Serotonin in CFS/ME & FM

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" Serotonin in Chronic Fatigue Syndrome & Fibromyalgia "

by Melvyn R. Werbach, Townsend Letter for Doctors and Patients

Nov. 2001

While the picture is far from clear, serotonin metabolism appears to play a role

in both chronic fatigue syndrome (CFS) and fibromyalgia -- although the

nature of that role appears to differ.

Tryptophan is the dietary precursor to serotonin and, for fibromyalgia, there is

some evidence that tryptophan levels are depressed. For example, in a study

of fibromyalgia patients suffering from severe pain, plasma free tryptophan

levels were inversely related to the severity of their pain. [1] Moreover, when

fibromyalgia patients were compared to normals, plasma tryptophan levels

tended to be lower in the patient group, and their transport ratio of tryptophan

to the other competing amino acids was significantly decreased, suggesting

that brain serotonin levels may also be depressed. [2]

Does the administration of a serotonin precursor help patients with

fibromyalgia? In the general population, tryptophan supplementation usually

provides a mild degree of analgesia. Moreover, it may be especially effective

for the subset of chronic pain patients with a disorder of serotonergic

transmission. [3]

As to fibromyalgia, a group of 50 patients received 100 mg 3 times daily of 5-

hydroxytryptophan, the metabolite of tryptophan and immediate precursor of

serotonin, in an open trial. After 3 months, nearly half of the group had a fair

to

good degree of overall improvement. There were highly significant

improvements in fatigue, the number of tender points, pain intensity, anxiety

and sleep quality. [4] These results were similar to those of an earlier double-

blind study by the same group of investigators, [5] and suggest that

fibromyalgia patients may respond to L-tryptophan supplementation similarly

to other patients suffering from anxiety, depression, insomnia and pain.

Turning to CFS, at least 3 studies have found L-tryptophan to be depressed in

the plasma of CFS patients [6-8] -- a finding already noted in fibromyalgia

patients. However, in contrast to fibromyalgia, there is evidence that OFS is

marked by serotonergic hyperactivity. One study found not only that CFS

patients had higher baseline plasma tryptophan levels, but also that these

levels failed to rise and fall normally during exercise, causing the researchers

to speculate that an abnormally high level of brain serotonin may cause the

persistent central fatigue. [9] (In healthy subjects, L-tryptophan

administration

can cause central fatigue. [10]) Moreover, several other studies have also

found evidence of increased serotonergic activity in CFS patients. " [11-14]

If CFS is marked by serotonergic hyperactivity, then medications that block

serotonin receptors may be beneficial. Indeed, a small pilot study found that

the use of serotonin (5-HT3) receptor antagonists was followed by at least a

35% improvement in about one-third of patients. [15]

Would nutritional supplements be equally effective while having less danger

of adverse side effects? The efficacy of nicotinamide adenine dinucleotide

(NADH), the reduced coenzyme form of niacin, has been investigated in a

double-blind crossover study. At baseline, CFS patients were found to have

elevated urinary concentrations of 5-hydroxyindoleacetic acid, the major

metabolite of the neurotransmitter serotonin. They received 10 mg daily of

NADH or placebo. Not only was NADH significantly more effective in reducing

CFS symptoms than placebo, but the elevated 5-HIAA levels dropped to

normal -- suggesting that the efficacy of NADH could well be due to an ability

to normalize serotonergic hyperactivity. [16]

Perhaps other nutritional approaches that reduce brain serotonin levels

would also be effective. For example, CFS patients could be placed on a low-

tryptophan diet, or they could be supplemented with the essential amino acids

that compete with tryptophan for brain uptake (phenylalanine, tyrosine,

leucine, isoleucine, and valine). Hopefully, researchers will eventually pursue

these lines of investigation.

Doctor Werbach cautions that the nutritional treatment of illness should be

supervised by physicians or practitioners whose training prepares them to

recognize serious illness and to integrate nutritional interventions safely into

the treatment plan.

References

(1.) Moldofsky H, warsh JJ. Plasma tryptophan and musculoskeletal pain in

non-articular rheumatism ('fibrositis syndrome'). Pain 5(1):65-71, 1978

(2.) Yunus MB et al. Plasma tryptophan and other amino acids in primary

fibromyalgia: a controlled study. J Rheumatol 19(1):90-4, 1992

(3.) Liberman HR et al. Mood, performance and pain sensitivity: Changes

induced by food constituents. J Psychiatr Res 17(2):135-45, 1982-3

(4.) Puttini PS, Caruso I. Primary fibromyalgia syndrome and 5-hydroxy.L-

tryptophan: a 90-day open study. J Int Med Res 20(2):182-9, 1992

(5.) Caruso I et al. Double-blind study of 5-hydroxytryptophan versus placebo

in the treatment of primary fibromyalgia syndrome. J Int Med Res 18(3):201-9,

1990

(6.) Bralley JA, Lord RS. Treatment of chronic fatigue syndrome with specific

amino acid supplementation. J Appl Nutr 46(3):74-8, 1994

(7.) Rigden S. Entero-hepatic resuscitation program for CFIDS. The CFIDS

chronicle, Spring, 1995:46-8

(8.) Vassallo CM et al. Decreased tryptophan availability but normal poot-

synaptic 5-HT2c receptor sensitivity in chronic fatigue syndrome. Psychol Med

31(4):585.91, 2001

(9.) Castell LM et al. The role of tryptophan in fatigue in different conditions

of

stress. Adv Exp Med Biol 467:697-704, 1999

(10.) Cunliffe A et al. A placebo controlled investigation of the effects of

tryptophan or placebo on subjective and objective measures of fatigue. Eur J

Clin Nutr 52:425-30, 1998

(11.) Bakheit AM et al. Possible upregulation of hypothalantic 5-

hydroxytryptamine receptors in patients with postviral fatigue syndrome. BMJ

304:1010-12, 1992

(12.) Cleare AJ et al. Contrasting neuroendocrine responses in depression

and chronic fatigue syndrome. J Affect Disard 34:283-9, 1995

(13.) Sharpe M et al. Increased brain serotonin function in men with chronic

fatigue syndrome. BMJ 315:164-5, 1997

(14.) Demitrack MA et al. Plasma and cerebrospinal fluid monoamine

metabolism in patients with chronic fatigue syndrome: preliminary findings.

Biol Psychiatry 32:1066-77, 1992

(15.) Spath M et al. Treatment of chronic fatigue syndrome with 5-HT3

receptor antagonists -- preliminary results. Stand J Rheumatol Suppl 113:72-

7, 2000

(16.) Forsyth LM et al. Therapeutic effects of oral NADH on the symptoms of

patients with chronic fatigue syndrome. Ann Allergy Asthma Immunol 82:185-

91, 1999

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