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New commentary in Nature Medicine explores placebo effects in clinical trials

Placebo effects

Dr. Matthew Burke, cognitive neurologist at Sunnybrook, and Dr. Daniel Blumberger, a psychiatrist at the Centre for Addiction and Mental Health (CAMH), contemplate blinding and placebo effects in clinical trials and how this relates to the recent wave of psychedelic treatments in psychiatry, in a new commentary “Caution at Psychiatry’s Psychedelic Frontier,” published in Nature Medicine.

“Blinding refers to whether or not an individual knows what treatment participants are receiving in a research study (active drug or placebo),” says Dr. Burke. “In a traditional double-blind study, this is referring to both the participant and the researcher being unaware of the treatment they are receiving.”

Blinding helps to reduce bias and ensures placebo effects are distributed evenly amongst study groups; however, challenges can arise when the effects of a treatment are immediately apparent to participants, like in the case of psychedelic treatment trials.

What are placebo effects and how can they affect clinical trial results?

“Placebo effects are beneficial therapeutic effects derived from the context and expectations surrounding the administration of a treatment, not the specific effects of the treatment itself,” says Dr. Burke.

“In an adequately blinded trial, these effects should be similar in both the active and treatment study groups, as participants do not know which they are receiving. However, if a participant is not properly blinded and they receive a placebo, they will know they are not receiving the active treatment and generate minimal placebo effects or even negative effects. Similarly, if an unblinded participant receives an active drug, they may have high expectations and beliefs that they are receiving the active treatment and may have very strong placebo effects,” says Dr. Burke. “This can taint the interpretation of clinical trial results.”

What is the concern with blinding and placebo effects in psychedelic treatment trials?

“Psychedelics, including ketamine, psilocybin and MDMA, yield immediate well-characterized dissociative and hallucinogenic effects,” says Dr. Burke. “You will likely know whether you are experiencing a high or taking a sugar pill, which may influence the study results as described above.”

Are there alternate study designs that can be considered for these trials?

Dr. Burke explains two main alternate options. “Active placebo controls — such as a drug that mimics the acute effects of the investigational treatment or a microdose of the same drug — can improve blinding and yet be presumably ineffective treatment.”

“A second option is an active drug comparison. This is often a standard of care treatment with known efficacy,” says Dr. Burke. He cautions that such alternate protocols have their own limitations and, in some instances, may not offer adequate blinding either.

What does this mean for the future of clinical trials?

Dr. Burke says the issue highlights the critical importance of collecting data on whether or not blinding is successful. “Recent high-profile psychedelic drug trials investigating MDMA and psilocybin did not formally collect or interrogate this data, despite known concerns about blinding challenges. This may seem like a no-brainer, but updates to international clinical trial guidelines removed requirements to measure blinding validity.”

He adds that evolving neuroscience research has demonstrated that placebo effects can meaningfully change brain circuits in ways that may be relevant to many brain disorders. Given this, the authors note that some may argue that there isn’t a need to be concerned about where the beneficial results arise from but this remains a very controversial topic.

“The question is whether we continue with current measurements and ignore the challenges to validity that these new treatment trials create,” says Dr. Burke “or begin to transform how we measure efficacy in psychiatry and other relevant fields in medicine.”

Read the commentary in Nature Medicine »