Characterizing psilocybin’s effects on nociception and thermoregulation in preclinical pain models

Psilocybin is a drug with renewed clinical interest because of its potential to treat psychiatric diseases. Preliminary human data suggest that psilocybin could be used to treat chronic pain, but whether psilocybin produces direct analgesia remains unclear, and existing human data have not resolved how it works if it does. The preclinical literature has conflicting results, with some studies reporting analgesia and others finding no effect. Existing preclinical studies have typically employed limited dose ranges, pain models, and assay types, so it is difficult to draw conclusions that are generalizable. Psilocybin also produces dose-dependent hypothermia in rodents, which is a physiological effect that could confound thermal pain assays but has not been controlled for. In this study, psilocybin was evaluated at 0.3, 2, and 10 mg/kg in the CFA model of inflammatory chronic pain and in the formalin model of acute pain. Marble burying was used to assess pain-suppressed motivated behavior, and cold plate testing was used to measure cold sensitivity. Buprenorphine was used as a positive control in the marble burying assay. Locomotion activity was assessed to rule out motor suppression, and infrared thermography was used to characterize psilocybin’s thermoregulatory effects. Psilocybin did not rescue pain-suppressed marble burying and further suppressed it at higher doses, an effect that resolved after 24 hours. Cold plate testing showed significant suppression of pain behaviors at the 10 mg/kg, but only at that dose. Locomotion revealed no change from baseline, and infrared thermography recorded a drop in surface body temperature at 10 mg/kg. The only dose that resulted in behaviors consistent with analgesia was the 10 mg/kg dose in the cold plate assay, which was also the only dose that produced significant hypothermia, and the temporal window of hypothermia overlapped with the behavioral testing period. The overlap in dose specificity and timing suggests that hypothermia likely confounds the outcome of thermal assays. Psilocybin’s physiological effects are not often controlled for in pre-clinical pain studies, and temperature monitoring alongside thermal assays should be standard going forwards.