Side Effects of 5-HTP

5-HTP is sold over the counter, but in terms of pharmacological activity it is closer to a medicine than to an ordinary amino acid. Most adverse reactions are mild and resolve on their own, yet rare serious complications also exist that are worth knowing about in advance. Our editorial team has organized the known side effects of 5-HTP and explained their mechanisms and the signs that call for medical help.

Where side effects come from

Practically all side effects of 5-HTP are explained by a single fact: the substance is converted into serotonin quickly and without regulatory limits. Unlike tryptophan, 5-HTP bypasses the rate-limiting enzyme of synthesis, so increasing the dose directly raises the amount of serotonin produced.

About 90% of the body's serotonin is found not in the brain but in the gut, where it regulates peristalsis, secretion and the sensation of nausea. A significant part of ingested 5-HTP is converted into serotonin already in the periphery, and the gut is the first to feel the excess. That is why gastrointestinal symptoms are the most common complaint.

In the brain, serotonin is involved in regulating mood, sleep, appetite, body temperature and muscle tone. Excessive serotonergic activity may manifest as drowsiness or, conversely, agitation, and in the extreme case as serotonin syndrome.

A separate group of risks is not related to the pharmacology of the substance itself but concerns product quality: plant-derived raw material requires thorough purification, and impurities may have their own toxicity.

Digestive disorders

Nausea is the most characteristic side effect of 5-HTP. It is linked to stimulation of serotonin 5-HT3 receptors in the gut and the vomiting center; it is precisely the blockade of these receptors that underlies the action of modern antiemetic drugs. Nausea occurs more often at the start of use and with large single doses.

Diarrhea, cramps and abdominal discomfort are explained by serotonin's enhancement of peristalsis. In some people these symptoms ease after a few days, but in others they persist and become a reason to stop the supplement.

In clinical studies these effects were described as the most common adverse reactions (Birdsall, 1998; Turner et al., 2006). Their intensity depends on the single dose: splitting the daily dose into several intakes and taking it with food often reduce the severity of symptoms.

It is also worth remembering the flip side: the reduction in appetite that is sometimes presented as an advantage of 5-HTP may partly be a consequence of exactly this mild nausea. This makes interpreting studies on «appetite control» more complicated.

The nervous system: drowsiness, headache, mood

Some people report drowsiness, lethargy or, conversely, vivid dreams and restless sleep. The reaction is individual and depends on the time of intake. Until you have assessed your own reaction, you should not drive a car or operate dangerous machinery.

Headache and dizziness occur less often. Serotonin affects the tone of the brain's blood vessels, and in people prone to migraine, taking serotonergic substances may theoretically both relieve and provoke attacks.

Mood deserves separate attention. In people with bipolar disorder, serotonergic agents, including antidepressants, can trigger a switch into a manic or hypomanic state. Isolated cases of similar reactions to 5-HTP have been described, so the supplement is not suitable for people with this diagnosis.

Anxiety, irritability and agitation have also been reported, especially when combined with other substances that affect monoamines. If mood worsens or unusual anxiety appears during use, the supplement should be stopped and a doctor consulted.

Serotonin syndrome

Serotonin syndrome is a potentially life-threatening condition caused by excessive serotonergic activity. The classic review by Boyer and Shannon (2005) describes it as a triad: changes in mental state, autonomic instability and neuromuscular disturbances.

On 5-HTP alone the development of the syndrome is unlikely, but the risk rises sharply when combined with drugs that increase serotonin levels. Most often these are antidepressants (SSRIs, SNRIs, MAOIs, tricyclics), tramadol, triptans, linezolid, dextromethorphan, as well as recreational substances such as MDMA.

Signs that require immediate medical attention:

• agitation, confusion, anxiety;
• tremor, involuntary muscle twitching (myoclonus), heightened reflexes;
• sweating, rapid heartbeat, elevated blood pressure;
• fever, muscle rigidity;
• diarrhea, dilated pupils.

Treatment consists of withdrawing all serotonergic agents and medical monitoring; in severe cases intensive care is required. The best prevention is not to combine 5-HTP with any medicines that affect serotonin without a doctor's agreement.

Raw-material quality, eosinophilia-myalgia and effects on lab tests

In 1989, an epidemic of eosinophilia-myalgia syndrome (EMS) broke out in the United States, a severe illness with muscle pain, high eosinophil counts and damage to the skin, nerves and lungs. It was linked to tryptophan from a single manufacturer, in whose product impurities were found.

Later, cases of a similar condition were described in people taking 5-HTP (Michelson et al., 1994), and analytical studies found in some commercial 5-HTP samples an impurity known as «peak X» (Klarskov et al., 2003). The safety review by Das and colleagues (2004) concluded that the link between 5-HTP and EMS is confined to isolated cases and is not proven as a systemic problem, but it stressed the role of product purity.

The practical conclusion is to buy 5-HTP only from manufacturers who provide certificates of analysis and undergo independent testing. The appearance of muscle pain, rash, swelling or shortness of breath during use must be discussed with a doctor immediately.

Another little-noticed effect concerns laboratory diagnostics. 5-HTP is metabolized to 5-hydroxyindoleacetic acid (5-HIAA), which is measured in urine to diagnose neuroendocrine (carcinoid) tumors. Taking the supplement can cause a false-positive elevation, so a doctor should be warned before such a test.

Editorial conclusions

The most common side effects of 5-HTP, nausea, diarrhea and abdominal discomfort, are linked to peripheral conversion into serotonin and depend on the single dose.

The most dangerous risk is serotonin syndrome when combined with antidepressants, tramadol, triptans and other serotonergic agents. The supplement is not suitable for people with bipolar disorder.

Raw-material quality is fundamentally important, and before a urine 5-HIAA test the supplement must be stopped and the doctor warned.

See also: «Who should not take 5-HTP», «How to take 5-HTP: dosage, timing, duration» and «5-HTP: available forms and which to choose».

References

1. Turner EH, Loftis JM, Blackwell AD. Serotonin a la carte: supplementation with the serotonin precursor 5-hydroxytryptophan. Pharmacol Ther. 2006;109(3):325–338.
2. Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998;3(4):271–280.
3. Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005;352(11):1112–1120.
4. Das YT, Bagchi M, Bagchi D, Preuss HG. Safety of 5-hydroxy-L-tryptophan. Toxicol Lett. 2004;150(1):111–122.
5. Michelson D, Page SW, Casey R, et al. An eosinophilia-myalgia syndrome related disorder associated with exposure to L-5-hydroxytryptophan. J Rheumatol. 1994;21(12):2261–2265.
6. 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.