Tryptophan was first isolated in 1901, from the milk protein casein, by Sir Frederick Gowland Hopkins. By feeding mice a diet devoid of tryptophan, he was later able to demonstrate that it is essential for animal life. As well, he demonstrated that tryptophan and several other amino acids cannot be manufactured in the body and must be obtained from the diet. He was awarded the Nobel Prize for his discovery of vitamins, produced by amino acids like tryptophan.

During the 1980s, consumers were using tryptophan as a sleep aid and as a natural antidepressant. Tryptophan was available without prescription until 1991 when the FDA prohibited its over-the-counter sale because a tryptophan manufacturer (Showa Denko KK) in Japan shipped a contaminated batch to the U.S. The contaminant caused, in selected individuals, a serious autoimmune illness called eosinophilia myalgia syndrome. About 1,500 individuals experienced this serious illness, including 37 deaths. All of the data available pointed to the contaminant as being the causative factor in the illnesses but the FDA suppressed the facts from the public and kept the ban in place for over ten years before allowing small scale controlled sales to the public.

Around 2002, tryptophan gradually became available by prescription through compounding pharmacies. L-tryptophan has only been openly available since 2007.

An interesting side note is the fact that before the ban L-tryptophan was one of the most widely consumed nutritional supplements in the world. Prescription antidepressants were around but were not commonly prescribed medications, being mainly prescribed by psychiatrists. Within weeks after the ban of L-tryptophan, Prozac® was released becoming one of the best selling medications of all time. Coincidence maybe, maybe not.

An evening milkshake spiked with the amino acid tryptophan may help clear the morning mental fog of the sleep-deprived, preliminary research suggests.

In a study of 28 healthy young adults, researchers found that accompanying an evening meal with a milkshake containing a protein powder called alpha-lactalbumin -- which delivers a high concentration of tryptophan -- seemed to improve morning alertness among participants who had mild sleep problems. "Good" sleepers, on the other hand, showed no such benefit.

Alpha-lactalbumin, or A-LAC, is a protein derived from the whey component of milk (as found in our Gold Isolate Plus - Whey Protein Powder). It contains a high concentration of the essential amino acid tryptophan, a protein building-block best known for its sleep-inducing effects. In the body, tryptophan serves as a precursor for the brain chemical serotonin, which, among other things, is thought to help regulate sleep.

Tryptophan is found in foods such as beef, chicken, dairy products and, most famously, turkey -- which is often blamed for the near-coma that follows Thanksgiving dinner. In reality, however, the relatively low concentration of tryptophan in turkey and other foods is unlikely to affect the brain because it must compete with other amino acids and nutrients for absorption.

In their study, Markus and his colleagues examined whether an A-LAC protein powder, with its high concentration of tryptophan, could increase the ratio of tryptophan to other amino acids in participants' blood -- and whether there would be any difference in their mental alertness the next morning. Fourteen men and women with mild sleep problems, and 14 others without sleep complaints took part in two experiments on separate evenings -- one in which they consumed a tryptophan - fortified milkshake with dinner and later for a snack, and one in which they had "placebo" milkshakes that did not contain the A-LAC supplement. The next morning, participants took a computerized test that measured their mental reaction times, while electrodes placed on their scalps recorded their brain activity. Markus and his colleagues found that participants' blood levels of tryptophan were more than twice as high on the night they dined on the supplemented milkshakes compared with the placebo milkshakes.

More importantly, men and women who normally had sleep problems performed better on the mental-alertness test on the morning after having the tryptophan - containing milkshakes. On the other hand, tryptophan made no difference to the performance of the 14 participants with no sleep problems. SOURCE: American Journal of Clinical Nutrition, May 2005.

Tryptophan and behavior

Social behaviour and mood in everyday life: the effects of tryptophan in quarrelsome individuals.
J Psychiatry Neurosci. 2006 Jul;31(4):253-62. aan het Rot M, Moskowitz DS, Pinard G, Young SN. Department of Psychiatry, McGill University, 1033 Pine Avenue West, Montreal, Quebec.
We hypothesized that increasing brain serotonin in healthy individuals with high scores on 2 self-report measures of trait quarrelsomeness would reduce quarrelsome behaviours and enhance agreeable behaviours when measured ecologically using an event-contingent recording method. We conducted a double-blind crossover study, in which participants took tryptophan at 3 grams a day and placebo for 15 days each and recorded how they behaved, felt and perceived others during everyday social interactions.

Tryptophan supplement use significantly decreased quarrelsome behaviours and increased agreeable behaviours and perceptions of agreeableness. Men also behaved less dominantly, whereas both men and women perceived others as more dominant. Tryptophan's effects on behaviours and perceptions, while more marked in the men, were generally positive and accompanied by improved affect. Increasing serotonin in quarrelsome people may not only reduce behaviours associated with a predisposition to various mental and physical disorders but also enhance socially constructive behaviours and improve social perceptions.

Tryptophan and the immune response

Effect of orally administered L-tryptophan on serotonin, melatonin, and the innate immune response in the rat.
Mol Cell Biochem. 2004 Dec;267(1-2):39-46.
To assess the effects of external administration of L- tryptophan on the synthesis of serotonin and melatonin as well as on the immune function of Wistar rats, 300 mg of the amino acid were administered either during daylight (08:00) or at night (20:00) for 5 days. Brain, plasma, and peritoneal macrophage samples were collected 4 h after the administration. The accumulation of 5-hydroxytryptophan ( 5HTP ) after decarboxylase inhibition was used to measure the rate of tryptophan hydroxylation in vivo. The results showed a diurnal increase in the brain 5HTP, serotonin (5-hydroxytryptamine, 5-HT), and 5-hydroxyindolacetic acid (5-HIAA) of the animals which had received tryptophan at 08:00 and were killed 4 h later. In the animals which received tryptophan during the dark period, the 5-HT declined but the 5-HT/5-HIAA ratio remained unchanged. There was also a significant increase in nocturnal circulating melatonin levels.

The results indicated that the synthesis of serotonin and melatonin, as well as the innate immune response, can be modulated by oral ingestion of tryptophan.

The appetite reducing effect of increasing doses of L-tryptophan in obese patients

Eat Weight Disord. 1997 Dec;2(4):211-5.
Serotonin synthesis in neurons is initiated by hydroxylation of the essential amino acid L-tryptophan. Treatments that raise the level of L-tryptophan in the brain can rapidly alter the rate at which it is converted to serotonin. This paper compares the effect of 1, 2 and 3 g L-tryptophan administered 1 h before a plated meal on total food intake and carbohydrate and protein consumption in 10 obese subjects versus a lactose placebo in another 10 obese subjects. There was a progressive decrease in carbohydrate consumption in function of the tryptophan dose: placebo 131 g; one g tryptophan 123 ; two g 114; three g 107. Protein consumption was less affected. These results provide further support for the view that serotoninergic mechanisms play a role in the regulation of human food intake. They are also consistent with the hypothesis that nutrients which increase serotonin availability selectively alter carbohydrate consumption. Further studies with modified molecules of naturally occurring tryptophan (hydroxytryptophan hydrochloride or diethylpropionate) may offer a potential field for the treatment of pathological ingestive behavior.

Comment: Those who consumed 3 grams of L-Tryptophan one hour before eating consumed 18% less carbohydrates than did the group receiving a placebo or 428 calories versus 524 calories consumed by the placebo group. At 3,500 calories to gain one pound of weight, the group that consumed 3 grams of L-tryptophan before eating would lose one pound of fat in a month. Dr. E

Pyridoxine, regardless of serotonin levels, increases production of 5-hydroxytryptophan in rat brain

Arch Med Res. 2004 Jul-Aug;35(4):271-4.
The aim of this study was to evaluate effects of pyridoxine (vitamin B6) and butylated hydroxytoluene (BHT) on lipid peroxidation and on levels of 5-hydroxy-tryptophan and serotonin. Thirty rats (30 days of age) were used in the survey, measuring levels of lipid peroxidation (TBARS), hemoglobin, 5-hydroxy tryptophan, and serotonin (5-HT) after intraperitoneal injections of pyridoxine HCl during 20 days and a single dose of BHT. RESULTS: Levels of TBARS and 5-HTP increased considerably in all vitamin B6 and/or BHT-treated groups, and serotonin increased partially only in B(6) with or without BHT-treated groups compared with control group.

CONCLUSIONS: Results suggest that pyridoxine (vitamin B6) plays a role in tryptophan metabolism, increasing production of 5-hydroxy tryptophan.

Acute administration of nutritionally sourced tryptophan increases fear recognition

Psychopharmacology (Berl). 2003 Aug;169(1):104-7.
The serotonin precursor tryptophan has been widely used as a nutritional supplement and antidepressant. Recently, however, the use of tryptophan has been severely restricted due to its association with the eosinophilic myalgic syndrome, an autoimmune disorder probably caused by ingestion of a contaminant produced in certain tryptophan manufacturing processes. To determine the bioavailability of a nutritional source of tryptophan obtained from milk protein and to assess whether administration of this material produced neuroendocrine and neuropsychological effects consistent with increased brain serotonin activity. METHODS: We studied 24 healthy subjects who ingested approximately 1.8 g of nutritionally-sourced tryptophan or placebo in a double-blind, parallel group, design. We carried out venous sampling for amino acid and hormone estimation and performed a test of emotional processing using a facial expression recognition task. RESULTS: The nutritionally-sourced tryptophan caused a substantial increase in the availability of tryptophan in plasma. Relative to placebo the tryptophan material produced some evidence of an increase in plasma cortisol, and enhanced the perception of fearful and happy facial expressions.

CONCLUSIONS: A nutritional source of tryptophan increased the availability of tryptophan for brain serotonin synthesis and produced endocrine and neuropsychological changes consistent with increased brain serotonin function. The effect of tryptophan on emotional processing may be relevant to its reported activity in primate studies of social behaviour.

Additional research data involving L-Tryptophan

The effect of a nutritional source of tryptophan on dieting-induced changes in brain 5-HT function

Psychol Med. 2003 Nov;33(8):1381-6.
Dieting in healthy women results in a decrease in the availability of tryptophan, the amino-acid precursor of serotonin, for brain serotonin synthesis. This is associated with increases in the prolactin response to serotonin drug challenge suggesting a 'super sensitivity' of serotonin neuroendocrine responses. The aim of the study was to assess whether increased tryptophan intake during dieting would prevent the changes in tryptophan availability and serotonin neuroendocrine function. Fifty female subjects underwent a 1000 kcal daily diet for 3 weeks. In the final week of the diet subjects were randomly allocated to receive either nutritionally-sourced tryptophan (1.8 g daily) or placebo in a double-blind, parallel group, design. RESULTS: Tryptophan supplementation failed to modify the dieting-induced reduction in fasting tryptophan availability to the brain. However, in contrast to placebo-treated subjects, subjects receiving additional tryptophan did not show enhanced prolactin responses to intravenous tryptophan challenge. CONCLUSIONS: The decrease in tryptophan availability produced by dieting may be due to increased tryptophan metabolism rather than decreased tryptophan intake. While tryptophan treatment did not increase fasting tryptophan availability it may have modified the effect of dieting on brain serotonin function. Further studies will be needed to see if this effect of tryptophan has consequences for the effectiveness of dieting as means of weight control.

Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment

Biol Psychiatry. 2003 Nov 1;54(9):906-14.
Tryptophan degradation into kynurenine (KYN) during immune activation may contribute to development of depressive symptoms during interferon (IFN)-alpha therapy. Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine (Paxil®), beginning 2 weeks before IFN-alpha treatment and continuing for the first 12 weeks of IFN-alpha therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-alpha treatment, measurements of tryptophan, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity. RESULTS: Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in tryptophan concentrations than did non-depressed, antidepressant-free patients. Moreover, in antidepressant-free patients, decreases in tryptophan correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. CONCLUSIONS: The results suggest that reduced tryptophan availability plays a role in IFN-alpha-induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-alpha, attenuates the behavioral consequences of IFN-alpha-mediated tryptophan depletion.

Lowering of serotonin by rapid tryptophan depletion increases impulsiveness in normal individuals

Psychopharmacology (Berl). 2002 Dec;164(4):385-91. Epub 2002 Oct 12.
Reduced serotonergic activity has been associated with impulsive behavior; however, intervention studies have been scarce. OBJECTIVES: To examine whether induced lowering of serotonin (5-HT) levels would increase behavioral measures of impulsivity. Twenty-four healthy young males ingested a mixture of the essential amino acids except for tryptophan in a balanced, randomized, double-blind, placebo-controlled, cross-over study design. The continuous-performance test-identical pairs was administered when the plasma concentration of tryptophan was expected to be at the lowest point. The plasma concentrations of 23 amino acids were measured at baseline and 5 h after the ingestion of the amino acid mixture. RESULTS: The intervention led to a dramatic fall in free and total plasma tryptophan, and the tryptophan /large neutral amino acids ratio. This in turn has been shown to lower the level of 5-HT in the central nervous system. The tryptophan depletion resulted in a statistically significant more impulsive- or disinhibited response style on the continuous-performance test-identical pairs when the subjects were solving verbal tasks. Depleted subjects exposed to spatial stimuli had fewer correct responses and a decreased ability to discriminate between stimuli. CONCLUSIONS: These results indicate that a rapid lowering of tryptophan increases impulsiveness and decreases discriminating ability in normal individuals.

The effect of serotonin depletion on discriminating ability in this study was similar to that previously reported in depressed patients.

Effects of a novel method of acute tryptophan depletion on plasma tryptophan and cognitive performance in healthy volunteers

Psychopharmacology (Berl). 2004 Jul 22
Disorders associated with low levels of serotonin (5-HT) are characterized by mood and cognitive disturbances. Acute tryptophan depletion is an established method for lowering 5-HT levels and an important tool to study the effects of reduced 5-HT on mood and cognition in human subjects. The University of Maastricht developed a new and inexpensive method for acute tryptophan depletion: a natural collagen protein (CP) mixture with low tryptophan content. The reductions in plasma tryptophan after taking this CP mixture were compared with the reductions achieved taking the traditional AA mixture, and effects on memory and reversal learning were studied. METHODS. Fifteen healthy young volunteers participated in a double-blind, counterbalanced within-subject study. Reversal learning, verbal memory and pattern recognition were assessed at baseline and 3-4 h after taking the CP mixture. RESULTS. The new acute tryptophan depletion method significantly reduced plasma tryptophan by 74% and the ratio between tryptophan and the other large AAs by 82%. The placebo mixture did not change these measures. Delayed recognition reaction time on the verbal learning task was increased following acute tryptophan depletion. No other cognitive effects were found. CONCLUSIONS. The CP mixture was shown to be an efficient tool for lowering plasma tryptophan in humans. The validity of this method with regard to behavioral changes remains to be established in healthy, vulnerable and clinical populations.

Effect of supplemental tryptophan, vitamin E, and a herbal product on responses by pigs to vibration

J Anim Sci. 2004 Aug;82(8):2410-20.
Economic losses related to increased stress during the transport of pigs are well documented. The effects of supplementing of tryptophan, vitamin E, or a herbal product via feed or drinking water were investigated in terms of effects on stress response in pigs during transport simulation. The study consisted of three analogous experiments. For the testing in each experiment, the pigs were allocated to one of two treatments, with and without supplementation of a product. The applied doses were tryptophan, vitamin E, and Sedafit. Sedafit is a commercial herbal product containing Valeriana officinalis L. and Passiflora incarnata L. as active components. Pigs supplemented with tryptophan tended to spend more time lying down during the second hour of vibration (transport simulation). Vitamin E decreased the peak heart rate, ventricular ectopic beats, and ST elevation. In conclusion, tryptophan had a positive behavioral effect in this experiment, and vitamin E and Sedafit mediated an increase in some heart variables, suggesting sedative and antianxiety effects.

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