5-HTP: what it is and how it works

5-HTP, or 5-hydroxytryptophan, is an intermediate compound on the path from the amino acid tryptophan to serotonin. In sports nutrition stores it is sold as a remedy "for mood, sleep and appetite control." To understand what can and cannot be expected of it, the editors examined the biochemistry of the substance, its pharmacokinetics and the state of the scientific data.

What 5-HTP is and where it comes from

5-hydroxytryptophan is an amino acid that is not part of proteins and exists in the body only as a short-lived intermediate product. It is formed by the enzyme tryptophan hydroxylase, which attaches a hydroxyl group to the tryptophan molecule. Almost all of the 5-HTP formed is quickly converted further into serotonin, so its concentration in tissues is negligible.

Commercial 5-HTP is obtained mainly from the seeds of the West African plant Griffonia simplicifolia, which contain this compound in significant amounts. The extract is purified and standardized, then sold in capsules or tablets. This distinguishes 5-HTP from most sports nutrition amino acids, which are obtained by fermentation.

The legal status of the substance differs across countries. In the USA and many European countries 5-HTP is sold as a dietary supplement; in some states oxitriptan (the international name for 5-HTP) is registered as a medicinal product. This already hints that we are dealing with a substance of notable pharmacological activity, not "ordinary nutrition."

5-HTP is not on the WADA Prohibited List, so for athletes the risk is associated not with doping status but with possible contamination of the product and interactions with medications.

The path from tryptophan to serotonin and melatonin

Serotonin synthesis consists of two stages. First, tryptophan hydroxylase converts tryptophan into 5-HTP; it is this stage that is rate-limiting, i.e. it determines the overall speed of the process. Then aromatic L-amino acid decarboxylase, with the participation of vitamin B6, removes the carboxyl group, and serotonin (5-hydroxytryptamine) is formed.

In the pineal gland, serotonin is converted at night into melatonin — a hormone that regulates circadian rhythms. That is why 5-HTP is often positioned as a remedy both for mood and for sleep, although a direct link between taking the supplement and sleep quality in humans is poorly proven.

A key feature of 5-HTP is that it bypasses the rate-limiting stage. Taking tryptophan does not guarantee a proportional increase in serotonin, because the enzyme regulates the rate; 5-HTP, however, goes straight to the second, fast stage. In addition, a significant part of the tryptophan in the body goes down the kynurenine pathway, whereas 5-HTP avoids this "loss" (Turner et al., 2006).

The decarboxylase that converts 5-HTP into serotonin is the same one that converts L-DOPA into dopamine. This explains some interactions of 5-HTP with drugs that affect the dopamine system.

Pharmacokinetics: absorption and peripheral conversion

5-HTP is well absorbed in the intestine; in the pharmacokinetic works summarized in the reviews by Birdsall (1998) and Turner and colleagues (2006), oral bioavailability is estimated at about 70%. Absorption does not require specific conditions, and the influence of food on the total amount of substance absorbed is minor.

Unlike serotonin, which does not cross the blood-brain barrier, 5-HTP enters the brain and is converted into serotonin there. However, a significant part of the substance is decarboxylated already in the periphery — in the intestine, liver and kidneys. Peripheral serotonin affects intestinal motility and is the main cause of the nausea and diarrhea that often accompany intake.

The half-life of 5-HTP is short — a few hours. That is why in clinical studies the daily amount was usually divided into several doses. Metabolism ends with the formation of 5-hydroxyindoleacetic acid (5-HIAA), which is excreted in the urine.

In some clinical studies 5-HTP was combined with carbidopa — a prescription inhibitor of peripheral decarboxylase — so that more of the substance would reach the brain. This is a medical approach that changes the risk profile, and it has nothing to do with taking the supplement on your own.

What 5-HTP was studied for

Most research concerns depression. The Cochrane review by Shaw and colleagues (2002) found only a small number of high-quality works and concluded that the data are insufficient to assess the effectiveness of 5-HTP and tryptophan. The later meta-analysis by Javelle and colleagues (2020) suggested a certain effect but emphasized the low quality and small size of the studies.

The second direction is appetite and body weight control. In the 1990s the Italian group led by Cangiano conducted several small studies on people with obesity and found reduced carbohydrate consumption and faster satiety with 5-HTP. These data are interesting but limited by small samples and still not confirmed by large trials.

The third is fibromyalgia: in the double-blind study by Caruso and colleagues (1990) an improvement in some symptoms compared with placebo was noted. 5-HTP was also studied for migraine and sleep disorders, but without convincing results.

• Depression:data limited, of low quality; does not replace treatment.
• Appetite and body weight:small studies showed faster satiety.
• Fibromyalgia:isolated positive results.
• Sleep, migraine:no convincing evidence.

Limitations and cautions

The main danger of 5-HTP is serotonin syndrome when combined with antidepressants (SSRIs, SNRIs, MAOIs), tramadol, triptans, linezolid and other serotonergic agents. This condition manifests as agitation, trembling, muscle rigidity, fever and can be life-threatening (Boyer, Shannon, 2005).

The second caution is historical. In the late 1980s, contaminated batches of tryptophan caused an epidemic of eosinophilia-myalgia. Later, impurities were found in some samples of 5-HTP that were analytically linked to this syndrome (Klarskov et al., 2003). This makes the quality of the raw material and independent manufacturer control fundamentally important.

The third is digestive disorders: nausea, diarrhea, abdominal discomfort, especially at the start of intake or with large single amounts. They are associated with peripheral conversion into serotonin.

Finally, 5-HTP is not suitable for pregnant women, breastfeeding women and children due to a lack of safety data. More on contraindications — in a separate article.

Editorial conclusions

5-HTP is a direct precursor of serotonin that bypasses the rate-limiting stage of its synthesis and is well absorbed. That is why it is pharmacologically more active than tryptophan and requires greater caution.

The evidence base regarding mood, appetite and sleep is small and mostly of low quality; none of these areas allows 5-HTP to be considered a replacement for treatment.

The most serious risks are serotonin syndrome when combined with drugs and the quality of the raw material.

We also recommend reading the editorial articles "The benefits of 5-HTP for athletes: the evidence base," "Side effects of 5-HTP" and "Who should not take 5-HTP."

References

1. Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998;3(4):271–280.
2. Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006;109(3):325–338.
3. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.
4. Javelle F, Lampit A, Bloch W, et al. Effects of 5-hydroxytryptophan on distinct types of depression: a systematic review and meta-analysis. Nutr Rev. 2020;78(1):77–88.
5. Cangiano C, Ceci F, Cascino A, et al. Eating behavior and adherence to dietary prescriptions in obese adult subjects treated with 5-hydroxytryptophan. Am J Clin Nutr. 1992;56(5):863–867.
6. Caruso I, Sarzi Puttini P, Cazzola M, Azzolini V. Double-blind study of 5-hydroxytryptophan versus placebo in the treatment of primary fibromyalgia syndrome. J Int Med Res. 1990;18(3):201–209.
7. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112–1120.
8. Klarskov K, Johnson KL, Benson LM, et al. Eosinophilia-myalgia syndrome case-associated contaminants in commercially available 5-hydroxytryptophan. Adv Exp Med Biol. 2003;527:183–192.