5-HTP is a plant-derived amino acid used by the body as a direct precursor to serotonin. It is produced commercially from the seeds of Griffonia simplicifolia, a shrub native to West and Central Africa. Therapeutically, 5-HTP is commonly supplemented to alleviate depression, aid sleep, promote weight loss, and improve symptoms of migraines and fibromyalgia. In addition, it is used by some MDMA users to ease the comedown and improve mood the days following, by increasing levels of depleted serotonin.
Table of Contents
- Overview
- History
- Pharmacology
- Effects
- Uses
- Studies & Research
- 5-HTP FAQ
1. Overview
What is 5-HTP?
5-HTP, also known as oxitriptan, is an over-the-counter dietary supplement used to increase serotonin production in the brain. While widely available in supplement form, it is also naturally produced by the body from the essential amino acid L-tryptophan in the biosynthesis of serotonin.
L-5-hydroxytryptophan
L-5-hydroxytryptophan (5-HTP) belongs to a class of organic compounds known as the indoles. 5-HTP is the 5-hydroxy analog of the essential amino acid tryptophan, that is, tryptophan substituted by a hydroxy group at position 5 on its indole ring. It is available commercially as the levorotatory (L) enantiomer, as the D-enantiomer is biologically inactive.
In the synthesis of serotonin, 5-HTP is the intermediate metabolite of L-tryptophan. L-tryptophan is converted into 5-HTP by the enzyme tryptophan hydroxylase with the help of iron. 5-HTP is then decarboxylated into serotonin (5-hydroxytryptamine, or 5-HT) by the enzyme aromatic L-amino acid decarboxylase with the help of vitamin B6. 5-HTP supplementation bypasses the first enzymatic step, leading to more efficient serotonin production.
Ways to Consume 5-HTP
5-HTP is most commonly consumed orally via capsules, enteric-coated tablets, flavored lozenges, or as a powder. It can also be consumed in liquid form as an extract, tincture, or spray that is absorbed sublingually.
It can be purchased alone or in a variety of herbal and multivitamin formulations. Regardless of the consumption route, 5-HTP is well-absorbed and can be taken with meals. Approximately 70% of a dose ends up in the bloodstream.
Once ingested, 5-HTP is rapidly eliminated from the body, with an elimination half-life of just 1.5 hours. With this in mind, some research findings suggest that slow-release formulations can more effectively enhance serotonin production, rendering it a more clinically viable drug with fewer side effects.
2. History
Indiginous Uses
5-HTP is found naturally in the seeds of Griffonia simplicifolia, a woody shrub native to Central and Western Africa. The seeds have a long history of use in Africa folk medicine, where they are used as an antibiotic, aphrodisiac, a purgative, as well as a remedy for stomach ache, vomiting, dysentery, and diarrhea. The seeds are rich in 5-HTP, containing approximately 20% 5-HTP by weight.
Discovery
Once 5-HTP was discovered to be the bioactive ingredient of the Griffonia simplicifolia seeds, it began to be extracted for commercial use.
In the 1990s, it became a popular supplement after L-tryptophan was removed from the market in 1989. L-tryptophan was discontinued in response to a contaminated batch, traced to a single manufacturer, that was causing outbreaks of eosinophilia-myalgia syndrome (EMS) in more than 1,500 people. EMS is a debilitating condition characterized by extreme muscle tenderness and blood abnormalities.
As a result of the outbreak, 5-HTP began to be marketed as a safer alternative to L-tryptophan. However, L-tryptophan was reintroduced to the US market in 2001 following a revised risk estimate by the Food and Drug Administration.
Prior to 1995 in the US, 5-HTP was a prescription-only medication used to treat conditions associated with serotonin deficiencies. Currently, as a dietary supplement, it is not subject to any controlled substance laws. In some European countries, however, it is prescribed as an antidepressant.
3. Pharmacology
Mechanism of Action
5-HTP readily crosses the blood-brain barrier and increases serotonin synthesis. Serotonin is a crucial neurotransmitter involved in mood, memory, cognition, sexual behavior, pain sensation, and satiety. Serotonin may be further converted into melatonin under conditions of darkness, a hormone that plays a key role in regulating sleep/wake cycles.
As described previously, 5-HTP is catalyzed into serotonin by an enzyme called aromatic L-amino acid decarboxylase (AAAD). AAAD also catalyzes L-dopa into dopamine, so long-term administration of 5-HTP can deplete levels of dopamine and other catecholamine neurotransmitters.
Since these neurotransmitters are also involved in mood disorders like depression, maintaining a proper balance between these neurotransmitters and their precursors is necessary for the best therapeutic outcomes when supplementing in the long term.
Toxicity
Research has demonstrated that 5-HTP is not toxic in daily doses of 50 mg/kg or less.
A portion of ingested 5-HTP is converted to serotonin in the liver, which can increase serotonin levels in the body. Preclinical findings suggest that serotonin’s long-term effects on the heart can increase the risk of heart valve disease, but there is no human evidence that 5-HTP damages the heart.
Interactions
5-HTP should not be taken with drugs that increase serotonin levels, as the combination can increase the likelihood of a potentially life-threatening neurotoxic reaction called serotonin syndrome. This includes selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants, tramadol, meperidine, MDMA, and dextromethorphan (DXM).
Common 5-HTP Dose
5-HTP typically comes in doses ranging from 50 to 400 mg. Users will often start with a low initial dose (50 mg) and then increase it over a period of weeks until an optimal target dose is reached.
| Threshold | 25 mg |
| Light | 50-100 mg |
| Common | 100-300 mg |
| Strong | 300-500+ mg |
Clinical trials have used doses anywhere from 20 mg to over 3.2g per day depending on the condition being treated. The majority of these trials have used doses of 200-300 mg per day.
Overdose
A 5-HTP overdose can lead to serotonin syndrome. Serotonin syndrome occurs when there is an excess of serotonin in the body. Too much serotonin in the body can produce a wide array of effects, including agitation, confusion, delirium, high blood pressure, abnormal heart rate, sweating, tremor, and diarrhea.
While there are no case reports of 5-HTP-induced serotonin syndrome in humans, it has been documented in animals. In rodents, 5-HTP induces serotonin syndrome at dosages of 100– 200 mg/kg.
5-HTP overdoses have been reported in dogs that have accidentally ingested the chemical, producing severe neurological and gastrointestinal effects at a minimum toxic dose of 23.6mg/kg and fatal overdoses at 23.6mg/kg.
Safety
According to the National Institute of Health, 5-HTP is “possibly safe” when taken by mouth in appropriate dose ranges. The authors claim it has been used safely in doses up to 400 mg for as long as a year. Higher doses, in the 6-10 gram range, have produced severe neurological and gastrointestinal symptoms, such as muscle spasms and stomach problems.
A 2004 study published in Toxicology Letters found that, in the decades of worldwide use, 5-HTP supplementation has not been associated with any toxic cases. The one noted exception is a case involving a Canadian woman who showed symptoms of eosinophilia-myalgia syndrome, though the case was linked to a contaminated batch rather than the substance itself.
Upon spectroscopic analysis, the impurity was identified as “peak X”, the same contaminant (albeit in lower quantities) linked to the EMS outbreak from impure L-tryptophan in 1989. Since 1998, the FDA has linked 10 cases of EMS possibly linked to 5-HTP supplementation. This has led some companies to advertise “Peak X free” on their 5-HTP products.
While 5-HTP supplementation is generally safe and well-tolerated in common dose ranges, it should be avoided in pregnant women, women who are breastfeeding as well as people with Down-syndrome and liver disease.
4. Effects
How Long Does it Take 5-HTP to Work?
Depending on the condition being treated, 5-HTP supplementation may take 1-6 weeks before the full effects are evident. When 5-HTP is taken for sleep or on an MDMA comedown, it should start ramping up serotonin production very quickly, as it reaches peak concentration in blood plasma in 1.5 hours.
Physiological Effects
Physiological effects are more likely to occur with higher doses, and can include:
- Decreased appetite
- Sedation
- Decreased pain (fibromyalgia and migraines)
- Stomach bloating
- Stomach cramps
- Nausea
- Dizziness
Psychological Effects
Common psychological effects of 5-HTP include:
- Antidepressant effects
- Mild euphoria
- Relaxation
- Feelings of calmness and well-being
- Improved tolerance for stress
- Increased mindfulness
- Enhanced motivation
- Improved sleep quality
- Drowsiness
Common Side Effects
5-HTP side effects commonly diminish with time and are mostly gastrointestinal in nature. Gradual dose increases are recommended to reduce the severity of potential side effects, which may include, especially at higher doses:
- Nausea
- Stomach pain
- Heartburn
- Diarrhea
- Low appetite
- Dizziness
- Drowsiness
- Vomiting
- Decreased libido
- Nightmares
Tolerance
Anecdotal reports have mentioned that 5-HTP initially works well and then tolerance develops over time.
With continuous use, 5-HTP can deplete levels of dopamine and other catecholamine neurotransmitters. When these neurotransmitters are out of balance, 5-HTP supplementation will produce a reduced effect. Tolerance is more likely to occur with long-term use, which can be alleviated by cycling 5-HTP supplementation (for example, 1 month on and 1 month off).
A rodent study found that 5-HTP produces cross-tolerance with LSD, but the animals that were behaviorally tolerant to LSD were not cross-tolerant to 5-HTP.
5 HTP vs Tryptophan
5-HTP and its precursor L-Tryptophan are both amino acids that are used in the synthesis of serotonin. Both are supplemented to alleviate conditions associated with a serotonin deficiency, including depression, anxiety, sleep disturbances, and pain conditions.
5-HTP is only available in supplement form. On the other hand, tryptophan can be supplemented or obtained from foods such as poultry, beans, nuts, milk, potatoes, and cheese.
One advantage of 5-HTP is that it more effectively crosses the blood-brain barrier to efficiently increase serotonin production. L-tryptophan requires a transport molecule to gain access to the central nervous system, thus competing with other amino acids for blood-brain barrier access.
Once 5-HTP is in the central nervous system, it is one enzymatic step away from becoming serotonin. This means it effectively bypasses the enzyme that is required to convert L-tryptophan to 5-HTP. This enzyme, called tryptophan hydroxylase, will not always efficiently catalyze L-tryptophan into 5-HTP. Indeed, it can be impeded by a multitude of factors, including insulin resistance, vitamin B6 and magnesium deficiencies, stress, and genetics.
Another advantage of 5-HTP supplementation is that it will all be used in the biosynthesis of serotonin, whereas tryptophan is used for the production of niacin (vitamin B3) and other proteins. Therefore, not all of the L-tryptophan ingested is used in the biosynthesis of serotonin.
5. Uses
Recreationally
Recreationally, 5-HTP is commonly used to mitigate neurotoxicity and restore serotonin levels associated with MDMA use. Typically, it is used for up to a week post-MDMA in doses ranging from 100-200 mg.
MDMA commonly produces an unpleasant comedown and a low mood hangover that can last for several days. Mechanistically, MDMA depletes serotonin levels in presynaptic cells and blocks the activity of tryptophan dehydrogenase, the enzyme that converts tryptophan to 5-HTP in the synthesis of serotonin.
For this reason, 5-HTP supplementation can bypass the enzymatic step inhibited by MDMA and help restore normal levels of serotonin in the days following MDMA use. While most of the evidence is anecdotal, one rodent study substantiates these claims, finding that MDMA-induced reductions in serotonin can be restored with 5-HTP.
Therapeutically
5-HTP may be therapeutically useful for conditions in which serotonin is low. Much of the clinical studies using 5-HTP have focused on the treatment of depression. In addition, there is limited evidence that 5-HTP supplementation can help with symptoms of fibromyalgia, obesity, insomnia, chronic headaches, anxiety, panic attacks, cerebellar ataxia, and other conditions associated with serotonin deficiencies.
In the next section, we will overview studies that have investigated the impact of 5-HTP on many of these conditions.
6. Studies & Research
Depression
According to one 1998 review article examining the clinical uses of 5-HTP, there have been more than 15 studies published on the use of 5-HTP for depression since the early 1970s. Of these small trials, 56% of the 511 subjects in total showed significant improvement in depressive symptoms from taking 5-HTP. In addition, more recent small clinical trials investigating the antidepressant potential of 5-HTP have found that daily supplementation for 8 weeks may be as effective as prescription antidepressants while posing fewer side effects.
A 2002 meta-analysis of 108 studies investigating the antidepressant effects of 5-HTP stated that it is better than a placebo at alleviating depression. However, the study authors note more studies are needed to determine the effectiveness and safety of 5-HTP before recommending its clinical use for depression.
Overall, 5-HTP may be beneficial for symptoms of depression, especially when combined with dopamine precursors, since it may deplete dopamine levels over time.
Anxiety
Due to the fact that serotonin plays an intimate role in regulating mood, 5-HTP may help to alleviate symptoms of anxiety. A 1985 study by Kahn and Westenberg investigated the anti-anxiety effects of 5-HTP in 10 patients with anxiety disorders. The patients were treated for 12 weeks with 300mg of 5-HTP per day, resulting in moderate reductions in anxiety as measured on three different anxiety scales.
Weight Loss
Low serotonin levels have been found to increase carbohydrate cravings and binge eating. By raising serotonin levels, 5-HTP may help to promote weight loss, reduce appetite, and thwart excessive carbohydrate consumption.
A 1992 study by Cangiano and colleagues administered 5-HTP (900 mg/day) or a placebo to 20 obese patients. The 5-HTP-treated group showed significant reductions in weight loss, decreased carbohydrate reduction, and earlier feelings of fullness compared to the placebo-treated group.
Insomnia
5-HTP may have therapeutic potential for insomnia because it is a precursor to melatonin, a hormone made from serotonin under conditions of darkness. Research has supported that 5-HTP may improve symptoms of insomnia by reducing the time it takes to fall asleep, increasing sleep quality, and enhancing REM sleep.
One study from 1971 investigating the effects of 5-HTP on sleep found that 600 mg taken before bed significantly increased REM sleep, from 5 to 53% of the placebo baseline. On average, the 8 subjects spent 16 more minutes per night in REM sleep compared to those who took a placebo.
Fibromyalgia
5-HTP supplementation has been found to ease fibromyalgia-related symptoms such as pain, sleep disturbances, and morning stiffness. A 1990 study by Caruso and colleagues administered 100 mg of 5-HTP or placebo three times daily to 50 fibromyalgia patients. Compared to placebo, 5-HTP significantly decreased the number of tender points and pain severity. In addition, the researchers found 5-HTP significantly improved morning stiffness, sleep patterns, anxiety, and fatigue ratings.
Migraines
Research is increasingly uncovering a link between low serotonin levels in blood vessels and the onset of migraines. To this end, a 1985 study by Benedittis and Massei found that 400 mg of 5-HTP administered twice daily resulted in a significant reduction in the severity and frequency of headaches compared to placebo.
Another study by Davalos et al. compared the efficacy of 5-HTP to methysergide, a commonly used migraine medication, in 124 migraine patients. The researchers found that 600 mg of 5-HTP taken twice daily for six months significantly improved the intensity and duration of migraines in 71% of the subjects.
7. 5-HTP FAQ
What Does 5-HTP Do For Your Body?
Being an immediate precursor to serotonin, 5-HTP increases the production of serotonin in the central nervous system.
How Much 5-HTP Can You Take in a Day?
In clinical trials, 5-HTP has been safely used in daily doses ranging from 20mg to 3.2g. The most common dose is in the 100-300 mg range. Higher doses (6-10g) have been associated with severe gastrointestinal side effects.
Is 5-HTP Safe to Take Everyday?
Yes, 5-HTP has been used safely in doses of 400 mg for up to a year. With that said, short-term dosing (less than four weeks) appears to grant users the most therapeutic benefit.
Does 5-HTP Increase Estrogen?
There is no evidence that 5-HTP increases estrogen levels. However, low levels of estrogen can decrease serotonin levels. On this front, there is limited evidence that suggests 5-HTP may help reduce symptoms associated with menopause, a period of time when estrogen levels can fluctuate.
Should You Take 5-HTP in the Morning or at Night?
The time of dosing depends on the reasons for taking 5-HTP. As an insomnia treatment, 5-HTP should be taken an hour before bed. For migraines, depression, and weight loss, 5-HTP is typically divided into 2 or 3 doses and taken with meals.
How Long Does it Take for 5-HTP to Start Working?
5-HTP is rapidly absorbed and reaches maximum plasma concentration in 1.5 hours. Once 5-HTP makes its way to the central nervous system, it is an immediate signal for the brain to start synthesizing serotonin. If 5-HTP is being taken for depression, migraines, or weight loss, it may take several weeks for the full effects to become apparent.
Can You Drink Alcohol with 5-HTP?
5-HTP should not be taken with alcohol. Both substances increase serotonin levels, so combining them can increase the chance of serotonin syndrome. Some individuals using this combination have reported blackouts, seizures, and other adverse effects.
How Long Does 5-HTP Stay in Your System?
Due to its rapid conversion to serotonin, 5-HTP does not stay in the system very long. 5-HTP has an elimination half-life of 1.5-2 hours, so after 7.5 to 10 hours, ~97% of a dose is eliminated from the body. 5-HTP’s short elimination half-life is thought to limit its therapeutic efficacy. For this reason, clinical trials have co-administered 5-HTP with decarboxylase inhibitors such as carbidopa and benserazide, which roughly doubled the half-life in order to maximize 5-HTP’s therapeutic potential.
RS Contributing Author: Dylan Beard
Dylan Beard is a freelance science writer and editor based in the beautiful Pacific Northwest. After finishing his physics degree and dabbling in neuroscience research at UC Santa Barbara in 2017, he returned to his first love: writing. As a long-term fan of the human brain, he loves exploring the latest research on psychedelics, nootropics, psychology, consciousness, meditation, and more. When not writing, you can probably find him on hiking trails around Oregon and Washington or listening to podcasts. Feel free to follow him on Insta @dylancb88.
