Dissociating psychedelic and therapeutic effects of psilocybin in treatment-resistant depression: a proof-of-concept study – PSILOTRAZ

Recent studies have shown that a single administration of psilocybin, the active compound of magic mushrooms, has a fast-acting and long-lasting efficacy in treatment-resistant depression. Psilocybin is also well-known to induce acute psychedelic effects, characterized by important changes in self and external world perception, and resulting from the activation of 5-HT2A receptors in the brain. The intensity and the duration of these acute subjective effects, which last 4 to 6 hours, hinder psilocybin integration in routine care. Indeed, they entail risks (anxiety, endangerment), lead to exclusion criteria and so far impose the continuous presence of a caregiver to prevent and manage side effects. Importantly, preclinical results suggest that psychedelic effects may not be necessary for psilocybin antidepressant effects. Instead, antidepressant effects may arise from a direct action of psilocybin on growth factor receptors in the brain, enhancing neuroplasticity regardless of 5-HT2A receptors activation and psychedelic effects. With this proposal, we aim at dissociating psilocybin therapeutic and psychedelic effects, by giving trazodone, an antidepressant with 5-HT2A receptor antagonist activity which counteracts psilocybin’s psychedelic effects, prior to psilocybin intake. In a proof-of-concept double-blind randomized controlled trial, patients with treatment-resistant depression (n = 100) will receive either psilocybin alone (n = 25) or preceded by one of two possible doses of trazodone (5 mg and 30 mg, n = 25 in each group) in order to partially or totally suppress its psychedelic effects ; or trazodone 30 mg and placebo (n = 25). On top of classical measures of improvement and side effects in each group, we will collect cognitive and neuroimaging measures (EEG and MRI) before, during and after treatment. We will characterize the neurocognitive substrates of the psychedelic experience in relation to 5-HT2A receptors availability and study factors underlying, predicting and mediating clinical response. More specifically, we will explore the mechanisms underpinning the psychedelic experience phenomenology. Using an innovative analytic approach allowing to decompose psychedelic experience into dimensions, we will map those dimensions onto perceptual and cerebral alterations at the individual level. Similarly, we will isolate therapeutic response dimensions and measure associated perceptual, emotional, motivational and neuroplasticity changes. This study has the potential to discover a novel single-shot, fast-acting and long-lasting antidepressant treatment combination, psilocybin-trazodone. This combination could be more efficient and less constraining than conventional antidepressants which have to be taken on a daily basis for weeks, on the one hand ; and safer and more accessible than psilocybin alone, on the other hand. Moreover, it will provide a mechanistic understanding of psychedelic effects on perception at the individual level, and reveal the cognitive and neural substrates of psilocybin fast-acting antidepressant property. Finally, this project, which could be the first academic study using psilocybin to treat depression in France, will boost the career of Lucie Berkovitch, the study’s principal investigator, and promote an evidence-based medicine approach which is crucial to prevent abuses in the psychedelic field. More broadly, this study is an opportunity to raise public awareness of current issues in mental health care.