When Lori Tipton saw an advert on social media seeking subjects for a study on post-traumatic stress disorder (PTSD), her curiosity was piqued. She had already tried antidepressants and anti-anxiety medications. She had been to therapists, social workers, psychiatrists and psychologists. When all that failed to quell her anxiety, panic attacks, insomnia and suicidal thoughts, she sought help from other sources: a dietitian, an endocrinologist, a shamanistic healer and an ayurvedic doctor. She even pursued a yoga teaching certification to become more present and mindful. Nothing had helped.

The trial would test whether the psychedelic drug MDMA (better known as ecstasy) could treat PTSD. She didn’t expect it to be successful, but with other options exhausted, she decided to give it a try.

Post-traumatic stress can develop in anyone who has faced danger or experienced chronic stress, the most common causes being disasters, sexual assault, domestic abuse and combat experience. Tipton’s PTSD stems from a series of traumatic events. When she was 20 years old, her brother died of a drug overdose in her apartment in New Orleans, Louisiana. When she was 25, her mother killed two family friends before turning the gun on herself. Tipton discovered the murder scene. The same year, Hurricane Katrina displaced her and her entire community. The following year she was raped, became pregnant and aborted the pregnancy. She recalls that the nurse in charge of her care had anti-abortion views, and shamed her, withheld pain medication, and was physically rough in examining her.

PTSD can manifest as recurrent, intrusive memories or, more rarely, as memory loss. The best-studied treatments are cognitive behavioural therapy, in which people are helped to identify patterns of negative thought and behaviours with a view to changing them, and exposure therapy, in which they confront things that trigger fear and anxiety in a safe setting. These are often combined with antidepressants and anti-anxiety medications. But relatively few people reach true remission and, for some, such as Tipton, the treatments provide, at best, little or transient relief.

In the past decade, an increasing number of combat veterans with chronic post-traumatic stress have sought relief in the psychedelic underground, trying everything from magic mushrooms to ayahuasca, a powerful psychedelic made from South American plants. But only in the past few years have researchers finally been able to properly test whether psychedelics can help. The decision of the US Food and Drug Administration (FDA) to approve esketamine for treatment-resistant depression in 2019 signalled a shift towards the potential acceptance of psychedelics as treatments for a variety of mental-health conditions. Clinical research on psychedelics has been pressing forwards at a mind-bending pace.

However, the enthusiasm for clinical trials, driven partly by anecdotal reports of success and partly by the desperation of people who have spent decades searching for relief, has led to a sense of optimism not fully grounded in evidence. How and why psychedelics work remains poorly understood. Many researchers think that holding clinical trials without understanding the biological mechanisms is putting the cart before the horse. “Psychedelics can represent a new paradigm of care, but we haven’t done the work yet,” says Rachel Yehuda, a psychiatry and neuroscience researcher at the Icahn School of Medicine at Mount Sinai in New York City.

Small steps

Some of the earliest clinical trials testing psychedelics to treat PTSD have focused on MDMA, which is not a ‘classic’ psychedelic or hallucinogen, because those exclusively activate the serotonin 5-HT2A receptor. Rather, MDMA is an entactogen or empathogen — a compound that increases feelings of empathy and connectedness. Results of a phase III trial, sponsored by the non-profit advocacy group Multidisciplinary Association for Psychedelic Studies (MAPS), based in San Jose, California, were published in 2021. There were 90 participants, and 67% of those in the MDMA arm no longer qualified for a PTSD diagnosis 2 months after treatment, compared with just 32% in the placebo group (J. M. Mitchell et al. Nature Med. 27, 1025–1033; 2021).

But the study was small and, as with all clinical trials of psychedelics so far, it had one big problem. Psychedelics are difficult to fake, so it was nearly impossible to keep the control group blinded. Subjects assigned to the placebo arm had no illusions about which group they were in, making true comparisons between experimental and control subjects nearly impossible.

Nonetheless, researchers are pressing ahead. A second phase III trial, also sponsored by MAPS, is now under way, as are other MDMA trials around the country. One of those is led by Yehuda, who is also the director for mental health at the James J. Peters VA Medical Center in New York City. Yehuda aims to enrol 60 combat veterans who struggle with PTSD to test for a difference between receiving two or three doses of MDMA, because reducing the number of doses would make the treatment easier to deliver. Each treatment session is preceded by three preparatory sessions of intense psychotherapy, during which patients and therapists get to know and trust each other. Each psychedelic experience lasts about 8 hours and involves two trained therapists who, during this stage, tend to ask gently leading questions and act more as guides than analysts. The following day there is an integration session that lasts several hours, and there are further psychotherapy sessions in the weeks and months that follow.

Despite the difficulty of running these trials, new facilities for studying therapeutic psychedelics are popping up at academic institutions across the globe. This drive is fuelled by enthusiasm for what many think could be one of the most potent treatments ever advanced for PTSD and other mental-health conditions.

“The studies thus far are tantalizing, but they’re fundamentally pilot studies,” says Charles Nemeroff, a neurobiologist and psychiatrist at the Dell Medical School at the University of Texas at Austin, and co-director of one of these new centres, the school’s Center for Psychedelic Research and Therapy. He helped found the centre because, he says, “we needed to bring some scientific rigour to this field.” He points out that most studies so far have been small and lack the statistical power of the studies with more than 1,000 subjects that typically accompany applications to the FDA seeking approval of a new treatment. And nothing yet addresses how clinicians might regulate multi-session therapeutic doses, let alone train practitioners to administer and guide patients through them.

Yehuda acknowledges that there are plenty of obstacles. “This is a big treatment,” she says. It requires a big team of researchers and is “not practical to deliver in standard healthcare settings”. Furthermore, PTSD is a complex issue, one she’s spent decades studying. She is “generally sceptical about anything that promises a quick fix”, she says. Once she realized that the drugs were being proposed not as a rapid cure, but as part of a long-term therapy based on robust phase II trial data, she was interested.

A group of men and women sit around a large table in a bright room at psychedelic retreat in Mexico

Military veterans and their partners have a therapy session at a psychedelic retreat in Mexico.Credit: Meredith Kohut/NYT/Redux/eyevine

For Tipton, MDMA is not a magic cure, but rather a psychological aid that requires hard work on her part. Even so, it provides an escape from the cycle of anxiety, panic attacks and suicidal ideation that had trapped her for years. “You know how when you’re in a maze and all you can see is the walls, and you’re just turning and trying to find your way out?” she says. “Imagine if all of a sudden, like in a video game, you switch your perspective so you’re above the maze and can guide yourself — so now you can see that you’ve just got to take three lefts and a right.” That’s how it felt when she was coached into mentally revisiting the murder scene, she says.

Previously, when she’d thought about that day and the people involved, she would wall herself off from her emotion. The drug radically changed that mind-set. “Under the influence of MDMA, with these two therapists, I was able to go into that specific memory, stay embodied, and also find a depth of understanding and empathy for everything that had eluded me all my life,” she says.

Previously, she had been terrified to feel anything — a common symptom of PTSD. The MDMA, she explains, allowed her to revisit her trauma while holding on to the emotion. “I could go into that specific memory, and see the person my mother was. The circumstances that led her to that horrific and final act allowed me to find empathy and understanding for her.”

Molecular mechanisms

The mechanism by which MDMA allows someone to revisit traumatic memories without anxiety remains unclear. Researchers know that, chemically, psychedelics resemble the naturally occurring neurotransmitter serotonin. “They can hijack the serotonin system,” says Robin Carhart-Harris, a neuroscience and psychology researcher who heads the new psychedelics division at the University of California, San Francisco (UCSF).

Different psychedelics tend to bind to specific serotonin receptors, so they result in different signalling cascades throughout the brain. But MDMA is “a broader brush”, Carhart-Harris says. It doesn’t act on a specific serotonin receptor. “It increases serotonin functioning in the brain and body quite broadly,” he says.

By triggering the release of extra serotonin, MDMA makes it available to bind to receptors throughout the brain. The drug also prompts the release of lesser amounts of noradrenaline and dopamine, potentially increasing a person’s sociability while decreasing their anxiety and negative emotions. “What MDMA allows you to do in the therapeutic context is to go there, to work through the traumatic memories without being overwhelmed,” says Carhart-Harris.

Although MDMA has received most of the attention, clinicians who treat PTSD are not limiting their search for useful mind-altering drugs to just this one. “The field is much more complicated than most people appreciate,” says Alan Schatzberg, a psychiatrist at Stanford University in California. Ketamine, cannabis and psilocybin — the active compound in magic mushrooms — have also attracted researchers’ interest. Psilocybin in particular is showing promise.

COMPASS Pathways, a pharmaceutical company in London, has already had modest clinical-trial success testing a psilocybin preparation against treatment-resistant depression (see page S87). However, COMPASS noted that a small number of subjects who received the highest dose also had suicidal thoughts. Despite that, the company is planning to test psilocybin against PTSD, and has announced recruitment for a phase II trial led by researchers at King’s College London.

A critical period

Reports of the clinical effects of psychedelic therapy — loosening memories and habits that are deeply embedded — are stacking up. “It’s not like cognitive behavioural therapy or prolonged-exposure therapy, where it feels like you’re chasing someone around the room to get them to talk about the thing that happened in Afghanistan. They just say it,” says Jennifer Mitchell, director of UCSF’s Institute for Translational Neuroscience and lead author of the phase III MDMA trial published last year. But there is a problem: no one is clear about how or why psychedelics do what they seem to do.

Gül Dölen, a neuroscientist at Johns Hopkins University in Baltimore, Maryland, is interested in the idea that psychedelics might somehow unlock an ability to learn that’s normally seen only in very young brains (see page S86). As young animals develop, their brains go through crucial times called critical periods when particular skills — social, emotional, physical and more — are most easily acquired. These are discrete windows of time and, when they end, the brain becomes less plastic and it becomes harder to learn new skills. But when Dölen and her colleagues gave MDMA to adult mice, the animals developed an appetite for social interactions normally seen only in juveniles (R. Nardou et al. Nature 569, 116–120; 2019). The effect lasted more than two weeks after the acute effects of the drug had worn off. “It was our first clue that MDMA was reopening this critical period,” says Dölen.

In Dölen’s view, the reason MDMA works so well for treating PTSD is because reopening that critical period for a few weeks provides the opportunity for neurological rewiring, and talking therapies can take advantage of that. “That long, open state induced by MDMA is able to give a person plenty of time to recontextualize insights they had about their trauma,” Dölen says. The drug, she explains, allows a person to return to a malleable brain state, where they can relearn what’s safe, what’s not, who’s trustworthy, and how to be more present in the world.

The researchers are also increasingly sure that MDMA is not the only psychedelic that can restore some degree of metaplasticity (a persistent state that allows neurons to make changes at their connections). “When we first started, the assumption was that this is going to be unique to MDMA because it’s the only psychedelic that has these strong pro-social properties,” Dölen says. “No one is taking LSD and doing a cuddle puddle.”

But the Dölen laboratory is finding evidence that other psychedelics might be doing it, too. Although the internal process and cellular signalling pathways of each drug might be quite different, she thinks there might be more similarities than anyone realized. And she is also looking at whether psychedelics could have a useful role in opening up other critical periods, not just those related to depression and anxiety.

Until Dölen and others can more completely describe what’s happening at the molecular, cellular and organ levels, however, clinicians are operating largely in the dark. They think that psychedelics can be helpful, but, like all drugs, are not without risk. MDMA can cause nausea and blurred vision, and also (more rarely) heart disease and stroke. Psilocybin can prompt nausea, headaches and increased blood pressure. There are also risks associated with opening up the emotional wounds of someone with PTSD without proper guidance, support and follow-up.

Psychedelic therapy can leave people feeling psychologically vulnerable, Yehuda says. “Like any treatment, it has to be administered with care, thoughtfulness and minimal risk by highly trained therapists who know how to work with trauma survivors, as well as with concern for the patient and sobriety by the investigative team.”

Few studies have consistently tracked PTSD subjects after psychedelic therapy — according to Yehuda, the longest study so far included 18 months of follow-up, so the long-term benefits remain unclear. For Tipton, though, the improvement has been enduring. She says she has continued to make progress in learning not to divorce herself from fear and panic.

For years, she felt a surge of anxiety every time she arrived home, put her key in the lock, and heard her dogs on the other side of the door, pacing on the tile floor and excited to welcome her home. Then one day, about two months after her final session, she decided to follow that emotion to its source — something she’d never previously been able to do. “From the MDMA experience I’ve learned to stay with my feelings,” she says. Suddenly, she remembered that while she was walking through the murder scene, her mother’s two dachshunds were pacing on a concrete floor behind a pet gate. From the moment she remembered that, she says, her anxiety was gone.

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