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.