After 16 years of preliminary clinical trials, the Food and Drug Administration (FDA) in late August gave expedited approval for multiple phase 3 trials of 3,4-methylenedioxymethamphetamine (MDMA) as a potential “breakthrough therapy” for treatment of posttraumatic stress disorder (PTSD).

The complex history and abuse of MDMA suggests additional thought be given to the evaluation of its clinical efficacy, says former APA President Paul Summergrad, M.D.

The focus on PTSD is based both on the insufficiency of current therapeutic approaches and the huge social and economic costs associated with the disorder, particularly among military veterans, commented Rick Doblin, Ph.D., the founder of the Multidisciplinary Association for Psychedelic Studies (MAPS), which has helped fund and coordinate MDMA clinical trials.

MAPS was founded in 1986 as a nonprofit educational and research organization with the goal of supporting research on the safe and therapeutic use of drugs such as psilocybin, LSD, and MDMA. Doblin holds a doctorate in public policy from Harvard, where he explored the medical, legal, and cultural ramifications of these substances during his graduate education.

The phase 3 trials will involve patients with severe PTSD from any cause, but are of special interest to the Department of Veterans Affairs (VA) and the Department of Defense (DoD). As of June 2016, more than 868,000 military veterans were getting disability compensation for PTSD at an annual cost to the VA of $17 billion.

MDMA, first synthesized in 1912, began to be used as a psychotherapeutic agent in the 1970s and 1980s, and then became a mainstay of Rave culture under the street name Ecstasy. This led to a backlash and subsequent criminalization in 1985. This history necessitates special caution in evaluation of its clinical efficacy, observed former APA President Paul Summergrad, M.D., who spoke on “The Future of Psychedelic Psychiatry” at the Psychedelic Science 2017 conference in California. He is also the author of an article on psilocybin in end-of-life care that was published in the December 2016 Journal of Psychopharmacology.

“The history of psychiatry is littered with enthusiasm for treatments that did not always turn out to be effective or beneficial,” said Summergrad in an interview.

According to MAPS, phase 3 trials will begin next spring in the United States, Canada, and Israel, with participants in the main portion of the trial randomized to receive three sessions of either MDMA or placebo in conjunction with psychotherapy over a 12-week period. The trials will be accompanied by three nondrug preparatory and three post-MDMA integration sessions. During the integration sessions, participants will discuss with their therapists what surfaced during the primary sessions. The MDMA will be administered in a single dose in three inpatient psychotherapy sessions spaced three to five weeks apart. The nondrug sessions will range from 60 to 90 minutes, while the MDMA-assisted sessions will last six to eight hours.

The participants randomized to placebo instead of MDMA will receive the same psychotherapy—including integration sessions—as those receiving MDMA, but they will have the option of repeating the therapy process with MDMA.

Charles Grob, M.D., who conducted the first FDA-approved phase 1 studies of the physiological and psychological effects of MDMA from 1993 to 1995, says that the FDA approval of phase 3 trials for MDMA-facilitated therapy under the “breakthrough” designation is “quite an accomplishment.”

The clinician-administered PTSD scale (CAPS-5), a semi-structured interview, will be the primary outcome measure employed and will be assessed by a blinded pool of independent raters.

In interviews for this story, a number of psychiatrists observed that it is important to tease out the effects of the intensive psychotherapy provided during the sessions from the effects of MDMA. This variable was assessed during phase 2 trials with 107 patients with chronic, treatment-resistant PTSD. The studies found that therapy alone resulted in a 23 percent remission of PTSD at initial follow-up. In those who received a combination of therapy with active MDMA in two sessions, the efficacy improved to 55 percent, and with a third MDMA-facilitated session two months later, efficacy rose to 61 percent. At one year-follow-up, 68 percent of those who had received the MDMA-facilitated therapy no longer had a diagnosis of PTSD.

If the phase 3 trials confirm such efficacy, the mechanism by which MDMA works will be a key topic of exploration in neuroscience, observed David Nutt, F.Med.Sci. Nutt is an Oxford-trained psychiatrist who heads a brain-imaging group at Imperial College in London, where he is a professor of neuropsychopharmacology. He is also the president of the European Brain Council and editor-in-chief of the Journal of Psychopharmacology and has been closely involved with brain imaging studies of MDMA and psychedelics including psilocybin and LSD.

As a result of both his clinical and imaging work, Nutt has concluded that the common characterization of MDMA as similar to LSD and psilocybin is wrong both in terms of its psychodynamic effects and its effects at the receptor sites. While psilocybin and LSD work through the 5HT2A receptor system, said Nutt, MDMA “dampens down the limbic system—probably through the 5H1A receptor.” MDMA acts so differently that it should not be compared with these other drugs, said Nutt. Rather, it is more accurately characterized as “an empathogenic and anxiolytic.”

“Unlike the classical psychedelics, which appear to work on depression “by breaking down persistent ruminations, MDMA helps those suffering from PTSD break down their trauma by confronting it,” Nutt commented. “What we think is that under MDMA, the emotions are not so powerful, so people can endure them better.”

In non-MDMA facilitated exposure therapy, the patient is provided an opportunity in a structured therapeutic setting to be in recall long enough to allow the emotional impact of the original trauma to extinguish, Nutt explained. The problem is that many patients are unable to endure such prolonged exposure and retreat psychologically from confronting their traumatic memories.

Neuroimaging studies suggest how MDMA may exert its therapeutic effects. In PTSD the emotional memory is so intense that it can disrupt the brain. Under MDMA, the amygdala, which orchestrates the conditioned response between memory and fear, is affected so that the patient is able to recall the trauma without being overwhelmed by fear, Nutt said.

Nutt does not believe MDMA would lead to abuse among patients. “PTSD is a very, very serious disorder. It disables people; it is associated with a high rate of suicide. This is not going to increase recreational use. It should be made available as medicine,” said Nutt. “It is not a panacea, but it is very powerful.”

Given the challenges of effective psychopharmacological psychotherapy for PTSD, the possibility of any new agent that may improve clinical outcomes is welcome, said Andrew J. Saxon, M.D., who chairs APA’s Council on Addiction Psychiatry. Current therapies for PTSD have at best about a 50 percent efficacy in terms of “clinically meaningful improvement,” said Saxon. Further, only two drugs are specifically approved for PTSD, sertraline and paroxetine, although clinicians use other SSRIs off label.

Charles Grob, M.D., conducted the first FDA-approved phase 1 studies of the physiological and psychological effects of MDMA from 1993 to 1995. Grob is a professor of psychiatry and pediatrics at the UCLA School of Medicine and director of the Division of Child and Adolescent Psychiatry at Harbor-UCLA Medical Center.

The FDA approval of phase 3 trials for MDMA-facilitated therapy under the “breakthrough” designation is “quite an accomplishment,” said Grob. This designation effectively expedites the approval process—“it speeds up the timeline,” Grob commented.

“We have a great opportunity here,” said Grob. “We have to learn the lesson of the 60s and not repeat the mistakes we made way back then. I would emphasize very strong ethical standards—that’s going to be key moving forward.” ■