“How Psychedelic Research Got High on Its Own Supply”, The New York Times
By Caty Enders, Sunday Review, August 25, 2024
Things weren’t supposed to go this way. The drug company Lykos Therapeutics had spent much of this year expecting to vault to meteoric heights. It had sent an application to the Food and Drug Administration seeking approval to use MDMA to treat post-traumatic stress disorder. Lykos expected F.D.A. approval; it was banking on it.
And then on Aug. 9, the F.D.A.’s decision came through: rejection. It was the capstone to months of increasingly loud concerns being voiced over the quality of Lykos’s clinical trials. And in the wake of the F.D.A. decision, the journal Psychopharmacology retracted three papers related to research on MDMA, citing “unethical conduct,” an apparent reference to allegations of sexual abuse on the part of an unlicensed therapist at one of the trial sites. Several of the authors of the retracted papers were affiliated with Lykos.
It is a shocking decrescendo for a drug that had been promoted for years as best positioned to lead a psychedelic mental health revolution. The F.D.A.’s rejection signals greater uncertainty for the future of psychedelic medicine. And it will take more than just additional clinical trials for advocates to get back on track — it might require changing the culture of the research community from within.
First synthesized by the drug company Merck in 1912, MDMA, also known as the party drug Ecstasy or molly, has both stimulant and hallucinogenic properties. It also has the ability to foster feelings of connectedness and to seemingly dissolve a person’s mental boundaries, which advocates say can help patients revisit their trauma more comfortably during psychotherapy sessions in order to heal from it. Lykos has spent years conducting clinical trials testing whether MDMA-assisted psychotherapy could alleviate the symptoms of PTSD. Its most recent drug trial showed that more than 86 percent of people treated had a measurable reduction in symptom severity. Even more impressive, the effect seemed to be lasting. Had the therapy been approved, it would have become the first new treatment for PTSD in decades and would have handed over administration and control of prescription MDMA to Lykos for at least five years.
More broadly, proponents hoped a green light from the F.D.A. would open the door to regulatory approval for other psychedelics in mental health treatment, an area of medicine that has been desperate for innovation. Mental health disorders are surging, with rates of depression, anxiety and PTSD all on the rise, and current drugs don’t work terribly well. The majority of patients diagnosed with depression do not benefit from the first medications they are given. Conditions like PTSD are challenging to treat, and veterans’ groups have been especially supportive of the potential for psychedelics to address the mental trauma suffered during combat. Amid growing enthusiasm, drug companies, clinicians and patients had enormous hope that psychedelics could relieve the symptoms of millions.
But that hope began to fray in June, when an advisory panel to the F.D.A. voted almost unanimously against recommending Lykos’s MDMA treatment. With what seemed to be audible irritation, the chair of the F.D.A. review panel, Dr. Rajesh Narendran, called Lykos’s study so poorly conducted as to be “meaningless,” adding that he was “not convinced at all” that MDMA could effectively treat PTSD.
Asked about the reasoning behind the formal rejection of Lykos’s application delivered on Aug. 9, an F.D.A. spokeswoman told me that significant limitations to the data “prevent the agency from concluding that this drug is safe and effective.” (The spokeswoman noted that the F.D.A. couldn’t legally share more details since Lykos has so far declined to make public the letter that contained the agency’s reasoning.)
If you had asked me some years ago whether the F.D.A. would and should approve this much-anticipated new drug, I would have given an enthusiastic yes. I was for a long time a psychedelic proponent, bullish on the idea that a once-illicit treatment could have widespread benefits for the many who are suffering. But through my own experience in the psychedelic community and proximity to the science of psychedelic therapy, I’ve come to realize that the field is plagued with poor clinical trial design and questionable practices that have led researchers and clinicians to premature confidence in what psychedelics can do. The recent F.D.A. decision has added to my concern that Western medicine’s promotion of psychedelics might have oversold hope to the most vulnerable among us while fueling an industry that was once projected to be worth over $7 billion by 2029.
My personal Summer of Love kicked off in 2018, when I first dropped acid and slipped into a community of medical professionals and researchers who both promoted and used psychedelics. The excitement for these drugs seemed to be in the very air of Cambridge, Mass., where I had moved for a science journalism fellowship, auditing classes at M.I.T. and Harvard. I attended a seminar taught by Michael Pollan before he released his 2018 book on the resurgent popularity and potential of psychedelics, “How to Change Your Mind.” Society seemed to be slowly opening up to these drugs, and it felt as though we were at the center of things. Taking MDMA also felt like a doorway to the purest form of love and truth I had ever experienced; it seemed obvious to me that MDMA had benefits.
In hindsight, the confidence we had in these substances before the clinical trials were finished should have been a warning sign that hype was outstripping the science. In November of 2018, I was invited to a dinner where the host rang up Rick Doblin, the founder and president of the nonprofit Multidisciplinary Association for Psychedelic Studies, which launched Lykos as its for-profit arm 10 years ago and is arguably the most prominent face of the current renaissance in psychedelics. Dr. Doblin gave an impromptu speech over speakerphone about the promise of MDMA for trauma. Barring an unforeseen derailment, he expected the F.D.A. to approve his company’s new drug application for MDMA-assisted psychotherapy in just a few years. (The F.D.A. does not regulate psychotherapy; its purview is solely whether to allow clinical use of these drugs.)
I had assumed, based on the enthusiasm of researchers and clinicians in Cambridge also taking psychedelics at the time and on my own experiences, that the evidence this treatment worked was overwhelmingly positive.
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But the potential for researchers to bias the outcomes of these trials has become a common criticism of the psychedelic research field. It is unusual for a drug under F.D.A. consideration to also be used personally and recreationally by the researchers studying it or even for clinical trial researchers and clinicians to be encouraged to test the drug themselves. But that’s exactly what Lykos has done with MDMA. In a phone conversation after the F.D.A. decision, Dr. Doblin told me that therapists should be “strongly encouraged” to have their own psychedelic experiences, as it “really helps therapists to better understand their patients.” He says almost all of the researchers in the Lykos Phase 3 clinical trials underwent MDMA experiences themselves, and many studying the drug are open about their own recreational use.
It’s difficult to disentangle the personal enthusiasm for psychedelics with the study of these drugs as therapeutic interventions. And the extraordinary claims of some of its leading researchers — Dr. Doblin has professed a belief that psychedelics will usher in world peace — as well as criticisms of the quality of the clinical trials only accentuate how much the enthusiasm has gotten ahead of the science.
After years of growing hype around psychedelics and their therapeutic potential, the F.D.A.’s rejection of Lykos’s application was sobering. But the decision draws from new studies and independent reviews calling into question the quality of research and data around MDMA, as well as the safety and efficacy of psychedelics as a treatment for mental disorders more broadly. Fundamental questions about risk factors, side effects and potential for abuse are still unanswered. Among the concernsraised by official reviews of the MDMA trials: skewed results caused by the fact that around 40 percent of all participants had prior experience with MDMA, participants’ propensity to guess correctly whether they’d received the drug or a placebo, small sample sizes, organizers’ failure to respond to allegations of abuse of patients and a lack of monitoring for adverse events and the likelihood that abuse of the drug will occur. Growing evidence elsewhere indicates that the placebo effect and the biasing of study participants, as well as the bias of the researchers themselves, might actually be what accounts for much of the improvements seen in psychedelic trial participants.
The psychedelic renaissance is now at a point of reckoning, and the extraordinary promise of these drugs to quickly and easily transform lives for the better is starting to look more like a fever dream.
Some of the criticisms of the current research and the ethics of its leaders have been present from the start. As part of a postwar pharmacological boom, psychiatrists in the 1950s explored psychedelics enthusiastically. About a thousand research papers were produced; tens of thousands of patients were prescribed LSD. But as the lines between scientific, clinical and recreational drug experimentation among researchers blurred, experts who once saw potential in psychedelics warned against their potential dangers.
“The trouble is, LSD attracts unstable therapists as much as it does the neurotic patient,” said Sidney Cohen, a leading psychedelic researcher and psychiatrist, in 1963. “It gives them an intoxicating sense of power to bestow such a fabulous experience on others.”
The Controlled Substances Act of 1970 turned many psychedelics, including psilocybin and LSD, into Schedule I drugs, meaning the government believed they had no accepted medical use and a high potential for abuse. (MDMA was classified as a Schedule I drug in 1985.) This hobbled research and sent much of the experimenting underground for more than a quarter century.
In the 1990s, researchers were able to gain limited government permission to study the psychedelics DMT and psilocybin, opening the door to renewed study of psychedelics for mental health disorders. One of the leaders to emerge from the underground was Dr. Doblin, who founded MAPS in 1986. MAPS and its corporate spinoff Lykos have emerged as leaders in psychedelic medicine, collecting hundreds of millions in donations and investment in psychedelic research and advocacy. That money has enabled and accelerated MDMA clinical trials through Lykos. Since he was 18,Dr. Doblin says, he has been committed to “bringing back psychedelics,” drawing on his ties to the LSD evangelist Timothy Leary and the New Age Human Potential Movement.
Despite spearheading the clinical trials for MDMA, Dr. Doblin is not a scientist. He holds a Ph.D. in public policy from Harvard’s Kennedy School of Government, where he did his dissertation on how to get psychedelics and marijuana adopted by Western medicine, and has openly said that he sees his role as finding a strategic route to popularize psychedelics. “We don’t actually do science; we do political science,” Dr. Doblin said of his work with MAPS in a 2021 podcast with the activist Marianne Williamson. He described his organization’s focus on veterans as a calculated public relations move. “In this country, there’s kind of a veneration of veterans,” he said. “That’s how I chose MDMA for PTSD.”
Critics have often cited Dr. Doblin’s public comments as overzealous and beyond the scope of treating mental health conditions. He has encouraged personal use of psychedelics, claiming they have the potential to change the world for the better. “I continue to be a drug user or a medicine user or whatever you want to call it,” Dr. Doblin said in a June podcast. This summer he repeated his hopes that MDMA could help achieve “a world of net zero trauma,” as well as “mass mental health and a spiritualized humanity.”
Neşe Devenot was once a believer. A psychedelic humanities researcher at Johns Hopkins University and a researcher at the Project on Psychedelics Law and Regulation at Harvard, Dr. Devenot, who uses they/them pronouns, used to volunteer for MAPS. But they began to have doubts about the organization’s work, in part because they argue that the therapeutic practices MAPS promotes increase the likelihood of boundary violations.
Lykos has maintained the importance of using MDMA in conjunction with its peculiar form of psychotherapy. The treatment manual for MAPS therapists includes several recommendations, such as using “nurturing touch” and the power of suggestion. The manual also instructs therapists to utilize “inner healing intelligence.” The idea, roughly, is that patients can heal themselves, provided they can connect with this personal spiritual force.
Dr. Devenot helped organize a formal petition to the F.D.A., released in April, calling for a slowdown in F.D.A. approval of MDMA-assisted psychotherapy for PTSD, signed by several dozen psychedelic scientists and clinicians from major research institutions. A co-author of the petition was Brian Pace, who teaches psychedelic studies at the Ohio State University and testified to the F.D.A. advisory committee that “Lykos is a therapy cult that uses the application under review to further mystical and utopian goals. This lens explains the mounting allegations against them regarding research misconduct and clinical trial participant harms.”
Dr. Doblin calls the allegations of cultlike behavior ridiculous. “Where are all my Rolls-Royces? Where’s all my stock options? Where’s everybody that agrees with me on everything?” he asked rhetorically over the phone. “That’s absurd. But it’s part of this idea of just making whatever wild allegations you can.”
He also dismissed criticisms of the clinical trials, telling me: “It’s very well known that it’s difficult to impossible to do double-blind studies with psychedelics.” He defended the scientific rigor of the MDMA trials and emphasized that Lykos consulted with the F.D.A. on the design of the trials. He sees the agency’s decision not as a scientific failure but as a failure by Lykos to communicate effectively to the public after submitting the new drug application.
Other extraordinary characters loom large over this scene. Another evangelist for the use of these drugs for therapeutic purposes is the psychiatrist Ben Sessa, who has trained with MAPS and helped lead training programs in Australia for new therapists after it became the first country to classify psychedelics as medicine. He has boldly argued that all psychedelics “work for everything” and have universal efficacy for treating all kinds of mental disorders. Earlier this year, news broke that a medical tribunal had temporarily suspended Dr. Sessa’s license for terminating his care of a female patient in 2021 so that he could have a sexual relationship with her.
Dr. Doblin credits the teachings of the psychiatrist Stanislav Grof, a New Age pioneer who’s put forth many controversial ideas about psychology and consciousness, as helping to lay the foundation for much of the theory that underpins the MAPS approach to psychedelic therapy. The MAPS manual does not mention his belief that these drugs allow you to tap into “cosmic consciousness” and meet demons and deities from other realms.
The actual data on psychedelics for mental health tend to fall short of some of the staunchest advocates’ most extraordinary claims.
Like many pharmaceuticals, it’s not known yet how psychedelics work in the brain, but proponents talk excitedly about these drugs’ ability to remove a patient’s mental armor. Scholars suggest these drugs work by turning up the volume of individuals’ surroundings, making them more suggestible and opening them up to ideas they might otherwise have shut out.
But how psychedelics — a loose term for a variety of different drugs with very different qualities — affect the brain can differ from person to person. Some effects might lead to improvement in mental health in some people by reducing anxiety, fear and depression. Others may experience no effect or see an increased risk of negative outcomes. Different drugs show different effects on memory and brain connectivity. Some might be desirable for some patients; others might not be. The recent death of the actor Matthew Perry from the acute effects of ketamine, a sedative anesthetic with psychedelic properties, highlights the risks of therapeutic use turning into harmful abuse.
Research also increasingly indicates a large placebo effect in many psychedelic trials. Despite its blockbuster popularity, the use of ketamine to treat depression has come under new scrutiny. A paper released in Nature Mental Health last fall found that people with depression who were treated with ketamine experienced substantial improvement — but no more than when they were treated with a placebo. Participants in both the active and control patient groups were under anesthesia and couldn’t tell which drugs they were receiving.
The senior author of the study, Boris Heifets, a longtime psychedelics researcher at Stanford, told me the results were a “wake-up call” for him. He expressed concern that the extraordinary hype around psychedelics as miracle cures could be responsible for positive clinical trial data.
“The placebo effect is still the strongest medicine we have,” said Dr. Heifets. “If we want interpretable science on psychedelics, we have to design better clinical trials.”
A systematic review published last year in The Journal of Psychopharmacology scrutinized all clinical trials to date that tested whether classical psychedelics could be used to treat addiction, depression, obsessive-compulsive disorder and anxiety. It found numerous flaws in the design of these studies, including a high participant dropout rate, small sample sizes and difficulties keeping patients blinded to whether they received the drug or a placebo. And it also found a high risk of bias in all trials but one. The psychedelics researcher Matthew Johnson filed a complaint last year to Johns Hopkins University, his former employer, claiming that his former colleague Roland Griffiths biased the results of his psilocybin trials by injecting personal beliefs and steering participants toward religious experiences. (Johns Hopkins did not respond to questions about the status of the investigation.)
Manoj Doss, a cognitive neuropsychopharmacologist at the University of Texas at Austin Dell Medical School, has found that psychedelics create a mix of novelty, familiarity and insight. This combination produces what he described as “noetic” understanding, or the undeniable feeling that one has gained some insight or knowledge. Critically, notes Dr. Doss, this noetic feeling “doesn’t have to be true.” Those mystical, significant feelings you experience while on psychedelics, he and his co-authors wrote in a recent Communication Psychology paper, aren’t necessarily helpful from a therapeutic perspective and might even contribute to false beliefs and further mental health issues.
In other words, a beautiful trip may feel profound, but it doesn’t necessarily translate into long-term mental health benefits.
If psychedelics make people more suggestible, they may also create feelings of possessing secret knowledge or insight — even for providers.
“I ain’t no snitch, but … most researchers I know have done these drugs themselves,” said Dr. Doss in a talk in April. “My guess is that they felt like they’re gaining insight into the mind. And yet when they come back, they’re not doing anything — that I can tell — that has proved anything new.”
Some of the most prominent figures from MAPS and Lykos have encouraged illicit, nonclinical use of psychedelics, by both clinicians and patients. Dr. Doblin himself has said that MDMA could be used by individuals with the help of a “trusted friend” or alone, in order for people to be able to “heal themselves.”
Dr. Sessa, who has trained countless practitioners in multiple countries in psychedelic therapy and guided clinical trials, speaks openly about his own recreational experiences and argues for normalizing unsupervised drug use to convince the broader public of psychedelic safety.
“We need everyday people to say, you know, ‘I take acid a few times a year.’ ‘I’ll take MDMA every now and then with my wife, and it brings us close together,’ you know?” Dr. Sessa said on a podcast in 2017. “I think the government will find that even harder to resist than data.”
But encouraging people to break the law and tear down their own boundaries has obvious risks, particularly while chemically stripping away patients’ fear responses. The F.D.A. review“identified cases where MDMA was used to perpetrate sexual assault.” Walter Dunn, a psychiatrist at U.C.L.A., wondered in an advisory panel meeting in June how many such cases were going underreported and urged the F.D.A. to work closely with state medical boards to try to get a handle on the extent of therapists’ abuses.
While I am now skeptical as to whether these drugs can be harnessed and used effectively in Western medical settings, I think it is worth continuing to research their effects. If breaking down boundaries is key to how these drugs might treat intractable mental illnesses, then medicine must be more vigilant about how they are studied and regulated. My own falling out with psychedelics took a long time, perhaps because of the strange faith people tend to have in these drugs and in those who provide them (a phenomenon Dr. Leary called “imprinting”). For many years, I accepted as normal the blurring of lines between clinical and research interests and recreational use. I failed to recognize the ways in which my own use made me more credulous and less clear about my own boundaries. Less like myself.
Lykos announced Dr. Doblin’s resignation on Aug. 15, the same day it said that the company was laying off 75 percent of its staff. He told me over the phone that what led him to step down were differences of opinion about how to handle communications with the public and whether therapists should be encouraged to take MDMA themselves. He still sees the path to “spiritualized humanity” as going through the F.D.A. and plans to use his position at MAPS to continue his mission of “bringing MDMA to the world.” Lykos did not respond to requests for comment.
Lykos has said that it plans to meet with the F.D.A. in the coming months to address the agency’s concerns and try to avoid having to conduct another costly clinical trial. I hope that the researchers who ran the MAPS trials would heed the criticisms of colleagues and participants who felt that much of the research was inconclusive and some of it so flawed that it needed to be retracted and redone.
The stakes are high; with them, the standards for psychedelic research will be set. The medical and research community owes it to the many patients who need better mental health treatments to do this research with rigor and care, so that those who are suffering are not subjected to undue risk and further harm.
Caty Enders is a science journalist and a Good Science Project-Johns Hopkins science writing fellow. She is working on a book about boundaries.