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5-Hydroxytryptophan
5-Hydroxytryptophan
5-Hydroxytryptophan
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5-Hydroxytryptophan
Skeletal formula
Ball-and-stick model
Names
IUPAC name
2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid
Other names
5-HTP; Oxitriptan; α-Carboxy-5-hydroxytryptamine; α-Carboxy-5-HT
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.022.193 Edit this at Wikidata
KEGG
MeSH 5-Hydroxytryptophan
UNII
  • 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)/t9-/m0/s1 checkY
    Key: LDCYZAJDBXYCGN-VIFPVBQESA-N checkY
  • InChI=1/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)/t9-/m0/s1
    Key: LDCYZAJDBXYCGN-VIFPVBQEBZ
  • O=C(O)[C@@H](N)Cc2c1cc(O)ccc1[nH]c2
Properties
C11H12N2O3
Molar mass 220.228 g·mol−1
Density 1.484 g/mL
Melting point 298 to 300 °C (568 to 572 °F; 571 to 573 K)
Boiling point 520.6 °C (969.1 °F; 793.8 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

5-Hydroxytryptophan (5-HTP), used medically as oxitriptan, is a naturally occurring amino acid and chemical precursor as well as a metabolic intermediate in the biosynthesis of the neurotransmitter serotonin.

5-HTP can be manufactured and used as a drug and supplement with the INNTooltip International Nonproprietary Name oxitriptan. Brand names include Cincofarm, Levothym, Levotonine, Oxyfan, Telesol, Tript-OH, and Triptum. As a drug, it is used in the treatment of depression and for certain other indications.

Production

[edit]

5-HTP is produced from the amino acid tryptophan through the action of the enzyme tryptophan hydroxylase. Tryptophan hydroxylase is one of the biopterin-dependent aromatic amino acid hydroxylases. Production of 5-HTP is the rate-limiting step in 5-HT (serotonin) synthesis. 5-HTP is normally rapidly converted to 5-HT by amino acid decarboxylase.[1]

Metabolism

[edit]

5-HTP is decarboxylated to serotonin (5-hydroxytryptamine or 5-HT) by the enzyme aromatic-L-amino-acid decarboxylase with the help of vitamin B6.[2] This reaction occurs both in nervous tissue and in the liver.[3] 5-HTP crosses the blood–brain barrier,[4] while 5-HT does not. Excess 5-HTP, especially when administered with vitamin B6, is thought to be metabolized and excreted.[5][6]

Metabolic pathway from tryptophan to serotonin.
Metabolic pathway from tryptophan to serotonin.
5-HTP AAAD Serotonin
 
PLP


Dietary sources

[edit]
See also: Tryptophan § Dietary sources

Though 5-HTP is found in food only in insignificant quantities, it is a chemical involved intermediately in the metabolism of tryptophan, an amino acid found in all unfractionated foods, with lower total amino acid content correlating with increased tryptophan absorption.[7]

Use as a medication and supplement

[edit]
Main article: Oxitriptan

5-HTP has been used medically and as a supplement under the name oxitriptan in the treatment of depression and for certain other indications. As of 2025, there are no current FDA approved medications containing 5-HTP.

It can be potentiated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor such as carbidopa or benserazide. These agents increase the strength and duration of oxitriptan. An investigational combination formulation is oxitriptan/carbidopa.

Research

[edit]

Psychedelic effects

[edit]
See also: Tryptophan § Psychedelic effects

5-HTP robustly produces the head-twitch response (HTR) in rodents when administered at relatively high doses.[8][9][10][11][12] It dose-dependently induces the HTR in mice across a dose range of 50 to 250 mg/kg via intraperitoneal administration, with an inverted U-shaped dose–response curve and maximal induction of the HTR at a dose of 200 mg/kg.[12][1] Similarly to the case of 5-HTP, intracerebroventricular injection of serotonin, but not peripheral administration of serotonin, produces the HTR.[9][8][11] The HTR is induced by serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin and is a behavioral proxy of psychedelic effects.[13][8]

The HTR of 5-HTP is blocked by serotonin 5-HT2A receptor antagonists, which block the hallucinogenic effects of serotonergic psychedelics in humans, is prevented by aromatic L-amino acid decarboxylase (AAAD) inhibitors, which block conversion of 5-HTP into serotonin, and is potentiated by monoamine oxidase A (MAO-A) inhibitors, which prevent the degradation of serotonin and other endogenous tryptamines.[9][8][10][11][12] It is also suppressed by the serotonin 5-HT1A receptor full agonist 8-OH-DPAT, is greatly augmented by the serotonin 5-HT2C receptor antagonist RS-102221, and is reduced by the trace amine-associated receptor 1 (TAAR1) antagonist EPPTB.[12] In addition, the HTR of 5-HTP is abolished by indolethylamine N-methyltransferase (INMT) inhibitors, which block conversion of serotonin and other endogenous tryptamines into N-methylated tryptamines, such as N-methylserotonin (NMS; norbufotenin), bufotenin (5-hydroxy-N,N-dimethyltryptamine; 5-HO-DMT), and N,N-dimethyltryptamine (DMT).[8][14][11] These N-methylated tryptamines are well-known for their psychedelic effects, whereas serotonin itself, without biotransformation, does not seem to produce psychedelic effects.[8][11] 5-HTP has not been found to produce psychedelic effects in humans, which has been attributed to the high doses required to produce such effects.[8][10] The 5-HTP doses that produce the HTR in rodents are orders of magnitude higher than the doses of 5-HTP that have been used safely and therapeutically in humans.[10][12] It remains unknown whether 5-HTP can produce psychedelic effects in humans.[15][12] The highest dosage of 5-HTP that is known to have been evaluated in humans is about 3,000 mg per day.[12][1] Serotonin syndrome and associated hallucinations have been reported with overdose of serotonin-elevating drugs, but psychedelic-like effects have not been reported.[12]

The lack of the HTR and psychedelic effects with serotonin itself has been attributed to the fact that these effects appear to be dependent on activation of a population of intracellular 5-HT2A receptors expressed in cortical neurons in the medial prefrontal cortex (mPFC) that lack the serotonin transporter (SERT) and are inaccessible to serotonin.[16][17] Serotonin itself is too hydrophilic to enter serotonergic neurons without the SERT, whereas serotonergic psychedelics and serotonin's N-methylated metabolites and analogues are lipophilic and readily enter these neurons.[16][17] These findings may also explain why selective serotonin reuptake inhibitors (SSRIs) and related serotonergic agents do not produce psychedelic effects.[16]

The properties of 5-HTP in animal drug discrimination tests have been studied.[18][19][20][21][22][23] 5-HTP generalizes with the serotonin releasing agent fenfluramine and its cue is markedly potentiated by the selective serotonin reuptake inhibitor (SSRI) fluoxetine.[18][19] However, numerous serotonin receptor antagonists, including methysergide, cyproheptadine, metergoline, methiothepin (metitepine), ketanserin, pirenperone, pizotifen, and mianserin, all failed to block the discriminative stimulus properties of 5-HTP.[18][19][20][21] Conflictingly however, in a subsequent study, pizotifen was able to fully block the discriminative stimulus properties of 5-HTP.[18][21] The inability of serotonin 5-HT2A receptor antagonists to block the discriminative stimulus properties of 5-HTP is in notable contrast to their ability to block the 5-HTP-induced HTR.[24] 5-HTP only partially substitutes for LSD in drug discrimination tests, whereas LSD and quipazine fully substitute for 5-HTP.[20] The full substitution of LSD and quipazine for 5-HTP can be blocked by the serotonin 5-HT2A receptor antagonist ketanserin.[20] The findings of drug discrimination tests suggest that 5-HTP has a more complex or compound discriminative stimulus compared to other agents like LSD and that its stimulus properties may not be readily explained by either the serotonin 5-HT1 or 5-HT2 receptors alone.[18][20][23] Instead, a combination of actions at these and/or other receptors may be involved in its stimulus effects.[18][20][23]

See also

[edit]

References

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

5-Hydroxytryptophan

View on Grokipedia
from Grokipedia
5-Hydroxytryptophan (5-HTP) is a naturally occurring that serves as the direct biochemical precursor to the serotonin (5-hydroxytryptamine, 5-HT), which plays essential roles in regulating mood, , , and . With the C₁₁H₁₂N₂O₃, 5-HTP is formed in the body through the of the L-tryptophan by the enzyme , bypassing the rate-limiting step in serotonin production, and is subsequently decarboxylated to yield serotonin without significant feedback inhibition. 5-HTP is not significantly present in common foods but occurs naturally in certain plants, with its primary commercial source being the seeds of the African plant Griffonia simplicifolia, from which it is extracted and purified for use in supplements and pharmaceuticals. As a dietary supplement, 5-HTP is commonly taken to elevate brain serotonin levels, potentially alleviating conditions associated with serotonin deficiency, such as depression, anxiety, insomnia, fibromyalgia, and migraines. Clinical studies suggest it may improve depressive symptoms, particularly in treatment-resistant cases or when used adjunctively, and enhance sleep quality in older adults, though evidence for broader efficacy remains mixed and further research is needed. Despite its benefits, 5-HTP supplementation requires caution due to potential side effects like , , drowsiness and fatigue (particularly with daytime dosing), and, in rare cases, eosinophilia-myalgia syndrome from contaminated products, as well as the risk of when combined with selective serotonin reuptake inhibitors (SSRIs) or other serotonergic drugs. Its use requires caution in conditions like due to potential risks such as seizures and may interact with carbidopa, commonly prescribed for . Overall, while 5-HTP offers a natural approach to modulating serotonin pathways, its therapeutic application should be guided by healthcare professionals to ensure safety and effectiveness.

Chemistry

Molecular Structure and Properties

5-Hydroxytryptophan (5-HTP), also known as oxitriptan, is a naturally occurring amino acid with the molecular formula C11_{11}H12_{12}N2_{2}O3_{3} and the IUPAC name (2S)-2-amino-3-(5-hydroxy-1H-indol-3-yl)propanoic acid. Structurally, 5-HTP features an indole ring system characteristic of tryptophan-derived compounds, but it is distinguished by a hydroxyl group attached at the 5-position of the indole ring, which imparts its specific biochemical role as a direct precursor to serotonin. In biological systems, 5-HTP predominantly exists as the L-enantiomer, which is the stereochemically active form involved in metabolic processes. As a solid, it presents as a white to off-white crystalline powder that is soluble in (approximately 0.4 g/100 mL at 25 °C) and has a of 298–300 °C, at which it decomposes.

Biosynthesis

5-Hydroxytryptophan (5-HTP) is endogenously synthesized from the essential amino acid L-tryptophan in a reaction catalyzed by the enzyme (TPH), which represents the rate-limiting and first committed step in the of serotonin and subsequently . TPH exists in two isoforms: TPH1, predominantly expressed in peripheral tissues, and TPH2, primarily in the . The enzyme requires (BH4) as a cofactor, along with molecular oxygen and ferrous iron (Fe²⁺), to facilitate the of L-tryptophan at the 5-position of the ring. In the brain, TPH2 is localized to serotonergic neurons within the of the , where it supports central serotonin production. Peripherally, TPH1 is mainly found in enterochromaffin cells of the , contributing to the majority of bodily serotonin synthesis. The activity of TPH is regulated by the availability of L-tryptophan, as substrate limitation can constrain the reaction rate given tryptophan's competition with other large neutral amino acids for transport across the blood-brain barrier. Endogenous 5-HTP concentrations remain low due to its rapid by to form serotonin, preventing significant accumulation in tissues.

Pharmacology

Absorption and Metabolism

5-Hydroxytryptophan (5-HTP) is rapidly absorbed from the following oral administration, exhibiting a of approximately 70% that reaches the systemic circulation. Plasma concentrations peak within 1 to 2 hours, often displaying a biphasic profile due to rapid uptake and distribution. This compound, as a large neutral , crosses the blood-brain barrier primarily via the L-type transporter 1 (LAT1), facilitating its entry into the where it can exert effects on synthesis. Although its absorption is not significantly impacted by the presence of food or other amino acids, taking 5-HTP with meals is often recommended to minimize gastrointestinal side effects such as nausea. Once absorbed, 5-HTP undergoes by (AADC) to form serotonin (5-HT) in both peripheral tissues and the . This enzymatic conversion occurs rapidly, contributing to a plasma of approximately 2-4 hours for 5-HTP. However, extensive peripheral decarboxylation significantly reduces the amount available for central effects, a limitation that can be mitigated by co-administration of peripheral AADC inhibitors, which enhance serotonin levels by preventing extracerebral . Serotonin produced from 5-HTP is further metabolized through oxidation by (MAO) to 5-hydroxyindoleacetaldehyde, which is subsequently converted to (5-HIAA) by . This primary metabolite, 5-HIAA, is predominantly excreted via the kidneys, serving as a key urinary for serotonin turnover. In the pineal gland, serotonin derived from 5-HTP contributes to synthesis, particularly during evening hours when circadian rhythms favor the N-acetylation and O-methylation pathways. The of 5-HTP are influenced by competition with other large neutral amino acids (e.g., , , , , ) for LAT1-mediated transport across the blood-brain barrier, which can reduce its central uptake under high-protein dietary conditions. Additionally, at higher doses, LAT1 transporters may become saturated, leading to nonlinear absorption and potentially altered .

Mechanism of Action

5-Hydroxytryptophan (5-HTP) serves as the immediate precursor to serotonin (5-hydroxytryptamine, 5-HT) in the biosynthetic pathway, bypassing the rate-limiting step catalyzed by (TPH), which converts L-tryptophan to 5-HTP. Upon administration, 5-HTP readily crosses the blood-brain barrier and is decarboxylated by (AADC) to yield serotonin, thereby elevating synaptic 5-HT levels in the without the regulatory feedback inhibition that limits TPH activity. This increase in serotonin availability indirectly enhances signaling at various 5-HT receptors, including presynaptic 5-HT1A autoreceptors that modulate neurotransmitter release and postsynaptic 5-HT2A receptors involved in mood regulation and sleep-wake cycles. In the , 5-HTP conversion to serotonin via AADC can further support biosynthesis, as the resulting 5-HT serves as a substrate for subsequent and methylation steps, potentially amplifying circadian rhythm-related effects. Elevated serotonin from 5-HTP also influences other systems; for instance, increased 5-HT tone can modulate by acting on 5-HT receptors in regions, potentially altering release and turnover, while serotonergic signaling may inhibit catechol-O-methyltransferase (COMT) activity, affecting the of and norepinephrine, particularly at higher doses. Peripherally, 5-HTP administration raises serotonin levels in the , where 5-HT acts on enteric neurons and to stimulate and secretion, promoting through activation of 5-HT3 and 5-HT4 receptors. In vascular tissues, the resultant increase in circulating 5-HT can engage 5-HT1B and 5-HT1D receptors on cranial blood vessels, contributing to that may underlie potential antimigraine effects by countering neurogenic . The dose-dependent nature of 5-HTP's actions typically involves lower doses (50-100 mg) sufficient to modestly elevate central serotonin for influences on mood and , whereas higher doses (200 mg or more) amplify systemic serotonin levels, heightening interactions with peripheral receptors and metabolic enzymes like COMT.

Therapeutic Uses

Established Applications

5-Hydroxytryptophan (5-HTP) has been investigated for the treatment of depression, with limited from small clinical studies suggesting potential efficacy at oral doses of 50–300 mg/day for mood support. In one randomized (n=60), 5-HTP showed effects comparable to in reducing depressive symptoms, with response rates of 73% versus 80%. However, overall remains preliminary, and 5-HTP is not a primary treatment. In these applications, 5-HTP serves as a direct precursor to serotonin, potentially helping to alleviate depressive symptoms through enhanced availability. For sleep disorders, particularly , 5-HTP is administered at 100-200 mg before bedtime to promote better , leveraging its conversion to serotonin and subsequently to . Evidence from small studies, including recent trials in older adults, shows improvements in sleep onset, duration, and , particularly in those with poor baseline . In migraine prophylaxis, dosages of 200-600 mg per day have been studied in older trials, with some patients experiencing reductions in frequency, though results are mixed and not always statistically significant. Such use is based on 5-HTP's role in modulating serotonin levels, which may help prevent episodes in responsive individuals. Regulatory status varies by region: 5-HTP is available as an over-the-counter in the United States and , while it is prescribed as oxitriptan in certain countries for conditions including and depression. To enhance delivery, 5-HTP is often combined with carbidopa, which inhibits peripheral (AADC) and reduces peripheral metabolism, thereby increasing brain serotonin levels. Historically, 5-HTP was introduced in the 1970s for psychiatric applications, including depression treatment, but faced scrutiny due to rare associations with eosinophilia-myalgia syndrome (EMS) in the late 1980s from contaminated sources; it experienced a resurgence post-1990 following resolution of contamination issues and improved manufacturing standards.

Investigational and Off-Label Uses

5-Hydroxytryptophan (5-HTP) has been investigated in small clinical studies for the management of symptoms, particularly and . In a double-blind, placebo-controlled involving 50 patients with primary fibromyalgia syndrome, oral administration of 100 mg 5-HTP three times daily for 30 days significantly improved clinical parameters including tender points, intensity, and compared to , with only mild transient side effects reported. An open-label study of 50 patients further demonstrated sustained efficacy over 90 days at the same dosage, with nearly half showing good or fair improvement in symptoms such as anxiety, sleep quality, and overall . Limited evidence suggests potential benefits of 5-HTP for anxiety disorders and (PMS)-related mood swings. Doses of 50-100 mg daily have been explored for alleviating premenstrual emotional symptoms, with preliminary reports indicating possible reductions in and anxiety, though robust clinical trials are lacking. For generalized anxiety, small trials and support anti-anxiety effects of 5-HTP, potentially through enhanced serotonin availability, but evidence remains inconclusive without large-scale validation. In , 5-HTP combined with carbidopa has shown promise in small trials for enhancing and promoting . A regimen of 750 mg 5-HTP daily with carbidopa led to substantial body weight reductions in preliminary studies, with one subject losing 24.4% over six months, attributed to increased central serotonin signaling that curbs . Combinations with other agents like phentermine further amplified effects while mitigating side effects. Exploratory research has examined 5-HTP for other conditions, including menopausal hot flashes, ADHD, as an adjunct, and autism spectrum disorder for social behaviors. For hot flashes, a trial of 150 mg daily showed no significant reduction in frequency, indicating limited efficacy. In ADHD, administration of 5-HTP as a serotonin precursor yielded no notable improvements in distractibility or core symptoms in a randomized . As an adjunct in , limited evidence suggests potential for improving sleep stability. In autism, 5-HTP increased blood serotonin levels in affected children but not controls, hinting at potential for addressing serotonergic imbalances related to social behaviors, though behavioral outcomes require further study. Recent studies also explore 5-HTP for cognitive function in aging, with a 2025 review noting potential benefits from increased serotonin levels. These applications are not FDA-approved, with 5-HTP available primarily as a rather than a . in integrative medicine has gained traction since the 2000s for conditions like mood and support, often in combination with other nutraceuticals. Challenges in 5-HTP's efficacy for these uses include variability across individuals, potentially stemming from differences in (TPH) activity, the rate-limiting enzyme in serotonin synthesis that influences 5-HTP conversion and response.

Research

Clinical Evidence

Clinical evidence for 5-hydroxytryptophan (5-HTP) primarily derives from small-scale trials and limited meta-analyses, with most studies conducted in the late and sparse high-quality research thereafter. Early investigations into depression, spanning the 1970s and 1980s, compared 5-HTP to and reported response rates of 60-70% in unipolar and bipolar depression, though these trials often suffered from methodological limitations such as small sample sizes and lack of standardization. A 2020 systematic review and of 13 studies confirmed modest effects, with a remission rate of 65% (95% CI, 0.55-0.78) and a large (Hedges' g = 1.11, 95% CI, 0.53-1.69), but highlighted high heterogeneity (I² = 76%) and called for larger randomized controlled trials (RCTs) to validate findings. A 2025 of clinical trials supported 5-HTP's benefits for mood disorders and cognitive dysfunction, consistent with prior findings but emphasizing need for larger studies. For insomnia, evidence is drawn from small 2010s-era trials involving 20-50 participants, which reported improvements in parameters. A 2009 double-blind, -controlled trial (n=18) found that an preparation including 5-HTP reduced sleep latency from 32.3 to 19.1 minutes (P=0.01) and increased duration from 5.0 to 6.83 hours (P=0.01) compared to , though long-term data remain limited and studies often combine 5-HTP with other compounds. In migraine prophylaxis, a 1985 double-blind crossover study (n=31 adults with chronic primary headache) with L-5-HTP (400 mg/day) showed that 48% of patients experienced more than 50% reduction in headache symptoms versus placebo, though the difference was not statistically significant, with good tolerability. Recent reviews up to 2023 support 5-HTP as an adjunct therapy but not first-line due to inconsistent results and small cohorts; for instance, a 1986 pediatric trial (n=27 children) showed temporary reductions in migraine index but no sustained superiority over placebo. Research gaps persist, including few post-2000 high-quality trials, underrepresentation of diverse populations, and a historical halt following the eosinophilia-myalgia syndrome (EMS) outbreak linked to contaminated L-tryptophan supplements, which extended to concerns over 5-HTP impurities in the and delayed revival until the late . Overall evidence quality is moderate (GRADE B equivalent) for depression and based on meta-analytic consistency despite biases, but low for and other conditions due to small sample sizes (often n<50), industry funding influences, and lack of replication. Recent preclinical developments from 2024-2025 explore TPH2 variants influencing serotonin synthesis, suggesting potential for personalized 5-HTP dosing to optimize efficacy in responsive individuals, though clinical is pending.

Neurological and Psychedelic Effects

5-Hydroxytryptophan (5-HTP) influences neurological function primarily through its conversion to serotonin, which modulates architecture and cognitive processes. Research indicates that 5-HTP supplementation enhances rapid eye movement (REM) duration, increasing the total percentage of stage REM without elevating associated behavioral episodes. This effect stems from serotonin's regulatory role in cycles, where elevated levels prior to can suppress early REM and promote rebound later in the night. Additionally, higher serotonin activity correlates with increased dream vividness, as observed in studies linking 5-HTP administration to more intense and recallable dream experiences. In low-serotonin states, 5-HTP exhibits potential effects, particularly for improving focus and . Animal models reveal that 5-HTP increases attentional persistence in subjects with low baseline performance, such as prolonging gaze duration in tasks requiring sustained . Human pilot studies support this, showing that daily doses around 100 mg enhance overall cognitive function, including executive tasks, in healthy individuals. These benefits are attributed to serotonin's role in modulating activity, though effects vary by baseline serotonin levels. High doses of 5-HTP exceeding 500 mg may theoretically produce mild perceptual alterations through overactivation of 5-HT2A receptors. Unlike classic psychedelics like , however, 5-HTP does not typically induce profound ego-dissolving experiences or full-spectrum hallucinations, and human studies confirm it lacks established psychedelic properties. Historical experiments in the 1970s focused on 5-HTP's mood-altering capabilities, demonstrating antidepressant-like elevations in mood and emotional stability without accompanying visual effects. At extreme doses, such overactivation carries risks like , characterized by acute neurological symptoms from excess serotonin. Research on these effects remains constrained to animal models and small-scale trials, with limited evidence. For instance, (PET) studies using [11C]5-HTP tracers in the have visualized increased serotonin synthesis in , highlighting acute activation in serotonergic pathways. Unlike L-tryptophan, which requires the rate-limiting enzyme (TPH) for conversion, direct 5-HTP administration bypasses TPH, enabling faster and more amplified serotonin elevation for these neurological outcomes. The U.S. has shown no interest in classifying 5-HTP as psychedelic, reflecting its primary consideration as a nutritional supplement rather than a .

Safety Profile

Common Adverse Effects

The common adverse effects of 5-HTP are typically mild and transient, with gastrointestinal symptoms being the most prevalent due to peripheral conversion of 5-HTP to serotonin, which can stimulate gut receptors. , , , stomach pain, and frequently occur, particularly at oral doses exceeding 200 mg daily, and are dose-dependent in nature. In one clinical study involving escalating oral doses, nausea and were the primary side effects, leading to treatment dropout in 6.6% of participants at 100 mg and 45.5% at 300 mg. Gastrointestinal effects are commonly reported in . Neurological symptoms such as drowsiness, , and are less common, and tend to be transient at low doses below 100 mg. Drowsiness and fatigue are particularly reported when 5-HTP is taken during the day, with user experiences often describing feelings of tiredness, mental fogginess, or grogginess; these sedative effects may arise from increased serotonin and subsequent melatonin production. Anecdotal reports from online forums frequently note these effects with daytime dosing. Belching and mild may also arise as secondary gastrointestinal complaints. These adverse effects usually onset within 1-2 hours of dosing and resolve within a few hours to days upon discontinuation or dose adjustment, with higher prevalence observed when taken on an empty . Management strategies include initiating therapy at low doses of 50 mg and administering with meals to mitigate gastrointestinal upset. Taking 5-HTP with meals or snacks can help reduce gastrointestinal side effects such as nausea and diarrhea. For sleep-related uses, taking it with dinner is an example of this approach. To minimize daytime drowsiness and fatigue, sources recommend taking 5-HTP in the evening or before bedtime, as its promotion of serotonin and melatonin pathways may induce sedation.

Serious Risks and Interactions

One of the most notable historical incidents associated with 5-hydroxytryptophan (5-HTP) supplements occurred in the context of the 1989 eosinophilia-myalgia syndrome (EMS) outbreak, which affected over 1,500 individuals in the United States and resulted in at least 30 deaths; this epidemic was linked to contaminated L-tryptophan products from a single manufacturer. The FDA banned L-tryptophan sales, while 5-HTP remained available as an alternative. Rare isolated cases of EMS have since been attributed to L-tryptophan or 5-HTP dietary supplements. The crisis was resolved through improved manufacturing standards and traceability, with the L-tryptophan ban lifted in 2005 after no further epidemics emerged. A separate 1998 incident involved the detection of a potentially toxic contaminant ("peak X") in some 5-HTP supplements, prompting renewed FDA warnings, but no widespread outbreak ensued, and modern products show no such associations when properly sourced. Serious risks from 5-HTP primarily stem from its potential to elevate serotonin levels excessively, with being a key concern when combined with serotonergic agents; this life-threatening condition manifests as , seizures, autonomic instability, and neuromuscular abnormalities, and is contraindicated in individuals with due to induction or untreated owing to cardiovascular fluctuations. Chronic elevation of serotonin from prolonged high-dose 5-HTP use has raised theoretical concerns for , akin to patterns observed in or with certain agonists that promote valvular fibrosis, though direct causal evidence in humans remains limited. 5-HTP is contraindicated during due to insufficient data and potential teratogenic effects, as indicate risks of embryonic resorption and placental from maternal serotonin exposure. Significant drug interactions amplify these risks: 5-HTP potentiates the effects of antidepressants like SSRIs and MAOIs, heightening likelihood, and enhances sedatives (CNS depressants), leading to excessive drowsiness, slowed breathing, and altered consciousness. Additionally, combining 5-HTP, typically derived from Griffonia simplicifolia, with other appetite suppressants—particularly serotonergic ones like Garcinia cambogia—may elevate the risk of serotonin syndrome due to additive serotonin level increases; symptoms include agitation, confusion, rapid heart rate, and high blood pressure, with rare reports of serotonin toxicity associated with Garcinia cambogia itself, though direct evidence for this specific combination remains theoretical based on mechanistic overlap, and general poly-supplementation without medical guidance increases potential for unknown interactions. In management, 5-HTP may reduce levodopa's efficacy by competing for aromatic amino acid decarboxylase, and its combination with carbidopa should be avoided except under strict medical supervision due to risks of and scleroderma-like symptoms. For long-term 5-HTP use, monitoring of liver and kidney function is recommended, particularly in those with pre-existing impairments, as amino acid supplements can strain these organs, and post-2020 regulatory emphases on supplement purity—via third-party testing for contaminants—help mitigate risks from adulterated products. With current high-quality formulations, the incidence of serious adverse events remains below 1%, far lower than historical contaminated batches.

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