Fig. 1: Psilocybin (1 mg/kg) improves hypersensitivity in male and female mice.

A Schematic of experimental design. Behavioural tests were performed before (baseline) and after SNI surgery until the end of experiments. Psilocybin (1 mg/kg) was injected when max sensitivity was fully developed (between day 12 and day 15). B Head-twitch response in male and female mice after injection of psilocybin (1 mg/kg) (male mice, n = 6; female mice, n = 5) or saline control (male mice, n = 6; female mice, n = 5); P < 0.001 unpaired independent sample t-test. C Static mechanical threshold of mice assessed using calibrated von Frey filaments before (Bs, baseline) and after SNI surgery. At maximum sensitivity day 12 (male) or on day 15 (female), mice received an IP injection of 1 mg/kg psilocybin or saline control (male mice, n = 8/8, two‑way repeated‑measures mixed‑model ANOVA, factor ‘treatment’ 3 h to D45: F = 10.05, P = 0.007; female mice, n = 8/8, two‑way repeated‑measures mixed‑model ANOVA, factor ‘treatment’ D15 + 3 h to D21: F = 12.1, P = 0.005) (on D21 psilocybin n = 5 mice). D Brush-evoked dynamic hypersensitivity before (Bs) and after SNI surgery (n = 5/5 mice, two‑way repeated‑measures mixed‑model ANOVA, factor ‘treatment’ D14–D45: F = 6.5, P = 0.034). E Cold allodynia assessed using Thermal Preference Test before (Bs) and after SNI surgery (n = 5/5 mice, two‑way repeated‑measures mixed‑model ANOVA, factor ‘treatment’ D13 to D30: F = 3.9, P = 0.085, with Bonferroni corrections D22, P = 0.09, D30, P = 0.02). F Acute effect of psilocybin on static mechanical threshold assessed using calibrated von Frey filaments. At maximum sensitivity day 12 mice received an IP injection of 1 mg/kg psilocybin or saline control. Behavioural measures taken at several time points after injections (30 min, 1 h, 2 h, 4 h, 8, 12 h and 24 h). (n = 6/6 mice, two‑way repeated‑measures mixed‑model ANOVA, factor ‘treatment’ 30 min to D13: F = 18.7, P = 0.002; with Bonferroni corrections 1 h, P = 0.085, 2 h, P = 0.005, 4 h, P = 0.004, 8 h, P < 0.001, 12 h, P = 0.004, 24 h, P = 0.022). G Schematic of experimental design. Von Frey test was performed before (baseline) and after SNI surgery until the end of experiments. Psilocybin (1 mg/kg) was injected 30 days before SNI surgery. H Static mechanical threshold of mice before (BS, Baseline) and after SNI surgery (D1–D85). (n = 5/5, two‑way repeated‑measures mixed‑model ANOVA, factor ‘treatment’ Bs to D85: F = 0.64, P = 0.45). I Schematic of experimental design. Von Frey test was performed before (baseline) and after SNI surgery until the end of experiments. On day13 mice received an injection of 0.032 mg/kg of volinanserin or saline control; 30 min later all mice received an IP injection of 1 mg/kg of psilocybin. J Head-twitch response in male mice after injection of psilocybin (1 mg/kg) and volinanserin (0.032 mg/kg) (n = 6/6 mice, P < 0.001 unpaired independent sample t-test). K Static mechanical threshold of mice before (BS, Baseline) and after SNI surgery (D1–D27). (n = 12/12 mice, two‑way repeated‑measures mixed‑model ANOVA, factor ‘treatment’ D13 + 3 h to D27: F = 11.9, P = 0.002). L Locomotor activity (distance travelled) after SNI surgery and subsequent injection of saline or psilocybin. Bar graph displays the total distance travelled (cm) by animals following SNI (“After SNI”) and after acute injection (“After injection”) of either saline + psilocybin (grey circles) or volinanserin + psilocybin (brown circles). Data are presented as mean ± SEM, with individual data points shown (n = 6/6 mice). Data are expressed as mean ± SEM throughout. Red arrows represent psilocybin injection. SNI, Spared Nerve Injury; IP, Intra-peritoneal. A, B, G, I, J created in https://BioRender.com/76ibtsy.