Letter to the Editor - Letter to the Editor

Alternative Medicine Review, Feb, 2001 by Alan C. Logan

Editor:

I would like to comment on the article written by Dr. Melvyn Werbach, "Nutritional Strategies for Treating Chronic Fatigue Syndrome."[1] While this is an excellent article, summarizing most of our current knowledge related to nutritional intervention in chronic fatigue syndrome (CFS), the section on L-tryptophan needs to be addressed.

With very few references, most of which are related to fibromyalgia, Dr. Werbach discusses the therapeutic value of L-tryptophan and 5-hydroxytryptophan. The author begins his consideration based on one peer reviewed study which shows a decrease in plasma L-tryptophan.[2] This follows with a reference to low levels of plasma tryptophan among fibromyalgia (FM) patients, perhaps indicating low levels of brain serotonin.[3]

While there is considerable symptom overlap between CFS and FM, it is important to note that the brain, pituitary, and adrenal neuroendocrine abnormalities of the two illnesses are not only different, they appear virtually opposite.[4] Regarding serotonin and FM, there is evidence which points to lower serotonergic activity,[5,6] but this does not appear to be the case in CFS. Researchers have found evidence of increased serotonergic activity in CFS through buspirone challenge (a serotonin agonist)[7] and D-fenfluramine administration (a serotonin reuptake inhibitor).[8,9] In addition, investigators have also found elevated levels of the serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA) in both plasma[10] and urine.[11] These findings also point to increased serotonergic activity.

Recent research has shown that baseline plasma tryptophan is higher among CFS patients and does not rise and fall with exercise as it does in normal controls. The authors in this study suggest an abnormally high level of brain serotonin leading to persistent fatigue.[12] It has also been found that the placebo-controlled administration of tryptophan (30 mg/kg) to healthy volunteers can lead to increased subjective and objective central fatigue.[13] This is important as it is the central fatigue which has been implicated in CFS, and the administration of branched chain amino acids (BCAA) has been suggested to lower plasma tryptophan and alleviate fatigue.[12]

In examining the specific symptoms of CFS, one can observe additional evidence for the involvement of peripheral serotonin. In a 1996 study, Komaroff et al examined common CFS symptoms in a group of 281 patients. They found 35 percent of patients experienced anorexia, 31 percent diarrhea, and 58 percent nausea.[14] This is of note as 90 percent of serotonin lies in the periphery, specifically the GI mucosa.[10] Here the serotonin receptor activity can account for and mediate all of the above mentioned symptoms.[15-17]

Increased serotonin activity is also thought to account for the allergic responses often observed in CFS.[10,11] Dr. Werbach mentioned the therapeutic benefit of oral nicotinamide adenine dinucleotide (NADH, niacinamide metabolite). In a study published in Annals of Allergy, Asthma and Immunology, oral NADH resulted in improvements in CFS symptoms, correlated with reductions in the 5-HIAA metabolite.[11] It appears that certain CFS patients do well with treatment that leads to reductions in serotonergic turnover.

If, as Dr. Werbach speculates, there is low serotonin activity, one would expect at least a significant improvement using selective serotonin reuptake inhibitor medications. In a study published in Lancet, Vercoulen et al found no improvement in CFS depression or quality of life when fluoxetine was compared to placebo.[18] A second trial of 136 patients using fluoxetine made no statistically significant improvement in the primary outcome measure of CFS fatigue.[19]

The evidence of over activity of the serotonin system in CFS has led investigators to study the use of medications that block serotonin receptors. A small preliminary study has shown that serotonin (5-HT3) receptor antagonists can be of benefit to CFS patients (35% [is greater than or equal to] improvement in approximately 33% of patients).[20] Larger studies will need to follow in order to properly evaluate this as a therapeutic tool.

Dr. Werbach makes reference to tryptophan being broken down by infectious disease processes. It is interesting to note that those who responded most markedly to serotonin receptor blockage in the above study were those who accurately reported post-infectious onset of illness. His speculation that gamma interferon is causing enhanced degradation of tryptophan is unlikely in CFS as numerous studies have reported normal levels of gamma interferon in these patients.[21-24]

The reason for increased serotonergic activity remains unclear, however it is likely due to one or more of the following factors: an increase in uptake of tryptophan through the blood brain barrier, an increase in serotonin production, upregulation of serotonin receptors, or increased availability in the pre-synaptic cleft. It is anticipated that research will shed light on serotonin and CFS pathophysiology.