MDMA-assisted therapy is associated with a reduction in chronic pain among people with post-traumatic stress disorder

Hendricks and colleagues place this analysis within a growing literature showing that MDMA-assisted therapy (MDMA-AT) can be a safe and effective treatment for post-traumatic stress disorder (PTSD) and that interest is expanding to other clinical indications. The paper emphasises that chronic pain and PTSD are frequently comorbid,互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互互 The extracted text does not clearly report the prevalence estimates cited in some background sentences, but the authors describe chronic pain as a common, complex condition that is often inadequately managed by long-term pharmacotherapy and that is well suited to biopsychosocial interventions. The present study set out to explore whether manualised MDMA-AT delivered in a Phase II open-label trial for severe PTSD was associated with changes in chronic pain severity. Using exploratory pain outcome data collected in the MP16 trial, the investigators examined pre- versus post-treatment scores on the Chronic Pain Grade Scale (CPGS) and tested whether within-sample subgroups defined by baseline pain severity (high, medium, low) showed differential change following MDMA-AT. The analysis is explicitly exploratory and framed as hypothesis-generating, intended to motivate further research into MDMA-AT for chronic pain and PTSD/chronic pain comorbidity.

Data came from MP16, a multi-site Phase II open-label study conducted by MAPS PBC between December 2017 and August 2019. The present analysis used a subset of participants who completed the CPGS at baseline and study termination (n = 32 of 33 enrolled). Eligibility for MP16 required severe PTSD, operationalised as a CAPS-5 total severity score ≥ 35; the trial excluded people with a substance use disorder within 60 days of screening and required psychiatric medications to be tapered and discontinued before drug sessions. Concomitant analgesics were permitted (NSAIDs, acetaminophen, gabapentin and certain opiates such as hydrocodone, morphine and codeine) while cannabis was prohibited during the study. MDMA-AT followed a manualised protocol delivered by a co-therapy dyad. Each participant received up to three MDMA sessions, each lasting 8 hours and spaced 3–5 weeks apart, with preparatory and integration non-drug 90-min psychotherapy sessions surrounding the drug sessions. Dosing was escalated: the first session provided 80 mg MDMA HCl with a supplemental 40 mg 1.5–2.5 hours later; the second and/or third sessions used 120 mg with a 60 mg supplemental dose. In two instances the supplemental dose was withheld for transient tachycardia and elevated blood pressure; neither required further medical intervention. The primary outcome for this exploratory analysis was chronic pain measured by the Chronic Pain Grade Scale (CPGS), a 7-item self-report instrument that yields pain intensity and pain-related disability subscales and a composite severity grade (0–IV). The CPGS was administered at Preparatory Session 3 (pre-first MDMA session) and at study termination (10–14 weeks after the final MDMA session), with participants asked to rate the period since treatment ended. The investigators also considered baseline Adverse Childhood Experiences (ACE) score and CAPS-5 PTSD severity as potential correlates. For analysis, R version 4.0.3 was used. The team applied bivariate linear and ordinal regression to examine pre-treatment associations, then used k-means clustering on baseline CPGS subscales to define three within-sample pain groups (high n = 9, medium n = 11, low n = 12). Pre–post comparisons of pain intensity, disability score, and composite severity grade were performed using paired t-tests and two-way ANOVA for multivariable analyses adjusting for age, sex and ethnicity (white vs. non-white). The authors note one deviation from the published CPGS: question 5 was worded differently in their administration, a point considered in interpretation.

Thirty-two participants had complete pre- and post-treatment CPGS data and were included in the analysis. The sample was 59% female (n = 19), 72% white (n = 23), with a median age of 38 years (IQR 31–47). Overall, 84% (n = 27) reported experiencing pain and 75% (n = 24) reported pain-related disability; median ACE score was 4 (IQR 3–7). The extracted text states that there were no strong pre-treatment associations between CPGS values and ACE score, CAPS-5 total severity, or demographic variables. K-means clustering divided participants into high (n = 9), medium (n = 11) and low (n = 12) baseline pain groups based on pain intensity, disability score and composite severity grade. Among participants in the highest pain cluster, mean values for pain intensity, disability score and overall CPGS severity grade were all significantly reduced post-treatment compared with baseline (n = 9, p < 0.05 in both bivariate t-tests and ANOVA). In the medium pain cluster, ANOVA showed a significant reduction in pain intensity post-treatment (n = 11, p = 0.020), although the paired t-test for pain intensity was p = 0.095; disability score and composite severity grade showed trends toward reduction in both bivariate and multivariable analyses but did not reach conventional significance. The paper reports that the majority of participants received the planned dose escalation and supplemental doses, with two supplemental doses withheld for cardiovascular signs but no further medical events recorded.

Hendricks and colleagues interpret their findings as demonstrating a high prevalence of pain among people with severe PTSD in this sample and an association between MDMA-AT and reduced chronic pain, particularly among those with higher baseline pain. Statistically significant within-subject reductions were observed for pain intensity, disability score and composite severity grade in the high pain cluster, and for pain intensity in the medium cluster. The investigators propose several potential mechanisms that could plausibly link MDMA-AT effects on PTSD to changes in pain: modulation of amygdala-based threat responses, enhanced fear extinction, increases in self-compassion and reduced self-criticism, oxytocin-mediated prosocial effects that may ameliorate social pain, improvements in therapeutic alliance, and reopening of neuroplastic ‘‘critical periods’’ that facilitate emotional and interpersonal learning. The authors note that baseline PTSD severity was not positively correlated with pain severity in this sample and discuss complex, sometimes paradoxical, pain-perception patterns reported in PTSD literature — for example, dissociation-related hypo-responsiveness to threshold pain yet greater supra-threshold ratings. They situate MDMA-AT within a biopsychosocial model of chronic pain, emphasising that many chronic pain conditions (so-called nociplastic pain) respond poorly to physical interventions alone and may benefit from psychotherapeutic approaches. The discussion stresses that MDMA-AT combines pharmacological and psychotherapeutic elements that could address fear, avoidance and catastrophising processes known to maintain both PTSD and chronic pain. Key limitations acknowledged by the investigators include the small sample size (n = 32) and limited power, especially within the high pain subgroup (n = 9), and the exploratory nature of the analyses without a hierarchical testing strategy raising the risk of Type I error. The CPGS was administered as an exploratory endpoint and one CPGS item was worded differently from the published instrument, which could bias disability scores. Potential confounders such as concurrent analgesic medication were not fully examined, and participants were recruited for PTSD rather than for chronic pain per se, limiting generalisability to standalone chronic pain populations. The sample was predominantly white, reducing external validity for other demographic groups. Given these constraints, the authors characterise the results as preliminary and hypothesis-generating and call for randomised, controlled trials specifically designed to evaluate MDMA-AT for chronic pain and for PTSD–chronic pain comorbidity.

These exploratory data show a high prevalence of pain among people with severe PTSD in this trial and indicate that, among participants with the highest baseline pain, pain intensity, disability and composite pain severity were significantly lower following MDMA-AT. The authors emphasise that these findings are limited and primarily hypothesis-generating but argue they, together with existing evidence for MDMA-AT in PTSD and shared mechanisms between PTSD and chronic pain, support further research into MDMA-AT as a possible intervention for chronic pain and for co-morbid PTSD and chronic pain.