Psychedelics

Abstract

Psychedelics are compounds that alter consciousness by acting on serotonin receptors in the brain. The term 'psychedelic', from the Greek for mind manifesting, refers to the drugs' subjective effects and was first proposed by Humphry Osmond in 1956. Other terms have been used to emphasize different aspects of the psychological experiences produced by various related compounds, including hallucinogens (perceptual), entheogens (spiritual), and empathogens or entactogens (social/emotional). The diversity in terminology reflects the existence of hundreds of potential psychedelic compounds with a spectrum of behavioral and neurobiological effects. Recent data on the effectiveness of psychedelics for treating mental illnesses has led to a resurgence of interest in their neurobiological effects. The purpose of this Primer is to provide those interested in the field of psychedelics with a concise and accessible overview of the scientific data.

Figure 1:. Psychedelic compounds.

Classic psychedelics can be grouped based on their chemical structures into three major subtypes: tryptamines, ergolines, and phenethylamines. Empathogens such as MDMA are phenethylamines but differ from other compounds in the group by their weak or lack of binding to serotonin receptors. Dissociatives and deliriants are compounds with related psychoactive properties. Some psychedelics can be found in natural sources (green), whereas others can only be synthesized in the lab (blue). The illustrations depict examples of natural sources including psilocybe caerulescens for psilocybin, bufo alvarius for 5-MeO-DMT, ipomoea corymbosa seeds for LSA, echinopsis pachanoi for mescaline, salvia divinorum leaves for salvinorin A, and amanita muscaria for muscimol. DMT, N,N-dimethyltryptamine. 5-MeO-DMT, 5-methoxy-N,N-dimethyltryptamine. LSD, lysergic acid diethylamide. LSA, d-lysergic acid amide. DOI, 2,5-dimethoxy-4-iodoamphetamine. DOM, 2,5-dimethoxy-4-methylamphetamine. 2C-B, 4-bromo-2,5-dimethoxyphenethylamine. MDMA, 3,4-methylenedioxymethamphetamine.

Figure 2:. Psychedelics act on the brain at multiple levels.

Using LSD as an example, the compound enters the brain and binds to receptors such as the 5-HT_2A subtype, activating signal transduction pathways within neurons. The consequences are alterations in gene expression, neural plasticity including remodeling of the synapses and dendrites, and spiking dynamics. At the network level, these effects can be observed as brain-wide changes in regional activation and functional connectivity involving hubs such as the default-mode network. Adapted from Kim et al., Cell, 2020, Savalia et al., Trends Neurosci, 2021, Preller et al., eLife, 2018.