Sex differences in the cognitive effects of repeated low-doses of LSD: a randomised, placebo-controlled study

Background: Psychedelic microdosing, i.e., the repeated use of small amounts of psychedelics, has recently gained scientific interest for its purported benefits on cognition. Observational studies describe perceived enhancements in concentration and memory [1], and improvements in inattention and hyperactivity/impulsivity symptoms in patients with ADHD [2]. Controlled studies, however, have yielded mixed findings alongside a substantial number of null effects [3,4], which may be driven by inter-individual variability in treatment response. Biological sex may emerge as a potential moderator of psychedelic effects due to sex-related differences in serotonergic function and pharmacokinetics [5], which can influence cognitive outcomes.

Aim: This study aims to further explore the inter-individual variability in the effects of low doses of LSD (15 mcg) on cognition, focusing specifically on the influence of biological sex.

Methods: A randomized, double-blind, placebo-controlled study with a between-subjects design was conducted among healthy volunteers, with participants receiving either four low doses of LSD (15 mcg) or placebo treatment over two weeks. At baseline, on the first and last administration days, and at follow-up, participants performed tasks assessing sustained attention (the psychomotor vigilance task: PVT), information processing (the digital symbol substitution test: DSST), and working memory (the prospective memory task: PMT). Differences between the placebo and LSD conditions across the four testing days were estimated using a linear mixed model (LMM) approach with Condition (two levels), Time (four levels), and Sex (two levels) as fixed factors, and Age as a covariate.

Results: In total, forty-eight participants (n=24 female; mean age=36.9) were included in the study. Significant sex differences were observed in the total number of correct “no go” trials on the PMT (p=.008), with females having fewer correct inhibitions compared to males. A significant main effect of Sex on PVT performance was also demonstrated, with females exhibiting overall slower reaction times (p=.012) and a higher number of attentional lapses (p=.033) compared to males. Post-hoc analyses indicated a significant Condition × Sex interaction for these two outcome variables, with females performing faster (p=.045) and with fewer attentional lapses (p=.031) on the PVT under LSD compared to placebo. For attentional lapses, this effect varied across testing days, indicated by a significant Condition × Time × Sex interaction (p=.006), with fewer lapses in females receiving LSD compared to placebo on the first administration day (p=.009), the last administration day (p=.012), and at follow-up (p=.021). Notably, performance on the PVT varied significantly between males and females in the placebo condition (reaction time: p=.003; lapses: p=.002), whereas this difference was absent under LSD. No consistent sex-specific effects of LSD were observed for information processing (DSST) outcomes.

Conclusion: These results highlight the heterogeneity of cognitive responses to low doses of LSD and suggest that biological sex may moderate treatment effects. Exploratory findings indicate selective improvements in women’s sustained attention under LSD compared to placebo, suggesting a potential attenuation of sex differences in this domain. These results underscore the need for cautious interpretation of the purported cognitive benefits of psychedelic microdosing and warrant further investigation into individual differences in response.

References

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