Sex Differences in Acute Responses to Psychedelics: Evidence for Greater Subjective Intensity and Impairment in Female Participants
Natasha L. Mason, Eline Chm Haijen-Bongers, Kim P. C. Kuypers, Aline Frick, Stefan W. Toennes, Pablo Mallaroni, Johannes G. Ramaekers
bioRxiv (Cold Spring Harbor Laboratory) July 13, 2026 preprint DOI: 10.64898/2026.07.08.737179 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Pooled analysis of two double-blind, placebo-controlled studies |
|---|---|
| Sample size | 72 |
| Population | Healthy volunteers |
| Interventions | Psilocybin 2C-B LSD |
| Dose | 15 mg, 20 mg, 50 μg |
| Topics | Psilocybin |
| Keywords | Empathy Feeling Interpersonal reactivity index Pharmacodynamics Young adult Affect linguistics Clinical psychology Developmental psychology Item response theory Depression economics Hallucinogen Sex characteristics |
| Key points | Female participants experienced more intense acute subjective effects and greater perceived impairment under psychedelics than male participants, independent of age and not explained by drug exposure. |
Abstract
Serotonergic psychedelics are advancing as psychiatric treatments, yet acute responses vary between individuals and the contribution of sex, a fundamental biological variable, remains largely unexamined. We pooled two double-blind, placebo-controlled studies in healthy volunteers (N = 72; 31 male, 41 female) comparing psilocybin 15 mg, 2C-B 20 mg, and LSD 50 μg. Linear mixed models tested sex differences in acute subjective effects (visual analogue scales), retrospective altered-states ratings (5D-8209; and 11-ASC), empathy (Multifaceted Empathy Test), and peak plasma blood concentrations (Cmax, AUC), with treatment, sex, their interaction, as fixed factors, and age as a covariate. Female participants reported numerically higher subjective ratings than male participants on most measures. After adjustment for age, sex differences remained significant for feeling under the drug's influence, reduced vigilance, and impaired control and cognition, with medium-to-large effects. These effects were largely consistent across the three drugs. No sex differences emerged on any empathy measure or in peak drug concentrations. Female participants may experience more intense acute subjective effects and greater perceived impairment under psychedelics, independent of age and not explained by drug exposure. These preliminary findings, implicating pharmacodynamic rather than pharmacokinetic mechanisms, have implications for dosing, informed consent, and safety monitoring, and underscore the need to treat sex as a biological variable in adequately powered psychedelic trials.
Comparable studies
Other randomized controlled trials on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Hallucinogen-naïve adults reporting regular participation in religious or spiritual... | 2006 | Double-blind study | n = 36 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |