Side effects of 5-HTP

5-HTP is sold over the counter, but in pharmacological activity it is closer to a medication than to ordinary amino acids. In most cases side reactions are mild and pass on their own, but there are also rare serious complications worth knowing about in advance. The editors have systematized the known side effects of 5-HTP, explained their mechanisms and the signs that require medical attention.

Where the side effects come from

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

About 90% of the body’s serotonin is located not in the brain but in the intestine, where it regulates peristalsis, secretion and the feeling of nausea. A significant part of the 5-HTP taken is converted into serotonin already in the periphery, and the intestine is the first to feel the excess. That is why gastrointestinal symptoms are the most frequent complaint.

In the brain, serotonin participates in the regulation of mood, sleep, appetite, body temperature and muscle tone. Excessive serotonergic activity can manifest as drowsiness or, conversely, agitation, and in the extreme case — serotonin syndrome.

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

Digestive disorders

Nausea is the most characteristic side effect of 5-HTP. It is associated with stimulation of serotonin 5-HT3 receptors in the intestine and the vomiting center; it is precisely on the blockade of these receptors that the action of modern antiemetics is based. Nausea occurs more often at the start of intake and with large single amounts.

Diarrhea, cramps and abdominal discomfort are explained by the fact that serotonin enhances peristalsis. In some people these symptoms weaken after a few days, but in others they persist and become a reason to abandon 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 amount: dividing the daily dose into several intakes and taking it with food often reduces the severity of symptoms.

It is also worth remembering the flip side: the appetite reduction sometimes presented as an advantage of 5-HTP may partly be a consequence of mild nausea. This makes interpreting studies on "appetite control" more difficult.

Nervous system: drowsiness, headache, mood

Some people note drowsiness, lethargy or, conversely, vivid dreams and restless sleep. The reaction is individual and depends on the timing 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 can theoretically both relieve and provoke attacks.

Mood deserves separate attention. In people with bipolar disorder, serotonergic agents, including antidepressants, can provoke 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 such a 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 intake, 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 disorders.

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 requiring immediate medical attention:

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

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

Raw material quality, eosinophilia-myalgia and effect on tests

In 1989 an epidemic of eosinophilia-myalgia syndrome (EMS) broke out in the USA — a severe disease with muscle pain, high eosinophil levels and damage to the skin, nerves and lungs. It was linked to tryptophan from one manufacturer, in whose products impurities were found.

Later, cases of a similar condition were described in people who took 5-HTP (Michelson et al., 1994), and analytical studies found in some commercial samples of 5-HTP 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 was based on isolated cases and not proven as a systemic problem, but emphasized the role of product purity.

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

One more inconspicuous effect concerns laboratory diagnostics. 5-HTP is metabolized into 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 the doctor should be warned before such a test.

Editorial conclusions

The most common side effects of 5-HTP — nausea, diarrhea and abdominal discomfort — are associated with peripheral conversion into serotonin and depend on the single amount.

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 of fundamental importance, and before a urine test for 5-HIAA, intake must be stopped and the doctor warned.

Read 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.