In a multicentre, double‑blind, placebo‑controlled phase 2 trial of 65 adults with chronic PTSD, once‑weekly oral TSND‑201 produced significantly greater reductions in clinician‑rated PTSD severity (CAPS‑5; LS mean difference 9.64, P = .01) and improvements in self‑reported symptoms, functioning and depression versus placebo. TSND‑201 was generally well tolerated — common adverse events included headache, decreased appetite, nausea, dizziness and transient blood‑pressure increases — supporting its potential as a rapid‑acting, durable treatment for PTSD.
Papers cited by this study that are also in Blossom
Mitchell, J., Bogenschutz, M. P., Lilienstein, A. et al. · Nature Medicine (2021)
Importance
The phase 2 data presented here support the development of TSND-201 for posttraumatic stress disorder (PTSD), a disorder for which there is a significant unmet need for rapid-acting and effective treatments. TSND-201 (methylone) is a highly selective, rapid-acting neuroplastogen that releases serotonin, norepinephrine, and dopamine without direct activity at 5-hydroxytryptamine (5-HT) 2A receptors that has shown rapid, robust, and long-lasting benefit for preclinical PTSD-related behaviors and has been well tolerated in phase 1 studies of healthy volunteers.
Objective
To evaluate the efficacy and safety of TSND-201 vs placebo in adults with PTSD.
Design, Setting, Participants
A Study to Assess the Use of Methylone in the Treatment of PTSD (IMPACT-1) part B was a phase 2, multicenter, double-blind, placebo-controlled, 10-week randomized clinical trial of TSND-201 in people with PTSD conducted between November 29, 2023, and February 19, 2025, across 16 sites in the US, UK, and Ireland. Adults aged 18 to 65 years who met DSM-5 criteria for current PTSD and 6 months or more of symptoms (Clinician-Administered PTSD Scales for DSM-5 [CAPS-5] ≥35) were eligible.
Interventions
Participants were randomized 1:1 to receive TSND-201 or placebo. There were 4 once-weekly oral dosing sessions (150 mg followed by 100 mg or placebo). No psychotherapy was provided; however, dosing sessions were monitored by mental health professionals using a nondirective approach. Participants were followed up for 6 weeks after the last dose.
Main Outcomes and Measures
The primary end point was change from baseline to day 64 in the CAPS-5 total severity score. Secondary end points included changes in PTSD Checklist for DSM-5 (PCL-5), Sheehan Disability Scale (SDS), and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Other measures included response (≥50% improvement from baseline), remission (≤11 total severity score), loss of PTSD diagnosis, changes in CAPS-5 symptom clusters, and incidence of treatment-emergent adverse events (TEAEs). Safety was assessed by monitoring adverse events, vital signs, and Columbia-Suicide Severity Rating Scale.
Results
Among the 65 participants (mean [SD] age, 43.7 [10.5] years; 39 female [60.0%]), TSND-201 demonstrated significantly greater improvement in CAPS-5 total score than placebo (least-squares mean difference, 9.64; 90% CI, −16.48 to −2.80; P = .01). PCL-5 (−28.46 vs −19.47; LS mean treatment difference, −8.99; 90% CI, −17.81 to −0.17), SDS (−8.29 vs −3.57; LS mean treatment difference, −4.72; 90% CI, −8.84 to −0.61), and MADRS (−13.94 vs −7.73; LS mean treatment difference, −6.21; 90% CI, −12.41 to −0.27) scores were also improved. Common TEAEs in the TSND-201 group included headache, decreased appetite, nausea, dizziness, blood pressure increased, dry mouth, insomnia.
Conclusions and Relevance
Results of this randomized clinical trial reveal that TSND-201 demonstrated statistically significant efficacy and was well tolerated, supporting its potential as a rapid-acting, durable treatment for PTSD.
A. and colleagues frame posttraumatic stress disorder (PTSD) as a common, debilitating condition with limited pharmacological options: only paroxetine and sertraline are FDA‑approved and both have delayed onset and limited effectiveness. There is an urgent need for rapid‑acting, durable treatments with acceptable safety profiles. The authors describe TSND‑201 (methylone) as a β‑ketone analogue of MDMA that functions as a selective, rapid‑acting “neuroplastogen” that promotes neuroplasticity by releasing serotonin, norepinephrine, and dopamine, but without direct 5‑HT2A receptor activity and without hallucinogenic effects in preclinical and early clinical work. This phase 2 study (IMPACT‑1, part B) was designed to test whether intermittent, once‑weekly oral dosing of TSND‑201 produces clinically meaningful and durable reductions in PTSD symptoms compared with placebo in adults meeting DSM‑5 criteria for PTSD. The authors set out to evaluate efficacy on clinician‑rated PTSD severity (CAPS‑5) as the primary outcome, alongside secondary measures of self‑reported PTSD symptoms, functioning, and depressive symptoms, and to characterise safety and tolerability.
IMPACT‑1 part B was a multicentre, phase 2, double‑blind, randomised, placebo‑controlled trial conducted at 16 sites across the US, UK and Ireland between November 2023 and February 2025. Eligible adults were 18–65 years old, met DSM‑5 criteria for current PTSD with a duration of at least 6 months, and had CAPS‑5 total scores ≥35 at screening and ≥28 at baseline. Participants were required to have previously tried at least one PTSD treatment. Key exclusions included a primary other DSM‑5 disorder, concurrent PTSD pharmacotherapy or psychotherapy, recent moderate/severe substance use disorder, recent suicidal behaviour, and psychedelic use within 12 months. Participants were randomised 1:1 (block size 4, no stratification) to TSND‑201 or matched placebo. The dosing regimen consisted of four once‑weekly oral sessions (days 1, 8, 15 and 22), each with an initial 150 mg dose followed 90 minutes later by a 100 mg booster (or matched placebo), administered under fasting constraints around dosing. No formal psychotherapy was provided; dosing sessions were monitored by graduate‑level clinicians using a nondirective approach. Each dosing session lasted at least 8 hours. Follow‑up efficacy and safety visits occurred through day 64 (week 10), i.e. 6 weeks after the last dose. The primary endpoint was change in CAPS‑5 total severity score from baseline to day 64 using the past‑week CAPS‑5 at on‑study visits. Secondary endpoints included change in PCL‑5, Sheehan Disability Scale (SDS) and Montgomery‑Åsberg Depression Rating Scale (MADRS). Additional outcomes were response (≥50% CAPS‑5 improvement), remission (CAPS‑5 ≤11), loss of PTSD diagnosis, and cluster‑level CAPS‑5 changes. Safety assessments covered treatment‑emergent adverse events (TEAEs), vital signs, ECG and C‑SSRS for suicidality. Efficacy analyses used a modified intention‑to‑treat (mITT) population (all randomised participants who received ≥1 dose and had ≥1 postbaseline assessment). The primary analysis applied a mixed model for repeated measures (MMRM) with treatment, visit and treatment×visit as fixed effects, baseline value and sex as covariates, and visit as the repeated effect. No additional imputation for missing data was performed. The study was sized to enrol approximately 64 participants to provide ~90% power to detect an ~11‑point between‑group difference on CAPS‑5, assuming a pooled SD of 12 and allowing for dropout. The statistical plan used one‑sided testing at α = .05 and reported two‑sided 90% confidence intervals as prespecified.
A Study to Assess the Use of Methylone in the Treatment of PTSD (IMPACT-1) trial was a 2-part multicenter study to assess TSND-201 for the management of symptoms of PTSD. The trial protocol and statistical analysis plan are available in Supplement 1 and Supplement 2, respectively. Part A was an open-label, noncontrolled assessment of TSND-201 to assess the safety and feasibility of TSND-201 before initiation of the placebo-controlled portion (part B). Part A results have been previously reported(eTable 1 and 2 and eFigure 1 and 2 in Supplement 3) and are included in the eAppendix in Supplement 3. Here, we present the results of part B, a double-blind, placebo-controlled randomized clinical study conducted between November 29, 2023, and February 19, 2025, at 16 sites across the US, UK, and Ireland. The trial was conducted in accordance with the International Council of Harmonisation guidelines for Good Clinical Practice, and relevant regulations in the countries where the research was conducted. The trial protocol and written informed consent were reviewed and approved by relevant ethics committee or institutional review board for each country. Results are consistent with the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Eligible participants were adults aged 18 to 65 years who met the DSM-5 criteria for current PTSD with at least 6 months of symptoms at screening assessed by the Clinician-Administered PTSD Scales for DSM-5 (CAPS-5).A CAPS-5 total score of 35 or greater at screening and 28 or greater at baseline was required. All participants must have tried at least 1 treatment for PTSD (eg, pharmacotherapy or psychotherapy). Participants self-reported race and ethnicity information, which included African American or Black, Asian, White, and other (ie, race not reported). Participant race and ethnicity information was collected per US Food and Drug Administration requirement. Key exclusion criteria were a primary diagnosis of any other DSM-5 disorder; concurrent use of antidepressants or other PTSD treatments including psychotherapy, antipsychotics, lithium, or other mood stabilizers; moderate or severe substance/alcohol use disorder (moderate alcohol use disorder in early remission was allowed); active suicidal ideation within 2 months of screening or any history of suicidal behavior within the last 5 years assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS); and use of a psychedelic within 12 months of screening. The current study had broad PTSD criteria, including complex PTSD without restrictions on age of trauma, duration since trauma, or trauma type (combat trauma was allowed). Full eligibility criteria are provided in the protocol in Supplement 1.
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Mitchell, J., Ot’alora G, M., van der Kolk, B. et al. · Nature Medicine (2023)
Poyatos, L., Lo Faro, A., Sprega, G. et al. · International Journal of Molecular Sciences (2022)
Poyatos, L., Pérez-Mañá, C., Hladun, O. et al. · Frontiers in Pharmacology (2023)
Schmidt, E. F., Warner-Schmidt, J., Stogniew, M. et al. · Frontiers in Neuroscience (2024)
Warner-Schmidt, J., Pittenger, C., Stogniew, M. et al. · Frontiers in Psychiatry (2023)
Heifets, B. D., Olson, D. E. · Neuropsychopharmacology (2023)
Krystal, J. H., Abdallah, C. G., Averill, L. A. et al. · Current Psychiatry Reports (2017)
Papers in Blossom that reference this study
Vargas, M. V., Hatzipantelis, C. J., Dunlap, L. E. et al. · ACS Chemical Neuroscience (2026)
Ramaekers, J. G., Kuypers, K. P. C., Vollenweider, F. X. · Molecular Psychiatry (2026)
Of 175 screened participants, 65 were randomised (TSND‑201 n = 32; placebo n = 33). The safety population comprised all 65; the mITT population included 60 participants (TSND‑201 n = 30; placebo n = 30) after accounting for early terminations (six participants). Mean (SD) age was 43.7 (10.5) years; 60.0% were female. Racial composition was predominantly White (58 of 65; 89.2%). Baseline mean CAPS‑5 total scores were similar between groups (45.8 for TSND‑201, 46.0 for placebo). Primary outcome: TSND‑201 produced a statistically significant greater improvement in CAPS‑5 total score from baseline to day 64 compared with placebo. The reported least‑squares mean difference was 9.64 with a 90% CI of -16.48 to -2.80 and P = .01 (as presented by the authors). Secondary and additional outcomes: TSND‑201 showed larger reductions than placebo on the PCL‑5 (mean change -28.46 vs -19.47; LS mean treatment difference -8.99; 90% CI -17.81 to -0.17), on functioning measured by SDS (-8.29 vs -3.57; LS mean difference -4.72; 90% CI -8.84 to -0.61), and on depressive symptoms among participants with baseline MADRS >20 (-13.94 vs -7.73; LS mean difference -6.21; 90% CI -12.41 to -0.27). Across the four CAPS‑5 symptom clusters (intrusion, avoidance, negative alterations in cognitions/mood, arousal/reactivity), TSND‑201 demonstrated improvements over placebo. Binary outcomes at day 64 favoured TSND‑201: response rates (≥50% CAPS‑5 improvement) were 57.1% vs 19.2% (treatment difference 37.9%; 90% CI 18.0%–57.9%; NNT = 3); remission rates (CAPS‑5 ≤11) were 32.1% vs 11.5% (treatment difference 20.6%; 90% CI 2.8%–38.4%; NNT = 5); and loss of PTSD diagnosis occurred in 60.7% vs 30.8% (treatment difference 29.9%; 90% CI 8.7%–51.2%; NNT = 3). Safety and tolerability: TEAEs were common but mostly mild or moderate and transient, typically occurring on the day of dosing and resolving shortly thereafter. All participants in the TSND‑201 group reported ≥1 TEAE compared with 72.7% in the placebo group. TEAEs occurring in ≥20% of TSND‑201 recipients included headache, decreased appetite, nausea, dizziness, increased blood pressure, dry mouth and insomnia. There were no study discontinuations due to TEAEs and no clear trends in suicidal ideation or behaviour. One severe event of suicidal ideation occurred in a TSND‑201 participant 6 days after the last dose and was considered unrelated. One serious adverse event—a brief seizure during a blood draw 7 days after the last dose—was reported in the TSND‑201 group; the investigator judged it unrelated based on prior history and timing relative to dosing. Blinding: 70% of TSND‑201 recipients correctly guessed they had active drug; 53.3% of placebo recipients correctly guessed placebo.
A. and colleagues interpret the phase 2 IMPACT‑1 findings as evidence that intermittent, once‑weekly dosing of TSND‑201 produced statistically significant and clinically meaningful reductions in PTSD symptom severity that persisted for at least 6 weeks after the final dose. The authors note concordant improvements on self‑reported PTSD symptoms, functioning and depressive symptoms, and argue the durability of effect despite a short (~6‑hour) half‑life is consistent with TSND‑201’s action as a rapid‑acting neuroplastogen that promotes synaptic plasticity, neurite outgrowth and neurotrophin expression, potentially yielding lasting circuit changes relevant to PTSD. Safety was described as acceptable: adverse events were generally mild or moderate, transient and resolved quickly with no discontinuations for adverse events. The authors emphasise that TSND‑201 lacks direct 5‑HT2A receptor activity and did not produce subjective hallucinogenic effects in earlier work, distinguishing it from classic psychedelics and from MDMA, with which it shares structural similarity but differs pharmacologically. The authors acknowledge several limitations. The trial included relatively few participants with military trauma, limiting generalisability to that population. High screening failure rates may also limit external validity. The study used one‑sided statistical testing as prespecified for this small phase 2 trial, although the authors state that primary and additional endpoints remain significant under two‑sided testing. The modest sample size precluded definitive analyses of predictors of response (for example, trauma type or age at trauma), which they plan to explore in larger future studies. The authors also note that blinding was imperfect, with a sizeable proportion of participants correctly identifying their treatment, a common issue in trials of psychoactive agents.
The extracted Conclusion is truncated in the provided text, but the authors conclude that intermittent treatment with TSND‑201 (four once‑weekly doses) was generally well tolerated and safe and was associated with statistically significant, clinically meaningful improvements in PTSD symptoms that persisted beyond the dosing period, supporting further development of TSND‑201 for PTSD.
Question Is the neuroplastogen TSND-201 (methylone) efficacious and well tolerated in people with posttraumatic stress disorder (PTSD)? Findings In this phase 2, double-blind, placebo-controlled randomized clinical trial in 65 people with severe PTSD, acute intermittent treatment with TSND-201 was associated with a statistically significant and clinically meaningful reduction in PTSD symptoms, measured by Clinician-Administered PTSD Scales for DSM-5 scores, compared with placebo. TSND-201 was generally safe and well tolerated; adverse events were typically transient, occurring on the day of dosing and resolving within a day. Meaning Study results demonstrate that TSND-201 has rapid, robust, and durable efficacy and is well tolerated in people with PTSD, supporting its further development as a treatment for PTSD. Eligible participants were randomized to receive either TSND-201 or placebo using an interactive web response system. The 1:1 randomization used a 4-block size without stratification by any covariates. TSND-201 (or matched placebo) was dosed orally as an initial administration of 150 mg (3 capsules), followed by a booster administration of 100 mg (2 capsules) 90 minutes later. TSND-201 and placebo capsules were identical. Because effects of methylone on blood pressure, for example, appear to track closely with its peak plasma concentrations (Cmax),a split or booster dose strategy was used to optimize efficacy while reducing Cmax and potential adverse effects. Doses were administered on days 1, 8, 15, and 22. Participants fasted for 2 hours before the initial dose and 2 hours after the booster dose. After treatment, participants entered a 6-week follow-up period. All participants, trial site personnel, central raters conducting efficacy assessments, and the sponsor were blinded to treatment assignment.
Following a screening period up to 28 days, eligible participants met with their dosing session monitor during a predosing visit to establish rapport and clarify any questions they may have about the dosing sessions. Each dosing session lasted at least 8 hours or until all study drug effects subsided. Participants attended a total of 4 dosing sessions, each separated by 1 week. During the dosing session, dosing session monitors monitored participants via a nondirective approach (ie, attending silently, letting participants talk or responding with simple utterances or minimal open-ended questions, rather than engaging in directive, structured psychotherapy). Dosing session monitors had graduate-level professional training, with clinical experience in psychotherapy, and were licensed to practice independently. The sponsor oversaw the monitors, including reviewing session videos (with participant consent) to ensure adherence to the nondirective approach. Monitors received regular supervision from trainers to support compliance with this approach. Efficacy assessments occurred 2 days after each dosing session. After the treatment period, follow-up efficacy and safety visits were conducted on days 29, 36, 43, 57, and 64 (end of study).
The primary end point was the mean change in CAPS-5 total score from baseline to day 64 (week 10) compared with placebo. The CAPS-5 is a validated structured interview used to assess PTSD diagnostic status and track symptom severity over time.The total score is calculated by summing severity scores for 20 DSM-5 PTSD-symptom items that are scored from 0 (absent) to 4 (extreme), whereas symptom cluster scores are calculated by summing individual-item severity scores for symptoms in a given cluster (criterion B [intrusion]: items 1-5; criterion C [avoidance]: items 6-7; criterion D [negative alterations in cognitions and mood]: items 8-14; criterion E [arousal and reactivity]: items 15-20). The CAPS-5 total score ranges from 0 to 80 points, with higher scores indicating greater PTSD symptom severity. The past-month version of the CAPS-5 was completed at screening, and the past-week version was used at all other visits. Additional end points related to the CAPS-5 were the percentage of participants with a treatment response (≥50% improvement from baseline on CAPS-5 total severity score), remission (a score of ≤11 on the CAPS-5 total severity score),and loss of PTSD diagnosis. Secondary end points included mean changes in PTSD Checklist for DSM-5 (PCL-5) score, Sheehan Disability Scale (SDS) mean domain score, and Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to end of study.
Adverse events (AEs) were collected from randomization until the end of study. Treatment-emergent AEs (TEAEs) were defined as any AE that occurred after the first administration of study drug and not more than 7 days after the last dose unless suspected to be related to study drug. Safety assessments included TEAEs, vital signs, electrocardiogram, and the C-SSRS to monitor suicidal ideation and behavior.
After completion of all 4 treatment visits (day 28), participants were asked to guess which treatment they received. Then, they selected a number from 0 to 10 corresponding to their confidence in that choice (0 = strong belief they received placebo; 10 = strong belief they received active drug). Scores of 0 to 3 were categorized as "likely received placebo," scores of 4 to 7 were categorized as "unsure which treatment received," and scores of 8 to 10 were categorized as "likely received active treatment."
A sample size of 64 participants was estimated to provide approximately 90% power to detect a between-treatment effect of approximately 11 points on the CAPS-5 with a pooled standard deviation of 12 points, anticipating an approximate 15% dropout rate, at a 2-sided significance test of .05. These assumptions were based on the phase 3 trial of MDMA for PTSD.All efficacy analyses were performed using the modified intention-to-treat (mITT) population defined as all randomized participants who received at least 1 dose of study drug and had at least 1 valid postbaseline assessment. The primary efficacy end point, past-week CAPS-5 total severity score change from baseline to day 64 compared with placebo, was estimated using a mixed model for repeated measures (MMRM) with SAS software, version 9.4 (SAS Institute). There was no additional statistical imputation for missing data. The MMRM model included treatment, visit, and treatment by visit interaction as fixed effects with visit as the repeated effect. The end points baseline value and sex were covariates. Least-squares (LS) mean change from baseline, SE, and the LS mean difference between TSND-201 and placebo at end of study and 90% CI were calculated. For the additional end point analyses, the percentage of participants meeting the predefined criteria was calculated and summarized by group. The between-group comparisons were calculated using the Cochran-Mantel-Haenszel test. All statistical tests were based on a 1-sided significance level of .05, and therefore, 2-sided 90% CI were calculated, as specified in the statistical analysis plan (Supplement 2), and finalized before unblinding of the study data. Safety assessments were analyzed using the safety population, which included all participants who received at least 1 administration of study drug. The number of participants experiencing TEAEs and SAEs was summarized by treatment group.
A total of 175 participants were screened, and 65 (mean [SD] age, 43.7 [10.5] years; 39 female [60.0%]; 26 male [40.0%]) were randomized to receive TSND-201 (n = 32) or placebo (n = 33) (Figure). Participants self-reported the following races and ethnicities: 2 African American or Black (3.1%), 2 Asian (3.1%), 58 White (89.2%), and 3 other race and ethnicity (4.6%). Dosing compliance remained high (>80%) in both groups for all dosing sessions. The safety population included all 65 participants, and the mITT population included 60 participants (TSND-201, n = 30; placebo, n = 30). Six participants from the safety population terminated from the trial early (TSND-201, n = 2; placebo, n = 4), with the most common reasons being withdrawal of consent followed by protocol deviation and loss to follow-up. Baseline demographics and characteristics were similar between groups (Table). The mean (SD) baseline CAPS-5 total scores were 45.8 (7.11) and 46.0 (5.42) in the TSND-201 and placebo groups, respectively.).
Across each of the 4 CAPS-5 symptom clusters, TSND-201 demonstrated meaningful improvements over placebo for criterion B (intrusion) (Figure), criterion C (avoidance) (Figure), criterion D (negative alterations in cognitions and mood) (Figure), and criterion E (arousal and reactivity) (Figure)). TSND-201 treatment resulted in more patients achieving a treatment response (≥50% improvement from baseline on CAPS-5) at day 64 than placebo (57.1% vs 19.2%; treatment difference, 37.9%; 90% CI, 18.0%-57.9%; number needed to treat [NNT] = 3). Remission rates (total score ≤11 on the CAPS-5) at the end of study were greater after treatment with TSND-201 compared with placebo (32.1% vs 11.5%; treatment difference, 20.6%; 90% CI, 2.8%-38.4%; NNT = 5). At the end of study, PTSD diagnostic status was lost in a greater number of TSND-201-treated participants compared with placebo (60.7% vs 30.8%; treatment difference, 29.9%; 90% CI, 8.7%-51.2%; NNT = 3). Secondary end point analyses revealed that at the end of study, TSND-201 showed a reduction in patient-reported PTSD symptoms on the PCL-5 (-28.46 vs -19.47; LS mean treatment difference, -8.99; 90% CI, -17.81 to -0.17), an improvement in functioning based on the SDS total score (-8.29 vs -3.57; LS mean treatment difference, -4.72; 90% CI, -8.84 to -0.61), and an improvement in depressive symptoms for patients with significant depression symptoms at baseline (MADRS >20; n = 27 and n = 28 for TSND-201 and placebo, respectively) on the MADRS (-13.94 vs -7.73; LS mean treatment difference, -6.21; 90% CI, -12.41 to -0.27).
TEAEs were generally mild or moderate. All participants in the TSND-201 group reported at least 1 TEAE, compared with 24 (72.7%) in the placebo group (Table). TEAEs were transient, with most occurring on the day of dosing and resolving shortly thereafter. The most commonly reported TEAEs occurring in at least 20% of participants administered TSND-201 were headache, decreased appetite, nausea, dizziness, increased blood pressure, dry mouth, and insomnia. There were no significant trends of suicidal ideation or behavior in either treatment group. One unrelated severe AE of suicidal ideation in a participant treated with TSND-201 occurred 6 days after the last dose during follow-up stemming from an isolated family incident. On the C-SSRS, there were no cases of suicidal behavior in either treatment arm and only 1 ideation score of 4 (active ideation with some intent to act without a specific plan) in the placebo arm. There was 1 serious AE of seizure reported within the TSND-201 group, which occurred 7 days after the last dose. The event lasted a few seconds, occurring during a blood draw, and the participant quickly recovered. After the event, she reported experiencing a similar event a few years prior. Based on the participant's prior history and time since the last dose (>25 halflives), the event was considered by the investigator as unrelated to the study drug.
When indicating how likely participants thought they received TSND-201 or placebo, 16 patients (53.3%) who received placebo correctly guessed that they likely received placebo, and 21 participants (70%) who received TSND-201 correctly guessed that they likely received active treatment.
In the phase 2 IMPACT-1 trial of TSND-201 in individuals with PTSD, TSND-201 was associated with a statistically significant, clinically meaningful 9.64-point greater TSND-201 was generally safe and well tolerated with an AE profile consistent with a neuroplastogen with mild stimulant properties and without hallucinogenic effects more typical of psychedelics. Nearly all participants had at least 1 TEAE (100% or 73% in the TSND-201 and placebo groups, respectively), and there were no study discontinuations due to TEAEs. The most common TEAEs in the TSND-201 group were mild or moderate in intensity, occurred on the day of dosing, and resolved within a day. Improvements on secondary end points (ie, patientreported PTSD symptoms [PCL-5], functioning [SDS], and depression [MADRS]) were observed with TSND-201 treatment, demonstrating consistent therapeutic benefit across multiple domains typically affected by PTSD. Despite its short (approximately 6 hours) half-life,weekly dosing with TSND-201 produced clinical effects lasting 6 weeks after the final dose. This durability may be due to its activity as a rapid-acting neuroplastogen, which promotes synaptic plastic ity, neurite outgrow th, and neurotrophin expression-processes disrupted by PTSD.Rapid and durable effects on neuroplasticity mechanisms may account for its prolonged efficacy and distinguishes TSND-201 from traditional antidepressants that require continuous daily dosing. Although structurally related to MDMA, TSND-201 has distinct pharmacological and subjective effects 7-10 likely due to greater selectivity for the monoamine transporters.Unlike MDMA, which is used as an adjunct to psychotherapy,there was no psychotherapy accompanying TSND-201 treatment in the current trial-raising the question of how such a brief, intermittent dosing regimen yields durable outcomes. One explanation is that TSND-201-induced neuroplasticity,a mechanism that underlies the activity of classic antidepressants and rapid-acting treatments in development,drives rapid and lasting changes in the brain circuitry that is affected by PTSD.
In the IMPACT-1 trial, there were a limited number of individuals with military trauma, a cohort that shows high rates of PTSDand typically shows poorer treatment outcomes compared with civilians.The generalizability of the results may also be limited by the high rate of screening failures. Also, for statistical analyses, a 1-sided P value was used due to this being a small phase 2 study; however, statistical significance is maintained for the primary (and additional) end points when a 2-sided test is applied. Finally, due to the sample size, it was not possible to draw definitive conclusions regarding predictors of responsiveness that have been considered in prior studies (eg, type of trauma, age at which trauma occurred, single vs multiple trauma, etc). This will be examined more closely in future, larger studies of TSND-201. Blinding questionnaires are becoming more common in clinical trials involving psychoactive medications. Our results suggest that 70% of participants were able to correctly guess that they received active treatment. This proportion of participants is similar to a recent meta-analysis of antidepressants, which reported between 45% and 71% of participants correctly guessed their treatment.
In the IMPACT-1 randomized clinical trial including adults with severe PTSD, intermittent treatment with TSND-201 (4 doses, 1 week apart) was generally well tolerated, safe, and associated with statistically significant and clinically meaningful improvements in PTSD symptoms that persisted well beyond the