Endogenous Metabolite

L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. In this review, after an look at the main natural sources of 5-HTP, the chemical analysis and synthesis, biosynthesis and microbial production of 5-HTP by molecular engineering will be described. The physiological effects of 5-HTP are discussed in both animal studies and human clinical trials. The physiological role of 5-HTP in the treatment of depression, anxiety, panic, sleep disorders, obesity, myoclonus and serotonin syndrome are also discussed. 5-HTP toxicity and the occurrence of toxic impurities present in tryptophan and 5-HTP preparations are also discussed.[2]

The serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) dose dependently (30-100 mg/kg i.p.) increased plasma prolactin and ACTH in the male rat. Prolactin and ACTH responses to 5-HTP (100 mg/kg) were attenuated by pretreatment with the non-selective 5-HT receptor antagonist, metergoline (0.5 mg/kg), and by the selective 5-HT2 receptor antagonists, ritanserin (0.4 mg/kg), ketanserin (2.5 mg/kg), ICI (5.0 mg/kg) and spiperone (1.0 mg/kg). The 5-HT1 receptor antagonists, propranolol (40 mg/kg) and pindolol (4.0 mg/kg), failed to antagonize the prolactin and ACTH responses to 5-HTP (100 mg/kg), as did the selective 5-HT3 receptor antagonist, BRL 43694 (1.0 mg/kg). The results suggest that the prolactin and ACTH responses to 5-HTP in the male rat are mediated by 5-HT2 receptors.[1]

Serotonin has a facilitatory role in the role of prolactin and adrenocorticotropin (ACTH) secretion. The serotonin precursor 5-hydroxy-L-tryptophan (5-HTP) dose dependently (30-100 mg/kg i.p.) increased plasma prolactin and ACTH in the male rat. Prolactin and ACTH responses to 5-HTP (100 mg/kg) were attenuated by pretreatment with the non-selective 5-HT receptor antagonist, metergoline (0.5 mg/kg), and by the selective 5-HT2 receptor antagonists, ritanserin (0.4 mg/kg), ketanserin (2.5 mg/kg), ICI (5.0 mg/kg) and spiperone (1.0 mg/kg). The 5-HT1 receptor antagonists, propranolol (40 mg/kg) and pindolol (4.0 mg/kg), failed to antagonize the prolactin and ACTH responses to 5-HTP (100 mg/kg), as did the selective 5-HT3 receptor antagonist, BRL 43694 (1.0 mg/kg). The results suggest that the prolactin and ACTH responses to 5-HTP in the male rat are mediated by 5-HT2 receptors. [1]

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Single-dose administration of 5-hydroxytryptophan (5-HTP) is regularly used as a challenge test of the serotonergic system. The use of 5-HTP has been limited by an apparent small window between the occurrence of neuroendocrine endpoints and the occurrence of side effects. Therefore, many dosing strategies have been tried with and without concurrent administration of carbidopa, a peripheral inhibitor of the decarboxylation from 5-HTP to serotonin. The aim of the current study was to assess the relation between pharmacokinetics and pharmacodynamics of 5-HTP. Twelve healthy male volunteers were included in a placebo-controlled, randomized, four-way crossover, double-blind, single-dose investigation of oral 5-HTP with or without coadministration of carbidopa. The four dose regimens were placebo, 5-HTP 100 mg, 5-HTP 200 mg, and 5-HTP 100 mg with coadministration of carbidopa 100 mg and 50 mg at 3 hours before and 3 hours after the administration of 5-HTP, respectively. The last regimen resulted in a doubling of the elimination half-life, an apparent clearance at least 14 times smaller, and a 15.4 times greater area under the curve compared with 5-HTP 100 mg without carbidopa. Furthermore, it was the only regimen to induce a significant change in cortisol and prolactin. It did not induce any change in subjective psychologic symptoms or cardiovascular parameters, but it was the only regimen to induce some nausea in three participants. The authors conclude that this regimen of 5-HTP 100 mg plus carbidopa is a relatively simple, effective, and tolerable challenge of the presynaptic serotonergic system. Further increase of the dose of 5-HTP might improve the size of the effect on endpoints as long as the tolerability remains good. [2]

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Previous research showed that lowering the availability of serotonin to the brain by tryptophan depletion increases the vulnerability of panic disorder patients for an experimental 35% CO(2) panic challenge. The results also suggested that increased availability of serotonin inhibits the response to such a challenge. In the present study, this latter possibility is examined. The reaction of 24 panic disorder patients and 24 healthy volunteers to a 35% CO(2) panic challenge was assessed following administration of 200-mg L-5-hydroxytryptophan (the immediate precursor of serotonin) or placebo. L-5-Hydroxytryptophan significantly reduced the reaction to the panic challenge in panic disorder patients, regarding subjective anxiety, panic symptom score and number of panic attacks, as opposed to placebo. No such effect was observed in the healthy volunteers. L-5-Hydroxytryptophan acts to inhibit panic, which supports a modulatory role of serotonin in panic disorder.[3]

Absorption, Distribution and Excretion
The immediate precursor in the serotonin synthetic route, 5-hydroxytryptophan (5-HTP), labeled with 11C in the beta position, has become available for studies using positron emission tomography (PET) to examine serotonin formation in human brain. Normalized uptake and intracerebral utilization of tracer amounts of (beta-11C)5-HTP were studied twice in six healthy male volunteers, three of them before and after pharmacological pretreatments ... Pretreatments with benserazide, p-chlorophenylalanine (PCPA), and unlabeled 5-HTP all significantly increased uptake of (beta-11C)5-HTP. The utilization rates in both striatal and frontal cortex were higher than those in the surrounding brain, indicating that PET studies using (beta-11C)5-HTP as a ligand quantitate selective processes in the utilization of 5-HTP.
The efficiency of absorption of 5HTP, as well as its decarboxylation product serotonin, is approximately 47% to 84%. Absorption of 5-HTP occurs by an active transport process. 5-HTP is transported by the portal circulation to the liver where approximately 25% of an administered dose is metabolized ... . 5-HTP that is not metabolized in the liver is transported by the general circulation to the various tissues of the body, including the brain. 5-HTP readily crosses the blood-brain barrier, and is converted to serotonin in brain cells.

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Metabolism / Metabolites
5-HTP is transported by the portal circulation to the liver where approximately 25% of an administered dose is metabolized via vitamin B6-dependent L-aromatic amino acid decarboxylase to 5-hydroxytryptamine (5-HT) /serotonin/. 5-HT is subsequently metabolized to 5-hydroxyindole acetaldehyde which is rapidly metabolized to 5-hydroxyindole acetaldehyde which is rapidly metabolized to 5-hydroxyindoleacetic acid (5-HIAA).
5-Hydroxytryptophan is decarboxylated to serotonin (5-hydroxytryptamine or 5-HT) by the enzyme aromatic-L-amino-acid decarboxylase with the help of vitamin B6. This reaction occurs both in nervous tissue and in the liver.

Toxicity Summary
5-Hydroxy-L-tryptophan is the immediate precursor of the neurotransmitter serotonin. An accumulation of 5-hydroxy-L-tryptophan in cerebrospinal fluid occurs in aromatic L-amino acid decarboxylase deficiency, accompanied by an increased excretion in the urine of the patients, which are indicative of the disorder. 5-Hydroxy-L-tryptophan easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. Supplementation with 5-hydroxy-L-tryptophan is hypothesized to normalize serotonin synthesis, which is putatively related to its antidepressant properties.

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Toxicity Summary
5-Hydroxy-L-tryptophan is the immediate precursor of the neurotransmitter serotonin. An accumulation of 5-hydroxy-L-tryptophan in cerebrospinal fluid occurs in aromatic L-amino acid decarboxylase deficiency, accompanied by an increased excretion in the urine of the patients, which are indicative of the disorder. 5-Hydroxy-L-tryptophan easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. Supplementation with 5-hydroxy-L-tryptophan is hypothesized to normalize serotonin synthesis, which is putatively related to its antidepressant properties.

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Health Effects
Chronically high levels of 5-hydroxytryptophan are associated with Aromatic L-Amino acid Decarboxylase Deficiency.

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Interactions
5-HTP may decrease the effectiveness of methylsergide and cyproheptadine.

DURATION OF /SRP:CNS DEPRESSION/ INDUCED BY ETHANOL (3.0 G/KG, IP) IN MICE OF BOTH SEXES WAS INCR BY PRETREATMENT WITH 5-HYDROXYTRYPTOPHAN (60 MG/KG, IP).

Concurrent use of 5-HTP with a selective serotonin reuptake inhibitors (SSRI) /citalopram, fluvoxamine maleate, fluoxetine, paroxetine, sertraline, venlafaxine/ may potentiate the antidepressant effect of the SSRI and may also increase the risk of adverse reactions.

Phenoxybenzamine inhibits the conversion of 5-HTP to serotonin.

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Antidote and Emergency Treatment
VET: Treatment consists of early decontamination, control of CNS signs (diazepam, barbiturates), thermoregulation (cool water both, fans), fluid therapy, and administration of a serotonin antagonist such as cyproheptadine ... .

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mouse LD50 intraperitoneal 200 mg/kg National Technical Information Service., AD277-689
mouse LD50 oral >6 gm/kg Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology., 69(523), 1973 [PMID:4546003]
mouse LD50 intraperitoneal 1080 mg/kg Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology., 69(523), 1973 [PMID:4546003]
mouse LD50 intravenous >400 mg/kg Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology., 69(523), 1973 [PMID:4546003]

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Interactions
5-HTP may decrease the effectiveness of methylsergide and cyproheptadine.
DURATION OF /SRP:CNS DEPRESSION/ INDUCED BY ETHANOL (3.0 G/KG, IP) IN MICE OF BOTH SEXES WAS INCR BY PRETREATMENT WITH 5-HYDROXYTRYPTOPHAN (60 MG/KG, IP).
Concurrent use of 5-HTP with a selective serotonin reuptake inhibitors (SSRI) /citalopram, fluvoxamine maleate, fluoxetine, paroxetine, sertraline, venlafaxine/ may potentiate the antidepressant effect of the SSRI and may also increase the risk of adverse reactions.
Phenoxybenzamine inhibits the conversion of 5-HTP to serotonin.
For more Interactions (Complete) data for 5-HYDROXYTRYPTOPHAN (16 total), please visit the HSDB record page.

[1]. Mediation of ACTH and prolactin responses to 5-HTP by 5-HT2 receptors. Eur J Pharmacol. 1990 Apr 10;179(1-2):103-9.

[2]. Placebo-controlled comparison of three dose-regimens of 5-hydroxytryptophan challenge test in healthy volunteers. J Clin Psychopharmacol. 2002 Apr;22(2):183-9.

[3]. Acute L-5-hydroxytryptophan administration inhibits carbon dioxide-induced panic in panic disorder patients. Psychiatry Res. 2002 Dec 30;113(3):237-43.

Therapeutic Uses
5-HTP has shown some usefulness in some conditions characterized, in part, by serotonin deficits, principally depression. It has also been shown to be useful in some with obesity, insomnia, fibromyalgia and chronic tension headache.
It has been long known that brain serotonin systems contribute to the modulation of food intake and satiety. An increase of intrasynaptic serotonin tends to reduce food consumption. Thus, one might consider that individuals taking 5-HTP might experience increase satiety and weight loss over a period of time. There are few studies on the effects of 5-HTP on obesity and they suggest an anorectic effect of 5-HTP.
There is some evidence that 5-HTP ... can improve postural equilibrium, dysarthria in patients with various inherited and acquired cerebellar ataxias, and particularly in those with lesions located precisely in the anterior lobe vermis. Improvements in coordination have been reported in patients with Friedreich"s ataxia; however, the effect is only partial and not clinically major.
Exptl Ther: Rats of the Dahl salt-sensitive (DS) and Dahl salt-resistant (DR) strains were placed on a 4% NaCl diet and blood pressures were monitored. Chronic subcutaneous infusion L-5-hydroxytryptophan (L-5-HTP, 12.6 mg/day) by osmotic minipumps significantly decreased the elevated systolic blood pressure of DS rats on a 4% NaCl diet. Blood pressures of DR rats were unaffected by treatment with L-5-HTP. Cardiac hypertrophy was associated with Dahl salt-induced hypertension. However, treatment with L-5-HTP failed to reduce the weight of the heart significantly. These results suggest that chronic administration of L-5-HTP was effective in reducing the elevated blood pressure in the DS model. The specific mechanisms by which L-5-HTP reduces the elevated blood pressure in DS rats is not clear and remains for further study.
For more Therapeutic Uses (Complete) data for 5-HYDROXYTRYPTOPHAN (6 total), please visit the HSDB record page.

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Drug Warnings
Other reported side effects, include nausea, diarrhea, loss of appetite, vomiting and difficult breathing. Neurological side effects, including dilation of the pupils, abnormally sensitive reflexes, loss of muscle coordination and blurring of vision, have been reported in those taking large doses of 5-HTP. Cardiac dysrhythmias have also been reported.
Eosinophilia and eosinophilia-myalgia syndrome (EMS) have been reported in those taking 5-HTP. The eosinophilia myalgia syndrome is similar to that caused by L-tryptophan and was linked to contaminants in the 5-HTP preparation, rather than 5-HTP itself. Changing the 5-HTP lot in one group of patients resolved the eosinophilia. A scleroderma-like skin condition has been reported in some taking a combination of 5-HTP and carbidopa.
5-HTP should be avoided by pregnant women and nursing mothers.
5-HTP should be avoided by those with ischemic heart disease (history of myocardial infarction, angina pectoris, documented silent ischemia), coronary artery spasm (e.g., Prinzmetal's angina), uncontrollable hypertension and any other significant cardiovascular disease.
For more Drug Warnings (Complete) data for 5-HYDROXYTRYPTOPHAN (8 total), please visit the HSDB record page.

C11H12N2O3

220.23

220.084

56-69-9

144

White to off-white solid

1.5±0.1 g/cm3

520.6±50.0 °C at 760 mmHg

298-300ºC

268.7±30.1 °C

0.0±1.4 mmHg at 25°C

1.737

-0.14

4

4

3

16

272

0

O([H])C1C([H])=C([H])C2=C(C=1[H])C(=C([H])N2[H])C([H])([H])C([H])(C(=O)O[H])N([H])[H]

LDCYZAJDBXYCGN-UHFFFAOYSA-N

InChI=1S/C11H12N2O3/c12-9(11(15)16)3-6-5-13-10-2-1-7(14)4-8(6)10/h1-2,4-5,9,13-14H,3,12H2,(H,15,16)

2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid; 5-hydroxy-DL-tryptophan

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (9.45 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (9.45 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 2.08 mg/mL (9.45 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: ≥ 2.0 mg/mL (9.4 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + + 45% Saline
≥ 2.0 mg/mL (9.4 mM) in 10% DMSO + 90% (20% SBE-β-CD in saline)
≥ 2.0 mg/mL (9.4 mM) in 10% DMSO + 90% Corn oil
5.8 mg/mL (26.0 mM) in PBS, clear solution
20 mg/mL (90.8 mM) in 0.5% CMC-Na/saline water, suspension

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Solubility in Formulation 5: 5.88 mg/mL (26.70 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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Solubility in Formulation 6: 20 mg/mL (90.82 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)