Sex Differences in Acute Responses to Psychedelics: Evidence for Greater Subjective Intensity and Impairment in Female Participants

Serotonergic psychedelics such as psilocybin and LSD are being developed for psychiatric treatment, but acute responses vary widely between people and the reasons for this variability are not well understood. The authors note that sex is a likely but under-studied biological factor. They point out that females experience adverse drug reactions more often than males, that fixed dosing can lead to higher drug exposure in females, and that sex hormones may influence the serotonin system targeted by classic psychedelics. Although preclinical work has suggested sex-dependent psychedelic effects, human evidence has been limited, even though women are routinely included in psychedelic trials. Mason and colleagues therefore set out to test whether healthy female and male participants differ in acute subjective responses and empathy after psychedelic administration. They pooled data from two placebo-controlled experimental studies spanning three psychedelics, psilocybin, 2C-B and LSD, to examine whether any sex differences were present and whether they might be explained by differences in plasma drug exposure. The study was framed as an exploratory first step with possible implications for dosing, informed consent and safety monitoring.

The authors conducted a pooled secondary analysis of two double-blind, placebo-controlled studies in healthy volunteers who had prior psychedelic experience. Study 1 used a randomised crossover design comparing 2C-B 20 mg, psilocybin 15 mg and placebo. Study 2 used a randomised within-subject design comparing LSD 50 µg and placebo. The extracted text states that both studies had ethics approval and were conducted in line with the Declaration of Helsinki. The pooled sample included 72 participants in total: 31 male and 41 female. Study 1 contributed 22 participants, Study 2 contributed 50 participants, and 22 participants contributed two active-drug sessions because they received both psilocybin and 2C-B. This created 94 active-drug observations overall. Analyses focused on drug-induced change for psilocybin, 2C-B and LSD, either from the active session directly or by subtracting the placebo session. Acute subjective effects were measured using visual analogue scales for feeling high, feeling under the drug's influence, good drug effect, bad drug effect and drug liking. These were summarised as Emax values, meaning the maximum post-dose rating for each item. Retrospective altered-state experience was measured using the 5D-ASC and 11-ASC questionnaires. Empathy was assessed with the Multifaceted Empathy Test, which included cognitive empathy and emotional empathy for positive and negative stimuli; because this test is not baseline-referenced, active-day scores were corrected by subtracting placebo-day scores. Blood sampling was used to quantify plasma concentrations of psilocin, 2C-B and LSD at predefined time points, with peak concentration (Cmax) and area under the curve (AUC) used as exposure measures; Cmax and AUC were z-scored within drug before pooling so that sex comparisons reflected relative exposure on a common scale. Outcomes were analysed with full factorial linear mixed models, with treatment, sex, treatment-by-sex interaction and age as fixed effects, and participant as a random intercept. Age was included because it differed between male and female participants. The authors also repeated the empathy analyses separately for positive and negative stimuli. Demographic variables such as age, education, lifetime psychedelic use and body mass index were compared between sexes using independent-samples t-tests. Statistical significance was set at p<0.05, no correction for multiple comparisons was applied because the analysis was exploratory, and effect sizes were emphasised alongside p values.

Male participants were older than female participants on average, with a statistically significant difference, but the groups did not differ in body mass index, lifetime psychedelic use or education. Age was therefore included as a covariate in the main models because younger participants were expected to show stronger acute effects. Female participants reported numerically stronger acute subjective drug effects on all five visual analogue scale items. After adjusting for age, the sex difference was significant for feeling under the drug's influence, with a medium-to-large effect size (F(1, 54.98)=6.86, p=.011, d=0.69). The other visual analogue scale outcomes were not statistically significant, although good drug effect and feeling high showed trends. A significant treatment-by-sex interaction was observed for feeling under the drug's influence, indicating that the sex difference was most pronounced under psilocybin; the supplementary analysis showed that this was driven by psilocybin, where females scored 23.1 points higher than males. There was no significant sex difference for this item under 2C-B or LSD. On the 5D-ASC, female participants scored numerically higher on all five dimensions, and the age-adjusted sex difference was significant for reduction of vigilance, again with a medium-to-large effect (F(1, 37.82)=8.83, p=.005, d=0.76). Sex differences on anxious ego dissolution, oceanic boundlessness, visionary restructuralisation and auditory alterations were not significant. Age was associated with four of the five 5D-ASC dimensions, but not with reduction of vigilance. No treatment-by-sex interactions were significant on this scale. On the 11-ASC, female participants again tended to score higher across most factors. After age adjustment, the sex difference was significant for impaired control and cognition (F(1, 27.29)=5.67, p=.024, d=0.59). No other 11-ASC factor showed a significant sex effect. Age was associated with six of the eleven factors. No treatment-by-sex interactions were significant. In contrast, the Multifaceted Empathy Test showed no significant sex differences for cognitive empathy, implicit emotional empathy or explicit emotional empathy, whether the data were pooled across valence or analysed separately for positive and negative stimuli. Age was only associated with cognitive empathy for negative stimuli. No treatment-by-sex interactions were significant. The plasma concentration analyses also showed no sex differences. After age adjustment, neither Cmax nor AUC differed between females and males, and there were no significant treatment-by-sex interactions for either exposure metric. The results were unchanged in unadjusted analyses. Overall, the data indicated greater subjective intensity and perceived impairment in female participants, but no corresponding difference in empathy or measured drug exposure.

Mason and colleagues interpret their findings as evidence that female participants experience more intense acute subjective effects from psychedelics, including greater perceived impairment, whereas empathy does not appear to differ by sex. They emphasise that the sex effects were seen across the pooled psychedelic dataset and remained after adjustment for age. The only clear treatment-specific pattern was for feeling under the drug's influence, where the female-male difference was strongest under psilocybin. The authors argue that these effects are unlikely to be explained simply by pharmacokinetics. Although fixed dosing can produce higher drug exposure in females in some settings, they found no sex difference in peak plasma concentration or total exposure, suggesting that the greater subjective intensity occurred at comparable measured drug levels. They note, however, that Cmax and AUC do not capture unbound exposure and do not address metabolism or plasma protein binding, so a pharmacokinetic contribution cannot be fully excluded. They therefore suggest that the observed pattern may reflect pharmacodynamic differences, meaning differences in sensitivity at the drug target rather than differences in exposure. To place the findings in context, the authors compare them with earlier controlled MDMA research that found stronger subjective effects and more acute adverse experiences in female participants. They also discuss preclinical work showing sex-dependent psychedelic responses in animals and the possible role of ovarian hormones, particularly through effects on the serotonin 2A receptor. They propose that menstrual-cycle phase and hormonal status could contribute to within-sex variability and should be measured in future studies. The authors further note that the broader psychopharmacology literature contains examples where sex differences have later changed practice, such as zolpidem dose recommendations for women, and they suggest that psychedelic research should similarly treat sex as a biological variable from the outset. In terms of implications, the authors say the findings matter for dosing, informed consent, pre-session preparation and monitoring. They caution that while lower doses might reduce perceived impairment, dose reduction could also blunt the subjective experience that is thought to contribute to therapeutic benefit, so optimisation should be guided by clinical outcome rather than acute intensity alone. They recommend that future trials be adequately powered to test sex effects, report sex-disaggregated outcomes, and document menstrual-cycle phase, hormonal contraceptive use and reproductive stage. The main limitations they acknowledge are that this was a secondary pooled analysis of studies not originally designed to test sex differences, that substantial within-sex variability among female participants remained unexplained, that menstrual-cycle phase and hormonal status were not assessed, and that the sample consisted of healthy volunteers with prior psychedelic experience, which may limit generalisability to clinical populations. They conclude that the study provides an initial step towards understanding sex differences in acute psychedelic response, but that the findings are preliminary.