5-HTP (5-hydroxytryptophan)

5-HTP (5-Hydroxytryptophan)

Identity, Chemical Nature, and Forms

Names and Chemical Identity

5-HTP is also known by the International Nonproprietary Name (INN) oxitriptan, and its full chemical name is L-5-hydroxytryptophan. 5-HTP is a naturally occurring amino acid and chemical precursor in the biosynthesis of serotonin, a neurotransmitter essential for regulating mood, sleep, appetite, and other physiological processes. 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), which is further transformed to melatonin (N-acetyl-5-methoxytryptamine).

Chemically, oxitriptan is classified as a centrally permeable monoamine precursor and prodrug of serotonin. It is an amino acid and a tryptamine. 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.

Natural Sources

The most cost-effective source of 5-HTP is from seeds of Griffonia simplicifolia D.C. (Baill.), a scandent climber or liana that is one of four species in a small genus in the tribe Cercideae. G. simplicifolia is widespread, occurring in a variety of habitats in eight West African countries: Benin, Cameroon, Côte d'Ivoire, Gabon, Ghana, Liberia, Nigeria, and Togo. All four Griffonia species are characterized by an unusual metabolic pathway that produces very high concentrations of 5-hydroxytryptophan in the seeds. Griffonia simplicifolia seeds contain up to 20% 5-HTP, making them one of the richest natural sources of this compound.

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. In humans, 5-HTP derives from the essential amino acid tryptophan, which is contained in egg whites, dairy products, meat, and fish, but also in dark chocolate and some seeds.

Common Preparations and Dosage Forms

In most European countries, 5-HTP is a commonly prescribed drug for multiple treatment purposes, while in the North American market it is sold as an over-the-counter dietary supplement. There are currently no approved drug products containing 5-HTP approved by the FDA. Its use in food supplements is very common, as it is a plant allowed in most European Union countries. Regarding the European regulatory picture, although Griffonia seeds are not considered novel in food supplements, the selective extraction of 5-HTP is considered novel food under EU Regulation 2015/2283, requiring prior authorization for its use as a highly concentrated extract in the EU market.

5-HTP is sold over-the-counter in the United States, France, Canada, Singapore, the Netherlands, and the United Kingdom as a dietary supplement. It is commercially available primarily as oral capsules and tablets, with some formulations in sublingual spray form. The food supplement has been investigated for multiple indications such as migraine, depression, anxiety, fibromyalgia, hypertension, insomnia, and obesity.

Traditional and Historical Use

Traditional Uses of Griffonia simplicifolia in African Medicine

In traditional West African medicine, Griffonia has been used for centuries to treat various ailments. It is particularly valued for its calming effect and its ability to increase well-being. The use of Griffonia simplicifolia, the botanical source of 5-HTP, has a long history in traditional African medicine. Indigenous peoples in West Africa historically used Griffonia seeds, leaves, and stems for a variety of purposes, including treating wounds, diarrhea, vomiting, and as an aphrodisiac.

Contemporary use as an antidepressant contrasts with traditional uses for insecticides, arachnicides, fodder, dyes, mordants, and chewing-sticks. Local healers used leaf extracts and seeds to help stabilize mood, reduce irritability, and support emotional well-being. Preparations from the plant were also occasionally applied to relieve minor pain or inflammation, and seeds were consumed in small amounts to reduce hunger or support overall health, a practice that parallels modern studies on appetite suppression. Beyond these uses, Griffonia also featured in rituals and cultural practices in certain regions, where it symbolized vitality, mental clarity, or spiritual protection.

Discovery of 5-HTP as a Scientific Entity

The specific compound 5-HTP was not identified and isolated until modern scientific research in the 20th century. The scientific exploration of 5-HTP began in earnest in the 1960s and 1970s, when researchers identified its role in serotonin biosynthesis and investigated its therapeutic potential for mood disorders and neurological conditions. Western phytotherapy began to take an interest in it in the 1970s, mainly because the seeds of this plant, belonging to the Fabaceae (pea family), are a vegetable source of 5-hydroxytryptophan (5-HTP). Oxitriptan (5-HTP) has been used clinically since at least the 1970s.

Although ancient systems like Traditional Chinese Medicine (TCM) and Ayurveda did not specifically use 5-HTP or Griffonia simplicifolia, the modern application of 5-HTP reflects the fusion of traditional botanical knowledge with contemporary nutritional science, allowing for the development of targeted supplements that leverage natural compounds to support specific neurotransmitter pathways.

Key Constituents and Active Compounds

Primary Bioactive Compound

The primary bioactive compound in Griffonia simplicifolia is 5-HTP, which serves as a direct precursor to serotonin (5-hydroxytryptamine). Although Griffonia simplicifolia is mainly known for its 5-HTP content, the plant may also contain other bioactive compounds that contribute to its health benefits. Further research is needed to understand the full spectrum of compounds contained in Griffonia simplicifolia and their effects on human health.

The characterization of 5-HTP along with the β-carboline alkaloid derivatives has also been conducted in studies aimed at authenticating G. simplicifolia seed extracts.

Mechanisms of Action

Biosynthetic Pathway

Serotonin is synthesized via a two-step metabolic pathway: tryptophan is first hydroxylated to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase (TPH), which is the rate-limiting step. This is followed by the decarboxylation of 5-HTP by aromatic L-acid decarboxylase to finally form 5-HT. 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. This reaction occurs both in nervous tissue and in the liver.

The rate-limiting step in the synthesis of serotonin is the conversion of L-tryptophan into 5-HTP by the enzyme tryptophan hydroxylase. To make more serotonin, it is more efficient to supply 5-HTP than to supply tryptophan (conversion rate 70% vs. 1–3%), because the body uses a large percentage of dietary L-tryptophan to make other compounds, such as kynurenine and vitamin B3. These differences make dietary 5-HTP more efficient than L-tryptophan at increasing serotonin levels in the brain.

Blood–Brain Barrier Permeability

5-HTP crosses the blood–brain barrier, while 5-HT (serotonin) does not. Since 5-HT is unable to penetrate through the blood–brain barrier (BBB), if one intends to elevate the level of 5-HT in the central nervous system (CNS), it is necessary to administer either tryptophan or 5-HTP, which are able to cross the BBB. The pharmacological mechanism of 5-HTP involves its ability to cross the blood–brain barrier and be converted to serotonin by the enzyme aromatic L-amino acid decarboxylase. This mechanism bypasses the rate-limiting step of tryptophan hydroxylase that normally controls serotonin production.

Following ingestion, 5-HTP easily crosses the blood–brain barrier and enters the central nervous system. The half-life of 5-HTP is approximately four hours, so steady state is reached within approximately one day.

Downstream Effects: Serotonin and Melatonin

Serotonin acts as a neurotransmitter within the central nervous system (CNS), where it is synthesized by raphe neurons in the brain stem; peripherally it can play multiple roles as a hormone, auto- or paracrine factor, and is synthesized by both gut neurons and enterochromaffin cells located in the gastrointestinal system. The blood–brain barrier keeps systemic and central serotonin pools distinct. The serotonin transporter (SERT) is responsible for the reuptake of free 5-HT in the synaptic cleft; this is the mechanism of action exploited by selective serotonin reuptake inhibitors (SSRIs), typically used as antidepressants or anxiolytic therapy.

In the pathway of 5-HT biosynthesis, TPH, a member of a family of pterin-dependent aromatic amino acid hydroxylases, catalyzes the formation of 5-hydroxy-L-tryptophan (5-HTP) from L-tryptophan, which is the first step in the biosynthesis of the neurotransmitter 5-HT. Aromatic L-amino-acid decarboxylase (AADC) subsequently mediates the production of 5-HT. Because 5-HTP is also a precursor to melatonin, decarboxylation of 5-HTP to serotonin represents an intermediate step, with serotonin further transformed to melatonin (N-acetyl-5-methoxytryptamine).

Scientific Evidence by Area of Use

Overview of the Research Landscape

The majority of clinical trials on 5-HTP are on depression, anxiety, panic attacks, and sleep disorders; however, the molecule has been demonstrated to be a promising support to reduce food/feed intake and to be potentially used for metabolic diseases like obesity and diabetes. In humans, 5-HTP has been used experimentally to treat depression, anxiety, myoclonus, fibromyalgia, migraine, headache, obesity, Parkinson's disease depression, L-DOPA dyskinesias in Parkinson's disease, sleep disorders, certain pediatric developmental disorders, and ataxic disorders.

1. Depression

Open trials and RCTs have suggested that 5-HTP is as effective as standard antidepressants. A Cochrane Review found only 2 of 108 trials of sufficient quality for inclusion, but in these trials, 5-HTP was superior to placebo. The Cochrane reviewers concluded that a large number of studies appeared to address the research questions, but few were of sufficient quality to be reliable. Available evidence does suggest these substances are better than placebo at alleviating depression.

A Cochrane review found that 5-HTP and tryptophan were better than placebo at alleviating depression, with the magnitude of benefit appearing roughly similar to that of SSRIs and tricyclic antidepressants. However, the reviewers noted that the evidence was not high enough quality to be conclusive. The clinical trials were small, and the body of research behind prescription antidepressants is far more rigorous.

Several small studies have compared 5-HTP to standard antidepressants. One notable six-week study of 63 people compared either 5-HTP (100 mg three times daily) or an antidepressant in the Prozac family (fluvoxamine, 50 mg three times daily). Researchers found equal benefit with the supplement and with the drug; however, 5-HTP caused fewer and less severe side effects. In another clinical trial, 5-HTP at 300 mg/day was found to be as effective as fluoxetine in alleviating symptoms of depression in patients.

A 2020 meta-analysis found oral 5-HTP supplementation had a large effect size on depression symptom severity. However, the included studies were considered relatively weak, and the methods and treatment duration varied between the seven studies examined. In women experiencing SSRI- or SNRI-resistant depression, the combination treatment with creatine and 5-HTP proved to be an effective augmentation strategy. Overall, the evidence base for 5-HTP in depression consists largely of small trials with methodological limitations, and the findings should be interpreted with caution.

2. Anxiety and Panic Disorders

The physiological role of 5-HTP in the treatment of anxiety and panic has been investigated in clinical trials. Griffonia extract also shows anxiolytic-like effects in available studies. Serotonin helps regulate mood and behavior, and 5-HTP may be helpful with anxiety and pain sensation. The evidence in this area is predominantly from small, older trials, and the overall quality is limited.

3. Sleep Disorders and Insomnia

Because 5-HTP is a precursor to both serotonin and, downstream, melatonin, it has been proposed as a modulator of the sleep–wake cycle. A 2024 randomized controlled trial tested 5-HTP supplementation in older adults over 12 weeks. The supplement raised blood serotonin levels and showed favorable effects on certain sleep quality measures. The 2024 RCT in older adults found that 5-HTP improved certain components of sleep quality, with a stronger effect seen in poor sleepers, and also showed changes in gut microbiota composition in that subgroup.

A single-center, randomized, double-blind placebo-controlled crossover trial in 18 patients with Parkinson's disease and REM sleep behavior disorder (RBD) gave patients either placebo or 50 mg of 5-HTP daily in a crossover design over 4 weeks. 5-HTP produced an increase in the total percentage of stage REM sleep without a related increase in RBD episodes, as well as a marginal, non-significant reduction in both arousal index and wake after sleep onset. Self-reported RBD frequency and clinical global impression were improved during 5-HTP treatment. Larger studies with higher doses and longer treatment duration were noted as needed to corroborate these preliminary findings.

Studies evaluating 5-HTP specifically for insomnia are limited. In one placebo-controlled trial, a single 100 mg nighttime dose of 5-HTP was sufficient to improve the duration and depth of sleep.

4. Obesity and Appetite Regulation

5-HTP has been evaluated for obesity. Preliminary findings suggest it may help decrease food intake and increase weight loss and early satiety. Appetite reduction and weight loss, averaging approximately 11 pounds in 12 weeks, has occurred with doses of 600–900 mg daily in early studies. Early research suggests that taking 5-HTP might help reduce appetite, caloric intake, and weight in obese people. Other research suggests that using a specific mouth spray containing 5-HTP and other extracts for 4 weeks can increase weight loss by approximately 41% compared to placebo.

Serotonin plays a role in satiety, which is why 5-HTP is sometimes studied for weight management. Some older studies supported this idea, but more recent research has been less convincing. An 8-week randomized controlled trial found no changes in total calorie intake or macronutrient consumption between the group taking 5-HTP and the group taking a placebo. The overall evidence for 5-HTP in obesity and appetite regulation remains preliminary and mixed.

5. Fibromyalgia

Early research suggests that taking 100 mg of 5-HTP by mouth three times daily for 30–90 days might improve pain, tenderness, sleep, anxiety, fatigue, and morning stiffness in people with fibromyalgia. In one controlled trial, 5-HTP at 300 mg per day was shown to be effective in reducing many symptoms of fibromyalgia, including pain, morning stiffness, sleep disturbances, and anxiety. Other preliminary studies suggest benefit for patients with fibromyalgia. Additional studies are needed to confirm these findings. There is currently no known cause of fibromyalgia, but low serotonin levels have been identified as a contributing factor. This has led researchers to investigate increasing serotonin levels via 5-HTP; early evidence suggests it may improve symptoms of fibromyalgia, including muscle pain, sleep problems, anxiety, and fatigue. The trials are small and the evidence should be considered preliminary.

6. Migraine and Headache

Evidence on the effects of 5-HTP for the prevention or treatment of migraines in adults is mixed. Some studies show that taking 5-HTP daily does not reduce migraines, while other studies show that it might be as beneficial as prescription drugs. 5-HTP does not appear to reduce migraines in children. There is some evidence that 5-HTP may help prevent migraines when taken at a dosage of 400 to 600 mg daily.

An eight-week, double-blind, placebo-controlled trial of 65 people (mostly women) with tension headaches found that 5-HTP at a dose of 100 mg three times daily did not significantly reduce the number of headaches experienced; however, it did reduce participants' need to use other pain-relieving medications. A few studies did not find 5-HTP helpful for migraines or chronic tension headaches. Putting all this evidence together, it appears likely that 5-HTP can help people with frequent migraine headaches if taken in sufficient doses, but further research is needed. In particular, what is needed is a large double-blind study that compares 5-HTP with a placebo over a period of several months.

7. Menopausal Symptoms

Early research suggests that taking 150 mg of 5-HTP daily for 4 weeks does not reduce hot flashes in postmenopausal women. Initial studies suggest 5-HTP is not helpful for hot flashes.

8. Cognitive Function and Mood in Older Adults

A 2025 RCT contributes to the understanding of the effect of 5-HTP supplementation on cognitive function in older Asian adults. There is a paucity of data in older Asian adults, and previous studies have focused on mood, sleep, and appetite outcomes, particularly in the Western population. Although the participants were not diagnosed with cognitive disorders, they were considered vulnerable to age-related cognitive decline.

9. Neurological Conditions: Parkinson's Disease and Myoclonus

5-HTP treatment has also been found to improve both levodopa-induced dyskinesias and depressive symptoms in Parkinson's disease patients in preliminary studies. The physiological role of 5-HTP in the treatment of myoclonus has also been investigated in clinical settings. The FDA permits drug compounders to use oxitriptan (5-HTP) to compound oral drugs for patients with a diagnosis of BH4 deficiency, a rare metabolic disorder where 5-HTP is used alongside L-DOPA to bypass an enzymatic block in neurotransmitter synthesis.

Body Systems and Health Areas Associated with 5-HTP

• Central Nervous System / Neurotransmission: Serotonin acts as a neurotransmitter within the CNS, synthesized by raphe neurons in the brain stem, and 5-HTP is its direct precursor.
• Mood and Psychiatric Health: 5-HTP may be helpful with mood, anxiety, and behavior regulation through its role in serotonin synthesis.
• Sleep and Circadian Regulation: Serotonin derived from 5-HTP is further transformed into melatonin, linking 5-HTP to sleep and circadian rhythm regulation.
• Gastrointestinal System: Peripherally, serotonin is synthesized by both gut neurons and enterochromaffin cells in the gastrointestinal system, and 5-HTP may influence gut function.
• Metabolic and Appetite Regulation: Preparations of G. simplicifolia containing high concentrations of 5-HTP are used to increase the feeling of satiety associated with a significant reduction of food intake and body weight with decreasing BMI.
• Musculoskeletal and Pain: 5-HTP has been studied in fibromyalgia, a condition characterized by muscle and joint pain.
• Vascular/Neurological (Migraine): Some studies suggest that the regular use of 5-HTP may help reduce the frequency and severity of migraines and may help other types of headaches.

Dosage Forms and Dosages Reported in Studies

The following dosage ranges appear in the published clinical literature and do not constitute recommendations. They are reported as documented in specific studies:

• Depression: 50 mg–300 mg daily for 35 days (as in the Sano 1972 study). In a Van Praag et al. (1972) double-blind trial in 10 patients with severe depression, the dose of 5-HTP ranged from 200 to 3,000 mg/day. 300 mg per day has been used in controlled trials for depression, though much of the research used 5-HTP in combination with other agents or was uncontrolled.
• Fibromyalgia: 100 mg three times daily (300 mg/day) for 30–90 days.
• Obesity: 900 mg daily for 12 weeks (Cangiano et al. 1992).
• Chronic/Migraine Headaches: Amounts ranging from 400–600 mg per day have been studied for reducing frequency and severity of migraine attacks in most clinical trials. 600 mg daily for 6 months was used in a chronic headache study (Titus et al. 1986).
• Tension Headaches: 100 mg three times daily in an eight-week, double-blind, placebo-controlled trial of 65 people.
• Insomnia: A single 100 mg nighttime dose was used in one placebo-controlled trial evaluating sleep duration and depth.
• REM Sleep Behavior Disorder (Parkinson's disease): 50 mg of 5-HTP daily in a crossover design over a period of 4 weeks.
• Half-life: The half-life of 5-HTP is estimated to be 4.3 ± 2.8 hours (Westenberg et al. 1982).

Safety Considerations and Drug Interactions

General Tolerability

Side effects of 5-HTP (oxitriptan) include appetite loss, nausea, diarrhea, vomiting, and serotonin syndrome. The side effects reported in trials are relatively mild: dizziness, nausea, and diarrhea were the most common.

Serotonin Syndrome

Antidepressants and anxiolytics (tricyclics, MAOIs, and SSRIs), because they can also raise serotonin levels, create a theoretical potential for increased risk of side effects or toxicities when combined with 5-HTP. Larger clinical trials are needed to understand the clinical relevance of these risks. Case reports document: mania following combined use of an MAOI and 5-HTP in a patient without personal or family history of bipolar disorder; and serotonin syndrome caused by an interaction between linezolid and 5-HTP.

Eosinophilia–Myalgia Syndrome (EMS) and Contamination Concerns

The use of L-tryptophan, the precursor of 5-HTP, as a dietary supplement was suspended in 1989 due to the occurrence of eosinophilia–myalgia syndrome (EMS), a rare, sometimes fatal neurological condition including debilitating myalgia and marked peripheral eosinophilia, that was traced to contaminated synthetic tryptophan from a single manufacturer (Showa Denko). An important safety consideration involving the use of 5-HTP, a derivative of L-tryptophan, is the historical association between L-tryptophan and EMS. EMS is marked by the development of flu-like constitutional symptoms, muscle aches, and eosinophilia. The association led the FDA to ban the sale of L-tryptophan in 1991. Subsequently, however, the development of EMS in association with L-tryptophan was related to contaminants in the supply produced by a particular manufacturer. The FDA lifted the ban on L-tryptophan in 2001.

The NIH warned in 2015 that "some people who have taken it have come down with eosinophilia-myalgia syndrome (EMS), a serious condition involving extreme muscle tenderness (myalgia) and blood abnormalities (eosinophilia)." Eosinophilia-myalgia syndrome and eosinophilia have been linked to a 5-HTP product that contained impurities, used by one family; symptoms resolved after the product was replaced with one that did not have these impurities. No definitive cases of toxicity have emerged despite worldwide usage of 5-HTP over 20 years, with the possible exception of one unresolved case. Extensive analyses of several sources of 5-HTP have shown no toxic contaminants similar to those associated with L-tryptophan, nor the presence of any other significant impurities.

Although 5-HTP is not metabolized along the kynurenine pathway, case reports link 5-HTP to an illness resembling eosinophilia-myalgia syndrome. The suspected culprit is a family of contaminants known as "peak X" that is commonly found in commercially available 5-HTP. Occasional case reports of EMS in association with 5-HTP have been made, and the NIH continues to urge that 5-HTP be used cautiously because the risk of EMS associated with 5-HTP has not been well established.

Other Reported Adverse Events

A scleroderma-like illness — including pain, swelling of hands and feet, skin rash, and weight loss — has been reported in a 70-year-old patient receiving combination therapy with carbidopa and 5-HTP. Taking very large doses of 5-HTP (more than 6 grams a day) can cause severe muscle spasms and stomach issues.

Drug Interactions

The use of 5-HTP may not be recommended in some humans, particularly in the case of serotonin syndrome risk when combined with serotonergic agents. The key documented and theoretically relevant interactions are:

• MAOIs: Case reports document mania following combined use of an MAOI and 5-HTP in a patient without personal or family history of bipolar disorder.
• SSRIs and SNRIs: Because 5-HTP can also raise serotonin levels, there is a theoretical potential for increased risk of side effects or toxicities when combined with SSRIs or other antidepressants.
• Linezolid (antibiotic with MAOI-like activity): Serotonin syndrome has been documented, caused by an interaction between linezolid and 5-HTP.
• Carbidopa: A scleroderma-like illness was reported in a patient receiving the combination of carbidopa and 5-HTP.

Regulatory Status Summary

In most European countries, 5-HTP is a commonly prescribed drug for multiple treatment purposes, while in North America it is sold as an over-the-counter dietary supplement. There are currently no approved drug products containing 5-HTP approved by the FDA. All available 5-HTP products are nutraceuticals and are as such not regulated or verified for purity, integrity, or clinical efficacy or safety. In the European Union, while whole Griffonia seed is permitted in supplements, the selective extraction of 5-HTP is considered a novel food requiring prior authorization under Regulation (EU) 2015/2283.

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• Wikipedia: 5-Hydroxytryptophan
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