Tryptophan is an essential amino acid that is the direct precursor of serotonin (5-hydroxytryptamine, 5-HT) — the neurotransmitter that regulates mood, anxiety, appetite, sleep, and the pain perception that is associated with migraine headache and other chronic pain conditions. Tryptophan is converted to serotonin by the enzyme tryptophan hydroxylase (TPH), which is expressed primarily in the raphe nuclei of the brainstem and in the enterochromaffin cells of the gut. The serotonin that is synthesised in the brain from tryptophan is one of the most important neurotransmitters in the regulation of mood and anxiety, and its deficiency is one of the primary mechanisms that underlies depression, anxiety disorders, and other conditions that are characterised by dysregulated mood. The selective serotonin reuptake inhibitors (SSRIs) — including fluoxetine, sertraline, paroxetine, citalopram, and escitalopram — are among the most widely prescribed medications in the world precisely because they are effective at increasing the synaptic concentration of serotonin and at relieving the symptoms of depression and anxiety in the majority of patients who take them.
The Tryptophan Depletion Test
The causal role of serotonin in mood regulation has been most convincingly demonstrated by the tryptophan depletion test — a research paradigm in which participants are given a mixture of amino acids that lacks tryptophan, causing a rapid and dramatic reduction in plasma tryptophan levels and in the synthesis of serotonin in the brain. In people with a history of depression (particularly those who have responded to SSRI medications), tryptophan depletion produces a marked and rapid recurrence of depressive symptoms within hours — demonstrating that the reduction in serotonin synthesis is sufficient to cause depression in susceptible individuals. In healthy people with no history of depression, tryptophan depletion produces a more modest reduction in mood and an increase in anxiety, demonstrating that serotonin is required for the maintenance of normal mood even in people who are not clinically depressed. The tryptophan depletion test is one of the most powerful pieces of evidence for the serotonin hypothesis of depression and has been replicated in hundreds of studies over the past 30 years.
The importance of tryptophan for serotonin synthesis is also relevant to the understanding of the antidepressant effects of light therapy (phototherapy) for seasonal affective disorder (SAD). The raphe nuclei of the brainstem (where the serotonergic neurons of the CNS are located) receive direct input from the retina via the retinohypothalamic tract, and this input is regulated by the ambient light levels — in conditions of low ambient light (winter, high latitudes, indoor work environments), the serotonergic neurons of the raphe nuclei are less active, serotonin synthesis is reduced, and the risk of depression is increased. Light therapy works by increasing the activity of the serotonergic neurons of the raphe nuclei through the direct retinal input that is activated by bright light, thereby increasing serotonin synthesis and relieving the symptoms of depression in SAD.
Tryptophan and the Kynurenine Pathway
When tryptophan is not used for serotonin synthesis, it is metabolised via the kynurenine pathway — a series of enzymatic reactions that generate several bioactive metabolites, including kynurenine, kynurenic acid, quinolinic acid, and nicotinamide adenine dinucleotide (NAD+). The kynurenine pathway is activated by inflammatory cytokines (including interferon-gamma, TNF-alpha, and IL-6), by stress hormones (including cortisol), and by the activation of the enzyme indoleamine 2,3-dioxygenase (IDO), which is expressed in immune cells and in the placenta during pregnancy. The activation of the kynurenine pathway during inflammation is one of the mechanisms by which chronic illness, infection, and inflammatory conditions produce depression — the tryptophan that would otherwise be used for serotonin synthesis is diverted to the kynurenine pathway, reducing serotonin synthesis and producing depressive symptoms. The kynurenine pathway metabolites themselves may also contribute to depression — quinolinic acid is an NMDA receptor agonist and a neurotoxin, and its accumulation in the brain during chronic inflammation may contribute to the neurodegeneration and cognitive impairment that are associated with depression in older adults.
Practical Application
For general tryptophan supplementation (as a mood support strategy), the evidence-based dose is 500-1,000mg of L-tryptophan daily, taken in the evening for its sleep-promoting effects (tryptophan is converted to melatonin in the pineal gland, and the tryptophan-induced increase in melatonin is one of the mechanisms of its sleep-promoting effects). Tryptophan should be taken on an empty stomach (at least 2 hours after the last meal) because it competes with the other large neutral amino acids for the same intestinal transporters, and the presence of protein in the gut reduces its absorption. Tryptophan is generally well-tolerated with no significant adverse effects at therapeutic doses, though very high doses can produce mild GI upset. For comprehensive mood support, tryptophan pairs well with the SSRIs (under medical supervision — combining tryptophan with SSRIs can precipitate the serotonin syndrome, a potentially life-threatening condition that is characterised by agitation, hyperthermia, tachycardia, and in severe cases, by seizures and coma), with 5-HTP (the intermediate between tryptophan and serotonin, which bypasses the rate-limiting TPH step and which has been shown in some studies to be more effective than tryptophan for increasing serotonin synthesis), with the omega-3 fatty acids (which have independent antidepressant effects and which are co-factors in the serotonin synthesis pathway), and with the B-complex vitamins (which are required for the function of the enzymes of the kynurenine pathway and for the synthesis of serotonin).
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