Why Aging People Become Depressed, Fatigued, and OverweightApril 2008
By William Faloon
A daily dose of 6,000 mg of L-tryptophan significantly decreased mood swings, tension, and irritability in women with premenstrual syndrome.49 The meta-bolism of tryptophan is impacted by the different phases of a woman’s cycle,50 and therefore hormonal changes during the menstrual cycle may negatively affect the availability of tryptophan for conversion into serotonin.
Carbohydrate Cravings and Weight Loss
Some obese people consume carbohydrate-rich foods frequently and preferentially, because they have a persistently low plasma tryptophan ratio, as well as low tryptophan uptake into the brain.51 Remember that serotonin levels are enhanced by carbohydrate ingestion as insulin release accelerates the serum removal of other amino acids that compete for transport through the blood-brain barrier.
Increasing the L-tryptophan levels in blood plasma is also known to have an appetite-suppressing effect that mainly impacts carbohydrate consumption.52,53 Presumably the supplemental tryptophan would enhance the release of serotonin from brain neurons to diminish appetite for carbohydrates, which helps with loss of body weight. In addition, obese subjects are often insulin-resistant, and diminished insulin action may cause low plasma tryptophan ratios33 because of the peripheral effects of insulin on the uptake and utilization of other amino acids.
A study was done to measure L-tryptophan in the blood plasma of obese patients to assess the plasma tryptophan ratio to large neutral amino acids (tyrosine + phenylalanine + leucine + isoleucine + valine). The results showed the plasma tryptophan ratio was well below the normal ratio for humans.51 If elevation of the tryptophan in relation to large neutral amino acids occurs, more tryptophan is allowed into the brain to induce serotonin synthesis and influence functions of serotonin (mood, appetite, sleep, and hunger). This study helps show why obese people often have uncontrollable appetites, i.e., they have too little tryptophan in relation to other large neutral amino acids in their blood.
When these obese patients were given 1,000 mg, 2,000 mg, or 3,000 mg doses of L-tryptophan one hour before meals to raise the amount of tryptophan relative to the large neutral amino acids, a significant decrease in caloric consumption was observed. The majority of the reduction in caloric intake was due to the amount of carbohydrates, not protein, consumed. The only side effects observed were a mild decrease in mental alertness, mild dizziness, and mild drowsiness.54
In a double-blind, placebo-controlled study, obese patients on protein-rich diets who received tryptophan (750 mg twice daily orally) had significant weight loss, compared with a placebo group. A moderate dose of tryptophan supplementation did not cause any side effects such as mid-day sleepiness or fatigue.55 The effects of reducing tryptophan levels were also studied in a 7-year-old girl with severe anorexia. When tryptophan levels were reduced, spontaneous eating occurred for the first time in 4.5 years. The spontaneous eating ceased when the tryptophan intake was increased.56
How Aging Reduces Tryptophan-Serotonin Levels
As a result of normal aging, inflammatory cytokine levels increase. A little-known adverse effect is that inflammatory cytokines (such as tumor necrosis factor alpha and interferon alpha) cause induction of the tryptophan-degrading enzyme IDO (indoleamine 2,3-dioxygenase).
You might think that aging people could compensate for the tryptophan-degrading effects of IDO by consuming higher doses of tryptophan supplements. The problem is that in the presence of high blood levels of tryptophan, the other tryptophan-degrading enzyme TDO is also elevated.
So consuming large amounts of L-tryptophan (oral doses of 4,000 mg and greater) will not generate more serotonin because TDO will be induced. Yet if aging people fail to get more tryptophan into their bodies, brain serotonin levels will plummet because the higher IDO enzyme activity will degrade what little tryptophan remains in the blood.
Engineering Around This Problem
Fortunately, the new understanding of how tryptophan is degraded in aging humans provides a basis for engineering a natural solution around this epidemic problem.
First of all, we know from studies in patients with high levels of systemic inflammation that if sufficient niacinamide is given, the degradation of tryptophan in the body is significantly reduced.57,58 We also know that the amino acid lysine competes with tryptophan in the same oxidative degradation pathway. This means that in the presence of lysine, less tryptophan is oxidized.59
Tryptophan, however, can still be degraded by the IDO enzyme that increases as humans age. Nutrients such as curcumin inhibit interferon-induced nuclear factor-kappa-B and COX-2 expression and may limit the induction of IDO, thus making more tryptophan available for conversion to serotonin in the brain.60
It is thus possible for aging people to supplement with a modest dose of tryptophan (1,000-1,500 mg per day) and significantly decrease tryptophan oxidation/degradation, as long as lysine, niacinamide, and the proper cytokine-suppressing nutrients are taken with it to neutralize the effects of the IDO enzyme.
Cofactors that facilitate the conversion of tryptophan to serotonin in the brain are vitamin B6, magnesium, and vitamin C.60-62 These nutrients are already taken by most health-conscious people.
An important factor in the decision to supplement with L-tryptophan is its excellent tolerability and the lack of development of tolerance during long-term use. Furthermore, L-tryptophan does not cause difficulties when trying to wake up the next morning.63
The minimal dose of L-tryptophan for effective treatment of insomnia may be at least 1,000 mg, and repeat administration of L-tryptophan may be required for improvement in chronic, well-established, sleep-onset insomnia or insomnia characterized by both sleep-onset and sleep-maintenance abnormalities.63 Low doses of L-tryptophan (250 to 500 mg) may not offer a significant benefit on sleep latency.64 For those with insomnia who wish to try L-tryptophan, a strong initial dose (1,000 to 4,000 mg) is recommended for the first week, followed by a lower maintenance dose (500 mg to 1,000 mg).
Evening oral doses of tryptophan as low as 250 mg have been shown to improve sleep quality, although the typical dosage range for sleep disorders and depression is 1,000-3,000 mg daily. Safe and effective dosages for other disorders range from 500 mg to 4,000 mg/day, while doses around 3,500 mg/day have been used short term as a smoking cessation intervention.65
Tryptophan is oxidized in the liver by tryptophan-2,3-dioxygenase (TDO), an enzyme that is induced both by glucocorticoids and by large doses of tryptophan itself. The enzyme activity of TDO increases after tryptophan administration66 and results in a relatively short half-life of tryptophan remaining in the plasma.67 Thus, tryptophan is often given in divided daily doses instead of a single dose. A single dose of 3,000 mg is sufficient to keep human brain serotonin synthesis maximized for about eight to twelve hours.68 Giving three daily doses of 2,000 mg will probably keep the rate-limiting tryptophan hydroxylase enzyme in the brain fully saturated for most of each 24-hour period, meaning that brain serotonin levels would be maintained at a constant optimal level.
Tryptophan Blackout Is Lifted!
American consumers can once again obtain tryptophan as a dietary supplement. Particularly compelling news is the discovery that aging people produce tryptophan-degrading enzymes, which can be neutralized by the simultaneous ingestion of nutrients that block pro-inflammatory cytokines and mitigate tryptophan depletion via other oxidative pathways.
A novel formula is now available that combines pharmaceutical-pure tryptophan with a blend of nutrients designed to nourish the brain with optimal levels of serotonin.
Based on hundreds of scientific studies, depletion of serotonin may contribute to age-related weight gain, depression, insomnia, anxiety, and loss of feeling of well-being.
By restoring serotonin to optimal levels, aging people can regain the neurotransmitter balance enjoyed in their youth. Those suffering from age-related weight gain or sleep difficulties could experience significant improvement by using tryptophan to increase their brain serotonin to youthful levels.
If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-800-226-2370.
To learn who should not take high-dose tryptophan supplements, refer to the Tryptophan Precautions section on the following page.
1. Payton A, Gibbons L, Davidson Y, et al. Influence of serotonin transporter gene polymorphisms on cognitive decline and cognitive abilities in a nondemented elderly population. Mol Psychiatry. 2005 Dec;10(12):1133-9.
2. Meltzer CC, Price JC, Mathis CA, et al. Serotonin 1A receptor binding and treatment response in late-life depression. Neuropsychopharmacology. 2004 Dec;29(12):2258-65.
3. Meltzer CC, Smith G, DeKosky ST, et al. Serotonin in aging, late-life depression, and Alzheimer’s disease: the emerging role of functional imaging. Neuropsychopharmacology. 1998 Jun;18(6):407-30.
4. Fernstrom JD, Wurtman RJ. Brain serotonin content: physiological dependence on plasma tryptophan levels. Science. 1971 Jul 9;173(992):149-52.
5. Fukuwatari T, Ohta M, Kimtjra N, Sasaki R, Shibata K. Conversion ratio of tryptophan to niacin in Japanese women fed a purified diet conforming to the Japanese Dietary Reference Intakes. J Nutr Sci Vitaminol (Tokyo). 2004 Dec;50(6):385-91.
6. Bell C, Abrams J, Nutt D. Tryptophan depletion and its implications for psychiatry. Br J Psychiatry. 2001 May;178:399-405.
7. Juhl JH. Fibromyalgia and the serotonin pathway. Altern Med Rev. 1998 Oct;3(5):367-75.
8. Cangiano C, Ceci F, Cairella M, et al. Effects of 5-hydroxytryptophan on eating behavior and adherence to dietary prescriptions in obese adult subjects. Adv Exp Med Biol. 1991;294:591-3.
9. Riemann D, Feige B, Hornyak M, Koch S, Hohagen F, Voderholzer U. The tryptophan depletion test: impact on sleep in primary insomnia - a pilot study. Psychiatry Res. 2002 Mar 15;109(2):129-35.
10. Demisch K, Bauer J, Georgi K, Demisch L. Treatment of severe chronic insomnia with L-tryptophan: results of a double-blind cross-over study. Pharmacopsychiatry. 1987 Nov;20(6):242-4.
11. Hartmann E, Lindsley JG, Spinweber C. Chronic insomnia: effects of tryptophan, flurazepam, secobarbital, and placebo. Psychopharmacology (Berl). 1983;80(2):138-42.
12. Schneider-Helmert D. Interval therapy with L-tryptophan in severe chronic insomniacs. A predictive laboratory study. Int Pharmacopsychiatry. 1981;16(3):162-73.
13. Gendall KA, Joyce PR. Meal-induced changes in tryptophan:LNAA ratio: effects on craving and binge eating. Eat Behav. 2000 Sep;1(1):53-62.
14. Ashley DV, Fleury MO, Golay A, Maeder E, Leathwood PD. Evidence for diminished brain 5-hydroxytryptamine biosynthesis in obese diabetic and non-diabetic humans. Am J Clin Nutr. 1985 Dec;42(6):1240-5.
15. Schloss P, Williams DC. The serotonin transporter: a primary target for antidepressant drugs. J Psychopharmacol. 1998;12(2):115-21.
16. Gross C, Zhuang X, Stark K, et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature. 2002 Mar 28;416(6879):396-400.
17. Available at: http://www.acnp.org/Docs/G5/CH2_15-34.pdf . Accessed January 5, 2008.
18. Altman PL, Dittmer DS (Editors). Metabolism Bethesda, Maryland: Federation of American Societies for Experimental Biology, 1968.
19. Hartmann E, Spinweber CL. Sleep induced by L-tryptophan. Effect of dosages within the normal dietary intake. J Nerv Ment.Dis. 1979 Aug;167(8):497-9.
20. Kepplinger B, Baran H, Kainz A, et al. Age-related increase of kynurenic acid in human cerebrospinal fluid - IgG and beta2-microglobulin changes. Neurosignals. 2005;14(3):126-35.
21. Sainio E-L, Pulkki K, Young SN. L-tryptophan: biochemical, nutritional and pharmacological aspects. Amino Acids. 1996 Mar;10(1):21-47.
22. Li JS, Han Q, Fang J, Rizzi M, James AA, Li J. Biochemical mechanisms leading to tryptophan 2,3-dioxygenase activation. Arch Insect Biochem Physiol. 2007 Feb;64(2):74-87.
23. Brown RR, Ozaki Y, Datta SP, et al. Implications of interferon-induced tryptophan catabolism in cancer, auto-immune diseases and AIDS. Adv Exp Med Biol. 1991;294:425-35.
24. MacKenzie CR, Heseler K, Müller A, Däubener W. Role of indoleamine 2,3-dioxygenase in antimicrobial defence and immuno-regulation: tryptophan depletion versus production of toxic kynurenines. Curr Drug Metab. 2007 Apr;8(3):237-44.
25. Schrocksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta. 2006 Feb;364(1-2):82-90.
26. Schroecksnadel K, Zangerle R, Bellmann-Weiler R, et al. Indoleamine-2, 3-dioxygenase and other interferon-gamma-mediated pathways in patients with human immunodeficiency virus infection. Curr Drug Metab. 2007 Apr;8(3):225-36.
27. Boasso A, Herbeuval JP, Hardy AW, et al. HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood. 2007 Apr 15;109(8):3351-9.
28. Potula R, Poluektova L, Knipe B, et al. Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis. Blood. 2005 Oct 1;106(7):2382-90.
29. Frick B, Schroecksnadel K, Neurauter G, Leblhuber F, Fuchs D. Increasing production of homocysteine and neopterin and degradation of tryptophan with older age. Clin Biochem. 2004 Aug;37(8):684-7.
30. Pertovaara M, Raitala A, Lehtimaki T, et al. Indoleamine 2,3-dioxygenase activity in nonagenarians is markedly increased and predicts mortality. Mech Ageing Dev. 2006 May;127(5):497-9.
31. Oldendorf WH, Szabo J. Amino acid assignment to one of three blood-brain barrier amino acid carriers. Am J Physiol. 1976 Jan;230(1):94-8.
32. Lucini V, Lucca A, Catalano M, Smeraldi E. Predictive value of tryptophan/large neutral amino acids ratio to antidepressant response. J Affect Disord. 1996 Jan 22;36(3-4):129-33.
33. Wurtman RJ, Wurtman JJ. Brain serotonin, carbohydrate-craving, obesity and depression. Obes Res. 1995 Nov;3 Suppl 4477S-80S.
34. Lieberman HR, Caballero B, Finer N. The composition of lunch determines afternoon plasma tryptophan ratios in humans.J Neural Transm. 1986;65(3-4):211-7.
35. Heraief E, Burckhardt P, Mauron C, Wurtman JJ, Wurtman RJ. The treatment of obesity by carbohydrate deprivation suppresses plasma tryptophan and its ratio to other large neutral amino acids. J Neural Transm. 1983;57(3):187-95.
36. Bender DA, Totoe L. High doses of vitamin B6 in the rat are associated with inhibition of hepatic tryptophan metabolism and increased uptake of tryptophan into the brain. J Neurochem. 1984 Sep;43(3):733-6.
37. Green AR, Aronson JK. Metabolism of an oral tryptophan load III: effect of a pyridoxine supplement. Br J Clin Pharmacol. 1980 Dec;10(6):617-9.
38. Korner E, Bertha G, Flooh E, et al. Sleep-inducing effect of L-tryptophane. Eur Neurol. 1986;25 Suppl 2:75-81.
39. Schmidt HS. L-tryptophan in the treatment of impaired respiration in sleep. Bull Eur Physiopathol Respir. 1983 Nov;19(6):625-9.
40. Lieberman HR, Corkin S, Spring BJ, Wurtman RJ, Growdon JH. The effects of dietary neurotransmitter precursors on human behavior. Am J Clin Nutr. 1985 Aug;42(2):366-70.
41. Booij L, Van der Does AJ, Haffmans PM, et al. The effects of high-dose and low-dose tryptophan depletion on mood and cognitive functions of remitted depressed patients. J Psychopharmacol. 2005 May;19(3):267-75.
42. Herrington RN, Bruce A, Johnstone EC, Lader MH. Comparative trial of L-tryptophan and amitriptyline in depressive illness. Psychol Med. 1976 Nov;6(4):673-8.
43. Kaye WH, Gendall KA, Fernstrom MH, et al. Effects of acute tryptophan depletion on mood in bulimia nervosa. Biol Psychiatry. 2000 Jan 15;47(2):151-7.
44. Wurtman RJ, Wurtman JJ, Regan MM, et al. Effects of normal meals rich in carbohydrates or proteins on plasma tryptophan and tyrosine ratios. Am J Clin Nutr. 2003 Jan;77(1):128-32.
45. Asheychik R, Jackson T, Baker H, et al. The efficacy of L-tryptophan in the reduction of sleep disturbance and depressive state in alcoholic patients. J Stud Alcohol. 1989 Nov;50(6):525-32.
46. van Praag H, de HS. Depression vulnerability and 5-hydroxytryptophan prophylaxis. Psychiatry Res. 1980 Sep;3(1):75-83.
47. van Hiele LJ. l-5-Hydroxytryptophan in depression: the first substitution therapy in psychiatry? The treatment of 99 out-patients with ‘therapy-resistant’ depressions. Neuropsychobiology. 1980;6(4):230-40.
48. Meyers S. Use of neurotransmitter precursors for treatment of depression. Altern Med Rev. 2000 Feb;5(1):64-71.
49. Steinberg S, Annable L, Young SN, Liyanage N. A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria. Biol Psychiatry. 1999 Feb 1;45(3):313-20.
50. Hrboticky N, Leiter LA, Anderson GH. Menstrual cycle effects on the metabolism of tryptophan loads. Am J Clin Nutr. 1989 Jul;50(1):46-52.
51. Breum L, Rasmussen MH, Hilsted J, Fernstrom JD. Twenty-four-hour plasma tryptophan concentrations and ratios are below normal in obese subjects and are not normalized by substantial weight reduction. Am J Clin Nutr. 2003 May;77(5):1112-8.
52. Wurtman, JJ, Wurtman RJ. Suppression of carbohydrate consumption at snacks and at mealtime by DI-fenfluramine or tryptophan. In S. Garattini &:R. Samamin, (Eds.), Anorectic agents:Mechanisms of action and tolerance. New York: Raven Press, 1981:169-82.
53. Wurtman JJ, Wurtman RJ, Growdon JH, Henry P, Lipscomb A, Zeisel SH. Carbohydrate craving in obese people: Suppression by treatments affecting serotoninergic transmission. Int J Eat Disord. 1981 1(1):2-15.
54. Cavaliere H, Medeiros-Neto G. The anorectic effect of increasing doses of L-tryptophan in obese patients. Eat Weight Disord. 1997 Dec;2(4):211-5.
55. Heraief E, Burckhardt P, Wurtman J, Wurtman R. Tryptophan administration may enhance weight loss by some moderately obese patients on a protein-sparing modified fast (PSMF) diet. Int J Eat Disord. 1985; 4(3):281-92.
56. Hyman SL, Coyle JT, Parke JC, et al. Anorexia and altered serotonin metabolism in a patient with argininosuccinic aciduria. J Pediatr. 1986 May;108(5 Pt 1):705-9.
57. Murray MF, Langan M, MacGregor RR. Increased plasma tryptophan in HIV-infected patients treated with pharmacologic doses of nicotinamide. Nutrition. 2001 Jul;17(7-8):654-6.
58. Chouinard G, Young SN, Annable L, Sourkes TL. Tryptophan-nicotinamide, imipramine and their combination in depression. A controlled study. Acta Psychiatr Scand. 1979 Apr;59(4):395-414.
59. Murray MF. Tryptophan depletion and HIV infection: a metabolic link to pathogenesis. Lancet Infect Dis. 2003 Oct;3(10):644-52.
60. Lee J, Im YH, Jung HH, et al. Curcumin inhibits interferon-alpha induced NF-kappaB and COX-2 in human A549 non-small cell lung cancer cells. Biochem Biophys Res Commun. 2005 Aug 26;334(2):313-8.
61. Cooper JR. The role of ascorbic acid in the oxidation of tryptophan to 5-hydroxytryptophan. Ann NY Acad Sci. 1961 Apr 21;92:208-11.
62. Freyre AV, Flichman JC. Spasmophilia caused by magnesium deficit. Psychosomatics. 1970 Sep;11(5):500-1.
63. Schneider-Helmert D, Spinweber CL. Evaluation of L-tryptophan for treatment of insomnia: a review. Psychopharmacology (Berl). 1986;89(1):1-7.
64. Ferrero F, Zahnd J. Tryptophan in the treatment of insomnia in hospitalized psychiatric patients. Encephale. 1987 Jan;13(1):35-7.
65. No authors listed. Monograph: L-Tryptophan. Altern Med Rev.2006 Mar;11(1):52-6.
66. Young SN, Oravec M. The effect of growth hormone on the metabolism of a tryptophan load in the liver and brain of hypophysectomized rats. Can J Biochem. 1979 Jun;57(6):517-22.
67. Green AR, Aronson JK, Curzon G, Woods HF. Metabolism of an oral tryptophan load. I: Effects of dose and pretreatment with tryptophan. Br J Clin Pharmacol. 1980 Dec;10(6):603-10.
68. Young SN, Gauthier S. Effect of tryptophan administration on tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid in human lumbar and cisternal cerebrospinal fluid. J Neurol Neurosurg Psychiatry. 1981 Apr;44(4):323-8.
69. Price WA, Zimmer B, Kucas P. Serotonin syndrome: a case report. J Clin Pharmacol. 1986 Jan;26(1):77-8.
70. Pope HG Jr, Jonas JM, Hudson JI, Kafka MP. Toxic reactions to the combination of monoamine oxidase inhibitors and tryptophan. Am J Psychiatry. 1985 Apr;142(4):491-2.
71. Avarello TP, Cottone S. Serotonin syndrome: a reported case. Neurol Sci. 2002 Sep;23 Suppl 2:S55-6.
72. Gerson SC, Baldessarini RJ. Motor effects of serotonin in the central nervous system. Life Sci. 1980 Oct 20;27(16):1435-51.
73. Sternbach H. The serotonin syndrome. Am J Psychiatry. 1991 Jun;148(6):705-13.
74. Glassman AH, Platman SR. Potentiation of a monoamine oxidase inhibitor by tryptophan. J Psychiatr Res. 1969 Dec;7(2):83-8.
75. Available at: http://www.drugdigest.org/DD/DVH/HerbsInteractions/0,3926,4031%7CL%252Dtryptophan,00.html. Accessed February 1, 2008.
76. Rossle M, Herz R, Mullen KD, Jones DB. The disposition of intravenous L-tryptophan in healthy subjects and in patients with liver disease. Br J Clin Pharmacol. 1986 Dec;22(6):633-8.
77. Available at: http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr071.pdf. Accessed February 1, 2008.
78. Marz RB. Medical Nutrition from Marz. 2nd edition. Portland, OR:Omni Press;1999.