Tryptophan

(USAN, rINN)
Tryptophan Chemical formula
Synonyms: Triptofán; Triptofanas; Triptófano; Tryptofaani; Tryptofan; L-Tryptophan; Tryptophane; Tryptophanum; W. yl)propionic acid.
Cyrillic synonym: Триптофан.

💊 Chemical information

Chemical formula: C11H12N2O2 = 204.2.
CAS — 73-22-3.
ATC — N06AX02.
ATC Vet — QN06AX02.

Pharmacopoeias.

In Chin., Eur., Jpn, and US.

Ph. Eur. 6.2

(Tryptophan). A white or almost white crystalline or amorphous powder. Sparingly soluble in water; slightly soluble in alcohol; dissolves in dilute mineral acids and in dilute solutions of alkali hydroxides. Protect from light.

USP 31

(Tryptophan). White to slightly yellowish-white crystals or crystalline powder. Soluble in hot alcohol and in dilute hydrochloric acid. pH of a 1% solution in water is between 5.5 and 7.0.

💊 Adverse Effects

Tryptophan-containing products have been associated with the eosinophilia-myalgia syndrome; for further details, see below. Other adverse effects that have been reported include nausea, headache, lightheadedness, and drowsiness. An increased incidence of bladder tumours has been reported in mice given L-tryptophan orally as well as in cholesterol pellets embedded in the bladder lumen. However, there was no increase in tumour incidence when only high-dose, oral tryptophan was given.

Eosinophilia-myalgia syndrome.

In late 1989 the first notification linking the eosinophilia-myalgia syndrome with the use of tryptophan-containing products was made in the USA.1 There followed a number of similar published case reports from the USA, Europe, and Japan. Reviews of tryptophan-associated eosinophilia-myalgia syndrome have noted that by early 1990 over 1500 cases were known in the USA.2,3 In early 1990 the CDC in the USA summarised the features and known reports concerning the syndrome.4 As the name implies the characteristic features are an intense eosinophilia together with disabling fatigue and muscle pain, although multisystem organ involvement and inflammatory disorders affecting the joints, skin, connective tissue, lungs, heart, and liver have also been recorded. Symptoms have generally developed over several weeks and the syndrome has occurred in patients who had been receiving tryptophan for many years previously with no untoward effect. In most patients slow and gradual improvement in the degree of eosinophilia and other clinical manifestations has followed the withdrawal of tryptophan, but in some patients the disease has progressed despite withdrawal and there have been fatalities.5-7 The inflammatory condition has necessitated the use of corticosteroids in some patients. The eosinophilia-myalgia syndrome has been reported in patients taking both tryptophan-containing prescription products for depression and non-prescription dietary supplements for a number of disorders including insomnia, the premenstrual syndrome, and stress; it does not appear to have occurred in patients receiving amino-acid preparations containing tryptophan as part of total parenteral nutrition regimens. The recognition of this syndrome led to the withdrawal of tryptophan-containing products or severe restrictions being imposed upon their use in many countries during 1990. Various theories were proposed as to the reason for the association of tryptophan with this syndrome. Confusion existed because the reports implicated a very wide range of products from different manufacturers. However, later evidence appeared to have confirmed that contaminated tryptophan had originated from a single manufacturer in Japan.8-10 Bulk tryptophan was imported from Japan for manufacture into finished pharmaceutical dosage forms and it was noted in one of these reports9 that a single product was often found to contain two or more lots of powdered tryptophan that were blended together during the production of tablets or capsules. Many trace contaminants have been found in batches of tryptophan associated with the syndrome.11One contaminant has been identified as 1,1′-ethylidenebis(tryptophan).12 Its inclusion in bulk tryptophan powder appeared to coincide with alterations in the manufacturing conditions that involved a change in the strain of Bacillus amyloliquefaciens used in the fermentation process and a reduction in the amount of charcoal used for purification.9 Other investigations indicated the presence of bacitracin-like peptides in batches of the contaminated tryptophan.13 However, further work14 has provided only weak support for an association between the syndrome and any one particular contaminant and the causative agent remains to be confirmed. Nonetheless, since the syndrome only appeared to be associated with tryptophan from one manufacturer, tryptophan preparations were reintroduced in the UK in 1994 for restricted use under carefully monitored conditions.15 In January 2005, the UK requirement for patient registration and monitoring was removed.
1. Anonymous. Eosinophilia-myalgia syndrome—New Mexico. MMWR 1989; 38: 765–7
2. Troy JL. Eosinophilia-myalgia syndrome. Mayo Clin Proc 1991; 66: 535–8
3. Milburn DS, Myers CW. Tryptophan toxicity: a pharmacoepidemiologic review of eosinophilia-myalgia syndrome. DICP Ann Pharmacother 1991; 25: 1259–62
4. Kilbourne EM, et al. Interim guidance on the eosinophilia-myalgia syndrome. Ann Intern Med 1990; 112: 85–6
5. Anonymous. Eosinophilia-myalgia syndrome associated with ingestion of -tryptophan—United States, through August 24, 1990. JAMA 1990; 264: 1655
6. Kaufman LD, et al. Clinical follow-up and immunogenetic studies of 32 patients with eosinophilia-myalgia syndrome. Lancet 1991; 337: 1071–4
7. Hertzman PA, et al. The eosinophilia-myalgia syndrome: status of 205 patients and results of treatment 2 years after onset. Ann Intern Med 1995; 122: 851–5
8. Slutsker L, et al. Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA 1990; 264: 213–17
9. Belongia EA, et al. An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 1990; 323: 357–65
10. Varga J, et al. The cause and pathogenesis of the eosinophiliamyalgia syndrome. Ann Intern Med 1992; 116: 140–7
11. Hill RH, et al. Contaminants in L-tryptophan associated with eosinophilia myalgia syndrome. Arch Environ Contam Toxicol 1993; 25: 134–42
12. Mayeno AN, et al. Characterization of "peak E", a novel amino acid associated with eosinophilia-myalgia syndrome. Science 1990; 250: 1707–8
13. Barnhart ER, et al. Bacitracin-associated peptides and contaminated -tryptophan. Lancet 1990; 336: 742
14. Philen RM, et al. Tryptophan contaminants associated with eosinophilia-myalgia syndrome. Am J Epidemiol 1993; 138: 154–9
15. CSM/MCA. L-Tryptophan (Optimax): limited availability for resistant depression. Current Problems 1994; 20: 2. Also available at: http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE& dDocName=CON2024457&RevisionSelectionMethod= LatestReleased (accessed 05/08/08)

💊 Precautions

Tryptophan has been associated with eosinophilia-myalgia syndrome (see above); caution is advised in patients receiving the drug who develop some, but not all, of the symptoms of this syndrome. It should not be used in those with a history of eosinophilia-myalgia syndrome associated with tryptophan treatment. Patients taking tryptophan may experience drowsiness and, if affected, they should not drive or operate machinery. For further details of the effects of antidepressant therapy on driving see under Amitriptyline. Abnormal metabolism of tryptophan may occur in patients with pyridoxine deficiency and tryptophan is thus sometimes given with pyridoxine supplements.

💊 Interactions

Although tryptophan has been given to patients receiving MAOIs in the belief that clinical efficacy may be improved, it should be noted that the adverse effects may also be potentiated. For further details, see Antidepressants under Interactions of Phenelzine. Use of tryptophan with drugs that inhibit the reuptake of serotonin may exacerbate the adverse effects of the latter and precipitate the serotonin syndrome. There have been occasional reports of sexual disinhibition in patients taking tryptophan with phenothiazines or benzodiazepines. For a report of tryptophan reducing blood concentrations of levodopa, see Nutritional Agents under Interactions of Levodopa.

💊 Pharmacokinetics

Tryptophan is readily absorbed from the gastrointestinal tract. Tryptophan is extensively bound to plasma albumin. It is metabolised in the liver by tryptophan pyrrolase and tryptophan hydroxylase. Metabolites include hydroxytryptophan, which is then converted to serotonin, and kynurenine derivatives. Some tryptophan is converted to nicotinic acid and nicotinamide. Pyridoxine and ascorbic acid are cofactors in the decarboxylation and hydroxylation, respectively, of tryptophan; pyridoxine apparently prevents the accumulation of the kynurenine metabolites.
1. Green AR, et al. The pharmacokinetics of -tryptophan following its intravenous and oral administration. Br J Clin Pharmacol 1985; 20: 317–21.

💊 Uses and Administration

Tryptophan is an amino acid that is an essential constituent of the diet. Tryptophan and DL-tryptophan have been used as dietary supplements. Tryptophan is a precursor of serotonin. Because CNS depletion of serotonin is considered to be involved in depression, tryptophan has been used in its treatment. Although it has been given alone, evidence of effectiveness is scant and tryptophan has generally been used as adjunctive therapy in depression. It has sometimes been given with pyridoxine and ascorbic acid, which are involved in its metabolism to serotonin (see Pharmacokinetics, above). In many countries preparations containing tryptophan have either been withdrawn from the market or their availability severely restricted or limited because of its association with the eosinophilia-myalgia syndrome. In the UK, tryptophan is restricted to use as an adjunct to other antidepressant medication or in patients who have failed to respond to an adequate trial of standard antidepressant drug treatment. Therapy should be started by hospital specialists; thereafter tryptophan may be prescribed in the community. In the treatment of depression the usual oral dose of tryptophan is 1 g given three times daily, but some patients may require up to 6 g daily in divided doses. Lower doses may be required in the elderly especially those with renal or hepatic impairment.

Depression.

Evidence of benefit for tryptophan when given alone for depression is lacking, though there is some suggestion of a weak antidepressant effect.1 It has therefore mainly been used with other antidepressants in the belief that it would potentiate their effects. Although beneficial effects have been reported in some patients given tryptophan with SSRIs, tricyclic antidepressants, or MAOIs, either alone or with lithium, evidence of efficacy is mainly limited to case reports and small controlled studies.2-4 After the publication of reports linking the use of tryptophan with the eosinophilia-myalgia syndrome (see under Adverse Effects, above) preparations containing tryptophan for depression were withdrawn from the market or their use restricted. For details of UK restrictions see Uses and Administration, above.
1. Shaw K, et al. Tryptophan and 5-hydroxytryptophan for depression. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2002 (accessed 24/11/05)
2. Barker WA, et al. The Newcastle chronic depression study: results of a treatment regime. Int Clin Psychopharmacol 1987; 2: 261–72
3. Smith S. Tryptophan in the treatment of resistant depression—a review. Pharm J 1998; 261: 819–21
4. Levitan RD, et al. Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects. J Psychiatry Neurosci 2000; 25: 337–46.

Dietary supplementation.

The use of tryptophan as a dietary supplement has been reviewed.1 However, because of its association with the eosinophilia-myalgia syndrome (see under Adverse Effects, above), the addition of tryptophan to food intended for human consumption is prohibited in some countries.
1. Li Wan Po A, Maguire T. Tryptophan: useful dietary supplement or a health hazard? Pharm J 1990; 244: 484–5.

Insomnia.

Tryptophan, sometimes in the form of dietary supplements, has enjoyed some popularity for the treatment of insomnia. However, in comparison with other hypnotics such as the benzodiazepines, the effects of tryptophan have been difficult to substantiate, and enthusiasm for tryptophan has waned considerably amongst sleep researchers.1 It should also be noted that since the publication of reports linking the use of tryptophan with the eosinophilia-myalgia syndrome (see under Adverse Effects, above) preparations indicated for insomnia have been withdrawn from the market in many countries.
1. Lahmeyer HW. Tryptophan for insomnia. JAMA 1989; 262: 2748.

💊 Preparations

Proprietary Preparations

Austria: Kalma; Canad.: Tr yptan; Ger.: Ardeydorm; Ardeytropin; Kalma; UK: Optimax. Multi-ingredient: Fr.: Vita-Dermacide; Ital.: Brioplus; Fisioreve; USA: PDP Liquid Protein.
Published December 18, 2018.