquorice root prior to beginning the Fludrocortisone treatment, my ‘crashing’ experienced a mild reduction in intensity. It appears that Fludrocortisone has had this same effect on me due to its similar mechanism of action as liquorice root.


Side effects of Fludrocortisone

I have not experienced any significant side effects while taking Fludrocortisone. I had a blood test two weeks ago and my electrolyte levels have remained normal despite taking the Fludrocortisone (I have been taking a potassium supplement, salt tablets and a slightly increased fluid intake accompanying the Fludrocortisone treatment.)


I will continue to take the Fludrocortisone and although it has only had a minor positive effect on my ME/CFS, I believe this effect warrants a continuation of this treatment. In 3 months time I will again reassess the Fludrocortisone treatment.


Low Dose Naltrexone

Two months ago, I wrote a blog entry explaining that I had ceased the Low Dose Naltrexone (LDN) treatment due to its lack of effects.

                                                                                                                                                                                                                                         After six months of LDN, I had not experienced any significant side effects and equally I did not believe that I had experienced any benefits from this treatment. After thwarting the LDN, the quality and length of my sleep began to diminish. After three weeks of this disturbed sleep, I restarted the LDN. After restarting the LDN, my sleep patterns were immediately rectified. During the six month course of LDN, although I didn’t notice it having a positive effect in terms of aiding my sleep quality or length, it may have been having a gradual effect in these areas. In other words, although I didn’t notice LDN providing an instantaneous or short term benefit, it may have been aiding my sleep quality and quantity when the six month treatment trial was analysed holistically. Another possibility is that my sleep quality and quantity may have deteriorated independently of the LDN during this six month period and the LDN maintained my high sleep quantity and quality level. A final possibility is that my body became accustomed to LDN’s mechanism of action and the three week period of diminished sleep quality and quantity was due to my body’s inability to adapt to this treatment change. Consequentially, I may have eventually retaining baseline levels of sleep quality and quantity once my body had adapted to the lack of LDN.


Gaining quality and plentiful sleep is regarded by many ME/CFS specialists as a prerequisite treatment for ME/CFS. I did not wish to experiment to determine the precise reason for my impaired sleep quality and quantity consequential of ceasing the LDN treatment. Due to this reason, I restarted the LDN treatment again. I will continue this treatment for an indefinite period.

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The Heterogeneity of ‘CFS’


The Prevalence of CFS

Gunn et al. (1) on behalf of the CDC estimated that the 1993 CFS prevalence was between 0.002% and 0.0073%. A 1991 study by Ho-Yen et al. (2) estimated that 0.13% percent of the UK population were inflicted with CFS. Reyes et al. (3) in 2003 figured that 0.24% of Wichita residents had CFS. This same study also determined that only 0.18% of the Wichita cohort had CFS for a duration of at least 1 year. A 1999 study by Jason et al. (4) determined that 0.42% of the United States population suffers from CFS. A Royal College Report (5) from 1996 estimated that between 1% and 2% of Britons had CFS. On behalf of the CDC, Reeves et al. (6) discerned that 2.54% of the US population had CFS as of 2007. In 1997, Wessely et al. (7) predicted that 2.6% of the Great Britain population was inflicted with CFS.  


The CFS prevalence estimates are not increasing uniformly with time hence this alone does not provide a mechanism for the inconsistent illness rate estimates. The differing CFS criteria used and the variable operationalized nature of these criteria are sufficient aspects to explain the varied CFS incidence figures. These aspects will be discussed in detail in subsequent sections.


The CDC itself as an autonomous institute, has over a 14 year period produced a CFS prevalence estimate that has increased over 1,500 fold (1) (6). The median CDC CFS incidence estimate of 0.24% by Reyes et al. (3) in 2003 determined that only 16% of their CFS cohort had been privy to their CFS diagnosis and received treatment. Since this 2003 estimate, the CDC (Reeves et al. (6)) has revised the CFS prevalence rate by increasing it a further 10 fold to 2.54%. Jason et al. (8) have hypothesised that this most recent CDC CFS prevalence estimate outlier can be attributed to a broadening of the Fukuda et al. CFS definition. It has been suggested that this criteria broadening is due to the misconstrued theoretical definition when applied in practise.


 The CDC’s discrepancy in estimating CDC criteria prevalence has eventuated from the same criteria- the Fukuda et al. criteria. Jason et al. (8) have emphasised that these criteria are polythetic in that only four criteria out of eight are necessary for a CFS diagnosis. Jason et al. continue to state that due to this polythetic criteria, different groups of patients are erroneously being compared. This is due to symptoms (that are often considered hallmark CFS symptoms) such as post-exertional malaise and cognitive impairments not being necessary for a CFS diagnosis. This can potentially skew the GET study results as the nature of post exertional malaise makes it inextricably linked to a worsening of symptoms after GET.


The Fukuda et al. criteria are also problematic when applied in an operationalized manner due to the lack of clarity and absence of a well-defined cohort. Jason et al. (9) have determined that 38% of the population with a major depressive disorder diagnosis were misdiagnosed with CFS under the Fukuda et al. CFS criteria. This is despite a concession by the CDC that “It is incorrect that…. CFS is a form of depression.” (10)                                                                                                                                                                                                                                                         In 2003, the CDC estimated that 0.24% of the population had CFS according to the 1994 CDC CFS criteria (3). In 2007, the CDC estimated that 2.54% of the population had CFS in accordance with the same 1994 CDC CFS criteria (6). This 10 fold increase in CFS prevalence as determined by the CDC highlights how studies using the same criteria are not necessarily using the same patients. Let us now hypothetically assume that the 2003 CDC CFS estimate can be considered as an accurate representation of the CFS cohort. This would invalidate the 2007 CDC CFS estimate. If a GET study was performed on this 2003 cohort, this group would only be representative of 10% of the 2007 CDC CFS estimate cohort. Let us now hypothetically assume that the 2007 CDC CFS estimate is representative of a true CFS cohort. Consequentially, the 2003 CDC CFS estimate would be erroneous. If GET was performed in this 2007 CDC cohort, then the results could not be extrapolated onto the 2003 CDC cohort due to it comprising a small subsection of the 2007 CDC cohort. Due to the aforementioned reasons in tandem with the broadness of the Fukuda et al. criteria, GET studies that are found to be effective for a non-ubiquitous percentage of a Fukuda cohort cannot be superimposed onto another Fukuda cohort. This is due to the absence of well-characterised CFS patients, nebulous criteria and the polythetic nature of the Fukuda criteria.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       In 1975, Spitzer et al. wrote that the usefulness of a diagnostic category is limited by its level of reliability. The extent that a diagnostic category is unreliable is consequentially limited by its validity for clinical research. These words by Spitzer et al. support the notion that the definitive flaws of the Fukuda criteria (and indeed wide discrepancy among CFS prevalence estimates) invalidate the bulk of GET related literature. The only conclusion that can be drawn from this GET literature using nebulous criteria is that GET is useful for those that it helped in the study. No further conclusions can be extrapolated, even for those CFS patients in an identical cohort. 



                                                                                                                                                                                                                          Physiological Abnormalities distinguishing CFS cohorts

Jason et al. (11) have presented research suggesting that key differences exist between CFS patients with high levels of infectious and inflammatory processes in comparison to those CFS patients with low levels of infectious and inflammatory processes. The authors also highlight a possible CFS subgroup that has cognitive impairments as a primary symptom and other symptoms of a lower intensity. Jason et al. conclude their paper by strongly advocating the use of subgrouping CFS cases in order to aid researchers in determining a higher level of understanding of this illness including possible preventions, treatments and cures.

                                                                                                                                                                                                                                                                                                                                                                                                                            The physiological effects of exercise on CFS patients will be discussed in a subsequent section within this meta-analysis. These physiological exercise effects do not present consistently across the Fukuda et al. CFS cohort. De Becker et al. (12) have written that; histological, metabolic, muscle oxidative capacity, atrophy of fast twitch fibres, lactic acid produced during exercise and myopathic features on electromyograms are all exercise related physiological effects that have found to be abnormal among CFS patients. De Becker et al. emphasise that these abnormalities are not consistent among CFS patients and the authors conclude that CFS is a heterogeneous illness. De Becker et al. also state that GET studies may be finding varied results among their CFS cohorts due to the variability in patient populations and subsequent muscle abilities. These inconsistent exercise related physiological abnormalities among CFS patients support the theory that even among a specific and autonomous CFS definition, CFS patients have varying abilities and will respond differently to exercise. Any GET conclusions from one CFS criteria subgroup studied will not be relevant to others fulfilling the same CFS criteria. This is due to the aforementioned exercise related physiological effects differing across CFS criteria. Rather than GET studies attempting to define CFS patients through criteria such as Fukuda et al. more relevant subgrouping should occur through patient fragmentation according to exercise related physiological abilities such as the previously mentioned De Becker et al. list of exercise effects on CFS patients.  

                                                                                                                                                                                                                                                                                                                                                                                                                       Lane et al. (13) performed a study to detect enterovirus sequences within the quadriceps of CFS patients. 20.8% of the CFS patients were positive for this test. Lane et al. also tested the entire CFS cohort in this study for abnormal lactate response to exercise. The authors stated that an abnormal lactate response to exercise indicates an impaired muscle energy metabolism. Lane et al. found an association between an abnormal lactate response to exercise and the presence of enterovirus sequences in the quadriceps. This studies correlation result provides evidence for the heterogeneity of CFS, especially in an exercise related domain. Lane et al. have demonstrated that regardless of CFS criteria, subgroups of CFS patients will respond differently to exercise.

                                                                                                                                                                                                                                                                                                                                                                                                                         DeLuca et al. (14) performed a cognitive based study on CFS patients fulfilling the 1994 CDC CFS criteria. Patients were excluded if; they had an illness onset exceeding four years, had symptoms of less than a moderate severity (at the time of testing) or had a psychiatric disorder up to five years prior to their CFS onset. In this study, patients with moderate to severe CDC 1994 defined CFS were divided into two groups. The first group of CFS patients had a current or previous psychiatric disorder (with an onset during the patients CFS) while the second group of CFS patients did not have a current or previous psychiatric disorder. These two groups were compared to a healthy although relatively sedentary control group. The CFS group without psychiatric disorders performed worse at the cognitive tests than the CFS patient cohort with a psychiatric disorder. This study result emphasises that the 1994 CDC CFS definition encompasses distinct groups of patients that either a) have separate illnesses under the CFS umbrella or b) have the same illness that manifests in different symptoms and consequential differing abilities. If a) is correct then a blanket GET treatment should not be recommended for completely distinct illnesses without studies into GET for these distinct illnesses that fall within the all-encompassing CDC’s CFS definition. If b) is correct then the heterogeneous nature of CFS including different patient’s abilities and symptoms requires CFS subgroups to be studied in regards to GET as a treatment as opposed to the current paradigms over simplistic panacea.

                                                                                                                                                                                                                                                                                                                                                                                                                            The DeLuca et al. cognitive impairment study result also supports the notion that those CFS patients with a psychiatric disorder component have a distinctly different illness than those CFS patients void of a psychiatric disorder. This is due to the neat psychiatric disorder dichotomy that correlates with the cognitive impairment symptom (or lack thereof.) The study result also highlights how different subgroups of CFS patients respond differently to stimuli. DeLuca et al. have speculated that the lack of consistent medical findings in the general CFS domain is a direct result of the heterogeneity of the CDC’s 1994 CFS criteria. The authors continue on to state that finding diagnostic variables may lead to identification of more homogeneous CFS subgroups which may consequentially aid in identification of causative agents.

                                                                                                                                                                                                                                                                                                                                                                                                                        Lerner et al. (15) performed a study on a specific subgroup of CFS patients who had severe CFS and collectively unique electrocardiogram abnormalities (when compared to control electrocardiogram abnormalities.) These CFS patients also had high antibodies to the human cytomegalovirus. These patients were treated with intravenous ganciclovir. 24 weeks after the IV treatment, 72% of the CFS patients had reached remission. The patients who didn’t respond to the ganciclovir intravenous treatment had lower human cytomegalovirus antibodies originally in comparison to the group that did respond to treatment.

                                                                                                                                                                                                                                                                                                                                                                                                                             See et al. (16) also performed a study that supports the CFS comprising distinct illness state hypothesis. This study provided CFS patients with alpha interferon in a placebo cross-over designed double blinded study. The only CFS patients who benefited from taking alpha interferon were the CFS patients who had a reduced Natural Killer cell function. These study result suggests that CFS patients don’t ubiquitously respond to treatments but rather a specific and well-defined subgroup of CFS patients may respond to a recommended CFS treatment. These studies therefore support the hypothesis that the term ‘CFS’ can currently be defined as an accumulation of multiple distinct illnesses that have unique etiologies and require individualised treatments. The blanket recommendation of any treatment to an apparent heterogeneous group of illnesses that are actually distinct illnesses is erroneous. GET should therefore not be recommended ubiquitously to CFS patients.

                                                                                                                                                                                                                                                                                                                                                                                                                             A 1993 CDC study by Mawle et al. (17) compared CFS patients fulfilling the 1988 CDC CFS criteria against demographically similar controls. The immune testing only revealed minor differences between the CFS group and the controls. The CFS patients were then grouped into how they were feeling on the testing day and the nature of their CFS onset. After this grouping, significant differences between the CFS groups and the controls became evident. The sudden onset CFS group had much higher levels of CD8 cells that were expressing CD11b. This group also had significantly higher levels of Il-2 than the corresponding controls. The gradual onset CFS group had lower levels of IL-1a and IL-1b than the controls. The gradual onset group also had a lower percent of CD56 cells. The more severely ill patients had higher IL-2 levels and lower CD8 cells that were expressing CD25. They also had lower levels of IL-1a when compared to the controls. This study result highlights that a holistic approach to “CFS” may reveal very few abnormalities when compared to controls however significant abnormalities are present in the patients when a reductionist approach is adopted. This relates to GET in that CFS patients need to be subgrouped if meaningful data is to be collected. Also this study result emphasises that different types of CFS, based on onset, immunological markers and severity, seem to indicate distinct illness groups. Rather than CFS data being collected for one group and extrapolated onto another CFS group, specific studies are required to determine if treatments such as GET may be beneficial for CFS subgroups. Until this data is obtained, a recommendation of GET for CFS patients is a fallaciously reasoned approach. This is due to the heterogeneous nature of CFS that consists of quite distinct subgroups with differing features that may indeed be distinct illnesses.

                                                                                                                                                                                                                                         Jason et al. (18) divided CFS patients into two groups- those with normal cortisol levels and those with abnormal cortisol levels (based on 5 testing occasions.) The CFS patients deemed to have abnormal cortisol levels did not improve over the study period in immunological or self reported areas. The CFS patients with normal cortisol levels experienced improvements in both immunological and self reported areas. This result indicates that a subset of CFS patients (those with normal cortisol levels based on a graph of 5 testings) may skew CFS study results due to spontaneous improvements. GET studies on CFS patients should therefore take this factor into account and determine cortisol levels over a period of time for the patients included in their study. It is conceivable that the CFS patients in GET studies are improving due to the nature of their CFS subgroup as opposed to their GET treatment. Having said this, some GET studies also involve a CFS control group that partakes in such activities as stretching as opposed to aerobic exercise. This Jason et al. result also supports the notion that determining accurate CFS subgroups is a prerequisite to determining relevant and applicable CFS treatments. This study supports the scientific literature previously mentioned that CFS is heterogeneous in nature and extrapolating GET study results onto other subgroups, different CFS criteria or indeed the same CFS criteria is erroneous due to these false, non-homogenous and poorly characterised divisions of CFS patients.

                                                                                                                                                                                                                                   Illnesses Beneath the CFS Umbrella

Chronic Fatigue Syndrome is in theory a distinct disorder that is well-characterised and homogeneous. In practise, many other conditions fulfil the CFS criteria. CFS criteria generally stipulate that an alternative diagnosis excludes a CFS diagnosis. This is problematic in practise due to the large number of CFS-like conditions that produce symptoms that satisfy the CFS criteria. These illnesses/conditions include; autoimmune disorders, cardiac and respiratory disease, connective tissue disorders, side effects of medications, thyroid disease, Addison’s Disease, Lyme disease, celiac disease, irritable bowel syndrome, immunodeficiency, multiple sclerosis, sleep disorders, rheumatic diseases, psychiatric disorders, psychological disorders, anxiety, CMV, EBV, HHV-6, parvovirus, fibromyalgia, malnutrition, mitochondrial dysfunction, neuropathy, Cushing syndrome, B12 deficiency, depression, enteroviruses, adrenal insufficiency, obesity, parasites, food allergies, hormonal abnormalities, coxsackie viruses, post viral fatigue, post traumatic stress disorder, seasonal affective disorder, multiple chemical sensitivity and systemic lupus.(19) (20) It is true that a number of these illnesses/conditions may not be included in GET studies on CFS due to exclusionary criteria however a sufficiently large portion of these aforementioned illnesses/conditions aren’t considered as exclusionary criteria in GET studies. GET studies do not require patients to have excluded the above list of conditions through testing in order to be included in a GET study. The GET studies do not perform these extensively listed tests on the CFS patients included. A large portion of patients included in GET studies will fulfil at least one of the above illnesses/conditions. Consequentially, the GET studies are including a scatter pot of illnesses/conditions and the results of these studies are therefore as equally as non-definitive. For GET studies on CFS patients to produce meaningful results, the study authors would be required to distinguish the above list of illnesses from one another in CFS patients. It is only then that GET studies would be comparing like with like. Once this fragmentation is made, results from the studies can be translated to the corresponding “CFS” subgroups.

                                                                                                                                                                                                                                              The CFS cohort is extremely nebulous and more difficult to subgroup due to the high number of CFS patients that have one or multiple illnesses/conditions from the above list. As mentioned previously, Lane et al. (13) demonstrated that the CFS subgroup with an enterovirus infection had an abnormal lactate response to exercise and an impaired muscle energy metabolism.  This was in contrast to an enterovirus-negative CFS patient cohort. The above list of CFS-like conditions with symptoms that can potentially mimic CFS provides evidence that the over simplistic viewpoint that GET studies are comparing similar patients is flawed. A haphazard array of illnesses is currently being studied in unison which is consequentially producing meaningless data. 

                                                                                                                                                                                                                                        Despite the similar illness exclusion stipulation that is part of the CDC’s 1994 CFS criteria, the CDC website (21) alludes to a study result which underlies the theory that CFS is heterogeneous. This study result dictates that EBV, Ross River virus and Coxiella burnetti virus will lead to a post-infective state that fulfils the CDC’s 1994 CFS criteria in 12% of instances. This consists of a 12% post virus state cohort that can be labelled and diagnosed as a post-viral fatigue cohort. The CDC criteria include this post-viral fatigue cohort amongst their broad CFS criteria. Consequentially, this cohort is studied as a CFS cohort however the uniqueness of this group’s onset requires a fragmentation from the CFS cohort to produce a subgroup. The inclusion of this 12% post-viral fatigue cohort into a CFS cohort is sufficient to skew study results. Rather than including the post-viral fatigue cohort into the omni-encompassing CFS cohort, an effort should be made to subgroup these symptomatically similar albeit clinically distinct illnesses.

                                                                                                                                                                                                                                             The post viral fatigue study that is referred to on the CDC website was performed by Hickie et al. (22) on behalf of the CDC. This study was one part of a subset study comprising the ‘Dubbo Studies.’ Hickie et al determined that following EBV, RRV and Coxiella burnetti onset, different patients took varying lengths of time to recover. The data indicates that 35% of this viral cohort had post viral fatigue at 6 weeks from baseline. 27% had post viral fatigue at three months, 12% at six months and 9% at 12 months. A parallel Dubbo study (23) determined that after 24 months, only 3% of the cohort still had post viral fatigue. The Fukuda et al. CFS criteria requires an illness duration of at least six months as a necessary prerequisite before the diagnosis of CFS can be given. The above data from Hickie et al. (22) shows a continuum that is atypical of a general CFS cohort, as opposed to this subgroup.

                                                                                                                                                                                                                                Professor Andrew Lloyd held a hegemonic role in the Dubbo studies. A graph titled ‘Natural History of Symptoms’ (24) presented by Professor Lloyd containing data from the Dubbo studies illustrates the post viral fatigue patients’ symptomatic percentage versus time. This graph illustrates that time, not treatment was the instigating factor leading to this cohort’s remission. After 24 months, virtually all of the former post viral fatigue (and interchangeable) ‘CFS’ patients had recovered. The mean illness duration of the CFS patients included in GET studies is typically 24 months. It is therefore conceivable that the GET patients studied have naturally reached remission based on time alone, independent of the GET treatment. The Hickie et al. data consisting of the high remission rates in the post viral fatigue cohort contrasts a Cairns et al. (25) review of CFS remission rates. Cairns et al. reviewed 14 studies that were primarily focused on determining CFS illness duration. The review concluded that the median recovery rate from CFS without systematic intervention was 5%. This result is the antithesis of the Hickie et al. result which saw the post viral fatigue cohort almost ubiquitously reach a remissions status within 24 months, with remission status being non-dependant on treatment. The Fukuda et al. criteria includes this post viral fatigue cohort within the heterogeneous CFS label. It is therefore evident that the CFS remission rates are heterogeneous depending on CFS subgroup. It is also apparent that post viral fatigue diagnosis should be an exclusionary criteria among GET CFS studies due to the almost ubiquitous remissions reached by this cohort within a short temporal frame.

                                                                                                                                                                                                                                     Vollmer-Conner et al. (26) performed a study titled ‘An empirical delineation of the heterogeneity of chronic unexplained fatigue in women.’ The authors concluded that chronic unexplained fatigue can be differentiated by; obesity, sleep hypnoea, depression, a physiological stress response, sleep disturbance, interoception and menopausal status. This list of conditions, previously in this meta-analysis, was deemed to be in some instances misclassified as CFS. The current Fukuda et al. CFS criteria fails to adequately distinguish CFS from this list of heterogeneous CFS-like conditions. A portion of GET studies attempt to exclude some of these conditions however no GET study has adequately excluded all of these conditions. This is partly due to the overlapping nature of fatigue as such symptoms as depression, obesity and sleep disturbance can be the primary cause of fatigue or indeed a secondary effect of the primary fatigue source. Determining this fatigue hierarchy is often difficult and problematic. This Vollmer-Conner et al. result is further evidence that the patients included in GET studies are not homogenous and the cohort comprises patients of different illnesses rendering the conclusions inadequate and nebulous.

                                                                                                                                                                                                                                                  A study by Jason (27) provides further evidence that the overlapping and secondary symptoms in CFS are the primary symptoms of unrelated disorders. Jason explains that major depressive disorder is a prime example of a psychiatric disorder that shares symptoms such as fatigue, sleep disturbance, joint pain, muscle pain and impaired concentration with CFS. These symptoms along with the fatigue accompanying major depressive disorder, provides a fulfilment of the Fukuda et al. CFS criteria. Jason writes that these patients could be misclassified as CFS patients in studies. Friedberg et al. (28) and Komaroff et al. (29) have shown that the fatigue accompanying CFS does not share equal prominence as the fatigue that often tandems depression. This provides further evidence that it is erroneous to include these depression causing fatigue patients in GET studies. Depressed patients may fulfil a Fukuda et al. diagnosis based on symptomatology alone however the nature, prevalence and severity of these symptoms clearly distinguishes depressed patients from CFS patients.

                                                                                                                                                                                                                        Comparing CFS Criteria

Institutes are recommending GET ubiquitously to all CFS patients regardless of subgroup or CFS criteria filled. The CDC website (30) even recommends GET to “Very ill people who are housebound or bedbound.” As discussed in Part 2 of this meta-analysis, GET studies have almost exclusively been performed on patients fulfilling either the Oxford CFS criteria or the Fukuda et al. CFS criteria. The extrapolation of this data onto other CFS criteria cohorts is erroneous. 

                                                                                                                                                                                                                                         Jason et al. (31) performed a study titled ‘A Comparison of the 1988 and 1994 Diagnostic Criteria for Chronic Fatigue.’ The Jason et al. study revealed that the patients fulfilling the 1988 criteria were a more severely functionally impaired cohort that were more symptomatic compared to those fulfilling only the 1994 CDC CFS criteria. Jason et al. concluded that those fulfilling the 1988 CDC criteria may be a clinically separate group of patients. The authors also wrote that the 1994 criteria may encompass a heterogeneous cohort of patients with a range of illness severities and disabilities. This study by Jason et al. highlights how patients fulfilling different criteria not only have different symptoms but also varying degrees of disability. It is therefore fallacious to impose the result of a study focused on one criteria onto a distinctly different criteria. If one disregards the heterogeneity of CFS in terms of distinct illness subsets, the scientific method requires specific studies targeted at the varying levels of CFS patients severity continuum. Studies performed on a mildly affected cohort such as the Fukuda et al. cohort should not be extrapolated onto severely affected patients. This is especially true of GET studies in which the very aspect being measured- functionality is what distinguishes these cohorts.

                                                                                                                                                                                                                                         Sampson (32) performed an extensive analysis of cohorts containing CFS, fatigued and mood disordered patients. Sampson concluded that broad CFS definitions such as the Oxford and Fukuda et al. definitions include patients with a psychological/psychiatric fatigue etiology. By including these primary psychological/psychiatric patients, Sampson suggests that the study results are clearly going to show that psychosocial factors are prevalent in CFS. It is a tautology and these studies such as GET studies provide us with no more information than we started with. These studies should focus their attention onto the underlying fatigue that is the product of CFS itself. The process of including fatigue caused by a psychological/psychiatric etiology results in two quite distinct cohorts being falsely linked. The consequential data and results are therefore not CFS typical but rather just fatigue typical. Due to fatigue’s heterogeneous nature, these studies are haphazard and reveal nothing about the differing components of various fatigue etiologies.  

                                                                                                                                                                                                                                       Jason et al. (33) performed a study comparing patients who fulfilled the Fukuda et al. CFS criteria and patients who filled a specific ME criteria. The authors also compared these two groups to a group that had chronic fatigue due to psychiatric causes. This Jason et al. study concluded that a significant difference existed between these three groups.  These differences were mainly consistent of neurological, fatigue, cardiopulmonary abnormalities neuropsychiatric and rheumatological symtoms. Jason et al. determined that those meeting the ME criteria were significantly different from those patients in the psychiatric fatigue group. Also the Fukuda et al. group resembled the psychiatric group much more than the ME group resembled the psychiatric cohort. Jason et al. speculated that it may be erroneous to synthesize CFS study results that use different definitions. This conclusion by Jason et al. is diametrically opposed to the actions of many GET studies and institutes which extrapolate specific CFS criteria GET results onto other CFS criteria groups.

                                                                                                                                                                                                                                          The Canadian Consensus Criteria for CFS

Carruthers et al. (34) compiled the actual Canadian Consensus Criteria (CCC) for CFS in a paper titled ‘Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. These CCC attempt to distinguish a more homogonous type of patient- an area in which the previous criteria such as the Oxford criteria and Fukuda et al. criteria have failed. The CCC specifies that the fatigue resulting from post-exertional malaise usually lasts for a 24 hour plus duration. This fatigue is also associated with an impairment of cognitive abilities. The CCC also states that this reactivity following exertion is often delayed to the point of occurring the next day or in some instances later.  The CCC continues on to emphasise that exercise will generally improve patients with fatigue caused by depression, in contrast, exercise will cause adverse effects on CCC patients. This CCC composed by Carruthers et al. distinguishes these CCC CFS patients from those heterogeneous CFS patients that fulfil the Oxford and/or Fukuda et al. criteria. In order for a patient to fulfil the CCC, exercise must be contraindicated in that patient. Therefore by definition, GET is not suitable for CCC patients. If a patient improves as a consequence of exercise, they are automatically excluded from the CCC.

                                                                                                                                                                                                                                              The CCC also questions a key aspect of the Fukuda et al. CFS criteria. This aspect involves the Fukuda et al. focus on one arbitrary symptom- long-lasting fatigue.  The CCC emphasise that this is just one symptom across the spectrum of CFS symptoms that are of great importance such as post-exertional malaise, pain, sleep disturbances and cognitive impairment. The CCC concludes that the Fukuda et al. criteria are flawed in that they make it very difficult for physicians to separate the fatigue consequential of CFS from the fatigue caused by other illnesses.

                                                                                                                                                                                                                                             The criteria aspect of the CCC stipulates that a patient fulfilling the CCC must meet criteria for fatigue, post-exertional malaise and/or fatigue, sleep dysfunction and pain. Combined with these, the patient must also have at least two neurological or cognitive manifestations and at least a symptom from two of the following categories; autonomic, neuroendocrine or immune manifestations. There are further criteria that need fulfilling for a patient to be diagnosed with CCC CFS however the above is an outline of some of the necessary conditions. It is evident that these CCC exclude the majority of patients fulfilling the Fukuda et al. criteria. Also these CCC would exclude most of the patients involved in GET studies.

                                                                                                                                                                                                                                         Jason et al. (35) have studied the CCC cohort and concluded that the CCC CFS patients share many key features. These include; similar symptoms, severe impairment, comparable levels of fatigue and weakness and similar neurological symptoms. The symptoms that are common to CCC patients can interfere with everyday living ability. Jason et al. concludes that CCC patients are a distinct group from chronic fatigue and psychiatrically fatigued patients. This study supports the notion that CCC patients comprise a distinct and homogonous subgroup. Due to the different symptoms and impairment degree in this CCC cohort, compared to a Fukuda et al. cohort, GET results from a Fukuda et al. cohort should not be transposed onto this CCC cohort.

                                                                                                                                                                                                                                               In contrast to the Fukuda et al. and Oxford CFS criteria, the CCC isn’t polythetic. By stipulating that specific symptoms are necessary for a CCC CFS diagnosis, the CCC is an improvement on the Fukuda et al. criteria due to the lack of broadness and unambiguousness in interpretation by practising clinicians. The patient that fulfils the CCC will be approximately homogonous and study results on this cohort can be extrapolated ubiquitously to CCC patients worldwide.

                                                                                                                                                                                                                                  Further Evidence that CFS is Heterogeneous

The CDC has recently stated (36) that “Because CFS is clinically heterogeneous and comprised of various subtypes, it is essential that treatable causes of the illness are identified to improve clinical management.” This indicates a definitive admission from the CDC that “CFS is clinically heterogeneous.” Despite this concession, the CDC website does not share this definitive viewpoint and isn’t committing to ruling out a common CFS etiology that explains all CFS cases. The CDC website (37) states that “While a single cause for CFS may yet be identified, another possibility is that CFS represents a common endpoint of disease resulting from multiple causes.” The varying nature of the diseases causing CFS already provide many specific and distinct mechanisms to explain the end disease state that fulfils the CDC’s CFS criteria. The range of responses to treatments also underlie the conclusion that CFS doesn’t represent a “common endpoint of disease” but rather a cluster of distinct diseases which have distinct endpoints however these diseases also incidentally fulfil the broad and omni-encompassing CDC CFS criteria.

                                                                                                                                                                                                                                            The recently conducted UK PACE trial (38) that attempts to treat CFS patients with GET alongside CBT produced a study protocol that was published in 2007. This study protocol explained in detail the precise methods and cohorts that would be studied amongst this trial. I will not provide a thorough critique of the PACE trial in this section however it is worth noting that the broad Oxford CFS criteria were the diagnostic criteria used in this study. When referenced to an International Classification of Disease ME/CFS cohort (39), only 10% of Oxford criteria patients are true CFS patients. This PACE trial study protocol states that “The trial will recruit new patients from secondary care clinics run by three different disciplines (immunology, infectious disease and psychiatry) in six different centres in both England and Scotland. This recruitment plan will ensure sufficient heterogeneity to allow generalisation of the findings.” As discussed in detail previously, the findings pertaining to one CFS broad criteria cohort such as Oxford of Fukuda et al. cannot be extrapolated or “generalised” onto other cohorts. This PACE trial also aimed to recruit a heterogeneous cohort rather than a homogonous cohort. This is problematic in that the immunological, infectious disease and psychiatric patients recruited have distinct illnesses with a common arbitrary symptom in fatigue. By blurring the boundary between these already subgrouped and distinct illness cohorts and by creating a less well defined CFS patient, the findings of this PACE trial cannot even be applied to any cohort, heterogeneous or homogeneous.

                                                                                                                                                                                                                                                   A study by Pierce et al. provides further evidence against the generalisation of GET findings onto CFS patients. This study states that in the most generous scenario, GET has only relived and not cured a specific and small minority of CFS patients. Also that the empirical evidence supports the notion that exercise is the primary cause of both the negative effects concerning physiology and quality of life in a significant portion of CFS patients. Pierce et al. continue on to state that due to the heterogeneity of CFS, a universal therapy such as GET is unsuitable unless the prescriber has a high degree of confidence that the patient’s condition will not deteriorate. The authors state that they cannot think of a more inappropriate therapy for CFS patients. Pierce et al. provide the further argument that blanket recommendations of GET are not appropriate for heterogeneous groups of patients such as CFS patients. A large portion of this cohort already respond in a negative manner to exercise hence an erroneous oversimplification of the CFS cohort as homogenous may be the key instigator of detrimental CFS treatments such as GET. Pierce et al. expand on their heterogeneous CFS argument by stating that no studies to date have managed to investigate all of the nuanced aspects relating to CFS. The large body of empirical evidence suggests that CFS is caused by a complex series of variable events that can potentially affect multiple bodily systems. The authors also mention that one of the defining factors of ‘CFS’ involves the large range of varying symptoms between patients which suggest that different bodily functions are affected when comparing different patients, all to varying degrees. This suggests that the bodily systems regulating the exercise response may not be affected in some CFS patients although in other CFS patients, these systems are likely to be severely affected. Consequentially, this differentiation between ‘CFS’ patients, requires therapies to be individually tailored to patients rather than broad and blanket recommendations such as GET imposed onto the entirety of CFS patients.

                                                                                                                                                                                                                                            The very nature of recruiting CFS patients to complete GET studies is fraught with difficulties. Jason (27) mentions that the current recruitment methods are inadequate due to the type of questions that the study authors ask the potential trial participants. He cites an example of the patient indicating that they have post-exertional malaise. Rather than asking subsequent questions pertaining to this symptom, GET study authors fail to gather details on this symptom. Jason suggests standardized questions that include the duration, frequency and severity of individual symptoms as well as onset, pattern, intensity and associated factor details. This detailed questioning of CFS patients is also endorsed in a study performed by Hawk et al. (41) Jason also uses the analogy of a lupus diagnosis which involves a combination of factors including clinical judgement, patient reports and objective measures to determine a diagnosis. It is impossible to complete this checklist when classifying CFS patients according to the Fukuda et al. criteria, due to the very nature of these criteria. Consequentially, GET studies using the Fukuda et al. criteria are limited by this criteria’s inadequacy in diagnosing a homogenous group of patients or indeed a true CFS group of patients.

                                                                                                                                                                                                                                             The application aspect of the Fukuda et al. criteria is also flawed due to the non-standardised nature of the criteria. Jason et al. (33) have discerned that the determining factor concerning whether a patient fulfils CFS criteria involves the very way the questions are phrased to the patients. This study discovered that the number of patients indicating post-exertional malaise or fatigue varied from between 40.6% to 93.8% depending on the manner in which the question was asked. This significant result requires CFS criteria such as the Fukuda et al. criteria to standardize their questions in order to fulfil the fundamental study reliability component. The very diagnosis of CFS is often contingent upon fulfilling a quotient of symptomatic criteria. This Jason et al. result indicates that a large portion of patients studied may be falsely diagnosed due to something as variable as the phrasing of questions.

                                                                                                                                                                                                                                               The very nature of many CFS criteria involves patients being asked if they have certain symptoms. This method of diagnosis is doubly problematic due to the potential for suggestive bias. If an individual presents undiagnosed to a clinician, it is imperative for the patient to expound upon their symptoms to avoid this suggestive bias. If the clinician or researcher  asks the patient if they have certain symptoms (as is the case in all GET studies), the possibility of suggestive bias arises. For instance, if the patient is asked if they are exhausted, a large majority of patients and indeed a large portion of the population will indicate “yes.” When a healthy cohort (42) were questioned as to if they were exhausted, 100% answered “yes.” When this same healthy cohort was asked if they were chronically exhausted, 30% still gave the self-evaluated answer- “yes.” If this exhaustion is a significant symptom for the patient then they will likely mention it to the clinician without the need for a symptomatic question response. By planting the symptom suggestion in the patients mind, a larger portion of subjects will state that they have the symptom as opposed to the patients presenting their symptoms independently of a clinical suggestion bias. This factor has the potential to produce patient cohorts that are more prone to suggestion bias than patient cohorts that legitimately have CFS that is affecting their functionality.

                                                                                                                                                                                                                                               The cohorts used in GET studies such as the Fukuda et al. criteria cohorts are also nebulous due to the lack of diagnostic tests used by the diagnosing clinicians. The symptomatic questionaries that require fulfilling are vague and lack the definitiveness of objective tests. The Barnum affect is defined as “the tendency to accept certain vague or worthless information (43).” The vague and descriptive writings that amount to CFS questionnaires can potentially influence GET studied cohorts in this manner. This cognitive bias parallels the suggestive bias discussed in the previous paragraph. There are several tests that should be used by CFS study authors to support a CFS criteria diagnosis. One such test is the Natural Killer cell function test. Fletcher et al. (44) found that “NKCC (natural killer cell cytotoxicity) was a good predictor of CFS status.” GET study authors have failed to make use of the range of objective tests in order to comprise their CFS study cohorts. This further compromises the accurate CFS diagnosis and homogenous nature of CFS patients involved in GET studies.

                                                                                                                                                                                                                                                 A study by Joyce et al. (45) on CFS criteria and remission or improvement status concluded that the less restrictive the CFS criteria used, the better the prognosis. This study result highlights how the broad CFS criteria such as Oxford and Fukuda et al. contain a higher portion of patients that will improve regardless of treatment. The GET studies that have found an improvement in CFS patient’s symptoms have all used a broad criteria such as Oxford of Fukuda et al. Consequentially, these cohorts have the best prognosis, indicating that either these patients have a distinctly separate illness to more restrictive CFS criteria cohorts, these patients aren’t as severely ill as other CFS criteria cohort patients or possibly these patients had symptoms that would have spontaneously improved, regardless of the GET treatment. This Joyce et al. study provides further evidence that broad CFS criteria studies are including very different patients to more restrictive CFS criteria cohorts.


It has been determined that the studies finding that GET is a beneficial CFS treatment have used an Oxford or Fukuda et al. criteria cohort. These criteria have been demonstrated to be; heterogeneous, containing distinct and incomparable illness entities, non-operational, non-standardised, too broad, polythetic, containing non-CFS fatigue causing conditions and lacking fundamental practical requirements. Consequentially, these aforementioned GET studies have produced non-applicable conclusions that have been fallaciously applied to all CFS patients. It is erroneous for these GET study results to be imposed on different CFS cohorts and it has been demonstrated that the flawed nature of the broad CFS criteria used by these GET studies makes superimposing the study results onto an identical CFS criteria cohort fallacious.


1.  Gunn, W.J., Connell, D.B., & Randall, B. (1993). Epidemiology of chronic fatigue syndrome: The Centers-for-Disease-Control study.  In B.R. Bock & J. Whelan (Eds.), Chronic Fatigue Syndrome.  (pp. 83-101). New York: John Wiley & Sons

2. Ho-Yen D O, McNamara I. 1991. General practitioners’ experience of the chronic fatigue syndrome. British Journal of General Practice. 41(349):324-326.

3. Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B, Stewart JA, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med 2003;163:1530-6

4. Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue syndrome. Arch Intern Med1999; 159: 2129-37.

5. Royal Colleges of Physicians, Psychiatrists and General Practitioners (1996). Chronic fatigue syndrome; Report of a joint working group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners. London, UK: Royal College of Physicians of London.

6. Reeves, W.C., Jones, J.J., Maloney, E., Heim, C., Hoaglin, D.C., Boneva, R., Morrissey, M., & Devlin, R. (2007). New study on the prevalence of CFS in metro, urban and rural Georgia populations. Population Health Metrics 2007, 5:5     doi:10.1186/1478-7954-5-5

7. Wessely, S., Chalder, T., Hirsch, S., Wallace, P., & Wright, D.  (1997). The prevalence and morbidity of chronic fatigue and chronic fatigue syndrome: a prospective primary care study. American Journal of Public Health, 87, 1449-1455.

8. Jason LA et al. (2010) The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition, American Journal of Biochemistry and Biotechnology 6 (2): 120-135, 2010

9. Jason, L.A., N. Najar, N. Porter and C. Reh, 2009a. Evaluating the centers for disease control’s empirical chronic fatigue syndrome case definition. J. Disabil. Policy Stud., 20: 93-100. DOI: 10.1177/1044207308325995American Journal of Biochemistry and Biotechnology 6 (2): 120-135, 2010

10.  http://www.cdc.gov/cfs/education/wb1032/chapter2-8.html

11.  Jason, L. A., Corradi, K., & Torres-Harding, S. (2007). Toward an Empirical Case Definition of CFS. Journal of Social Service Research, 34(2), 43-54.

12.  De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K. (2000), Exercise capacity in chronic fatigue syndrome. Arch Intern Med. 2000 Nov 27;160(21):3270-7.

13.  Lane RJ, Soteriou BA, Zhang H, Archard LC (2003). Enterovirus related metabolic myopathy: a postviral fatigue syndrome. J Neurol Neurosurg Psychiatry. 74 (10): 1382–1386.

14.  DeLuca, J., Johnson, SK., Ellis, SP and Natelson, BH. Cognitive functioning in patients with chronic fatigue syndrome devoid of psychiatric disease. Journal of Neurology, Neurosurgery, and Psychiatry, 1997, 62, 151-155.

15.  Lerner AM, Zervos M, Dworkin HJ, Chang, CH and O’Neill W. A unified theory of the cause of chronic fatigue syndrome. Infectious Diseases in Clinical Practice 1997;6:230-243. 

16.  See DM, Tilles JG. Alpha interferon treatment of patients with chronic fatigue syndrome. Immunol Invest 1996; 25: 153-164.

17.  Mawle AC, Reyes M, Schmid DS. Is chronic fatigue syndrome an infectious disease? Infect Agents Dis. 1993 Oct;2(5):333-41.

18.  Jason, L.A., Torres-Harding, S., Maher, K., Reynolds, N., Brown, M., Sorenson, M., Donalek, J., Corradi, K., Fletcher, M.A., & Lu, T. Baseline cortisol levels predict treatment outcomes in chronic fatigue syndrome non-pharmacologic clinical trial. Journal of Chronic Fatigue Syndrome, 14, 39-59 (2007).

19.  http://www.cfids-cab.org/cfs-inform/Overlap/overlap.html

20.  http://www.nzgg.org.nz/guidelines/0084/040518_matrix.pdf

21.  http://www.cdc.gov/cfs/general/causes/

22.  Hickie et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study, BMJ. 2006 September 16; 333(7568): 575.

23.  http://aboutmecfs.org/Conf/HHV6PtII.aspx

24.  http://www.mecfscanberra.org.au/actmecfs/CFS_Research_Lloyd.ppt

25.  R. Cairns and M. Hotopf, A systematic review describing the prognosis of chronic fatigue syndrome, Occupational Medicine 2005;55:20–31

26.  Vollmer-Conna U, Aslakson E, White PD. An empirical delineation of the heterogeneity of chronic unexplained fatigue in women.

27.  Jason. L, Problems with the New CDC CFS Prevalence Estimates, http://www.iacfsme.org/IssueswithCDCEmpiricalCaseDefinitionandPrev/tabid/105/Default.aspx 

28.  Friedberg, J.R., & Jason, L.A. (1998). Assessment and treatment of Chronic Fatigue Syndrome. Washington, D.C.: American Psychological Association.

29.  Komaroff, A.L., Fagioli, L.R., Geiger, A.M., Doolittle, T.H., Lee, J., Kornish, R.J., Gleit, M.A., Guerriero, R.T. (1996). An examination of the working case definition of Chronic Fatigue Syndrome. The American Journal of Medicine, 100, 56-64.

30.  http://www.cdc.gov/cfs/toolkit/get.html

31.  Jason et al. A Comparison of the 1988 and 1994 Diagnostic Criteria for Chronic Fatigue Syndrome,


33.  Jason LA, Helgerson J, Torres-Harding SR, Carrico AW, Taylor RR. Variability in diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns of symptoms and disability. Eval Health Prof 2003 Mar;26(1):3-22

34.  Carruthers et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols

35.  Jason et al, Comparing the Fukuda et al. Criteria and the Canadian Case Definition for Chronic Fatigue Syndrome, Jason et al.

36.  https://livingwithchronicfatiguesyndrome.wordpress.com/2010/09/16/the-cdc-responds/

37.  http://www.cdc.gov/cfs/general/causes/index.html

38.  White et al. Protocol for the PACE trial: A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy BMC Neurology 2007, 7:6doi:10.1186/1471-2377-7-6

39.  Neilson 2002, http://www.cfids-cab.org/cfs-inform/CFS.case.def/me.cfs.canadian.def03.txt

40.  S. Pierce & P.W. Pierce, The physiology of exercise intolerance in patients with myalgic encephalomyelitis (ME) and the utility of graded exercise therapy

41.  Hawk, C., Jason, L.A., & Torres-Harding, S. (2007). Reliability of a chronic fatigue syndrome questionnaire. Journal of Chronic Fatigue Syndrome, 13, 41-66.

42.  https://livingwithchronicfatiguesyndrome.wordpress.com/2010/08/29/conversing-with-professor-simon-wessely-part-2/

43.  http://dictionary.reference.com/browse/Barnum+effect

44.  Fletcher et al. Biomarkers in Chronic Fatigue Syndrome: Evaluation of Natural Killer Cell Function and Dipeptidyl Peptidase IV/CD26. PloS ONE, May 2010

45.  Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue and chronic fatigue syndromes: a systematic review. QJ Med 1997;90:223-233.

                                                                                                                                                                                                                                              This was part 3 of my Meta-Analysis of the Efficacy of Graded Exercise Therapy in Treating CFS

Part 1 can be found here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/09/10/a-meta-analysis-of-the-efficacy-of-graded-exercise-therapy-in-treating-cfs-part-1/

Part 2 can be found here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/09/10/a-meta-analysis-of-the-efficacy-of-graded-exercise-therapy-in-treating-cfs-part-2/

Part 4 is currently being written


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Fucoidan for CFS

                                                                                                                                                                                                                                    Fucoidan is a sulfated polysaccharide that is found in various types of brown seaweeds. Approximately 4% of certain brown seaweeds contain Fucoidan. There are two types of Fucoidan, F-Fucoidan and U-Fucoidan.

                                                                                                                                                                                                                                           The Potential Effects of Fucoidan

On Pubmed there are over 850 studies examining the use of Fucoidan. The following is a list of some of the possible benefits of Fucoidan:

  • It may have anti-retroviral properties as it might block HIV-1 replication


  • It may also be able to inhibit cell to cell contact and hence stop the spread of HTLV-1


  • It may modulate the immune system


  • It may stimulate production of the cytokine, interferon gamma


  • It may increase Natural Killer cell levels


  • It may increase T-Cell numbers


  • It may increase antioxidant levels in the body


  • It might have antiviral properties against the herpes simplex virus (including drug resistant strains of herpes) including effects against the human cytomegalovirus


  • It may have antiviral properties against a range of other viruses


  • It might be able to slow the rate of growth of leukemia cells


  • It may be anti-coagulant


  • It may help treat osteoarthritis


  • It may reduce bodily inflammation


  • It may have anti-tumour effects


  • It may have anti-cancer effects for specific cancers (it caused apoptosis in human lymphoma cell lines)


  • It may induce adult stem cell release from bone marrow


  • It may reduce the transmission levels of sexually transmitted diseases


  • It may reduce allergic reactions


Possible Negative of Taking Fucoidan

1. A study was performed in which the first group of rats were given Fucoidan as a pre-treatment while the second group were not. Both groups of rats were infected with meningitis and then given an antibiotic. 21 out of 45 of the group of rats that took Fucoidan died compared to 5 deaths out of the 29 rats that were not given Fucoidan. The abstract of this study can be found here: http://gateway.nlm.nih.gov/MeetingAbstracts/ma?f=102265296.html

2. Many of the possible benefits of Fucoidan listed above are based on in vitro or in vivo in mice studies. The results of these studies don’t always translate into comparable results in vivo in humans. Conclusions on how Fucoidan may affect various human diseases may therefore be premature.

 3. Based on the dose of Fucoidan I will be taking (see the ‘dose’ section below) Fucoidan will cost me approximately $400 Australian per month. This is very expensive for a supplement without proven mechanisms against CFS.  The Fucoidan would be much cheaper if I took it at a lower dose however the effects of Fucoidan may be dose dependant (see the study in the dose section below.)

4. There are only a handful of anecdotal reports online of CFS patients taking Fucoidan. These reports are almost identical in that no follow up of Fucoidan treatment is provided and Fucoidan was only taken at a low dose. It is therefore somewhat experimental for me to be taking Fucoidan at a high dose.

                                                                                                                                                                                                                                     Possible Responses to the Negatives of Taking Fucoidan

1. The rats Fucoidan study,  is the only “negative” Fucoidan study that I could find out of over 850 Fucoidan studies on Pubmed. As I do not have meningitis, there is little risk involved in me taking Fucoidan.  Also many studies have determined that Fucoidan is completely safe to take.  Out of the thousands of people who have taken Fucoidan, I have not read of any adverse side effects to it.

                                                                                                                                                                                                                                               2. Although most of the Fucoidan studies are in vitro or in vivo (in mice), there are still many human Fucoidan studies. These studies have produced many favourable results indicating that many of the in vitro and in vivo (in mice) effects may translate into comparable results in humans.

                                                                                                                                                                                                                                               3. Although Fucoidan is expensive, it is a treatment that I haven’t tried to date. I am taking it as a secondary treatment at the moment, concurrent with Fludrocortisone.  I do not consider Fucoidan to be a serious CFS treatment and am hence only taking it on the side, next to more conventional and prescription CFS treatments. Other than money, there is very little to lose by trying Fucoidan as a treatment.

                                                                                                                                                                                                                                               4. There is not enough data to determine if Fucoidan is effective in any way for CFS patients. Although Fucoidan for CFS is somewhat more experimental that other CFS treatments, the Fucoidan safety aspect confirmed by numerous studies makes Fucoidan not dangerously experimental.


I am taking Fucoidan in capsule form. It is also available in various other forms such as gel and liquid however tablets seem to contain the highest dosage of Fucoidan. My source of Fucoidan contains 35% of U-Fucoidan and 11% of F-Fucoidan per 600mg tablet. Not enough human dosage studies of Fucoidan have been performed to determine optimal dosage levels. For illnesses with a well defined cohort such as cancers, various websites recommend differing daily dosages, hence there is not much consensus regarding specific illness dosages. The dosage I will be taking is based on an Osteoarthritis study in which Fucoidan was assigned to two groups. The first group took 100mg a day while the second group took 1000mg per day. Both groups took Fucoidan for 12 weeks.  The average COAT score of group 1 was reduced by 18% while the average COAT score of group 2 was reduced by 52%. Other studies support this study’s conclusion in that the effects of Fucoidan are dose dependant. I will therefore be taking approximately 1000mg of Fucoidan per day. This is the same dose as group 2 in the Osteoarthritis study. Fucoidan has been deemed as safe at this dose by several studies. I will be taking Fucoidan for 8 weeks and possibly longer if it has any positive effects on me.

I started taking Fucoidan on the 10th of September 2010 and gradually increased the dose to a maximum dose of approximately 1000mg. I plan to take Fucoidan for 8 weeks. I take 4 capsules of Fucoidan with breakfast and 4 capsules of Fucoidan with lunch every day.


Many of the possible effects of Fucoidan have the potential to benefit CFS patients. Despite this, I could not find any evidence online that CFS patients have benefited from taking Fucoidan. I am being somewhat of a guineapig (although not taking much of a risk) by taking Fucoidan at such a high dose as a CFS patient. I will blog again in the coming weeks about whether Fucoidan had any effect on me.

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Cochrane Review on Exercise Therapy for CFS

Edmonds et al. investigated the effectiveness of exercise therapy as a treatment for CFS in a 2004 Cochrane Review (1). The analysis included 5 randomised controlled studies. The primary measure being assessed was fatigue, according to the Chalder Fatigue Scale. The Cochrane Review concluded that some CFS patients may benefit from exercise therapy. The review stipulated that CFS patients who are similar to those included in the 5 studies should be offered exercise therapy. The review speculated that higher intensity exercise may lead to a poorer outcome and that 40% VO2 max exercise may be preferable to 75% VO2 max exercise.

                                                                                                                                                                                                                                            The Cochrane Review emphasised that functional work capacity in the exercise group was not statistically significant from the control group after 12 weeks. The review also demanded higher quality studies of exercise therapy that incorporated different types of CFS patient groups. The review also encouraged a larger range of outcomes to be measured. It suggested adverse effects and quality of life be measured. The review also recommended that the outcome measures should be performed over a longer period of time to gauge the long term effectiveness of exercise therapy as a treatment for CFS patients.

                                                                                                                                                                                                                                             The 5 Cochrane Review Examined Studies

The 5 studies that the Cochrane Review analysed were; Appleby 1995 (2), Fulcher 1997 (3), Moss-Morris 2003 (4), Powell 2001 (5) and Wallman 2004 (6). I will analyse each of these 5 studies independently. My analysis of the 5 studies will be distinct from the Cochrane Review, in that it will be more critique orientated as opposed to appraisal oriented.

                                                                                                                                                                                                                               Appleby 1995

Appleby et al. (2) used only an Oxford CFS criteria cohort for their exercise study. This cohort contains approximately 10% of CFS patients (When referenced to an International Classification of Disease ME/CFS cohort (7).)  Consequentially, approximately 90% of the cohort studied were not true CFS patients.

                                                                                                                                                                                                                                       Appleby et al. divided the study into four distinct groups. Group 1 were assigned GET and Fluoxetine, group 2 did GET and took a drug placebo, group 3 had an exercise placebo and took Fluoxetine and group 4 were given an exercise placebo and a drug placebo. Exercise therapy was performed 3 times a week for a period of 20 minutes. The intensity of the exercise was 75% of the individuals VO2 max.

                                                                                                                                                                                                                                            The study concluded that there was no statistically significant difference between exercise therapy and the control group regarding functional work capacity. This was determined at 12 weeks and 26 weeks. The Appleby et al. study didn’t result in exercise therapy helping fatigue, when compared to the control group. This study also included the highest dropout rate, relative to the other four Cochrane Review studies.

                                                                                                                                                                                                                                              The cohort used in the Appleby et al. study had a median CFS duration of just 2.3 years. This is a relatively short illness duration (for CFS) and hence any conclusions from this study should emphasise the relatively short median CFS duration of the Appleby cohort. Also the mandatory 20 minutes per session exercise therapy is a duration that exceeds the capacity of moderate and severely affected CFS patients. It can therefore be concluded that patients with only mild CFS were included in this Appleby et al. study.

                                                                                                                                                                                                                      Conclusions: Exercise therapy at 75% VO2 max is not useful for patients fulfilling the Oxford CFS criteria, with mild CFS and a short illness duration. The high dropout rate of the Appleby study may signify that 75% VO2 max exercise is contraindicated in the aforementioned CFS cohort.


Fulcher 1997 

Fulcher et al. (3) used only an Oxford CFS criteria cohort for their exercise study. This cohort contains approximately 10% of CFS patients (When referenced to an International Classification of Disease ME/CFS cohort (7).)  Consequentially, approximately 90% of the cohort studied were not true CFS patients. 66 Oxford defined, CFS patients were divided into two groups. The first group were prescribed at least 5 sessions a week of GET. The initial sessions lasted between 5 and 15 minutes long and the exercise was graded up to a maximum length of 30 minutes. The first group performed at an intensity of 40% VO2 max, which is approximately 50% of the maximum heart rate. The first group were given the choice of walking, swimming or cycling. An exercise physiologist negotiated with each individual patient regarding adapting the exercise to the patient’s capacity and grading the exercise. The second group were prescribed flexibility and relaxation for 12 weeks. This ‘flexibility and relaxation’ mainly consisted of stretching. The second group performed this routine for 5 days a week starting at 10 minutes a day and increasing to a maximum of 30 minutes a day.

                                                                                                                                                                                                                                         None of the ‘CFS’ patients included in this study had an appreciable sleep disturbance. Having sleep disturbance is a necessary condition to fulfil the Canadian Consensus Criteria (CCC) (8). It can therefore be concluded that none of the patients in this study fulfilled the CCC for CFS. In a De Becker et al. study (9), 94.8% of patients fulfilling the Holmes criteria (10) had a sleep disturbance. This study included 951 patients and those with a sleep disturbance graded it as 2.5 out of 3 in terms of severity. The De Becker et al. study also analysed 1578 patients fulfilling the Fukuda criteria (11) for CFS. 91.9% of the patients had a sleep disturbance, averaging 2.4 out of 3 in severity. It can therefore be concluded that the results of the Fulcher et al. study cannot be extrapolated to those suffering from CCC, Holmes criteria or Fukuda criteria CFS.

                                                                                                                                                                                                                                            The Fulcher et al. study cohort comprised only patients who had been referred to a general hospital department of psychiatry. Patients fulfilling the Oxford criteria with a psychiatric disorder, comorbid disorder and/or a comorbid phobia were included in the Fulcher et al study. 41% of the study participants had in the past been treated for a comorbid disorder. The median illness duration of the study cohort was just 2.7 years which is a relatively short illness period for CFS patients. 5 outpatients that were too ill to attend the psychiatric department were excluded from the study.

                                                                                                                                                                                                                                                It must be noted that patients with severe CFS would not have been eligible for this study due to the intensity and length of exercise required to be completed. Also the exercise group (group 1) started their exercise at 40% VO2 max which is roughly equivalent to 50% of the maximum heart rate. Many Postural Orthostatic Tachycardia Syndrome (POTS) patients and CFS patients would therefore be ineligible for this study due to their heart rate exceeding this percentage at rest. POTS (which often overlaps CFS) has the hallmark symptom of an increase in heart rate by over 30 beats per minute to 120 beats per minute on standing (12). The general formula to predict a healthy person’s maximum heart rate (in beats per minute) is 220-age. CFS patients often have a lower maximum heart rate than those healthy controls of a similar age. It can therefore be concluded that many CFS patients would not be typical of this studies cohort. This is due to many CFS patients exceeding 50% of their maximum heart rate at rest.

                                                                                                                                                                                                                                             The patients contained within the exercise group (group 1) who rated themselves as better, didn’t show a significant improvement in muscle strength or peak oxygen consumption.  Also over 40% of the patients in the study showed no or little improvement. Fulcher et al. were even cautious in their conclusion and emphasised that GET should only be prescribed appropriately and not in all circumstances.

                                                                                                                                                                                                                       Conclusions: Some of those patients fulfilling only the Oxford criteria and not the Holmes criteria, Fukuda criteria or the CCC for CFS may benefit from a certain type of exercise. The specific Oxford criteria patients that may benefit do not have an appreciable sleep disorder and may have a psychiatric disorder, comorbid disorder and/or a comorbid phobia and only have a short illness duration. Some patients within this select subset (which is very much an atypical CFS and unique subset) may benefit from starting GET at 40% of their VO2 max for several minutes a day.


Moss-Morris 2003

This study isn’t freely available hence I have only read the abstract and not the details of the study. A small amount of information about this study is available in the Cochrane review (although the Moss-Morris study had just been submitted for publication when the Cochrane Review was published.) I will attempt to utilise this information and critique this study albeit in an inhibited manner.

                                                                                                                                                                                                                                        Moss-Morris et al. (4) used the 1994 CDC CFS criteria cohort for their exercise study. This cohort contains approximately 40% of CFS patients (When referenced to an International Classification of Disease ME/CFS cohort (7).)  Consequentially, approximately 60% of the cohort studied were not true CFS patients. The Cochrane Review rated the Moss-Morris study as the study that was of the least quality, relative to the other 4 studies reviewed. All 5 studies quality was evaluated by the CCDAN quality rating system which includes 23 different criteria.

                                                                                                                                                                                                                                            The Moss-Morris study divided patients into 2 groups. Group 1 was prescribed GET for 12 weeks while group 2 was told to continue treatment as usual. Group 1 were told to exercise 4-5 times a week at 40% of their VO2 max, for a period of up to a maximum of 30 minutes.  Exercising at 40% VO2 max equates to approximately 50% of the individuals maximum heart rate. The same criticisms of study exclusion apply to this Moss-Morris study as the previously discussed Fulcher et al. study. The criticisms that also apply to this study include using a CFS cohort that can reach 50% maximum heart rate while exercising compared to other CFS cohorts exceeding the 50% maximum heart rate while resting or standing. Consequently, this studies result can only be extrapolated onto a specific type of CFS patient.

                                                                                                                                                                                                                                            The median length of illness in the Moss-Morris study was 3.1 years. This is a relatively short period when compared to other CFS cohorts. As a result of this short illness period being studied, the results of this study should not be imposed on those CFS patients with a long or medium illness duration. Only 11 out of 59 CFS patients in this study were unemployed. This is a relatively low number when compared to other CFS cohorts. As over 80% of this study cohort were working, it implied a level of CFS disability in this cohort that is mild as opposed to moderate or severe. The results of this study are therefore reflective mainly of mildly affected CFS patients.

                                                                                                                                                                                                                                             The Moss-Morris study didn’t report on the CFS patients doing GET after 12 weeks. Consequently, the long term affects of GET have not been determined by this study. Also this study fails to measure many symptoms that are central to CFS such as pain, sleep, neurological symptoms and endocrine symptoms. The general effect of GET on CFS patients is therefore nebulous as the results of this study exclude the central components and potential biomarkers of CFS.

                                                                                                                                                                                                                                          Moss-Morris et al. conclude that the reason GET was a partially effective treatment in this study may be due to “self-reported improvement by reducing the degree to which patients focus on their symptoms.” The authors continue to state that “there is no evidence that CFS patients disproportionately focus on symptoms, rather that common CFS definitions fail to describe patients’ symptomology adequately.”


Conclusions: I am not qualified to draw any definitive conclusions from this study as I have not read the study in its entirety, but rather secondary sources about the study. Having said that, I have cautiously determined that the results of this study mean that: CFS patients fulfilling only the CDC 1994 criteria, with mild CFS and CFS of a short duration may benefit from performing low (approximately 40% VO2 capacity) intensity GET. The benefit this specific subgroup will possibly gain may be due to “reducing the degree” they “focus on their symptoms” as the study authors state. This may only be a perceived and not a physiologically significant improvement.


Powell 2001

Powell et al. (5) used only an Oxford CFS criteria cohort for their exercise study. This cohort contains approximately 10% of CFS patients (When referenced to an International Classification of Disease ME/CFS cohort (7).)  Consequentially, approximately 90% of the cohort studied were not true CFS patients. Patients were divided into four groups. Group 1 were told to continue treatment as usual. Group 2 were the “minimum intervention group” and included two face to face sessions with a health professional totalling 3 hours, in combination with a prescription of GET. Group 3 were the “telephone intervention group” which involved 7 telephone calls of 30 minutes each with a health professional. Also GET was assigned to group 3. Group 4 were the “maximum intervention group” which entailed the same involvement as the “minimum intervention group” in conjunction with 7 one hour face to face sessions with a health professional. This Powell et al. study was not a pure GET study but rather a hybrid GET and cognitive behaviour therapy (CBT) study.

                                                                                                                                                                                                                                       Patients were excluded from this study if they were confined to a wheelchair or bed which implies that the severely affected CFS cohort were barred from this study. Patients were also excluded from the study if they were taking any treatments. The paper doesn’t describe very articulately what treatments resulted in patient exclusion from the study, only to stipulate “other treatments.” Presumably this refers to any treatments outside of the realm of GET and CBT.  A large portion of CFS patients are dependent on specific medications (and in most cases, many medications), hence a CFS cohort not taking any treatment is an atypical CFS cohort. The notion that only mildly or moderately affected patients were included in this study gains support when the intervention group criteria is analysed. This included up to 10.5 hours in consultations on top of the GET schedule. This temporally immense consultation duration would exceed the limits of severely affects CFS patients and some moderately affected patients. This is further evidence that the CFS patients in this study were only comprised of a unique subgroup.

                                                                                                                                                                                                                                            The study originally selected 160 patients to be assigned to one of the 4 groups. Twelve of the eligible patients out of the 160 “refused to participate.” This makes the subgroup being studied even more atypical due to the possibility that these non-included patients had previously suffered from the effects of GET. Out of the 148 patients that continued to participate in the study, 21 dropped out which equates to 14%. This dropout number was not reflective in the published results of the study and such a high dropout rate could completely skew the results.


The Powell et al. study concludes that the improvement as a consequence of the treatment can be explained in terms of the changes of behaviour by the CFS group. This was due to the “physiological explanations they were given for their symptoms.” Prior to treatment, 81% of patients believed their condition was due to a virus however post treatment, only 23% maintained this belief. Prior to treatment, 67% believed their condition was due to a physical illness while 13% held this belief after treatment. 15% thought their condition was due to physical deconditioning prior to the study, while 81% held this view post treatment.


These results are not entirely surprising as the 3 intervention groups were told that their illness was not organic ad nauseum. The purpose of involving the intervention groups in this study was to convince them that their illness was psychosomatic and a result of deconditioning. This study did not reference any other organic illness studies in which the patients were told that their illness was psychosomatic. I suspect that regardless of the illness, organic or psychosomatic, that when health professionals continue to state that the illness is psychosomatic, a large portion of patients will believe this. This is especially true for studies such as this Powell et al. study in which success of treatment can be measured in terms of changed illness beliefs. If a study was to be conducted on cancer patients, with an identical methodology to the Powell et al. study, yet the cancer patients hadn’t been told of their diagnosis, a similar result to the Powell et al. study is likely. This is due to the suggestible nature of humans relating to appropriate authorities diagnosing illnesses. Also the study participants will be deemed to have not changed their illness beliefs and hence “failed” if they do not give an improved subjective outcome score. The Moss-Morris et al. (4) study authors support my argument by stating that alike studies may appear to be effective due to “self-reported improvement by reducing the degree to which patients focus on their symptoms.”


To clarify the above argument, let me demonstrate a hypothetical example from the Powell et al. study. As an individual in the study, I enter the study with the belief that my virus is organic. I am told by the medical professionals that this is not the case. I am told that my illness is psychosomatic and by not focusing on my symptoms, my illness will dissipate. Correspondingly, when I evaluate my symptoms as part of the study evaluation, I have two fundamental options. 1. I can state that my symptoms have not changed however this will indicate that I did not believe what the health professional told me and hence I did not complete the treatment correctly. 2. My success will be gauged upon stating that my symptoms have improved. I have been told that my symptoms are essentially imaginary hence if I write that my symptoms have improved, I am simply fulfilling what was asked of me by the health professional. This type of study is full of cognitive biases and to scientifically draw conclusions from it, a reference study is needed such as the hypothetical cancer study I have mentioned. Powell et al. have failed to provide a reference study to determine whether the same interventions with definitively diagnosed organic illness patients will yield different results. This is the vicious cycle that in the current paradigm renders CBT studies non-calibrated. Until this calibration has occurred, studies like this Powell et al. study are pseudoscience in nature.


A further criticism of this Powell et al. study involves the lack of information regarding what type of GET was performed. All of the other studies investigated by the Cochrane Review provide details pertaining to the type, duration and intensity of GET performed. As this information has been omitted, any conclusions drawn from this study are spurious. The study authors’ concede that one of the limitations of this study was the lack of placebo control group receiving therapist’s time. This lack of placebo, makes the results of this study even more nebulous as it cannot be determined if GET or CBT individually or in tandem were the effective treatment/s.


The study authors also concede that a further limitation of this study involved the subjective nature of the primary outcome measure- fatigue. Other studies analysed by the Cochrane Review determined outcome benefit by more objective, physiological means such as VO2 max. Self-reported measures are largely unreliable in the scientific and medical domain. It is therefore questionable as to why easily obtained objective measurements were not taken in this study.
                                                                                                                                                                                                                      Conclusions:  I am reluctant to draw any conclusions from this study. Even the study participants- with mild to moderate Oxford defined CFS, not taking any treatments, that didn’t dropout of the study may not benefit from GET and patient education. The non-calibrated education fragment of the study and the entirely subjective primary outcome measure make this study largely unscientific. Also the type, duration and intensity of GET was not specified in this study. As the Appleby et al. (2) study resulted in less than favourable results at 70% VO2 max GET, the intensity of GET performed is highly relevant to the study outcome. To draw any conclusions from this study would be to neglect a highly relevant aspect of GET- exercise intensity.



Wallman 2004

Wallman et al. (4) used the 1994 CDC CFS criteria cohort for their exercise study. This cohort contains approximately 40% of CFS patients (When referenced to an International Classification of Disease ME/CFS cohort (7).)  Consequentially, approximately 60% of the cohort studied were not true CFS patients. Patients were divided into 2 groups. Group 1 was prescribed GET which involved; walking, cycling or swimming. GET started at between 5 and 15 minutes duration and worked up to a maximum of 30 minute sessions. Intensity of exercise was determined by the mean heart rate that the patients achieved during the initial submaximal exercise test. Group 2 were prescribed relaxation and flexibility exercises such as stretching. Both groups performed their prescribed workout 3-4 times per week. 

                                                                                                                                                                                                                                             The cohort used in this study were not severely ill as they were initially able to do at least 5 minutes of exercise. Also they were able to attend weekly testing sessions at a University laboratory. Both of these tasks are generally unattainable tasks for those severely affected CFS patients. The study authors also concede that a skewed sample of “more robust and healthier subjects” may have been involved in this study. This was partly due to the maximal oxygen consumption testing that may “deter some people with CFS from participating.” The authors’ continue to question the suitability of using the maximal effort oxygen test for people with debilitating fatigue which is according to the authors, “exacerbated by physical activity.” This initial maximal effort oxygen test would not only deter those with severe CFS but a large portion of those with moderate CFS from participating in this study.

                                                                                                                                                                                                                                                7 subjects out of the study group of 68 withdrew from the trials partway. Also 6 subjects out of the 68 were diagnosed with a major depressive order. A further 2 subjects had been diagnosed with dysthymia. The participants in this study were recruited from notices placed in medical surgeries and newspapers. A CDC 1994 CFS diagnosis was also required by each participant’s doctor in order to be included in the study. This step may have also skewed the study cohort as a large portion of doctors are unfamiliar with diagnosing CFS. A more accurate method to determine a study cohort could have been achieved through CFS specialists who are familiar with providing a CFS diagnosis. The hope of participating in the study may have also led some participants to “modify” their symptoms to fit into the CDC 1994 CFS definition. To overcome this method, the authors’ should have not alerted each individual to the required specific CFS diagnosis needed.

                                                                                                                                                                                                                                                 A further criticism of this Wallman et al. study involves the omission of the patient’s illness duration. This study was the only Cochrane Review study to not include this information. Also the number of study participants who were employed was also not supplied. This figure is useful if functional work capacity is to be determined as an outcome. The Wallman et al. study lasted for only 12 weeks hence the long term affects of GET aren’t clear from this study.

                                                                                                                                                                                                                                            The study also fails to report or monitor many physical symptoms that are central to CFS including pain, sleep, neurological symptoms or endocrine symptoms. Wallman et al. speculate that the improvements noted in this study may be due do the abandonment of “avoidance behaviours.” It is therefore questionable if the GET itself had a beneficial effect by increasing fitness levels. The Wallman et al. study authors even concede that GET is not a cure for CFS.


Conclusion: Some patients fulfilling only the CDC 1994 CFS criteria and with mild CFS may benefit from a GET routine. This GET routine must be carefully structured and a heart rate monitor should be worn to determine exercise intensity levels. The target heart rate that should be aimed for has not been specified by Wallman et al.



Overall Conclusion Based on the Five Studies

The Cochrane Review concluded that there is “evidence that some patients may benefit from exercise therapy.” Also “Patients with CFS who are similar to those in these trials should be offered exercise therapy and their subsequent progress monitored.” Based on my analysis of the five Cochrane Review investigated studies, the patients with CFS “similar to those in the trials” that may benefit from GET are 

  • (My conclusion from the Fulcher et al. (3) study) Some of those patients fulfilling only the Oxford criteria that do not have an appreciable sleep disorder and may have a psychiatric disorder, comorbid disorder and/or a comorbid phobia and have only be ill for a short period.
  • (My conclusion from the Moss-Morris et al. (4) study) Some CFS patients fulfilling only the CDC 1994 criteria, with mild CFS and CFS of a short duration.
  • (My conclusion from the Wallman et al. (6) study) Some patients fulfilling only the CDC 1994 CFS criteria and with mild CFS.


Those patients that fulfil one of the subgroups above are the ones that may benefit from GET, although an increase in work capacity is unlikely as a result of the GET. The GET that these specific patients should have the option of performing involves low intensity exercise, 40% VO2 max and a heart rate monitor should be worn to monitor exercise intensity. Also an expert health practitioner should personally tailor this GET program for the specific individual and help monitor progressive measures to help avoid illness deterioration.


Based on the Cochrane Review’s conclusion, only these specific subgroups of CFS patients should be offered a certain type of GET. Therefore the Cochrane Review does not recommend GET for those CFS patients who don’t satisfy one of the aforementioned, atypical three CFS subgroups.

                                                                                                                                                                                                                                            Part 1 of this meta-analysis can be found here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/09/10/a-meta-analysis-of-the-efficacy-of-graded-exercise-therapy-in-treating-cfs-part-1/

Part 3 is in the process of being written.



  1. Edmonds M, McGuire H, Price J. Exercise therapy for chronic fatigue syndrome (Cochrane Review). In: The Cochrane Library, Issue 3, 2004. Chichester, UK: John Wiley & Sons, Ltd.
  2. Appleby L. Aerobic exercise and fluoxetine in the treatment of chronic fatigue syndrome. National Research Register 1995.
  3. Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with chronic fatigue syndorme. BMJ 1997;314(7095):1647-52. and White PD, Fulcher KY. A randomised controlled trial of graded exercise in patients with a chronic fatigue. Royal College of Psychiatrists WinterMeeting, Cardiff. 1997.
  4. Moss-Morriss R, Wash C, Tobin R, Baldi JC. Mechanisms of change during a randomized controlled graded exercise trials for Chronic Fatigue Syndrome. Submitted for publication 2003.
  5. Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised controlled trial of patient education to encourage graded exercise in chronic fatigue syndrome. BMJ 2001;322(7283):387-90.
  6. Wallman KE, Morton AR, Goodman C, Grove R, Guilfoyle AM. Randomised controlled trial of graded exercise in chronic fatigue syndrome. Medical Journal of Australia 2004;180(9):444-8.
  7. Neilson 2002, http://www.cfids-cab.org/cfs-inform/CFS.case.def/me.cfs.canadian.def03.txt
  8. Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. J CFS 2002;11(1):7 – 116
  9. De Becker P, McGregor N, De Meirleir K. A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med 2001;250:234-240.
  10. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, et al. Chronic fatigue syndrome: a working case definition. Ann of Intern Med 1988;108:387-389.
  11. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A, and the International Chronic Fatigue Syndrome Study Group. Chronic Fatigue Syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994;121:953-959
  12. http://www.ninds.nih.gov/disorders/postural_tachycardia_syndrome/postural_tachycardia_syndrome.htm
  13. http://whatis.pantoday.com/page/4984-what-is-myalgic-encephalomyelitis

Read Full Post »

I am currently in the process of writing this meta-analysis. I originally planned on posting all of the sections in one long post. The length of the sections that I have completed so far exceed the length that many CFS patients can read hence I will post this meta-analysis in parts. As I complete each part, I will post it. After I have completed all parts, I will combine them and post the meta-analysis in its entirety.



Graded exercise therapy (GET) is physical activity that starts slowly and gradually increases over time (1). GET is often recommended as a treatment for Chronic Fatigue Syndrome (CFS.) This meta-analysis will examine the theoretical basis for recommending GET for CFS. This article will also scrutinize the studies contained within the scientific literature on GET and CFS.  Following this, the physiological effects that GET may have on CFS will be examined.


The Theory Behind Recommending GET for CFS

The psychosocial model for CFS is the underlying theory for recommending GET for CFS (2). This model proposes that the CFS patient can recover by modifying beliefs, behaviour and addressing deconditioning. GET and Cognitive Behaviour Therapy (CBT) are often recommended as tandem treatments under the psychosocial model of CFS. This meta-analysis will primarily analyse GET for CFS, not CBT, although both of these treatments share many commonalities including arising from the same theory that underlies the psychosocial model for CFS (2). Despite the aforementioned inextricable link between GET and CBT, it is often theorised that GET will specifically benefit CFS patients by creating a reversal of the deconditioning process (2). There exist nuanced variations of the psychosocial model for CFS however they all share the common premise that GET should be used as a primary treatment to halt and then reverse the deconditioning process in CFS.


Fulcher et al. typify a large portion of the psychosocial school by supporting the notion that the physical weakness accompanying CFS is directly caused by physical deconditioning, as a consequence of inactivity. Fulcher et al. cite the improvement in well-being scores correlating with an increase in strength and exercise capacity from GET. Fulcher et al hypothesise that the disability that accompanies CFS is a consequence of both physical deconditioning and a low threshold for specific somatic perceptions (3).


Kinesiophobia (the fear of movement) has been linked with CFS patients (4) (5) (6). Several studies have suggested that the avoiding of physical activity may cause a greater burden for CFS patients (7) (8) (9). These studies hypothesis that by CFS patients avoiding physical activity, it causes them to engage in maladaptive behaviour that may perpetuate their illness. These studies continue on to state that this is part of the rationale for GET as a treatment of CFS.


There exist two competing hypothesis advocating the use of GET for CFS. The first hypothesis proposes that the pathophysiology of CFS is mainly irreversible however GET can lead to an improvement in the quality of life for the CFS patient (10).  The second hypothesis suggests that the pathophysiology of CFS is entirely reversible and that the treatments of GET and CBT can potentially cure CFS (10). 


 Criticisms of the Theory Behind Recommending GET for CFS

The theory that the deconditioning that accompanies CFS is an etiological factor causing disability or indeed CFS itself is a position that contrasts many studies. Friedberg et al. and Lapp et al. have found that patients with CFS are already functioning at their maximum ability in regards to energy (11) (12). This suggests that although disability in CFS correlates with degree of physical functioning, it does not cause an impaired degree of functioning. Therefore a more likely scenario than the “deconditioned theory” is that CFS patients have a low degree of physical activity due to the nature of having a debilitating, chronic and physiological illness. The “deconditioning theory” is also problematic due to several studies finding that physical and mental exertion by CFS patients cause an impermanent yet significant decline in functioning (13) (14) (15). If deconditioning was an etiological factor in CFS, it would be expected that exertion would cause an improvement in functioning ability, not decline.


 Lane et al. conducted a study that concluded that CFS patients have an impaired muscle energy metabolism which cannot be explained by physical inactivity or a psychiatric disorder (16). The Lane et al study claims that the heart rate response to exercise by CFS patients suggests that CFS patients were no more deconditioned that those with a normal lactate response (16). A study was performed by Bazelmans et al. examining various physical conditioning biomarkers in CFS patients and controls, before and after exertion. This study concluded that physical deconditioning is not a perpetuating factor in CFS (17).


Sampson et al. (23) found that the amount of bed rest CFS patients indulge in at illness onset was not predictive of having a fatigue syndrome 6 months later. The authors’ concluded that CFS has no relationship to over-resting or deconditioning but rather a yet to be identified physical abnormality. Sampson et al. are critical of studies that link CFS to deconditioning as these studies have no data regarding the original fitness of the CFS patient, prior to illness. Sampson et al. conclude that deconditioning is a result of the chronic illness, CFS, this is as opposed to the chronic illness that is CFS being perpetrated by deconditioning. Sampson et al. found no relationship between fitness and bed rest at CFS onset.


The countless anecdotal reports of athletes contracting CFS (as opposed to athletic burnout) is in itself proof to nullify the argument that deconditioning is a necessary condition accompanying CFS. Many athletes, in their prime, have been diagnosed with CFS. If deconditioning played a major role in the pathophysiology of CFS, athletes would be immune from CFS. The medical literature suggests that athletes are often CFS patients hence the psychosocial model that definitively states that CFS disability is always caused by physical deconditioning is flawed.


The theory that kinesiophobia (the fear of movement), plays an integral part in the pathophysiology of CFS is a viewpoint that contradicts many studies. Nijs et al. performed a study on exercise in CFS patients with widespread muscle or joint pain. The study authors’ concluded that there is no correlation between kinesiophobia and exercise capacity or activity limitations in CFS patients (18).  A study by Gallagher et al. concluded that patients with CFS (and without a co-morbid psychiatric disorder) do not have an exercise phobia (19). These studies support the notion that CFS patients do not have kinesiophobia but rather are cautious about overexertion as this may have debilitating physiological consequences on their illness.


One of the leading proponents of the psychosocial model of CFS, Professor Wessely, found that CFS patients don’t have negative attitudes towards psychiatry. The Wessely and Woods study compared various mental attitudes of CFS patients with rheumatoid arthritis patients. The authors found no difference between both groups of patients in regard to perfectionism, attitudes towards mental illness, defensiveness, social desirability or sensitivity to punishment (20). This study result suggests that psychological factors don’t play a significant role in CFS, when it is compared to other chronic illnesses. Le Bon et al found that personality structure doesn’t play a major role in CFS (21). Vollmer-Conna et al concluded that psychosocial factors including psychiatric history, mood, coping style and personality have no major effect on CFS patients’ illness outcomes (21).  These study results suggest that maladaptive behaviour is not prevalent among CFS patients. Maladaptive behaviour was proposed as the mechanism behind the supposed kinesiophobia among CFS patients.

 Part 2 of this meta-analysis can be found here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/09/10/a-meta-analysis-of-the-efficacy-of-graded-exercise-therapy-in-treating-cfs-part-2/



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  11. Friedberg,F. & Krupp,L.B. (1994) A comparison of cognitive behavioral treatment for chronic fatiguesyndrome and primary depression. Clinical Infectious Diseases, 18 Suppl 1, S105-S110.
  12. Lapp,C.W. (1997) Exercise limits in chronic fatigue syndrome. American Journal of Medicine, 103, 83-84.
  13. Paul,L., Wood,L., Behan,W.M., & Maclaren,W.M. (1999) Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome. European Journal of Neurology, 6, 63-69.
  14. Levine,P.H., Snow,P.G., Ranum,B.A., Paul,C., & Holmes,M.J. (1997) Epidemic neuromyasthenia and chronic fatigue syndrome in west Otago, New Zealand. A 10-year follow-up. Archives of Internal Medicine, 157, 750-754.
  15. Blackwood,S.K., MacHale,S.M., Power,M.J., Goodwin,G.M., & Lawrie,S.M. (1998) Effects of exercise on cognitive and motor function in chronic fatigue syndrome and depression. Journal of Neurology, Neurosurgery & Psychiatry, 65, 541-546.\
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  23. Sampson et al. Close analysis of a large published cohort trial into fatigue syndromes and mood disorders that occur after documented viral infection. http://iacfsme.org/BULLETINSUMMER2010/Summer2010SampsonAnalysisCohortTrial4481/tabid/435/Default.aspx

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                                                                                                                                                                                                                                                  I discussed using Low Dose Naltrexone (LDN) for CFS in a blog entry here: https://livingwithchronicfatiguesyndrome.wordpress.com/2010/02/26/low-dose-naltrexone-for-cfs/

I have now completed the LDN treatment.

I have taken LDN for almost 6 months.

I have taken the ‘maximum’ dose of LDN, 4.5mg, for 4 months.

I did not experience any improvement in CFS symptoms while taking LDN.


The Effects LDN had on me

  • During the first several weeks of taking LDN, I experienced vivid dreams. This is a common effect that LDN has on those who take it. The vivid dreams stage lasted for approximately 4 weeks before the vividness of my dreams gradually returned to normal.
  • Upon waking some mornings, I noticed my arms and legs feeling slightly ‘wired.’ This ‘wired’ feeling was only mild and it felt like endorphins were causing this feeling.
  • The main effect LDN had on me was an increase in nasal mucus discharge. I would typically have 2 weeks of going through a normal amount of tissues for me (1000 a day) followed by 2 weeks of using a higher number of tissues (around 2000 daily.) This oscillating pattern continued for the entire period that I took LDN. I normally cough up a lot of mucus which uses up a large number of tissues however LDN caused my nose to run.


My family described the amount of mucus discharge I was experiencing while taking LDN as “Like a severe cold that lasts for months.” I experienced a similar increase in mucus discharge nasally while taking artesunate. One possible explanation for the increase in mucus discharge nasally is that I had a quasi-Herxheimer reaction to the LDN.

Below is a photo of the scene next to my bed. This is the number of tissues I went through daily while on LDN. I normally go through half this number when not on LDN, just with my normal CFS.



                                                                                                                                                                                                                                                A Possible Reason Why LDN Didn’t Improve my CFS Symptoms

A pilot study was conducted that examined the use of LDN on Fibromyalgia patients. This study’s abstract can be found here: http://www.ncbi.nlm.nih.gov/pubmed/19453963

The authors concluded that “Baseline erythrocyte sedimentation rate predicted over 80% of the variance in drug response (to LDN.) Individuals with higher sedimentation rates (indicating general inflammatory processes) had the greatest reduction of symptoms in response to low-dose naltrexone.”

My most recent blood test on the 5th of July 2010 showed my ESR levels to be 4mm/h. The normal range is 1-15. I have never had a blood test showing high ESR levels hence this may be the reason, or a contributing factor, that explains why I didn’t respond to LDN.


LDN is considered an ‘experimental’ treatment for CFS. Dr Bihari reports that approximately 50% of CFS patients are helped my LDN. Unfortunately I was not one of these patients. I am pleased to have at least tried LDN because its mechanism of action has the potential to help CFS symptoms.

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