Endogenous Metabolite
5-hydroxytryptophan (5-HTP) targets 5-HT2 receptors [1]

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]

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In male Wistar rats, intraperitoneal administration of 5-hydroxytryptophan (5-HTP) (100 mg/kg) significantly increased plasma ACTH and prolactin levels. The ACTH response was elevated by ~2.8-fold, and prolactin by ~3.2-fold compared to control. Pretreatment with 5-HT2 receptor antagonists (ritanserin, ketanserin) completely blocked these hormonal responses [1]
- In healthy volunteers (n=12), oral administration of 5-hydroxytryptophan (5-HTP) (100, 200, 400 mg) in a placebo-controlled crossover study induced dose-dependent increases in plasma prolactin and cortisol. At 400 mg, prolactin levels peaked at 2 hours (increase by ~3.5-fold) and cortisol at 1 hour (increase by ~1.8-fold). The 400 mg dose showed the most robust hormonal responses without severe adverse effects [2]
- In patients with panic disorder (n=10), oral administration of 5-hydroxytryptophan (5-HTP) (200 mg) significantly inhibited carbon dioxide (CO2)-induced panic attacks. The frequency of panic attacks was reduced by ~65%, and panic severity scores (0–10 scale) decreased from ~8.2 to ~3.1 compared to placebo. It also reduced subjective anxiety and respiratory discomfort during CO2 challenge [3]

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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\nSingle-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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\nPrevious 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]

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\n5-HT2 receptor-mediated hormonal response rat model: Male Wistar rats (200–250 g) were randomly divided into control, 5-HTP alone, and 5-HTP + 5-HT2 antagonist groups. 5-hydroxytryptophan (5-HTP) was dissolved in normal saline and administered intraperitoneally at 100 mg/kg. 5-HT2 antagonists (ritanserin, ketanserin) were administered intraperitoneally 30 minutes before 5-HTP. Blood samples were collected via cardiac puncture 30 minutes after 5-HTP administration, and plasma ACTH and prolactin levels were measured by radioimmunoassay [1]

Absorption, Distribution and Excretion
5-hydroxytryptophan (5-HTP), a direct precursor in the serotonin synthesis pathway, is labeled with β-11C and is now available for positron emission tomography (PET) studies to detect serotonin production in the human brain. This study measured the uptake and brain utilization of (β-11C)5-HTP tracers twice in six healthy male volunteers, with measurements performed before and after drug pretreatment in three of the volunteers… Pretreatment with benserazide, p-chlorophenylalanine (PCPA), and unlabeled 5-HTP significantly increased the uptake of (β-11C)5-HTP. Utilization rates in the striatum and frontal cortex were higher than in peripheral brain tissue, indicating that PET studies using (β-11C)5-HTP as a ligand can quantitatively analyze the selective processes involved in 5-HTP utilization. The absorption efficiency of 5-HTP and its decarboxylation product serotonin is approximately 47% to 84%. Absorption of 5-HTP occurs via an active transport process. 5-HTP is transported to the liver via the portal vein circulation, where approximately 25% of the administered dose is metabolized… 5-HTP not metabolized in the liver is transported through systemic circulation to tissues throughout the body, including the brain. 5-Hydroxytryptophan (5-HTP) readily crosses the blood-brain barrier and is converted to serotonin in brain cells. Metabolites/Metabolites: 5-HTP is transported to the liver via the portal vein circulation, where approximately 25% of the administered dose is metabolized to 5-hydroxytryptophan (5-HT)/serotonin by vitamin B6-dependent L-aromatic amino acid decarboxylases. 5-HT is subsequently metabolized to 5-hydroxyindoleacetaldehyde, which is rapidly metabolized to 5-hydroxyindoleacetic acid (5-HIAA).
With the help of vitamin B6, 5-hydroxytryptophan is decarboxylated to serotonin (5-hydroxytryptamine or 5-HT) by aromatic L-amino acid decarboxylases. This reaction occurs in nerve tissue and the liver.

Toxicity Summary
5-Hydroxy-L-tryptophan is a direct precursor to the neurotransmitter serotonin. Aromatic L-amino acid decarboxylase deficiency leads to the accumulation of 5-hydroxy-L-tryptophan in the cerebrospinal fluid, accompanied by increased urinary excretion of 5-hydroxy-L-tryptophan, a typical manifestation of the disease. 5-Hydroxy-L-tryptophan readily crosses the blood-brain barrier and effectively increases serotonin synthesis in the central nervous system (CNS). Supplementation with 5-hydroxy-L-tryptophan is believed to restore normal serotonin synthesis, possibly related to its antidepressant properties. 5-Hydroxy-L-tryptophan readily crosses the blood-brain barrier and effectively promotes serotonin synthesis in the central nervous system (CNS). Supplementation with 5-Hydroxy-L-tryptophan is thought to normalize serotonin synthesis, which may be related to its antidepressant properties.

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Health Effects
Long-term high levels of 5-hydroxytryptophan are associated with aromatic L-amino acid decarboxylase deficiency.

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Interactions
5-HTP may reduce the efficacy of methylergoline and cyproheptadine.
In male and female mice, the duration of CNS depression induced by ethanol (3.0 g/kg, intraperitoneal injection) was prolonged by pre-administration of 5-hydroxytryptophan (60 mg/kg, intraperitoneal injection).
When 5-HTP is used concomitantly with selective serotonin reuptake inhibitors (SSRIs) such as citalopram, fluvoxamine maleate, and fluoxetine, paroxetine, sertraline, and venlafaxine may enhance the antidepressant effects of SSRIs and may also increase the risk of adverse reactions.
Phenoxybenzamine inhibits the conversion of 5-HTP to serotonin.

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Antidotes and Emergency Treatment
Veterinarians: Treatment includes early decontamination, control of central nervous system symptoms (diazepam, barbiturates), thermoregulation (cold water baths, fans), intravenous fluid therapy, and the use of serotonin antagonists, such as cyproheptadine…

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Intraperitoneal LD50 in mice: 200 mg/kg, National Technical Information Service, AD277-689
Oral LD50 in mice: > 6 g/kg, Japanese Journal of Pharmacology. Japanese Journal of Pharmacology, 69(523), 1973 [PMID:4546003]
Intraperitoneal LD50 in mice >1080 mg/kg t Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology, 69(523), 1973 [PMID:4546003]
Intravenous LD50 in mice >400 mg/kg t Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology, 69(523), 1973 [PMID:4546003]

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Interaction
5-HTP may reduce the efficacy of ergotamine and cyproheptadine.
In both male and female mice, the duration of central nervous system depression induced by ethanol (3.0 g/kg, intraperitoneal injection) was prolonged by prior administration of 5-hydroxytryptophan (60 mg/kg, intraperitoneal injection).
Concomitant use of 5-HTP with selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluvoxamine maleate, fluoxetine, paroxetine, sertraline, venlafaxine) may enhance the antidepressant effect of SSRIs and may also increase the risk of adverse reactions.
Phenoxybenzamine inhibits the conversion of 5-HTP to serotonin.
For more (complete) data on interactions of 5-hydroxytryptophan (16 in total), please visit the HSDB record page.

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Oral administration of 5-hydroxytryptophan (5-HTP) (100–400 mg) was well tolerated in healthy volunteers. Mild adverse reactions included transient nausea (17% of subjects in the 400 mg group), headache (12% in the 400 mg group), and dizziness (8% in the 200–400 mg group), which subsided within 2–4 hours [2].
- In patients with panic disorder, oral administration of 5-hydroxytryptophan (5-HTP) (200 mg) did not cause significant adverse reactions. No changes were observed in vital signs (blood pressure, heart rate) or laboratory parameters (liver function, kidney function) [3]

[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 therapeutic effects in certain diseases characterized by serotonin deficiency, primarily including depression. It has also been shown to be effective in some cases of obesity, insomnia, fibromyalgia, and chronic tension headaches. The serotonin system in the brain is well known to help regulate food intake and satiety. Increased intrasynaptic serotonin levels tend to reduce food intake. Therefore, it might be thought that people taking 5-HTP might experience increased satiety and weight loss over a period of time. Research on the effects of 5-HTP on obesity is limited, and existing studies suggest that 5-HTP has an anorexic effect. Some evidence suggests that 5-HTP can improve postural balance and dysarthria in patients with various types of hereditary and acquired cerebellar ataxia, particularly those with lesions precisely located in the anterior lobe of the cerebellar vermis. Improved coordination has been reported in patients with Friedreich ataxia; however, this improvement is only partial and not clinically significant.
Experimental Treatment: Rats of Darwinian salt-sensitive (DS) and Darwinian salt-tolerant (DR) strains were placed in a 4% NaCl diet, and their blood pressure was monitored. Continuous subcutaneous infusion of L-5-hydroxytryptophan (L-5-HTP, 12.6 mg/day) via an osmotic pump significantly reduced elevated systolic blood pressure in DS rats on a 4% NaCl diet. Blood pressure in DR rats was unaffected by L-5-HTP treatment. Cardiac hypertrophy was associated with Darwinian salt-induced hypertension. However, L-5-HTP treatment failed to significantly reduce heart weight. These results suggest that long-term administration of L-5-HTP can effectively reduce elevated blood pressure in DS model rats. The specific mechanism by which L-5-HTP reduces blood pressure is unclear. The blood pressure status of DS rats is still unclear and requires further investigation.
For more complete data on the therapeutic uses of 5-hydroxytryptophan (6 types), please visit the HSDB record page.
Drug Warnings Other reported side effects include nausea, diarrhea, loss of appetite, vomiting, and dyspnea. Neurological side effects have been reported in patients taking high doses of 5-HTP, including mydriasis, abnormally sensitive reflexes, loss of muscle coordination, and blurred vision. Cardiac arrhythmias have also been reported. Eosinophilia and eosinophilic-myalgia syndrome (EMS) have been reported in patients taking 5-HTP. Eosinophilic-myalgia syndrome is similar to that caused by L-tryptophan and is associated with contaminants in the 5-HTP formulation, not 5-HTP itself. Eosinophilia was relieved in one group of patients after switching to a different batch of 5-HTP. Scleroderma-like skin conditions have been reported in some patients taking 5-HTP in combination with carbidopa. Pregnant and breastfeeding women should avoid using 5-HTP. Patients with ischemic heart disease (with a history of myocardial infarction, angina, or confirmed asymptomatic myocardial ischemia), coronary artery spasm (e.g., variant angina), uncontrolled hypertension, and any other serious cardiovascular disease should avoid using 5-HTP.
For more complete data on drug warnings for 5-hydroxytryptophan (8 in total), please visit the HSDB record page.

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5-hydroxytryptophan (5-HTP) is a direct precursor of the neurotransmitter serotonin (5-HT) in the brain and peripheral tissues. [1,2,3]
- Its biological effects are mediated by conversion to 5-hydroxytryptophan (5-HT), which activates 5-HT2 receptors, thereby regulating hormone secretion (ACTH, prolactin) and modulating anxiety/panic-related neural pathways. [1,3]
- It has been used as a research tool to assess serotonergic function and to study the pathophysiology of panic disorders, mood disorders, and hormonal regulation. [2,3]
- The hormonal response of 5-hydroxytryptophan (5-HTP) is highly dependent on the activation of 5-HT2 receptors, as confirmed by the blocking effect of specific 5-HT2 antagonists. [1]

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.)