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

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.