Clinical Trials of Psilocybin and Ecstasy As Treatments for Depression And

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;

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

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. chiatric disease. Rutter’s automatic circuit. Some studies evaluating psychedelics have Researchers started exploring the biological “People get locked into disorders like attempted to address this by giving people effects of psychedelics in the late 1990s, using depression because they develop this system in the control group a pill containing niacin, neuroimaging techniques such as positron of thinking which is efficient, but wrong,” which elicits a physical sensation — usually a emission tomography5 before and after vol- says David Nutt, a psychopharmacologist at flushing response in the skin. Mitchell says that unteers used the drugs, or in conjunction with Imperial College London and an outspoken some participants in her MDMA study who’ve antagonists that dampen some of their effects. supporter of evidence-based reforms to gov- been given the drug thought they received The studies show similarities in how brains ernment policies concerning illegal drugs. the placebo, while some taking the placebo respond to psychedelics such as psilocybin Psychiatry has a term for such thinking: rumi- believed that they had been given the drug. and LSD, as well as to N,N-dimethyltryptamine nation. The idea behind psychedelic therapy The studies’ designers must also tackle how (DMT), the active ingredient in ayahuasca, is that the receptive state that the drug con- important the non-drug aspects of the trial are and to mescaline, a psychedelic compound fers opens the door to fresh ideas about how to the results. These include the mindset of the derived from the peyote cactus. They all act to think about the past and future, which the individual going into the experience, and the on receptors for serotonin, a neurotransmitter therapist can reinforce. “There is a growing environment in which it takes place. that affects mood. evidence base to the principle that this is very The vibe is definitely hotel spa at the treat- Serotonin is also the target of the predomi- much about a synergy between drug-induced ment rooms for the COMPASS study at Utrecht nant class of psychiatric drugs known as selec- hyper-plasticity and therapeutic support,” University Medical Centre in the Netherlands. tive serotonin reuptake inhibitors, or SSRIs. says Carhart-Harris, who trained with Nutt. There’s a Mexican-style blanket folded at the Rutter says his journey with Carhart-Harris foot of a twin-size bed. Beanbag chairs hug a PSYCHEDELICS TAKE FLIGHT 17 trials was focused, but flexible. When Rutter first potted palm in the corner. And a poster of Van Over the past decade, there has been an removed a pair of eye shades after the drug Gogh’s Almond Blossom adorns one wall. All increase in clinical trials testing psilocybin, MDMA and LSD for use in psychiatric took effect, the therapist appeared “fractured” 24 sites in the study are similarly decorated. conditions, including depression, drug and seemed to have another eye in the cen- Then there’s the training and experience dependency and anorexia nervosa. tre of his forehead. “I should imagine I look of the therapists guiding both the dosing ses- = 1 trial quite strange to you now,” Carhart-Harris said. sions and the drug-free integration sessions. Psilocybin MDMA LSD Rutter burst out laughing and Carhart-Har- COMPASS, which became a public company ris joined him. When the laughter stopped, in September and earned a stock-market val- the two men started talking. Rutter wanted uation exceeding US$1 billion, developed a to discuss his resentments, which led to pon- five-tier training programme for therapists in dering about the word ‘relent’ and its etymol- its trial. Company co-founder and chief inno-

2010 2012 2014 2016 2018 2020 ogy. Carhart-Harris looked it up for him on his vation officer Ekaterina Malievskaia says site DIMENSIONS SOURCE:

COMPASS PATHWAYS COMPASS The setting for a psilocybin therapy session (shown in this mock-up) must be carefully replicated for clinical trials.

investigators must adhere to the training if the the control and placebo groups in its MDMA taking psychedelics. Those who are attracted company expects to win regulators’ approval. trial (see go.nature.com/362xsvp). But the to this type of experience, she argues, might be Madras goes further to say that the condi- company won’t say more about the results more likely to say positive things about it. Nutt tions of the trial will have to be replicated for until it releases the full data some time this has said that working with experienced users any wider roll-out of the drugs. They “have to year. It is also recruiting for a second phase III of the drugs minimizes the chance of adverse be approved under the stringent conditions in study using MDMA therapy for people with events. But there are other potential confound- which they were investigated”, she says. But the moderate-to-severe PTSD, which it aims to ers, according to Madras. “The consent forms path forward for mandating such conditions is complete before the end of the year. COMPASS tell you what the expectations are,” she says. “So unclear. For the US FDA, there is a mechanism expects to have results from its phase IIb study there’s bias on the part of the subjects.” to ensure that drugs are administered in a spe- on psilocybin by that time, and the company Rutter says that despite all that, he is cific way: Risk Evaluation and Mitigation Strat- says it is planning a phase III study. convinced that the treatment he received egies, or REMS. Through REMS, the agency can Robert Malenka, a psychiatrist and neuro- in 2015 changed his life for the better. In the require prescribing physicians and pharma- scientist at Stanford University in California weeks after his sessions, he found himself won- cists to be certified for a treatment strategy who has studied MDMA’s effects on rodents, dering whether the automatic circuit would designed to mitigate the risks associated with says he thinks that some psychedelic drugs return. “I was terrified,” he says, “and I realized a drug — such as addiction and dependency will eventually earn approval as treatments I’ve got a little bit of control over this, right?” for opiate prescription. REMS could be used for certain conditions. “They have potential The thought had never occurred to him before. with psychedelics, Dunn says. The effect would to be — I want to use the right analogy — a A week or so later, he was out with friends be to bundle the delivery of the drug with the part of our toolset for treating patients,” he at a shopping centre and sensed the return of therapy component, and potentially certify says. But he warns against overzealousness, optimism and openness. “It felt like somebody practitioners. A source working on one of the particularly a brand of evangelism he’s seen had opened a window in a stuffy room.” Five trials says that discussions are under way with among some of the underground purveyors years later, his depression has not returned. the FDA over whether therapists who admin- of psychedelic-assisted psychotherapy. “I don’t ister the drugs ought to be trained, what that think they’re going to be miracle cures,” he says. Paul Tullis is a journalist based in Amsterdam. training might involve and whether therapist He argues that the hypotheses for how the 1. Davis, A. K. et al. JAMA Psychiatry http://doi.org/10.1001/ certification should be required. drugs might be working in the brain still need jamapsychiatry.2020.3285 (2020). Certification could mean legitimizing thera- further research, and that investigating com- 2. Agin-Liebes, G. I. et al. J. Psychopharmacol. 34, 155–166 pists who have been ‘treating’ individuals with pounds that provide the same benefits without (2020). 3. Carhart-Harris, R. L. et al. Psychopharmacology 235, the drugs illegally for as long as 30 years. But the hallucinatory effects could prove worth- 399–408 (2018). some of these therapists might resist the while in the long run. Others point out that 4. Vollenweider, F. X. & Preller, K. H. Nature Rev. Neurosci. 21, advice, or the involvement, of a government SSRIs work for many individuals without cli- 611–624 (2020). 5. Vollenweider, F. X. et al. Neuropsychopharmacology 16, that has driven them underground. nicians fully understanding their mechanism. 357–372 (1997). Approvals still have a long way to go. Regarding the clinical work, however, Madras 6. Zhang, G. et al. Neuropharmacology 64, 403–413 (2013). Towards the end of 2020, MAPS reported in says she’s concerned by the studies’ size and 7. Hutten, N. R. P. W. et al. ACS Pharmacol. Transl. Sci. https://doi.org/10.1021/acsptsci.0c00099 (2020). a news release that there are statistically sig- design. She noted that many of them recruit 8. Lebedev, A. V. et al. Hum. Brain Mapp. 37, 3203–3213 nificant differences in the response between people who have had previous experience (2016).