Controversy Erupts About Safety of 5-HTP 

This article first appeared in the 
March, 1997 
issue of VRP's Nutritional News 

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Read "5-Hydroxytryptophan: The Serotonin Solution" to learn more about 5-HTP and depression.

Controversy Erupts About Safety of 5-HTP
James South

Last month, a "WARNING ABOUT 5-HYDROXYTRYPTOPHAN" was mailed to many members of the life extension/nutritional supplementation community. This "Warning" alleges that little, if any, benefit is to be gained through use of 5 -Hydroxytryptophan (5-HTP), and that anyone using it is actually risking death! 

What are the claims made against 5-HTP in this "Warning", and what can be said about the relevance and truth of these allegations? 

The "Warning" claims that 5-HTP should be used (if at all) only with a peripheral decarboxylase inhibitor (PDI). Yet large numbers of studies reviewed by Zmilacher et al (1) found 5-HTP more effective without PDI's than with them and with fewer and less serious side effects. Zmilacher's own study of 5-HTP both with and without a PDI reported in the same article found notably more, and more serious, side effects from 5-HTP when combined with a PDI. Thus, the relevant scientific literature simply does not support the claim that 5-HTP is neither safe nor effective without a PDI. 

The "Warning" claims that without a PDI most or all of the 5-HTP will be converted to serotonin in the bloodstream outside the brain; and since serotonin does not cross the blood-brain barrier, this would nullify any hoped-for brain benefit from 5-HTP. Yet successful studies (only some of many published) using 5-HTP without a PDI (1,2,4,6,11) clearly refute this contention. Furthermore, studies infusing tryptophan or 5-HTP directly into the bloodstream of human subjects have been performed, and these studies have not found any increase in blood serotonin caused by increased blood 5-HTP. Thus, one report states: "Six healthy male subjects received ... 5-hydroxy-L-tryptophan (5-HTP) ... on two occasions in a randomized cross-over study. There were marked increases in urinary 5-HTP and 5-HT [serotonin] excretion after infusion of [5-HTP] ... . This occurred without significant changes in blood 5-HT [serotonin] levels measured in platelet-rich plasma." (23) Another report using intravenous tryptophan infusion stated: " ... 5-hydroxy-Trp [5-HTP] rose rapidly and massively after Trp[tryptophan] infusions, at the 5 g dose more than ... 20-fold[!] ... and declined rapidly to about 5-fold baseline levels within 2 hours. Whole blood serotonin levels were almost unaffected by the Trp [tryptophan] infusions [in spite of the massive conversion of the tryptophan to 5-HTP in the blood]." (24) Thus, both clinical studies and blood serotonin measurements in response to dramatically increased blood 5-HTP levels fail to support the "Warning" claims that 5-HTP without PDI will only elevate blood serotonin and not brain serotonin levels. 

The "Warning" circulating in the life extension/nutrition community also states that the high blood levels of serotonin (allegedly) ensuing from using 5-HTP without PDI, would cause blood platelets to clot up, triggering a heart attack, or cause a spasm of heart arteries (coronary artery vasospasm), also triggering a heart attack. Again, if this were a real-world-problem, then the many test subjects taking 5-HTP without PDI's should have suffered numerous heart attacksyet nowhere is this mentioned in the vast literature on 5-HTP! It should be noted here that platelet -aggregation and vasospasm heart attacks can be triggered in moments, even in perfectly healthy and non-occluded arteries. Thus, even a single dose of 5-HTP, not to mention weeks or months of 5-HTP use, would be sufficient to elicit a heart attack, if this were really a serious problem. As Byerley et al note in a major review article on 5-HTP use: "Researchers who reported on the results of various laboratory functions (hematologic [i.e., blood], liver, kidney, etc.) found that 5 -HTP caused no significant changes ... . Oral administration of 5-HTP, with or without carbidopa [a PDI], is associated with few adverse side effects." (2) As Poeldinger et al note: "In general, 5-HTP-induced adverse events worthy of note are rare within the therapeutic dosage range." (4) 

Those concerned about even the theoretical possibility of 5-HTP use triggering platelet-aggregation heart attacks or coronary artery vasospasm heart attacks may minimize any such risks through a nutrient supplement program that specifically inhibits these two problems (which, of course, can and do occur in people who never take 5-HTP). According to MelvynWerbach, M.D., 1 gm of vitamin C three times daily, 400 - 600 iu vitamin E daily, 500 -1000 mg calcium daily, 400 - 600 mg magnesium daily, 200 mcg selenium daily, and 1.5 gm EPA from fish oil daily will significantly reduce risk of platelet -aggregation and vasospasm heart attacks. (27,28) 

The "Warning" also claims that Americans' use of vitamin B-6 supplements further worsens 5-HTP's (alleged) danger, since B-6 activates the enzyme that could convert 5-HTP to serotonin in the bloodstream. Yet experiments with monkeys (18) and rats (19) fed even "moderate excess" amounts of B-6, increased brain serotonin production up to 60%an impossible finding if B-6 would cause the bulk of ingested 5-HTP to be prematurely converted to serotonin outside the brain. And College Pharmacy of Colorado, one of America's premier mail-order compounding pharmacies, has been selling (by prescription) a 100 mg 5-HTP with 12.5 mg B-6 (and no PDI) since 1990 with no problems. 

The "Warning" also offers the scary scenario that a rare type of serotonin-secreting tumor, called "hind-gut carcinoid," may also be associated with fibrosis of the heart muscle and heart valves, and heart failure. However, the "Warning" offers no evidence (and doesn't really claim, but merely implies) that taking 5-HTP supplements at reasonable doses would actually cause these tumors, or the heart damage occasionally associated with them (one study found 19 out of 604 carcinoid patients with high blood serotonin and valvular heart damage). (20) Furthermore, studies of carcinoid heart patients have been done which find no correlation between blood levels of serotonin and the heart disease sometimes found with carcinoid syndrome. Thus one report notes: "We have also studied the correlation between plasma hormone levels (e.g., 5-hydroxytryptamine {5-HT} [serotonin] and substance P) and the degree of cardiac involvement... No correlation between blood levels of 5-HT or substance P and heart involvement was found." (25) Another report states: "Analysis of the data shows that unlike animal models, there is no difference in serum serotonin and urinary 5 hydroxyindole acetic acid [the chief serotonin metabolite] levels in patients with carcinoid syndrome with or without cardiac involvement" (26) Nonetheless,prudence suggests that in those rare individuals suffering metastatic carcinoid disease, 5-HTP use should probably be undertaken only with a physician's recommendation and supervision. 

The same paragraph mentions a "tribe of South Sea islanders with right heart fibrosis as a result of eating green banana mush, which poisons them with its serotonin content." Firstly, it should be noted that 5-HTP is not serotonin, and the brain's rapid absorption of 5-HTP from the blood provides an "escape hatch" from the bloodstream for ingested 5-HTP, before it can be converted to serotonin in the blood. If preformed serotonin were ingested and absorbed (as from the "green banana mush"), it would not have this same "brain escape hatch" to remove it from the blood. When high serotonin diets have actually been studied, (21) increases of blood serotonin have been neither consistent, nor as high as that seen in the carcinoid patients. 

Lastly, the "Warning" asserts that taking 5-HTP is safe only if one has regular tests to determine urinary levels of 5-hydroxyindole acetic acid (5HIAA). 5HIAA is the chief breakdown metabolite of serotonin. The "Warning" asserts 5-HTP is safe only if urinary 5HIAA levels remain low. Yet the 1992 Italian obesity study11 which used 900 mg 5-HTP daily (without PDI) for 12 weeks found a 50-fold increase in urinary 5HIAA compared to the placebo-control patients. It also found no blood chemistry abnormalities in the 5-HTP group and no difference in side effects between the 5-HTP and placebo patients. The study concluded by stating: "... the good tolerance to 5-HTP treatment observed suggest[s] that this substance may be safely used in the long-term treatment of obesity." The "Warning" claims that "Some people ... could suffer from a lethal serotonin peripheral overload [from 5-HTP ingestion]." Yet in the hundreds of papers published on 5-HTP during the past 30 years, I have not been able to uncover a single reported incident of death or serious injury from oral 5-HTP use. The "Warning" also does not cite even a single published medical reference to any such presumed death or injury. 

In summary, the anti-5-HTP allegations made by the "Warning" are falsified by the vast body of published scientific literature on 5-HTP. The main side effect occasionally experienced by 5-HTP users reported in the scientific literature is gastrointestinal (GI) upsetgas, nausea, diarrhea, and cramping. This GI upset happens only to a minority of users, and even then, only occasionally. It usually lessens or disappears in the first few days or weeks of use. The published studies also indicate that taking 5-HTP with food (i.e., partway through a meal or snack) also minimizes the risk of GI upset. Starting with a low dose (25-50 mg) and increasing the dose slowly (every 3 - 5 days) up to a maximum of 200 - 300 mg daily will also minimize risk of GI upset. Total daily intake should be divided into 2 - 4 doses, with no more than 100 mg per dose. Those suffering from gut disorders, such as ulcers, irritable bowel disease, Crohn's disease, celiac disease (sprue), etc., and those with just an extremely "sensitive" GI tract, should probably use 5-HTP with great caution, or not at all. The use of aloe vera juice/gel and/or ginger extracts may lessen or eliminate the occasional GI side effects of 5-HTP. 

A final note of caution: 5-HTP may intensify the effects of various antidepressant drugs. Van Praag notes that 5-HTP combined with the tricyclic antidepressant clomipramine proved more effective than clomipramine alone. (22) Yet because of the potentially powerful but unpredictable synergy to increase brain serotonin when 5-HTP is combined with serotonin-potentiating drugs, those using MAO-inhibitor drugs, tricyclic antidepressants, SSRI's such as Prozac, Paxil or Zoloft, and the diet drugs Pondimin (DL-fenfluramine) or Redux (D-fenfluramine), should use 5-HTP only with medical supervision. Similarly, those wishing to reduce or eliminate their serotonin-potentiating drugs with 5-HTP, should do so only with medical supervision. 

References

1. K. Zmilacher, et al. L-5-Hydroxytryptophan Alone and in Combination with a Peripheral Decarboxylase Inhibitor in the Treatment of Depression. Neuropsychobiology. 1988; 20: 28-35. 

2. W. Byerley, et al. 5-Hydroxytryptophan: A Review of Its Antidepressant Efficacy and Adverse Effects. J Clin Psychopharmacol 1987; 7: 127-37. 

3. S. Risch and C. Nemeroff. Neurochemical Alterations of Serotonergic Neu ronal Systems in Depression. J Clin Psychiatry. 1992; 53: 3-7. 

4. W. Poeldinger, et al. A Functional-Dimensional Approach to Depression: Serotonin Deficiency as a Target Syndrome in a Comparison of 5 -Hydroxytryptophan and Fluvoxamine. Psychopathology. 1991; 24: 53-81. 

5. H. van Praag. Management of Depression with Serotonin Precursors. Biol Psychiatry. 1981; 16: 291-310. 

6. S Takahashi, et al. Effect of L-5-Hydroxytryptophan on Brain Monoamine Metabolism and Evaluation of Its Clinical Effect in Depressed Patients. Psychiat Res 1975; 12: 177-87. 

7. R. Kahn and H. Westenberg. L-5-Hydroxytryptophan in the Treatment of Anxiety Disorders. J Affect Disord, 1985; 8: 197-200. 

8. V. Linnoila and M. Virkkunen. Aggression, Suicidality, and Serotonin. J Clin Psychiatry. 1992; 53: 46-51. 

9. L. Buydens-Branchey, et al. Age of Alcoholism Onset. II. Relationship to Susceptibility to Serotonin Precursor Availability. Arch Gen Psychiatry. 1989; 46: 231-36. 

10. J. Wurtman. Carbohydrate Craving, Mood Changes and Obesity. J Clin Psychiatry. 1988; 49: 37-39. 

11. C. Cangiano, et al. Eating Behavior and Adherence to Dietary Prescrip tions in Obese Adult Subjects Treated with 5-Hydroxytryptophan. Am J Clin Nutr 1992; 56: 863-7. 

12. D. Murphy et al. Obssessive-Compulsive Disorder as a 5-HT Subsytem -Related Behavioural Disorder. Bri J Psychiatry. 1989; 155: 15-24. 

13. C. Maurizi. The Therapeutic Potential for Tryptophan and Melatonin: Possible Roles in Depression, Sleep, Alzheimer's Disease and Abnormal Aging. Med Hypoth. 1990; 31: 233-42. 

14. G. DeBenedittis and R. Massei. 5-HT Precursors in Migraine Prophy laxis: A Double-Blind Cross-Over Study with L-5-Hydroxytryptophan versus Placebo. Clin J Pain. 1986; 3: 123-29. 

15. J. Robertson and T. Monte. Natural ProzacLearning to Release Your Body's Own Anti-Depressants. San Francisco: Harper; 1997. 

16. A. Gaby. B6The Natural Healer. New Canaan: Keats: 1984. 

17. H. van Praag. Studies of the Mechanism of Action of Serotonin Precur sors in Depression. Psychopharmacol Bull. 1984; 20: 599-602. 

18. P. Hartvig et al. Pyridoxine Effect on Synthesis Rate of Serotonin in the Monkey Brain Measured with Positron Emission Tomography. J Neural Trans. 1995; 102: 91-7. 

19. K. Dakshinamurti, et al. Influence of B Vitamins on Binding Properties of Serotonin Receptors in CNS of Rats. Klin Wochenschr. 1990; 68: 142-45. 

20. M. Jacobsen, et al. Cardiac Manifestations in Mid-gut Carcinoid Disease. Eur Heart J. 1995; 16: 263-68. 

21. Y. Hoshino, et al. Serum Serotonin Levels of Normal Subjects in Physi ological State and Stress Conditions. Jpn J Psychosom Med. 1979; 19: 283-93. 

22. H. van Praag. Central Monoamine Metabolism in Depressions. I. Seroto nin and Related Compounds. Compreh Psychiatry. 1980; 21: 30-43. 

23. T. Li Kam Wa, et al. Blood and Urine 5-Hydroxytryptamine [Serotonin] Levels after Administration of Two 5-Hydroxytryptophan Precursors in Normal Man. Bri J Clin Pharmacol. 1995; 39:327-29. 

24. G. Huether, et al. The Metabolic Fate of Infused L-Tryptophan in Men: Possible Clinical Implications of the Accumulation of Circulating Tryptophan and Tryptophan Metabolites. Psychopharmacol (Germany). 1992; 109: 442-32. 

25. K. Tornebrandt, et al. Heart Involvement in Metastatic Carcinoid Disease. Clin Cardiol. 1986; 9 (1). 

26. R. Arora and R. Warner. Do Indole Markers Predict Carcinoid Heart Dis ease? Chest. 1986; 90: 87-9. 

27. M. Werbach. Nutritional Influences on Illness, 2nd ed. "Atherosclerosis," 57-102. Tarzana, CA: Third Line Press; 1996. 

28. P. Turlapaty and B. Altura. Magnesium Deficiency Produces Spasms of Coronary Arteries: Relationship to Etiology of Sudden Death Ischemic Heart Disease. Science. 1980; 208: 198-200. 
 

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