Abstract Title: Behavioral and neural mechanisms supporting psilocybin assisted therapy for chronic phantom limb pain
Background:
Background: Chronic phantom limb pain (cPLP), characterized as the persistent subjective experience of pain in a missing limb, is a centralized pain condition estimated to occur in ~65% of patients after limb amputation (Limakatso et al., 2020; Limakatso et al., 2024). Chronic PLP is not effectively relieved by existing treatments and analgesics (Flor, 2002), which rarely outperform placebo (Alviar et al., 2016). Amorphological interactions between the default mode network (DMN) (Carhart-Harris et al., 2017; Smigielski et al., 2019; Gattuso et al., 2023), a midline cortical neural network supporting egocentric pain and affective-appraisals (Hamilton et al., 2011; Baliki et al., 2014), and lower-level sensory processing (Giummarra et al., 2007; Makin et al., 2015b; Risso et al., 2022) have been observed in cPLP. Nonetheless, the mechanisms through which cPLP can be modulated remain poorly characterized. The public health consequences of cPLP make it a debilitating and intractable condition (Aternali and Katz, 2019), signifying the importance of developing new, fast-acting cPLP treatments.
Purpose/Objectives: Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine), a classical psychedelic that elicits profound changes in sensory perception and the sense of self (Gattuso et al., 2023), has shown promise in treating depression (Carhart-Harris et al., 2017; Goodwin et al., 2022; Raison et al., 2023; von Rotz et al., 2023), alcoholism (Bogenschutz et al., 2015, 2022), and pain (Ramachandran et al., 2018; Lyes et al., 2023; Agrawal et al., 2024; Cavarra et al., 2024). Converging lines of evidence indicate that psilocybin may improve well-being by modulating self-referential processing and affective appraisals, as evidenced by changes in the DMN (Carhart-Harris et al., 2017; Smigielski et al., 2019; Gattuso et al., 2023). However, no placebo-controlled clinical trials have examined the safety, efficacy, and brain mechanisms supporting psilocybin-induced cPLP relief. Thus, we conducted a randomized, double-blinded and placebo-controlled functional magnetic resonance imaging (fMRI) pilot study (NCT05224336), comparing psilocybin (n=5) to niacin (n=4) for relief of cPLP.
Methods: Nine amputees (4 female) diagnosed with cPLP (≥3/10; mean duration=5.06 years) completed the study. Following a psychiatric screen and physical, self-reported weekly phantom and residual (i.e., stump) limb pain (NRS: 0=“no pain sensation”; 10=“worst pain imaginable”) was assessed at baseline alongside resting state blood-oxygen-level dependent (BOLD) fMRI (MRI-1; 10-min, eyes closed). After baseline testing, volunteers participated in three separate psilocybin-focused preparatory sessions. On a subsequent day, participants were administered 25 mg of psilocybin (n=5) or 100 mg niacin (n=4) orally. At the post-intervention MRI session, the day after dosing (MRI-2), we performed the same methods as in the baseline session. Online follow-up pain surveys were collected at 2- and 4-weeks post dosing. Vitals (blood pressure, heart rate) and adverse events (e.g., suicidality) were monitored throughout the course of the study to test the hypothesis (HPY) that HPY-1: psilocybin is safe to administer in patients with cPLP. Linear mixed models tested whether HYP-2: psilocybin elicits greater reductions in phantom and residual limb pain from baseline to 2- and 4-weeks. Whole brain DMN resting state BOLD functional connectivity analyses were carried out with demeaned residual pain score regressors to determine if HYP-3: DMN-thalamic decoupling was associated with relief of cPLP.
Results: No serious adverse events or clinically significant changes in vital signs or suicidality were observed. Significant time X group interactions were associated with psilocybin-induced reductions in cPLP from baseline to two (-60%; p = 0.04; Cohen’s D = -2.67) and four (-43%; p = 0.09; Cohen’s D = -2.11) weeks, when compared to the change in pain from baseline in the niacin group at two (-18%) and four (-1%) weeks. Further, significant time X group interactions were associated with significant psilocybin-induced reductions in residual limb pain, from baseline to two (- 64%; p = 0.002; Cohen’s D = -5.98) and four (-55%; p = 0.002; Cohen’s D = -5.70) weeks when compared to the niacin group at two (+9%) and four (+37%) weeks. DMN-thalamic decoupling and increases in DMN-somatosensory cortex functional connectivity at MRI-2 predicted phantom limb pain relief at 4-weeks (fixed effects; z-score 3.1; p < .05).
Conclusions/Implications for future research and/or clinical care: This is the first known actively-controlled study to show the safety and efficacy of psilocybin for eliciting potentially clinically-meaningful (≥30%) and sustained reductions in chronic pain and the associated brain mechanisms. Planned follow-up studies will test these hypotheses in adequately powered sample sizes. Results from these trials will be of importance to the millions of individuals suffering from phantom limb pain. More broadly, this work may afford insight into how and why psilocybin has a long-lasting impact on a much larger range of treatment-resistant conditions involving chronic physical and psychogenic pain (e.g., fibromyalgia; complex regional pain syndrome), potentially helping to advance psilocybin as a scientifically validated treatment modality.
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