Chemistry and Form

Levotryptophan,L-tryptophan.

Physiology and Function

Tryptophan is one of eight essential amino acids that must be obtained from the diet. Its primary functions include its role in niacin synthesis and as a precursor to both serotonin and melatonin. Approximately 98% of dietaryL-tryptophan is metabolized into nicotinic acid (niacin), and only a very small amount is metabolized into serotonin via the intermediary stage of 5-hydroxytryptophan (5-HTP). The unusual indole side chain of tryptophan serves as the nucleus of serotonin. Serotonin is synthesized through a two-step process involving a tetrahydrobiopterin-dependent hydroxylation reaction (catalyzed by tryptophan-5-monooxygenase) and then a decarboxylation catalyzed by aromaticL-amino acid decarboxylase. Tryptophan hydroxylase (TPH) is the rate-limiting biosynthetic enzyme in the serotonin pathway, regulates levels of serotonin, and is normally only about half-saturated. Serotonin is present at highest concentrations in platelets and in the gastrointestinal (GI) tract. Lesser amounts are found in the brain and the retina. Serotonin in the central nervous system (CNS) is metabolized by monoamine oxidase to 5-hydroxyindoleacetic acid (5-HIAA).

Melatonin ( N-acetyl-5-methoxytryptamine) is derived from serotonin within the pineal gland and the retina, where the necessary N-acetyltransferase enzyme is found.

Known or Potential Therapeutic Uses

Anodyne, antidepressant, antihyperglycemic, antihypertensive, galactagogue, melatonin precursor, niacin precursor, sedative, serotonin precursor.

Possible Uses

Agalactia, anorexia, bulimia, appetite suppression, bipolar disorder, carcinoid syndrome, dementia, depression, fibromyalgia, Hartnup's disease, hypertension, insomnia, mania, menopausal symptoms, migraine headaches, obesity, pain syndromes, parkinsonism, phenylketonuria, psychosis, premenstrual syndrome, schizophrenia, serotonin deficiency syndrome.

Deficiency Symptoms

A deficiency of tryptophan may lead to depression, edema, hair depigmentation, insomnia, lethargy, liver damage, muscle loss, pellagra, slowed growth in children, and suicidal thoughts. Metabolic disturbances associated with tryptophan deficiencies are carcinoid syndrome and Hartnup's disease. Symptoms of serotonin deficiency syndrome (SDS) include nervousness, anxiety, sleep disorders, mood disorders, and excessive appetite.

Dietary Sources

Tryptophan is the least abundant amino acid in foods. It tends to be deficient in most dietary proteins and has an uneven distribution. The richest dietary sources include fish, meat, dairy, eggs, nuts, and wheat germ. The seeds of evening primrose are a particularly rich plant source of tryptophan. There is lingering controversy as to the degree to which dietary levels of tryptophan intake affect serotonin and melatonin levels.

Dosage Forms Available

Capsule.

Source Materials for Nutrient Preparations

SyntheticL-tryptophan is manufactured by a fermentation process using pure glucose as a substrate. The products of fermentation are then separated and purified by filtration and purification procedures.

Dosage Range

Adult

• Dietary:   Minimum daily requirements are estimated as 0.25 g for males and 0.15 g for females.
  • Average U.S. daily intake: 1.0 to 1.5 g.
  • Recommended dietary allowance (RDA): 200 mg per day.
• Supplemental/Maintenance:   Supplementation usually not necessary.
• Pharmacologic/Therapeutic:   0.5 to 4.0 g per day, short-term use. Occasionally, doses of 8 to 12 g daily, given in three or four equally divided doses, are used in the treatment of depression.

WhenL-tryptophan is prescribed within the context of integrative clinical management, the dosage will typically start low and increase gradually as needed. Clinical response will often require 60 days to demonstrate full benefits. Daily dosage usually does not exceed 1 gram per 100 pounds of body weight (1 g/100 lb).

Toxic: 7 g per 150 lb body weight.

Overview

L-Tryptophan is an essential amino acid generally considered to have a low risk of toxicity, when used at typical dietary or supplemental intake levels, barring contraindications.

Nutrient Adverse Effects

General Adverse Effects

Anorexia, dizziness, drowsiness, dry mouth, headache, nausea, sexual disinhibition.

Long-term supplementation or treatment with tryptophan may increase plasma levels of other amino acids, potentially resulting in various adverse effects.

Adults

Studies in humans have shown that 100 mg/kg/day of tryptophan, corresponding to 7 g/150 lb, can cause gastric irritation, vomiting, and head twitching. A dosage of 800 mg/kg given to rhesus monkeys did not produce detectable clinical adverse effects.

Although tryptophan is a naturally occurring substance in the body, controversies surround serious adverse reactions to reported contaminants in bothL-tryptophan and 5-HTP.

Special Issues

During 1989, 35 deaths and many cases of severe allergic reaction, in the form of the eosinophilia-myalgia syndrome characterized by high eosinophil counts, scleroderma-like muscle pain, and thickening of the skin, were associated with consumption of tryptophan supplements. The Food and Drug Administration (FDA) removedL-tryptophan from the U.S. market by pursuant to these events. Subsequent investigation determined that a single manufacturer in Japan had employed a new bacterial strain to synthesizeL-tryptophan, and that this bacterium had introduced toxic byproducts that contaminated particular batches of the product.

As a serotonin precursor,L-tryptophan intake could theoretically contribute to “serotonin syndrome,” an excess accumulation of serotonin in the synapses, characterized by altered mental states, autonomic dysfunction, and neuromuscular abnormalities (see later discussion).

Mutagenicity

Animal tests involving oral or subcutaneous administration ofL-tryptophan or its metabolites have not yielded evidence of statistically significant increases in incidence of neoplasms. However, evidence indicates that foods containing tryptophan may carry an increased risk of carcinogenicity, especially to breast and bladder tissues, when they have been charbroiled or heated to high temperatures.

Life Stage

Inadequate research-based evidence exists to demonstrate any particular age-related effects on pediatric or geriatric populations as a result of increased tryptophan intake.

Pregnancy and Nursing

Well-designed controlled clinical trials with human subjects have not been undertaken, nor have case reports been qualified and systematically analyzed, regarding effects ofL-tryptophan during pregnancy or breastfeeding. In some animals the equivalent of 8 g per day was found to be teratogenic. However,L-tryptophan intake by pregnant women and lactating mothers has not been shown to cause birth defects or other pregnancy or lactation problems. It is not known whetherL-tryptophan passes into breast milk. However,L-tryptophan has not been reported to cause problems in nursing babies. Nevertheless, caution should be used with supplementation or administration during pregnancy or breastfeeding, and any such usage during pregnancy should be supervised and closely monitored.

Laboratory Values

Tryptophan levels in the blood vary greatly when measured by different laboratories. Tryptophan can be measured by fluorometric and high-performance liquid chromatography (HPLC) techniques. Some experts believe chromatography may be the most accurate. Other, indirect methods can also be employed, such as the tryptophan load test. This test involves measuring a metabolite of tryptophan, xanthurenic acid, in the urine after a standard 2-g dose is given. The more xanthurenic acid found in the urine, the greater is the need for either vitamin B6or tryptophan.

Contraindications

Achlorhydria, bladder cancer, cataracts, diabetes mellitus, female infertility, pregnancy, psoriasis; sensitivity toL-tryptophan. May exacerbate rheumatoid arthritis.

Precautions and Warnings

L-Tryptophan is best taken with a low-protein, carbohydrate-rich meal or snack to minimize risk of digestive distress. Also, an insulin response to carbohydrate facilitates transfer of serum tryptophan into the CNS (thought to be the reason serotonin-deficient people crave carbohydrates). Minimizing concomitant protein intake decreases competition between tryptophan and other dietary protein–derived amino acids for transport through the blood-brain barrier.

Strategic Considerations

The therapeutic effects ofL-tryptophan, especially as an antidepressant, are related to its ability to increase serotonin synthesis in the CNS. Emerging research indicates that baseline availability ofL-tryptophan, prolactin, and large, neutral amino acids (LNAAs) are key factors that predict response to antidepressant treatment in major depression. The major concern with tryptophan supplementation or administration with regard to drug interactions is the risk of inducing serotonin syndrome. This potentially dangerous situation results from an excess serotonin availability in the CNS at the 5-HT1A receptor; some interaction with dopamine and 5-HT2 receptors is also likely to be involved. Clinical trials have demonstrated thatL-tryptophan causes a significant increase in the level of the serotonin metabolite, 5-HIAA, in the lumbar cerebrospinal fluid, corresponding to an increased turnover of serotonin in the CNS.

Serotonin syndrome carries potentially serious clinical consequences and is characterized by the triad of altered mental status, autonomic dysfunction, and neuromuscular abnormalities. The serotonin syndrome is similar to the neuroleptic malignant syndrome and is usually differentiated by the setting of recent addition of a serotonergic agent. Specific symptoms can include agitation, anxiety, ataxia, confusion, delirium, diaphoresis, diarrhea, fever, hyperreflexia, myoclonus, incoordination, shivering, nausea, vomiting, or tremor. This phenomenon most often occurs in the presence of selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase (MAO) inhibitors, opioids, and other serotonergic agents, when the serotonin system has been modulated by another serotonergic agent or compromised by illness. SSRIs, particularly fluoxetine, are most frequently involved in reported instances of drug interactions inducing serotonin syndrome; as a consequence of their long elimination half-life (1 week for fluoxetine), the risk of interactions persists for several days or even weeks after SSRI withdrawal.

Many clinicians and some researchers have investigated potential synergistic benefits from coadministration of tryptophan and various psychoactive pharmaceutical agents. Although the consequences of adverse effects can be clinically significant, the available evidence suggests that such risk is less probable, and adverse effects less severe, with tryptophan than with 5-HTP. Caution is requisite to use of tryptophan, in any dose, during antidepressant or other medication therapy, and this warrants close supervision and regular monitoring within an integrative context. 5-HTP should never be combined with SSRIs or MAO inhibitors in any dose, except possibly in a carefully monitored inpatient clinical research setting.

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