Tomorrow, a Food and Drug Administration advisory committee will meet to discuss whether the U.S. should approve the first psychedelic drug. The fate of this treatment — an MDMA-assisted treatment for post-traumatic stress disorder — will depend on how the FDA interprets data from two studies. Clinical Trials On the surface, the drug looks promising. Long-suffering patients who took it in conjunction with intensive talk therapy Approximately twice as likely Treated patients recovered from PTSD, as did those who received a placebo.
If approved this summer, the treatment could bring relief to some of the roughly 13 million Americans who suffer from PTSD — and serve as a model for other psychedelics that meet FDA regulatory standards. But underlying the two clinical trials is a conundrum that has plagued nearly all efforts to study psychedelics.
In clinical trials, participants (and the researchers who study them) typically do not know whether they are taking an actual drug or a placebo, to avoid people’s expectations of the treatment shaping their response to it. This method is called “blinding” and is a key component of randomized controlled clinical trials (RCTs). RCTs are medicine’s gold standard for proving that a drug actually works. But few people can take a hallucinogen and not know it.
Some experts believe that unblinding could undermine the entire field of psychedelic research, because researchers wouldn’t know whether the initial promise of the drug in clinical trials was real or whether it was a hallucination caused by a placebo effect or inflated expectations of the drug’s power. But others argue that RCTs themselves are problematic. For them, psychedelics expose flaws in our long-ignored gold standard, especially when it comes to testing psychoactive drugs.
If randomized controlled trials are properly designed, “there is no substitute for them,” Stanford neuroscientist Boris Heifetz told me. In RCTs, participants are randomly assigned to two groups to receive either the treatment or a placebo. Scientists have prized such trials since the 1960s for their power to rule out all non-drug reasons why someone receiving a new drug might get better. Chief among those reasons is the placebo effect, in which improvement comes from the patient’s belief in the treatment, not the drug or procedure itself. If trial participants enter with very high expectations (as experts suspect many psychedelic trials do), knowing they’ve been given a drug can encourage a positive response, while knowing they haven’t been given one can provoke a negative response. “We’ve made a lot of mistakes by trusting unblinded results,” says David Lind, chief medical officer of the Institute for Clinical and Economic Review, a nonprofit that evaluates new treatments.
Although RCTs have many advantages, “I think it’s clear that they’re not suitable for studying psychedelics,” Heifets says. In cancer drug trials, participants don’t know the difference between a saline drip and a drug. To test a new surgical procedure, a control group might be cut open and sutured without receiving any actual treatment. But psychedelics like psilocybin and LSD put people into a hallucinatory state that distorts space and time. MDMA, known to many as ecstasy, is less extreme but still evokes widespread feelings of love and empathy. “Participants will know within 30 minutes whether they’ve been assigned to the experimental or placebo condition,” Michiel van Elk, a cognitive psychologist at Leiden University, told me. In a clinical trial of MDMA run by the pharmaceutical company Lykos Therapeutics, nearly all participants correctly guessed which group they were in.
Many scientists hope to get around this problem by designing better blinds: Some labs are trying to keep patients in the dark by administering drugs. Under anesthesia or use mind-altering drugs Methamphetamine Since the 1960s, psychedelic researchers have known that the beliefs and expectations a person brings to a trip can influence whether it’s a cure or a nightmare. (That’s why most psychedelic therapy protocols include multiple psychotherapy sessions before, during, and after treatment.) By trying to separate the drug’s effects from the context in which it’s administered (therapist to patient, both hoping for a cure), blinded studies may not get the whole picture.
In this light, a high rate of unblinding in positive psychedelic trials doesn’t necessarily mean the results are invalid. “What contributes to the improvement is how people relate to the effects and to the therapist,” Eduardo Schönberg, a neuroscientist at Instituto Phaneros, a nonprofit psychedelic drug research center in Brazil, told me. Recent research backs this up: One small study found stronger bonds between therapists and patients (the drug’s empathy-inducing effects help build bonds) among chronic PTSD patients who received MDMA-assisted therapy.Predicting Treatment SuccessGiven the importance of context, even the most perfectly designed RCTs may not capture how helpful these drugs are outside of the trial, Dr. Schenberg said.
Such failures, if they existed, would likely extend not only to hallucinogens but also to several classes of psychoactive drugs. For example: 2022 Analysis Many antidepressant trials have found it impossible to effectively blind participants because of side effects. 80 percent “Half of the treatment responses with antidepressants are due to placebo responses,” Amelia Scott, a clinical psychologist at Macquarie University who co-authored the study, told me. But the reality is that antidepressants work for many people, and RCTs don’t fully capture what these drugs do. And limiting ourselves to treatments that can be fully blinded might mean ignoring helpful mental health interventions. “We shouldn’t be afraid to question the gold standard,” Schenberg told me. “Different types of illnesses and treatments might require slightly different standards.”
RCTs aren’t likely to lose their status as the gold standard for evaluating psychedelics or anything else anytime soon, but they could be complemented by other kinds of studies that broaden our understanding of how psychedelics work, Matt Butler, a neuroscientist at King’s College London, told me. Scientists are already experimenting with open-label trials, where participants know what treatment they’ll receive and measure expectancies as well as treatment effects. Track how your treatment is working The study, conducted in an actual clinic, can provide more detail on what treatment settings are most effective. “This level of evidence is not as good as an RCT,” Butler said, but it could help improve understanding of when non-RCT-compliant treatments may be most effective.
That’s not to say that Lycos’ flawed RCT data is enough to convince FDA advisers that MDMA should be made available to Americans with PTSD. Some groups, including the American Psychiatric Association, have expressed concern Prior to the advisory meeting, there had been controversy over the trial. Problems with blinding, plus allegations that therapists had encouraged participants to report favorable outcomes and conceal adverse events, led the Institute for Clinical and Economic Review to criticize the study. Doubtful reports About the study. Lycos CEO Amy Emerson fired back in a statement, saying, “We are confident in the quality and integrity of our research and development program.” Still, some researchers remain uneasy. “If this trial sets a precedent that the data are acceptable, what does that mean for the future?” Suresh Muthukumaraswamy, a neuropharmacologist at the University of Auckland, told me.
Recent cases suggest that blinding may not be a problem for the FDA. In 2019, the FDA Supravato Esketamine Nasal Spray— A type of ketamine — to treat depression Concerns FDA to unblind clinical trials Worked with Lycos The FDA has been working on designing clinical trials for MDMA therapy since it received breakthrough therapy designation in 2017. An FDA spokesperson said in an email that while blinded RCTs provide the most rigorous level of evidence, “unblinded studies are also considered adequate and well-controlled as long as they have a valid comparison with a control.” In such cases, the regulator can take into account factors such as the size of the treatment effect to determine whether the treatment is significantly better than a placebo, the spokesperson said.
Even if the FDA were to give the nod, rolling out psychedelic therapies before scientists fully understand the interactions between expectations, therapies and drugs could mean missing an opportunity to force companies to provide data that would meaningfully advance research into these drugs, Muthukumaraswamy said. It also risks undermining the value of these treatments in the long run. If sky-high expectations are ultimately what’s driving the positive results we’re seeing now, the FDA could end up approving treatments that become less effective as the novelty wears off. That’s especially true if they’re missing key elements that make these treatments work or put people at risk for bad experiences. Research beyond the gold standard may be needed to better answer these questions about psychedelics and other psychoactive drugs.
