5-HTP (5-Hydroxytryptophan) | Supplementopedia

Overview

5‑Hydroxytryptophan (5‑HTP) is a naturally occurring amino acid precursor to the neurotransmitter serotonin.
It is derived from the essential amino acid L‑tryptophan.
It is commonly taken as a dietary supplement to support mood, sleep, and appetite regulation by increasing central serotonin synthesis.

Clinical trials and meta‑analyses have shown that 5‑HTP can modestly improve depressive symptoms, especially in mild‑to‑moderate depression (e.g., a 2002 Cochrane review).
It is also effective in reducing nocturnal awakenings and increasing total sleep time, likely through its influence on serotonin and melatonin pathways.
Moderate evidence supports 5‑HTP in reducing appetite and modest weight‑loss when combined with a calorie‑restricted diet.
Some studies suggest a reduction in migraine frequency and intensity, possibly via serotonergic modulation of vascular tone.
Evidence for cognitive enhancement is limited; however, modest improvements in subjective mood and anxiety have been documented in randomized trials.
Overall, the strongest data relate to mood regulation, sleep quality, and appetite control.

After oral ingestion, 5‑HTP is absorbed in the small intestine via active transport.
It crosses the blood–brain barrier using the large‑neutral‑amino‑acid transporter.
In neurons, aromatic‑L‑amino‑acid decarboxylase (AADC) converts 5‑HTP to serotonin (5‑HT) in a one‑step reaction that bypasses the rate‑limiting step of tryptophan hydroxylase.
Elevated central 5‑HT enhances signaling at 5‑HT₁A, 5‑HT₂, and 5‑HT₃ receptors, influencing mood, sleep, and appetite circuits.
In the pineal gland, increased 5‑HT is converted to melatonin, supporting circadian regulation.
Peripheral 5‑HTP may also affect gastrointestinal motility via enteric serotonergic pathways, contributing to its satiety‑enhancing effects.
Because AADC is ubiquitous, peripheral conversion can occur, which is why peripheral decarboxylase inhibitors (e.g., carbidopa) are sometimes used experimentally to isolate central effects.

Typical over‑the‑counter formulations range from 50 mg to 300 mg per capsule.
For mood support, clinical trials have used 150–300 mg daily, divided into two or three doses taken with meals to improve absorption and reduce gastrointestinal upset.
For sleep, 100–200 mg taken 30‑60 minutes before bedtime is common.
Weight‑management protocols often employ 250 mg before dinner, combined with a reduced‑calorie diet.
A “low‑start” approach (e.g., 50 mg nightly for 2–3 days) can mitigate nausea or headache.
When used with a peripheral decarboxylase inhibitor (e.g., carbidopa), lower doses (50‑100 mg) are sufficient because peripheral conversion is blocked, allowing more 5‑HTP to reach the brain.
It is advisable to avoid doses > 500 mg/day without medical supervision because of increased risk of serotonin syndrome.

Common adverse effects are mild and include nausea, gastrointestinal upset, and vivid dreams.
Rarely, individuals experience headache, anxiety, or mild insomnia.
5‑HTP can precipitate serotonin syndrome when combined with serotonergic drugs (SSRIs, MAOIs, tramadol, St. John’s‑wort, or triptans); thus, concurrent use is contraindicated.
Patients with bipolar disorder, uncontrolled hypertension, or a history of serotonin toxicity should avoid it.
Pregnant or lactating women lack sufficient safety data and should refrain from use.
Carbidopa co‑administration can reduce peripheral side effects but increases the risk of severe serotonin syndrome if combined with other serotonergic agents.
Because 5‑HTP can raise plasma homocysteine, individuals with cardiovascular risk may need monitoring.
Renal or hepatic impairment may slow clearance, requiring dose reduction.

5‑HTP’s chemical formula is C₁₁H₁₂N₂O₃, with a molecular weight of 220.23 g mol⁻¹.
Its IUPAC name is 3-(2‑amino‑ethyl)-5-hydroxyindole.
The molecule consists of an indole ring (a fused benzene‑pyrrole) bearing a hydroxyl group at the 5‑position and an attached side chain (−CH₂‑CH₂‑NH₂) at the 3‑position, which is the same side chain as in tryptophan but lacks the carboxyl group; instead, it has a terminal amino group.
The compound is a white crystalline powder, soluble in water and slightly soluble in ethanol.
Its pKa values (≈9.5 for the amine, ≈2.4 for the phenolic hydroxyl) influence its ionization at physiological pH, allowing efficient transport across the intestinal epithelium and the blood‑brain barrier via the large‑neutral‑amino‑acid transporter.
The molecule is chiral; the natural L‑enantiomer is the biologically active form.

Commercial 5‑HTP is primarily extracted from the seed coats of the African plant Griffonia simplicifolia, which contains up to 20 % 5‑HTP in dry weight.
The seeds are milled, and 5‑HTP is isolated through aqueous extraction followed by purification steps such as ion-exchange chromatography and crystallization.
Synthetic routes exist, typically via oxidation of L‑tryptophan with a hydroxylation step, but these are less common due to cost.
Quality‑grade supplements should be standardized to ≥ 95 % pure L‑5‑HTP, be free of heavy metals, and comply with GMP (Good Manufacturing Practice) standards.
Third‑party testing (e.g., USP, NSF) confirms potency and lack of contaminants.
Because the seed also contains other indole compounds, reputable manufacturers use purification to avoid co‑extraction of untested alkaloids.
For maximal bioavailability, capsules with enteric coating can protect 5‑HTP from gastric degradation.