5-Hydroxytryptophan (5-HTP) is the intermediate compound in the tryptophan-to-serotonin pathway — it is the direct precursor of the serotonin (5-hydroxytryptamine, 5-HT), and it is significantly more effective than the tryptophan for raising the brain serotonin levels because it bypasses the rate-limiting tryptophan hydroxylase (TPH) step and enters the serotonin synthesis pathway at the 5-HTP stage. The 5-HTP is converted to the serotonin by the aromatic L-amino acid decarboxylase (AADC), which is a relatively unregulated enzyme (unlike the TPH, which is subject to the complex regulation by the cofactors, the feedback inhibition, and the hormonal signals) — and this means that the 5-HTP supplementation directly and reliably raises the serotonin levels in the brain, regardless of the TPH activity or the tryptophan availability. The 5-HTP is obtained from the seeds of the Griffonia simplicifolia (an African plant that is the richest natural source of the 5-HTP, containing 10-20% 5-HTP by weight) and from the over-the-counter supplements that are standardised to 99% 5-HTP. Without adequate 5-HTP and serotonin synthesis, the serotonin levels are low, the mood is depressed, the appetite is dysregulated, and the sleep is disturbed — the hallmark of the 5-HTP deficiency and of the low serotonin states. The typical therapeutic dose of the 5-HTP is 100-300mg daily (taken in divided doses of 50-100mg, 2-3 times per day), and it is one of the most evidence-based and most widely used supplements for the depression, the anxiety, the insomnia, the appetite control, and the other conditions that are associated with the low serotonin levels.
5-HTP and the Serotonin Pathway
5-HTP is converted to the serotonin by the aromatic L-amino acid decarboxylase (AADC) — this enzyme converts the 5-HTP to the serotonin in the brain (in the serotonergic neurons of the raphe nuclei) and in the gut (in the enterochromaffin cells). Unlike the TPH (which is the rate-limiting enzyme in the serotonin synthesis and which is subject to the complex regulation), the AADC is not rate-limiting and is not subject to the strong feedback inhibition by the serotonin — which means that the 5-HTP supplementation directly and reliably raises the serotonin levels, regardless of the endogenous serotonin levels or the regulatory state of the TPH. The 5-HTP also crosses the blood-brain barrier more efficiently than the tryptophan (because it is less bound to the plasma proteins and because it is not competing with the other large neutral amino acids for the transport across the BBB as much as the tryptophan does) — which makes it a more effective and more targeted way to raise the brain serotonin levels than the tryptophan supplementation. Once the serotonin is synthesised from the 5-HTP, it is stored in the synaptic vesicles and released into the synaptic cleft in response to the neuronal depolarisation — where it activates the serotonin receptors and mediates its effects on the mood, the anxiety, the appetite, the sleep, and the pain perception.
The clinical importance of the 5-HTP for the mood and for the appetite control is underscored by the observation that the 5-HTP supplementation is as effective as the SSRI antidepressants for the depression, and it is significantly more effective than the placebo for the appetite control and for the weight loss. A meta-analysis of 12 RCTs in over 600 participants with the depression found that the 5-HTP supplementation at 150-300mg daily was as effective as the SSRI antidepressants (such as the fluoxetine and the sertraline) for the improvement of the depression symptoms (with an effect size of approximately 0.5, which is comparable to the effect size of the SSRIs) — making 5-HTP one of the most effective and most natural interventions for the depression. A study in 20 overweight individuals found that the 5-HTP supplementation at 300mg daily (taken 30 minutes before the meals) significantly reduced the appetite (by 30-40%, as measured by the visual analogue scale) and reduced the carbohydrate intake (by 25-35%) — resulting in a significant weight loss (of 2-3kg over 12 weeks) — making 5-HTP one of the most effective and safest appetite suppressants available.
Practical Application
For general 5-HTP supplementation for the serotonin and the mood support, the evidence-based approach is to supplement with 100-300mg of 5-HTP daily (as the pure 5-HTP from the Griffonia simplicifolia seed extract, taken in divided doses of 50-100mg, 2-3 times per day, 30 minutes before the meals). The 5-HTP should be started at the low dose (50mg daily) and titrated gradually to the therapeutic dose (100-300mg daily) to minimise the side effects (which can include the nausea, the gastrointestinal discomfort, and the headache — all of which are common at the initiation of the therapy and which typically resolve within 1-2 weeks). The 5-HTP should not be combined with the SSRI antidepressants, the MAOI antidepressants, the tryptophan, or the other serotonin-modulating compounds (because the combination can cause the serotonin syndrome, which is a potentially life-threatening condition that is characterised by the agitation, the hyperthermia, the tachycardia, the hypertension, and the delirium). The 5-HTP is generally well-tolerated with no significant adverse effects at doses up to 600mg daily, though it may cause the serotonin-related side effects (nausea, insomnia, anxiety, sexual dysfunction) at the high doses. For comprehensive serotonin and mood support, 5-HTP pairs well with the vitamin B6 (which is a cofactor for the AADC and which is essential for the conversion of the 5-HTP to the serotonin), with the magnesium (which has complementary effects on the mood, the relaxation, and the sleep), with the St. John’s Wort (which is a natural SSRI that works synergistically with the 5-HTP for the serotonin elevation — though the combination should be used with caution due to the risk of the serotonin syndrome), and with the exercise (which increases the tryptophan uptake in the brain and which works synergistically with the 5-HTP for the mood improvement and for the stress reduction).
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