Brain mechanisms supporting mindfulness-assisted psilocybin therapy for chronic pain - Chronic low back pain (cLBP) is the most common clinical pain condition with an average prevalence of 30% and is the leading cause for disability. The pervasiveness of cLBP has exponentially increased Medicare expenditures for steroid and opioid treatments. These staggering statistics highlight the importance of identifying the active mechanisms supporting fast-acting, non-pharmacological approaches that can reliably and directly assuage pain in individuals with cLBP. Chronic pain severity and corresponding comorbidities are driven by amplified sensory, self-referential, and negative affective appraisals that intensify the transition of acute to chronic pain. These maladaptive pain-related processes are mediated by interactions between the default mode network (DMN) and nociceptive relay centers such as the thalamus. Chronic LBP is further sustained by blunted reward (mesolimbic) function and pain-related anhedonia, motivational disruptions increasingly implicated in the maintenance of chronic pain. Thus, pain therapies that target the DMN and thalamus may produce durable improvements in pain and corresponding symptomologies. To this extent, psilocybin, a classic psychedelic drug, and mindfulness meditation, a practice premised on cultivating non-reactive awareness to the present moment, have been shown to remediate maladaptive self-referential processes by modulating the DMN. We recently found that psilocybin is safe to use in patients living with chronic pain. Our preliminary findings indicate that mindfulness meditation and psilocybin-assisted therapy (PAT) can produce clinically meaningful improvements in chronic pain by modulating DMN-thalamic interactions. However, these pilot data also indicated that the analgesic effects of psilocybin, although still clinically meaningful, attenuated over time. Thus, we postulate that combining our validated mindfulness meditation intervention with PAT (mPAT) will buffer against said efficacy drifts. To date, there are no clinical trials that have identified the effects and neural mechanisms supporting PAT or mPAT for chronic pain. In the proposed clinical trial, 80 patients with cLBP will be randomized to psilocybin (25mg) assisted therapy combined with a 6-session mindfulness meditation intervention (mPAT; n = 40) or psilocybin (25mg) assisted therapy alone (PAT; n=40). To provide a no-treatment comparison, each participant will additionally serve as their own within-subject waitlist control, completing a baseline scan followed by a 4-week waitlist period with no intervention prior to the pre-dosing scan. Resting state fMRI (rsFC) will be performed before dosing, 1- and 4 weeks after dosing to measure for between group differences in DMN-thalamic rsFC. The straight leg raise test (SLR), a validated and safe radicular cLBP evocation procedure, will also be used as an analog to the experience of evoked cLBP during fMRI. Using a multimodal fMRI approach, patients will additionally complete the Monetary Incentive Delay (MID) reward task and a negative affective challenge (passively viewing negative, neutral, and positive International Affective Picture System images), analyzed with whole-brain multivariate signatures (the negative affect signature, NAPS; the Brain Reward Signature, BRS), a priori affective (amygdala, anterior insula, subgenual ACC) and reward (nucleus accumbens/ventral striatum, VTA, ventromedial PFC) regions of interest, and complementary behavioral measures (affective image ratings, MID incentive speeding). The primary aim of the proposed study is to identify neural mechanisms supporting the synergistic effects of mPAT on patients with cLBP as compared to PAT. We aim to also identify the brain mechanisms supporting the direct modulation of pain (via SLR) by meditation. In an exploratory aim, we will determine whether mPAT reduces negative affective processing, in a valence-specific manner, and restores reward processing relative to PAT. The primary hypothesis is that m
