The effects and mechanisms supporting psilocybin induced pain relief

About This Grant

Chronic phantom limb pain (cPLP) is a debilitating chronic pain disorder that is experienced by up to 64% of the 356 million people with amputations worldwide. The prevalence of cPLP is rapidly rising due to the increased incidence of severe diabetes mellitus and vascular diseases. The primary symptom of cPLP is pain, which, in the majority of cases, is severe, treatment resistant and consequently signifies the importance of developing fast acting cPLP treatments. Chronic pain severity and corresponding comorbidities are driven by amplified sensory, self-referential, and negative affective interactions that intensify the transition of acute to chronic pain. Thus, pain therapies that reliably target nociceptive specific and affective mechanisms may produce durable improvements in pain symptomology and well-being. The recent “psychedelic renaissance” has generated wide-reaching interest into the potential efficacy of psilocybin as a pain therapeutic. Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine), a hallucinogenic drug that modifies self-referential processes, has shown promise at reducing cPLP. Mechanistic appreciation of if and how psilocybin modifies pain is needed. The default mode network (DMN), a midline cortical neural network supporting egocentric and affective pain appraisals, has been revealed as a neural target for chronic pain and psilocybin. Yet, the analgesic effects and supporting brain mechanisms through which psilocybin can modulate chronic pain are unknown. The proposed research activities will significantly expand our understanding of the impact of psilocybin on chronic pain and the corresponding neural mechanisms. In a recently completed pilot clinical trial, 25mg of psilocybin (n = 5) was found to be a safe and feasible treatment for cPLP as compared to niacin (100mg; n = 4). Importantly, four weeks after dosing, psilocybin was associated with reductions in weekly cPLP (- 43%). In contrast, the niacin group exhibited no change in cPLP four weeks after dosing as compared to baseline. Weaker resting state functional connectivity (rsFC) between the DMN and thalamus predicted greater psilocybin-based cPLP relief 4 weeks after dosing. The proposed R01 application will expand on our pilot study and aims to identify the neural processes supporting the effects of psilocybin on cPLP. In the proposed mechanistic clinical trial, 60 patients with lower limb amputations and cPLP will be recruited and randomized to receive double blind administration of 25mg psilocybin (n=30) or 50mg niacin (n=30) after completing baseline assessments. “Past week” cPLP will be assessed at baseline and 1 day, 2-, 4- and 12-weeks post-dosing. Functional MRI will be acquired at baseline, and 1 day and 4 weeks post-dose. We hypothesize that psilocybin induced cPLP relief will be associated with weaker DMN–thalamic rsFC four weeks after dosing when compared to baseline. Exploratory analyses will also test if psilocybin elicits greater cPLP relief when compared to niacin. The knowledge gained from the proposed work will provide novel mechanistic understanding of psilocybin-induced cPLP relief.