The hype around psychedelics grew to a crescendo in 2023, when the Denver Convention Center played host to the largest psychedelic convention in history.
The MAPS Psychedelic Science Conference brought in 12,000 attendees and hundreds of speakers — scientists, policymakers, governors, and even high-profile celebrities like NFL quarterback Aaron Rodgers.
“I’m not tripping — culture is tipping,” said MAPS founder Rick Doblin, perhaps realizing for the first time that he was within sniffing distance of a legitimate psychedelic therapy, and this momentum might be just enough to carry him through.
The Multidisciplinary Association for Psychedelic Studies (MAPS) and its for-profit spinoff, Lykos Therapeutics, were behind clinical trials that the FDA reviewed earlier this month — trials that looked to “transform mental healthcare.” The results showed that MDMA-assisted psychotherapy led to a significant reduction in symptoms for people with post-traumatic stress disorder (PTSD); so substantial that 71.2 percent of the participants no longer met the criteria for a PTSD diagnosis.
It’s been 25 years since the FDA last approved treatments for the disorder. While SSRIs remain the most commonly prescribed treatment for PTSD, several patients do not respond to these medications; problems are further compounded by high dropouts and low remission rates, as well as the appearance of co-occurring conditions.
According to the Department of Veterans Affairs, anywhere from 7 to 30 percent of U.S. combat veterans experience PTSD; the VA had been pressured for years, recently creating an internal “Psychedelic Charter” and funding studies. It made the enthusiasm of veteran groups, lawmakers, billionaire investors, and community activists for MDMA-assisted therapy understandable.
Approval seemed all but assured until things began winding down earlier this year. The Institute of Clinical and Economic Review (ICER) published a report in March, rating the data for MDMA-assisted therapy as “insufficient,” and raising questions about possible misconduct.
At a subsequent FDA advisory committee meeting in June, significant misgivings about the clinical trial control were highlighted; the proceedings culminated in the ad comm voting 10 to 1 that the risk of MDMA outweighed its benefits.
While the FDA doesn’t have to go with the ad comm’s decision, it usually does; the agency chose to reject Lykos’ application. They couldn’t approve the treatment “based on data submitted to date,” requesting Lykos conduct an additional Phase 3 study — which would take “several years.”
Here’s the statement from Lykos CEO Amy Emerson:
The FDA request for another study is deeply disappointing, not just for all those who dedicated their lives to this pioneering effort, but principally for the millions of Americans with PTSD, along with their loved ones, who have not seen any new treatment options in over two decades. While conducting another Phase 3 study would take several years, we still maintain that many of the requests that had been previously discussed with the FDA and raised at the Advisory Committee meeting can be addressed with existing data, post-approval requirements or through reference to the scientific literature.
The company has been dealing with the fallout since: A day after the rejection, the journal Psychopharmacology retracted three papers related to MDMA-assisted therapy, citing “protocol violations amounting to unethical conduct,” particularly in one Phase 2 trial. On Thursday, Lykos announced that it would cut 75 percent of its staff, with the company’s founder stepping down from its board.
So what went wrong? Interestingly, most of the concerns addressed weren’t focused on MDMA itself, but on Lykos’ ability to conduct rigorous science. Central to this is the fact that
clinical trials involving psychedelics are fundamentally different.
Randomized controlled trials, or RCTs, are considered the gold standard of clinical research for their ability to minimize selection bias.
Neither participants nor the researchers studying them are told whether they’re dealing with the actual drug or a placebo, a practice to avoid allowing people’s outsize expectations about a treatment to shape their responses to it. “Blinding,” as this practice is called, may also equalize the placebo effect across groups.
But virtually no one can take a psychedelic drug and not know it. This “unblinding” upends the entire research, since researchers can’t conclusively determine whether results appear due to the drug’s effectiveness.
Scientists do have some theoretical workarounds: Researchers have been experimenting with what they’re calling active placebos, which involves giving the control group a substance that induces a physical effect that mimics that of the drug.
For example, in some studies with ayahuasca, which is a potent psychedelic drink, the researchers brewed control drinks that were similar in taste, color, and odor, and even causing some gastrointestinal discomfort characteristic of ayahuasca. In these studies, about 30 percent of the placebo group wrongly guessed that they were in the active group.
For trials involving MDMA and psilocybin, this is a little more difficult because you don’t have these physical cues — the smell and the taste. But even if Lykos and other companies could integrate these active placebos, there exists
a more serious conundrum plaguing psychedelic therapy: the therapy bit itself.
For years, doctors have held the stance that many drugs work best when taken in a therapeutic context — say antidepressants and psychotherapy. Psychedelic therapy, however, traditionally depends on it.
In this case, patients take the psychedelic in order to open them up to other types of psychological therapy. MDMA, an empathogen, supposedly breaks down the barriers around deep-seated trauma in a manner “that doesn’t make you withdraw or detach out of shame or fear, but instead helps you to accept and heal,” according to one of the authors on the Lykos study.
The idea is that in this post-psychedelic state, the brain is particularly flexible and receptive. This altered state —what some experts refer to as afterglow — coupled with therapeutic guidance, provides a new perspective for patients when working through trauma.
But therapy, in itself, is pretty complex. While commonly discussed as if it were a singular treatment, hundreds of distinct theoretical models remain currently in use; therapists mix and match different techniques, since every client needs a slightly different form of support. The practice is in part supported by the “Dodo bird verdict,” which claims that all models are equally effective in the end (although things are hardly that way).
A key tenet of Lykos’ version of MDMA-assisted therapy is that people possess an intuition that “might have a sense for how to move forward.” Look at Lykos’ publicly accessible treatment manual, and you’ll see several references to this “inner healing intelligence,” which is “a person’s innate capacity to heal the wounds of trauma.” But across nearly all psychedelic studies,
the role of talk therapy isn’t rigorously examined.
For starters, there’s no robust science confirming the existence of this nurturing “inner self.” Moreover, these studies are meant to isolate the effects of the drugs, and the psychotherapy is more or less held constant for either group. This is understandable since companies like Lykos have little incentive to research therapy itself. The greater their treatment relies on the administration of their proprietary MDMA-concoction, the better their chances of approval.
Right now, most trials are designed to test one psychedelic in combination with one style of therapy. Some researchers rely more on traditional and more extensively researched models — such as cognitive behavioral therapy — when creating potentially breakthrough psychedelic treatments.
But, like in machine learning, these trials leave a bit of a black-box problem: They reveal a connection exists, but not how it works. These trials can’t examine which elements of therapy are actually beneficial.
As a field, we don’t really understand how much therapy contributes to the efficacy of the drug, and Lykos’ data couldn’t clarify this question. Their approach to therapy isn’t the only option in psychedelic medicine, and they failed to explore others.
So what they’re proving right now is that a certain psychedelic, MDMA in this case, is beneficial when combined with psychotherapy; but
we have no evidence if one form of therapy pairs better with this substance than another.
Lykos could’ve improved its case, as one psychedelic clinical trials organization suggested, with a study designed to separate the effects of the psychedelic from the therapy component by running four arms of the trial: psychedelic with psychotherapy, psychedelic alone, placebo with psychotherapy, and placebo alone.
It also made the case for robust therapist training and monitoring, as well as a more evidence-based therapy model rather than the more intuitive model Lykos went with. But such trials are expensive. The cost of testing more variables in different combinations isn’t easily justified for a field that mostly relies on private money.
So to better fit through the specific regulation requirements of the FDA, biotechs could adapt their treatments — eventually doing away with therapy itself.
Certain companies are already pushing a therapy-lite model: MindMed earned an FDA breakthrough therapy designation for the use of LSD in the treatment of generalized anxiety disorder; a treatment that they repeatedly emphasized involved “no additional therapeutic intervention.”
We may witness something akin to the Ozempic effect in the field of psychotherapy: A drug that could do all the work would simply take away the need for conventional talk therapy, and it could come to dominate the market, but also spawn rip-offs and an alternative set of side-effects in the process.
This approach does have its own advocates: Certain experts argue that we may be going through a societal overreliance on talk therapy. If a psychedelic-only approach could prove beneficial, it could come to become the treatment of choice. But whether it happens at the expense of optimum treatment for patients, we’ll just have to see.
(Featured Image: Unsplash)