In an exploratory analysis of 32 participants from a Phase 2 open‑label trial of manualised MDMA‑assisted therapy for PTSD, 84% reported chronic pain and 75% reported pain‑related disability. MDMA‑AT was associated with significant reductions in pain intensity, disability and overall Chronic Pain Grade Scale severity in the high‑pain subgroup and reduced pain intensity in the medium‑pain subgroup, supporting further investigation of MDMA‑AT for comorbid chronic pain.
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Introduction
Increasing evidence demonstrates 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy (MDMA-AT) may be a safe and effective treatment for post-traumatic stress disorder (PTSD). There is growing interest in MDMA-AT to address a range of other health challenges. Chronic pain and PTSD are frequently comorbid, reciprocally interdependent conditions, though the possible role of MDMA-AT in treating chronic pain remains under-investigated. The present analysis examined the impact of manualized MDMA-AT on chronic pain severity among participants with PTSD who were enrolled in a Phase 2 clinical trial investigating MDMA-AT for PTSD (NCT03282123).Materials and methodsExploratory data from a subset of participants who completed chronic pain measures (n = 32) were drawn from a Phase 2 open-label study sponsored by the Multidisciplinary Association for Psychedelic Studies (MAPS). Multivariable analysis of variance (ANOVA) was utilized to compare pre- vs. post-treatment Chronic Pain Grade Scale (CPGS) values, adjusting for demographics (age, sex, and ethnicity). K-means clustering was then used to group the sample into three clusters to denote high (n = 9), medium (n = 11), and low (n = 12) baseline pain severity, and the same analysis was repeated for each cluster.
Results
Among the 32 participants included in this analysis, 59% (n = 19) were women, 72% (n = 23) were white, and median age was 38 years [interquartile range (IQR) = 31–47]. Overall, 84% (n = 27) reported having pain, and 75% (n = 24) reported disability associated with their pain. Significant reductions in CPGS subscales for pain intensity and disability score, and overall CPGS severity grade were observed among participants in the highest pain cluster (n = 9, p < 0.05), and for pain intensity in the medium pain cluster (n = 11, p < 0.05) post- vs. pre-treatment.
Discussion
Findings demonstrate a high prevalence of chronic pain in this sample of people with severe PTSD and that chronic pain scores among medium and high pain subgroups were significantly lower following MDMA-AT. While these data are preliminary, when considered alongside the frequency of comorbid chronic pain and PTSD and promising efficacy of MDMA-AT for treating PTSD, these findings encourage further research exploring the role of MDMA-AT for chronic pain.
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.
Data (December 2017 to August 2019) were drawn from a subset of participants enrolled in a multi-site Phase 2 openlabel study known as MP16 (n = 33) conducted by MAPS Public Benefit Corporation (MAPS PBC). This study served as a lead-in to Phase 3 studies investigating manualized MDMA-assisted therapy (MDMA-AT) to treat severe PTSD. The researchers designed the study to model the structure of planned Phase 3 trials, and to prepare and supervise sites planning to be part of the Phase 3 studies. The study took place across 12 sites in the United States and followed well-established protocols for MDMA-AT. Details and primary outcomes of the study have been previously described. The primary outcome measure for the MP16 study was the Clinician Administered PTSD Scale according to DSM-5 (CAPS-5), a semi-structured interview addressing PTSD symptom clusters. Exploratory data were collected including participants' Adverse Childhood Experiences (ACE) score at Baseline, and the Chronic Pain Grade Scale (CPGS) questionnaire at Baseline and Study Termination, which were of interest for the present analysis. Eligibility required confirmation of severe PTSD, defined as a CAPS-5 total severity score of 35 or greater. Participants could not have a diagnosis of substance use disorder within 60 days of screening, and psychiatric medications were tapered and discontinued prior to commencing study drug sessions. Participants were allowed to continue concomitant analgesic medications including nonsteroidal anti-inflammatory drugs (NSAIDS), acetaminophen, gabapentin, and opiates limited to hydrocodone, morphine and codeine. Participants taking other opiates at enrollment were cross-tapered to an allowable opiate during the preparatory period. Concomitant use of cannabis was prohibited from enrollment to study termination. The protocol for MDMA-AT involved a series of therapy sessions delivered by two clinicians in a "co-therapy" dyad, and participant eligibility and screening were managed by a physician. MDMA administration occurred on three occasions and each session was 8-h in duration in the presence of the co-therapy dyad. These study drug sessions were spaced 3-5 weeks apart and were preceded and/or followed by three non-drug 90-min sessions that served to prepare for and/or facilitate psychotherapeutic integration of each study drug session. According to the flexible dosing schedule, in the first study drug session, all participants received an initial dose of 80 mg MDMA HCl, followed 1.5-2.5 h later by a supplemental dose of 40 mg MDMA HCl. In the second and/or third study drug sessions, participants received an increased dose of 120 mg MDMA HCl followed by a supplemental dose of 60 mg MDMA HCl, 1.5-2.5 h later. All participants followed this dose escalation. The supplemental dose was withheld by the investigator in two instances due to tachycardia and elevated blood pressure following the initial dose, though neither required further medical intervention. The primary outcome for the present analysis was chronic pain, as measured by the CPGS questionnaire, which was administered twice, at Preparatory Session 3 (prior to the first MDMA session), and at study termination which occurred 10-14 weeks after the final MDMA session. Participants were asked to base their responses at study termination on the period since the end of treatment. Secondarily, we looked for associations between chronic pain, childhood adversity and PTSD severity at baseline. The CPGS questionnaire is a 7-item self-report instrument that measures two dimensions of overall pain severity: pain intensity and pain-related disability, and is valid and reliable for measuring change in severity of chronic pain over time. Data encompass current pain, as well as past 6 months pain and pain-related disability and is suitable for use in all chronic pain conditions. Pain intensity and disability score subscales are combined with disability points score to assign a chronic pain severity grade (0-IV); individual subscales as well as overall severity grade have demonstrated validity and reliability(for definitions of CPGS severity grade (0-IV), see Table). Demographic variables included age, sex, and ethnicity (white vs. other).
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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.
Statistical analyses were performed using R version 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria).
The present study found a high prevalence of pain among this sample of individuals with PTSD, in keeping with other published data demonstrating high rates of comorbid pain and PTSD. Statistically significant within subjects reductions in CPGS subscales including pain intensity, disability score, and composite chronic pain severity grade were observed following MDMA-AT among participants in the highest pain cluster (n = 9), and for pain intensity only in the medium pain cluster (n = 11), suggesting that MDMA-AT may be associated with reduction in chronic pain and pain-related disability. Significant reductions in pain and pain-related disability among participants in the highest pain cluster may be due to higher baseline pain values allowing greater margin for improvement; there may also be a mechanism related to an amygdala-based threat response to higher levels of pain being positively impacted by MDMA-AT, since overlapping brain areas have been shown to be active in both pain related threat perception, and anxiety and fear-based threat perception as typified by PTSD. Interestingly, among this sample baseline pain severity and PTSD severity were not positively correlated (Table). We speculate that differences in pain perception among individuals with PTSD symptoms may account for this finding; for example, high PTSD severity may distract from pain symptomatology, and vice versa, but this warrants further investigation. Previous research has demonstrated a unique and paradoxical pain perception pattern (hypo-responsiveness and hyper-sensitivity) in experimental and chronic pain among people with PTSD: PTSD-related dissociation was associated with higher pain threshold, whereas supra-threshold pain stimulus ratings were higher in those with PTSD in comparison to controls. Pain hyper-responsiveness was positively associated with anxiety sensitivity, but negatively correlated with dissociation levels. Anxiety and dissociation are intercorrelated in PTSDyet their relationship to pain perception among people with PTSD has not been systematically studied and warrants further investigation. To our knowledge, this is the first study to demonstrate an association between MDMA-AT and reduced pain among individuals with PTSD. Chronic pain is an international public health emergency for which new treatments are desperately needed. While chronic pain is frequently comorbid with PTSD, few studies have examined treatments designed to effectively address both conditions concurrently, yet when outcomes are assessed related to psychological interventions for both disorders in individual studies, moderate effects for PTSD and small effects for pain emerge, suggesting transdiagnostic effects. International best practice recommendations involve understanding and addressing chronic pain within a biopsychosocial model, with personalized multidisciplinary treatment approaches that include both physical and psychological interventions. Many chronic pain conditions, such as fibromyalgia, tension headache, and non-specific low back pain, involve alterations in central nervous system pain pathways leading to abnormal processing of pain signals, and are known collectively as "nociplastic" type pain. History of psychological, emotional, sexual, or physical abuse or a combination of these predispose to nociplastic pain. These conditions tend to respond poorly to physical treatment (medication or procedural interventions), and more readily to non-pharmacological approaches, such as educational, behavioral and psychotherapy interventions. MDMA is a psychoactive compound that promotes serotonin release, and may exert therapeutic effects by enhancing fear memory extinction, promoting greater self-compassion, reducing self-criticism, reducing PTSD-related shame and angerand causing acute prosocial and interpersonal effects that support the quality of the therapeutic alliance in psychotherapy. MDMA promotes oxytocin release, which helps increase interpersonal focus, feelings of interpersonal trust and social affiliation, and has been shown to reduce pain associated with social rejection. MDMA-AT has been associated with changes in personality persisting at two-month follow-up, notably increased personality trait Openness and reduction in Neuroticism. It has been suggested that MDMA may serve to acutely widen a "window of tolerance" in autonomic regulatory capacity which, combined with therapy, enables participants to approach and reprocess highly charged traumatic content without becoming overwhelmed or limited by hyperarousal or dissociative processes. MDMA may also re-open oxytocin-dependent "critical period" neuroplasticity in social learning that may also function to enhance or accelerate therapeutic change. Given the high comorbidity of PTSD and chronic pain reflected in the present analysis, and the growing literature suggesting shared mechanisms both predisposing to and maintaining both conditions, it is conceivable that some of these proposed mechanisms explaining the efficacy of MDMA-AT for PTSD may be relevant for treating chronic pain. In particular, MDMA-AT effects related to enhanced fear extinction and approaching rather than avoiding negatively charged content may be relevant to fear and avoidance phenomena that are known to intensify and perpetuate chronic pain. Self-compassion, enhanced through MDMA, has also been linked with improved pain outcomes. Treatment with an existential focus may play an important role in chronic pain recoveryparticularly when combined with other psychological and pharmacological approachesand has been shown to be effective in decreasing pain-related disability. MDMA-related improvements in intrapersonal attitudes including reduced self-criticism may impart benefit to chronic pain-associated existential challenges to related to identity, social roles, meaning and purpose, which are relevant yet underrepresented areas of treatment focus for chronic pain. Interpersonal effects that enhance therapeutic alliance may also be of relevance since psychological interventions for chronic pain require a strong therapeutic relationship to maximize benefit. Additionally, MDMA-enhanced perception of social connection and support may target chronic pain-related social isolation, a factor that exacerbates pain symptomatology, and when reduced, is associated with improvements in emotional and physical functioning among chronic pain patients. The potential for MDMA-AT to promote change in personality including reduced trait Neuroticism may also be of relevance, since neuroticism predicts poor adjustment to chronic pain. Our data demonstrate a high median ACE score among this sample (4; IQR 3-7) and are consistent with previous research in the intersecting fields of chronic pain and trauma, that indicate an association with adverse childhood experiences (ACE). Stress response psychobiology is of particular relevance to this discussion. While short term stress responses support an individuals' immediate survival, chronic adversity and/or repeated stressors, particularly during vulnerable developmental periods, can lead to long term changes to the structure and function of hormonal, neurological and psychological systems in ways that predispose to poor health outcomes, such as chronic pain. The capacity to tolerate increased levels of stress and to recover quickly, known as resilience, relies upon optimal environmental conditions whereby interacting psychobiological systems can develop ideal responses, and healthy attachment relationships are of particular importance. The potential of MDMA to re-open critical period neuroplasticity related to social reward learning, combined with interpersonal effects such as enhanced empathy and trust, may create optimal conditions within the MDMA-AT therapeutic relationship to improve resilience and thus create more favorable conditions for recovering from chronic pain and other chronic conditions that are negatively impacted by stress.