Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics

Psychedelics are pharmacologically active compounds that induce profound alterations in perception, cognition and sensory processing, with a history of ceremonial and medicinal use across many cultures. Early experimental psychiatry explored their effects in relation to schizophrenia and other psychiatric conditions, and interest in therapeutic applications rose through the mid-20th century before regulatory restrictions curtailed research. In the 21st century a resurgence of clinical trials has reported promising, sometimes long-lasting improvements in depression, anxiety and substance use disorders, but the molecular mechanisms that might explain those sustained therapeutic adaptations remain incompletely understood. Jaster and colleagues set out to review contemporary preclinical and clinical evidence on molecular targets, intracellular signalling and neural circuits implicated in the acute and post-acute effects of classical serotonergic psychedelics. The review focuses on serotonin receptor pharmacology, receptor structure and biased agonism, intracellular and circuit-level mechanisms of plasticity, and the translational links between rodent models and human clinical outcomes, highlighting unresolved questions about which molecular targets mediate therapeutic benefits versus subjective hallucinogenic experiences.

This paper is a narrative review that synthesises molecular, cellular, behavioural and clinical findings from recent preclinical and human studies of classical psychedelics. The authors examine pharmacological profiles of representative compounds (tryptamines, phenethylamines, ergolines), receptor binding data, X-ray/cryo-EM structural studies of 5-HT2A and related receptors, transcriptomic and signalling experiments in rodents and cell systems, as well as human imaging and clinical trial outcomes. The extracted text does not present a formal literature search strategy, inclusion/exclusion criteria, or systematic review methods, so the review appears to be selective and integrative rather than a meta-analysis with a reported search protocol. Emphasis is placed on studies that probe receptor-level mechanisms (including genetic knockouts and site-directed mutagenesis), intracellular signalling pathways (G protein coupling, β-arrestin recruitment, downstream kinases), and neural-circuit and plasticity measures (dendritic spine changes, immediate early gene expression, electrophysiology, and behavioural assays such as the head-twitch response). Clinical trial data discussed include randomized and open-label trials of psilocybin and LSD across indications (depression, anxiety in life-threatening illness, smoking cessation, alcohol use disorder), with reports of follow-up outcomes; preclinical addiction- and depression-relevant rodent paradigms are also surveyed. Where available, the authors integrate structural biology findings (receptor binding poses and key residues) with functional pharmacology and behavioural readouts.

Chemical families and receptor pharmacology: The authors describe classical serotonergic psychedelics as falling into tryptamines (psilocybin/psilocin, DMT), phenethylamines (mescaline, DOI) and ergolines (LSD). Binding affinity profiles vary across compounds: psilocin shows moderate affinity for multiple 5-HT receptor subtypes and high affinity for 5-HT2B/7, psilocybin itself is a prodrug converted to psilocin, LSD binds tightly to multiple 5-HT and some dopamine receptors, DOI has high affinity at 5-HT2A/2C, and mescaline is relatively selective for 5-HT2A. Effective human doses and durations differ markedly between compounds (examples in the text: mescaline 200–400 mg, psilocybin via 1–5 g dried mushrooms, LSD 0.05–0.2 mg), and routes of administration influence pharmacokinetics. 5-HT2A as principal target for subjective effects: Across human and rodent evidence, activation of cortical 5-HT2A receptors—particularly on frontal cortical pyramidal neurons projecting subcortically—is presented as necessary for hallucinations and for the head-twitch response (HTR) in rodents. Antagonists such as ketanserin and risperidone block subjective effects in humans and HTR in animals, and 5-HT2A knockout mice do not show HTR, supporting a central role of that receptor in acute perceptual effects. Structural biology and binding modes: Recent X-ray and cryo-EM structures of 5-HT receptors reveal conserved features of the orthosteric pocket and an extended binding cavity. LSD adopts a relatively shallow pose and interacts with extracellular loop 2, forming a ‘‘lid’’ that may slow dissociation and contribute to long-lasting subjective effects. Key conserved residues implicated include D1553.32 (salt bridge with ligand), the PIF motif (P5.50, I3.40, F6.44) involved in activation-related helix movements, and serine residues (S239/242/5.46) linked to functional differences between ligands. Structural comparisons show differences between psychedelic and non-psychedelic agonists in engagement of the extended pocket, which correlates with biased signalling. Biased agonism and intracellular signalling: Transcriptomic and signalling studies indicate that psychedelic versus non-psychedelic 5-HT2A agonists elicit distinct molecular fingerprints. For example, psychedelic agonists consistently induce Egr-1 and Egr-2 transcription in mouse frontal cortex while both psychedelics and non-psychedelics induce c-Fos. Some psychedelics require pertussis-toxin-sensitive Gi/o coupling to augment Egr transcripts and ERK1/2 phosphorylation, whereas non-psychedelics like lisuride rely on Gq/11-dependent PLC-β signalling for c-Fos induction. β-arrestin involvement is complex: 5-HT-mediated actions engage β-arrestin-2, whereas some psychedelics (DOI) produce β-arrestin-independent HTR; genetic deletion studies reported reduced LSD-induced HTR in β-arrestin-2, but not β-arrestin-1, knockout mice. These data support ligand-dependent signalling bias at 5-HT2A. Receptor crosstalk, localisation and genetic variability: The review highlights functional interactions between 5-HT2A and mGlu2 receptors, with mGlu2 agonists attenuating psychedelic effects and mGlu2 knockout abolishing HTR for DOI/LSD. Subcellular localisation is discussed as a potential source of ‘‘location bias’’—a sizeable intracellular pool of 5-HT2A receptors has been documented, and membrane-permeable agonists appear necessary to elicit some plasticity effects in cultured neurons. Single nucleotide polymorphisms (SNPs) in the 5-HT2A gene alter ligand bias profiles in vitro, with some variants (e.g. H452T) changing relative Gq versus β-arrestin recruitment for specific ligands, suggesting genetic variability could underlie differences in clinical responsiveness. Acute effects and preclinical proxies: Human acute effects include hallucinations, ego dissolution and mystical-type experiences, alongside physiological changes (blood pressure, heart rate, nausea). EEG studies report reductions in alpha oscillations under psilocybin, with attenuation by ketanserin. In rodents the HTR is widely used as a behavioural proxy for psychedelic potential; other assays include drug discrimination, prepulse inhibition, locomotion and intracranial self-stimulation (ICSS). Classical psychedelics show low reinforcing potential in self-administration models and often depress ICSS, consistent with low addictive liability but capacity to disrupt behaviour. Post-acute therapeutic effects and clinical outcomes: Clinical trials reviewed report sustained benefits of psychedelics across conditions. Long-term follow-up of psilocybin patients found 60–80% showed clinically significant anxiolytic or antidepressant effects at 4.5 years, and 71–100% attributed positive life changes to treatment in that cohort. In a Johns Hopkins prospective 12-month follow-up, two-dose psilocybin with supportive therapy produced decreased depressive symptoms at 1, 3, 6 and 12 months, with 72% showing a significant treatment response and 58% remission. An open-label smoking cessation pilot reported 67% biologically confirmed abstinence at 6 months after two to three psilocybin sessions combined with CBT. A double-blind trial in alcohol use disorder reported reductions in heavy drinking days and mean consumption sustained to 36 weeks. Preclinical mechanisms of plasticity: Rodent and cellular studies demonstrate that single doses of psychedelics can induce structural and functional plasticity—examples include rapid increases in cortical dendritic spine formation, up to one-month persistence of dendritic growth after psilocybin, enhanced excitatory postsynaptic potentials in hippocampal neurons, chromatin remodelling at enhancers of synaptic genes, and possible TrkB (BDNF receptor) allosteric interactions reported for psilocybin and LSD. These plasticity changes are often associated with antidepressant-like behavioural readouts such as reduced immobility in forced swim tests and accelerated fear extinction. Heterogeneity and conflicting mechanistic evidence: The review emphasises mixed results on whether post-acute therapeutic effects require 5-HT2A activation. Genetic ablation of 5-HT2A blocks some plasticity effects after DOI, psilocybin and 5-MeO-DMT, while other stress-model studies report antidepressant-like effects that persist despite pharmacological 5-HT2A blockade. Differences in antagonist specificity, dosing, pretreatment timing, polypharmacology of psychedelics and choice of behavioural/outcome measures are cited as contributors to inconsistent findings. Sex-specific effects are underexplored but some rodent studies report sex-dependent behavioural responses to psychedelics.

The authors interpret the assembled evidence as indicating that classical psychedelics induce robust acute subjective effects via cortical 5-HT2A receptor activation, while post-acute therapeutic adaptations are plausibly mediated by downstream signalling, synaptic plasticity and network-level reorganisations. They highlight structural and functional plasticity, lasting changes in gene expression and altered global connectivity as convergent biological substrates that could underlie sustained clinical benefits observed in multiple small clinical trials. Jaster and colleagues stress that the field faces several unresolved questions: foremost, whether the molecular targets that produce the acute psychedelic experience are the same as those responsible for long-term therapeutic outcomes. They note conflicting preclinical data on 5-HT2A dependence for post-acute effects, emphasising methodological sources of heterogeneity such as antagonist selectivity, dosing regimens, timing of pretreatment, different stress or disease models, and the polypharmacology of many psychedelics. Genetic variation (SNPs) and receptor subcellular localisation add further complexity, potentially explaining inter-individual differences in response. Limitations acknowledged by the authors include the translational challenge of modelling subjective human experiences in animals, the selective nature of available preclinical models (many focused on antidepressant-like rather than addiction-related paradigms), and the lack of standardised protocols across clinical trials which complicates comparisons. They also point to risks in clinical populations, noting reports of non-responders and some adverse outcomes including increased suicidality in certain treatment-resistant depression cohorts, underscoring the need to study negative responders systematically. For future research directions the review highlights several priorities described by the authors: conducting antagonist or ‘‘blockade’’ experiments in humans and animals to test dependence on subjective experience, expanding trial populations to improve demographic diversity, investigating non-hallucinogenic analogues and structure–function relationships to dissociate therapeutic from hallucinogenic pathways, improving preclinical models of drug-seeking and reinstatement, and fostering multidisciplinary collaboration to bridge molecular, circuit and clinical findings. They also call for more sex-specific analyses and for mechanistic work that integrates receptor structure, biased signalling and downstream plasticity pathways.

The authors conclude that psychedelic research has advanced rapidly, producing evidence that these compounds can promote lasting structural and functional neural plasticity, alter gene expression, and modulate large-scale brain networks in ways that align with reported clinical improvements. Nevertheless, fundamental mechanistic questions remain unresolved, particularly whether the same molecular targets mediate both the acute subjective effects and the sustained therapeutic outcomes. Jaster and colleagues advocate for rigorous, multidisciplinary studies that address methodological confounds, explore individual variability, and directly test the causal links between receptor-level signalling, neuroplasticity and clinical efficacy to determine whether psychedelics represent a uniquely effective therapeutic modality or an overextended panacea.