[LSD revisited: Mechanisms of action and therapeutic potential in mental health].
Amel Bouloufa, Sarah Delcourte, Thomas Delannay, Nasser Haddjeri
L'Encephale April 9, 2026 DOI: 10.1016/j.encep.2026.02.008 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Population | Major depressive disorder |
| Topics | Depression LSD |
| Keywords | Fast-acting antidepressants Psychedelics Psychédéliques |
| Key findings | LSD's modulation of the 5-HT2A serotonin receptor and glutamatergic system, linked to neuroplasticity, is hypothesized to underlie rapid and sustained antidepressant responses observed in early clinical studies for 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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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LSD's modulation of the 5-HT2A serotonin receptor and glutamatergic system, linked to neuroplasticity, is hypothesized to underlie rapid and sustained antidepressant responses observed in early clinical studies for treatment-resistant depression.
Synthesized
Comparable studies
Other narrative reviews on LSD for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. General population | 2019 | Integrative review | |
| Registered clinical studies investigating psychedelic drugs for psychiatric disorders. Registered clinical trials on clinicaltrials.gov evaluating psychedelics for... | 2021 | Review | n = 70 |
| Top Ten Tips Palliative Care Clinicians Should Know About Psychedelic-Assisted Therapy in the Context of Serious Illness. Palliative care clinicians and patients | 2022 | Review | |
| Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action? | 2023 | Narrative review | |
| Role of psilocybin in the treatment of depression | 2016 | Review |