Some clinical trial participants expect psychedelics to be a magic pill. “Participants think that once they take the drug, their problems will go away – but it doesn’t work like that,” says Johns Hopkins University assistant professor of psychiatry and behavioural sciences Albert Garcia-Romeu, PhD. Unrealistic expectations are triggered by multiple factors. Participants’ heightened anticipation is due to them lacking benefit from available therapies and from often being vulnerable individuals with serious mental health disorders. Exaggerated metaphors from the mainstream media also fuel expectations, as well as from certain pockets of the psychedelic research community.
Psychedelic clinical trials tough to blind
Researchers are trying to find ways to effectively blind placebo-controlled psychedelic trials. Due to psychedelics’ obvious physical effects, participants and investigators can tell if the person received an investigational product or a placebo.
Utilising an active placebo may be a solution. For example, the lowest dose of an investigational drug can be used as an active comparator. Mental healthcare company Compass Pathways ran a Phase II trial (NCT03775200) investigating its psilocybin COM-360 in treatment-resistant depression (TRD). Participants were placed in one of three groups: 1mg (active placebo), 10mg (moderate dose), or 25mg (high dose). The idea is to manage expectancy bias.
Investigators conduct critical in psychedelic trials
Participants who have no prior recreational use of psychedelics may be easier to blind, but the trial staff they interact with would still likely be able to tell which arm a participant belongs to, says the University of Alabama at Birmingham professor Peter Hendricks, PhD. This allows the risk of investigator bias, he adds.
It is therefore crucial for investigators’ behaviour to be as unbiased as possible during dosing sessions, says University of California, San Francisco associate clinical professor, Andrew Penn. Investigators should be discouraged from internal or active verbal speculations on what drug the subject had received, adds Penn, who works as a psychiatric nurse practitioner in clinical trials.
Overhyped expectations need to be tempered
External hype surrounding psychedelic trials is fuelled by exaggerated mainstream media coverage and by scientists themselves, and is further pushing expectations higher, says Dr Katrin Preller, Yale University adjunct assistant professor. Levine highlights the importance of staying humble and honest with patients by not overpromising potential benefits and reinforcing the fact that there are other options for treatment.
Hope and hype raise unrealistic expectations. And this can create cognitive dissonance in participants, Penn says. If a patient expects a good response but, when self-reporting, they come to a realisation that the intervention was not as beneficial as expected, it can be very disappointing, he adds.
Not all psychedelic trials recruit swiftly
While psychedelic clinical trials in depression and post-traumatic stress disorder (PTSD) have a long list of potential participants due to high interest from patients and from the field, there are indications that find it challenging to recruit for studies.
One example is substance use disorders. In general, although addiction research is growing, slow progress is likely caused by a negative societal view of addiction, Garcia-Romeu notes. People with PTSD are treated with sympathy but people suffering from substance abuse are seen as morally deficient, he adds.
Eating disorders are another indication that faces recruitment challenges. Dr Natalie Gukasyan, psychiatrist and researcher at Johns Hopkins University, is part of an 18-participant Phase I study (NCT04052568) investigating psilocybin in patients with anorexia nervosa. Even though the trial received participant interest after advertising on social media, Gukasyan notes that the trial is still challenging to recruit as such patients are less motivated to get treatment.
Inclusion criteria a bottleneck
Psychedelic trials’ tight inclusion criteria also put additional pressure on recruitment, Penn says. Many psychedelic trials request potential participants to stop the psychiatric medication before enrolment because some medications can blunt the effect of psychedelics. This can be a deal breaker for some people, he adds.
Time commitment is another challenge. In general, trial participants need to attend 20 to 50 hours of face-to-face psychotherapy over the course of a relatively short amount of time, usually a couple of months, Penn adds. If a person has occupational commitments or lives further from the trial site, it is likely that they will not complete the treatment, he adds.
High bar to argue for reclassification
Psychedelic drugs are under Schedule I in the US and Class A in the UK, classifying them as having no medical value and holding a high potential for abuse. While caution should be exercised, psychedelics have not shown any significant addictive or habit-forming properties, Levine says. The research community has a lot of work ahead to prove that the classification of these drugs needs to be reconsidered, adds Preller, who is a principal investigator in a Phase II psilocybin trial (NCT04141501) in alcohol use disorder.
But to generate the level of evidence to argue for a reclassification, large clinical trials would be needed. And large trials require financial investment, which is often not feasible for academic research groups, Gukasyan says. The pharma industry would be the sector with the resources to run such large trials, Levine added.
Psychedelic drugs carry heavy cultural baggage as it makes their way through the drug development pipeline. And the only way to lighten the load is to generate robust data that can debunk negative perceptions and finally prove the worth of this drug class. But practical issues delay progress. Until then, patients will have to wait to find out if psychedelics can offer an answer.