Long Strange Trip Continues for Psychedelics in PTSD, TRD

Putting psychedelic drugs to work in treating mental illness encountered a seeming setback in August when the FDA rejected an application for use of MDMA (3,4-methylenedioxymethamphetamine), also known as ecstasy, as a treatment for PTSD.

This may not have been surprising to some in the medical community. In draft guidance issued in 2023, the FDA set a high bar for approval of these agents for medicinal purposes.

The use of psychedelics comes with altered mental states that the FDA prefers to classify as adverse events and potential catalysts for substance abuse, two hurdles that make the risk-reward profile of these agents difficult to accept.

Next up at bat will likely be a new drug application (NDA) from Compass Pathways for a psilocybin treatment for treatment resistant depression (TRD). MDMA is a synthetic psychedelic whereas psilocybin is a natural substance found in a certain species of mushroom.

Initial results of a pivotal phase 3 trial are expected in the fourth quarter of 2024.

In phase 2 results reported in November 2022, investigators said a one-time 25 milligram (mg) dose of psilocybin reduced TRD significantly more than a 1 mg dose over a three-week period, although adverse events were associated with treatment.

MDMA is known for its empathogenic and euphoric effects, whereas psilocybin is known for mystical and introspective effects, which has made it a candidate treatment for mood disorders and existential anxiety.

In the PTSD and TRD patient communities, there is a significant unmet need for effective therapies. Roughly 30% of patients with major depressive disorder will have TRD. For participants in the Compass phase 2 trial, psilocybin was a third-, fourth-, and even a fifth-line treatment.

Many experts believe that psychedelics will eventually overcome the stigma attached to use of these substances and find a place in the legitimate armamentarium.

For Compass Pathways to mount a successful NDA, it will at least have to demonstrate to the FDA they have managed the many moving parts of a psychedelic trial more effectively than did Lykos for its MDMA product.

In highly positive phase 3 results, Lykos reported 86.5% of participants experienced a clinically meaningful improvement in PTSD symptoms at 18 weeks post baseline, but the devil was in the details. An FDA review panel found fault with numerous aspects of the trial, calling a talk therapy component too loosely structured, finding unanswered questions about the potential for substance abuse and noting an inherent failure to adequately blind the trial because the hallucinogenic effects made it obvious to participants who was receiving the active substance and who had been randomly assigned to take the placebo.

One inescapable reality is that psychedelics are Schedule 1 controlled substances that are going to be handled with extreme prejudice.

The limited guidance that the FDA has put out on psychedelic clinical trials has iis more a minefield than a blueprint for success.

“Because this is an emerging area of drug development, there is limited experience as to the configuration of programs that may support approval of a psychedelic drug,” the FDA wrote in its 2023 draft guidance document.