When lasting trauma is caused by callous acts of violence, the key to recovery can be making meaning out of meaninglessness.

Although such trauma is difficult to treat, the drug MDMA – known on the street as Ecstasy or Molly – appears to help when used as an adjunct to psychotherapy.

This year, UConn Health will host a phase three FDA trial for patients with post-traumatic stress disorder that will test whether the drug MDMA is a safe and effective treatment. While many people have a tough time handling the standard therapy for PTSD, MDMA has shown promise not only by making therapy more tolerable, but also by opening a door for the patient into their own mind. The insight allows them to process a shattering, horrific event into something that makes them stronger.

The American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders defines PTSD as when a person is traumatized in some way and then continues to re-experience it through flashbacks, nightmares, or unwanted intrusive memories. The person with PTSD avoids people or places associated with the trauma; becomes overly negative in thoughts and speech about themselves and other people; and has heightened arousal that can include a hair-trigger startle reflex, inability to sleep, hypervigilance, irritability, and aggression. At its worst, people are unable to cope with everyday life and may even become suicidal.

Often the source of the trauma is a shocking event involving interpersonal violence like rape, combat, or sexual abuse. Racial discrimination and harassment, particularly when it is shocking or pervasive, can also cause PTSD. UConn psychologist Monnica Williams, UConn Health’s principal investigator in the phase 3 trial, began focusing on race-based trauma when she was at the University of Pennsylvania and a very successful, high-achieving, black client came in with PTSD stemming from racial discrimination she’d suffered on the job. Williams was taken aback, and began studying the link between racism and post-traumatic stress disorder.

The path a chemical takes from experimental compound to approved medication is long and typically takes years.

It begins when a researcher identifies a chemical compound that looks promising. The researcher will test it in animals. These animal tests show whether the compound is toxic in animals and at what dosage; whether it causes birth defects; whether it has any unexpected side effects; and finally whether it might actually be effective against the illness it is under development for.

If the compound does seem to be effective and not too toxic, the sponsor – most often a drug company – applies to the Food and Drug Administration (FDA) for permission to test it in humans. This is called an Investigational New Drug application, and it must be approved by both a local panel of scientists, doctors, and medical ethicists who work at nearby hospitals and research institutions, as well as by the FDA itself.

If the sponsor’s Investigational New Drug application is approved, the new drug must go through three phases of testing. In phase 1, the drug is tested on healthy volunteers to determine how people metabolize it (how long it takes our bodies to break it down and pee it out) and what its most common side effects are.

If phase 1 shows the drug is safe to try in humans, it moves to phase 2 trials. In a phase 2 trial, patients with the condition the drug is intended to treat are recruited to test the drug’s effectiveness.

If the drug works in phase 2 trials, the drug moves to a phase 3 trial. Typically, phase 3 trials are large and have hundreds to thousands of participants. The trials try to gather as much information as possible on how the drug works in different types of people (old and young, male and female, different ethnicities) in different dosages, and in combination with different drugs. This is the stage MDMA for post-traumatic stress disorder is at now. UConn Health is one of the sites hosting the phase 3 trial.

After each phase, the evidence is evaluated and often results are published in scientific journals. Sponsors need to prove the safety (phase 1) and efficacy (phase 2) of the drug before they can move on to the next phase of testing.

If the investigational new drug shows itself to be safe and effective for many different people in the phase 3 trial, the sponsor then applies for approval to market it as a medicine in the U.S. Sponsors continue to track the safety and efficacy of new drugs even after they are approved.

The phase 3 study is organized by the Multidisciplinary Association for Psychedelic Studies, a non-profit pharmaceutical company that explores the beneficial medical uses of psychedelic substances. They had not previously had many people of color participate in their trials, and they reached out to Williams for advice. She made some recommendations, and UConn Health became one of the 12 U.S. sites participating in the phase three trial. Uniquely among the test sites, UConn Health will specifically recruit people from communities of color who have PTSD, with an emphasis on experiences of racial violence, harassment, or discrimination.

But no matter what type of trauma causes the PTSD, the most effective treatment for it is exposure-based therapy, such as ‘prolonged exposure.’ Essentially, the therapist has the patient discuss the traumatic event in excruciating detail, over and over again, until it ceases to cause overwhelming fear and anxiety.

Prolonged exposure works – indeed, it’s got the most research evidence behind it. But it’s terribly difficult for the patients, who often get visibly upset during sessions; and many quit therapy because the experience is too much like reliving the original trauma.

MDMA-assisted psychotherapy could be one way to change that. It stimulates the release of neurotransmitters that promote a feeling of trust and well-being, and might also help the brain rewire itself.

When she first heard of it, however, Williams was skeptical. “It sounded weird, like junk science, and I didn’t want to be part of that,” she says.

But she agreed to take a look at an article in Psychopharmacology. She was fascinated to see that researchers had used MDMA as an adjunct to psychotherapy for PTSD, and gotten really good results. And she was pleasantly surprised again when she first watched a video of an MDMA-assisted therapy session.

“People were sitting in a chair, relaxed. They’re processing it on their own, and would sometimes share new insights with the therapist,” Williams says. It was utterly unlike the distress, tension, and fear PTSD patients typically show during prolonged exposure. “They would say things like, ‘Wow. Now I understand the trauma didn’t happen to me because I’m a bad person – I was just in the wrong place at the wrong time.’ And we’re like ‘Yes! Yes! They finally get it!’” she recalls.

The MDMA helps them look at the big picture, to understand that the violence against them didn’t mean what they thought it had.

It can take a while for psychoactive drugs to work their way through the FDA approval process. The Multidisciplinary Association for Psychedelic Studies has been testing MDMA-assisted therapy for PTSD for more than a decade. Many of the early participants experienced lasting improvement.

“I did 20 years of psychotherapy,” prior to participating in an MDMA-assisted therapy session, says Rachel Hope, who experienced a cascade of abusive events as a child that left her with severe PTSD. “When I got into the outer limits of the really hardcore stuff, I’d start to destabilize and get sicker … I’d start vomiting or have to leave the room. I knew that I had to tell it – the story has a soul of its own. It’s got to be seen, got to be known. It’s got to come out. But I couldn’t get it out.”

Hope had had good therapists and managed to run a real estate development company, but eventually the PTSD got so bad she couldn’t leave the house. Finally, her personal assistant threatened to quit if she didn’t go back into therapy. And that’s how she came to participate in the MDMA-assisted psychotherapy trial in 2005. It was a revelation.

“The MDMA was a terrific anti-anxiety medicine,” but didn’t make her fuzzy headed like most anti-anxiety meds had. “It amplified access to memories and, really, I had access to everything, and I wasn’t terrified. I could actually tell someone, for the first time in my life, what had happened to me. I had so much access to my own mind.”

She describes it as the perfect tool to help work through the trauma. “I was rebooting my mind under my own directive,” Hope says.

Williams agrees that the MDMA seems to help patients rapidly make connections and breakthroughs in a single therapy session. Typically, a patient in psychotherapy might have just one such realization every few months.

The participants in the phase three trial at UConn Health will have a total of 20 therapy sessions, three of which will include MDMA. Each session will have two therapists present. The MDMA-assisted sessions will be six to eight hours long, after which the participant stays overnight in the hospital to rest, supervised by a night attendant. And as part of their effort to recruit participants from communities of color, all but one of the therapists participating at UConn Health identify as ethnic, racial, and/or sexual minorities.

Terence Ching, a clinical psychology doctoral student involved in the study, comes from Singapore, where he was part of the majority ethnic population, but was curious how it felt to be Malay, Indian, or one of the other minorities. In the other places where he has lived – Australia, New Zealand, and Louisville, Kentucky – he was not part of the majority ethnic group. “That led me to critically introspect my place in society as someone with many different identities. Having that multifaceted perspective allows me to experience a lot of empathy for people from marginalized groups in the U.S.,” he says.

To get a better understanding of what the MDMA-assisted psychotherapy would be like for study participants, Ching participated in a session himself as part of his training.

“It felt like a lot of insights happening, constantly,” he says. “It’s been a year since the experience, and every now and then, I have a moment when I remember an insight from my experience, and/or have another one.”

He hopes that the participants benefit from their MDMA-assisted psychotherapy the same way he did. “For someone who has experienced trauma, MDMA-assisted psychotherapy might help them be able to make meaning of it,” Ching says. “I really believe in this work.”