The neural basis of psychedelic action

Abstract

Psychedelics are serotonin 2A receptor agonists that can lead to profound changes in perception, cognition and mood. In this review, we focus on the basic neurobiology underlying the action of psychedelic drugs. We first discuss chemistry, highlighting the diversity of psychoactive molecules and the principles that govern their potency and pharmacokinetics. We describe the roles of serotonin receptors and their downstream molecular signaling pathways, emphasizing key elements for drug discovery. We consider the impact of psychedelics on neuronal spiking dynamics in several cortical and subcortical regions, along with transcriptional changes and sustained effects on structural plasticity. Finally, we summarize neuroimaging results that pinpoint effects on association cortices and thalamocortical functional connectivity, which inform current theories of psychedelic action. By synthesizing knowledge across the chemical, molecular, neuronal, and network levels, we hope to provide an integrative perspective on the neural mechanisms responsible for the acute and enduring effects of psychedelics on behavior.

Figure 1.. Chemical phylogeny of psychedelics.

(a) The basic psychedelic pharmacophore is highlighted in blue. Tryptamine and phenethylamine pharmacophores are highlighted in gray and yellow, respectively. Ergolines (LSD, 1P-LSD) can be viewed chemically as a specialized case of tryptamines. Branches indicate structurally related compounds. Natural products are indicated with asterisks. (b) LSD has the phenethylamine substructure (yellow) embedded and can thus contains the key elements of both psychedelic structural families. (c) Structures of non-hallucinogenic psychedelic analogs with therapeutic potential, which may contain the tryptamine-like (gray) or phenethylamine-like (yellow) pharmacophore.

Figure 2.. The 5-HT_2A receptors and molecular signaling pathways.

(a) Intracellular signal transduction pathways. Downstream of the 5-HT_2A receptor, activation of heterotrimeric G proteins and subsequent intracellular signaling (Ca²⁺ release and diacylglycerol (DAG) production) synergistically activate additional downstream effects, which ultimately lead to altered neuronal firing. (b) left: Structure of the 5-HT_2A receptor; right: A model of the 5-HT2A receptor signaling complex in the membrane.

Figure 3.. Regional differences in psychedelic action on neurophysiology.

(a) In the medial frontal cortex (red), psychedelics are thought to acutely increase dendritic excitability due to the dendritic localization of 5-HT_2A receptors, but the overall effect on postsynaptic currents and spiking activity in vivo remains unclear. On the days following administration, psychedelics cause receptor internalization (resulting in fewer receptors being expressed) and promote the formation of new dendritic spines. (b) In the primary visual cortex (blue), psychedelics reduce visually evoked spiking activity (right panel). Orientation tuning remains intact, but surround suppression is reduced (middle panel). Black, baseline; red, after drug administration (c) In the dorsal raphe (yellow), systemic or local administration of psychedelics causes a cessation of spiking activity. Black, baseline. Red, after drug administration. Black arrows, times of drug infusion. The schematics are based on data from Shao et al. for (a), Michaiel et al. for (b), and Aghajanian et al. for (c).

Figure 4.. Network-level models of psychedelic action.

(a) The cortico-striatothalamo-cortical (CSTC) model focuses on altered thalamic gating and subsequent changes in sensory vs. association processing induced by psychedelics^, . (b) The ‘relaxed beliefs under psychedelics and the anarchic brain’ (REBUS) model posits increased bottom-up signaling, concurrent with a disintegration of association cortices and reduced top-down predictions, which are postulated to underlie psychedelic-induced effects. (c) The strong prior (SP) model suggests that psychedelic experiences arise from a reduction of bottom-up sensory inputs and an aberrant reliance on top-down expectations. This model does not make predictions about specific anatomical substrates. (d) The cortico-claustro-cortical (CCC) model centers on disrupted claustrum activity and functional connectivity, leading to a desynchronization of cortical networks. Red arrows: increased functional connectivity/control. Blue arrows: decreased functional connectivity/control. Red circles: increased integration. Blue circles: decreased integration. VS: ventral striatum. CT: claustrum.