Tryptophan

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References

Adachi J, Ueno Y, Tatsuno Y, Gomez M, Smith CC, Sternberg EM. A comparative study of tissue distribution and excretion among three substances implicated in eosinophilia-myalgia syndrome. Adv Exp Med Biol. 1996;398:365-370.

Adachi J, Gomez M, Smith CC, Sternberg EM. Accumulation of 3-(phenylamino)alanine, a constituent in L-tryptophan products implicated in eosinophilia-myalgia syndrome, in blood and organs of the Lewis rats. Arch Toxicol. 1995;69(4):266-270.
Abstract: 3-(Phenylamino)alanine (PAA), a newly discovered impurity in case-associated L-tryptophan tablets, has been investigated as a possible contributing factor in the etiology of eosinophilia-myalgia syndrome (EMS). We have studied distribution and elimination of PAA in rats which were administered a single 5 mg/kg dose of PAA by gastric gavage. PAA concentrations in blood, brain, kidney and liver were measured by high-performance liquid chromatography (HPLC) with electrochemical detection. The concentration of PAA in each tissue reached a maximum at 5 h, and then gradually declined. A high level of PAA still remained at 24 h, indicating gradual elimination. The concentration of PAA in brain at 5 h was 2139 ng/g tissue, demonstrating passage through the blood-brain barrier. Consecutive administration of PAA (5 mg/kg) for 4 days resulted in approximately double the concentration in all tissues. Chronic treatment using PAA incorporated into food pellets for 6 weeks resulted in similar accumulations in each tissue, and following 12 days on a PAA free diet, levels of this drug were still detectable in all tissues.

Adams PW, Rose DP, Folkard J, Wynn V, Seed M, Strong R. Effect of pyridoxine hydrochloride (vitamin B6) upon depression associated with oral contraception. Lancet 1973 Apr 28;1(7809):899-904.

Adams PW, Wynn V, Folkard J, Seed M. Influence of oral contraceptives, pyridoxine (vitamin B6), and tryptophan on carbohydrate metabolism. Lancet 1976 Apr 10;1(7963):759-764.
Abstract: Carbohydrate metabolism and vitamin-B6 status were assessed before and after pyridoxine administration in 46 women taking combined oestrogen-progestagen oral contraceptives (O.C.). 18 women had evidence of tissue depletion of vitamin B6, although all the women had abnormal tryptophan metabolism, including increased urinary xanthurenic acid (X.A.) excretion. In the women with vitamin B6 deficiency, administration of this vitamin caused elevation of fasting blood-pyruvate levels, and reduction in plasma glucose, insulin, and blood-pyruvate responses after an oral glucose load. These changes in carbohydrate metabolism were not found in the 28 non-vitamin-B6-deficient women. These results indicate that carbohydrate intolerance in women on O.C. is unlikely to be mediated by the formation of a complex of X.A. with insulin, as has formerly been proposed. Since the synthesis of the tryptophan metabolite quinolinic acid, an inhibitor of the heptaic enzyme phosphoenolpyruvate carboxykinase, may be enhanced by the administration of pyridoxine, it is suggested that this metabolite might be the important factor in the improvement of glucose tolerance in the vitamin-B6-deficient women. This conclusion is supported by the improvement in glucose tolerance observed in 6 women on O.C. and in 4 patients with glucocorticoid excess who were not vitamin-B6 deficient, when they were given tryptophan to augment the synthesis of quinolinic acid.

Alvine G, Black DW, Tsuang D. Case of delirium secondary to phenelzine/L-tryptophan combination. J Clin Psychiatry 1990 Jul;51(7):311. (Letter)

Bamji MS, Safaya S, Prema K. Low dose injectable contraceptive norethisterone enanthate 20mg monthly - II. Metabolic side effects. Contraception 1981 Jan;23(1):23-36.
Abstract: Metabolic effects of a long-acting low dose injectable contraceptive, norethisterone enanthate 20-mg, monthly injections (Neten-20), was tested in 13 women belonging to the low income groups over a period of 1 year. No change was observed in hemoglobin, hematocrit, glucose tolerance, plasma lipids, iron, calcium, or serum glutamate-oxaloacetate transaminase after treatment. Marginal rise in albumin and fall in some globulin fractions was observed. The slight fall seen in serum alkaline phosphatase could be attributed to a change in lactation status. Vitamin A, pyridoxine and riboflavin status were not altered. A peculiar aberration in the tryptophan-niacin pathway as indicated by rise in kynurenic acid excretion after tryptophan load was observed. This could be corrected by multivitamin therapy. These data suggest that the use of Neten-20 for one year does not lead to adverse metabolic effects analogous to those seen with combination type oral contraceptives.

Barr LC, Heninger GR, Goodman W, Charney DS, Price LH. Effects of fluoxetine administration on mood response to tryptophan depletion in healthy subjects. Biol Psychiatry. 1997 May 1;41(9):949-954.
Abstract: Short-term reduction in plasma tryptophan (tryptophan depletion) produces a relapse of depressive symptoms in 60% of previously depressed patients recently recovered with serotonin reuptake inhibitor treatment. Tryptophan depletion does not consistently increase depressive symptoms in unmedicated depressed patients or in depressed patients whose symptoms are remitted with a norepinephrine reuptake inhibitor. These data suggest that serotonin reuptake inhibitor treatment itself may confer vulnerability to the development of depressive symptoms during tryptophan depletion. In order to further investigate this possibility, six healthy individuals underwent double-blind placebo-controlled tryptophan depletion before and following six weeks of treatment with fluoxetine 20 mg/day. No increased vulnerability to the mood-lowering effects of tryptophan depletion occurred as a result of fluoxetine treatment. Additionally, fluoxetine treatment itself was not associated with changes in mood or quality of life in these healthy volunteers. These data indicate that serotonin reuptake inhibitor treatment alone does not produce the depressive effects of tryptophan depletion that are observed in serotonin reuptake inhibitor-treated depressed and obsessive compulsive disorder patients.

Brenneman DE, Page SW, Schultzberg M, Thomas FS, Zelazowski P, Burnet P, Avidor R, Sternberg EM. A decomposition product of a contaminant implicated in L-tryptophan eosinophilia myalgia syndrome affects spinal cord neuronal cell death and survival through stereospecific, maturation and partly interleukin-1-dependent mechanisms. J Pharmacol Exp Ther. 1993 Aug;266(2):1029-1035.
Abstract: The L-tryptophan eosinophilia myalgia syndrome (L-TRP-EMS), an inflammatory syndrome characterized by eosinophilia, myalgias, perimyositis, fasciitis and neuropathies, occurred in epidemic proportions in the United States in the summer and fall of 1989. The neuropathic clinical features in L-TRP EMS are complex and mixed. In the present study, one of the impurities most highly associated with development of L-TRP EMS, 1,1'-ethylidenebis[L-tryptophan] (EBT), and two of its diastereoisomeric breakdown products, were compared for evidence of neurotoxicity in vitro. In 1-month-old spinal cord cultures derived from fetal mice, synthetic (-)-(1S,3S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1S-beta-C) produced a 30 to 35% loss in numbers of neurons. Toxicity was not apparent after treatment with the R-isomer of the same compound or with the parent compound, EBT. Cotreatment of cultures with 1S-beta-C and neutralizing antiserum to interleukin-1 alpha (IL-1 alpha), or with 1S-beta-C and neutralizing antiserum against the murine IL-1 receptor, prevented neuronal cell death associated with 1S-beta-C. Recombinant IL-1 alpha also produced neuronal killing that was not additive to that observed with the 1S-beta-C treatment. In contrast, in immature spinal cord neuronal cultures, the 1S-beta-C, but not the 1R-beta-C or EBT, prevented the 30% cell death which normally occurs in these cultures. Neither neutralizing anti-IL-1 antibody, nor anti-IL-1 receptor antibody blocked the neuronal survival effect, suggesting that 1S-beta-C induces neuronal survival through a receptor-mediated mechanism independent of IL-1.

Brown RR, Rose DP, Leklem JE, Linkswiler HM. Effects of oral contraceptives on tryptophan metabolism and vitamin B6 requirements in women. Acta Vitaminol Enzymol 1975;29(1-6):151-157.
Abstract: To evaluate the effect of oral contraceptive usage on the nutritional requirement for vitamin B6, control women and oral contraceptive users were depleted of vitamin B6 for 1 month followed by a month of repletion with 0.8, 2.0, or 20.0 mg of pyridoxine hydrochloride per day. At weekly intervals a number of indices of vitamin B6 nutrition were measured. Marked elevation in excretion of tryptophan metabolites occurred in oral contraceptive users after tryptophan loads. However, other indices of vitamin B6 nutritional state, including urinary 4-pyridoxic acid excretion, urinary cystathionine excretion, plasma pyridoxal phosphate concentrations, and erythrocyte aspartate and alanine aminotransferases were not different between controls and oral contraceptive users. The excretion of metabolites after oral loading doses of L-kynurenine (which bypasses tryptophan oxygenase) was elevated in oral contraceptive users indicating that abnormal metabolism of tryptophan was not due only to induced tryptophan oxygenase. The data indicate that use of oral contraceptives does not generally change the requirement for vitamin B6 but rather produces a specific change in activity of enzymes beyond kynurenine in the pathway of tryptophan metabolism.

Byerley WF, Judd LL, Reimherr FW, Grosser BI. 5-hydroxytryptophan: A review of its antidepressant efficacy and adverse effects . J Clin Psychopharmacol 1987 Jun;7(3):127-137. (Review)
Abstract: Alterations in serotonin metabolism may be an important factor in the etiology and treatment of depression. In this regard, 5-hydroxytryptophan (5-HTP), a serotonin precursor, has been given to patients with depression. Although a review of these studies suggests that 5-HTP possesses antidepressant properties, additional trials are clearly indicated. Following a discussion of the pharmacology of 5-HTP, the authors highlight adverse effects associated with its administration to depressed patients, neurologic subjects, and normal individuals. Relatively few adverse effects are associated with its use in the treatment of depressed patients.

Cangiano C, Ceci F, Cascino A, Del Ben M, Laviano A, Muscaritoli M, Antonucci F, Rossi-Fanelli F. Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan. Am J Clin Nutr. 1992 Nov;56(5):863-867.
Abstract: Previous observations have shown that oral administration of 5-hydroxytryptophan (5-HTP) without dietary prescriptions causes anorexia, decreased food intake, and weight loss in obese subjects. To confirm these data over a longer period of observation and to verify whether adherence to dietary restriction could be improved by 5-HTP, 20 obese patients were randomly assigned to receive either 5-HTP (900 mg/d) or a placebo. The study was double-blinded and was for two consecutive 6-wk periods. No diet was prescribed during the first period, a 5040-kJ/d diet was recommended for the second. Significant weight loss was observed in 5-HTP-treated patients during both periods. A reduction in carbohydrate intake and a consistent presence of early satiety were also found. These findings together with the good tolerance observed suggest that 5-HTP may be safely used to treat obesity.

Caruso I, Sarzi Puttini P, Cazzola M, Azzolini V. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. J Int Med Res 1990 May-Jun;18(3):201-209.
Abstract: A double-blind, placebo-controlled study of the efficacy and tolerability of 5-hydroxytryptophan (5-HTP) was conducted in 50 patients with primary fibromyalgia syndrome. All the clinical parameters studied were significantly improved by treatment with 5-HTP and only mild and transient side-effects were reported. Further controlled studies are required to define properly the value of 5-HTP in patients with primary fibromyalgia syndrome.

Ceci F, Cangiano C, Cairella M, et al. The effects of oral 5-hydroxytryptophan administration on feeding behavior in obese adult female subjects. J Neural Transmission 1989;76(2):109-117.
Abstract: Nineteen obese female subjects with body mass index ranging between 30 and 40 were included in a double-blind crossover study aimed at evaluating the effects of oral 5-hydroxytryptophan administration on feeding behavior, mood state and weight loss. Either 5-hydroxytryptophan (8 mg/kg/day) or placebo was administered for five weeks during which patients were not prescribed any dietary restrictions. Feeding behavior was investigated by means of a questionnaire designed to establish the onset of anorexia and related symptoms. Food intake was evaluated using a three-day diet diary. BDI, SI, STAI-T, and STAI-S were used to assess mood state. The administration of 5-hydroxytryptophan resulted in no changes in mood state but promoted typical anorexia-related symptoms, decreased food intake and weight loss during the period of observation.

Chan BS, Graudins A, Whyte IM, Dawson AH, Braitberg G, Duggin GG. Serotonin syndrome resulting from drug interactions. Med J Aust 1998 Nov 16;169(10):523-525.
Abstract: We describe six patients diagnosed with serotonin syndrome after exposure to drugs with serotonergic activity. Drug interactions occurred as a result of a combination of tricyclic antidepressants, selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors or monoamine oxidase inhibitors. Management included supportive care and the use of non-specific serotonin antagonists (cyproheptadine, benzodiazepines and chlorpromazine). All patients made uneventful recoveries.

De Benedittis G, Massei R. Serotonin precursors in chronic primary headache. A double-blind cross-over study with L-5-hydroxytryptophan vs. placebo. J Neurosurg Sci. 1985 Jul-Sep;29(3):239-248.
Abstract: Serotonin (5-HT) plays a crucial role in mediating the descending pain inhibitory systems and in the pathophysiology of migraine. Previous studies regarding the use of 5-Hydroxytryptophan (5-HTP), the active precursor of 5-HT, in the treatment of Chronic Primary Headache (CPH) have been inconclusive so far. In order to assess the efficacy of the serotonin active precursor in chronic headache prophylaxis, a double-blind cross-over study has been carried out in 31 patients with CPH, comparing L-5-HTP to placebo. Clinical syndromes included: (a) migraine (16 patients); (b) mixed headache (6 patients); (c) psychogenic headache (5 patients); (d) muscle contraction headache (4 patients). L-5-HTP was administered for two months at daily doses of 400 mg p.o. The reduction in severity and frequency of headache in patients taking the active drug and placebo was noted. Mood patterns were also taken into consideration. L-5-HTP proved to be more effective than placebo in reducing both headache frequency and severity, but the difference was not statistically significant. Favourable responses (greater than 50% average reduction in headache symptoms) were obtained in 48% of the cases after the second month of treatment. No significant difference in therapeutic response was observed as related to different clinical syndromes, except for psychogenic headache patients, who responded poorly to the active drug. Side effects, experienced in 19% of the cases, were generally mild and transient. We conclude that L-5-HTP is a medication of moderate efficacy and remarkable safety, providing us with another alternative approach to CPH prophylaxis.

De Giorgis G, Miletto R, Iannuccelli M, Camuffo M, Scerni S. Headache in association with sleep disorders in children: A psychodiagnostic evaluation and controlled clinical study—L-5-HTP versus placebo. Drugs Exptl Clin Res 1987;13:425-433.

den Boer JA, Westenberg HG. Behavioral, neuroendocrine, and biochemical effects of 5-hydroxytryptophan administration in panic disorder. Psychiatry Res 1990 Mar;31(3):267-278.
Abstract: L-5-Hydroxytryptophan (5HTP) was administered to 20 patients suffering from panic disorder and to 20 healthy controls. Subjects received 60 mg 5HTP in 300 ml saline solution. Before, during, and up to 2 hours after 5HTP administration, symptoms of anxiety and depression were assessed. In addition, plasma 5HTP, 3-methoxy-4-hydroxyethylglycol (MHPG), cortisol, beta-endorphin, and melatonin levels were measured at several time points, and the kinetics of 5-hydroxytryptamine (5HT) in blood platelets were measured. During and after the infusion of 5HTP, none of the patients showed an increase in anxiety or depressive symptoms, despite the presence of severe side effects. Some patients even experienced the 5HTP infusion as a relief. In contrast to the patients, nine control subjects reported depressed mood, although no increases in anxiety were noted. In both patients and controls, the 5HTP infusion led to substantial increases in plasma cortisol and beta-endorphin levels, while the plasma MHPG level was unchanged. Plasma melatonin increased significantly after 5HTP administration, suggesting that increasing 5HT availability in man might affect melatonin synthesis. The results of this study are at odds with the hypothesis that there is a supersensitivity of 5HT2 receptors in panic disorder.

Fuller RW. Biochemical pharmacology of the serotonin system. Adv Neurol. 1986;43:469-480. (Review)

Goff DC. Two cases of hypomania following the addition of L-tryptophan to a monoamine oxidase inhibitor. Am J Psychiatry 1985 Dec;142(12):1487-1488.
Abstract: The combination of L-tryptophan and a monoamine oxidase inhibitor (MAOI) has been reported to be an effective antidepressant regimen. Neurotoxicity has previously been associated with this combination. The author presents two cases of hypomania following the addition of L-tryptophan to an MAOI.

Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998, 82-83.

Irwin MR, Marder SR, Fuentenebro F, Yuwiler A. L-5-hydroxytryptophan attenuates positive psychotic symptoms induced by D-amphetamine. Psychiatry Res. 1987 Dec;22(4):283-289.
Abstract: Brain serotonin has been hypothesized to be involved in the modulation of psychotic symptoms in at least some forms of schizophrenia. We examined the effects of the serotonin precursor L-5-hydroxytryptophan (5HTP) on D-amphetamine induction of acute psychotic symptoms in schizophrenic patients. Preadministration with 5HTP significantly antagonized amphetamine-elicited elevations in thought disturbance, activation, and hallucinations.

Kimball RW, Friedman AP, Vallejo E. Effect of serotonin in migraine patients. Neurology 1960;10:107-111.

Lee NS, Muhs G, Wagner GC, Reynolds RD, Fisher H. Dietary pyridoxine interaction with tryptophan or histidine on brain serotonin and histamine metabolism. Pharmacol Biochem Behav. 1988 Mar;29(3):559-564.
Abstract: We studied the metabolic effects of high dietary intakes of pyridoxine and of the substrate-cofactor interaction between dietary histidine or tryptophan and pyridoxine in rat brain. In the substrate-cofactor interaction study, histamine and serotonin levels were determined in rats fed elevated or requirement levels of substrate (histidine: 0.3% and 0.8%, tryptophan: 0.15% and 0.6%) and excess or requirement levels of pyridoxine HCl (7 mg vs. 3,000 mg/kg). Excess pyridoxine intake caused a differential effect on brain histamine concentration--inhibitory with the requirement level of histidine (-29%), and stimulatory (+21%) with the elevated level of histidine. When dietary tryptophan was fed at the requirement level, excess pyridoxine caused essentially no changes in hypothalamic serotonin and 5HIAA (-2%, -2%). With elevated tryptophan intake, excess pyridoxine significantly increased serotonin and 5HIAA (+32%, +20%) in the hypothalamus. These results indicate a clear interaction between substrate and coenzyme precursor which influences brain metabolism of histamine and serotonin.

Levy AB, Bucher P, Votolato N. Myoclonus, hyperreflexia and diaphoresis in patients on phenelzine-tryptophan combination treatment. Can J Psychiatry 1985 Oct;30(6):434-436.
Abstract: Three cases are presented on patients on an MAOI who developed a transient syndrome of myoclonus, hyperreflexia, jaw quivering, teeth chattering and diaphoresis after L-Tryptophan was added. Caution is advised when considering the addition of a serotonergic agent to MAOI's.

Livingston MG, et al. Monoamine oxidase inhibitors. An update on drug interactions. Drug Saf. 1996 Apr;14(4):219-27. (Review)
Abstract: After initial enthusiasm, the use of monoamine oxidase inhibitors (MAOIs) has been limited by the wide range of MAOI-drug and MAOI-food interactions that are possible, particularly with sympathomimetic medications or tyramine-containing foods, resulting in hypertensive reactions. Despite their clinical benefits, this has led to a reduction in use of such medications. Discovery of the 2 main subgroups of monoamine oxidase, types A and B, led to the synthesis of MAOIs selective for one or other of these isoenzymes. Consequently, selegiline (deprenyl), a selective MAO-B inhibitor, was developed for the treatment of idiopathic Parkinson's disease. This drug is useful in the treatment of the early stages of the disease and later on as an adjunct to other drug therapies. Although the selective MAO-A inhibitor, clorgiline (clorgyline), was found to be effective in the treatment of depression, it still retained the potential to cause hypertensive reactions. Recently, agents that are not only selective, but reversible in their inhibition of MAO-A (RIMAs) have been synthesised (e.g. moclobemide and toloxatone), and have proven antidepressant efficacy. While they are less likely to induce hypertensive reactions with the concomitant administration of sympathomimetic drugs or with tyramine-rich foodstuffs, it still seems wise to advocate care in co-prescribing potentially interacting medications and to advise a degree of caution with regard to the dietary intake of foodstuffs likely to contain a high tyramine content. Although these newer drugs represent an advance in safety, their use has, as yet, only been established in the treatment of depression. RIMAs also retain a potential for adverse interaction with other drugs. Concomitant prescription of serotonin-enhancing drugs should only be undertaken with caution for patients on moclobemide, toloxatone or selegiline. Coprescription of sympathomimetic drugs should also be avoided with these newer MAOIs and patients should be advised against purchasing over-the-counter preparations that may contain sympathomimetic drugs.

Maissen CP, Ludin HP. Comparison of the effect of 5-hydroxytryptophan and propranolol in the interval treatment of migraine . Schweiz Med Wochenschr. 1991 Oct 26;121(43):1585-1590. [Article in German]
Abstract: The efficacy of 5-hydroxytryptophan and propranolol has been studied in the interval treatment of migraine. 39 migraine patients have participated in a double-blind trial. After a placebo run-in of one month, the patients received either 5-hydroxytryptophan or propranolol for 4 months. The treatment with both substances resulted in a statistically significant reduction in frequency of migraine attacks. Furthermore, in the propranolol group the duration of the attacks and the number of analgesics used for treatment of the attacks were significantly reduced. Although propranolol, which is considered a reference for the interval treatment of migraine, is more effective, 5-hydroxytryptophan is a possible alternative for many patients.

Marley E, Wozniak KM. Interactions of non-selective monoamine oxidase inhibitors, tranylcypromine and nialamide, with inhibitors of 5-hydroxytryptamine, dopamine or noradrenaline re-uptake. J Psychiatr Res 1984;18(2):191-203.
Abstract: Rats pretreated with tranylcypromine and given clomipramine, developed head and body twitches, forelimb flexor-extensor movements and wet dog shakes, phenomena which failed to develop when pretreatment incorporated p-chlorophenylalanine (PCPA) but were unabated when this included alpha-methyl-p-tyrosine (AMPT). Locomotor activity, itself enhanced by tranylcypromine, was further and significantly elevated compared to saline, by clomipramine or imipramine in grouped rats (n = 3) but not in single or paired rats; desipramine lacked such action. This effect of clomipramine was prevented when PCPA was incorporated into the pretreatment and that of imipramine by including PCPA or AMPT. Brain monoamine oxidase (MAO) A inhibition was 92% and that of MAO B, 80%. Cortical hydroxytryptamine (5-HT) and noradrenaline concentrations as well as hypothalamic 5-HT, were significantly elevated by tranylcypromine, as was dopamine in the striatum, nucleus accumbens and tuberculum olfactorium. Hyperthermia developed in tranylcypromine pretreated rats given paroxetine or fluoxetine. Myoclonic phenomena were elicited by paroxetine, fluoxetine, clomipramine or imipramine in nialamide pretreated rats but these were less intense than in rats pretreated with phenelzine or tranylcypromine. Fatalities were fewer than in rats pretreated with tranylcypromine or phenelzine. Brain MAO A inhibition was 92% and that of MAO B, 69%.

Marz, Russell. Medical Nutrition From Marz. Second Edition. Portland, OR. 1997.

Mathew NT. 5-hydroxytryptophan in the prophylaxis of migraine. Headache 1978;18:111-113.

Meltzer H, Bastani B, Jayathilake K, Maes M.  Fluoxetine, but not tricyclic antidepressants, potentiates the 5-hydroxytryptophan-mediated increase in plasma cortisol and prolactin secretion in subjects with major depression or with obsessive compulsive disorder. Neuropsychopharmacology. 1997 Jul;17(1):1-11.
Abstract: It has been suggested that the clinical efficacy of chronic treatment with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and perhaps all antidepressants is due to their ability to enhance serotonergic activity. The effects of chronic treatment with fluoxetine or tricyclic antidepressants on the L-5-hydroxytryptophan (200 mg, L-5-HTP; PO)-induced increases in plasma cortisol and prolactin (PRL) concentrations were studied in patients with major depression or obsessive compulsive disorder (OCD). Administration of L-5-HTP increased plasma cortisol and PRL levels in medicated and unmedicated patients with major depression or OCD. The L-5-HTP-induced cortisol and PRL responses were significantly higher in fluoxetine-treated than in tricyclic-treated or unmedicated major depressed patients. The latter two groups did not differ significantly in their cortisol or PRL responses to L-5-HTP. The L-5-HTP-induced increases in cortisol and PRL in fluoxetine-treated patients with major depression or OCD were not significantly different. The results suggest that fluoxetine, but not tricyclic antidepressants, potentiates 5-HT receptor-mediated stimulation of cortisol and PRL secretion in humans, consistent with available evidence that fluoxetine treatment, but not tricyclic antidepressants, increases central serotonergic activity in patients with MD or OCD by a presynaptic mechanism.

Messiha FS. Fluoxetine: adverse effects and drug-drug interactions. J Toxicol Clin Toxicol 1993;31(4):603-630.
Abstract: This overview summarizes the major and minor side effects and drug interactions of fluoxetine. The adverse reactions include the "serotonin syndrome", cardiovascular complications, extrapyramidal side effects such as akathisia, dyskinesias, and parkinsonian-like syndromes and an apparently increased risk of suicidality. Fluoxetine-induced mania and hypomania, seizures and sexual disorders are evaluated along with minor symptoms of allergic reactions, stuttering, hematological changes, psoriasis, and inappropriate secretion of the antidiuretic hormone. The major fluoxetine-drug interactions involve the amino acids L-dopa and L-tryptophan, anorexiants, anticonvulsants, antidepressants, anxiolytics, calcium channel blockers, cyproheptadine, lithium salts, and drugs of abuse. The underlying mechanism and the paradoxical effects of fluoxetine are addressed.

Meyer JS, Welch KM, Deshmukh VD, Perez FI, Jacob RH, Haufrect DB, Mathew NT, Morrell RM. Neurotransmitter precursor amino acids in the treatment of multi-infarct dementia and Alzheimer's disease. J Am Geriatr Soc. 1977 Jul;25(7):289-298.
Abstract: Ten patients with severe dementia due to Alzheimer's disease (AD) or multi-infarct dementia (MID) or both, were treated with the precursor amino acids of the neurotransmitters serotonin and dopamine. The precursor amino acids (PAA) were given orally in a preparation that included tyrosine (4 gm daily) and 5-hydroxy-tryptophan (5-HTP) (800 mg daily), plus carbidopa (100 mg daily) as an aromatic amino-acid decarboxylase inhibitor. Diagnosis was established by an electroencephalogram, brain scan, computerized axial tomographic scan, and in one case by necropsy findings. Serial clinical evaluations and measurements of neuropsychologic function were performed. Levels of homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) were determined before and after administration of probenecid. Side effects of the PAA therapy were diarrhea, drowsiness, nausea, vomiting and agitation, all of which were controlled by reducing the dosage. One patient with MID and one with AD+MID showed clinical and psychologic improvement, but the others did not improve. Analysis of the cerebrospinal fluid for HVA and 5-HIAA before and after the probenecid test indicated some improvement in the metabolic turnover of these acid metabolites of serotonin and dopamine after administration of their precursor amino acids.

Michelson D, Page SW, Casey R, et al. An eosinophilia-myalgia syndrome related disorder associated with exposure to L-5-hydroxytryptophan. J Rheumatol 1994 Dec;21(12):2261-2265.
Abstract: OBJECTIVE. To determine whether L-5-hydroxytryptophan (L-5-HTP) associated with eosinophiliamyalgia syndrome (EMS) like illness contains impurities in a fashion similar to that described in L-tryptophan associated with EMS. METHODS. Members of a family who became ill after exposure to L-5-HTP were evaluated at the National Institutes of Health. Data from patients with extended exposure to L-5-HTP were also examined. Samples of L-5-HTP were examined using high performance liquid chromatography. RESULTS. One member of the family had EMS, and 2 others had eosinophilia. No patient in the other group reviewed developed the syndrome, although 2 patients developed eosinophilia. The L-5-HTP used by the family contained an impurity not present in samples from the other patient group. After replacement with L-5-HTP not containing this impurity, eosinophilia in 2 family members resolved. CONCLUSION. Some L-5-HTP contains impurities that may be related to L-5-HTP associated EMS.

Poldinger W, Calanchini B, Schwarz W. A functional-dimensional approach to depression: Serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine. Psychopathology 1991;24(2):53-81.
Abstract: H.M. van Praag has been suggesting a reappraisal of syndromes in psychiatry for over 20 years. He has tried to define syndromes originating from the same biochemical disorder. He has denoted this concept as 'functional psychopathology'. As an example of such a functional syndrome, he has cited the serotonin-shortage syndrome which unifies various psychiatric symptoms under a new point of view. The treatment of the serotonin-shortage syndrome is best served by psychopharmaca which raise the metabolism of serotonin in the synaptic cleft, e.g. the selective serotonin re-uptake inhibitors. Borrowing F. Freyhan's concept of 'target symptoms', one can now speak of 'functional target syndromes', within the frame of functional psychopathology.

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):491-492.
Abstract: The combination of monoamine oxidase inhibitors and tryptophan--a recognized antidepressant regimen--has been reported to cause behavioral or neurologic toxicity. The authors present eight cases of delirious syndromes apparently attributable to this combination of agents.

Pronsky, Zaneta. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991, 60.

Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: MacMillan, 1984.

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.

Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985.

Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds. Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.

Rose DP, Adams PW. Oral contraceptives and tryptophan metabolism: effects of oestrogen in low dose combined with a progestagen and of a low-dose progestagen (megestrol acetate) given alone. J Clin Pathol 1972 Mar;25(3):252-258.

Russell IJ, Michalek JE, Vipraio GA, Fletcher EM, Javors MA, Bowden CA. Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome. J Rheumatol 1992 Jan;19(1):104-109.
Abstract: The density of serotonin reuptake receptors on peripheral platelets from 22 patients with primary fibromyalgia syndrome (FS) and the serum serotonin concentrations in 9 patients with FS were compared with those of matched healthy controls. The mean serum serotonin concentration was lower (p = 0.01) in FS than in controls, while the binding of 3H-imipramine was higher (p = 0.035) and normalized with treatment using a combination of ibuprofen and alprazolam. Improvement in selected clinical measures of FS disease activity during treatment correlated with the change in platelet 3H-imipramine binding. These findings support the proposed hypothesis of aberrant pain perception in FS resulting from a deficiency of serotonin.

Schneider-Helmert D, Spinweber CL. Evaluation of L-tryptophan for treatment of insomnia: A review. Psychopharmacology (Berl) 1986;89(1):1-7.
Abstract: Sleep laboratory and outpatient studies of the hypnotic efficacy of the amino acid L-tryptophan are reviewed, with particular emphasis on evaluation of therapeutic effectiveness in the treatment of insomnia. In younger situational insomniacs, whose sleep problem consists solely of longer than usual sleep latencies, L-tryptophan is effective in reducing sleep onset time on the first night of administration in doses ranging from 1 to 15 g. In more chronic, well-established sleep-onset insomnia or in more severe insomnias characterized by both sleep onset and sleep maintenance problems, repeated administration of low doses of L-tryptophan over time may be required for therapeutic improvement. In these patients, hypnotic effects appear late in the treatment period or, as shown in some studies, even after discontinuation of treatment. The improvement in sleep measures post-treatment has given rise to use of a treatment regimen known as "interval therapy", in which L-tryptophan treatment alternates with an L-tryptophan-free interval until improvement occurs. The absence of side effects and lack of development of tolerance in long-term use are important factors in the decision to embark upon a trial of L-tryptophan treatment. In addition, L-tryptophan administration is not associated with impairment of visuomotor, cognitive, or memory performance, nor does it elevate threshold for arousal from sleep.

Silver RM, McKinley K, Smith EA, Quearry B, Harati Y, Sternberg EM, Heyes MP. Tryptophan metabolism via the kynurenine pathway in patients with the eosinophilia-myalgia syndrome. Arthritis Rheum 1992 Sep;35(9):1097-105.
Abstract: OBJECTIVE. To investigate the metabolism of L-tryptophan (LT) via the kynurenine pathway in patients with the eosinophilia-myalgia syndrome (EMS). METHODS. Measurement of LT, L-kynurenine, and quinolinic acid in plasma and cerebrospinal fluid (CSF) from subjects with EMS, from asymptomatic users of LT, and from normal subjects. RESULTS. Plasma LT concentrations were lower in untreated EMS patients (n = 5) than in corticosteroid-treated EMS patients (n = 5; P less than 0.05) and in asymptomatic users of LT (n = 5; P less than 0.05). Untreated EMS patients, who had discontinued LT weeks to months prior to study, had significantly higher plasma levels of L-kynurenine and quinolinic acid than did corticosteroid-treated EMS patients (P less than 0.05), normal subjects (P less than 0.02), and asymptomatic users of LT (P less than 0.05). EMS patients also had significantly elevated levels of L-kynurenine (P less than 0.05) and quinolinic acid (P less than 0.001) in CSF compared with normal subjects. After a 1-gm oral dose of LT, untreated EMS patients (n = 4) showed lower peak levels of LT and accentuated synthesis of L-kynurenine and quinolinic acid, compared with these values in corticosteroid-treated EMS patients (n = 2), who responded like normal subjects (n = 5). CONCLUSION. These data demonstrate that during the active phase of EMS, LT metabolism via the kynurenine pathway was accentuated, probably secondary to induction of the enzyme indoleamine-2,3-dioxygenase. Ingestion of large amounts of LT (median daily dose 1.5 gm) resulted in high concentrations of kynurenine-pathway metabolites in blood and extrahepatic tissues, which was accentuated in EMS patients and which may have played a significant role in the pathogenesis of the disease.

Smith KA, Fairburn CG, Cowen PJ. Symptomatic relapse in bulimia nervosa following acute tryptophan depletion. Arch Gen Psychiatry 1999 Feb;56(2):171-176.

Soulairac A, Lambinet H. [Clinical studies of the effect of the serotonin precursor, L-5-hydroxytryptophan, on sleep disorders]. Schweiz Bundschau Med (PRAXIS) 1998;77(34a):19-23. [Article in French]

Sternberg EM, Van Woert MH, Young SN, Magnussen I, Baker H, Gauthier S, Osterland CK. Development of a scleroderma-like illness during therapy with L-5-hydroxytryptophan and carbidopa. New Engl J Med 1980 Oct 2;303(14):782-787.
Abstract: A scleroderma-like illness developed in a patient treated with L-5 hydroxytryptophan (L-5HTP) and carbidopa for intention myoclonus. The patient had high plasma kynurenine levels that remained high when the L-5HTP-carbidopa combination was discontinued, However, levels rose futher on drug rechallenge, suggesting that the drug unmasked an abnormality in one of the enzymes that catabolize kynurenine. Plasma kynurenine was also determined to be high in seven of 15 patients wth idiopathic scleroderma, but not in eight patients with intention myoclonus treated with L-5HTP and a decarboxylase inhibitor and in whom scleroderma did not develop or in 10 patients with Parkinson's disease treated wth L-dopa and carbidopa. Our data and studies in the literature suggest that two factors may be important in the pathogenesis of some scleroderma-like illness: high plasma serotonin and the abnormality associated with elevated kynurenine.

Sternberg EM. Pathogenesis of L-tryptophan eosinophilia myalgia syndrome. Adv Exp Med Biol 1996;398:325-330.
Abstract: Taken together, these studies suggest that many different etiologic agents alone or together may initiate the common final pathways of tissue pathologic response resulting in the clinical syndrome of eosinophilia, myalgias and fasciitis. Tryptophan itself may contribute to some of the scarring features of the illness, while impure L-tryptophan, and one or more of the impurities cause the characteristic features of the illness. The altered tryptophan metabolism in EMS is secondary to inflammation.

Threlkeld DS, ed. Central Nervous System Drugs, Antidepressants, Selective Serotonin Reuptake Inhibitors. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparison, Apr 1997.

Titus F, Davalos A, Alom J, Codina A. 5-hydroxytryptophan versus methysergide in the prophylaxis of migraine. Eur Neurol. 1986;25(5):327-329.
Abstract: One hundred and twenty-four migraineurs were treated randomly with 5-hydroxytryptophan (5-HTP) or with methysergide (M). The two groups were homogeneous without significant statistical differences with respect to age, sex, pill use, type of migraine and frequency of attacks before entry. A significant improvement was observed in 75% of the patients treated with M and in 71% of the cases treated with 5-HTP. The most beneficial effect of 5-HTP appears to be felt with regard to the intensity and duration rather than the frequency of the attacks. Side effects were more frequent in the M group than in the 5-HTP group. These results suggest that 5-HTP could be a treatment of choice in the prophylaxis of migraine.

van Praag HM, Lemus C. Monoamine precursors in the treatment of psychiatric disorders. Nutrition and the Brain. Vol. 7, eds. RJ Wurtman, JJ Wurtman. New York: Raven Press, 1986. (Review)

Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review).

Williamson BL, Tomlinson AJ, Glleich GJ, et al. Problems with over-the-counter 5-hydroxytryptophan. Nature Med 1998 Sep;4(9):983.

Wolfe F, Russell IJ, Vipraio G, Ross K, Anderson J. Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population. J Rheumatol 1997 Mar;24(3):555-559.
Abstract: OBJECTIVE: To investigate the association of serum serotonin with fibromyalgia (FM), and to study the relationship of serotonin to clinical variables associated with FM. METHODS: Serum samples (n = 292) were obtained on subjects without pain, with regional pain, and with widespread pain during a population survey. The tender point examination was made according to American College of Rheumatology examination criteria by an examiner blind to the subjects' complaints. Serotonin was determined by high performance liquid chromatography coupled to an electrochemical detector. RESULTS: No associations between clinical variables and serotonin levels were found in the group as a whole. Subjects with FM had lower serotonin levels unadjusted (p = 0.019) and adjusted for age and sex (p = 0.059) than those without FM. Within the FM group, associations between serotonin and tender point count (r = 0.563) and depression (r = 0.549) were noted, but the direction of association was opposite to previous reports and expectations. CONCLUSION: Serum serotonin levels are significantly lower in persons with FM compared to those without FM, but the range of values is wide. Difficult to explain correlations with reversed directions are noted for tender point count, dolorimetry, depression, and anxiety among those with FM. Serotonin is not correlated with any clinical variables in the general population, and separate pain groups cannot be distinguished.

Wynn V, Adams PW, Folkard J, Seed M. Tryptophan, depression and steroidal contraception. J Steroid Biochem 1975 Jun;6(6):965-970.

Yunus MB, Dailey JW, Aldag JC, Masi AT, Jobe PC. Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study. J Rheumatol. 1992 Jan;19(1):90-94.
Abstract: To test the hypothesis that plasma tryptophan and/or its transport ratio is decreased in primary fibromyalgia (PF), we measured plasma tryptophan and its transport ratio in 29 patients with PF and 30 healthy controls without significant pain, in a blinded manner. Twenty-one other amino acids were also similarly analyzed among these study subjects. Transport ratio of tryptophan was found to be significantly (p less than 0.01) decreased in PF compared with the control group (0.09 +/- 0.02 vs 0.10 +/- 0.02). Plasma tryptophan level was lower in PF (45 +/- 10 nmol/ml) than in healthy controls (51 +/- 15 nmol/ml), showing a trend towards significance (p less than 0.09). Additionally, plasma histidine and serine levels were found to be significantly (p less than 0.01) lower in patients with PF than in controls. Our results suggest that a decreased brain serotonin level, as possibly reflected by a decreased transport ratio of plasma tryptophan, may play a pathophysiologic role in PF.

Zmilacher K, Battegay R, Gastpar M. L-5-hydroxytryptophan alone and in combination with a peripheral decarboxylase inhibitor in the treatment of depression. Neuropsychobiology 1988;20(1):28-35.
Abstract: In an open study 25 depressed patients were treated with L-5-hydroxytryptophan (L-5-HTP) either alone or in combination with a peripheral decarboxylase inhibitor. The therapeutic efficacy of L-5-HTP was considered as equal to that of traditional antidepressants. There was no difference in efficacy between the two treatments. Best results were obtained in patients with an anxious-agitated depressive syndrome and in patients with an endogenous depression if the illness had been acute. The onset of action was rapid (within 3 or 5 days). Gastrointestinal side effects proved to be dose-dependent and occurred more frequently in patients receiving L-5-HTP alone, whereas psychopathological side effects (especially acute anxiety states) have mainly been reported in patients receiving L-5-HTP in combination with a peripheral decarboxylase inhibitor.