psychedelic drugs have yet to prove their worth in clinical trials

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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 that way,” says Albert Garcia-Romeu, PhD, assistant professor of psychiatry and behavioral sciences at the University. Johns Hopkins.

Unrealistic expectations are triggered by multiple factors. The heightened anticipation of the participants is due to the fact that they do not benefit from the available therapies and that they are often vulnerable people suffering from serious mental disorders. The overblown metaphors of the mainstream media are also fueling expectations, as well as those of certain pockets of the psychedelic research community.

experts Clinical Trials Arena spoke with cautioned that the field is still in its infancy, with the efficacy value of psychedelics yet to be proven.

Making research difficult are existing barriers to performing the study. Blinded studies are difficult because the effect of psychedelic drugs is obvious, and there is concern that investigator bias may impact patient perceptions. Some trials are also struggling to recruit patients, despite some indications having a deep pool of participants willing to enroll.

The sooner these issues can be addressed, the sooner expectations can be brought back to reality.

Hard-to-Blind Psychedelic Clinical Trials

Researchers are trying to find ways to effectively perform blinded placebo-controlled psychedelic trials, adds Garcia-Romeu. Because of the obvious physical effects of psychedelics, participants and investigators can tell whether the person received an experimental product or a placebo, he explains.

The use of an active placebo can be a solution. For example, the lowest dose of an investigational drug can be used as an active comparator. Mental health care company Compass Pathways conducted a Phase II trial (NCT03775200) investigating its psilocybin COM-360 in treatment-resistant depression (TRD). Participants were placed in one of three groups: 1 mg (active placebo), 10 mg (moderate dose) or 25 mg (high dose). The idea is to manage the expectation bias, says the company’s senior vice president of patient access and medical affairs, Dr. Steve Levine.

Another potential active placebo is to use a completely different substance, says Garcia-Romeu. Instead of a sugar pill, active placebo participants can be given methylphenidate or niacin because they can induce physical effects that can mask which arm a participant may be on, he adds. Still, there will be participants who know which arm they were randomized to based on previous experience, he adds.

Investigator conduct is critical in psychedelic trials

Participants who have never used psychedelics recreationally may be easier to blind, but the trial staff they interact with would still be able to tell which arm a participant belongs to, says Peter Hendricks, PhD, professor at the University of Alabama at Birmingham. This allows for the risk of investigator bias, he adds.

“As much as [investigators] try to stick to protocol and treat every patient the same, I’m sure our own bias impacts outcomes,” adds Hendricks, lead researcher evaluating psilocybin-facilitated treatment for cocaine use.

It is therefore crucial that the behavior of investigators be as unbiased as possible during dosing sessions, says Andrew Penn, associate clinical professor at the University of California, San Francisco. Investigators should be discouraged from internal or active verbal speculation about the drug the subject had received, adds Penn, who works as a psychiatric nurse practitioner in clinical trials.

Exaggerated expectations should be tempered

Investigators should appear as unbiased as possible because trial participants already have high expectations. Psychedelic trials recruit vulnerable people who have gone through the healthcare system unsuccessfully, adds Garcia-Romeu.

The external hype surrounding psychedelic trials is fueled by exaggerated mainstream media coverage and by scientists themselves, and drives expectations even higher, says Dr. Katrin Preller, senior researcher, psychologist and neuroscientist at the University of Zurich and at Yale University. Levine emphasizes the importance of remaining humble and honest with patients by not over-promising potential benefits and reinforcing that there are other treatment options.

Hope and hype raise unrealistic expectations. And that can create cognitive dissonance in participants, Penn says. If a patient expects a good response but, when self-reporting, realizes that the intervention has not been as beneficial as expected, this can be very disappointing, he adds. .

High expectations can also influence the data reported by participants. In fact, knowing other people with the same issues can impose a self-created pressure to respond positively to a trial, which can then skew participants’ reported results, Penn adds. “As clinicians or researchers, we discourage people from inflating their improvements to make the data look more beneficial than it was. But I could see the participants having this inner feeling.

Not all psychedelic trials recruit quickly

While psychedelic clinical trials for depression and post-traumatic stress disorder (PTSD) have a long list of potential participants due to high patient and field interest, there are indications that make recruitment difficult for studies.

An example is substance use disorders. In general, although addiction research is growing, the slow progress is likely caused by a negative societal view of addiction, notes Garcia-Romeu. People with PTSD are treated sympathetically, but people with drug addiction are seen as morally deficient, he adds.

Hendricks is leading a phase II trial of psilocybin (NCT02037126) in cocaine use disorder, with diphenhydramine as a placebo comparator. Even as it nears its goal of 40 participants, recruiting cocaine users presents its own challenges, as researchers work in the context of income disparity and a long history of racial injustice, he notes. he.

Eating disorders are another indication that faces recruitment challenges. Dr. Natali Gukasyan, a psychiatrist and researcher at Johns Hopkins University, is part of an 18-participant phase I study (NCT04052568) of psilocybin in patients with anorexia nervosa. Even though the trial sparked interest among participants after a social media advertisement, Gukasyan notes that the trial is still difficult to recruit because these patients are less motivated to seek treatment.

Inclusion criteria are a bottleneck

The strict inclusion criteria for psychedelic trials also put additional pressure on recruitment, Penn says. Many psychedelic trials ask potential participants to stop psychiatric medications before enrollment because some medications can dull the effect of psychedelics. This can be a deal breaker for some people, he adds.

Time commitment is another challenge. Typically, trial participants must attend 20 to 50 hours of face-to-face psychotherapy over a relatively short period of time, typically a few months, Penn adds. If a person has work obligations or lives further away from the trial site, they are unlikely to complete treatment, he adds.

The high bar for pleading for reclassification

Psychedelic drugs fall under Schedule I in the US and Class A in the UK, classifying them as having no medical value and having a high potential for abuse. While caution should be exercised, psychedelics have shown no significant addictive or habit-forming properties, Levine says. The research community has a lot of work to do to prove that the classification of these drugs needs to be reconsidered, adds Preller, who is a principal investigator in a Phase II trial of psilocybin (NCT04141501) in drug use disorder. alcohol.

But to generate the level of evidence to argue for 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 pharmaceutical industry would be the sector with the resources to conduct such large trials, Levine added.

Currently, psychedelic clinical trials are primarily sponsored by academia. In psilocybin, only 22 of the 99 ongoing and planned Phase I-III trials are industry-sponsored versus 43 institution-sponsored, and most psilocybin trials are in early phases, according to the Research Database. GlobalData clinical trials. GlobalData is the parent company of Clinical Trials Arena.

As with other psychedelics, 27 Phase I-III trials are underway and planned for lysergic acid diethylamide (LSD) and 31 studies for 3,4-methylenedioxymethamphetamine (MDMA).

Psychedelic drugs carry a heavy cultural baggage as they move through the drug development pipeline. And the only way to lighten the load is to generate solid data that can debunk negative perceptions and finally prove the value of this class of drugs. But practical problems are holding back progress. Until then, patients will have to wait and see if psychedelics may offer an answer.

Take away food :

  • Blinding psychedelic trials are difficult because the experimental active triggers obvious effects. An active placebo can be used to alleviate some blinding issues.
  • The buzz around psychedelic trials can lead to high expectations, and this needs to be managed. It can be as simple as clinical trial investigators behaving as impartially as possible during dosing sessions.
  • While some indications have a long list of enthusiastic trial participants, there are other indications that struggle to find patients due to social perceptions as well as the economic issues attached to them.
  • There is a high efficacy bar that psychedelics must cross to demystify negative value perceptions. However, most psychedelic trials are conducted by academic sponsors, who may not have the funding for large trials for solid data.
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