The neural basis of psychedelic action

This paper is a narrative review rather than a systematic review or meta-analysis; the extracted text does not clearly report formal literature-search methods, databases or inclusion criteria. Instead, the authors organise and synthesise findings from molecular pharmacology, structural biology, preclinical electrophysiology and plasticity studies, and human neuroimaging and pharmacological challenge studies to draw connections across scales. The review draws on a mixture of human and animal data: receptor-binding and structural studies (including X-ray and cryo-EM structures of serotonin receptors), animal behavioural assays (drug discrimination and the mouse head-twitch response), in vivo electrophysiology and imaging in rodents and larger mammals, transcriptional and structural plasticity assays (in vitro, ex vivo and in vivo), and human PET, fMRI, EEG and MEG studies. Where relevant, the authors integrate medicinal chemistry and computational-design efforts aimed at generating novel agonists or non-hallucinogenic psychoplastogens. Because the focus is on basic neurobiology, clinical trial results and behavioural descriptions are summarised briefly and used mainly to motivate mechanistic questions.

Chemistry and pharmacokinetics: The authors describe a common psychedelic pharmacophore: an aromatic group separated from a basic amine by a two-carbon linker, with two principal structural families — tryptamines (indole C3-substituted) and phenethylamines (phenyl-based). Ergolines, such as LSD, are discussed as rigidified tryptamine-like scaffolds. Structural rigidification often increases receptor affinity and potency by reducing entropic penalties, which helps explain LSD's high potency. Substitutions on the aromatic ring and modifications to the basic amine (for example, N-benzylation) can enhance potency or metabolic stability. Many classical psychedelics follow the ‘rule of three’ physicochemical profile, enabling high brain penetrance and rapid CNS action. Pharmacokinetics strongly influence in vivo activity: constitutional isomers (psilocin versus bufotenin) and differences in lipophilicity or pKa produce large differences in bioavailability and potency. Receptors and molecular signalling: Human and animal pharmacology converges on 5-HT2A receptors as central to the hallucinogenic effects: antagonist pretreatment (for example, ketanserin) reduces subjective effects, and receptor occupancy correlates with intensity. Animal assays (drug discrimination, head-twitch response) and knockout studies further support the importance of 5-HT2A. Nevertheless, psychedelics have complex polypharmacology, interacting with many serotonin receptor subtypes and other monoaminergic targets (dopamine and adrenergic receptors). Species differences in receptor residues (for example, S242 in primates versus A242 in rodents) can alter ligand kinetics and complicate translation. Downstream of 5-HT2A, activation of Gq-like G proteins, mobilisation of intracellular Ca2+ and protein kinase C signalling are emphasised, with arrestin pathways and other signalling modalities also implicated; in vivo evidence for pathway-specific contributions remains limited. Actions at 5-HT2B receptors are highlighted as a safety concern because chronic 5-HT2B agonism is associated with valvulopathy. Preclinical behavioural assays and structural biology: The review summarises the main animal readouts—drug discrimination (learned lever-press tasks) and the head-twitch response (innate behaviour)—and notes their predictive validity for human hallucinogenic potency while also pointing out their limitations as surrogates for subjective experience. Recent high-resolution receptor structures (LSD and other ligands bound to 5-HT2 receptors) are described as enabling new mechanistic and medicinal chemistry efforts. Drug-discovery efforts: Structural insights and large-scale in silico screens are facilitating the design of novel chemotypes, selective agonists and biased ligands. The authors discuss prodrugs to improve oral bioavailability and efforts to create non-hallucinogenic psychoplastogens that retain putative therapeutic plasticity effects but lack perceptual effects. Desired properties include 5-HT2A selectivity (to limit off-target actions), signalling bias (towards Gq or away from arrestin as experimentally warranted) and absence of 5-HT2B agonism. Neuronal and circuit effects — acute: In cortex, 5-HT2A receptors are enriched on apical dendrites of deep-layer pyramidal neurons, suggesting increased dendritic excitability after agonism. In vivo responses are heterogeneous: systemic administration of DOI produced mixed changes in frontal cortical firing rates. In visual cortex, psychedelics tend to suppress stimulus-evoked spiking and reduce surround suppression while preserving feature tuning, implying altered contextual processing. The dorsal raphe nucleus shows pronounced, rapid suppression of firing after psychedelics, likely via somatodendritic 5-HT1A mechanisms, although its causal role in subjective effects is uncertain. Psychedelics also modulate firing and synaptic transmission in hippocampus, locus coeruleus and other regions. Neuronal and circuit effects — longer-term: Single doses lead to rapid transcriptional changes (upregulation of immediate early genes such as Fos, Arc, Egr2) and increases in neurotrophic factors in some regions. Structural plasticity is a reproducible finding: in neuronal cultures and in vivo, psychedelics increase dendritic spine density and size and promote dendritic growth. Longitudinal two-photon imaging in mouse medial frontal cortex showed increased spine density and size within 24 hours after a single psilocybin dose, with elevated spine density persisting for up to 1 month. The parallels and distinctions between psychedelic-induced plasticity and that produced by ketamine (also linked to spine changes) are noted but not resolved. Network- and whole-brain findings: Early PET and SPECT studies reported regionally heterogeneous metabolic and blood-flow changes. Human fMRI and connectivity studies have two fairly consistent findings: acute disintegration or reduced activity and functional connectivity within association networks including the default-mode network, and concurrent increases in connectivity among sensory regions. LSD and psilocybin also increase thalamocortical functional connectivity, particularly between thalamus and sensory cortex. Pharmacological blockade confirms 5-HT2 receptor involvement in network reconfiguration. Recent work correlating spatial maps of gene expression and receptor density with drug-evoked fMRI responses implicates region-specific roles for 5-HT2A and possibly dopamine and glutamate receptors. Longitudinal imaging hints at network changes detectable for at least 1 week after a single dose, but durable network–clinical links remain underexplored. Theoretical models: The review outlines multiple explanatory frameworks. The cortico-striato-thalamocortical (CSTC) model emphasises disrupted thalamic gating and increased feedforward sensory information. The REBUS model (relaxed beliefs under psychedelics) posits weakened top-down priors and increased bottom-up signal flow, raising neural entropy. The strong prior (SP) model argues that reduced bottom-up sensory input paired with aberrant reliance on top-down expectations can produce hallucinations. The cortico-claustro-cortical (CCC) model implicates disrupted prefrontal–claustrum interactions. The authors note that empirical findings support different aspects of these models and that reconciliation will require more precise definitions and mechanistic data. Open questions: Key uncertainties include whether therapeutic effects are separable from hallucinogenic effects at the molecular level, the causal role of 5-HT2A (and related 5-HT2C) signalling in plasticity and clinical benefit, and the lack of selective pharmacological tools to disentangle receptor contributions. Cell-type specificity, species differences, and the causal chain linking receptor activation to enduring clinical outcomes remain important gaps.

The authors interpret the assembled evidence as pointing to 5-HT2A activation as the dominant proximate mechanism for psychedelic-induced hallucinations, but they emphasise the complex polypharmacology and downstream signalling that complicate attribution of therapeutic benefits to a single receptor or pathway. Structural receptor data and advances in transcriptomic and proteomic brain atlases are presented as enabling tools to bridge molecular interactions and large-scale network effects. Kwan and colleagues position their synthesis relative to prior research by highlighting both convergent findings (for example, consistent imaging signatures such as default-mode network disintegration and increased thalamocortical connectivity) and divergent or unresolved observations (for example, heterogeneous single-unit responses, variable roles of dorsal raphe suppression, and conflicting predictions of computational models). They stress that some prominent theories — REBUS, CSTC, SP and CCC — capture useful but differing facets of psychedelic action, and that integration of implementation- and computation-focused approaches will be necessary for a unified account. The review acknowledges multiple limitations and uncertainties: the narrative-review format does not offer systematic coverage; species differences in receptor sequences and pharmacokinetics complicate translation from animals to humans; many studies predate current cell-type resolution and therefore leave open which neuronal subtypes mediate observed effects; selective pharmacological agents for 5-HT2A versus 5-HT2C and for pathway-biased signalling are lacking; and longitudinal neuroimaging and causal interventional studies linking neurobiological changes to clinical outcomes are sparse. For future research and clinical translation, the authors recommend several directions that they expect will be fruitful: exploiting high-resolution receptor structures and large-scale computational screening to design selective and biased ligands (including non-hallucinogenic psychoplastogens); using genetic and circuit-level manipulations in preclinical systems to test pathway-specific hypotheses; expanding electrophysiological and optical imaging across brain regions to map dendritic excitability and spiking dynamics at cell-type resolution; conducting well-powered, repeated-measure neuroimaging studies to characterise time courses and individual differences; and integrating receptor/transcriptomic atlases into biophysically grounded computational models. These steps are framed as necessary to clarify whether the subjective experience is separable from therapeutic mechanisms and to enable precision approaches to psychedelic-assisted therapies.