The news last week that the compound 3,4-methylenedioxymethamphetamine (MDMA), popularly called ecstasy, alleviated post-traumatic stress disorder (PTSD) in a phase 3 trial was a milestone in efforts to turn psychedelic drugs into mainstream treatments. It also highlighted a therapeutic marriage that is getting increasing attention: providing a mind-altering drug while a patient receives care from a trained therapist. “This is really kind of a new zeitgeist in psychiatry,” says Barbara Rothbaum, a clinical psychologist at Emory University.
Researchers funded by the nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS) reported in Nature Medicine that after “MDMA-assisted therapy,” two-thirds of treated participants no longer met the diagnostic criteria for PTSD. MAPS hopes to confirm the results in an ongoing second study and seek approval for the therapy from the U.S. Food and Drug Administration (FDA) as early as 2023. In 2017, the agency granted MDMA a “breakthrough” designation, which comes with extra guidance during the trial process and an expedited review.
The idea that psychedelic drugs and talk therapy work in synergy raises complex questions about how to optimize—and regulate—the drug experience. “It’s not understood what the role of MDMA or [another] psychedelic is in facilitating the psychotherapy, and what’s happening neurobiologically,” says Atheir Abbas, a neuroscientist and psychiatrist at Oregon Health & Science University. Because taking psychedelics without guidance can lead to negative experiences, “a guided, more psychotherapy-oriented approach is probably warranted,” he says. “But it’s not clear what aspects of that guidance are critical.”
As MDMA and other tightly controlled psychedelic compounds inch closer to regulatory approval, careful supervision from therapists may help overcome their reputation as illicit substances and fears of indiscriminate use. “MAPS has done very well to really emphasize that they’re not just trying to promote a compound,” says Rachel Yehuda, who directs the Center for Psychedelic Psychotherapy and Trauma Research at the Icahn School of Medicine at Mount Sinai.
MAPS researchers have worked for more than 3 decades to turn MDMA into a prescription medicine. The substance doesn’t produce the vivid hallucinations associated with either LSD or psilocybin, found in magic mushrooms. But it increases the brain’s levels of certain neurotransmitters, including serotonin and dopamine, to create a sense of well-being and heightened empathy. That might allow trauma survivors who face intrusive flashbacks to reflect on disturbing memories with less fear and judgment. “It gives you this fascinating ability toward self-compassion,” says Jennifer Mitchell, a neuroscientist at the University of California, San Francisco, and an investigator in the MAPS trial.
The psychotherapy the trial used looks different from the most thoroughly studied PTSD psychotherapies. Many of these direct a patient to confront painful memories. In one such approach, called prolonged exposure therapy, “we have them go back in their mind’s eye to the time of the traumatic event and recount it out loud, in the present tense, over and over,” Rothbaum says. “It’s a good therapy, but it’s also a hard therapy.”
In the MAPS approach, therapists are advised not to steer the conversation toward trauma, but to create a safe space to “support the participant’s own unfolding experience,” according to MAPS’s manual. The manual also describes carefully curated surroundings for patients, advising “fresh flowers and artwork.” Rothbaum, who studies and practices prolonged exposure therapy, describes MAPS sessions as “the sweetest therapy in the world for PTSD.”
In the trial, 79 participants underwent three 90-minute preparatory therapy sessions; three 8-hour “experimental sessions” with either MDMA or a placebo, spaced about 1 month apart; and nine 90-minute “integration sessions” to process their experiences. Of 42 people who got MDMA, 67% no longer met the diagnostic criteria for PTSD 2 months after their last experimental session. For the placebo group, that rate was 32%. Improvements in the placebo recipients were comparable to those observed in studies of existing approaches such as exposure therapy, says MAPS’s chief scientific officer, Berra Yazar-Klosinski.
Yehuda, who has long worried that prolonged exposure therapy can retraumatize some patients and discourage them from continuing treatment, says the research offers a new direction. But MDMA-assisted therapy needs to go head to head in clinical trials with established psychotherapies and the antidepressant drugs already approved for PTSD, says Arash Javanbakht, who directs the Stress, Trauma, and Anxiety Research Clinic at Wayne State University. Others want to test MDMA alongside more mainstream talk therapies. Rothbaum’s team hopes to launch a pilot study this year that combines the drug with prolonged exposure therapy. Psychologist Anne Wagner of the mental health clinic Remedy is preparing to launch a pilot study that brings an approach called cognitive processing therapy into the pre-and post-MDMA sessions. Adding this more structured psychotherapy might improve results for some patients, she says.
Should MDMA win FDA approval, the MAPS psychotherapy approach is likely to dominate at least at first. FDA doesn’t regulate psychotherapy, but Yazar-Klosinski says FDA has indicated any approval would stipulate that the drug be used alongside therapy from trained providers. (FDA declined to comment on how it might address supportive therapy in an approval.) A subsidiary of MAPS would manufacture the drug and hopes to receive a 5-year exclusivity period on marketing the drug for PTSD. It would sell MDMA only to providers who undergo MAPS’s 100-hour training program.
Uncertainty about the right talk therapy pairings extends to research on other psychedelic drugs. Albert Garcia-Romeu, a psychologist at Johns Hopkins University School of Medicine, is testing psilocybin-assisted addiction treatment. For a recent study of cigarette smokers, the team made “kind of our best guess” to pair the drug with cognitive behavioral therapy, a common addiction talk therapy, he says.
Potential FDA decisions on psilocybin and MDMA are still years off. But in November 2020, Oregon became the first state to legalize psilocybin for therapeutic use. It has appointed an advisory board to help make a plan for regulating the compound by December 2022.
Oregon’s measure describes a system of state-licensed providers and “a multisession, facilitator-guided, psychotherapy-type experience,” says Abbas, who sits on the advisory board but was speaking only for himself. What type of psychotherapy experience should that be? And what qualifies a facilitator? “That’s something the board is likely to have to tackle.”