Fig. 1: A single dose of psilocybin induces rapid and durable reversal of mechanical hypersensitivity in SNI and CFA mice.
a, Schematic of experiment timeline. Repeated electronic vF test (vFT, down arrow) was performed before and after pain-inducing interventions (SNI (left) and CFA (right)) and tracked out to 40 days. Psilocybin (red dashed line) injection was performed on day 27. b, Total HTR induced by psilocybin following a range of dosing. Moreover, 0.5 mg kg−1 dose produced peak HTR over 30 min (n = 6) collection window as compared with 0.25 mg kg−1 (n = 6; one-way analysis of variance, P < 0.0001) and 1 mg kg−1 (n = 6, P = 0.0153) dosed animals. c, Total distance traveled over 30 min in open field over the same dosing range as in b. 0.5 mg kg−1 group shows a substantial reduction in total movement compared with vehicle controls (VC) (Kruskal–Wallis (22), P = 0.047 followed by Dunn’s multiple comparison: P = 0.048). d,f, Normalized hindlimb withdrawal thresholds in SNI (d; n = 30, P = 0.00233 on day 7 and P < 0.0001 on days 12, 19 and 26) versus sham (n = 22) mice and CFA (f; n = 22, P < 0.0001 on days 2, 7, 12, 19 and 26) versus saline (n = 15) mice revealed a persistent state of mechanical hypersensitivity in the affected hindlimb, but not contralateral hindlimb, before treatment. Psilocybin reversed mechanical sensitivity to pre-injury levels on day 28 that persisted for the next 12 days (SNI versus sham, P > 0.05 on days 28 and 40; CFA versus saline controls, P > 0.05 on days 28 and 40). VC (beige line) indicate no improvement in either SNI (d; n = 6) or CFA (f; n = 5) conditions. e,g, Normalized hindlimb withdrawal threshold separated by sex for SNI/sham (e; SNI male, n = 16; SNI female, n = 14; sham male, n = 11; sham female, n = 11) and CFA/saline (g; CFA male, n = 11; CFA female, n = 11; saline male, n = 10; saline female, n = 5) mice. No significant difference in withdrawal thresholds between SNI males and females (P > 0.05 on days 2, 7, 12, 19, 26 and 40) or CFA males and females (P > 0.05 on days 2, 7, 12, 19, 26, 28 and 40). Data are presented as mean ± s.e.m. Two-way repeated measures analysis of variance in d–g. ****P < 0.0001, **P < 0.01, *P < 0.05. Detailed statistics are reported in Supplementary Table 1a. TN, tibial nerve; CPN, common peroneal nerve; SN, sciatic nerve; NS, not significant. Panel a created with BioRender.com.
