Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants

Kadriu and colleagues situate their review in the context of a paradigm shift in antidepressant pharmacotherapy triggered by subanesthetic ketamine, which produces rapid and relatively sustained antidepressant effects contrary to the long lag time typical of conventional monoaminergic treatments. They note that ketamine has provided a clinical and methodological blueprint for evaluating other compounds with abuse liability and that recent clinical studies suggest classic serotonergic psychedelics (SPs) such as psilocybin, LSD, ayahuasca (DMT), and 5-MeO-DMT may also produce rapid, durable reductions in depressive symptoms following a transient psychoactive period. This paper aims to summarise areas of overlap between ketamine and SP research rather than provide an exhaustive clinical review. Specifically, the authors review converging cellular and molecular mechanisms, electrophysiological and neuroimaging observations, and the therapeutic relevance of the psychoactive state, and they consider whether a common downstream, glutamate-dependent mechanism could underlie rapid-acting antidepressant (RAAD) effects across these pharmacologically distinct agents. They emphasise that modern SP research remains preliminary and that rigorous investigation is required to clarify safety, efficacy, and mechanisms.

The extracted text does not report a formal methods section or a systematic search strategy; instead, Kadriu and colleagues present a narrative review that integrates findings from randomized clinical trials, open-label and observational studies, preclinical rodent and in vitro experiments, electrophysiological and neuroimaging studies, and mechanistic work on molecular signalling pathways. The authors draw on published randomized, placebo-controlled psilocybin and ayahuasca trials in clinical populations, ketamine randomized trials and meta-analyses, preclinical gene-expression and synaptogenesis studies, MEG/EEG/MEG complexity analyses, and fMRI connectivity studies. Because this is a narrative synthesis, the review emphasises conceptual integration over systematic aggregation: the authors compare clinical outcomes (response/remission rates and time-course) and subjective-state measures (for example, the Mystical Experience Questionnaire and the 5-Dimensional Altered States of Consciousness scale) alongside cellular markers (BDNF, Arc, mTOR, AMPAR activity) and network-level observations (global brain connectivity, default mode network connectivity, spectral power changes). Where available, the authors report sample sizes, psychometric instruments, and key temporal patterns from the cited trials, but the review does not provide formal inclusion/exclusion criteria, risk-of-bias assessment methods, or meta-analytic pooling methods in the extracted text.

Clinical and psychoactive-state findings: The review summarises clinical trial evidence indicating that ketamine and several SPs can produce rapid antidepressant effects after a transient psychoactive period. A meta-analysis of nine ketamine randomized, placebo-controlled trials is reported to show antidepressant effects beginning around 40 minutes post-infusion, peaking at 24 hours, and losing superiority to placebo after about 10–12 days. By contrast, several psilocybin trials in terminally ill patients and in treatment-resistant depression (TRD) samples reported large, sometimes long-lasting symptom reductions: two randomized, placebo-controlled crossover trials (n=51 and n=29) observed substantial HADS score reductions with psilocybin, with one trial reporting >80% meeting remission criteria the day after administration and 60–80% meeting response criteria at or beyond six months. An open-label TRD study (n=20) found large group reductions in QIDS-SR scores six months after two psilocybin sessions (Cohen's d=1.4). An ayahuasca trial in 29 TRD participants reported a 50% symptom reduction at Day 7 in 64% of participants. Observational data after inhaled 5-MeO-DMT (n=43) showed symptom reductions up to four weeks. The authors caution that SP studies are preliminary, often small, and frequently lack rigorous blinding and controls. Regarding the link between subjective experience and outcome, psilocybin studies consistently indicate that measures of mystical-type experiences (for example, MEQ30 scores) mediate sustained symptom reductions in several trials, and altered music experience during sessions predicted outcome in one open-label trial. For ketamine, evidence linking dissociative or psychoactive experiences to antidepressant response is mixed and generally weak: a systematic review of eight studies found inconsistent associations, and when present the explained variance was modest (12–21%). Psychometric instruments used for ketamine (for example, CADSS) may not fully capture its psychoactive profile, and few studies have evaluated setting effects for ketamine versus the more carefully prepared settings used in SP trials. Cellular and molecular findings: Preclinical data indicate both ketamine and certain SPs rapidly facilitate neuroplasticity, including neurite growth, spine formation, and synaptic strengthening. Rodent studies link ketamine's antidepressant-like effects to increased Bdnf expression, induction of plasticity-related genes (Arc, Homer1a), increased spine synapse numbers in the prefrontal cortex, and a requirement for mTOR and AMPA receptor (AMPAR) activity for synaptogenesis and behavioural effects. SPs (notably DOI, LSD, and DMT in preclinical assays) have been shown to increase expression of Bdnf and multiple immediate-early genes, to increase spine density and dendritic branching in cortical cultures and in vivo, and to promote synaptogenesis. Some comparative work reported that SPs were more potent than ketamine at promoting neuritogenesis in vitro, and SP-induced plasticity effects were blocked by mTOR inhibition or antagonism of 5-HT2A or TrkB receptors. Both drug classes appear to trigger a glutamate surge in cortex: for ketamine this is well documented, and for SPs several rodent and some human MRS/PET data indicate region-dependent increases in glutamatergic signalling. AMPAR throughput is implicated as a critical downstream mediator for ketamine, with fewer direct studies on AMPAR's role in SPs. Electrophysiology and neuroimaging: Acute increases in electrophysiological signal complexity (Lempel-Ziv complexity) have been observed with subanesthetic ketamine, LSD, and psilocybin in healthy volunteers, consistent with elevated conscious experience during the psychoactive state. Both drug classes commonly produce reductions in low-frequency power, notably alpha-band power, which tracks hallucinatory effects. Findings for gamma-band power are heterogeneous: ketamine typically increases gamma acutely and delayed gamma increases have been proposed as a biomarker of antidepressant response, while SPs have shown mixed gamma changes across tasks and studies. Functional MRI studies report alterations in resting-state functional connectivity after RAAD administration. Some ketamine studies suggested increased global brain connectivity (GBC) in prefrontal and subcortical regions among responders, though replication is mixed; in contrast, LSD acutely decreased PFC GBC in healthy volunteers. Changes in the default mode network (DMN) are a recurring observation—often decreased within-network connectivity and increased between-network connectivity—although timing and direction vary across studies and agents. One psilocybin study in TRD found increased DMN connectivity one day after the second dose that predicted sustained response five weeks later. Drug-induced changes in amygdala responsivity to emotional faces have been observed but appear to differ by drug: psilocybin-related increases in amygdala response to fearful stimuli predicted antidepressant improvement, whereas ketamine studies have reported reductions in amygdala responsivity to negative faces correlated with symptom improvement. Limitations in the evidence base: The authors emphasise that preclinical and clinical data are far more extensive for ketamine than for SPs. Many SP findings derive from small, uncontrolled, or open-label studies, and for several SPs the mechanistic data come primarily from DOI or other compounds not yet tested clinically. The inability to measure central BDNF directly, functional unblinding in trials, small samples, and heterogeneity of designs are identified as important constraints.

Kadriu and colleagues propose that ketamine and serotonergic psychedelics may share a common downstream mechanism whereby acute drug-induced alterations in cortical network activity produce a glutamate-dependent rise in excitatory signalling, increased AMPAR throughput, BDNF/TrkB activation, and engagement of mTOR signalling, ultimately driving rapid neuroplastic changes such as spinogenesis and synaptogenesis. In this framework, the transient psychoactive or entropic brain state reflects the initial network perturbation, and the ensuing plastic state enables functional "rewiring" of circuits implicated in mood regulation, producing the sustained antidepressant effects observed for both classes of agents. The authors position these ideas relative to the existing literature by noting substantial mechanistic evidence for ketamine—spanning preclinical, translational, electrophysiological, and clinical studies—while underscoring that SP research is more nascent and less conclusive. They highlight converging observations (glutamate surge, gene induction, altered network connectivity) but also note important mechanistic differences: ketamine appears to disinhibit pyramidal cells via effects on GABAergic interneurons, whereas SPs directly stimulate pyramidal neurons via 5-HT2A receptor agonism and may induce extrasynaptic glutamate spillover. Such differences may explain disparities in psychoactive phenomenology and in the duration of antidepressant effects. Key limitations and uncertainties acknowledged by the authors include the preliminary quality and small sample sizes of many SP clinical trials, the frequent lack of blinding and control conditions which risks functional unblinding, and the absence of direct links in rodent depression models between SP-induced molecular changes and antidepressant efficacy. They also note the technical limitation that peripheral measures (for example, plasma BDNF) cannot directly index central neurotrophic activity. The relationship between the subjective psychoactive experience and therapeutic outcome remains unclear: psilocybin studies provide some evidence that mystical-type experiences mediate sustained benefit, whereas ketamine studies show inconsistent associations. For future research, the authors advocate applying the rigorous experimental paradigms developed in ketamine research to SPs: specifically, measuring glutamate surges, AMPAR potentiation, and plasticity markers in a preclinical-to-clinical translational framework; using active placebos to mitigate functional unblinding; evaluating the necessity of psychological support during SP administration; and investigating inflammatory mechanisms and determinants of treatment durability. They conclude that identifying convergent downstream mechanisms across pharmacologically distinct RAADs could accelerate development of new rapid-acting antidepressant therapies and improve understanding of depression's neurobiology.