This randomised, open-label, wait-list-controlled trial (n=20) found that MDMA-assisted therapy reduced social anxiety symptoms more than waiting for treatment and improved functioning in adults with social anxiety disorder (SAD).
Papers cited by this study that are also in Blossom
Bershad, A. K., Miller, M. A., Baggot, M. J. et al. · Journal of Psychopharmacology (2016)
Background
±3,4-methylenedioxymethamphetamine (MDMA) has positive effects on socio-emotional processing and MDMA-Assisted Therapy (MDMA-AT) showed promise for treating SAD in a previous placebo-controlled trial.
Aims
Develop a preliminary estimate of clinical response and safety for MDMA-AT versus waitlist in adults with SAD. Secondary aims included refinement of a standardized psychotherapy manual and assessment of candidate therapeutic processes.
Method
This randomized, open-label, wait-list controlled clinical trial recruited and enrolled 20 participants diagnosed with SAD from April, 2022 to March, 2024. They were randomly assigned to either immediate treatment with MDMA-AT or a 16-week waitlist condition followed by MDMA-AT equivalent to the immediate treatment arm. MDMA-AT consisted of three 90-minute preparation sessions, two MDMA sessions, and six 90-minute integration sessions. The preregistered primary outcome was the Leibowitz Social Anxiety Scale; secondary outcomes were functioning, shame, acceptance, belongingness, self-concealment, and self-compassion.
Results
Across 20 participants (45% women, 40% men, 15% transgender; 85% White; mean age 38) we observed a mean difference on the Leibowitz Social Anxiety Scale at 16-week primary outcome of −43.3 (SD = 14.7; 95% CI, −29.5 to −57.1; p < .0001; Hedge’s g = 2.8) indicating greater improvement in the MDMA-AT condition. No serious adverse events occurred; adverse events were mild to moderate and transient.
Conclusion
MDMA-AT resulted in a significant reduction in social anxiety symptoms and improvement in functioning compared to waitlist. There were no serious adverse events. Findings provide preliminary data for efficacy, safety, and feasibility of MDMA-AT for SAD, supporting the need for further investigation.
Social anxiety disorder (SAD) is described as a common and often chronic condition marked by fear of negative evaluation in social settings, with substantial effects on functioning, quality of life, employment, and risk of later mental health problems. The authors note that although cognitive-behavioural therapy and medications such as SSRIs and SNRIs are established treatments, access is limited and many people do not respond well, relapse, or drop out. They also point to earlier research suggesting that MDMA-assisted therapy (MDMA-AT) may help in other psychiatric conditions and that one earlier placebo-controlled trial in autistic adults with SAD found promising reductions in social anxiety, but broader evidence in non-autistic SAD populations was lacking. Luoma and colleagues state that this early-phase trial aimed to extend that work by estimating the clinical response and safety of MDMA-AT versus wait-list in adults with SAD. A secondary aim was to refine a standardised psychotherapy manual and examine candidate therapeutic processes that might change during treatment. The paper is positioned as a preliminary study designed to inform larger future trials rather than to provide definitive efficacy evidence.
This was a randomised, open-label, wait-list controlled clinical trial conducted in an outpatient private clinic. Recruitment was open from April 2022 to March 2024, and the last primary outcome data were collected in February 2025. Participants were English-speaking adults aged 18 to 65 years who met DSM-5 criteria for current SAD and had moderate-to-severe symptoms at screening, defined as a Liebowitz Social Anxiety Scale (LSAS) score of at least 60. They also needed to name a support person, have a suitable home environment, and agree to lifestyle modifications. The exclusion criteria were extensive and included recent or excessive prior Ecstasy/MDMA use, several psychiatric conditions such as psychotic disorders, bipolar disorder type 1, autism spectrum disorder, active eating disorders, substance use disorders other than caffeine or nicotine, certain personality disorders, current PTSD, and serious suicide risk. Medical exclusions covered conditions that might increase risk, including uncontrolled hypertension and QT/QTc prolongation. Recent antidepressant use, some other medications, recent ketamine use, and pregnancy were also exclusionary. Recruitment occurred through email, websites, healthcare provider referrals, and study registries. Screening included surveys, clinician-rated and self-report assessments, psychiatric and medical history, physical examination, laboratory tests, and electrocardiography. Randomisation used permuted blocks of 2 and 4 and was carried out by a PhD scientist not involved in the trial. The research team remained blind to assignment until participants were informed of their condition at an enrolment confirmation meeting. Outcome raters were blinded to condition and time point, but participants were not blinded. Ten participants were assigned to immediate treatment and ten to the 16-week wait-list, after which the wait-list group also received MDMA-AT. The intervention comprised three 90-minute preparation sessions, two MDMA sessions, and six 90-minute integration sessions. Therapists were licensed psychologists or social workers with at least 100 hours of MDMA-AT training plus individual consultation. Each participant had a primary therapist throughout, and a secondary therapist joined selected sessions. The psychotherapy was manualised but deliberately iterative: the manual began with elements adapted from prior MDMA-AT work and was refined during the trial to include more active, structured approaches tailored to SAD. Preparation focused on alliance building, assessment of social anxiety history and cultural background, psychoeducation, values clarification, informed consent about touch, session logistics, and safety. Integration sessions focused on making sense of the MDMA experience and applying insights to daily life. In the first medication session, the initial MDMA dose was 80 mg; in the second, it was 120 mg unless the team judged otherwise. In both sessions, a supplemental 40 mg dose was given 1.5 to 2 hours later unless contraindicated. During medication sessions, participants alternated between ‘internal’ periods with eyeshades and music and ‘outward’ periods of interaction with therapists. Brief phone check-ins were conducted during the week after medication sessions for safety monitoring. Primary and secondary outcomes were assessed at baseline and at the primary endpoint, which was post-treatment for the immediate group and 16 weeks for the wait-list group. The main outcome was LSAS score. Prespecified secondary outcomes included disability, shame, acceptance of shame and embarrassment, thwarted belongingness, hidden self/inauthenticity, and self-compassion. Suicide risk was monitored with the Columbia Suicide Severity Rating Scale at each session and assessment point. The authors used independent-samples t-tests for between-group comparisons at the primary endpoint and paired t-tests for pre-post changes in the full sample. Hedges’ g was reported as the effect size, and Spearman correlations were used to examine associations between changes in secondary variables and changes in LSAS. Missing data were described as rare, though details were said to be in supplementary materials.
All procedures involving human subjects/patients were approved by WCG IRB (protocol ID IUSA5;. Written consent was collected from all participants and we followed CONSORTsee Figure) reporting guidelines. The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2013.
Recruitment and enrollment for this randomized waitlist-controlled trial were open between April 13, 2022 and March 2024. To be eligible, participants had to be English-speaking adults aged 18-65 who met DSM-5 criteria for current SAD with moderate-to-severe symptoms (LSAS total score ≥60) at screening. They needed to designate a support person, have a suitable home environment, and agree to comply with lifestyle modifications. Participants were excluded if they had used Ecstasy (the street name for MDMA) more than 10 times in the past decade or at all within six months of the first session. Psychiatric exclusions included recent electroconvulsive treatment, primary psychotic disorder, bipolar disorder type 1, autism spectrum disorder, active eating disorders, substance use disorders (excluding caffeine/nicotine), personality disorders (except avoidant), current PTSD, and serious suicide risk. Medical exclusions encompassed medical conditions that could create safety risks, such as uncontrolled hypertension or QT/QTc interval prolongation. Additional exclusions included antidepressant use within the last six months, certain other medications, recent ketamine use, or pregnancy (for detailed eligibility criteria and screening procedures, see our published trial protocoland supplementary material). Recruitment occurred via email and website. Participants were both referred by healthcare providers and self-volunteered. Local healthcare providers were notified of the study and potential participants discovered it through a website and clinicaltrials.gov. Prescreening consisted of a survey and brief interview. Following informed consent, participant screening involved web-based surveys, clinician-rated assessments, self-report measures, medical and psychiatric history, a physical examination, review of laboratory tests, and electrocardiogram. Randomization was performed by a PhD scientist not involved with the trial and consisted of permuted block randomization with random blocks of 2 and 4. The randomization sequence was stored on a secure drive. The study team was blind to assignment until participants were informed of condition at an enrollment confirmation meeting. Raters who conducted clinician assessments were blinded to condition and time point. Participants were assigned to either the immediate treatment or waitlist arm (see Figure). Those who were randomized to the waitlist subsequently received MDMA-AT equivalent to the immediate treatment arm after a 16week delay. All assessment and intervention sessions were conducted in an outpatient clinical setting in a private clinic. The last primary outcome data was collected in February, 2025.
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Feduccia, A. A., Mithoefer, M. C. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2018)
Luoma, J. B., Lear, M. K. · Frontiers in Psychiatry (2021)
Mitchell, J., Ot’alora G, M., van der Kolk, B. et al. · Nature Medicine (2023)
Nichols, D. E. · Frontiers in Psychiatry (2022)
The researchers were contacted by 1,199 people, 94 signed consent, and 20 were enrolled and randomised equally between conditions. The sample was mostly White, with 45% cisgender women, 40% cisgender men, and 15% transgender participants. All participants completed the intervention sessions. At the primary endpoint, the immediate treatment group showed substantially greater improvement in social anxiety than the wait-list group. The LSAS between-group difference was reported as -43.3, with a standardised mean difference of 14.7, 95% CI -57.1 to -29.5, t(18) = 6.6, p < .0001, and Hedges’ g = 2.8. The authors also report that all prespecified secondary outcomes favoured the immediate treatment group at the primary endpoint. These included disability, shame, acceptance of shame and embarrassment, thwarted belongingness, hidden self/inauthenticity, and self-compassion, with effect sizes ranging roughly from g = 1.2 to g = 2.0. The exact sign of some reported mean differences is difficult to reconstruct from the extracted text, but the direction of benefit was consistently described as favouring MDMA-AT. When the full sample of 20 participants was examined pre- to post-treatment, the LSAS improved markedly, with a reported standardised mean change of 44.2, SD 21.1, t(19) = 6.0, p < .0001, and g = 2.0. Secondary outcomes also improved over time. Responder analyses suggested that 80% met responder criteria, 80% fell below the LSAS threshold of 60, 55% no longer met SAD diagnosis on MINI interview, and 25% were in remission. Exploratory correlations showed that changes in acceptance of shame and embarrassment, internalised shame, and hidden self/inauthenticity were associated with changes in LSAS, whereas self-compassion and thwarted belongingness were not clearly associated in the prespecified analyses. Safety findings were favourable in the sense that no serious adverse events or adverse events of special interest occurred. Among 54 adverse events, 87% were mild and 13% moderate. The most common were headache, nausea, bruxism, muscle tightness, dizziness, general body pain, insomnia, and tachycardia. Blood pressure and heart rate typically rose modestly during sessions and returned near normal by discharge. Two participants had transient tachycardia above the study’s contact threshold and one had transient high blood pressure, but none required treatment. There was no suicidal ideation or behaviour during the study.
The authors interpret the findings as preliminary evidence that MDMA-AT may substantially reduce social anxiety symptoms and improve functioning in adults with SAD. They emphasise that this is, to their knowledge, the first study of MDMA-AT in a non-autistic SAD sample, and they describe the between-group effect on blinded social anxiety ratings as very large. They also note that the functional gains were sizeable and that the full-sample pre-post results were broadly similar to the primary comparison. Luoma and colleagues place these effects in the context of earlier work by noting that the observed effect size appears large relative to prior studies of cognitive-behavioural therapy, SSRIs/SNRIs, and combined psychotherapy-pharmacotherapy for SAD, although they do not claim a direct head-to-head comparison. They suggest that MDMA may aid psychotherapy by influencing social bonding, threat, reward, and related psychological processes, and they point to the correlated changes in shame, acceptance, and inauthenticity as potentially relevant. However, they stress that these process findings are exploratory, may reflect shared method variance among self-report measures, and do not establish mediation or mechanism. The authors report no serious adverse events and no suicidal ideation or behaviour, which they say supports feasibility for larger studies. At the same time, they caution that the sample was very small, so uncommon harms could easily have been missed. They also note that the adverse event profile was broadly consistent with earlier MDMA-AT studies and mainly involved expected transient effects such as headache, nausea, bruxism, and short-lived cardiovascular changes. The paper’s limitations are stated clearly. The sample was small, highly screened, and not very diverse, with many participants having relatively good functioning and prior treatment exposure, which limits generalisability. Participants were not blinded, so expectancy effects may have inflated outcomes. The psychotherapy manual changed during the trial, introducing heterogeneity in the intervention. The wait-list control did not match nonspecific treatment factors such as therapist contact or expectancy, so the between-group effect may be larger than would be seen against an active control. The authors therefore frame the effect estimates as preliminary and likely unstable, and they call for larger, adequately powered trials with stronger control conditions to refine efficacy estimates, examine longer-term outcomes, and test mechanisms in more diverse and comorbid populations.
The authors conclude that MDMA-AT was associated with significant symptom reduction in adults with SAD in this randomised, open-label, wait-list trial, with no serious adverse events and only mainly mild, transient adverse effects. They state that the study provides preliminary evidence of feasibility, safety, and clinical response, and they argue that these findings justify further trials to replicate the results, assess durability, and test MDMA-AT in broader patient populations.
The intervention consisted of three 90-minute preparation sessions, a first medication session, three 90-minute integration sessions, a second medication session, and three more 90minute integration sessions. Study therapists were licensed psychologists and social workers who had at least 100 hours of training in MDMA-AT offered by MAPS PBC plus individual consultation on cases. Each participant had a primary therapist who attended all sessions and a secondary therapist who attended the first preparation session, the third preparation session, both MDMA sessions, and the first integration session following each MDMA session. As the development of a consistent treatment manual was one of the secondary aims of the study, a draft treatment manual was created for the initial participant and was iteratively refined as the study progressed based on clinical observations, outcome data, and theoretical rationales for how MDMA could benefit people with SAD. All preparation sessions included a focus on developing a robust therapeutic alliance and a thorough assessment of the client's social anxiety history and relevant cultural background. Preparation also included psychoeducation about SAD and MDMA, clarification of the clinical focus of MDMA sessions, and values clarification. Preparation also involved extensive discussion and informed consent around supportive touch options, familiarizing clients with the therapy room and session logistics, coordinating with support persons, and providing detailed expectations about MDMA session structure and approach. Therapists also encouraged willingness to approach difficult experiences and established protocols for maintaining participant safety. Integration sessions were flexible and responsive to clients' needs. The first session following the MDMA session typically focused on debriefing the medication session and identifying integration activities to apply any insights elicited during the MDMA session. The second integration session following each MDMA session emphasized continued reflection on insights and emerging experiences and consider how they might be applied to daily life. The third integration session included additional elements to prepare for the next MDMA session and final integration session included a review of treatment and provision of referrals for ongoing therapeutic support if needed. In the first medication session, the initial dose of MDMA was 80 mg. In the second medication session, the initial dose of MDMA increased to 120 mg unless contraindicated in the judgment of the research team in consultation with the study physician. In both medication sessions, the participant was administered a supplemental 40 mg dose between 1.5 and 2 hours after the initial dose unless contraindicated. The medication was provided in capsules manufactured by and purchased from Lykos Therapeutics. During medication sessions, participants spent periods of time "internal" listening to musical playlists selected by the therapists while wearing eyeshades, and other periods of "outward" time interacting with the therapists, which included both active, focused therapeutic interventions and less directive interactions. Therapists led four brief (typically under 10 minute) phone check-ins intended to address safety concerns and collect safety data over the week following medication sessions. Due to the secondary goal of developing a well-specified treatment manual, the content of the psychotherapy sessions varied during the trial. The psychotherapy methods were initially guided by the MDMA-AT manual for PTSD developed by Multidisciplinary Association for Psychedelics Studies. After six participants, a review was conducted and the treatment manual was rewritten to incorporate more active treatment elements based on evidence-based principles of behavior change related to SAD and on the research literature on the mechanisms of action for MDMA. As the study progressed, the treatment manual became increasingly well-specified and treatment became more active and structured. In the immediate condition, primary and secondary outcome data were collected at baseline and 16 week follow up, with the LSAS also collected at screening and after the second preparatory session. The waitlist condition completed the same assessments as the immediate condition, but after a 16-week delay. Additional exploratory assessments were conducted at baseline; before and after intervention sessions; as part of a daily survey administered one week before and after each medication session; and at post-treatment. Exploratory assessments were self-report, behavioral, physiological, and qualitativeand are planned to be reported elsewhere.
All primary and secondary outcomes compared mean scores at the post-treatment assessment point in the immediate arm to the 16-week assessment in the waitlist arm. Primary outcomes were scores on the Liebowitz Social Anxiety Scale; assessed by raters blind to condition and time point). Prespecified secondary outcomes included the Sheehan Disability Scale (SDS;Internalized Shame Scale (ISS;Acceptance of Shame and Embarrassment Scale (ASES;the Thwarted Belongingness subscale from the Interpersonal Needs Questionnaire (INQ;The Hidden Self Scale (HSS;and the Self-Compassion Scale-Short Form (SCS;Secondary outcomes were included to assess functional outcomes as well as changes in putative therapeutic processes. Suicide risk was assessed using the Columbia Suicide Severity Rating Scaleat each session and assessment point.
A statistical analysis plan was created prior to the start of the study (cdn.clinicaltrials.gov/large-docs/68/NCT05138068/SAP_000.pdf) and updated to include safety variables after data collection was complete (osf.io/8cn9b). Primary and secondary outcome analyses compared mean scores at primary outcome assessment in the immediate treatment condition (n = 10) to the 16-week assessment in the waitlist condition (n = 10). We used a twotailed independent samples t-test with α = .05 to compare means across groups. For analyses of pre-to-post changes for the full sample, we used a two-tailed paired-samples t-test with α = .05. Hedges' g is reported as a measure of effect size. To test for association between secondary variables and primary outcome, we calculated bivariate Spearman correlations between change scores for the LSAS and change in each secondary outcome measure. Spearman was selected due to non-normality of variables. Details on responder analyses and missing data, which were rare, are in the supplementary materials. Power calculations were based on a previously published trial of MDMA-AT for SAD in autistic adults that reported a between group placebo-subtracted effect at primary outcome point of d = 1.4Our estimates assumed the same effect size, which results in an a priori power estimate of .88 to detect a statistically significant difference between groups at the primary endpoint. Due to the use of a waitlist control in this study, rather than a placebo control, we anticipated potentially observing larger between-group effects than the previous trial. All analyses were performed between February, 2025 and July, 2025 using Stata 15.1 or R (version 2024.04.1).
We were contacted by 1199 participants, 94 signed informed consent forms, and 20 participants were enrolled, of whom 45% were cisgender women, 40% cisgender men, and 15% transgender; 60% were heterosexual, 20% bisexual, 10% gay, and 10% pansexual; 85% were White, 15% mixed race, and 5% Latino/Hispanic (additional demographics in Table). All participants completed all intervention sessions. Ten were randomized to each condition (see Figure). At the primary outcome point, the standardized mean difference in LSAS between conditions was -43.3 (14.7) (95% CI, -29.5 to -57.1; t(18) = 6.6, p < .0001; g = 2.8; see Figure). Figurepresents LSAS scores over time by condition. For secondary outcomes, significant between-group differences were found on all variables at the primary outcome point (Figure). For the SDS, the standardized mean (SD) difference was -8.2 (4.0) (95% CI, -4.4 to -12.1); t(18) = 4.5, p < .001, g = 2.0. For the ISS, -21.3 (12.7) (95% CI, -9.3 to -33.3; t (18) = 3.74, p = .002, g = 1.6, ASES, 20.6 (11.3) (95% CI, -9.6 to -31.6; t(18) = 4.1, p = .001, g = 1.7, INQ, -12.5 (9.1) (95% CI, -4.0 to -21.0; t(18) = 3.1, p < .001, g = 1.3, HSS, -2.8 (2.2) (95% CI, -.8 to -4.9; t(18) = 2.9, p < .001, g = 1.2, and SCS, 1.1 (.6) (95% CI, -0.6 to -1.7; t(18) = 4.2, p < .001, g = 1.8. Using the entire sample of 20 participants from pre-to-post treatment, the standardized mean change (SD) for the LSAS was 44.2 (21.1) (95% CI, -34.3 to -54.0; t(19) = 6.0, p < .0001; g = 2.0). Change in secondary outcomes were as follows:3) t (19) = 6.3, p <.001, g = 1.3, HSS, -2.7 (2.2) (95% CI, -1.7 to -3.8 ; t(19) = 2.9, p < .0001, g = 1.2, and SCS, -1.2 (.6), (95% CI, -1.5, -1.0; t(19) = 10.0, p <.0001, g = 2.1. Responder analyses showed that 80% were responders, 80% were below the threshold for a likely SAD diagnosis based on an LSAS cutoff of 60, 55% no longer met SAD diagnosis based on MINI interview, and 25% were in remission (see Figureand supplementary materials for definitions). Prespecified exploratory correlational analyses showed that changes in ASES, rho (19) = -.57, p = .01), ISS, rho (19) = .65, p = .002, and HSS, rho (19) = .47, p = .04 were all correlated with changes in the LSAS from baseline to primary outcome, but the SCS, rho (19) = -.28, p = .24, and INQ, rho (19) = .41, p = .07, were not. No serious adverse events (AEs) or adverse events of special interest (certain cardiac events and signs of abuse potential) occurred, with 87% of AEs classified as mild and 13% as moderate severity. A total of 54 AEs were reported with the most common events being headache (65%), nausea (45%), bruxism (35%), muscle tightness (15%), dizziness (10%), general body pain (10%), insomnia (10%), tachycardia (10%) with all others at 5% or less of the sample (see Supplementary document for more detail). Typically, blood pressure and heart rate were mildly elevated and returned to near normal by discharge from MDMA sessions. Two participants experienced transient tachycardia (HR = 121 and 135 at peak) and one high blood pressure (BP = 173/111 at peak) that exceeded pre-determined limits to contact the study physician during MDMA sessions, but neither required treatment (see supplementary materials for more on AEs, heartrate, and blood pressure). Of note, the cardiovascular effects of MDMA are well-knownand are thought to primarily result from increased monoamine signaling and heightened sympathetic nervous system activity, increasing vitals within the range of moderate exercise. Cardiac health was a significant screening consideration (see Supplementary document for detailed eligibility criteria); and, while these suprathreshold values in our study were monitored more closely by the study physician, there was no indication of more severe cardiac adverse events. There was no current suicidal ideation or behavior at screening for any participant or at any point during the study.
To our knowledge, this is the first study to examine the effects of MDMA-AT in a sample of people with social anxiety disorder who were not autistic. MDMA is an entactogen that promotes monoamine reuptake inhibition and release, which is thought to enhance memory reconsolidation and fear extinctionincrease affiliative behavior, release social neuropeptides such as oxytocin and vasopressin, and induce subjective effects related to social cognition and emotion. Our primary endpoint analysis compared immediate versus waitlist controls at 16-week primary outcome on blinded social anxiety symptoms ratings and found a very large between groups effect (g = 2.8). This difference is large compared to other trials comparing cognitivebehavior therapy (g = .87-.91;) SSRI/SNRIs (g = .91;, or treatments that combined psychotherapy and pharmacotherapy (g = 1.30;for SAD compared to waitlists. Functional outcomes were also greatly improved in the immediate treatment compared to waitlist (g = 2.0). Analysis of the full sample of 20 people who received MDMA-AT found similar levels of improvement as the immediate treatment group. These data provide preliminary evidence of a potential benefit and support the conduct of larger, adequately powered trials with stronger control conditions to obtain more precise estimates. We have previously hypothesized that MDMA may enhance psychotherapy for SAD via affecting brain systems and hormones related to social bonding, while simultaneously modulating neurobiological and psychological processes related to social threat and rewardSecondary outcomes showed pre-post changes in several prespecified candidate processes we hypothesized might be engaged during MDMA-AT (e.g., acceptance, shame, belonging, self-compassion, and inauthenticity). In addition, changes from pre-to-post treatment in acceptance, shame, and inauthenticity were correlated with changes in social anxiety. Because these self-report measures may be intercorrelated and share method variance, and because we did not test mediation, these findings should be viewed as exploratory and cannot establish mechanisms; rather, they highlight candidate processes for future trials. These data are, however, consistent with the idea that MDMA-AT may reduce avoidance and safety behaviors related to social situations, reduce shame, increase social reward, increase selfcompassion, and aid people in acting and speaking more authentically. No serious adverse events occurred and there was no suicidal ideation or behavior during the study. However, with only 20 participants, the absence of serious adverse events does not rule out uncommon harms. The types of AEs observed were similar to that reported in previous studies with MDMA-AT and are supportive of the feasibility of larger trials of MDMA-AT with this population. The most common AEs were headache, nausea, and bruxism. No medical intervention was required for any AEs outside of over-the-counter medications.
Strengths of this early-phase study include the use of an iterative treatment-development approach that integrated theory-driven and evidence-based components for SAD with ongoing review of empirical data from the sample; the inclusion of a somewhat treatment-resistant population (19/20 indicated prior mental health treatment); and the use of blinded, multi-method assessments to examine candidate therapeutic processes. The small sample, as well as strict eligibility requirements, limits generalizability. In particular, participants were highly screened, excluding individuals with many common psychiatric comorbidities (e.g., PTSD, bipolar disorder, substance use disorders, some personality disorders), of limited racial diversity, highly educated, and of relatively good overall functioning (e.g., 90% employed), limiting generalizability to broader clinical populations with more complex presentations. When assessing prior mental health treatment, we did not assess which were focused on social anxiety, nor reliably record which involved psychotherapy versus medication, limiting our ability to assess how treatment-resistant the sample was. Participants were not blinded to study condition, likely increasing expectancy effects; however, outcome raters were blinded to condition and time point. Sample size was probably inadequate in statistical power for exploratory correlational analyses, which were only powered to detect large effects, and thereby should be seen as tentative. Given the small sample and early-stage nature of the study, observed effect sizes are likely unstable estimates and may overestimate the true effect size, requiring replication; secondary outcomes should be considered exploratory. The iterative development of the treatment manual during the trial introduced heterogeneity in the psychotherapy intervention. In addition, a waitlist/delayed-treatment control does not match nonspecific factors (e.g., therapist contact and expectancy) and may inflate between-group effects. Therefore, effect sizes in the present study should be viewed as preliminary and likely larger than effect sizes that would be observed in studies comparing MDMA-AT to attention-matched or active-control designs. Larger, adequately powered trials using stronger control conditions are needed to provide more accurate effect size estimates and to isolate MDMA-specific effects from nonspecific factors.
In this randomised, open-label, wait-list clinical trial, MDMA-AT was associated with significant reduction in symptoms of social anxiety disorder among adults with SAD. No serious adverse events occurred, and no suicidal ideation or behavior was observed during the study; reported adverse events were mainly mild, expected, and transient (including short-lived elevations in blood pressure/heart rate). In addition, this study observed concurrent changes in measures of putative psychological processes hypothesized to be modified during MDMA-AT. The results add to the growing evidence base for MDMA-AT across psychiatric conditions and provide evidence of preliminary estimate of clinical response, feasibility, and safety to support future trials. Further research is warranted to replicate these findings, evaluate long-term outcomes, examine the processes of change underlying MDMA-AT, and determine the safety and effectiveness of MDMA-AT in more diverse and comorbid clinical populations. mailto:jbluoma@portlandpsychotherapy.comAcknowledgments: We would like to thank Hailey Gilmore and Vignesh Ravichandran for their ongoing support throughout the project the raters, interviewers, and study assistants who made this study possible. Finally, we'd like to acknowledge Oregon Research Institute Community and Evaluation Services for their organizational support. Jason Luoma had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. editing purposes. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the published article.