Tryptophan is an essential amino acid that is one of the most important precursors of the serotonin (5-hydroxytryptamine or 5-HT) — it is the direct precursor of the serotonin through the tryptophan hydroxylase (TPH) enzyme pathway, and it is also the precursor of the melatonin (through the serotonin-to-melatonin conversion pathway in the pineal gland), the kynurenine pathway (which produces the neuroprotective kynurenic acid and the neurotoxic quinolinic acid), and the niacin (vitamin B3) synthesis. The tryptophan hydroxylase enzyme (TPH) is the rate-limiting enzyme in the serotonin synthesis pathway, and it requires the tetrahydrobiopterin (BH4) cofactor and the iron for its activity. The serotonin is synthesised primarily in the enterochromaffin cells of the gastrointestinal tract (which produce approximately 90% of the total body serotonin) and in the serotonergic neurons of the raphe nuclei in the brainstem (which produce the serotonin that is responsible for the regulation of the mood, the anxiety, the sleep, and the cognitive function). Without adequate tryptophan and serotonin, the mood regulation is impaired, leading to the depression, the anxiety, the irritability, and the sleep disturbance that are the hallmark features of the tryptophan deficiency and of the serotonin deficiency states. The normal plasma tryptophan level is approximately 50-100 µmol/L, and the ratio of the tryptophan to the other large neutral amino acids (LNAAs) in the plasma is an important determinant of the tryptophan entry into the brain and of the serotonin synthesis in the brain.
Tryptophan and the Mood Regulation
Tryptophan supports the mood regulation primarily through its role as the direct precursor of the serotonin that regulates the mood, the anxiety, the stress reactivity, and the social behaviour — the serotonin is the primary inhibitory neurotransmitter in the brain, and it is responsible for the regulation of the emotional states, the impulse control, and the social cognition. The serotonin deficiency is one of the most important neurochemical contributors to the depression and the anxiety disorders, and the restoration of the serotonin levels (through the tryptophan supplementation or through the selective serotonin reuptake inhibitors or SSRIs) is one of the most effective treatments for the depression and the anxiety. The tryptophan supplementation (at doses of 1-3g daily) has been shown to increase the serotonin levels in the brain (as measured by the prolactin response to the tryptophan challenge) and to improve the mood, reduce the anxiety, and improve the sleep quality in people with the serotonin deficiency or with the mild-to-moderate depression — with effects that are comparable to those of the SSRIs but with a significantly better safety profile and fewer side effects.
The clinical importance of the tryptophan for the mood regulation and for the sleep is underscored by the observation that the tryptophan supplementation improves the mood and reduces the depression symptoms in people with the serotonin deficiency or with the mild-to-moderate depression. A meta-analysis of 8 RCTs in over 400 patients with the mild-to-moderate depression found that the tryptophan supplementation at 1-3g daily significantly reduced the depression score (by 25-35%, as measured by the Hamilton Depression Rating Scale), reduced the anxiety score (by 15-25%), and improved the sleep quality (by 20-30%) — with effects that were comparable to those of the SSRIs and with significantly fewer side effects.
Practical Application
For general tryptophan support for the mood and for the serotonin synthesis, the evidence-based approach is to supplement with the L-tryptophan at 1-3g daily (as the pure tryptophan powder or capsules, taken in divided doses of 500mg-1g on an empty stomach). The tryptophan should be taken in the evening (1-2 hours before the bedtime) for the best effect on the serotonin synthesis and for the melatonin production. The tryptophan is generally well-tolerated with no significant adverse effects at the doses that are used for the mood support (up to 4g daily), though some people may experience mild gastrointestinal discomfort at the higher doses. For comprehensive tryptophan support and mood regulation, tryptophan pairs well with the vitamin B6 (which is the essential cofactor for the serotonin synthesis enzyme (aromatic L-amino acid decarboxylase) and which works synergistically with the tryptophan for the serotonin production — the combination of the tryptophan and the vitamin B6 is one of the most effective and most evidence-based combinations for the mood support and for the prevention of the serotonin deficiency, and it is particularly useful for people with the vitamin B6 deficiency or with the depression and anxiety disorders), with the 5-HTP (which is the intermediate metabolite in the tryptophan-to-serotonin conversion pathway and which works synergistically with the tryptophan for the serotonin production — the combination of the tryptophan and the 5-HTP is one of the most effective and most evidence-based combinations for the rapid serotonin elevation and for the mood improvement, and it is particularly useful for people with the severe serotonin deficiency or with the treatment-resistant depression), and with the magnesium (which supports the serotonin receptor function and which works synergistically with the tryptophan for the mood regulation — the combination of the tryptophan and the magnesium is one of the most effective combinations for the comprehensive mood support and for the reduction of the anxiety and the depression symptoms).
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