Highlights
TSND-201 (methylone) demonstrated a statistically significant reduction in CAPS-5 total severity scores compared to placebo at day 64 (p = .01).
Significant improvements were observed across secondary endpoints, including the PTSD Checklist for DSM-5 (PCL-5), Sheehan Disability Scale (SDS), and Montgomery-Åsberg Depression Rating Scale (MADRS).
The intervention utilized a once-weekly dosing schedule over four weeks without concurrent psychotherapy, suggesting a standalone pharmacological benefit.
TSND-201 was generally well tolerated, with transient treatment-emergent adverse events such as headache, nausea, and mild blood pressure increases.
The Unmet Need in PTSD Treatment
Posttraumatic stress disorder (PTSD) remains one of the most challenging psychiatric conditions to treat, characterized by intrusive memories, avoidance behavior, negative alterations in cognition and mood, and marked hyperarousal. Current standard-of-care treatments, primarily selective serotonin reuptake inhibitors (SSRIs) like sertraline and paroxetine, often require weeks or months to show efficacy and frequently result in incomplete remission. Furthermore, evidence-based psychotherapies, while effective, suffer from high dropout rates and limited accessibility. There is a critical clinical demand for rapid-acting, durable, and well-tolerated pharmacological interventions that address the underlying neurobiology of trauma-related disorders.
TSND-201: A Mechanistic Departure from Classic Psychedelics
TSND-201, chemically known as methylone, is categorized as a neuroplastogen. Unlike classic psychedelics such as psilocybin or LSD, which primarily function as direct agonists at the 5-hydroxytryptamine (5-HT) 2A receptor to induce hallucinogenic effects, TSND-201 acts as a highly selective releaser of serotonin, norepinephrine, and dopamine. Crucially, it lacks direct activity at the 5-HT2A receptor, which may account for its improved safety profile and reduced potential for intense perceptual distortions. Preclinical models have suggested that TSND-201 promotes rapid synaptic remodeling and enhances extinction learning, which are vital processes for the resolution of PTSD symptoms.
Study Design and Methodology: The IMPACT-1 Trial
The IMPACT-1 (Part B) trial was a phase 2, multicenter, double-blind, placebo-controlled randomized clinical trial conducted across 16 sites in the US, UK, and Ireland. The study enrolled 65 participants aged 18 to 65 who met the DSM-5 criteria for PTSD with a duration of symptoms exceeding six months and a baseline Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) score of 35 or higher, indicating moderate to severe symptoms.
Intervention Protocol
Participants were randomized 1:1 to receive either TSND-201 or a placebo. The dosing regimen consisted of four once-weekly oral sessions. In the active group, participants received 150 mg followed by 100 mg during each session. A notable feature of this trial was the absence of structured psychotherapy; instead, dosing sessions were monitored by mental health professionals who utilized a nondirective approach to ensure safety and provide support if needed. Follow-up continued for six weeks following the final dose to assess the durability of the response.
Primary and Secondary Endpoints
The primary endpoint was the change from baseline to day 64 in the CAPS-5 total severity score. Secondary outcomes included changes in the PCL-5 (self-reported PTSD symptoms), the Sheehan Disability Scale (functional impairment), and the MADRS (depressive symptoms). The researchers also evaluated response rates (defined as a 50 percent or greater improvement), remission rates (CAPS-5 score of 11 or lower), and the loss of PTSD diagnosis.
Key Findings: Efficacy and Clinical Significance
The trial met its primary endpoint, demonstrating that TSND-201 was significantly more effective than placebo in reducing PTSD symptom severity. At day 64, the least-squares (LS) mean difference in CAPS-5 total score between the TSND-201 group and the placebo group was 9.64 (90% CI, -16.48 to -2.80; P = .01). This finding is particularly striking given the relatively small sample size, suggesting a robust effect size.
Secondary Outcomes and Functional Recovery
The benefits of TSND-201 extended beyond the primary clinician-rated scale:
1. PTSD Checklist (PCL-5): The TSND-201 group showed an LS mean reduction of 28.46 compared to 19.47 in the placebo group (treatment difference: -8.99; 90% CI, -17.81 to -0.17).
2. Functional Disability (SDS): Significant improvements were noted in work, social, and family life, with an LS mean treatment difference of -4.72 (90% CI, -8.84 to -0.61).
3. Depressive Comorbidity (MADRS): Depressive symptoms, which often co-occur with PTSD, were significantly reduced in the TSND-201 group compared to placebo (treatment difference: -6.21; 90% CI, -12.41 to -0.27).
Response and Remission
Participants receiving TSND-201 were more likely to achieve clinical response and remission. The rapid onset of action was a hallmark of the treatment, with differences from placebo appearing early in the dosing phase and persisting through the six-week follow-up period.
Safety and Tolerability Profile
Safety is a paramount concern for monoamine-releasing agents. In the IMPACT-1 trial, TSND-201 was generally well tolerated. The most frequently reported treatment-emergent adverse events (TEAEs) included headache, decreased appetite, nausea, dizziness, and dry mouth. Some participants experienced transient increases in blood pressure, which is consistent with the sympathomimetic effects of norepinephrine release. Insomnia was also reported, likely due to the stimulant-like properties of the compound. Importantly, no serious adverse events related to the study drug were reported, and monitoring via the Columbia-Suicide Severity Rating Scale showed no increase in suicidal ideation or behavior.
Expert Commentary and Mechanistic Insights
The success of TSND-201 in this trial highlights a shift in the psychiatric paradigm toward neuroplasticity-based treatments. By facilitating the release of serotonin and dopamine while avoiding the hallucinogenic 5-HT2A pathway, TSND-201 may offer a “middle ground” between traditional antidepressants and more intensive psychedelic-assisted therapies. One of the most significant implications of this study is the efficacy observed without concurrent intensive psychotherapy. While MDMA-assisted therapy (currently under regulatory review) relies heavily on a specific psychotherapeutic framework, the TSND-201 data suggests that the pharmacological effect alone may be sufficient for substantial symptom relief, potentially simplifying the clinical rollout and reducing costs.
However, clinicians should note the study’s limitations, including the small sample size and the relatively short follow-up period of six weeks post-treatment. Larger Phase 3 trials will be necessary to confirm these findings and better characterize the long-term durability of the treatment effect.
Conclusion
The Phase 2 IMPACT-1 trial provides compelling evidence that TSND-201 is a promising candidate for the treatment of PTSD. With its rapid onset of action, significant impact on functional disability, and manageable safety profile, it addresses many of the shortcomings of current therapies. As the field of neuroplastogens continues to evolve, TSND-201 stands out as a potential breakthrough for patients who have long struggled with the debilitating effects of trauma.
Funding and Registration
This study was funded by Transcend Therapeutics. ClinicalTrials.gov Identifier: NCT05741710.
References
Jones A, Warner-Schmidt J, Kwak H, et al. Efficacy and Safety of the Neuroplastogen TSND-201 for the Treatment of PTSD: A Randomized Clinical Trial. JAMA Psychiatry. Published online February 18, 2026. doi:10.1001/jamapsychiatry.2025.4625
Krystal JH, Abdallah CG, Averill LA, et al. Synaptic Loss and the Pathophysiology of PTSD: Implications for Novel Therapeutics. Current Psychiatry Reports. 2017;19(10):74.
Olson DE. Neuroplastogens: Signaling Pathways Mediating the Therapeutic Effects of Psychoplastogens. Journal of Medicinal Chemistry. 2022;65(19):12506-12525.
