[LSD revisited: Mechanisms of action and therapeutic potential in mental health].

Major depressive disorder affects over 350 million people worldwide, and about one-third of patients do not achieve remission with standard antidepressants, a condition known as treatment-resistant depression. Lysergic acid diethylamide (LSD) modulates the 5-HT2A serotonin receptor and the glutamatergic system, which are involved in neuroplasticity, and early clinical studies suggest rapid and sustained antidepressant responses. Clinical trials are underway to test LSD's safety and efficacy for major depressive disorder, though methodological challenges include creating meaningful placebos and the need for specialized therapist training. LSD-assisted therapy remains experimental, but its therapeutic potential is increasingly recognized given the limitations of current treatments for treatment-resistant depression.

Study at a glance

Abstract

Major depressive disorder (MDD) represents a colossal worldwide burden of health, affecting more than 350 million individuals. While traditional antidepressants with mechanisms of action at the serotonin, dopamine, or norepinephrine pathways are routinely prescribed, approximately one-third of patients fail to achieve adequate remission and develop treatment-resistant depression (TRD). This therapeutic shortfall underscores the necessity for novel approaches to treatment. Over the past two decades there has been a resurgence of scientific interest in psychedelics, such as lysergic acid diethylamide (LSD). LSD's primary pharmacological effect is modulation of the 5-HT2A serotonin receptor and the glutamatergic system, both of which have been involved in neuroplasticity. It has been hypothesized that it is these neurobiological effects that are likely to be behind the rapid and sustained antidepressant responses observed in the early clinical studies. Clinical trials are currently underway to determine the safety and efficacy of LSD for the treatment of MDD. However, psychedelic research is not without methodological hurdles, such as providing meaningful placebos to account for LSD's idiosyncratic subjective effects. Also, physicians need specialized training to help navigate these deeply psychologically immersive states experienced in the context of psychedelic-assisted therapy. While LSD-assisted therapy remains experimental, its therapeutic potential is increasingly recognized, especially given the limitations of available treatments for TRD. Continued rigorous research is necessary to achieve careful integration of psychedelic therapies into standard clinical practice.