5-HTP or Melatonin: what is the difference

5-HTP and melatonin are connected by one biochemical link: from 5-hydroxytryptophan serotonin is formed, and from serotonin in the pineal gland — melatonin. Because of this, 5-HTP is often advertised as a «natural path to melatonin». But between a «precursor of a precursor» and the hormone itself there is a great distance — in mechanisms, in evidence and in risks. The editorial team explains what exactly the difference is.

One synthesis pathway — different links

It all starts with the essential amino acid tryptophan, which we obtain from protein food. The enzyme tryptophan hydroxylase converts it into 5-hydroxytryptophan (5-HTP). It is this stage that limits the speed of the whole process.

Next, aromatic amino acid decarboxylase converts 5-HTP into serotonin. In the pineal gland at night serotonin is first acetylated and then methylated — this is how melatonin is formed. The key enzyme of this link is activated in the dark under the control of the circadian clock.

A 5-HTP supplement bypasses the rate-limiting stage and increases serotonin formation — and not only in the brain but also in peripheral tissues, primarily in the intestine. A melatonin supplement delivers the final product directly.

It is important that the conversion of serotonin into melatonin is regulated by light and time of day. That is, taking 5-HTP does not guarantee a proportional rise in melatonin: more serotonin does not automatically mean more of the nighttime hormone.

What 5-HTP is

In supplements 5-HTP is obtained mainly from the seeds of the West African plant Griffonia simplicifolia. The substance is well absorbed and, unlike serotonin itself, crosses the blood-brain barrier.

The main interest in 5-HTP is connected not with sleep but with mood and appetite: since serotonin takes part in the regulation of emotions, satiety and pain, 5-HTP was studied in depression, fibromyalgia, migraine and obesity.

The Cochrane review by Shaw et al. (2002) on tryptophan and 5-HTP in depression found only a few small studies of acceptable quality and concluded that there is insufficient evidence for recommendations.

Regarding sleep there are few dedicated quality studies of 5-HTP. So the claim that 5-HTP «improves sleep through melatonin» relies more on biochemical logic than on clinical results.

What melatonin in supplements is

Melatonin in supplements is a synthetic hormone identical to the one produced by the pineal gland. It acts through MT1 and MT2 receptors and signals to the body about the onset of night, shifting the phase of the circadian rhythm.

The evidence base of melatonin is much broader. The meta-analysis by Ferracioli-Oda et al. (2013) showed a shortening of the time to fall asleep in primary sleep disorders, and the Cochrane review confirmed effectiveness in jet lag.

Melatonin has clear medical indications: in the EU a prolonged-release 2 mg form is registered for treating insomnia in people aged 55 and over. For 5-HTP there are no similar registered indications regarding sleep.

Thus, from the point of view of sleep, melatonin is a direct and studied tool, and 5-HTP an indirect and much less researched one.

Comparison of key characteristics

The table summarizes the main differences between the substances.

As we can see, these substances are only formally ºbout the same thing». By pharmacological profile they are substantially different, and the choice between them depends on the goal and the safety profile.

It is also important that 5-HTP affects serotonin in the intestine, which explains the frequent stomach side effects, whereas melatonin almost never creates such problems.

Safety: where 5-HTP requires more caution

The most serious risk of 5-HTP is serotonin syndrome when combined with medications that raise serotonin levels: antidepressants of the SSRI and SNRI groups, MAO inhibitors, tramadol, triptans, linezolid. This is a potentially life-threatening condition with tremor, fever, agitation and muscle rigidity.

Historically, an outbreak of eosinophilia-myalgia syndrome was associated with tryptophan supplements in the late 1980s, which was attributed to impurities in one manufacturer's products. The safety review by Das et al. (2004) found no convincing evidence of such a risk for 5-HTP itself but emphasized the importance of raw material quality.

• Do not combine 5-HTP with antidepressants and other serotonergic medications.
• Do not take 5-HTP during pregnancy and breastfeeding.
• Combine melatonin cautiously with anticoagulants, immunosuppressants and fluvoxamine.
• Both substances can increase drowsiness when combined with alcohol and sedatives.

People with depression or anxiety disorders should not self-medicate with 5-HTP but see a doctor: effective and safe methods of treating these conditions exist.

Editorial conclusions

5-HTP and melatonin lie on the same biochemical pathway but occupy different places on it: 5-HTP raises serotonin throughout the body, melatonin acts directly as a signal of night.

For sleep problems melatonin has a better evidence base and clearer indications. 5-HTP was studied mainly for mood and appetite, and even there the evidence is scant.

The safety profile of 5-HTP requires special attention because of the risk of serotonin syndrome when combined with common medications.

We also recommend our articles on choosing between 5-HTP and melatonin for different situations, on melatonin and glycine and on tryptophan in the diet.

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. Das YT, Bagchi M, Bagchi D, Preuss HG. Safety of 5-hydroxy-L-tryptophan. Toxicol Lett. 2004;150(1):111–122.
4. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxytryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.
5. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112–1120.
6. Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8(5):e63773.
7. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev. 2002;(2):CD001520.