All clear for the decisive trial of ecstasy in PTSD patients

One of the main targets in the war on drugs could well become a drug to treat the scars of war. The U.S. Food and Drug Administration (FDA) has designated 3,4-methylenedioxymethamphetamine (MDMA), better known as the illegal drug ecstasy, a "breakthrough therapy" for posttraumatic stress disorder (PTSD), a status that may lead to faster approval.

The agency has also approved the design for two phase III studies of MDMA for PTSD that would be funded by the Multidisciplinary Association for Psychedelic Studies (MAPS), a nonprofit in Santa Cruz, California. MAPS announced the "breakthrough therapy" designation, made by FDA on 16 August, on its website today; if the group can find the money for the trials, which together could cost an estimated $25 million, they may start next spring and finish by 2021.

That an illegal dancefloor drug could become a promising pharmaceutical is another indication that the efforts of a dedicated group of researchers interested in the medicinal properties of mind-altering drugs is paying dividends. Stringent drug laws have stymied research on these compounds for decades. "This is not a big scientific step," says David Nutt, a neuropsychopharmacologist at Imperial College London. "It’s been obvious for 40 years that these drugs are medicines. But it’s a huge step in acceptance."

Since 2012, FDA has designated close to 200 drugs as breakthrough therapies, a status that indicates there’s preliminary evidence that an intervention offers a substantial improvement over other options for a serious health condition. The agency aims to help develop and review these treatments faster than other candidate drugs.

In people with PTSD, a small sensory trigger such as a sound or a smell can bring a traumatic memory rushing back. “The disabling element of PTSD is the fact that when the memory starts, the emotions completely override you and overwhelm the brain,” Nutt says. Studies suggest that MDMA can dampen the emotional response to the memory, allowing people to relive their trauma and work through it, he says. The MDMA-treatment consists of several sessions of psychotherapy, some conducted while the patient is under the influence of the drug.

MAPS Executive Director Rick Doblin set up the group in 1986, one year after the U.S. Drug Enforcement Administration made MDMA an illegal drug, because he was convinced of its therapeutic potential. Since then, MAPS has poured millions into trials of MDMA, for PTSD and other conditions, and has taken the lead in conducting them. The FDA designation is "kind of a public acknowledgement of the promise of this research,” Doblin says.

A small U.S. study that first suggested MDMA could help treat PTSD was published in 2011. Since then, researchers in Canada, Israel, and the United States have jointly carried out larger phase II trials funded by MAPS; their results, which remain unpublished but have been reviewed by the FDA, were very good, says Doblin. Overall, 107 participants who had suffered from PTSD for an average of 17.8 years were treated in the phase II trials, Doblin says. Of the 90 patients who were available to be studied 12 months later, 61 no longer had PTSD.

In late July, says Doblin, MAPS and FDA agreed on how the coming phase III trials—usually the last hurdle before seeking a drug's approval from regulators—should be conducted. A key issue that has dogged randomized controlled trials of MDMA and other mind-altering drugs is how to minimize bias. In many trial designs, some patients receive a drug while others are in a control group that receives a placebo. The participants aren’t told which they received, but patients who get MDMA can often tell, which might have an effect all by itself.

In past studies, patients in the control arm received a low dose of MDMA—a so-called "active placebo"—that made it harder for them to tell in which group they were. But that had a negative effect on the outcome of their psychotherapy, says Doblin, making MDMA look better by comparison. A low dose "activates people, but it does not provide the fear reduction that the full doses would and so they are more uncomfortable, more unhappy,” Doblin says.

That's why FDA decided it would be better to test MDMA-assisted psychotherapy against psychotherapy with an inactive placebo. But the agency and MAPS agreed on additional measures to ensure that the doctors who evaluate the patients don’t know if they received the real drug.

The biggest hurdle now is raising the money for the two phase III trials, which together will include between 200 and 300 participants. So far MAPS has raised only $12.75 million, about half of its goal, and an effort to crowdfund the rest has been disappointing. "I think the money will come from major donors,” Doblin says. "We are going to people in the tech world and family foundations, but we're also trying with the Veterans Administration.” The first phase III trial will start no matter what, he says. "It’s always been the philosophy of MAPS that if we can do the work, the money will follow.”

MAPS has not conducted trials in Europe yet but is planning to start discussion with the European Medicines Agency, the European Union's regulatory body, soon. Nutt says that after overcoming major regulatory hurdles, he is about to start a trial using MDMA to treat alcohol addiction.