When the Placebo Wins—and Sometimes Loses: Navigating the Complexities of Psychedelics and Pain Therapies
GH Research's psychedelic drug, Vertex's suzetrigine approval, and why both psychedelics and non-opioid pain drug developers need to think more critically about PBO-effect
Introduction
This topic has been on my mind lately because of two big news events in biopharma that put the placebo effect front and center. First, GH Research released impressive Phase 2 data in treatment-resistant depression, showing the potential of psychedelic therapies to change psychiatric care. Second, Vertex achieved a landmark approval for suzetrigine in acute pain, marking the first non-opioid pain medication approval in nearly 20 years.
The common thread between these two breakthroughs? The challenge of placebo. But in each case, that challenge looks very different. Psychedelics, by their very nature, are nearly impossible to placebo-control against—patients either feel the effects or they don’t. This makes them somewhat immune to the pitfalls of a high placebo response rate, but it also raises important questions about study design, particularly when it comes to blinding and proving efficacy in a regulatory setting. On the flip side, non-opioid pain drugs like suzetrigine face the opposite problem: placebo responses are so strong in pain trials that they can completely obscure a drug’s real effect. This makes proving efficacy in chronic pain incredibly difficult, even when a drug could provide meaningful benefit.
This post explores how the placebo effect is shaping the futures of these two drug classes and why smart trial design will be essential in ensuring that both psychedelics and non-opioid pain medications reach their full potential.
Psychedelics: A Powerful Therapy, But a Trial Design Challenge
Psychedelics like psilocybin and MDMA hold transformative potential for psychiatric diseases, but their clinical development faces a paradox. On one hand, their effects are so profound that they naturally sidestep many of the issues faced by conventional antidepressants, which often struggle against high placebo response rates. When a patient experiences a psychedelic trip, they know they received the active treatment, which eliminates much of the placebo-driven uncertainty seen in psychiatric trials.
But this same effect presents a major challenge for study design. How do you maintain a blind trial when patients can so easily tell whether they received the drug? Without proper blinding, there’s a risk of overestimating efficacy due to expectation bias. Some trials have used active placebos, low doses of psychedelics, or drugs that mimic side effects, but even these methods have limitations.
Perhaps psychedelic trials need to move toward an active control model, more akin to oncology studies, where a new treatment is compared not to placebo but to an existing standard of care. In this case, rather than pitting psilocybin against an inert placebo, a trial could compare it to an approved antidepressant. This approach could provide a clearer understanding of the true benefits of psychedelics while avoiding the pitfalls of unblinding. Whatever the path forward, solving this study design challenge is essential if this class of medicines is to reach regulatory approval and thrive in the real world.