Life Extension Magazine®

The FDA’s Cruel Hoax

Back in 1990, the FDA restricted the importation of tryptophan into the United States. The biological casualty of this governmental action can be seen in the widespread deficits of the neurotransmitter serotonin in the brains of aging human beings. Read how this cruel hoax may be partially responsible for the record number of Americans suffering from obesity, depression, anxiety, and insomnia.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in August 2023. Written by: William Faloon.

William Faloon 
William Faloon

Do you remember how popular tryptophan was in the 1980s? Back in those days, people seeking to lose weight, improve sleep, or alleviate depression used tryptophan to safely increase serotonin levels in their brain.

Serotonin is the natural compound that promotes feelings of well-being, satiety, and relaxation. A serotonin deficiency can result in sleep disturbance, anxiety, depression, and a propensity to overeat.

In 1989, the FDA restricted the importation of tryptophan. This forced American consumers to switch to expensive prescription drugs that produced only partial effects at best.

Tryptophan is an amino acid found naturally in the foods that we eat. The reason its sale was stopped was because of defective tryptophan made by a sub-standard company.

We believe that the FDA’s prejudicial position against tryptophan caused Americans to suffer widespread deficiencies of serotonin in their brains. A result of serotonin deficiency may be reflected in today’s epidemic of obesity, depression, anxiety, and insomnia.

Tryptophan Is Back!

Despite intense lobbying efforts by pharmaceutical companies, the FDA could not rationally continue to block the sale of tryptophan. After all, tryptophan is not only found in food, but the very tryptophan that the FDA restricted is still used in infant formulas and intravenous feeding solutions. If there were any danger to tryptophan, we would have known about it long ago.

Pharmaceutical-pure tryptophan can now be imported for use in dietary supplements. This means that aging Americans may be able to discard certain prescription drugs and once again treat their serotonin deficiency disorder with what Mother Nature intended all along… the amino acid tryptophan itself!

Why Aging People Need Tryptophan

Startling research findings reveal that brain serotonin levels decline sharply in most humans as they age!1-5 This helps explain why so many people suffer common age-related disorders such as depressed mood and sleep difficulties. Based on these discoveries, aging humans may improve their overall feeling of well being by restoring brain serotonin.

Why Aging People Need Tryptophan

It was long ago established that tryptophan is the amino acid needed to produce serotonin in the brain. Regrettably, the amount of tryptophan in a typical diet is barely enough to meet basic metabolic requirements, let alone provide optimal brain serotonin levels.

Since tryptophan supplements were removed from the market, there have been increasing numbers of overweight and obese Americans. It would appear that serotonin deficiency may play an important role in the record number of Americans suffering from depression, insomnia, and excess weight gain.

Depressed People Are Often Tryptophan-Deficient

In people with major depression, blood levels of tryptophan are often significantly below normal.6-9 A number of studies indicate that normal mood depends in large part on adequate brain serotonin stores.7,10,11

Human studies have shown that reducing serotonin levels (by depriving the brain of tryptophan) can induce depression within hours and that supplementation with tryptophan can alleviate depressive symptoms.7,9,11

Why the Aging Process Causes Tryptophan Deficit

Depression is one of the most common health disorders affecting elderly people. Doctors still consider it to be a normal consequence of aging.

Recent studies, however, have identified specific age-related mechanisms that cause the degradation of tryptophan in elderly individuals.12-15 The encouraging news is that there are ways for people to counteract the loss of their precious mood-elevating tryptophan.

Depressed People Are Often Tryptophan-Deficient

It turns out that pro-inflammatory cytokines cause tryptophan to degrade in the blood. This occurs because these pro-inflammatory cytokines activate specific enzymes that deplete tryptophan in the bloodstream. The result of diminished blood levels of tryptophan is serotonin deficiency in the brain (and the onset of depression).

Pro-inflammatory cytokines are specialized biochemicals secreted by immune cells that are only supposed to be activated in response to acute infection or trauma. As people age, they often chronically overproduce pro-inflammatory cytokines, which subsequently cause inflammatory-related diseases such as arthritis,16-19 cancer,20,21 dementia and depression,22-26 and atherosclerosis.27-29

Health-conscious Americans are already taking nutrients (such as fish oil,30-41 green tea,42-48 borage oil,49-51 curcumin,52-56 and flavonoids),57-61 which help suppress pro-inflammatory cytokines.

The new findings about cytokine-induced degradation of tryptophan explain how aging humans become depressed and why nutrients like fish oil alleviate depression.62-65

To give you an idea of how devastating inflammatory cytokines are to tryptophan levels, just look at what happens to people who are given a cytokine drug called interferon-alpha. When interferon-alpha is given to hepatitis C victims, one of the most dangerous side effects is the onset of depression so severe that users of this drug can become suicidal.63 It turns out that interferon drugs cause tryptophan-degrading enzymes to surge, thus depleting tryptophan in the blood and making less tryptophan available for conversion to serotonin in the brain.63,64,66 It would appear that supplemental tryptophan could enable those with hepatitis C to benefit from interferon drugs without encountering severe depression.

In a fascinating new study, scientists measured levels of tryptophan degradation metabolites in the brain. It turns out that people over age 50 had 30% more of these tryptophan degradation metabolites in their brains compared with people under age 50. The doctors who conducted this study stated that their research indicates a 95% probability that older people will have increased levels of these metabolites, reflecting excessive degradation of tryptophan in their brains.12

This finding further explains why depression is one of the most common mental health problems in adults age 60 and beyond and suggests that supplemental tryptophan, along with cytokine-suppressing agents, could help restore serotonin to more youthful levels and subsequently alleviate depression.

Tryptophan and Sleep

Poor sleep affects a significant percentage of older individuals. Trouble falling asleep, waking not rested, waking too early, and difficulty maintaining sleep are the chief sleep complaints in this age group. In response to complaints of poor sleep, more Americans are prescribed sleeping pills than ever before.

Tryptophan and Sleep

Before tryptophan was taken off the market, it was an enormously popular supplement used to alleviate chronic insomnia. Between 1962 and 1982, 40 controlled studies described the effects of tryptophan on human sleepiness and/or sleep.67 During the 1980s, placebo-controlled human studies documented the sleep-inducing effects of tryptophan.68-71

With the new knowledge that tryptophan-depleting enzymes increase as people age, there is now a biochemical basis to help explain why so many older individuals suffer sleep deprivation miseries. Serotonin enables one to calm down and relax. Without adequate serotonin to naturally tranquilize the brain, it becomes excruciatingly difficult for older people to get to sleep.

After low-cost tryptophan supplements were restricted, the door swung wide open for pharmaceutical companies to earn billions of dollars selling prescription benzodiazepine drugs such as Xanax® and Halcion®, as well as other sleep-inducing medications such as Ambien®.

Tryptophan Deficiency and Obesity

When the brain is flooded with serotonin, satiety normally occurs. A serotonin deficiency has been associated with the carbohydrate binging that contributes to the accumulation of excess body fat.72 Obese individuals have low blood tryptophan levels,73 which indicate that their overeating patterns may be related to a serotonin deficiency in the brain.

Tryptophan Deficiency and Obesity

In a study of obese subjects, levels of tryptophan and the ratio of tryptophan to the other large neutral amino acids in the blood were measured over a 24-hour period. Compared with normal subjects, low tryptophan and a low ratio of tryptophan to other amino acids were seen in the obese study subjects throughout the 24-hour period.74 The significance of this low ratio of tryptophan is that the other amino acids compete with tryptophan for transport through the blood-brain barrier. If there are high levels of other amino acids in relation to tryptophan in the blood, relatively little tryptophan will enter the brain, causing a chronic serotonin deficiency. This explains the constant hunger that causes so many people to become and remain obese.

Why Diets So Often Fail to Induce Sustained Weight Loss

For those who try to lose weight by consuming fewer calories, the failure rate is well established. In a study that evaluated both depressed and non-depressed women, the effect of dieting was evaluated in relation to blood tryptophan levels. The results showed that in response to consuming a very low calorie diet (1,000 calories/day), blood tryptophan levels plummeted.75

This finding indicates that the intense hunger that occurs in response to reduced calorie intake is at least partially caused by the tryptophan deficiency that ensues. The implication is that it may be impossible for certain people to chronically reduce their calorie intake because a deficit of tryptophan/serotonin would cause unbearable chronic hunger.

Low Serotonin Induces Carbohydrate Craving

It is well known that carbohydrate binging plays a role in unwanted weight gain, yet Americans consume more carbohydrates than ever. Despite numerous books extolling the fat-loss benefits of “low-carb” diets, few people are able to avoid excess carbohydrate ingestion over the long term.

Low Serotonin Induces Carbohydrate Craving

One reason that people eat too many high-glycemic carbohydrates is the brain’s need to achieve “feel good” levels of serotonin. While serotonin is made from the amino acid tryptophan, eating protein-rich foods does little good since other amino acids in the food compete for transport into the brain. When carbohydrates are ingested, the resulting insulin surge causes a depletion of these competing amino acids in the blood by increasing their uptake into muscle, thus sparing tryptophan to more readily transport into the brain for conversion to serotonin.

The need for tryptophan can most easily be understood by the carbohydrate binging that occurs when people become serotonin-deficient.

Why Dietary Tryptophan Is Inadequate

In any normal diet, be it omnivorous or vegetarian, protein-based tryptophan is the least plentiful of all amino acids.

A typical diet provides only 1,000 to 1,500 mg/day of tryptophan, yet there is much competition in the body for this scarce amino acid. Tryptophan is used to make various proteins that form structures of the body. In people with low-to-moderate intakes of vitamin B3 (niacin), tryptophan may be used to make B3 in the liver at the astounding ratio of 60 mg tryptophan to make just 1 mg of vitamin B3.76 This means that in vitamin B3-deficient people, virtually all dietary tryptophan may be used to synthesize B3, leaving none available for conversion to tranquilizing serotonin in the brain.

In people who are even marginally deficient in vitamin B6, tryptophan may be rapidly degraded into mildly toxic metabolites.77 Thus, the brain typically receives less than 1% of ingested tryptophan from dietary sources.

Dietary tryptophan contributes very little actual tryptophan to the brain, yet tryptophan is the only normal dietary raw material for serotonin synthesis in the brain. Is it any wonder that so many people today suffer from disorders (depression, insomnia, excess weight gain) associated with a serotonin deficiency?

A Financial Windfall for the Drug Companies

At the time that the FDA restricted tryptophan, it was one the most popular dietary supplements sold in the United States. Perhaps it is a coincidence, but since 1989, the percentages of overweight and obese adult Americans have soared. Could it be that a nationwide serotonin deficiency has led to the high-carbohydrate overeating syndrome that so many Americans suffer from today?

The removal of tryptophan created an economic windfall for the drug companies. Sales of drugs that interfere with the brain’s reuptake of serotonin (like Prozac®, and later Paxil® and Zoloft®) shot through the roof, earning tens of billions of dollars of profits for drug companies. While these drugs caused large numbers of unpleasant and possibly lethal side effects, the FDA withdrew none of them.

The ensuing epidemic of weight gain and sleeplessness resulted in dozens of anti-obesity and anti-insomnia drugs being approved by the FDA, some of which had horrendous side effects, and others that had virtually no efficacy.

Critics contend that the contaminated tryptophan coming from one sub-standard Japanese company provided a convenient excuse for the FDA to restrict the sale of all tryptophan dietary supplements. The FDA’s actions guaranteed that Americans would become tryptophan-deficient, and therefore turn to prescription drugs for relief from a host of disorders related to insufficient serotonin in the brain.

What You Need to Know: Green Tea
  • Population studies in humans, laboratory studies in animals and in cell culture, and clinical studies in human subjects suggest a wealth of health benefits associated with green tea.

  • Green tea is rich in healthful polyphenols, particularly a catechin known as EGCG, which is a potent antioxidant.

  • Green tea may help prevent or manage cancer, heart and vascular disease, diabetes, obesity, Alzheimer’s disease and other neurological degenerative diseases, bacterial and viral infections, and other conditions.

  • In Japanese populations, green tea consumption has been linked to longer life, especially in subjects drinking five cups or more daily. Western populations consume relatively little green tea.

  • Green tea extract supplements may facilitate adequate consumption for maximal health benefits—without requiring lifestyle changes.

  • Green tea supplements also avoid potential risks of esophageal cancer associated with drinking hot tea. This risk is thought to be related to the high temperature of traditionally prepared tea, because green tea itself has no known toxicity.

Pharmaceutical-Pure Tryptophan Now Available

Consumers now have access to pharmaceutical-pure tryptophan as an over-the-counter dietary supplement. According to the FDA, it is now the responsibility of the company who sells the tryptophan to ensure that it is not contaminated.

For 19 years, aging Americans have been forced to settle for less-than-optimal levels of tryptophan/serotonin in their bodies. Based on what has been published in the peer-reviewed scientific literature, it would appear that consumers have suffered enormously from a host of disorders related to lack of serotonin in the brain.

Pharmaceutical companies, on the other hand, have accumulated exorbitant wealth, as depressed, overweight, and sleep-deprived consumers were forced to experiment with costly and side effect-laden drugs in order to combat the effects of serotonin deficiency.

If tryptophan dietary supplements provide relief to those suffering from common age-related disorders such as anxiety, depressed mood, sleeplessness, and unwanted weight gain, the FDA’s nearly two-decade restriction on this natural agent may turn out to be one of the cruelest hoaxes of all time.

In this month’s issue, we provide an in-depth discussion on tryptophan, including suggested dosing, precautions to look out for, and optimal ways to safely benefit from it.

For longer life,

For Longer Life 

William Faloon


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 Pychiatry. 2005 Dec;10(12):1133-9.

2. Hesse S, Barthel H, Murai T, et al. Is correction for age necessary in neuroimaging studies of the central serotonin transporter? Eur J Nucl Med Mol Imaging. 2003 Mar;30(3):427-30.

3. Yamamoto M, Suhara T, Okubo Y, et al. Age-related decline of serotonin transporters in living human brain of healthy males. Life Sci. 2002 Jul 5;71(7):751-7.

4. Kuikka JT, Tammela L, Bergstrom KA, et al. Effects of ageing on serotonin transporters in healthy females. Eur J Nucl Med. 2001 Jul;28(7):911-3.

5. Fukagawa NK, Minaker KL, Rowe JW, Young VR. Plasma tryptophan and total neutral amino acid levels in men: influence of hyperinsulinemia and age. Metabolism. 1987 Jul;36(7):683-6.

6. Porter RJ, Mulder RT, Joyce PR, Miller AL, Kennedy M. Tryptophan hydroxylase gene (TPH1) and peripheral tryptophan levels in depression. J Affect Disord. 2008 Jan 4.

7. Booij L, Van der Does AJ, Haffmans PM, Riedel WJ, Fekkes D, Blom MJ. 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.

8. Almeida-Montes LG, Valles-Sanchez V, Moreno-Aguilar J, et al. Relation of serum cholesterol, lipid, serotonin and tryptophan levels to severity of depression and to suicide attempts. J Psychiatry Neurosci. 2000 Sep;25(4):371-7.

9. 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.

10. Ruhe HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007 Apr;12(4):331-59.

11. 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.

12. 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.

13. 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.

14. 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.

15. Caballero B, Gleason RE, Wurtman RJ. Plasma amino acid concentrations in healthy elderly men and women. Am J Clin Nutr. 1991 May;53(5):1249-52.

16. Joosten LA, Netea MG, Kim SH, et al. IL-32, a proinflammatory cytokine in rheumatoid arthritis. Proc Natl Acad Sci USA. 2006 Feb 28;103(9):3298-303.

17. Mosaad YM, Metwally SS, Auf FA, et al. Proinflammatory cytokines (IL-12 and IL-18) in immune rheumatic diseases: relation with disease activity and autoantibodies production. Egypt J Immunol. 2003;10(2):19-26.

18. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, et al. Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci USA. 2003 Jul 22;100(15):9090-5.

19. Saklatvala J. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature. 1986 Aug 7;322(6079):547-9.

20. O’Connor MF, Irwin MR, Seldon J, Kwan L, Ganz PA. Pro-inflammatory cytokines and depression in a familial cancer registry. Psychooncology. 2007 May;16(5):499-501.

21. Caruso C, Lio D, Cavallone L, Franceschi C. Aging, longevity, inflammation, and cancer. Ann NY Acad Sci. 2004 Dec;1028:1-13.

22. Kim YK, Na KS, Shin KH, et al. Cytokine imbalance in the pathophysiology of major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 30;31(5):1044-53.

23. Kiecolt-Glaser JK, Belury MA, Porter K, et al. Depressive symptoms, omega-6:omega-3 fatty acids, and inflammation in older adults. Psychosom Med. 2007 Apr;69(3):217-24.

24. Craddock D, Thomas A. Cytokines and late-life depression. Essent Psychopharmacol. 2006;7(1):42-52.

25. Spalletta G, Bossu P, Ciaramella A, et al. The etiology of poststroke depression: a review of the literature and a new hypothesis involving inflammatory cytokines. Mol Psychiatry. 2006 Nov;11(11):984-91.

26. Paganelli R, Di IA, Patricelli L, et al. Proinflammatory cytokines in sera of elderly patients with dementia: levels in vascular injury are higher than those of mild-moderate Alzheimer’s disease patients. Exp Gerontol. 2002 Jan;37(2-3):257-63.

27. Sbarsi I, Falcone C, Boiocchi C, et al. Inflammation and atherosclerosis: the role of TNF and TNF receptors polymorphisms in coronary artery disease. Int J Immunopathol Pharmacol. 2007 Jan;20(1):145-54.

28. Schulz S, Schagdarsurengin U, Rehfeld D, et al. Genetic impact of TNF-beta on risk factors for coronary atherosclerosis. Eur Cytokine Netw. 2006 Sep;17(3):148-54.

29. Patel S, Celermajer DS, Bao S. Atherosclerosis-Underlying inflammatory mechanisms and clinical implications. Int J Biochem Cell Biol. 2007 Dec 7 [Epub ahead of print].

30. Wu D, Han SN, Meydani M, Meydani SN. Effect of concomitant consumption of fish oil and vitamin E on production of inflammatory cytokines in healthy elderly humans. Ann NY Acad Sci. 2004 Dec;1031:422-4.

31. Grimble RF. Nutritional modulation of immune function. Proc Nutr Soc. 2001 Aug;60(3):389-97.

32. Jolly CA, Muthukumar A, Avula CP, Troyer D, Fernandes G. Life span is prolonged in food-restricted autoimmune-prone (NZB x NZW)F(1) mice fed a diet enriched with (n-3) fatty acids. J Nutr. 2001 Oct;131(10):2753-60.

33. Curtis CL, Hughes CE, Flannery CR, et al. n-3 fatty acids specifically modulate catabolic factors involved in articular cartilage degradation. J Biol Chem. 2000 Jan 14;275(2):721-4.

34. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr. 2000 Jan;71(1 Suppl):343S-8S.

35. Venkatraman JT, Chu WC. Effects of dietary omega-3 and omega-6 lipids and vitamin E on serum cytokines, lipid mediators and anti-DNA antibodies in a mouse model for rheumatoid arthritis. J Am Coll Nutr. 1999 Dec;18(6):602-13.

36. Kelley DS, Taylor PC, Nelson GJ, et al. Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men. Lipids. 1999 Apr;34(4):317-24.

37. Lo CJ, Chiu KC, Fu M, Lo R, Helton S. Fish oil decreases macrophage tumor necrosis factor gene transcription by altering the NF kappa B activity. J Surg Res. 1999 Apr;82(2):216-21.

38. Khalfoun B, Thibault F, Watier H, Bardos P, Lebranchu Y. Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human endothelial cell production of interleukin-6. Adv Exp Med Biol. 1997;400B:589-97.

39. Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ. The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr. 1996 Jan;63(1):116-22.

40. Espersen GT, Grunnet N, Lervang HH, et al. Decreased interleukin-1 beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids. Clin Rheumatol. 1992 Sep;11(3):393-5.

41. Terano T, Salmon JA, Higgs GA, Moncada S. Eicosapentaenoic acid as a modulator of inflammation. Effect on prostaglandin and leukotriene synthesis. Biochem Pharmacol. 1986 Mar 1;35(5):779-85.

42. Han MK. Epigallocatechin gallate, a constituent of green tea, suppresses cytokine-induced pancreatic beta-cell damage. Exp Mol Med. 2003 Apr 30;35(2):136-9.

43. Katiyar SK. Skin photoprotection by green tea: antioxidant and immunomodulatory effects. Curr Drug Targets Immune Endocr Metabol Disord. 2003 Sep;3(3):234-42.

44. Haqqi TM, Anthony DD, Gupta S, et al. Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea. Proc Natl Acad Sci USA. 1999 Apr 13;96(8):4524-9.

45. Adcocks C, Collin P, Buttle DJ. Catechins from green tea (Camellia sinensis) inhibit bovine and human cartilage proteoglycan and type II collagen degradation in vitro. J Nutr. 2002 Mar;132(3):341-6.

46. Yang F, de Villiers WJ, McClain CJ, Varilek GW. Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model. J Nutr. 1998 Dec;128(12):2334-40.

47. Chan MM, Fong D, Ho CT, Huang HI. Inhibition of inducible nitric oxide synthase gene expression and enzyme activity by epigallocatechin gallate, a natural product from green tea. Biochem Pharmacol. 1997 Dec 15;54(12):1281-6.

48. Tipoe GL, Leung TM, Hung MW, Fung ML. Green tea polyphenols as an anti-oxidant and anti-inflammatory agent for cardiovascular protection. Cardiovasc Hematol Disord Drug Targets. 2007 Jun;7(2):135-44.

49. Rothman D, DeLuca P, Zurier RB. Botanical lipids: effects on inflammation, immune responses, and rheumatoid arthritis. Semin Arthritis Rheum. 1995 Oct;25(2):87-96.

50. Kremer JM, Lawrence DA, Petrillo GF, et al. Effects of high-dose fish oil on rheumatoid arthritis after stopping nonsteroidal antiinflammatory drugs. Clinical and immune correlates. Arthritis Rheum. 1995 Aug;38(8):1107-14.

51. Kast RE. Borage oil reduction of rheumatoid arthritis activity may be mediated by increased cAMP that suppresses tumor necrosis factor-alpha. Int Immunopharmacol. 2001 Nov;1(12):2197-9.

52. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). J Altern Complement Med. 2003 Feb;9(1):161-8.

53. Antony S, Kuttan R, Kuttan G. Immunomodulatory activity of curcumin. Immunol Invest. 1999 Sep;28(5-6):291-303.

54. Zhang F, Altorki NK, Mestre JR, Subbaramaiah K, Dannenberg AJ. Curcumin inhibits cyclooxygenase-2 transcription in bile acid- and phorbol ester-treated human gastrointestinal epithelial cells. Carcinogenesis. 1999 Mar;20(3):445-51.

55. Jobin C, Bradham CA, Russo MP, et al. Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol. 1999 Sep 15;163(6):3474-83.

56. Pendurthi UR, Williams JT, Rao LV. Inhibition of tissue factor gene activation in cultured endothelial cells by curcumin. Suppression of activation of transcription factors Egr-1, AP-1, and NF-kappa B. Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3406-13.

57. O’Leary KA, de Pascual-Tereasa S, Needs PW, et al. Effect of flavonoids and vitamin E on cyclooxygenase-2 (COX-2) transcription. Mutat Res. 2004 Jul 13;551(1-2):245-54.

58. Manthey JA, Grohmann K, Guthrie N. Biological properties of citrus flavonoids pertaining to cancer and inflammation. Curr Med Chem. 2001 Feb;8(2):135-53.

59. Murakami A, Nakamura Y, Ohto Y, et al. Suppressive effects of citrus fruits on free radical generation and nobiletin, an anti-inflammatory polymethoxyflavonoid. Biofactors. 2000;12(1-4):187-92.

60. Manthey JA, Grohmann K, Montanari A, Ash K, Manthey CL. Polymethoxylated flavones derived from citrus suppress tumor necrosis factor-alpha expression by human monocytes. J Nat Prod. 1999 Mar;62(3):441-4.

61. Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996;14:397-440.

62. Oxenkrug GF. Genetic and Hormonal Regulation of Tryptophan Kynurenine Metabolism: Implications for Vascular Cognitive Impairment, Major Depressive Disorder, and Aging. Ann NY Acad Sci. 2007 Dec;1122:35-49.

63. Wichers M, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol. 2002 Dec;5(4):375-88.

64. Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D. Neopterin production, tryptophan degradation, and mental depression—what is the link? Brain Behav Immun. 2002 Oct;16(5):590-5.

65. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007 Jul;68(7):1056-61.

66. Wirleitner B, Neurauter G, Schrocksnadel K, Frick B, Fuchs D. Interferon-gamma-induced conversion of tryptophan: immunologic and neuropsychiatric aspects. Curr Med Chem. 2003 Aug;10(16):1581-91.

67. Hartmann E. Effects of L-tryptophan on sleepiness and on sleep. J Psychiatr Res. 1982;17(2):107-13.

68. Schneider-Helmert D, Spinweber CL. Evaluation of L-tryptophan for treatment of insomnia: a review. Psychopharmacology (Berl). 1986;89(1):1-7.

69. Korner E, Bertha G, Flooh E, et al. Sleep-inducing effect of L-tryptophane. Eur Neurol. 1986;25(Suppl 2):75-81.

70. Schmidt HS. L-tryptophan in the treatment of impaired respiration in sleep. Bull Eur Physiopathol Respir. 1983 Nov;19(6):625-9.

71. 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.

72. 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.

73. Brandacher G, Hoeller E, Fuchs D, Weiss HG. Chronic immune activation underlies morbid obesity: is IDO a key player? Curr Drug Metab. 2007 Apr;8(3):289-95.

74. 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.

75. Smith KA, Williams C, Cowen PJ. Impaired regulation of brain serotonin function during dieting in women recovered from depression. Br J Psychiatry. 2000 Jan;176:72-5.

76. 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.

77. Guilarte TR, Wagner HN Jr. Increased concentrations of 3-hydroxykynurenine in vitamin B6 deficient neonatal rat brain. J Neurochem. 1987 Dec;49(6):1918-26.