This review (2020) review looks at the common mechanisms that underly the effects of ketamine and classical psychedelics. Although the research is in its infancy, the authors identify neuroplasticity via glutamatergic common downstream mechanisms.
Background
The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.
Methods
This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed.
Results
Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research.
Conclusions
Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.
Papers cited by this study that are also in Blossom
Abdallah, C. G., Averill, L. A., Collins, K. A. et al. · Neuropsychopharmacology (2016)
Agin-Liebes, G. I., Malone, T., Yalch, M. M. et al. · Journal of Psychopharmacology (2020)
Atasoy, S., Vohryzek, J., Deco, G. et al. · Progress in Brain Research (2018)
Barrett, F. S., Griffiths, R. R. · Current Topics in Behavioral Neurosciences (2017)
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.
Our understanding of antidepressant pharmacotherapy dramatically changed with the discovery that subanesthetic doses of the glutamatergic modulator ketamine exert antidepressant effects in a matter of minutes, and that these effects persist long after drug excretion. For nearly half a century, the antidepressant effects of most conventional monoaminergic antidepressants took weeks to months to manifest, a considerable lag time between regimen initiation and realization of therapeutic effects. In the past two decades, multiple randomized, placebo-controlled trials have shown that intravenous subanesthetic-dose ketamine has rapid, robust, and relatively sustained antidepressant effects in individuals with major depressive disorder (MDD)or bipolar depression. Ketamine also offers hope to the roughly 33% of individuals with treatment-resistant depression (TRD) who do not respond to conventional antidepressants. A metaanalysis of nine randomized, placebo-controlled trials found that a single ketamine infusion exerted antidepressant effects that typically began 40 minutes post-infusion, peaked 24 hours later, and lost superiority to placebo 10-12 days post-infusion. Despite this encouraging antidepressant profile, ketamine is associated with psychoactive effects that peak at about 40 minutes post-infusion, requiring medical supervision during administration. For the purposes of this paper, psychoactive states are defined as profound alterations in consciousness, including domains of perception, mood, thought, and self-awareness; these effects are also alternatively referred to as hallucinogenic, psychotomimetic, or psychedelic. Building on these findings, investigators have scrutinized ketamine's pharmacological profile in order to not only understand its antidepressant mechanism of action but also to develop similar, glutamatergic-based agents that lack ketamine's psychoactive effects. More broadly, ketamine trials have created a blueprint for studying novel pharmaceuticals in the field. In particular, thoughtfully-designed ketamine studies have shown that agents with abuse potential in non-medical settings can nevertheless be administered in a safe and scientifically rigorous fashion. The paradigm shift triggered by ketamine's therapeutic success has also created a model whereby investigators can methodically explore the potential therapeutic value of new or existing (but repurposed) substances that carry abuse liability risk. At the forefront of such work, several recent studies have suggested that "classic" serotonergic psychedelics (SPs) may also have antidepressant efficacy; in particular, they appear to produce rapid, sustained antidepressant effects after a transient psychoactive period. Indeed, prior to being banned as Schedule I drugs in 1967, SPs showed promise for treating a number of psychiatric disorders, including depression, anxiety, obsessive-compulsive disorder, and alcoholism. However, by today's standards these studies had serious methodological flaws, including lack of control groups, lack of adverse events reporting, lack of blinding, and unvalidated outcome measures. From the outset it should be noted that modern research into the antidepressant effects of SPs is in its infancy, and the rigor of these studies remains questionable. Broadly, recreational use of SPs in the 1960s resulted in wide mistrust in the medical community. These agents exert powerful and potentially life-altering effects. Adverse risks associated with SP therapy include distressing experiences, prolonged psychosis, flashbacks, or persisting perceptual disturbances. The characteristics that might predict unacceptable risks, such as personal or family history of psychosis, also remain unknown. Furthermore, because SPs acutely increase serotonin levels-an effect that alters neural plasticitythese powerful agents can have both positive (e.g., improved capacity to recover) and negative (increased vulnerability to depression) effects. Nevertheless, their safety in clinical and research settingsas well as abuse/addiction liabilityare considered to be within acceptable limits, although more research is clearly needed to definitively establish their therapeutic safety profile. Pharmacologically, SPs are defined as drugs that induce subjectively similar psychoactive states via agonism at the 5-HT 2A receptor and binding at other serotonergic receptors. Specific SPs currently under investigation for the treatment of mood and anxiety disorders include psilocybin (the active ingredient in "magic mushrooms"), lysergic acid diethylamide-25 (LSD), 2,5-Dimethoxy-4-iodoamphetamine (DOI), Ayahuasca (a plant brew whose active component is N,Ndimethyltryptamine, or "DMT"), and 5-methoxy-DMT (5-MeO-DMT from the Bufo alvarius toad). These compounds have been used for centuries in traditional rituals and ethno-medicinal settings by indigenous peoples, particularly in the Americas. Two randomized, placebo-controlled, crossover trials, one using low-dose psilocybin (1 or 3mg/70kg) as an active placebo (n=51) and the other using niacin (n=29), found that psilocybin (22 or 30mg/70kg) decreased Hospital Anxiety & Depression Scale (HADS) scores in terminally ill cancer patients with mood disorders; in one trial, more than 80% of participants met remission criteria (>50% HADS reduction to <7 overall score) the day after administration. Furthermore, in both trials, 60-80% of participants met response criteria (>50% HADS reduction) at or beyond six months. A third randomized, placebo-controlled, crossover trial that examined psilocybin (0.2 mg/kg) versus a niacin placebo (n=12) reported significant improvement in Beck Depression Inventory (BDI) scores in individuals with advanced-stage cancer and anxiety disorders, but only after six months. Finally, an open-label trial of 20 TRD participants reported large group reductions (Cohen's d=1.4) in Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) scores six months after two psilocybin sessions. In light of these findings, the FDA granted psilocybin Breakthrough Therapy Designation for two multi-site, Phase 2 clinical trials for TRD, and in 2019 the European Medicines Agency approved psilocybin for a Phase 3 clinical trial for TRD. Though psilocybin is the most studied agent, antidepressant effects have also been reported for other SPs. A randomized trial of Ayahuasca using a zinc-oxide brew that mimicked Ayahuasca's appearance and nausea-inducing side effects as an active placebo found that 64% of 29 Ayahuascanaive TRD participants had a 50% reduction in depressive symptoms from baseline seven days later. In this study, as well as in two open-label trials of sixand 14depressed participants given Ayahuasca, significant reductions in depressive symptoms were observed the following day. In addition, a placebo-controlled pilot study found that LSD produced trend-level reductions in HADS scores two months post-administration in 12 participants experiencing end-of-life anxiety. Finally, a recent observational study found that 43 participants who inhaled 5-MeO-DMT had significant reductions in depressive, anxiety, and stress symptoms within 24 hours, and that these effects persisted for four weeks; approximately three-quarters of the participants were healthy volunteers (HVs), and the remaining participants suffered from a variety of psychiatric disorders. While this evidence is still preliminary, future studies may well suggest that SPs should be added to the armamentarium of rapid-acting antidepressant drugs (RAADs). This, of course, begs the question: why do pharmacotherapies such as ketamine and SPs-which are mechanistically distinct and do not share the same pharmacodynamic profile-nevertheless share such similar fundamental characteristics with regard to their ability to rapidly alter mood? Uncovering how serotonergic RAADs work would bring the field closer to being able to optimize their application, develop novel drugs, and generally improve our understanding of the molecular, neural, and pathophysiological underpinnings of depression. Rather than exhaustively review the clinical evidence for these pharmacotherapies, this paper seeks to summarize areas of overlap between SP and ketamine research-including converging cellular and molecular mechanisms as well as physiological, imaging, and behavioral findings-and considers the possibility of a common, downstream mechanism of action.
Arguably the most salient feature of these pharmacotherapies is their rapid and transient induction of psychoactive symptoms. With regard to ketamine, a major goal of current research is to produce a widely-distributable antidepressant agent that lacks psychoactive side effects. Thus, ketamine research has largely sought to understand the mechanisms underlying its antidepressant efficacy rather than study its psychoactive profile. Furthermore, ketamine's antidepressant effects occur at subanesthetic doses (0.5 mg/kg) that appear to be relatively well tolerated and create mild, transient psychoactive effects. For instance, a recent study assessing side effects associated with a 0.5 mg/kg ketamine infusion in 163 participants with TRD across four clinical trials reported that only 50% experienced SP-like psychoactive effects (e.g., the sensation of floating), and 80% reported "feeling strange, weird, or bizarre". This is not to say that ketamine's psychoactive effects are not well-documented. In fact, the earliest descriptions of subanesthetic-dose ketamine (0.5 mg/kg) administration in HVs reported effects such as altered perception of time and space, loss of a sense of self, and visual hallucinations. Since then, multiple studies have confirmed that psychoactive effects occur at or below this standard antidepressant dose. Nevertheless, due to the dosing disparity between ketamine and SPs, the prevalence of any kind of psychoactive effect is far more common in clinical trials of SPs than of ketamine. While the lowest dose of various SPs needed to produce antidepressant effects is presently unknown, the high dose of psilocybin (~30mg/70kg) used in antidepressant trials causes strong psychoactive effects in virtually all participants, and therapeutic Ayahuasca doses are typically the same as those used to elicit "visions" in religious ceremonies (~1.67 mg/kg DMT). Furthermore, far more research has examined the therapeutic relevance of psychoactive effects with regard to SPs than ketamine. In particular, growing evidence suggests that particular experiences during the psychoactive period are uniquely predictive of therapeutic outcome with SPs. The most consistent finding thus far with regard to SPs is that "mystical experiences" increase the likelihood and magnitude of depressive symptom reductions. Mystical experiencesreportedly stable across time periods and cultures-are broadly defined as psychological phenomena where individuals report experiences of bliss, sacredness, transcendence of space and time, and encounter with greater truths. With SP therapy, such experiences appear to increase the likelihood and magnitude of depressive symptom reductions. In one of the three randomized, double-blind, placebo-controlled psilocybin trials discussed above, scores on the 30-item Mystical Experience Questionnaire (MEQ30) mediated the sustained reductions in HADS scores observed five weeks later (n=51). In another such study, sustained reductions in HADS and BDI scores 6.5 months after treatment were again mediated by MEQ30 scores (n=29). In addition, in the open-label study of 20 TRD participants treated with psilocybin on two occasions, sustained QIDS-SR reductions at five weeks were predicted by scores on a 5-Dimensional Altered States of Consciousness Rating Scale (5D-ASC) subscale approximating the MEQ30. Therapeutic insights are not reported in qualitative studies of ketamine treatment and may help explain the heightened duration of antidepressant effects associated with. However, the necessity of Downloaded fromby guest on 01 December 2020 such insights for the therapeutic efficacy of both SPs and ketamine remains to be systematically investigated. It should also be noted that the effects of subjective experiences on overall drug action have not been detected in every study. For instance, in the randomized, double-blind, placebo-controlled study of Ayahuasca in 29 TRD participants, researchers reported a negative correlation between an MEQ30 subscale ("transcendence of time and space") and reduction in Montgomery-Asberg Depression Rating Scale (MADRS) scores at Day 7. In addition, the follow-up to Ross and colleagues' clinical trial found that persisting antidepressant effects 3.2-4.5 years later were no longer mediated by individuals' acute MEQ30 scores, though the sample size had been reduced by ~50% in this analysis. While the connection between ketamine's psychoactive and therapeutic effects has received far less attention, it appears to be considerably weaker. For instance, a systematic review of eight studies found that the relationship between dissociation and antidepressant effect was mixed, and only three of the eight analyses found a relationship between antidepressant response to ketamine and psychosis scores assessed via the Clinician-Administered Dissociative States Scale (CADSS). Furthermore, for those studies that did observe a significant relationship, the explained variance of dissociative experiences for antidepressant response was 12-21%. Most clinical studies investigating ketamine's psychoactive effects in TRD trials have used the CADSS, but the only psychometric evaluation of the CADSS for this purpose found that it failed to capture much of ketamine's psychoactive profile. One observational study of 31 participants undergoing repeated infusions at a community ketamine clinic used the 5D-ASC, a questionnaire capable of assessing the full spectrum of ketamine's psychoactive effects, and found that participants' subjective experience (e.g, drug-induced anxiety) during the first in a series of ketamine infusions negatively predicted MADRS score reductions at the end of approximately two Downloaded fromby guest on 01 December 2020 weeks of infusions. Unlike results observed with psilocybin, the 5D-ASC subscale score-which approximates the MEQ30-was not associated with long-term antidepressant effects. It is also important to note that differences in therapeutic setting constitute a major confound for comparing subjective experiences and efficacy associated with these compounds. In accordance with guidelines established by Johnson and colleagues, SPs are typically administered after extensive psychological preparation in soothing surroundings that may include attractive furnishings and supportive music; research suggests that such measures may reduce the chance of distressing reactions. In an open-label trial of psilocybin for TRD (n=19), the manner in which music was experienced during psilocybin administration predicted outcome at one week, while participants' subjective ratings of peak drug effect intensity did not. In contrast, virtually nothing is known about the relationship between the setting in which ketamine infusions take place, subjective experience, and outcome; ketamine is typically administered in more clinical settings such as hospitals or clinics. While some clinicians have argued that the context in which ketamine is administered heavily influences subjective experience and efficacy, this claim requires further investigation. Thus, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies, the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research. The evidence linking ketamine's antidepressant effects to its psychoactive effects is weak and, although early evidence suggests that psychoactive effects observed in SP trials may be linked to antidepressant effects, it is difficult to draw firm conclusions given small sample sizes, often improper trial designs, and functional unblinding. Indeed, though some evidence suggests that type of psychoactive experience influences outcome, the hypothesis that the psychoactive effects of RAADs
Studies suggest that both ketamine and SPs rapidly facilitate changes in neuroplasticity such as neurite growth, synapse formation, and strengthened synaptic connections (Table). In particular, evidence suggests that both ketamine and SPs increase the expression of neuroplasticityregulating genes. In rodents, intraperitoneal ketamine injections resulted in an antidepressant response observed concurrently with increased brain-derived neutrotrophic factor (Bdnf) gene expression and translation in the hippocampus and across the cortex. BDNF is known to promote neuronal growth and plasticity and has often been implicated in the pathophysiology of depression. Other studies have shown that ketamine also induces glutamate signaling-related neuroplasticity genes such as Activity Related Cytoskeletal protein (Arc) and Homer1a (de. With regard to SPs, DOI injections have been found to induce Bdnf expression in the rat neocortex, and both LSD and DOI administration in rodent models increased expression of Bdnf, Arc, Nor1, egr-1, sgk, Ania3, C/EBP-β, and Iκβ-α. All of these genes have in some way been linked to synaptic strength or neuronal growth and can be induced through G-protein-coupled receptor pathways linked primarily to stimulation of 5-HT 2A receptors. This gene induction may promote neuroplasticity and some of the key downstream effects associated with RAADs. Ketamine's neuroplastic effects are well established (see2018) for a review). Briefly, in rats, ketamine administration increased spine synapse number and synaptic strength in the prefrontal cortex (PFC); both this effect and ketamine's antidepressant-like effects were abolished by pharmacological blockade of mechanistic target of rapamycin (mTOR) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). In addition, in the Flinders Sensitive Line (FSL) rat model of depression, ketamine rapidly restored apical dendritic spine deficits in pyramidal neurons of the hippocampal CA1 region within 60 minutes of infusion. Other studies have reported that BDNF is required for ketamine's antidepressant and synaptogenic effects. In addition, preclinical studies have suggested that these neuroplastic effects may lead to antidepressant effects by altering cortical connectivity and subsequent functionality. For instance, a recent mouse model study of depression-like phenotypes found that ketamine infusion selectively reversed stress-induced loss of dendritic spines and coordinated the multicellular ensemble activity of PFC neurons two days post-treatment, an effect associated with a sustained, but not immediate, antidepressant response. Evidence suggests that SPs similarly promote neuroplasticity. In a recent study, DMT, LSD, and DOI all led to increased spine density, dendritic branching, and synapse formation in cultured rat cortices as measured by super-resolution structured illumination microscopy. In vivo treatment with LSD and DOI caused the same effects in Drosophila brains, and ex vivo slice recordings also revealed synaptic potentiation in the form of increased spike amplitudes and frequencies. In addition, intraperitoneal administration of DMT at antidepressant-like concentrations led to spinogenesis in rat cortices examined hours later. This effect was abolished by mTOR blockade or antagonism of either the 5-HT 2A receptor or tropomyosin-related kinase B (TrkB), BDNF's primary target and an upstream activator of mTOR. When researchers performed the same assays with ketamine, they found that SPs were significantly more potent and effective than ketamine in promoting neuritogenesis, suggesting that the longer duration of antidepressant effects associated with SP Downloaded fromby guest on 01 December 2020 administration may result from more efficacious neurotrophic induction. Similar results were obtained via intracerebroventricular injections of 5-MeO-DMT in adult mice; researchers reported increased neuronal proliferation in the dentate gyrus as measured by a significant increase in Bromodeoxyuridine (BrdU+) cells as well as increased dendritic tree complexity in granule cells (Lima da. Although many of these neuroplastic effects still need to be verified in humans, clinical evidence supports BDNF's role in the rapid-acting properties of RAADs. However, the evidence is mixed for ketamine, with some studies supporting these findingsand other studies finding no such evidence. With regard to SPs, one clinical trial of Ayahuasca for TRD (n=28) found that BDNF levels increased 48 hours post-treatment, and that this increase correlated with MADRS score reductions (de. However, another study found no changes in plasma BDNF levels in 28 HVs given LSD. Regardless of the therapeutic agent examined, a key limitation for all of these studies is the inability to directly assess BDNF activity in the brain. In terms of immediate drug effects, both ketamine and SPs appear to trigger a "glutamate surge". For ketamine, this effect is well documented and widely believed to be relevant to its antidepressant effects. Studies similarly suggest that SPs cause a glutamate surge, primarily in layer V pyramidal neurons expressing 5-HT 2A receptors. For instance, systemic LSD or DOI administration increased glutamate concentrations as measured by in vivo microdialysis in rat prefrontal and somatosensory cortices. In both cases, 5-HT 2A receptor antagonists abolished the glutamate surge. Another rat study found that DOI injection increased expression of the early-activation gene cFos, a marker of neuronal activity, in a subset of 5-HT 2A receptor-expressing neurons. This active population was localized primarily to the medial prefrontal cortex (mPFC), somatosensory cortex, orbital cortex, and claustrum-regions overwhelmingly composed of glutamate-releasing pyramidal neurons. The increases in cortical glutamate noted in preclinical ketamine studies have been confirmed via carbon-13 magnetic resonance spectroscopy ( 13 C MRS) in both HVs and depressed human participants. Such proof-of-concept studies are sparse for SPs. One PET study reported that LSD administration in HVs increased metabolism in the primarily glutamatergic frontal cortices, suggesting increased glutamate signaling. A recent, double-blind, placebo-controlled trial using ultra-high field 7T MRS found that psilocybin (0.17 mg/kg) acutely induced region-dependent alterations in PFC glutamate levels that correlated with behavioral changes during the psychoactive state. With regard to ketamine, the glutamate surge associated with its administration translates into increased AMPAR throughput, which likely triggers BDNF release and activates mTOR. This AMPA activity appears to be critical, as rodent studies found that AMPA antagonists abolished ketamine's behavioral, antidepressant, and mTOR-stimulating effects. To date, few studies have directly examined the relevance of AMPAR throughput in SPs, although AMPAR activation is known to be necessary for the behavioral effects and sustained glutamatergic activity of DOI in rodents. Despite the evidence suggesting that SPs may exhibit similar molecular and cellular effects as ketamine (see Table, Figure), it should be noted that this evidence exists only for a few SPs and primarily for DOI, which has not been clinically investigated. Hence, there is far more evidencebased data stemming from preclinical and translational research for ketamine's cellular and molecular mechanisms than for that of SPs (see Table). Moreover, no studies investigating SPs have yet established a link between these molecular/cellular effects and antidepressant efficacy in Downloaded fromby guest on 01 December 2020 rodent models of depression-a gap that should be addressed in future preclinical studies. However, studies have shown that DMT, LSD, and psilocybinall have antidepressant-like effects in rats, as assessed via the forced swim test. Interestingly, and consistent with the clinical literature, one such study reported that LSD and psilocybin-but not ketamine-produced antidepressant-like effects that persisted five weeks later. It should also be noted that, although similar, important differences remain with regard to the precise mechanisms underlying these drugs' actions in the brain. For example, ketamine disinhibits thalamo-cortical communication specifically via upstream cortical and subcortical somatostatin and parvalbumin gamma aminobutyric acid (GABA)-ergic neurons, whereas SPs seem to directly activate pyramidal neuronsas well as cause extrasynaptic glutamate spillover. Such differences may explain the varied psychoactive phenomenology and/or duration of antidepressant efficacy between ketamine and SPs and warrant additional study.
The psychoactive effects of both ketamine and SPs are accompanied by acute (during administration) and delayed (measured hours after dosing) electrophysiological and hemodynamic changes in brain activity (see Table). A recent study in HVs reported that subanesthetic-dose ketamine, LSD, and psilocybin all similarly increased spontaneous magnetoencephalography (MEG) signal complexity as measured by Lempel-Ziv complexity (LZC); notably, LZC measures the number of different electrophysiological timeseries patterns and their rate of occurrence-here, a canonical measure for "level of consciousness". In that study, the psychoactive effects of both SPs and ketamine led to greater signal complexity than normal waking consciousness, reflecting an elevated level of consciousness following drug administration. One MEG study that directly compared ketamine, LSD, and psilocybin found that all three drugs induced altered states of consciousness characterized by decreased spectral power and lower source-level functional connectivity. Indeed, power reductions in lowfrequency signals as measured by resting-state MEG/EEG are among the most consistently reported observations following ketamine and SP administration, with reduced alpha band power most closely tracking psychoactive/hallucinatory effects. Similar alterations in alpha band power have also been reported in response to illusory stimuli following psilocybin administration in HVs. Such reductions in low-frequency oscillations may also indicate a general trend toward decreased long-range communication and increased modularity during psychoactive states. Interestingly, while ketamine has consistently been reported to acutely increase gamma band power in HVs (Gilbert and Zarate, 2020)-a phenomenon linked to pyramidal cell disinhibition downstream of NMDAR antagonism-studies assessing the effects of SPs on gamma power have yielded mixed results. For example, in HVs, decreased gamma power was observed in frontal and motor regions following psilocybin administration during a visuomotor task, and increased resting-state gamma power was noted one hour after Ayahuasca ingestion. Gamma power may be of particular interest because delayed gamma power increases following ketamine's psychoactive period may be a putative biomarker of antidepressant response in TRD, potentially reflecting increased synaptic efficiency and synaptogenesis mediated by AMPAR glutamatergic throughput. To our knowledge, no study has yet examined the delayed effects of SPs on gamma power in TRD. These acute electrophysiological findings are complemented by functional magnetic resonance imaging (fMRI) studies measuring resting-state functional connectivity (RSFC) changes Downloaded fromby guest on 01 December 2020 following drug administration (see Table). However, little of this work has examined SPs. Three studies exploring ketamine's effects on connectivity measured via global brain connectivity (GBC)-a graph-based measure of intrinsic whole-brain network connectivity-suggested it may be a biomarker of antidepressant response; individuals who resonded to ketamine had higher delta GBCr values in the PFC, caudate, and insula. Nevertheless, a recent, randomized, placebo-controlled trial did not replicate this finding 48 hours post-ketamine. Although only one study examined the effect of SPs on GBC, it found that, unlike ketamine, LSD acutely decreased GBC in the PFC in HVs. Another area of particular interest is alterations in default mode network (DMN) functional connectivity, consistent with a growing body of literature reporting the relevance of DMN activity to the pathophysiology of depression (Whitfield-Gabrieli and Ford, 2012;. A double-blind, placebo-controlled, crossover study of 33 individuals with MDD and 25 HVs who received ketamine found that the MDD group had increased connectivity between the DMN and other nodes two, but not 10, days post-treatment. RSFC between the DMN and the insula (part of the salience network), which was reduced in MDD participants compared to HVs prior to treatment, normalized in MDD participants following ketamine and returned to baseline at the time point when most participants relapsed. As regards SPs, a recent study looked at changes in RSFC in 19 TRD participants one day after the second of two psilocybin administrations (eight days after the first) and found increased DMN connectivity post-treatment (Carhart-Harris and Goodwin, 2017); stronger RSFC between particular nodes predicted sustained response five weeks later. One consistent fMRI finding is that the effects of RAADs correlate with increased functional connectivity between resting-state functional networks and decreased within-network functional connectivity, sometimes referred to as "network disintegration". As regards the DMN in particular, one randomized, double-blind, placebo-controlled, crossover study of 24 HVs given subanesthetic-dose ketamine recently replicated findings from an earlier study of eight HVs reporting acute decreases in functional connectivity to the mPFC node of the DMN. The earlier study also noted between-network disintegration; the strength of the typical anticorrelations between the DMN and other functional networks was significantly weaker postketamine administration. Similarly, an uncontrolled study of 15 HVs who received psilocybin found decreased mPFC activity and functional connectivity with the posterior cingulate cortex (PCC) node of the DMN. In another study of 10 HVs, Ayahuasca decreased activity in all DMN nodes and decreased functional connectivity between the PCC and precuneus nodes. Finally, an LSD study of 20 HVs also observed decreased RSFC within the DMN coupled with increased connectivity between the DMN and other large-scale brain networks. One final area of research overlap concerns drug-induced changes in emotional face processing in the amygdala. Separate analyses of fMRI data collected from TRD participants in an open-label psilocybin trial found that increased Day 1 amygdala activation in response to fearful versus neutral face stimuli predicted QIDS-SR score reductions at one week; in addition, reduced ventromedial PFC-amygdala functional connectivity correlated with Ruminative Response Scale scores at Day 7. In contrast, near-opposite findings have been reported in response to ketamine. For example, reductions in MADRS scores correlated with reduced amygdala responsivity to angry face stimuli and increased responsivity to happy face stimuli two days post-ketamine in 33 TRD participants. In another study of 27 MDD participants, repeated doses of ketamine decreased amygdala responsivity to both fearful and happy face stimuli one to three days after four serial ketamine infusions. These intriguing preliminary findings suggest that the antidepressant effects of both ketamine and SPs involve changes in brain network connectivity and functionality; nevertheless, the small sample sizes Downloaded fromby guest on 01 December 2020 and lack of controls in SP studies, as well as the large variety of ketamine studies, suggest that few converging findings can confidently be concluded at this time. Additional research is needed to better illuminate these links.
Taken together, the evidence reviewed above suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. These different RAADs, though seemingly distinct, both appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. In this context, the first step in serotonergic RAAD pharmacotherapy is molecular binding (see Figure). Notably, serotonergic RAADs primarily exert their actions by stimulating 5-HT 2A receptors, which, in turn, leads to glutamate-dependent increases in pyramidal neuron activity in the PFC, thus modulating prefrontal network activity. This extracellular glutamate surge also triggers the activation of AMPARs located in the same neurons throughout the cortex. Given the central and ubiquitous role that glutamate-AMPA signaling plays in the cortex and in conscious experience, this increase in cortical excitatory signaling may be the origin of the entropic brain state underlying these agents' psychoactive effects. In this model, high AMPA throughput would lead to BDNF release and mTOR signaling, triggering upregulation of plasticity genes associated with neural growth, strengthening certain synapses, and causing new synapses to form. In this manner, the effects of SPs and of ketamine would be accompanied by a highly plastic brain state capable of "rewiring" functional brain circuits. At present, however, the preliminary nature of many of the SP studies discussed above means that a common mechanism between SPs and ketamine remains largely speculative; further investigation is warranted.
As reviewed above, RAADs currently under investigation may share downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be applied to the investigation of entirely new classes of antidepressants with rapid and robust actions. In this context, research examining the therapeutic mechanisms of SPs should assess the "glutamate surge", potentiation of AMPAR throughput, and plasticity properties in SPs as rigorously as in ketamine studies, connecting them to preclinical models of depression. A more complete understanding of the cellular and molecular mechanisms of SPs could lead to convergent drug targets with ketamine research, accelerating antidepressant drug development. As noted throughout this article, research into the mechanisms of action of RAADs remains in its infancy, and multiple research avenues of likely relevance exist. As one notable example, multiple preclinicaland clinicalstudies suggest that ketamine may exert its antidepressant effects at least in part by reducing inflammatory tone, and similar evidence is emerging for SPs. Another key area of research is whether SPs would exert similar pharmacological efficacy in the absence of concomitant psychological support. Another domain for further research includes understanding the disparity in symptom relief duration for ketamine versus SPs; in particular, understanding how SPs confer sustained symptom relief may be key to characterizing treatments that best reduce risk of relapse. An important caveat, however, is that, to date, the quantity and robustness of the preclinical and clinical data for ketamine far supersede that currently available for Downloaded fromby guest on 01 December 2020 needs to be addressed-and often conducted in participants with subsyndromal illness or mild depressive or anxious symptomswho are not representative of the TRD population studied in ketamine trials. In the short term, rigorously controlled studies using active placebos that minimize issues of functional unblinding (an issue that also plagues ketamine research) should examine SPs in order to investigate the most successful ways to elicit antidepressant effects. Given the powerful and potentially life-altering effects of these agents, further research is particularly needed to determine clinical efficacy, optimal dosing, and administration characteristics. Ultimately, identifying common downstream mechanisms of action for rapid-acting-but pharmacologically differentantidepressants has the potential to improve treatments for depression and other stress-related brain disorders. + + ++ + ++NEE NEE + + +) Increased AMPA Throughput + + +NEE NEE NEE NEE +Neuroplasticity Gene Induction + + + (de+ + ++NEE NEE + +Necessity of BDNF/TrkB Signaling + + +
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