Psychedelics ‘promising but not prime time,’ say researchers

University of Toronto researchers say that while psychedelics show great promise for treating psychiatric disorders, a first-of-its-kind study demonstrates the way the efficacy of these drugs is measured in randomized clinical trials needs improvement.

The research – published recently in JAMA Psychiatry – shows that many people involved in randomized clinical trials of psychedelic drugs are aware they are consuming them, not placebos, which means that the effects they report experiencing may not be scientifically sound.

Researchers say that decent “blinding integrity,” when people are unaware of whether they’ve consumed a placebo or the actual substance being studied, is important because it promotes scientific accuracy in assessing the impact of the drugs.

The study says if “functional unblinding” occurs in a psychedelic study, where people know they have taken psychedelics due to the psychoactive effects of the drug, it may “bias outcomes through expectancy effects, challenging the validity of efficacy estimates and regulatory acceptance.” The same can apply if people receive a placebo and do not have any psychoactive effects, researchers note.

Josh Rosenblat, an associate professor at the Temerty Faculty of Medicine and the study’s corresponding author, and Diana Orsini, a second-year Temerty Medicine PhD candidate in pharmacology and toxicology who is the study’s first author, did the research.

The researchers found in the systemic review they conducted that out of 112 randomized controlled trials of certain psychedelics, only 33 (or 29.5 per cent) looked at blinding integrity.

These included trials of psilocybin, lysergic acid diethylamide (LSD), ketamine, ayahuasca, noribogaine, methylenedioxymethamphetamine (MDMA),  and dimethyltryptamine (DMT).

The study also determined that more than 90 per cent of people involved in randomized clinical trials of psilocybin, LSD, and ayahuasca experienced blinding failures.

“The main takeaway of the study is that psychedelics are promising but not prime time from the perspective that a lot of people are assuming that we should just start prescribing psychedelics today, and it should just be available. But, given the methodological limitations, chiefly the functional blinding issue, we really need more research to figure this out,” says Rosenblat, who is an associate professor in the departments of psychiatry and pharmacology and toxicology, as well as the Institute of Medical Science.

“We really want to test if these interventions are helpful and safe. The focus really needs to be on more research focused on if psychedelics work, rather than clinical implementation,” says Rosenblat, who is also research and academic development program lead at University of Health Network (UHN) and the Krembil Brain Institute’s mental health program. Orsini is also a graduate research student at UHN’s Krembil Brain Institute.

Randomized clinical trials with good blinding integrity are “the gold standard” for ensuring the drugs being tested actually work – and not the result of a placebo effect a participant is experiencing, says Orsini. Therefore, blinding integrity is pivotal, she says.

Orsini noted that up to 85 per cent of participants in placebo controlled MDMA trials also experienced blinding failures.

“As we know with psychedelics, they often induce this acute subjective experience in which patients are reporting having an altered state of consciousness, and that means the participants can be functionally unblinded, and they now know which treatment they’re receiving,” says Orsini.

“This can be a really big methodological issue for randomized clinical trials as the whole principle of them is that they are supposed to be blinded studies and therefore we can confidently say that the treatment effects are due to just to the treatment, not just the patient believing they are getting a medication.”

Due to its findings, the study ultimately concludes that functional unblinding is “pervasive among participants and raters,” which leads to “concerns about the validity of efficacy findings.” The study also highlights the necessity in future for “standardized, validated measures and innovative designs [in randomized clinical trials] to separate true pharmacological effects from expectancy-driven responses.”

For example, in 2024, the U.S. Food and Drug Administration rejected the use of methylenedioxymethamphetamine (MDMA) for treatment of Post-Traumatic Stress Disorder, when combined with psychotherapy, in part because of concerns over functional unblinding in studies looking at its use, says Orsini.

Rosenblat says there has been a lot of media coverage over the use of psychedelics as a form of treatment for different health issues, and that the science around their use needs to be strong.

“This is the second wave of psychedelic research. With the first wave in the 1950’s and 1960’s, there was a lot of bad science happening,” he says.

“In this second wave of research, we’re really focusing on rigour and doing things in a high-quality, scientific way, and one of the pieces of that is this issue of functional unblinding and placebo effects. For psychedelics to become mainstream, and for psychedelics to become FDA and Health Canada approved for treating medical conditions, we need high-quality science and high-quality clinical trials.”