LSD acutely impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision-making.
BACKGROUND
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.


METHODS
We examined the acute effects of LSD (100 µg) alone and in combination with the 5-HT2A antagonist ketanserin (40 mg) 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.


RESULTS
Compared to placebo, LSD significantly impaired executive functions, cognitive flexibility, and working memory on the IED and SWM, but did not influence the quality of decision-making and risk taking on the CGT. Pretreatment with the 5-HT2A antagonist ketanserin normalized all LSD-induced cognitive deficits.


CONCLUSIONS
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.
['Pokorny|Thomas|T|0000-0001-8185-8874', 'Duerler|Patricia|P|', 'Seifritz|Erich|E|', 'Vollenweider|Franz X|FX|', 'Preller|Katrin H|KH|']
D000328:Adult D003071:Cognition D003657:Decision Making D004311:Double-Blind Method D056344:Executive Function D005260:Female D064368:Healthy Volunteers D006801:Humans D007650:Ketanserin D008238:Lysergic Acid Diethylamide D008297:Male D008570:Memory, Short-Term D009483:Neuropsychological Tests D012702:Serotonin Antagonists D017366:Serotonin Receptor Agonists D055815:Young Adult
LSD working memory executive functions cognition risk-based decision-making 5-HT2A receptor spatial memory