[Mechanisms of action and therapeutic perspectives of LSD: Current status].

About 30% of people with major depressive disorder do not respond to at least two standard antidepressants, a condition called treatment-resistant depression. LSD (lysergic acid diethylamide) is being investigated as a potential fast-acting antidepressant because it modulates both the serotonin system, especially the 5-HT2A receptor, and the glutamatergic system, which may enhance neuroplasticity and produce rapid, sustained mood improvements. Ongoing clinical trials are testing LSD-assisted therapy for treatment-resistant depression, but methodological challenges include designing proper placebo controls and providing adequate psychological support during the acute psychedelic experience. Further research is needed to confirm its clinical utility and establish safe protocols.

Study at a glance

Abstract

Major depressive disorder (MDD) is a prevalent and disabling condition affecting over 350 million individuals worldwide. Although conventional antidepressants targeting serotonin, dopamine, and noradrenaline pathways provide benefit for many, a substantial proportion of patients experience inadequate response. Treatment-resistant depression (TRD), defined by failure to respond to at least two antidepressant trials, affects approximately 30% of patients with MDD and poses significant clinical challenges. Emerging research is exploring novel therapeutics such as psychedelics, notably LSD (lysergic acid diethylamide). Unlike standard antidepressants that target singular pathways, LSD modulates both the serotonin system, particularly the 5-HT2A receptor, and the glutamatergic system, which are critical in neurocircuitry underlying mood regulation. This dual mechanism may enhance neuroplasticity, potentially accounting for the rapid and sustained antidepressant effects observed in preliminary studies. Ongoing clinical trials aim to evaluate the efficacy and safety of LSD-assisted therapy in MDD, especially TRD. Methodological challenges include designing appropriate placebo controls and ensuring rigorous psychological support to manage the acute psychedelic experience. While still investigational, LSD-assisted therapy represents a promising avenue that may complement existing treatments. Further research is necessary to confirm its clinical utility and establish protocols for safe integration into psychiatric practice.