Interest in clinical research on cannabis and psilocybin (a psychedelic compound found in many fungi species) is soaring.1-4 However, current barriers to studying these controlled substances raise ethical questions.

“These drugs, particularly psychedelics, show incredible early potential for treating a number of disorders. There is a real ethical issue with not conducting cautious research to explore that therapeutic potential,” says Matthew W. Johnson, PhD, associate director of the Johns Hopkins Center for Psychedelic & Consciousness Research and lead investigator in multiple psilocybin studies.5,6

Many psilocybin clinical trials are underway, including a randomized study of the drug’s effect on 100 participants with depression.7 Psilocybin was effective for treatment-resistant depression, according to a recently published study.8 David Nutt, DM, FRCP, FRCPsych, FSB, FMedSci, one of the study’s authors, sees no significant ethical issues with studying cannabis and psilocybin. “There is lots of evidence of safety. But for other more harmful drugs, like fentanyl or synthetic cannabis receptor agonists, there may be issues.”

Under federal law, using and possessing cannabis is illegal. However, state laws have evolved significantly over the past decade. Depending on the state, cannabis might be legal for medicinal or recreational purposes (or both). Meanwhile, laws on psilocybin remain strict across the board, although some cities are beginning to loosen restriction. Regardless, regulatory hassles can add significant costs to research in these areas.

“There is an emerging realization that the banning of these drugs was politically driven, not by true health concerns,” says Nutt, deputy head of the Centre for Psychedelic Research and the Edmund J. Safra Professor of Neuropsychopharmacology Imperial College London.

The extra hurdles for these particular drugs, says Nutt, are “a waste of time and money. It also slows research that could help people with significant mental health issues that current therapies don’t help.”

If studies do reveal benefit, substances remain unavailable to many patients, including the clinical trial participants themselves. “Some people respond, then relapse. They can’t re-access the treatment that they know helped them, as the license is just for research on psychedelic-naïve patients,” Nutt explains.

When access to cannabis and/or psilocybin is unequal, that “could be framed as an issue of justice,” says Daniel J. Hurst, PhD, ThM, MSc, director of medical professionalism, ethics, and humanities at Rowan University School of Osteopathic Medicine in Stratford, NJ.

Society’s changing views on various controlled substances can facilitate research, or it can add obstacles. Stigma around medical marijuana use is evaporating.9,10 “But it’s a different story with mushrooms. People are not as prepared for that to be brought to mass market use,” Hurst says.

Some convincing evidence could change that, in light of increased awareness of the need for better mental health treatments. “Give it some good data, with grassroots advocates, and we very well may see increasing acceptance of it,” Hurst offers.

For now, federal agencies remain reluctant to fund such studies.11 “From my point of view, psilocybin still carries significant stigma. This is a significant barrier to overcome for clinical application,” Hurst laments.

Yet in the financial world, investors appear eager to fund research on psychedelics.12 “This surely coincides with the lessening of stigma in society associated with mental health issues,” Hurst suggests.

Patient safety always is top of mind with informed consent for clinical trials. In the case of controlled substances, there are some extra hurdles. Participants likely will have to agree not to drive a car or operate machinery for specific periods. “Researchers have a moral onus to ensure, to the best of their ability, that participants will abide by safety precautions,” Hurst stresses.

Where psychedelics are concerned, the research likely will be conducted at inpatient facilities. “This would mitigate many risks and would allow for researchers to monitor vitals and how the body responds,” Hurst says.

When studying drugs that carry abuse potential, appropriate safety mechanisms are paramount. “There is both a risk of undertreating people and also a risk of using treatments prematurely in the practice of medicine,” Johnson says.

Elsewhere, pain management professionals are pushing for more research on controlled substances. For example, vaporized cannabis is a safe, potentially effective treatment for chronic pain caused by sickle cell disease.13 Participants reported that pain interfered less with activities as the five-day study progressed. This particular study, unlike others, was a crossover, randomized, double-blind, placebo-controlled investigation. “You have to do a very well-validated study; otherwise, we cannot draw any relevant conclusions. It has to be double-blind to prevent bias,” says Kalpna Gupta, PhD, one of the study’s senior authors.

With cannabis research in particular, the question of exactly what is under investigation becomes crucial.

“The problem is that there are so many cannabis products available through dispensaries and other sources, but none of them are controlled for under any regulatory compliance,” says Gupta, professor of medicine in the University of California, Irvine division of hematology/oncology.

The ethical concern is patients with chronic pain will obtain cannabis products expecting to experience the same benefits identified by a study, when the product is not the same as what was studied.

“What is the difference between one product and all of the other products being sold? To find out, we would have to test each of them pharmacologically and in clinical trials,” Gupta explains.

Cannabinoids obtained at dispensaries often do not contain what they claim and may even contain harmful ingredients. 14-16 To obtain valid results, “the product, the amount, the route all has to be determined in a case-by-case, disease-by-disease basis,” Gupta says.

Another issue is some confuse studies on vaporized cannabis with vaping. Because of possible confusion on this point, “there is potential for cannabinoids to be used inappropriately,” Gupta notes.

As for funding, regulatory bodies might agree to fund cannabis studies initially, but there are subsequent roadblocks. Sometimes, says Gupta, “it goes to peer review and it gets shot down.” One potential solution is for regulatory bodies to, instead, allocate a set amount of funding specifically for cannabis research and find ways to complete those studies.

But on top of all this, recruitment also is challenging for cannabis studies. For instance, many forms of cannabis products already are available without constraints; there is no need to participate in a study to obtain them. Also, inpatient admission is needed, as with the participants in the sickle cell disease trial, to ensure participants use only the drug tested and are monitored for safety. “Larger studies with more participants are needed to give more information on the benefits of cannabis,” Gupta says.

Some previous cannabis studies showed benefits but the authors could not recruit the number of participants needed to achieve statistical significance. In that case, researchers might need to secure permission from the funding agency to continue recruitment for a longer period.

“We should be identifying a problem we are trying to solve, instead of going by a specific deadline where you are done no matter what you have,” Gupta argues.

Overall, says Gupta, “the problem is that the literature on cannabis is promising, but it’s not very well-proven scientifically, to withstand the need for validated clinical use in the majority of cases.”

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