Feasibility and Tolerability of Psilocybin for Phantom Limb Pain

J Pain. 2026 Aug 7:106404. doi: 10.1016/j.jpain.2026.106404. Online ahead of print.

ABSTRACT

Phantom limb pain (PLP) is a refractory condition defined by pain experienced in a missing limb. Psilocybin, a classical serotonergic psychedelic drug, can alleviate various treatment-resistant disorders but has scantly been investigated for chronic pain. This placebo-controlled, double-blind, randomized clinical pilot trial (NCT05224336) tested the feasibility, tolerability, and preliminary safety of psilocybin in individuals living with PLP. Nine participants (mean±SD 37±13 years) with one amputation and PLP were randomized to receive a single 25-mg oral dose of psilocybin (n=5; 2 female) or 100-mg niacin (n=4; 2 female). The dosing sessions were supervised by two monitors who met with participants during three pre-dosing preparatory sessions and a 1-day post-dosing integration session. Suicidality was assessed across all visits. Blood pressure (BP), heart rate (HR), and adverse drug effects were assessed during the dosing session. Headache was evaluated during the dosing and integration sessions. No emergent suicidality or serious adverse events were observed. In both groups, adverse drug effects (anxiety, psychological/physical discomfort) and transient elevations in BP and HR after drug administration resolved spontaneously prior to discharge. After psilocybin administration, two participants reported nausea and three reported headache. Exploratory self-reported ratings for weekly PLP intensity showed trends toward reduction (>30%) two- and four-weeks post-psilocybin administration but these effects may be attributed to the small sample size and functional unblinding. This is the first trial providing evidence of the tolerability of a 25-mg oral dose of psilocybin for PLP, a debilitating, enigmatic and treatment-resistant chronic pain condition. PERSPECTIVE: This article demonstrates that psilocybin was tolerable when administered to five individuals suffering from phantom limb pain, a unique, treatment-resistant and centralized pain syndrome. These phase 1 feasibility findings support future placebo-controlled trials investigating the efficacy and mechanisms of serotonergic psychedelics for refractory pain syndromes.

PMID:42567236 | DOI:10.1016/j.jpain.2026.106404