PROJECT SUMMARY/ABSTRACT This R33 application proposes a mechanistic clinical trial testing the effects of psilocybin on affective mechanisms of chronic pain in patients with comorbid chronic low back pain and depression (CLBP+D). CLBP is the top cause of disability worldwide, and is highly comorbid with depression. Patients with CLBP+D face a fragmented and limited set of treatment options that insufficiently address their pain and depression symptoms. As such, CLBP treatment guidelines call for a shift away from a sole outcome focus on pain intensity and toward treatments that enhance affective function. Positive and negative affect, pain catastrophizing, and positive affective pain inhibition are well-characterized, modifiable, biologically-mediated mechanisms of chronic pain that we propose to target in this study of patients with CLBP+D. Psilocybin, a classic (5-HT2A receptor-mediated) psychedelic, is a promising non-opioid candidate for the treatment of CLBP+D that reliably and durably improves affective function in healthy individuals, patients with major depressive disorder, and patients with a life-threatening cancer diagnosis. We aim to test whether psilocybin will benefit patients with CLBP+D by durably improving positive affect, negative affect, and pain catastrophizing, and augmenting the ability of positive affect to inhibit pain. The proposed study addresses an important unmet need, as it will be the first, to our knowledge, to test the ability of psilocybin to target pain-related affective function in patients with chronic pain. We propose a double-blind, randomized, controlled trial comparing the administration of high- dose psilocybin (25mg absolute dose; n=20) to an active control (methylphenidate 40mg absolute dose; n=20) among patients with CLBP+D. Psilocybin or methylphenidate will be administered once in the laboratory under close supervision and supportive monitoring. Primary outcomes will be positive and negative affect (Aim 1), pain catastrophizing (Aim 2), and positive affective pain inhibition (Aim 3). Ecological momentary assessment will be used to evaluate the hypotheses that aggregated momentary reports of positive and negative affect and pain catastrophizing will improve from baseline to 1-week post-session to a greater extent in patients in the psilocybin versus the methylphenidate condition. Quantitative sensory testing will be used to evaluate the hypothesis that positive affective pain inhibition will increase from baseline to 1-week post-session to a greater extent in patients in the psilocybin versus the methylphenidate condition. The durability of outcomes will be tested at 1-month post-administration in secondary analyses. By testing the effects of psilocybin on affective function in CLBP+D, we will develop critical data that will provide mechanistic insight into the utility of psilocybin as a pain management medicine. These data will build off our extensive preliminary findings in support of psilocybin’s efficacy for major depressive disorder, and pave the way for future pivotal efficacy trials for psilocybin as a primary treatment for patients with CLBP+D.

PROJECT NARRATIVE Treatments are needed to improve affective function in patients with comorbid chronic low back pain and depression. Psilocybin is a non-opioid therapeutic that has already demonstrated efficacy for the treatment of depression and holds promise for use as a pain management medicine. This project will test the effect of psilocybin on affective function in patients with comorbid chronic low back pain and depression.