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 memoryrelated 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.