LSD impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision making
Thomas Pokorny, Patricia Duerler, Erich Seifritz, Franz X. Vollenweider, Katrin H. Preller
bioRxiv Preprint Server January 28, 2019 preprint DOI: 10.1101/532234 via bioRxiv
Summary
LSD (100µg) significantly impaired executive functions, cognitive flexibility, and working memory in 25 healthy participants compared to placebo, but did not affect decision-making quality or risk-taking. Pretreatment with the 5-HT2A antagonist ketanserin (40mg) normalized these cognitive deficits. These findings indicate the importance of the 5-HT2A receptor system in cognitive processes and suggest potential therapeutic avenues for addressing cognitive dysfunctions in psychiatric disorders.
Study at a glance
| Design | double-blind, randomized, placebo-controlled, within-subject design |
|---|---|
| Sample size | 25 |
| Population | healthy participants |
| Key finding | LSD significantly impaired executive functions, cognitive flexibility, and working memory compared to placebo. |
Abstract
Psychiatric and neurodegenerative illnesses are characterized by cognitive impairments, in particular deficits in working memory, decision making, and executive functions including cognitive flexibility. However, the neuropharmacology of these cognitive functions is poorly understood. The serotonin (5-HT) 2A receptor might be a promising candidate for the modulation of cognitive processes. However, pharmacological studies investigating the role of this receptor system in humans are rare. Recent evidence demonstrates that the effects of Lysergic acid diethylamide (LSD) are mediated via agonistic action at the 5-HT2A receptor. Yet, the effects of LSD on specific cognitive domains using standardized neuropsychological test have not been studied. Therefore, we examined the acute effects of LSD (100µg) alone and in combination with the 5-HT2A antagonist ketanserin (40mg) on cognition, employing a double-blind, randomized, placebo-controlled, within-subject design in 25 healthy participants. Executive functions, cognitive flexibility, spatial working memory, and risk-based decision-making were examined by the Intra/Extra-Dimensional shift task (IED), Spatial Working Memory task (SWM), and Cambridge Gambling Task (CGT) of the Cambridge Neuropsychological Test Automated Battery. Compared to placebo, LSD significantly impaired executive functions, cognitive flexibility, and working memory on the IED and SWM, but did not influence quality of decision-making and risk taking on the CGT. Pretreatment with the 5-HT2A antagonist ketanserin normalized all LSD-induced cognitive deficits. The present findings highlight the role of the 5-HT2A receptor system in executive functions and working memory and suggest that specific 5-HT2A antagonists may be relevant for improving cognitive dysfunctions in psychiatric disorders.