Tryptophan is the essential amino acid that is the direct precursor of the serotonin (5-hydroxytryptamine, 5-HT) and of the melatonin (the pineal hormone that regulates the sleep-wake cycle) — and it is one of the least abundant amino acids in the diet, which makes it the rate-limiting factor for the serotonin synthesis in the brain. The tryptophan is obtained exclusively from the diet (it is not synthesised in the human body), and it is found in the highest concentrations in the turkey, the chicken, the eggs, the dairy, the nuts, the seeds, and the chocolate. The typical dietary tryptophan intake is 200-400mg daily (from approximately 100-200g of turkey or chicken), and the therapeutic doses for the serotonin and the mood support are 500-2000mg of the tryptophan supplement daily — making it one of the most evidence-based and most widely used amino acid supplements for the depression, the anxiety, the insomnia, and the other conditions that are associated with the low serotonin levels. Without adequate tryptophan and serotonin synthesis, the serotonin levels are low, the mood is depressed, the anxiety is high, and the sleep is disturbed — the hallmark of the tryptophan deficiency and of the low serotonin states. The serotonin is one of the most important neurotransmitters in the brain — it regulates the mood, the anxiety, the appetite, the sleep, the pain perception, and the cognitive function, and it is the target of the most widely used antidepressants (SSRIs such as the fluoxetine, the sertraline, the paroxetine, and the citalopram). The low serotonin levels are associated with the depression, the anxiety, the OCD, the panic disorder, the PTSD, the social anxiety disorder, the insomnia, the appetite disorders, and the chronic pain — making the tryptophan one of the most important and most versatile amino acids for the mental health and for the general well-being.
Tryptophan and the Serotonin Pathway
Tryptophan is converted to the serotonin in the brain and in the enterochromaffin cells of the gut through the sequential action of the tryptophan hydroxylase (TPH) enzyme and the aromatic L-amino acid decarboxylase (AADC) enzyme — the TPH is the rate-limiting enzyme in the serotonin synthesis (it is regulated by the glucocorticoids, by the circadian signals, and by the serotonergic feedback inhibition), and it requires the tetrahydrobiopterin (BH4) as a cofactor and the iron and the oxygen as co-substrates. The serotonin that is synthesised in the brain is stored in the synaptic vesicles and released into the synaptic cleft in response to the neuronal depolarisation — where it activates the serotonin receptors (5-HT1A through 5-HT7, with multiple subtypes) and mediates its effects on the mood, the anxiety, the appetite, the sleep, and the cognitive function. The serotonin is also the precursor of the melatonin — it is first converted to the 5-hydroxytryptophan (5-HTP) by the TPH, then to the serotonin by the AADC, and then to the N-acetylserotonin (NAS) by the arylalkylamine N-acetyltransferase (AANAT), and finally to the melatonin by the acetylserotonin O-methyltransferase (ASMT). This conversion of the serotonin to the melatonin is the primary mechanism by which the tryptophan supports the sleep — and it explains why the tryptophan supplementation is so effective for the insomnia and for the improvement of the sleep quality.
The clinical importance of the tryptophan for the mood and for the sleep is underscored by the observation that the tryptophan supplementation improves the symptoms of the depression, the anxiety, and the insomnia. A meta-analysis of 8 RCTs in over 400 participants with the depression found that the tryptophan supplementation at 1-3g daily significantly improved the depression symptoms (by 20-30%, as measured by the Hamilton Depression Rating Scale and the Beck Depression Inventory) — making tryptophan one of the most effective and safest interventions for the depression, with a safety profile that is superior to the SSRIs and the other antidepressant drugs.
Practical Application
For general tryptophan supplementation for the serotonin and the mood support, the evidence-based approach is to supplement with 500-2000mg of tryptophan daily (as the pure L-tryptophan powder or capsule, taken 30-60 minutes before the bedtime for the sleep, or in the morning and in the early afternoon for the mood support). The tryptophan should be taken on the empty stomach (30-60 minutes before the meals or 2 hours after the meals) for the optimal absorption, and it should not be combined with the SSRI antidepressants, the MAOI antidepressants, or the tryptophan hydroxylase inhibitors (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 tryptophan is generally well-tolerated with no significant adverse effects at doses up to 6g daily, though it may cause the nausea, the drowsiness, and the sexual dysfunction at the high doses. For comprehensive serotonin and mood support, tryptophan pairs well with the vitamin B6 (which is a cofactor for the aromatic L-amino acid decarboxylase and which is therefore essential for the conversion of the tryptophan to the serotonin), with the 5-HTP (which is the intermediate in the serotonin synthesis pathway and which bypasses the rate-limiting tryptophan hydroxylase step — the combination of the tryptophan and the 5-HTP is synergistic for the serotonin elevation), with the magnesium (which is a cofactor for the tryptophan hydroxylase and which has complementary effects on the mood and on the relaxation), and with the exercise (which increases the tryptophan uptake in the brain and which works synergistically with the tryptophan for the mood improvement and for the stress reduction).
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