[LSD revisited: Mechanisms of action and therapeutic potential in mental health].
Amel Bouloufa, Sarah Delcourte, Thomas Delannay, Nasser Haddjeri
L'Encephale April 9, 2026 Peer reviewed DOI: 10.1016/j.encep.2026.02.008 via PubMed
Summary
Major depressive disorder affects over 350 million people, with about one-third of patients developing treatment-resistant depression. Traditional antidepressants often fail these individuals, prompting interest in psychedelics like LSD, which may offer rapid and sustained antidepressant effects through neurobiological mechanisms. Clinical trials are investigating LSD's safety and efficacy for major depressive disorder, though challenges such as placebo effects and the need for specialized physician training exist.
Study at a glance
| Population | individuals with major depressive disorder, particularly those with treatment-resistant depression |
|---|---|
| Key finding | LSD may provide rapid and sustained antidepressant responses, highlighting its potential for treating treatment-resistant depression. |
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.