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. Trial Registration ClinicalTrials.gov Identifier: NCT05741710