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

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 decisionmaking 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.

Psychedelic Therapy's Transdiagnostic Effects: A Research Domain Criteria (RDoC) Perspective

“…Similarly, psilocybin decreased attentional tracking ability in HCs, which the authors speculated was due to the inability to inhibit distracting stimuli (303). More recently, retreatment with ketanserin (40 mg) normalized all LSD-induced cognitive deficits (302). Psychedelic induced impairment of aspects of cognitive flexibility was also observed in a probabilistic reversal learning paradigm in 19 HCs who received IV LSD (75µg) or placebo at two sessions, two weeks apart (Kanen 2021).…”

“…Psychedelics transiently impair certain aspects of cognition in a dose-dependent manner (142,(300)(301)(302). For example, a study in HCs showed that LSD (100 µg) compared to placebo acutely impaired executive functions, cognitive flexibility, and working memory on the Intra/Extra-Dimensional shift task, and Spatial Working Memory task, but did not influence the quality of decision-making and risk taking on the Cambridge Gambling Task (302). Similarly, psilocybin decreased attentional tracking ability in HCs, which the authors speculated was due to the inability to inhibit distracting stimuli (303).…”

“…Psychedelics acutely and dose dependently impair attention (328,329), memory task performance (142,300,302) and spatial working memory (212). On the other hand, it appears that other domains such as the recall and vividness of autobiographical memory may be accentuated (142)(143)(144)(145).…”

Differences in personality, cognitive abilities, illicit drug use, and white matter structural integrity between hallucinogen users and matched controls

“…The median estimated dosage reported in this survey of recreational use was 4g of dried mushroom, which is roughly equivalent to the 25mg (high) dose of psilocybin that is used as a therapeutic dose in laboratory settings 4,5,13 Investigations of the psychological and neural mechanisms underlying therapeutic effects of hallucinogens are still in a nascent stage. While most studies of the acute effects of hallucinogens demonstrate impairments in a number of perceptual and cognitive domains [26][27][28][29][30] , one recent study suggested a potential minute, acute attentional bene t of microdoses of LSD 31 . Another recent study demonstrated an improvement in cognitive exibility in patients with MDD after treatment with psilocybin 32 .…”

On The Cinco Sins of Psychedelic Research. An interview with Manoj Doss

“…However, it is essential to acknowledge the limitations of relying exclusively on standardized methods. Cognitive batteries in psychedelics studies, such as those by Pokorny et al (2020), o en indicate cognitive impairments, but these results may not be very informative on their own. Instead, a more in-depth examination of speci c tasks related to attention, memory, and other cognitive processes is necessary, as well as studies that directly compare di erent drugs, like dextromethorphan and psilocybin.…”