Safety of Tryptophan

Written by Chrystal Moulton, Staff Writer. Overview of general intake and safety of tryptophan supplementation.

Tryptophan is an amino acid necessary for normal growth, nitrogen balance, as well as production of niacin,  melatonin, and  serotonin.(1) It is generally recognized as the amino acid responsible for managing mood and sleep.(1,2) Tryptophan is an essential amino acid meaning it can only be obtained through the diet. Recommended daily allowance for tryptophan in the US is 5mg/kg per day (or 350mg) for an average individual weight of 70kg (154lbs).(2) However, people generally consume much more than the recommended daily allowance through their diet alone. (3) Since tryptophan is well-known for its psychological benefits for mood and sleep, some individuals supplement with tryptophan. This raises concerns about the safety of tryptophan supplementation.

In the current review, the author provides information on the safety of tryptophan since its discovery as a psychotrophic amino acid in the 1960s.(4)  The desired outcome of tryptophan supplementation is serotonin and melatonin. Serotonin allows our bodies to relax while melatonin allows us to fall asleep.(4) The body makes serotonin from tryptophan in a two-step process that occurs fairly rapidly. Serotonin is converted to melatonin in an additional step under low light conditions.(5) Production and release of both hormones are highly regulated in the body and quantitatively, less than 10% of available tryptophan is converted to serotonin in the body.(1) Some studies have demonstrated serotonin increase in the brain of experimental rats with a dose as little as 12.5mg/kg (equivalent to 2mg/kg in humans or 140mg for a 154 lb. person), indicating the body’s sensitivity to the presence of tryptophan.(6) In humans, tryptophan is absorbed in the small intestine with maximum concentration achieved within 2-3 hours of consumption.(7) Further studies in rats showed that with meals high in protein, increase in brain concentration of tryptophan and release of serotonin was seen within 30 minutes to an hour after ingestion.(8) In general, a healthy diet contains 1- 1.5g of tryptophan daily from protein.(3) Uptake of tryptophan into the brain is limited by the presence of other large neutral amino acids such as leucine, isoleucine, and tyrosine. Also, serotonin synthesis is limited by the presence of a specific enzyme that converts tryptophan to 5-hydoxytryptophan (5-HTP). Currently, however, there is no substantial evidence to determine a level of tryptophan that would constitute a deficiency, but inadequate protein consumption is linked to depression, in which tryptophan plays an important role. (9, 10) More research is needed to determine deficient values of tryptophan in serum.(11)  Tryptophan is generally used to aid in sleep and management of mood. Specifically for mood, tryptophan has been used clinically in conjunction with antidepressant drugs. (see Table 1) Since its discovery as a mood altering hormone in the 1960s, well over 60 clinical trials with tryptophan doses ranging from 50mg/d to 3000mg/d have been conducted in humans worldwide. In all the studies, no significant side effects were found with tryptophan supplementation.(7)

Table 1. Overview of tryptophan trials in humans

abbreviations: t.i.d, three times daily; MAOI, monoamine oxidase inhibitor (antidepressant drug); TCAD, tricyclic antidepressant drugs; REM, rapid eye movement (in sleep commonly referred to as the dream state)

Side effects of tryptophan

Side effects that are normally attributed to tryptophan supplementation include drowsiness, fatigue, nausea, and light-headedness. However depending on the objectives of the study, drowsiness, the most common side effect of tryptophan supplementation, may be considered an adverse event if it is used for depression, but becomes desirable if used for sleep. It should be noted that many of the studies that have been conducted failed to report on adverse events. This lack of clear reporting makes it hard to adequately determine a daily dose of tryptophan that triggers the side effects. Even more, after a serious medical condition (eosinophilia myalgia) linked to tryptophan consumption emerged in 1989, the FDA banned sale of any imported tryptophan products to consumers. At that time, tryptophan continued to be used in the hospitals without any serious or rare side effects. Reports later confirmed that contaminated batches from a single manufacturer in Japan (Showa Denko K.K.) were responsible for the sudden outbreak.(22-24) Further tests were conducted to find out what caused the outbreak but no definitive chemical was to blame. Furthermore, in 1994, the Mayo Clinic analyzed a sample of tryptophan linked to another incident of eosinophilia myalgia and found an unusual peak in the analytical tests which they called “Peak X”. It is believed that this unusual peak found is made up of several impurities. However, they are not sure if this may have been the cause of the outbreak in 1989. The FDA now requires that all tryptophan products be tested for “Peak X”. (7, 25) Since that time, no serious adverse events have been reported for tryptophan.  Toxicological information on tryptophan is two-fold. There still remains the record of the 1989 tryptophan induced eosinophilia myalgia. However, other published toxicological information show that side effects were few and usually attributed to high doses. For example, studies using 2-3g of tryptophan caused drowsiness and faintness in some individuals, while doses of 5g or more caused severe prolonged lethargy, headache, and nausea. (26, 27).

Overall, much more research is needed to determine a clear dose/response relationship for tryptophan. Since effects may vary from person to person, tryptophan should be used only under the supervision of a trained health professional. Furthermore, individuals taking antidepressants should seek advice from their healthcare provider before supplementing with tryptophan as it may cause a serious condition known as serotonin syndrome. Tryptophan toxicity, however, is generally low with very mild side effects. Please be sure to communicate with your healthcare provider about any pre-existing conditions and all medications you may taking before supplementing with tryptophan.

Source: Fernstrom, John D. “Effects and side effects associated with the non-nutritional use of tryptophan by humans.” The Journal of nutrition (2012): jn-111.

© 2012 by the American Society for Nutrition

Posted April 10, 2014.

Chrystal Moulton BA, PMP, is a 2008 graduate of the University of Illinois at Chicago. She graduated with a bachelor’s in psychology with a focus on premedical studies and is a licensed project manager. She currently resides in Indianapolis, IN.

References:

1. Le Floc’h N, Seve B. Biological roles of tryptophan and its metabolism: Potential implications for pig feeding. Livestock Science, October 2007, (112)1: 23-32.
2. Panel on Macronutrients, Panel on the Definition of Dietary Fiber, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board. Protein and amino acids. Dietary Reference Intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids.Washington, DC.: National Academies Press; 2002. p. 589–768.
3. Hudson C, et al. Protein source tryptophan versus pharmaceutical grade tryptophan as an efficacious treatment for chronic insomnia. Nutr Neurosci. 2005 Apr;8(2):121-7.
4. Fernstrom JD. Effects and Side Effects Associated with the Non-Nutritional Use of Tryptophan by Humans. J Nutr. December 1, 2012, 142(12): 2236S-2244S.
5. Wada K, et al. A tryptophan-rich breakfast and exposure to light with low color temperature at night improve sleep and salivary melatonin level in Japanese students. J Circadian Rhythms. 2013 May 25;11(1):4.
6. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological dependence on plasma tryptophan levels. Science. 1971;173:149–52.
7. DasYT, et al. Safety of 5-hydroxy-L-tryptophan. Toxicol Lett. 2004 Apr 15;150(1):111-22.
8. Orosco M, et al. Alpha-lactalbumin-enriched diets enhance serotonin release and induce anxiolytic and rewarding effects in the rat. Behav Brain Res. 2004;148:1–10.
9. Branchey L, et al. Depression, suicide, and aggression in alcoholics and their relationship to plasma amino acids. Psychiatry Res. 1984 Jul;12(3):219-26.
10. DeMyer MK, et al. Plasma tryptophan and five other amino acids in depressed and normal subjects. Arch Gen Psychiatry. 1981 Jun;38(6):642-6.
11. ” Chapter 10 Protein and Amino Acids .” Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) . Washington, DC: The National Academies Press, 2005 .
12. Coppen A, et al. Potentiation of the antidepressive effect of a monoamine-oxidase inhibitor by tryptophan. Lancet. 1963;1:79–81.
13. Pare CMB. Potentiation of monoamine-oxidse inhibitors by tryptophan. Lancet. 1963;2:527–8.
14. Jensen K, et al. Tryptophan/imipramine in depression. Lancet. 1975;2:920.
15. Wälinder J, et al. Potentiation of the antidepressant action of clomipramine by tryptophan. Arch Gen Psychiatry. 1976;33:1384–9.
16. Rao B, Broadhurst AD. Tryptophan and depression. BMJ. 1976;1:460.
17. Griffiths WJ, et al. Tryptophan and sleep in young adults. Psychophysiology. 1972;9:345–56.
18. Hartmann E, et al. Hypnotic effects of L-tryptophan. Arch Gen Psychiatry. 1974;31:394–7.
19. Brown CC, et al. Effects of L-tryptophan on sleep onset insomniacs. Waking Sleeping. 1979;3:101–8.
20. Domino EF, Krause RR. Plasma tryptophan tolerance curves in drug free normal controls, schizophrenic patients and prisoner volunteers. J Psychiatr Res. 1974;10:247–61.
21. Moskowitz DS, et al. The effect of tryptophan on social interaction in everyday life: a placebo-controlled study. Neuropsychopharmacology. 2001;25:277–89.
22. FDA. Information paper on L-tryptophan and 5-hydroxy-L-tryptophan. Office of Nutritional Products, Labeling, Dietary Supplements. Center for Food Safety and Applied Nutrition. February 2001.
23. Hill RH Jr, et al. Contaminants in L-tryptophan associated with eosinophilia myalgia syndrome. Arch Environ Contam Toxicol. 1993 Jul;25(1):134-42.
24. Belongia E.A., Hedberg C.W., Gleich G.J., et al. An Investigation of the Cause of the Eosinophilia–Myalgia Syndrome Associated with Tryptophan Use.  N Engl J Med 1990; 323:357-365.
25. FDA/CDER, 1998. ANDAs: Impurities in Drug Substances. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Rockville, Maryland.
26. Greenwood MH, et al. The acute effects of oral (–)-tryptophan in human subjects. Br J Clin Pharmacol. 1975;2:165–72.
27. NAS, Food and Nutrition Board, Institute of Medicine; Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). National Academy Press, Washington, D.C., pg. 733, 2009. Available from, as of March 10, 2010.