The cholinergic hypothesis leads to the question . . .

Can Galantamine Help
Chronic Fatigue?

CFS is not just “in your head” and
something can be done about it now
By Will Block

W e all know someone who, after getting the flu, has flu-like symptoms that go on … and on … and on. (Maybe that someone is you?) How can we possibly comprehend this phenomenon, which is generally called chronic fatigue syndrome (CFS)? Unfortunately at this time, an understanding of what CFS is and what can be done about it is obscured beneath a myriad of conditions diagnosed by criteria that include prolonged and severe fatigue, body aches, and other symptoms, many of which are intractable.

“It’s all in their heads!” Haven’t we heard that before? CFS has long comprised a mystery ailment, and for that reason patients are sometimes suspected of malingering or having psychiatric problems rather than genuine physical ones. Yet there is an objective foundation to build the case for the reality of CFS, with symptoms such as swollen/enlarged lymph nodes, sore throat, cognitive impairment, headache, mental and physical exhaustion, muscle and joint pains, and tiredness following activity, in addition to fatigue that lasts for more than six months, leading to disability and a condition that does not improve with rest. For those so stricken, CFS is a health nightmare.


For those so stricken,
chronic fatigue syndrome is a
health nightmare.


And we don’t have many clues; to date there have been no substantiated conclusions concerning the etiology (origination) of the syndrome. While fatigue is a common symptom in many illnesses, CFS is a multi-systemic disease. Thus, CFS patients may report additional symptoms including muscle weakness, hypersensitivity, orthostatic intolerance (a disorder of the autonomic nervous system, occurring when an individual stands up), digestive disturbances, depression, poor immune response, and cardiac and respiratory problems. It is unclear if these symptoms represent co-morbid conditions or are produced by an underlying etiology (causality) of CFS. All diagnostic criteria require that the symptoms must not be caused by other medical conditions.

Without causal explanation, the illness is intensely frustrating to doctors because there is no effective (or even suggested) treatment, no diagnostic laboratory test or biomarker, and many patients are sick for a long time. It is sad to say that between 1 and 4 million Americans are affected,1 and often so badly that their lives practically grind to a halt.

Purported Identification of CFS Cause

The syndrome, which reverberates around the world, strikes many millions more, so a recent article in the New York Times about a possible cause for CFS was welcomed . . . at least at first.2 In this piece, referencing a paper published in the journal Science,3 the Times reports that out of a group of 101 individuals with the syndrome, 67 percent were infected with an infectious virus, known as XMRV (a retrovirus and a member of the same family of viruses as the AIDS virus), and that in comparison only 3.7 percent of 218 healthy people were infected. According to the Times, after the Science article was published, continued work by the authors found the virus in nearly 98 percent of about 300 patients with the syndrome. Good news? Not entirely (and maybe not at all). Although the tendency has been to look for a viral cause for CFS because of the influenza association, a current article in PLoS found that scientists who tried to duplicate the experiment were unable to confirm it, instead finding no such relationship.4

A commentary in Science expressed chagrin: “Here we go again. The search for the cause of chronic fatigue syndrome, which just months ago seemed to be gaining traction, now seems likely to descend into the same confusion and acrimony that characterized it for years, as a supposed viral link to CFS published just last autumn might be unraveling.”5

Evidence for a Cholinergic Deficit Connection

For unknown reasons CFS occurs most often in people in their 40s and 50s, more often in women than men, and is less prevalent among children and adolescents. Full recovery from the condition occurs in only 5–10% of cases, meaning that once you get it, life is likely to never be the same again.


The search for the cause of
chronic fatigue syndrome, now seems
likely to descend into the
same confusion and acrimony that
characterized it for years.


That said, there is new hope for victims of this terrible malady with new evidence for identifying the cause—or a least what may be a significant portion of the cause—as cholinergic deficit. Until now, this has been just a hypothesis. For starters, in an uncontrolled study conducted 15 years ago, galantamine was administered to CFS patients with slight psychiatric features for two weeks at a dose of 10 mg/day, and it was reported that fatigue, sleep disorder, and myalgia (muscle pain) symptoms improved significantly.6 Following this, in 2004, another paper investigating the effect of galantamine (at either 2.5, 5, 7.5 or 10 mg/day) for CFS was published.7 However, the investigation’s trial did not demonstrate any benefit of galantamine over placebo in the treatment of patients with CFS. Despite the failure to show, the researchers concluded that there was some evidence to suggest that further trials might prove valuable.

A New Day for Chronic Fatigue?

Picking up the baton of the earlier research, a recent study published in Psychiatry Investigation of work done at Erciyes University Medical School in Kayseri, Turkey by Tayfun Turan, MD, et al. has found that the objective mental fatigue, cognitive disorders and sleep disturbances seen in CFS may be attributed to cholinergic deficit and galantamine may help to alleviate these conditions.8

Essentially, the researchers found that a functional deficiency of cholinergic neurotransmission* may cause the hypothalamic-pituitary-adrenal (HPA) axis hypoactivity seen in CFS, a stress-related disorder, and prevent adequate stress management. When CFS patients were given the selective acetylcholinesterase inhibitor galantamine, at 8 mg/day for 4 weeks, the deficiency was rectified through normalization of HPA axis activity.


* The cholinergic neurotransmission system involves the neurotransmitter acetylcholine. The parasympathetic nervous system is entirely cholinergic. Also influenced are neuromuscular junctions, preganglionic neurons of the sympathetic nervous system, the basal forebrain, and brain stem complexes. And much more.

† The HPA axis governs direct influences and feedback interactions among the hypothalamus, the pituitary gland, and the adrenal glands. Altogether, the complex interactions among these organs comprise the HPA axis, a significant part of the neuroendocrine system, the prime responsibilities of which are the control of stress and the regulation of a wide variety of body processes, such as the immune function, digestion, and energy storage and expenditure, along with mood, emotions, and sexuality.


Using 29 untreated CFS patients and 20 healthy controls, the basal levels of cortisol and DHEAS (dehydroepiandrosterone sulfate) were measured according to Centers for Disease Control criteria. The pre-treatment basal cortisol levels of the patients were significantly lower than those of the controls. In the patient group, four weeks after galantamine treatment, cortisol and DHEAS levels were measured again. After the treatment, 22 patients who stayed in study were divided into two subgroups as responders and nonresponders according administered tests.


CFS occurs most often in
people in their 40s and 50s,
more often in women than men.


In the responders to treatment with galantamine (10 out of 22), pretreatment basal DHEAS levels and DHEAS/cortisol molar ratios were higher than the controls. This led to the conclusion that CFS patients who started with high levels of stress might be an indicator of their responsiveness to treatment. Furthermore, the findings that galantamine can normalize stress management gives support to the cholinergic deficit hypothesis in CFS. Galantamine did not alter cortisol levels.

Galantamine treatment did not provide benefits for CFS patients who had lower cortisol levels at baseline. Rather, the benefits were chalked up to those with higher initial DHEAS values and higher DHEAS/cortisol molar ratios. Galantamine succeeded in normalizing these after 4 weeks of treatment at 8 mg/day. There have been other studies showing that patients with CFS suffer HPA axis dysregulation, along with adrenal insufficiency and especially the underproduction of cortisol (hypocortisolism). However, it is not clear whether low cortisol levels and HPA dysfunction in CFS are a cause or result of the illness.

HPA Changes are Part and Parcel to CFS

When the findings of the Turan et al. study are accounted for, the researchers believe that they can infer that HPA changes for those with CFS are part and parcel to the disease. However, once again, they could not conclude that these HPA disturbances were cause or consequence of the syndrome. It is interesting to note that the mere reduction of HPA axis activity has also been blamed for some of the symptoms of CFS. These include headaches, reduced energy, and post-exertional malaise. In another study referenced by the Turkish researchers, hydrocortisone therapy found substantial benefits for fatigue, indicating the plausibility that hypocortisolism is a defining part of CFS.

The researchers point out that they were not alone in their finding that galantamine did not alter cortisol level; the 2004 study by Blacker et al. also found that to be true. This led to the question of why, although cortisol levels remained lower throughout the galantamine treatment, in some CFS patients there was some symptomatic improvement. It may be that when there is a functional deficiency of cholinergic activity, the result may downregulate HPA axis activity under stress conditions. This may play a pathophysiological role in CFS.


The objective mental fatigue,
cognitive disorders and
sleep disturbances seen in CFS
may be attributed to cholinergic
deficit and galantamine may help to
alleviate these conditions.


We know that cholinergic neurotransmission is intimately involved in growth hormone stimulation and insulin-like growth factor 1 (IGF-1) secretions. These are involved in the regenerative functions of the peripheral nerves and skeletal muscles. Increased cholinergic activity by galantamine might trigger well-being completely apart from cortisol levels in some patients, indicating that in these patients it might not be necessary to normalize cortisol levels to bring about relief from the syndrome. What is needed is long-term follow-up to understand the role of cortisol levels in CFS. In some CFS patients, other types of dysregulation involving other part cholinergic system, along with dysregulation of the HPA axis, could be involved.

The Importance of DHEAS Levels

Remember that galantamine did not alter cortisol levels, which were low at baseline and after treatment. However, although it is counterintuitive—given what we know about DHEA—DHEAS levels declined with treatment, while DHEAS/cortisol molar ratios were elevated after treatment. This suggests that there may be a disturbance in the “metabolic shift” from androgens (one of which is DHEAS) to glucocorticoids (both are synthesized in the adrenal cortex).

In this context, DHEA/cortisol and DHEAS/cortisol molar ratios have been shown to reflect the homeostasis between androgens and glucocorticoids at the adrenal level. In one study, performed in CFS patients without psychiatric comorbidity, researchers found that DHEA and DHEAS levels were lower than in healthy controls, suggesting that mild adrenal cortical failure, secondary to adrenocorticotropic hormone (ACTH) deficiency, could explain this finding.9 The researchers of this study did not find any difference between CFS patients, depressives, and healthy controls regarding basal cortisol levels.

Hydrocortisone Lowers DHEAS Levels Too

Another study demonstrated that even when basal DHEA levels were normal, DHEA responses to ACTH stimulation were muted in CFS patients.10 Unfortunately, cortisol levels were not reported. There were higher basal DHEA levels in CFS patients with no psychiatric comorbidity versus healthy controls in a study conducted by Cleare et al.; however, DHEAS levels differences were not reported.11 Furthermore, the researchers found no differences between patients and controls with respect to cortisol/DHEA molar ratios. When the investigators gave low dose hydrocortisone to CFS patients, there were significant decreases in DHEA levels in patients reporting fatigue reduction with treatment. DHEAS were lowered also after hydrocortisone treatment.

Back to the Turkish study (Turan et al.), the researchers also found lower DHEAS levels after galantamine treatment in CFS patients. In their interpretation, the acetylcholinergic effect of galantamine facilitates the release of corticotropin-releasing hormone which in turn causes DHEAS levels to decrease through recovering the existing tentative disturbance in metabolic shift from cortisol to DHEAS. Whew!

Higher Cortisol/DHEA Molar Ratios as Best Indicators

Other studies have reported low and some normal morning DHEAS levels in CFS patients. There has even been a report of slightly high DHEA levels in CFS patients, and in another study, involving 140 female CFS patients, DHEAS levels were reported as 20% above the reference limit.12 In Turan et al., increased pre-treatment DHEAS/cortisol molar ratio may have been due to either impaired HPA axis activity and decreased cortisol levels, or a defect in metabolic shift from androgen to glucocorticoid production. It is possible that literature findings about higher cortisol/DHEA molar ratios in major depression were the best indicators of excessive cortisol exposure of the brain.

On the other hand, the finding of high DHEAS/cortisol molar ratios in Turan et al. could precipitate additional decreases in the effects of low cortisol on the brain, but only basal levels were investigated. The differences of all the studies might be attributed to the differences in clinical characteristics, methodological differences (such as the timing of blood sampling or laboratory techniques), and other factors that might affect functions of the HPA axis, such as inactivity. It was an advantage of the Turan et al. study to include pure and untreated CFS patients.

Responders and Non-Responders to Treatment

Figure 1. Basal serum DHEAS values of responders and
non-responders before and after treatment and the controls.
The patients in the Turan et al. study were divided into two subgroups, as responders and non-responders to treatment. As has been noted, pretreatment basal DHEAS levels and DHEAS/cortisol molar ratios of the responders were significantly higher than those of the controls. (See Fig. 1.) What was especially interesting was the finding that the levels and ratios of the non-responders were similar to the controls, findings that are unique in the literature.

An Indicator of the Responsiveness to Treatment

Indeed, the high pre-treatment basal DHEAS levels and DHEAS/cortisol molar ratio in responders along with the decrease in DHEAS levels with galantamine treatment in all CFS patients—and especially in responders—may ring the proverbial bell. High pre-treatment DHEAS levels and DHEAS/cortisol molar ratio in responders may be due to hypocortisolism that might be characteristic of CFS. Hypocortisolism was improved with treatment, and that fact alone might provide a return to the normal DHEAS pattern. But the researchers did not observe any significant increase in cortisol levels, suggesting that a longer period of time might be needed for such a finding. A possible explanation is that some abnormalities in the metabolic pathway of DHEAS might lead to higher pre-treatment DHEAS synthesis. Moreover, normalization of high DHEAS levels in responders may be secondary to improvement in some clinical features such as sleep disturbances, anxiety or some depression symptoms, which may occur in these patients.

Strong Support for the Cholinergic Deficiency Hypothesis

In fact, the positive correlation between reduction of DHEAS levels with galantamine treatment and recovery in clinical depression and anxiety scales only in respondent patients offers strong support for the cholinergic deficiency hypothesis. Another contributing reason is that abnormal glucocorticoid receptor sensitivity may improve with treatment and production may shift from DHEAS to cortisol. Finally, the cholinergic effect of galantamine that facilitates release of corticotropin-releasing hormone may cause reduction in DHEAS levels and the normalization of high DHEAS/cortisol molar ratio. The short duration of the experimental treatment may not have been sufficient to show these changes.

How to Make the Study Better

Limitations of the study include the small number of patients and the absence of placebo control group, which might have prevented the identification of more accurate therapeutic and hormonal effects of galantamine. Also, the short duration of the treatment might obscure the long-term effects of galantamine on fatigue scores or on the hormones, such as cortisol.

In summation, decreases in basal DHEAS levels and DHEAS/cortisol molar ratios in CFS patients with galantamine treatment promote the hypothesis that cholinergic deficit may be present in CFS. Also, the DHEAS findings of responders suggest that high pre-treatment values of this hormone may be an indicator of the treatment responsiveness. If DHEA and DHEAS levels play an important role in CFS physiopathology, Turan et al. think that the evaluation of DHEAS levels with response to stressors such as exercise or social stress in future studies will add additional facets of understanding.

Rays of Light for CFS

At this time, it may not be a new day for CFS, but at least some rays of light are creaking through. If you or a loved one is afflicted with CFS, it may be a good idea to test your DHEAS levels and DHEAS/cortisol molar ratios, to determine whether you are a good candidate for galantamine treatment. Yet because about half of the test subjects were responders, alternatively, you could try galantamine and see what it does, which at the levels indicated (8 mg/d for 4 weeks) has an excellent safety record.

References

  1. Centers for Disease Control and Prevention. Chronic Fatigue Syndrome Page. http://www.cdc.gov/cfs. Updated April 28, 2009. Accessed January 14, 2010.
  2. Grady D. Virus is found in many with chronic fatigue. New York Times, October 8, 2009.
  3. Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome. Science 2009 Oct 23;326(5952):585-9.
  4. Erlwein O, Kaye S, McClure MO, Weber J, Wills G, Collier D, Wessely S, Cleare A Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PLoS One. 2010 Jan 6;5(1):e8519.
  5. Kean S. An indefatigable debate over chronic fatigue syndrome. Science 2010 Jan 15; 327(5963):254-5.
  6. Snorrason E, Geirsson A, Stefansson K. Trial of a selective acetylcholinesterase inhibitor, galantamine hydrobromide, in the treatment of chronic fatigue syndrome. J Chron Fatigue Syndr 1996;2:35-54.
  7. Blacker CV, Greenwood DT, Wesnes KA, Wilson R, Woodward C, Howe I, Ali T. Effect of galantamine hydrobromide in chronic fatigue syndrome: a randomized controlled trial. JAMA 2004 Sep 8;292(10):1195-204.
  8. Turan T, Izgi HB, Ozsoy S, Tanriverdi F, Basturk M, Asdemir A, Besirli A, Esel E, Sofuoglu S. The Effects of Galantamine Hydrobromide Treatment on Dehydroepiandrosterone Sulfate and Cortisol Levels in Patients with Chronic Fatigue Syndrome. Psychiatry Investig 2009 Sep;6(3):204-10.
  9. Scott LV, Salahuddin F, Cooney J, Svec F, Dinan TG. Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health. J Affect Disord 1999;54:129-137.
  10. De Becker P, De Meirler K, Joos E. Attenuated DHEA response to i.v. ACTH injection in patients with chronic fatigue syndrome. Poster Communication, 1st World Cong. On Chronic Fatigue Syndrome and Related Disorders, Brussels;1995.
  11. Cleare AJ, O’Keane V, Miell JP. Levels of DHEA and DHEAS and responses to CRH stimulation and hydrocortisone treatment in chronic fatigue syndrome. Psychoneuroendocrinology 2004;29:724-32.
  12. Goldberg M, Lichten J. High androgen levels in chronic fatigue patients. J Clin Endocrinol Metab 1995;80:3390-1.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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