A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

Psychedelic compounds and dissociatives such as psilocybin, LSD and ketamine produce atypical conscious states and have attracted growing interest for their therapeutic potential in mood disorders. Savalia and colleagues note that ketamine, at subanaesthetic doses, produces rapid antidepressant effects within hours that can last at least a week, and small clinical studies suggest serotonergic psychedelics may produce rapid and sometimes enduring mood improvements. A central puzzle is that these compounds act at distinct molecular targets yet show convergent behavioural and plasticity-related outcomes: both ketamine and serotonergic psychedelics have been reported in rodents to increase synaptic proteins, promote dendritic spine formation or remodeling, and engage neurotrophic signalling pathways. This opinion article develops a conceptual, dendrite-focused framework to account for these similarities. Rather than emphasising a single receptor-level mechanism, the authors propose that ketamine and serotonergic psychedelics converge functionally on dendritic excitability—each drug class producing both excitatory and suppressive effects on dendrites by different pathways. The framework aims to explain selectivity of drug action across cell types and brain regions, dose–response boundaries affecting toxicity, and how acute dendritic effects could initiate Ca2+-dependent plasticity that outlasts the short plasma half-lives of the drugs (reported plasma half-lives noted in the extraction are ~79 min for ketamine and ~74 min for psilocybin).

This paper is an integrative opinion piece that synthesises findings from electrophysiology, imaging, molecular biology, pharmacology and behavioural studies to build a mechanistic framework. Rather than reporting a single new experiment, the authors draw on prior in vivo and in vitro studies (for example, two-photon calcium imaging of interneuron and dendritic activity, microiontophoresis, electrophysiological recordings from identified pyramidal neurons) and on molecular and transcriptomic datasets to illustrate regional and cell-type patterns of receptor and interneuron expression. Where the extracted text includes explicit re-analyses, the authors used publicly available resources: in situ hybridization data (Allen Institute) to compare regional expression of Sst and Pvalb mRNA and to visualise Htr1a and Htr2a distribution against measures of cortical hierarchy; and a public single-cell RNA-sequencing dataset (>10 000 cells from mouse anterolateral motor cortex) to profile 5-HT receptor expression across neuronal subclasses. Details such as exact statistical procedures, preprocessing steps for the transcriptomic visualisations, and sample sizes/dates for the underlying datasets are not fully reported in the extracted text. The authors also reference experimental interventions in the literature (e.g., receptor knockdowns, interneuron-targeted manipulations, behavioural paradigms such as the Wisconsin Card Sorting Task) to ground the conceptual arguments.

Savalia and colleagues organise evidence to show that ketamine and serotonergic psychedelics produce opposing actions on dendritic excitability, but through different proximate mechanisms, and that these competing effects can account for shared neural and behavioural consequences. Ketamine: Pharmacologically, ketamine is a noncompetitive NMDAR antagonist with use-dependent trapping in receptor channels. Directly on pyramidal neuron dendrites, NMDAR blockade is expected to reduce membrane excitability. Indirectly, however, ketamine antagonises NMDARs on GABAergic interneurons (notably soma-targeting parvalbumin-expressing (PV) cells and dendrite-targeting somatostatin-expressing (SST) cells), producing disinhibition of pyramidal neurons. Empirical support includes increased glutamate efflux and heightened pyramidal firing rates in medial frontal cortex after systemic NMDAR antagonism, attenuation of PV interneuron activity, and two-photon imaging showing marked reduction of SST interneuron activity accompanied by elevated Ca2+ influx in apical dendritic spines within an hour of ketamine. Functional perturbations of interneuron NMDARs (e.g., knockdown in PV cells) can block ketamine-like behavioural responses in rodents, and blocking ketamine’s action on prefrontal SST interneurons prevented certain drug-induced behaviours. The net effect is a push–pull on dendritic excitability: a direct suppressive influence balanced by indirect disinhibitory increases in excitability. Serotonergic psychedelics: Active metabolites such as psilocin bind multiple 5-HT receptor subtypes and other monoaminergic receptors. The authors focus on 5-HT2A and 5-HT1A receptors because of their contrasting intracellular coupling and cortical roles: 5-HT2A (Gq-coupled) activation depolarises pyramidal neurons and increases firing, especially localised to the proximal apical dendritic trunk and postsynaptic dendritic compartments; 5-HT1A (Gi/o-coupled) activation tends to hyperpolarise neurons and suppress excitability. Transcriptomic and histological data cited indicate that roughly 60% of frontal cortical neurons have detectable Htr1a or Htr2a transcripts and that ~80% of those coexpress both subtypes, implying within-cell competition between excitatory and inhibitory receptor signalling. Subcellular localisation differs between the receptors (with high 5-HT2A density in proximal apical dendrites), providing a substrate for spatially heterogeneous effects on the dendritic tree. Five mechanistic consequences the authors extract from this opposing-action hypothesis are described. First, opposing actions can promote long-term plasticity: increased dendritic excitability elevates Ca2+ influx through NMDARs and voltage-gated Ca2+ channels, driving BDNF and mTOR signalling implicated in spine growth and synapse formation; the authors argue plasticity will be spatially restricted to dendritic ‘‘hot spots’’ where excitation predominates. Second, acute perturbation of dendritic excitability alters synaptic integration and sensory filtering, consistent with perceptual distortions and hallucinations during intoxication; experimental disruptions of dendrite-localised 5-HT2A receptors abolish specific drug behaviours (e.g., head-twitch response in rodents). Third, regional selectivity may arise from differing balances of SST versus PV interneuron expression and Htr2a:Htr1a ratios across cortex: the authors report higher Sst:Pvalb and higher Htr2a:Htr1a ratios in prefrontal regions, which could make medial frontal cortex particularly susceptible to drug-induced dendritic disinhibition and 5-HT2A-driven excitation. Fourth, cell-type selectivity follows gradients of receptor expression: single-cell RNA-seq re-visualisation indicates intratelencephalic (IT) neurons are enriched for Htr2a, predicting IT neurons will be more excited by psychedelics, while other neuronal subclasses show different receptor profiles (e.g., Htr1a bias in SST interneurons). Fifth, competing excitatory and inhibitory actions may temper toxicity and create an inverted-U dose–response for dendritic excitability: examples include ketamine’s transition from antidepressant to anaesthetic at higher doses, and LSD’s large therapeutic ratio (therapeutic ratio cited as 280, with effective dose = 50 μg and lethal dose = 14 000 μg in the extracted text), whereas highly selective ligands (e.g., NBOMe) can produce more severe adverse outcomes. The authors also note inconsistencies and caveats within the empirical base: other NMDAR antagonists do not consistently replicate ketamine’s antidepressant effects, ketamine metabolites (such as hydroxynorketamine) may act via different targets yet still engage neurotrophic cascades, and 5-HT receptor signalling is complex (including heteromeric receptor complexes and agonist-directed signalling). Quantitative details about some analyses (for example exact methods for transcriptomic visualisations) are not fully specified in the extracted text.

Savalia and colleagues interpret their synthesis to suggest that dendritic signalling is a useful intermediate level to reconcile how pharmacologically distinct agents can produce similar plasticity-related and behavioural outcomes. They argue that spatial mismatches in opposing drug actions across the dendritic tree could steer Ca2+-dependent plasticity to specific dendritic branches, synapses and cell types, thereby producing selective circuit remodelling despite widespread drug exposure. The framework links immediate biophysical effects (changes in dendritic excitability and Ca2+ influx) to downstream neurotrophic cascades (BDNF, TrkB, mTOR) that are implicated in sustained antidepressant responses. The authors position this view relative to prior work by emphasising different proximate mechanisms: ketamine’s disinhibitory microcircuit effects via PV and SST interneurons versus psychedelics’ receptor coexpression within single neurons. They note that these mechanisms are not mutually exclusive and may interact with broader network and regional influences, including inputs from thalamus, amygdala and neuromodulatory systems. Important limitations are acknowledged: precise measurements of drug effects across entire dendritic arbors are technically challenging and largely lacking; species differences and developmental regulation may alter receptor and interneuron distributions; not all NMDAR antagonists replicate ketamine’s effects, and 5-HT signalling involves complex intracellular pathways and receptor adaptations (desensitisation/downregulation). The authors also acknowledge that the relationship between acute psychotomimetic effects (dissociation, hallucinations) and antidepressant efficacy remains unclear. Implications and future directions highlighted by the authors include mapping drug actions across dendritic trees with advanced imaging, characterising the relative expression of 5-HT receptor subtypes in relation to functional outcomes, dissecting the relative contributions of PV- versus SST-mediated disinhibition for ketamine’s effects, and testing whether targeted stimulation during the proposed critical window of increased plasticity can guide and augment therapeutic synapse changes. The authors present a set of outstanding questions aimed at empirically testing the framework and clarifying how dendrite-level actions relate to clinical benefit.

In their concluding remarks, the authors restate that ketamine and serotonergic psychedelics, despite differing molecular targets, appear to converge on dendritic signalling as a key locus for initiating plasticity that could underlie rapid and sustained antidepressant effects. They emphasise that spatially heterogeneous, opposing actions on dendritic excitability may explain selectivity across synapses, cell types and regions, and could limit toxicity through an effective inverted-U dose response. The authors call for focused basic science work to map these competing mechanisms in detail so that insights can guide the therapeutic application and optimisation of these emerging pharmacological approaches.