Exploring Psilocybin as a Tool for Studying Parkinsonism-Related Psychosis: A Narrative Review Supplemented with a Computational Approach

Parkinson’s Disease Psychosis (PDP) is one of the most prevalent non-motor features of Parkinson’s Disease (PD) and is associated with increased mortality, caregiver burden, and nursing home placement. It moreover poses a difficulty in treatment because typical antipsychotics, which have long been in use, were shown to negatively affect motor function, hence it is becoming increasingly important to understand the underlying principles of PDP and find adequate treatment. The last decade has witnessed a renaissance in psychedelic research and increased interest in their application in medicine and treatment of neuro- degenerative, as well as mental, disorders. Psychedelics include all substances that have an agonist or partial agonist effect on serotonin 5-HT2A receptors in the brain, such as LSD, mescaline, or psilocybin. Psilocybin causes a vast number of psychotomimetic effects including VH, but not auditory hallucinations which is a trait characteristic of PDP. The primary objective of this study is to comprehensively review the pharmacology of classical psychedelics, with a particular emphasis on psilocybin and LSD. Moreover, employing computational methodologies, we investigate and provide further insights into the potential suitability of psilocybin as a promising candidate molecule for inducing psychotic-like states in experimental animal models that exhibit similarities to Parkinson's psychosis. In addition, we propose psilocybin as a valuable tool for studying and understanding Parkinsonism-related psychosis.