Dietary L-Tryptophan Modulation of Sertraline Pharmacodynamics: A Randomized Controlled Trial Evaluating Nutritional Augmentation in Major Depressive Disorder

Abstract

Background: Major depressive disorder (MDD) is a major global health problem, and incomplete response to selective serotonin reuptake inhibitor (SSRI) therapy remains a significant clinical challenge. Nutritional modulation of serotonergic neurotransmission through dietary L-tryptophan supplementation represents a potential adjunctive therapeutic strategy. Objective: To evaluate the effect of controlled dietary L-tryptophan supplementation on sertraline pharmacodynamics in adults with major depressive disorder. Methods: A 12-week randomized, double-blind, parallel-group clinical trial was conducted involving 120 adults diagnosed with MDD. Participants were assigned to receive background sertraline therapy (50 mg/day) with either no supplementation, 1 g/day L-tryptophan, or 2 g/day L-tryptophan under a standardized reference diet. Depression severity was assessed using the HAM-D-17 scale, and plasma L-tryptophan and 5-HIAA concentrations were measured as biochemical markers. Results: L-tryptophan supplementation significantly improved depressive symptom scores compared with control treatment (p < 0.01). The maximum clinical benefit was observed with 1 g/day supplementation (Cohen’s d = 0.68), while increasing the dose to 2 g/day produced minimal additional improvement (Cohen’s d = 0.09), indicating a plateau effect. Plasma L-tryptophan and 5-HIAA levels increased in a dose-dependent manner and were negatively correlated with depression severity (r = −0.42, p < 0.01). Adverse event incidence, including sexual dysfunction, was comparable across groups.