It’s easy to understand why more than 90% of patients in psychedelic trials know they received the study drug. Even when trials use a drug in the comparison group that produces a noticeable effect, those alternatives typically don’t trigger hours of the trippy perceptual or emotional changes psychedelics are known for.
“Niacin has been tried … Either people met God or they got itchy,” said Dr. Joshua Woolley, associate professor in residence of psychiatry and behavioral sciences at the University of California, San Francisco.
Not being able to blind participants in a study’s control group can be a problem. When patients know if they’re taking the study drug it can skew the outcome, potentially shrinking the placebo response, which may make the trial drug look more effective than it may be in real-world use.
“Placebo response in psychedelic trials is about half the placebo response in SSRI and ketamine trials,” Woolley noted.
Woolley and his co-authors of a recent JAMA Psychiatry viewpoint are advocating for trial design changes to gain a clearer picture of how psychedelic drugs are truly performing. For example, the authors proposed using a combination of drugs that can more closely mimic the effects of psychedelics, or being more selective about the trial details disclosed to patients to make it harder for them to tell whether they’re taking the active drug.
“We should try more aggressive things because it's really important that we get an answer to this,” Woolley said. “And maybe we'll fail, but we shouldn't just give up without trying.”
Are psychedelics performing as promised?
Woolley has spent more than a decade working on psychedelic research and is hopeful the drugs will offer patients better treatments for mental health conditions with high unmet needs.
Psychedelic drug R&D has been ramping up for a range of neurological and psychiatric conditions, drawing increased investment from big pharmaceutical companies. Eli Lilly, for example, recently completed its acquisition of AtaiBeckley and its pipeline of psychedelic-based drugs for about $2.8 billion upfront, with up to another $1 billion tied to development and regulatory milestones.
And Woolley has witnessed the “dramatic improvements” psychedelics can produce in patients.
“These are things that I've never seen as a psychiatrist, like someone with very severe depression, who had tried 12 medications and many psychotherapies and then we give them one dose, and the next day, they're like, ‘I feel like I'm in a new body,’” Woolley said.
Clinical results from candidates like Compass Pathways’ COMP360 appear to affirm this effectiveness. The psilocybin-based therapy for treatment resistant depression notched several phase 3 wins and could become the first classic psychedelic to gain FDA approval. The U.K.-based company expects to complete its FDA approval application sometime in the fourth quarter.
Even so, taking a more detached look at the overall data from psychedelic trials, Woolley questions whether psychedelics will deliver on their promise in the real world.
“I can be optimistic about psychedelics, but still want to put them to a rigorous test."
Dr. Joshua Woolley
Associate professor, University of California, San Francisco
One study published in JAMA Psychiatry hints that psychedelic performance may not be as strong when the blinding issue is addressed. For the study, researchers compared psychedelic drug trials to open-label trials of traditional antidepressants to level the playing field when it comes to measuring outcomes.
“You just take somebody and you give them an SSRI and you see how they do. There's no control condition, which is what we do clinically,” Woolley explained. “When they did that, they found that the within-group improvements in the open-level SSRI trials and the psilocybin trials were about the same.”
The results raised eyebrows among some researchers because in psilocybin clinical trials, the therapy has demonstrated what one study described as “acute-phase effect sizes often more than double those for conventional antidepressants.”
“The field kind of freaked out. A lot of people were like, ‘What does this mean?’” Woolley said.
The results were not entirely unfavorable, he pointed out, because the psychedelics still performed as well as a highly effective drug class. But a question still hangs over the psychedelic space: Is the difficulty of blinding trials affecting the results being published by drug developers?
Tackling the challenge of blinding psychedelic drug trials
Researchers have tried to solve this masking issue using several different strategies. One of those is using a lower dose of the psychedelic as a control. But low-dose groups don’t feel the same drug effects, so it doesn’t really solve the problem, Woolley said.
“The most aggressive proposals have been using other active drugs like THC or dextromethorphan or salvinorin A,” he said.
These options can also produce acute experiences, but they also aren’t a perfect match, he said. Effects might be present but may not last as long. They can also create new complications when measuring results. For example, dextromethorphan, a drug similar to ketamine, is also an antidepressant.
“We don't know what a single high dose of dextromethorphan does for depression, so you get these real thorny issues,” Woolley said.
Instead, Woolley and his colleagues recommend a new method — unidentifiable multidrug blinding with reduced, authorized awareness, or UMBRAA. The approach would use a cocktail of active drugs to simulate the effects of a psychedelic that might include a stimulant, sedative, anticholinergic and/or a cannabinoid. They haven’t settled on the exact combination just yet, he said.
“Combining classes can also extend the duration and mitigate dose-limiting adverse effects of individual agents,” the study authors wrote in the JAMA viewpoint.
The plan also calls for researchers to give participants fewer details about the trial design to help prevent them from figuring out which study group they’re in. But they would be told that they are getting an incomplete disclosure and why, Woolley said.
The idea has raised some questions about safety, Woolley admitted. But the approach is not without precedent. Some surgical trials, for example, have relied on sham surgeries, using anesthesia and incisions, as a placebo control. Woolley said the multidrug placebo approach would need to be developed carefully to ensure safety, starting with lower doses.
“We need to know this answer and there’s no other way to answer it,” he said.
Because the proposed approach would also produce acute effects similar to psychedelics, it could also answer another question about these drugs — is it the drug or the experience that brings the antidepressant benefits?
In the meantime, there are risks to approving drugs using trial methods that may not hold up in the real world. Psychedelic drugs can be expensive to administer, requiring a lot of time, Woolley said. People could opt for them over other effective therapies, which is harmful if they don’t work as promised.
The researchers are now working to further study their approach with the ultimate goal of finding a reliable way to solve this masking problem.
“Hopefully we'll have some empirical papers soon to try out some of these ideas with the incomplete disclosure and multi-drug placebos,” Woolley said, noting that his research team is hoping to secure federal grants to support their work.
“I can be optimistic about psychedelics, but still want to put them to a rigorous test,” Woolley said. “That's what we've been trying to do.”
