“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.
[..] 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. [..]
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. [..]
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.
But the potential for researchers to bias the outcomes of these trials has become a common critique 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 [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] 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. [..]
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 concerns raised 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 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 admitted 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.” [..]
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.” [..]
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. [LSD evangelist Timothy] 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. [..]
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.”
Full editorial, C Enders, New York Times, 2024.8.23