LSD treatment affects working memory-related brain function in patients with major depressive disorder
Friederike Holze, Kristian Larsen, Brice Ozenne, Gitte M. Knudsen, Anna M Becker, Mihai Avram, Stefan Borgwardt, Matthias E. Liechti, Felix Müller, Patrick M. Fisher
Translational Psychiatry October 8, 2026 DOI: 10.1038/s41398-026-04522-4 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, parallel-group trial Peer reviewed |
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| Sample size | 43 |
| Population | Patients with major depressive disorder |
| Intervention | LSD |
| Dose | two low-dose (25 µg) or two high-dose (100 and 200 µg) oral LSD treatments |
| Duration | Two treatments 4 weeks apart; fMRI before and approximately 1 week after the second treatment |
| Measures | n-back working memory task, functional magnetic resonance imaging (fMRI) |
| Topics | Depression LSD |
| Registration | NCT03866252 |
| Key findings | High-dose LSD treatment significantly increased working memory-related brain responses compared with low-dose treatment (p = 0.007) in regions including the dorsolateral prefrontal cortex, parietal cortex, insula, striatum, and thalamus. These brain responses correlated with task performance and subjective perceptual changes but not with treatment response, which the authors say suggests LSD may boost neural function while task-related brain activity may involve different mechanisms than mood change. |
Abstract
Abstract Classic psychedelics, including lysergic acid diethylamide (LSD), are currently under investigation for the treatment of major depressive disorder (MDD). Cognitive dysfunction is common in MDD, but effects of psychedelic treatment on cognitive brain function, measured by magnetic resonance imaging, are sparsely reported. The present study investigated effects of LSD treatment on working memory-related brain function in patients with MDD. In a randomized, double-blind, parallel-group trial, 43 patients with MDD received either two low-dose (25 µg) or two high-dose (100 and 200 µg) oral LSD treatments 4 weeks apart. Functional magnetic resonance imaging during an n-back working memory task was conducted before and approximately 1 week after the second treatment. The treatment × time interaction effect on working memory-related brain responses (2-back and 1-back vs . 0-back) was assessed using linear mixed effects models. We also explored associations between brain responses and depression severity, task performance, and subjective psychedelic experiences. Compared with low-dose treatment, high-dose LSD treatment significantly increased working memory-related brain responses ( p = 0.007) within task-activated regions, including the dorsolateral prefrontal cortex, parietal cortex, insula, striatum, and thalamus. Working memory-related brain responses correlated with task performance and subjective perceptual changes but not treatment response. Our observations provide the first evidence that LSD treatment in patients with MDD affects cognitive brain function. Contrary to our hypothesis, high-dose LSD significantly increased brain responses. These responses positively correlated with task performance, suggesting a potential LSD-induced boost in neural function. The absence of an association with depressive symptoms indicates that task-related brain activity may underlie different mechanisms than changes in mood. Trial registration: Clinicaltrials.gov Identifier: NCT03866252.
In the evidence
This study is part of the evidence base for 3 syntheses in the library. Here is how each one recorded it.
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High-dose LSD increased working memory-related brain responses compared with low-dose LSD, but these responses did not correlate with treatment response.
Synthesized
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State of the evidence: Depression Supports
High-dose LSD increased working-memory-related brain responses versus low dose, but these responses correlated with task performance and perceptual changes, not with treatment response.
Synthesized
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State of the evidence: LSD Supports
High-dose LSD treatment significantly increased working-memory-related brain responses in task-activated regions compared with low-dose treatment, and these responses correlated with task performance and subjective perceptual changes but not treatment response.
Synthesized
Comparable studies
Other randomized controlled trials on LSD for depression, most cited first.