Posttraumatic stress disorder (PTSD) is a chronic and disabling psychiatric condition characterized by intrusive memories, avoidance, negative mood and cognition, and hyperarousal. Current pharmacologic options—primarily selective serotonin reuptake inhibitors such as sertraline and paroxetine—have limited efficacy, delayed onset, and potential long-term adverse effects. These limitations highlight the need for rapid-acting and durable treatments. TSND-201 (methylone) is a novel neuroplastogen that increases serotonin, norepinephrine, and dopamine release and promotes neuroplasticity without direct activity at the 5-HT2A receptor, meaning it lacks hallucinogenic effects associated with classic psychedelics. Preclinical studies and phase 1 trials suggested rapid and sustained therapeutic effects with favorable tolerability, supporting its investigation as a potential treatment for PTSD.

The IMPACT-1 part B trial was a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted at 16 sites across the United States, United Kingdom, and Ireland between November 2023 and February 2025. Adults aged 18–65 years with DSM-5 PTSD and symptoms lasting at least six months were eligible if they had moderate-to-severe symptom severity (Clinician-Administered PTSD Scale for DSM-5 [CAPS-5] ≥35). Participants were randomized 1:1 to receive TSND-201 or placebo. Treatment consisted of four once-weekly dosing sessions (150 mg followed by a 100 mg booster dose 90 minutes later). Sessions were monitored by trained mental health professionals using a nondirective supportive approach, but no formal psychotherapy was provided. Participants were followed for six weeks after the final dose.

The primary endpoint was a change in CAPS-5 total score from baseline to day 64 (week 10). Secondary outcomes included the PTSD Checklist for DSM-5 (PCL-5), Sheehan Disability Scale (SDS), and Montgomery-Åsberg Depression Rating Scale (MADRS), along with response, remission, and loss of PTSD diagnosis rates. Safety was assessed via adverse events, vital signs, and the Columbia-Suicide Severity Rating Scale.

Sixty-five participants were randomized (mean age 43.7 years; 60% female). Baseline PTSD severity was comparable between groups, with mean CAPS-5 scores around 46. TSND-201 produced significantly greater reductions in PTSD symptoms than placebo. The least-squares mean change in CAPS-5 score at day 64 was -23.28 for TSND-201 compared with -13.64 for placebo (Figure 1; treatment difference -9.64; 90% CI, -16.48 to -2.80; P = .01). Improvements were observed as early as day 10 (after the second dose) and persisted through the end of the study.

Secondary outcomes also favored TSND-201, including improvements in patient-reported PTSD symptoms (PCL-5), functional impairment (SDS), and depressive symptoms (MADRS). Response rates (≥50% CAPS-5 improvement) were higher with TSND-201 (57.1%) compared with placebo (19.2%), and remission rates were also greater (32.1% vs 11.5%).

Adverse events were generally mild to moderate and transient. The most common treatment-emergent adverse events included headache, decreased appetite, nausea, dizziness, increased blood pressure, dry mouth, and insomnia. Most occurred on dosing days and resolved shortly afterward. No meaningful increases in suicidal ideation or behavior were observed.

In this phase 2 randomized clinical trial, intermittent treatment with TSND-201 resulted in statistically significant and clinically meaningful reductions in PTSD symptoms compared with placebo. Improvements were rapid, emerging after two doses, and durable, persisting weeks after treatment completion. TSND-201 was generally safe and well tolerated, with mostly transient adverse effects. These findings support further investigation of TSND-201 as a rapid-acting and potentially durable pharmacologic treatment for PTSD.

Reference:

Jones A, Warner-Schmidt J, Kwak H, et al. JAMA Psychiatry 2026;Epub ahead of print. Abstract