Using a health state-transition model, midomafetamine-assisted therapy for chronic, moderate-or-higher PTSD produced a 0.377 QALY gain over five years at an incremental cost of $31,613, yielding an ICER of $83,845 per QALY. These results indicate MDMA-AT is likely cost-effective versus placebo with therapy at a $150,000 willingness-to-pay threshold (assuming a $12,000 per-session drug price).
Objective
To explore the cost-effectiveness of midomafetamine-assisted therapy (MDMA-AT) compared to placebo with therapy (PT) in US healthcare settings.
Methods
A health state-transition model was used to analyze the cost-effectiveness of MDMA-AT for treating patients with chronic PTSD of moderate or higher severity. Both treatment arms consisted of 3 preparation (90-min), 3 interventional (8-h), and 9 integration (90-min) sessions, lasting ~4 months total. All sessions included psychotherapy, with interventional also including MDMA or placebo. After receiving treatment, patients were distributed across health states of No PTSD (not meeting PTSD diagnostic criteria), Non-Severe PTSD (treatment responders), Severe PTSD (treatment non-responders), and death. Each state had unique healthcare costs and utilities sourced from real-world data analysis and patient data from MDMA-AT clinical trials (including long-term follow-up). The base-case analysis considered the payer’s perspective with a 5-year horizon, 3.5% annual cost and effect discounts, and an assumed MDMA medication price of $12,000 per session. Trial-derived utilities and US life tables mortality data were used to calculate quality-adjusted life years (QALY). The main outcome was an incremental cost-effectiveness ratio (ICER) with a $150,000 willingness-to-pay (WTP) threshold.
Results
The base-case ICER was $83,845 per QALY. Total direct costs were $64,745 in the MDMA-AT and $33,132 in the PT arms ($31,613 increment). The costs of intervention were $48,376 for MDMA-AT and $12,376 for PT. The highest MDMA medication cost to fit under the WTP threshold was $20,314 per session. Costs related to PTSD healthcare visits and other PTSD treatments were lower with MDMA-AT than PT (-$2,511 and -$1,877 increments, respectively). Utility benefits were higher in MDMA-AT than PT, with 3.691 and 3.314 QALYs generated over 5 years, respectively (0.377 QALY increment).
Conclusion
These data suggest MDMA-AT may be a cost-effective treatment compared to PT for patients with chronic PTSD of moderate or higher severity.
Papers cited by this study that are also in Blossom
Wagner, M. T., Mithoefer, M. C., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2017)
Mitchell, J., Ot’alora G, M., van der Kolk, B. et al. · Nature Medicine (2023)
Mitchell, J., Bogenschutz, M. P., Lilienstein, A. et al. · Nature Medicine (2021)
Marseille, E., Mitchell, M. J., Khan, J. G. · PLOS ONE (2022)
PTSD is a common and burdensome psychiatric condition arising after exposure to traumatic events; prevalence estimates in the US reach up to 9.1% among civilians and 50.2% among military personnel. The condition is heterogeneous in onset and course, with certain subgroups (for example, females, those with childhood adversity, comorbid mental illness, low socioeconomic status or poor social support) at higher risk. Chronic PTSD carries substantial clinical comorbidity (depression, anxiety, substance use), increased premature mortality, and a sizeable economic burden: an incremental per-patient cost in the US was estimated at about $19.6k in 2018, higher among military cohorts. Stanicic and colleagues note that existing pharmacotherapies and psychotherapies have important limitations, including need for long-term use, adverse events, treatment discontinuation and substantial non-response. Midomafetamine-assisted therapy (MDMA-AT) combines manually delivered psychotherapy with MDMA sessions and has shown efficacy in Phase III randomized trials versus placebo with therapy. The present study therefore aims to evaluate the cost-effectiveness of MDMA-AT compared to placebo with therapy for adults with chronic PTSD of moderate or higher severity in a US payer context, using trial and real-world economic data to populate a state-transition model.
The investigators developed a health state-transition (Markov-style) economic model and reported according to CHEERS guidance. Model coding and calculations were performed in Microsoft Excel and trial data were analysed with IBM SPSS. Licensed, de-identified individual participant data from two Phase III trials (MAPP1 and MAPP2) and their long-term follow-up study (MPLONG) were used alongside a real-world burden-of-illness (BOI) study to derive inputs for costs, utilities and utilisation. The model population comprised adults with chronic PTSD of moderate or higher severity. The clinical intervention mirrored the trial protocol: three 90-minute preparation psychotherapy sessions, three 8-hour interventional sessions (MDMA or placebo administered with two therapists), and nine 90-minute integration psychotherapy sessions, with interventional sessions spaced about four weeks apart. MDMA dosing was modelled as split doses: 80 mg + 40 mg (120 mg total) in the first session and 120 mg + 60 mg (180 mg total) in sessions two and three. The comparator arm had identical psychotherapy but placebo during the interventional sessions. Health states were No PTSD (loss of DSM-5 diagnosis measured by CAPS-5), Non-severe PTSD (treatment responders who still meet PTSD criteria or patients with moderate PTSD who retain diagnosis), Severe PTSD (non-responders or withdrawals), and death. Treatment response was defined as a ≥10-point decrease in CAPS-5. The structural model time frame was up to 25 years with annual cycles, but the base-case economic horizon reported in the analysis was 5 years. Durability and transition probabilities beyond the 4-month trial endpoint were informed by MPLONG data (mean follow-up 17 months) and extrapolated to 1-year and subsequent cycles using a best-fit (log) approach; where necessary, proportions transitioning were allocated between Non-severe and Severe PTSD states as described. Cost inputs comprised three components: one-time intervention costs (MDMA medication plus therapist time for MDMA-AT, or psychotherapy-only for comparator), ongoing PTSD-related healthcare visit costs (outpatient, inpatient, ED) from the BOI study, and regular PTSD treatments (psychotherapy utilisation from MPLONG, and medication costs from BOI). Unit costs for psychotherapy were scaled from a 90-minute session cost to estimate an 8-hour session cost and adjusted for two therapists per session. Utilities were derived from EQ-5D-5L data collected in MAPP1, MAPP2 and MPLONG and aggregated per health state and arm to produce QALY estimates. Base-case assumptions included a payer perspective, a 5-year horizon, 3.5% annual discounting of costs and utilities, and a willingness-to-pay (WTP) threshold of $150,000 per QALY. Uncertainty was explored with one-way sensitivity analyses (OWSA) varying parameters ±10% and probabilistic sensitivity analysis (PSA) with 5,000 Monte Carlo iterations. A scenario/goal-seek analysis calculated the maximum MDMA medication cost per session consistent with specified WTP thresholds. The primary outcome was the incremental cost-effectiveness ratio (ICER), calculated as incremental cost divided by incremental QALYs between MDMA-AT and placebo with therapy.
In the base-case (payer perspective, 5-year horizon, 3.5% discounting), the ICER for MDMA-AT versus placebo with therapy was $83,845 per QALY, indicating cost-effectiveness at the predefined $150,000 WTP threshold. The per-patient MDMA-AT treatment course cost was $48,376, composed of $36,000 for MDMA medication (assumed $12,000 per MDMA session) and $12,376 for psychotherapy components. The per-session breakdown reported a single MDMA-AT session cost of $16,125 ($12,000 MDMA, $2,357 for the 8-hour psychotherapy component, and $1,768 corresponding to preparation and integration sessions). The comparator intervention cost was $12,376. Total direct PTSD-related costs over 5 years were $64,745 for the MDMA-AT arm versus $33,132 for placebo with therapy, an incremental cost of $31,612 driven largely by the higher intervention cost in the MDMA-AT arm. However, MDMA-AT incurred lower downstream costs: PTSD visit costs were $4,831 versus $7,342 in the comparator, and PTSD treatment expenditures were $11,538 versus $13,414. Utility outcomes favoured MDMA-AT: total QALYs were 3.691 versus 3.314 (increment 0.376 QALY). One-way sensitivity analysis identified utility inputs, particularly the utility assigned to the No PTSD state in the MDMA-AT arm over multiple cycles, as the most influential parameters. For example, decreasing the MDMA-AT utility in the No PTSD category by 10% across cycles 2–25 increased the ICER to $247,773 per QALY, while a 10% increase lowered the ICER to $50,460 per QALY. Varying the same utility only in the first cycle produced ICERs of $101,243 (-10%) and $71,549 (+10%). Probabilistic sensitivity analysis (5,000 iterations) produced mean direct PTSD expenditures of $64,805 (MDMA-AT) and $33,106 (placebo), a mean cost increment of $31,699 (±$5,378) and a mean QALY increment of 0.376 (±0.305), yielding an estimated mean ICER of $84,240 per QALY. MDMA-AT’s ICER was below the $150,000 threshold in 72.12% of PSA iterations. Scenario analysis found that a maximum MDMA medication price of $20,314 per session would yield an ICER of approximately $149,998 per QALY; the corresponding maximums to meet $100,000 and $50,000 WTP thresholds were $14,030 and $7,746 per session, respectively.
Stanicic and colleagues interpret their findings as indicating that MDMA-AT is cost-effective relative to placebo with therapy for adults with chronic PTSD of moderate or higher severity under the base-case assumptions, with an ICER of $83,845 per QALY. They emphasise that model inputs combined individual patient data from two Phase III trials and their long-term follow-up with a real-world BOI analysis to capture intervention costs, downstream healthcare use and quality-of-life changes, aiming to reduce reliance on assumptions used in earlier economic models. The reported MDMA-AT course cost ($48,376) and the QALY gains produced the principal drivers of the favourable ICER. The authors situate their results within prior economic evaluations of MDMA-AT and other PTSD interventions. Earlier models (for example, Marseille et al. and analyses using Phase II data) also suggested MDMA-AT could be cost-effective or dominant over standard care at longer horizons, but those studies used different model structures, smaller samples, more assumptions and limited long-term data. The present study’s use of larger Phase III trial data and BOI inputs is cited as a comparative strength. The investigators also reference broader PTSD economic evaluations which have shown heterogeneity in methods and quality, underscoring the need for rigorous, data-driven economic studies. Key limitations acknowledged include dependence on the quality and generalisability of the BOI study and clinical trial inputs, potential lack of representativeness given sample sizes and heterogeneity of patient characteristics, and the choice of comparator: trials used placebo with therapy rather than an active, real-world standard-of-care comparator. The authors also note the mismatch between the model’s long (25-year) structural horizon and the average MPLONG follow-up of 17 months, which constrains certainty about very long-term outcomes despite reporting a shorter 5-year base-case to improve reliability. Sensitivity analyses showed that quality-of-life (utility) gains were the most influential drivers of ICER estimates, and PSA results were broadly consistent with base-case conclusions. The authors suggest that, given these caveats, MDMA-AT may represent a novel therapeutic option that could reduce disease and economic burden after a single treatment course, while calling for continued data collection to refine long-term estimates.
The study concludes that MDMA-AT was more cost-effective than placebo with therapy for adults with chronic PTSD of moderate or higher severity under the modelled assumptions. Quality-of-life improvements were the inputs with the largest impact on cost-effectiveness, and results were robust across 5,000 probabilistic simulations. The authors suggest MDMA-AT could reduce PTSD-related disease and economic burden following a single course of treatment, while recognising the need for further data to address uncertainties identified in sensitivity analyses and limitations of input sources.
Model development and reporting of findings are aligned with the updated Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. The research is based on the principles of mathematical modeling, published peer-reviewed literature, publicly available US statistics, and de-identified clinical trial data. The study does not require ethics board approval as there are no relevant or potential conflicts with ethical principles in medicine and research. Clinical trial data supporting the study findings were used under license from Lykos Therapeutics and are publicly unavailable. Data access may be granted by the authors upon reasonable request and gained approval from Lykos Therapeutics. Any data that might be shared would be released via a data use agreement. The model development and cost-effectiveness analysis were performed using Microsoft Office Excel1 software (version Office 365). Clinical trial data were analyzed using the IBM SPSS Statistics1 software (version 23.0).
Discount rates of 3.5% per year of modeling were applied to cost and utility inputs. The predefined willingness-to-pay (WTP) threshold was $150,000. ICER was the main study outcome, calculated as the ratio of healthcare costs increment and quality-adjusted life years (QALY) increment between MDMA-AT and psychotherapy.
This cost-effectiveness analysis estimated the healthcare costs per QALY in patients with chronic PTSD of moderate or higher severity, comparing MDMA-AT and placebo with therapy. Model inputs were based on data from three clinical trials (two phase III and one longterm follow-up), a real-world economic BOI analysis, and treatment patterns in modern clinical practice to minimize assumptions and provide the most accurate price estimate. The analysis yielded a cost of $48,376 for the MDMA-AT treatment course, including three preparation 90-minute sessions ($442 per session), three interventional sessions consisting of MDMA medication administration ($12,000 per session) and 8-hour psychotherapy ($2,357 per session), and nine 90-minute integration psychotherapy sessions ($442 per session). Using these cost estimates, the reported ICER was $83,845 per QALY. This was considered cost-effective as the WTP value in the model was $150,000 per QALY. The threshold was defined by the World Health Organization recommendation stating that the cost-effective boundary should be between one and three times the Gross Domestic Product (GDP) per capita. The World Bank data for 2022 reported $76,329.58 GDP per capita for the US, yielding a cost-effective threshold range between $76,330 and $228,989 per QALY, which corresponds to the MDMA medication cost of $11,056 to$30,242 per session. However, the authors used a median value (approximately $150,000) to have a fair comparison and considered it relevant for the modern US healthcare system. Regarding sensitivity analyses, univariate OWSA (10% parameter variation) identified utility changes due to MDMA-AT treatment as the most impactful parameter on study findings. The results were also consistent with 5,000 simulations in PSA. The ICER was lower than the WTP threshold in 72.12% of iterations. There are several published cost-effectiveness analyses including MDMA-AT for PTSD treatment. The most recent was published in 2022 by Marseille et al., including phase III clinical trial findings. Although the model had a different design than this study and was based on the Markov principles, it also demonstrated the cost-effectiveness of MDMA-AT over the standard of care comparator with ICER of $47,554 per QALY at 1-year follow-up. In addition, standard of care was dominated by MDMA-AT at 10-and 30-year periods after receiving the intervention. The cost of full-course MDMA-AT treatment was $11,537 per patient. However, the Marseille et al. model was based on multiple assumptions due to a lack of real-world economic and treatment patterns data. The authors used only MAPP1 clinical trial data as MAPP2 and MPLONG trials were not available at the time. Therefore, the Marseille et al. model was developed for patients with chronic severe PTSD, excluding those with moderate disease severity. Also, the long-term follow-up estimate may not be reliable since the phase III trial followed patients for only 4 months, and the model horizon covered a 30-year period after MDMA-AT administration. Another Marseille et al. economic model with an identical design used the findings of six phase 2 clinical trials in which MDMA-AT showed superiority to the standard of care arm among chronic, severe, treatment-resistant PTSD patients. MDMA-AT was cost-effective at 1-year endpoint (ICER $26,427 per QALY) and dominated standard of care at 10-and 30-year periods. The estimated price of two MDMA-AT (which included two interventional sessions) was $7,543 per patient. However, the model was based on small sample trials in patients with severe and treatment-resistant PTSD. Although the findings from a long-term assessment of phase II trials completers were incorporated in the model (mean follow-up 45.4 months), it included only 19 patients, which significantly limited the generalizability of results on 1,000 patients for the 30-year period. Unlike the previous MDMA-AT health economic models, the inputs in this study were purely based on the real-world evidence and data of two phase III clinical trials, including a long-term observation of a larger sample of participants, to provide the best possible estimate. Despite the model covering 25-year period, primary findings presented benefits for a shorter time horizon (5 years), ensuring a higher level of reliability since the average length of follow-up in MPLONG from the parent trial baseline was 17 months. In addition, the long-term phase II clinical trial conducted by Mithoefer et al. demonstrated sustainable effects of MDMA-AT during an average of 3.8-year follow-up period, without significant changes in CAPS scores compared to baseline. Mavranezouli et al. performed a network meta-analysis using available literature sources, supplemented by expert opinion, to populate a health economic model that compared 10 PTSD interventions with no treatment from the UK healthcare setting perspective. The authors pointed out substantial between-study heterogeneity, mainly originating from the differences in PTSD patient characteristics and included interventions, which significantly affect the reliability of the findings. The results imply that Eye Movement Desensitization and Reprocessing (EMDR) was the most cost-effective PTSD intervention, with a 1.8 QALY increment and £33,928 net monetary benefit (NMB) per patient. EMDR was followed by combined somatic/cognitive therapies (£33,364 NMB), self-help with support (£32,880 NMB), and psychoeducation (£32,754 NMB). The most cost-effective medication treatment compared to no treatment was the use of a selective serotonin reuptake inhibitor (SSRI) with an NMB of £32,316. A systematic literature review by von der Warth et al. captured all economic evaluations of PTSD patients published until February 2020 regardless of the sample population, traumatic experience, or intervention type. The findings denoted that most published studies were lowto-moderate quality, lacked relevant reported information, and had inappropriate designs. Trauma-focused cognitive-behavioral therapy (TF-CBT) was the most assessed treatment with an ICER of $13,162 per QALY gained compared to usual treatment and $39,366 per additional PTSD remission compared to breathing retraining and psychoeducation comparator. Authors identified the need for accurate and comprehensive economic evaluations of PTSD interventions. Hence, our study addresses this unmet need in the published literature by providing precise estimates of PTSD economic burden and extensive reporting of model findings. The health economic analyses of medications in PTSD are lacking in the published literature, with limited studies that evaluate cost-effectiveness of pharmacological treatments for PTSD. Mihalopoulos et al.compared SSRIs and trauma-focused CBT to standard treatment practice for adults with PTSD in the Australian healthcare setting. The median ICER for trauma-focused CBT was $19,000 per QALY, with 100% uncertainty iterations falling beneath a $50,000 per QALY threshold. SSRIs showed a much lower ICER of only $200 per QALY, most likely due to a very low price, but the results were highly uncertain. Another costeffectiveness analysis by Le et al.compared prolonged exposure psychotherapy to sertraline in a double-randomized treatment preference trial. Prolonged exposure psychotherapy was dominant to sertraline treatment with lower healthcare costs (-$262) and more QALY gained (0.056). The probability of cost-effectiveness with a $100,000 per QALY threshold was 93.2%.
Create a free account to open full-text PDFs.
Marseille, E., Kahn, J. G., Yazar-Klosinski, B. et al. · PLOS ONE (2020)
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T. et al. · Journal of Psychopharmacology (2012)
Papers in Blossom that reference this study
Marseille, E., Chernoloz, O., Orlov, |. O. · World Medical & Health Policy (2025)