by Eugene Rubin MD, PhD and Charles Zorumski MD

Posttraumatic stress disorder (PTSD) is a disabling illness. It follows exposure to significant traumas such as military violence, sexual abuse, child abuse, major traffic accidents, and other violent events. As outlined in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), symptoms include intrusive symptoms associated with a traumatic event—for example, recurrent, involuntary, and distressing memories, flashbacks, and recurrent distressing dreams; avoidance behaviors; negative changes in thinking and mood; and heightened arousal or reactivity—for example, hypervigilance. Currently approved pharmacologic treatments for PTSD include two selective-serotonin reuptake inhibitors—sertraline and paroxetine. These medications often have limited effectiveness. Various psychotherapies have also been utilized to treat PTSD, but they often do not result in major improvement.

Prior research suggests that 3-4 methylenedioxymethamphetamine (MDMA, Ecstasy) together with psychotherapy may be helpful in alleviating symptoms of PTSD. However, issues with the design of MDMA clinical trials have led to concerns about the results.

Recently, Amanda Jones and colleagues published the results of a clinical trial of methylone for treatment of PTSD in the journal JAMA Psychiatry. Methylone is a synthetic compound produced by modifying the chemical structure of MDMA. According to the authors, methylone “increases the release of serotonin, norepinephrine, and dopamine, leading to rapid and long-lasting effects on neuroplasticity in brain areas affected by PTSD, including increased neurotrophic support as well as direct effects on neurite outgrowth.”

Study Design

This study was a multicenter, double-blind, placebo-controlled, randomized clinical trial. It took place at 16 sites in the U.S., U.K., and Ireland between November 29, 2023, and February 19, 2025. Participants were 18 to 65 years old and met DSM-5 criteria for current PTSD with at least six months of symptoms. The investigators assessed symptoms with the Clinician-Administered PTSD Scales for DSM-5 (CAPS-5). This instrument evaluates twenty symptoms categorized into four clusters. Total scores range from 0 to 80, with higher scores indicating worse symptoms.

To be enrolled in the trial, an individual had to have a CAPS-5 total score of at least 35 at screening and at least 28 at baseline. All participants had received previous treatment with pharmacotherapy, psychotherapy, or both at least once. Criteria for exclusion included a primary diagnosis of another DSM-5 disorder, current use of antidepressants or other treatment for PTSD (including psychotherapy), moderate or severe substance use disorder, active suicidal ideation, and use of a psychedelic drug within 12 months of screening.

Individuals were randomized to one of two groups: those receiving methylone or placebo. To minimize increases in blood pressure, the dose of methylone was divided into an initial 150 mg dose followed by a 100 mg dose 90 minutes later. Similarly, people in the control group received split administration of placebo. Participants were observed for at least eight hours during the dosing session; however, no psychotherapy was administered. They received weekly dosing sessions for four weeks and then entered a 6-week follow-up period.

Participants were evaluated two days after each dosing session and at regular intervals during the 6-week follow-up, up to day 64. The CAPS-5 total scores as well as symptom cluster scores were determined at each visit. The cluster scores measured intrusion, avoidance, negative alterations in cognitions and mood, and arousal and reactivity.

Sixty-five individuals (average age 44 years; 60 percent women) participated in the study. The average duration of their PTSD symptoms was 19 years. Two-thirds had been treated with medications, and over 75 percent had received psychotherapy. Forty-five percent had experienced sexual trauma, 8 percent military-related trauma, and 47 percent other types of traumas, including traffic accidents, abuse, or other kinds of violence.

Key Findings

At the end of the study (day 64), the CAPS-5 total score improved by over 23 points in the methylone group and less than 14 points in the placebo group. This difference was both statistically and clinically significant. Improvement was noted by day 10. Improvement was also evident for each of the four CAPS-5 symptom clusters.

A treatment response (defined as 50 percent or greater improvement in total scores) occurred in over 57 percent of those receiving methylone compared to 19 percent of those receiving placebo. Remission (defined as a total score of 11 or less) occurred in 32 percent of those in the methylone group versus 11.5 percent in the placebo group. At the end of the study, 61 percent of those receiving methylone no longer fulfilled criteria for PTSD versus 31 percent of those receiving placebo.

Post-Traumatic Stress Disorder Essential Reads

Side effects of methylone were generally mild or moderate and transient, usually occurring on the day of dosing and resolving within a day. Common side effects included headache, decreased appetite, nausea, dizziness, increased blood pressure, dry mouth, and insomnia.

About 53 percent correctly guessed they had received placebo. About 70 percent guessed correctly that they had received active drug.

Thoughts

Severe PTSD is disabling and often does not respond well to current treatments. The results of this study suggest that methylone may be effective in alleviating symptoms of this disorder. Importantly, the beneficial effects were still present six weeks after the last dose of medication.

It is important to note that no psychotherapy was administered in conjunction with the drug. Study staff monitored participants during dosing days, but their roles were to be available in case of adverse effects and briefly answer questions.

PTSD resulting from military-related trauma may be particularly treatment-resistant. In this study, only 8% of participants had experienced this type of trauma and therefore the results cannot address the effectiveness of methylone in this group of individuals.

Methylone’s side effects resembled those of a mild stimulant. Seventy percent of the methylone group correctly guessed they received active medication, and more than 50 percent correctly identified being treated with placebo. This is at the upper end of the range of individuals in antidepressant trials who guessed correctly that they were in active treatment and is a limitation in drawing conclusions from clinical trials of this type.

This clinical trial was a phase 2 study. Such studies evaluate a relatively small group of participants to test a drug’s efficacy and safety. To our understanding, the pharmaceutical company developing methylone is planning to launch a large, phase 3 study, which is critically important if the drug is to gain approval for clinical use because phase 3 studies often fail to reproduce the results of smaller, phase 2 studies. If methylone proves effective in larger studies, it is possible that an effective treatment for PTSD will become available within the next five years. Studies of the misuse/abuse potential of methylone will also be important going forward.