Abstract
Classical psychedelic drugs, e.g., psilocybin and LSD, stimulate the serotonin 2A receptor (5-HT2AR) and have recently been intensely investigated for their clinical effects in various brain disorders. At the ECNP “New Frontiers meeting” in March 2023, scientific experts in psychedelics met to identify key knowledge gaps in the mechanism of action of psychedelics as investigated using preclinical models and clinical neuroimaging. Key themes included the development of appropriate behavioural models for measuring acute and persisting effects, dose optimisation, molecular mechanisms of action, sex differences, and the acute and persisting effects of psychedelics on neurotransmitter release and functional brain activity.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 103929 |
| Tidsskrift | Neuroscience Applied |
| Vol/bind | 3 |
| Antal sider | 7 |
| ISSN | 2772-4085 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:Positron Emission Tomography (PET) is a powerful tool that leverages radiolabelled compounds to map neurochemical properties of the brain (Heurling et al., 2017). The establishment of the drug occupancy curve with PET brain scanning in humans is the state-of-the-art method to establish which dose to use in subsequent clinical trials (Gunn and Rabiner, 2017). With the right study design and quantification methods, tight correlations between plasma concentration and occupancy can be obtained (Laurell et al., 2022). Occupancy studies demonstrate blood-brain barrier permeability, verify interaction with target and determine the drug dose or plasma concentration resulting in 50% occupancy (ID50 and IC50, respectively). The studies are not inexpensive, but given the risk of failure of subsequent trials if a wrong dose is chosen, it is worthwhile to do, when feasible. This can be applied in psychedelic science e.g., estimating the dose-occupancy relationship at targets of interest, e.g., 5-HT2AR using the radioligand [11C]Cimbi36 (Ettrup et al., 2016). Such occupancy studies will be especially important when comparing novel \u201Cnon-psychedelic\u201D 2A agonists currently being in development, and classical psychedelics. This strategy is highlighted by what is to date the only plasma concentration-occupancy psychedelic study, estimating psilocybin occupancy of brain 5-HT2AR (Madsen et al., 2019). Psychedelics are pharmacologically promiscuous and further characterization of binding to other receptors in humans in vivo may reveal additional, relevant mechanisms. For example, many psychedelics bind to the inhibitory serotonin 1A receptor (5-HT1AR), which can be measured with [11C]WAY100635 or [11C]CUMI-101 PET (Forster et al., 1995). Currently, only one new occupancy study is ongoing, measuring the occupancy at a range of doses of LSD at 5-HT2AR using [11C]Cimbi36 using simultaneous PET-MR (https://aspredicted.org/gn3un.pdf). Although less tightly associated with plasma psilocin levels, subjective drug intensity has been shown to be related to the occupancy of psilocin at the 5-HT2AR (Madsen et al., 2019), and thus, future drug-development programs may consider this measure in lieu of PET-occupancy studies if these are not available. Such an approach is obviously not applicable for novel psychedelic-based compounds with muted or absent subjective drug effects. Novel psychedelics may exhibit different relations between 5-HT2AR occupancy and subjective drug intensity depending on, e.g., non-2A receptor binding or partial/biased 5-HT2AR agonism. Finally, an evaluation of direct target engagement is advised by regulatory bodies such as the FDA (See FDA brochure \u201CPopulation Pharmacokinetics Guidance for Industry\u201D Section A. 1 published February 2022), supporting the regulatory relevance of PET occupancy studies for novel compounds.
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