Feature THE RISE OF PSYCHEDELIC PSYCHIATRY Clinical trials of psilocybin and ecstasy as treatments for depression and post-traumatic stress disorder are starting to give results, but approvals will be challenging. By Paul Tullis n a sunny day in London in 2015, Kirk lovely, and especially Robin,” Rutter recalls. bejewelled structures. Then his mind went to Rutter rode the Tube to Hammer- Carhart-Harris led him to a room with a mag- work on his grief. smith Hospital in hopes of finally netic resonance imaging (MRI) machine, so The Imperial study was one of a spate of putting an end to his depression. researchers could acquire a baseline of his clinical trials launched over the past few years Rutter had lived with the condi- brain activity. Then he showed Rutter where using illicit psychedelic drugs such as psilo- tion off and on for years, but the he would spend his time while on the drug. cybin, lysergic acid diethylamide (LSD) and burden had grown since the death Carhart-Harris asked him to lie down and played MDMA (3,4-methylenedioxymethampheta- of his mother in 2011, followed by a him some of the music that would accompany mine, also known as molly or ecstasy) to treat Orelationship break-up and a car accident the the session. He explained that he would have mental-health disorders, generally with the year after. It felt as if his brain was stuck on on hand a drug that could neutralize the hallu- close guidance of a psychiatrist or psycho- what he describes as “an automatic circuit”, cinogen, if necessary. Then the two practised a therapist. The idea has been around for dec- repeating the same negative thoughts like a grounding technique, to help calm Rutter in the ades — or centuries in some cultures — but the mantra: “‘Everything I do turns to crap.’ I actu- event that he became overwhelmed. Without momentum has picked up drastically over the ally believed that,” he recalls. warning, Rutter burst into tears. past few years as investors and scientists have The visit to Hammersmith was a preview. “I think I knew this was going to be unpack- begun to champion the approach again (see He would be returning the next day to partici- ing a lot — I was carrying a bit of a load at the ‘Psychedelics take flight’). pate in a study, taking a powerful hallucinogen time,” Rutter says. Once dismissed as the dangerous dalliances under the guidance of Robin Carhart-Harris, When Rutter returned the next day, one of of the counterculture, these drugs are gaining a psychologist and neuroscientist at Imperial the researchers handed him two pills contain- mainstream acceptance. Several states and College London. Years of talking therapy and a ing a synthetic form of psilocybin, the psycho- cities in the United States are in the process variety of anti-anxiety medications had failed active ingredient found in magic mushrooms. of legalizing or decriminalizing psilocybin to improve Rutter’s condition, qualifying him Rutter lay down on the bed and put on head- for therapeutic or recreational purposes. And for the trial. phones and an eye mask. Soon, images of San- respected institutions such as Imperial; Johns “Everyone was super nice, like really skrit text appeared to him. Later, he saw golden Hopkins University in Baltimore, Maryland; 506 | Nature | Vol 589 | 28 January 2021 ©2021 Spri nger Nature Li mited. All rights reserved. ©2021 Spri nger Nature Li mited. All rights reserved. the University of California, Berkeley; and to grapple with how to implement that safely. the Icahn School of Medicine at Mount Sinai “The clinical trials that have been reported in New York City have opened centres devoted on depression have been done under highly to studying psychedelics. Several small stud- circumscribed and controlled conditions,” ies suggest the drugs can be safely adminis- says Bertha Madras, a psychobiologist at Har- tered and might have benefits for people with I THINK I KNEW THIS vard Medical School who is based at McLean ILLUSTRATION BY GIZEM VURAL BY ILLUSTRATION intractable depression and other psycholog- WAS GOING TO BE Hospital in Belmont, Massachusetts. That will ical problems, such as post-traumatic stress make interpreting results difficult. A treat- disorder (PTSD). One clinical trial involv- UNPACKING A LOT. I WAS ment might show benefits in a trial because ing MDMA has recently ended, with results the experience is carefully coordinated, and expected to be published soon. Regulators CARRYING A BIT OF A everyone is well trained. Placebo controls will then be considering whether to make the pose another challenge because the drugs treatment available with a prescription. LOAD AT THE TIME.” have such powerful effects. Psychedelic-assisted psychotherapy could And there are risks. In extremely rare provide needed options for debilitating psychiatrist at the University of California, instances, psychedelics such as psilocybin mental-health disorders including PTSD, Los Angeles, who sometimes advises the and LSD can evoke a lasting psychotic reac- major depressive disorder, alcohol-use dis- US Food and Drug Administration (FDA) tion, more often in people with a family history order, anorexia nervosa and more that kill on psychiatric drugs. Most drugs that treat of psychosis. Those with schizophrenia, for thousands every year in the United States, and depression and anxiety can be picked up example, are excluded from trials involving cost billions worldwide in lost productivity. at a neighbourhood pharmacy. These new psychedelics as a result. MDMA, moreover, But the strategies represent a new frontier approaches, by contrast, use a powerful is an amphetamine derivative, so could come for regulators. “This is unexplored ground as substance in a therapeutic setting under the with risks for abuse. far as a formally evaluated intervention for close watch of a trained psychotherapist, and But many researchers are excited. Sev- a psychiatric disorder,” says Walter Dunn, a regulators and treatment providers will need eral trials show dramatic results: in a study Nature | Vol 589 | 28 January 2021 | 507 ©2021 Spri nger Nature Li mited. All rights reserved. ©2021 Spri nger Nature Li mited. All rights reserved. Feature published in November 2020, for example, It is now thought that these antidepressants laptop. “That was a lovely moment, actually,” 71% of people who took psilocybin for major work not by flooding the brain with the neu- Rutter says. He returned for a second session depressive disorder showed a greater than rotransmitter, as was initially assumed, but by with a stronger dose of the drug, followed by 50% reduction in symptoms after four weeks, stimulating neuroplasticity — the brain’s ability a second MRI and an ‘integration’ session, to and half of the participants entered remis- to forge new neuronal connections. There is discuss the experiences. sion1. Some follow-up studies after therapy, some evidence that psychedelic drugs, such The treatment “made me look at grief dif- although small, have shown lasting benefits2,3. as psilocybin, enhance neuroplasticity in ani- ferently”, Rutter says. “It was a realization that “Sometimes with a therapeutic, you look mals6, and limited evidence suggests that the actually it wasn’t helping, and letting go wasn’t at the data and think, ‘It slightly moved the same might happen in human brains7,8. Clinical a betrayal.” needle,’” says Jennifer Mitchell, a neurologist studies also suggest that the biological effects at the Weill Institute for Neurosciences at the work best in concert with human guidance. Clinical hurdles University of California, San Francisco, who The drugs “activate a therapeutic, dreamlike Testing these drugs effectively and translating worked on the recently finished MDMA trial. state, intensifying sensory perception, and the clinical research into actual treatments “Then you see MDMA and you’re like, ‘Never memories pop up like little films”, says Franz will prove challenging, however. Two of the mind that.’ It’s a very different effect size.” Vollenweider, a psychiatrist and neurochem- most closely watched studies have grappled Rutter was so moved by his experience with ist at the University Hospital of Psychiatry in with this. One is the recently completed MDMA psilocybin that he has consulted for one of the trial, which was testing the approach in peo- companies sponsoring trials of the compound. ple with severe PTSD. It was a phase III study, usually the final stage before drug regulators Rave new world decide whether to approve a treatment, and The current wave of interest in the therapeu- it involved 90 participants at 15 sites around tic potential of psychedelics is something of a THEY HAVE POTENTIAL the world. The Multidisciplinary Association renaissance. In the 1950s and 1960s, scientists for Psychedelic Studies (MAPS), a non-profit published more than 1,000 articles on using TO BE A PART OF OUR organization in San Jose, California, spon- psychedelics as a psychiatric treatment; the sored the study, but has not so far released drugs were tested on around 40,000 people TOOLSET FOR TREATING the results. in total4. Then, as recreational use of the drugs Meanwhile, the mental-health-care com- spread, they were banned and the FDA con- PATIENTS.” pany COMPASS Pathways in London is running stricted supplies for research. Only recently a phase IIb trial — testing different dosages of have neuroscientists and psychopharmacol- Zurich, Switzerland, and one of the pioneers psilocybin for treatment-resistant depression. ogists such as Carhart-Harris had the technol- of the modern era of psychedelic research. He Evaluating the results won’t be simple. One ogy to start unpicking how they work in the thinks that this receptive state of mind pro- concern revolves around controls. Most indi- brain. That has given them some insights as vides an opportunity to help people escape viduals given a placebo will know that they to how these compounds might help in psy- from rigid patterns of thought, not unlike are not receiving a powerful hallucinogen.