Neuroplastogen TSND-201 promising in severe PTSD

TSND-201 (methylone), a rapid-acting neuroplastogen, shows statistically significant improvements in post-traumatic stress disorder (PTSD) symptoms in a recent phase II randomized clinical trial (RCT).

“Current standard treatment with selective serotonin reuptake inhibitors [SSRIs] has a delayed onset of efficacy and potential for significant, chronic adverse effects,” wrote the researchers. “TSND-201 is a highly selective, rapid-acting neuroplastogen that has shown rapid, robust, and long-lasting benefit for preclinical PTSD-related behaviours and has been well tolerated in phase I studies involving healthy volunteers.”

Rapid and durable efficacy

To evaluate the efficacy and safety of TSND-201 vs placebo in PTSD, the phase II, multicentre IMPACT Part B RCT was conducted between 29 November 2023 and 19 February 2025 across 16 sites in the US, UK, and Ireland. [JAMA Psychiatry 2026;doi:10.1001/jamapsychiatry.2025.4625]

A total of 65 patients with severe PTSD (mean age, 43.7 years; female, 60.0 percent) were randomized 1:1 to receive acute intermittent treatment with TSND-201 (initial administration of 150 mg [3 capsules], followed by a booster administration of 100 mg [2 capsules] 90 minutes later) or placebo over four once-weekly oral dosing sessions. No psychotherapy was provided.

“The current study had broad PTSD criteria, including complex PTSD without restrictions on age of trauma or duration since trauma,” noted the researchers.

The primary endpoint was change from baseline to day 64 (end of study) in Clinician-Administered PTSD Scales for DSM-5 (CAPS-5) total severity score.  “TSND-201 was associated with a statistically significant, clinically meaningful 9.64-point greater reduction in CAPS-5 total score vs placebo [90 percent confidence interval (CI), -16.48 to -2.80; p=0.01],” noted the researchers.

Greater improvement was demonstrated with TSND-201 after the second dose (day 10; least-squares [LS] mean difference, -8.00; 90 percent CI, 13.75–2.26; p=0.01). The benefits were maintained until the end of the trial.

Benefit across multiple domains

Additionally, PTSD Checklist for DSM-5 (PCL-5; -28.46 vs -19.47; LS mean treatment difference, -8.99; 90 percent CI, -17.81 to -0.17), Sheehan Disability Scale (SDS, -8.29 vs -3.57; LS mean treatment difference, -4.72; 90 percent CI, -8.84 to -0.61), and Montgomery-Åsberg Depression Rating Scale (MADRS; -13.94 vs -7.73; LS mean treatment difference, -6.21; 90 percent CI, -12.41 to -0.27) scores were improved with TSND-201 vs placebo.

“Improvements in patient-reported PTSD symptoms [PCL-5], functioning [SDS], and depression [MADRS] were observed with TSND-201, demonstrating consistent therapeutic benefit across multiple domains typically affected by PTSD,” the researchers reported.

Mild or moderate, transient TEAEs

All patients in the TSND-201 group reported ≥1 treatment-emergent adverse event (TEAE), compared with 72.7 percent in the placebo group. Common TEAEs occurring in ≥20 percent of patients treated with TSND-201 were headache, decreased appetite, nausea, dizziness, increased blood pressure, dry mouth, and insomnia, but there were no significant trends of suicidal ideation or behaviour.

“TEAEs were generally mild or moderate, and transient, with most occurring on the day of dosing and resolving shortly thereafter,” noted the researchers.

“TSND-201 has rapid, robust, and durable efficacy and is well tolerated in patients with PTSD, supporting its further development as a treatment for PTSD,” concluded the researchers.