The investigational MDMA analogue, TSND-201 (methylone), significantly reduced posttraumatic stress disorder (PTSD) symptom severity compared with placebo in a phase 2 randomized, placebo-controlled trial, with effects emerging rapidly and persisting for weeks after the final dose.

Adults with severe PTSD treated with TSND-201 experienced a nearly 10-point greater improvement on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) than peers given a placebo, meeting the primary endpoint and supporting further development of the drug as a potential rapid-acting treatment option for PTSD.

Results of the IMPACT-1 (Part B) study were published online on February 18 in JAMA Psychiatry.

‘Urgent Unmet Need’

PTSD is a debilitating condition marked by intrusive memories, avoidance behaviors, negative mood and cognition changes, and hyperarousal. Currently, only two selective serotonin reuptake inhibitors — paroxetine and sertraline — are FDA approved for PTSD, yet onset can be slow and the overall effectiveness limited.

There is an “urgent unmet need” for effective, fast-acting treatments for this condition, the investigators noted.

TSND-201 is a highly selective, rapid-acting neuroplastogen in clinical development for PTSD. TSND-201 is the beta-ketone analogue of MDMA which has shown benefit for PTSD in clinical trials in combination with psychotherapy.

The investigators noted that “despite its structural similarity, TSND-201 shows distinct pharmacological and subjective effects compared with MDMA, due at least in part to greater selectivity for the serotonin, norepinephrine, dopamine transporters.”

In addition, the investigators noted that the drug has no direct agonist or antagonist activity at the serotonin 5HT2A receptors, consistent with no hallucinogenic activity in humans.

The IMPACT-1 (Part B) study enrolled 65 adults (mean age, 43.7 years; 60% women) who met DSM-5 criteria for current PTSD and 6 months or more of PTSD symptoms (CAPS-5 severity score ≥ 35). All participants had tried at least one prior PTSD treatment, either pharmacotherapy or psychotherapy.

They were randomly assigned (1:1) to receive either TSND-201 or placebo, consisting of four once-weekly oral dosing sessions (150 mg followed by 100 mg or placebo). Follow-up continued for 6 weeks after the final dose.

Unlike MDMA-assisted therapy, which has relied heavily on structured psychotherapy, the current trial tested TSND-201 without structured psychotherapy, using only monitored dosing sessions supported by mental health professionals employing a nondirective approach.

‘Clinically Meaningful’ Improvement

The trial met its primary endpoint — demonstrating a statistically significant and “clinically meaningful” improvement from baseline to day 64 in the CAPS-5 total severity score with TSND-201 compared with placebo (-23.28 vs -13.64 points; least squares [LS] mean difference, 9.64 points; P = .01), the authors reported.

Notably, statistically significant separation from placebo was observed as early as day 10 (LS mean difference, 8.00 points; P = .01), they added.

TSND-201 also led to significant improvement on several key secondary measures, including patient-reported PTSD symptoms on the PTSD Checklist for DSM-5, functional impairment on the Sheehan Disability Scale, and depressive symptoms on the Montgomery-Åsberg Depression Rating Scale.

More than half of the TSND-201-treated participants met criteria for response — defined as at least a 50% improvement in the CAPS-5 score (57.1% vs 19.2% with placebo) — corresponding to a number needed to treat (NNT) of 3.

Remission — defined as a CAPS-5 score ≤ 11 — was achieved in 32.1% of the TSND-201 group compared with 11.5% of the placebo group (NNT = 5). In addition, 60.7% of TSND-201-treated participants no longer met diagnostic criteria for PTSD at the end of the study compared with 30.8% of those in the placebo group (NNT = 3).

It is unclear how a brief, intermittent dosing schedule produced sustained benefits, but the investigators speculated that TSND-201 may promote neuroplasticity — a mechanism believed to underlie the effects of traditional antidepressants and other rapid-acting therapies.

Adverse events were generally mild to moderate and typically occurred on dosing days and resolving within about a day. The most common treatment-emergent adverse events in the TSND-201 group included headache, decreased appetite, nausea, dizziness, increased blood pressure, dry mouth, and insomnia.

There were no discontinuations due to adverse events and no significant trends in suicidal ideation or behavior. One severe adverse event involving suicidal ideation occurred during follow-up but was considered unrelated to the drug.

One seizure occurred during a blood draw 7 days after the last dose and was also considered unrelated, given the participant’s history and the time since dosing.

Limitations of the study included its small sample size and relatively few participants with military trauma. Furthermore, 70% of TSND-201 participants correctly guessed they received the active drug — a common issue in trials involving psychoactive agents.

TSND-201 has received FDA breakthrough therapy designation. The company plans to launch the phase 3 program of TSND-201 in patients with PTSD in the coming months.

A Clearer Pathway to Approval?

Commenting for Medscape Medical News, Charles B. Nemeroff, MD, PhD, professor and chair, Department of Psychiatry and Behavioral Sciences, Mulva Clinic for the Neurosciences, UT Health Austin, and member of the American Psychiatric Association Council on Research, said the study’s results are of “considerable interest.”

“The magnitude of the effect is quite robust, and the separation between the drug treatment and placebo is highly statistically and clinically significant,” said Nemeroff, who wasn’t involved in the study.

“In contrast to the previous MDMA studies, no evidence-based or manualized therapy was combined with the drug treatment. If these results can be replicated in large phase 3 trials, the pathway for FDA approval would appear to be clear,” said Nemeroff.

But Matthew W. Johnson, PhD, professor at Johns Hopkins University in Baltimore, said he is “skeptical that this drug is unique from MDMA and more likely to be approved.”

As previously reported by Medscape Medical News, the FDA rejected MDMA-assisted therapy for PTSD in August 2024.

“The issues with the FDA rejection of MDMA were not really inherent to the drug but more about the conduct of the trial,” Johnson noted.

He also cautioned against assuming that neuroplasticity alone explains the clinical response of TSND-201.

“We do not know that neuroplastic effects were responsible for the efficacy seen here, and just because no formal psychotherapy was administered, it does not mean that psychotherapeutic process is not responsible for potential efficacy,” said Johnson.

He pointed to his own published research on recreational psychedelic use, describing how therapeutic responses can arise from “the insights, changes in perspective taking, and learning that is reported as a result of the drug experience. That may very well be the case here.”

Overall, Johnson said the results are “promising” but questioned “whether the drug is unique from MDMA and holds differential potential or that neuroplasticity, rather than psychedelic-type subjective effects, are responsible for the apparent efficacy.”

The study was funded by Transcend Therapeutics. Several authors disclosed having relationships with the company. Nemeroff disclosed having relationships with Bracket (Clintara), Fortress Biotech, Intra-Cellular Therapies, Janssen Research and Development, Magstim, Navitor Pharmaceuticals, and other pharmaceutical companies. Johnson disclosed having relationships with Ajna Labs; AWAKN Life Sciences; Beckley Psytech, Ltd.; Clarion Clinics; Mind Medicine; Negev Capital; Otsuka Pharmaceutical Development & Commercialization; and Reunion Neuroscience.