Trends in
Pharmacological Sciences
Review
Neuroplasticity as a convergent mechanism of
ketamine and classical psychedelics
Lily R. Aleksandrova1,* and Anthony G. Phillips1,*
The emerging therapeutic efficacy of ketamine and classical psychedelics for
depression has inspired tremendous interest in the underlying neurobiological
mechanisms. We review preclinical and clinical evidence supporting neuroplasticity
as a convergent downstream mechanism of action for these novel fast-acting
antidepressants. Through their primary glutamate or serotonin receptor targets,
ketamine and psychedelics [psilocybin, lysergic acid diethylamide (LSD), and N,
N-dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes,
particularly in pyramidal neurons in the prefrontal cortex. These include increased
glutamate release, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, brain-derived neurotrophic factor (BDNF) and mammalian
target of rapamycin (mTOR)-mediated signaling, expression of synaptic proteins,
and synaptogenesis. Such influences may facilitate adaptive rewiring of pathological neurocircuitry, thus providing a neuroplasticity-focused framework to explain
the robust and sustained therapeutic effects of these compounds.
Highlights
Region-specific dysregulation of
neuroplasticity is implicated in depression.
Ketamine (NMDAR antagonism) and classical psychedelics (5-HT2AR agonism)
trigger a long-lasting state of enhanced
glutamate-driven neuroplasticity in
frontocorticolimbic pyramidal neurons.
Shared neurobiological mechanisms
involve complex interactions between
glutamate, serotonin, and regional
synaptic homeostasis.
Effects may 'reset the system' by
counteracting synaptic deficits, neuronal atrophy, and loss of connectivity
in depression, leading to behavioral
plasticity and symptom reduction.
Novel pharmacotherapies for disorders of neuroplasticity
Ketamine (see Glossary), a glutamate N-methyl-D-aspartate receptor (NMDAR) antagonist,
and classical serotonergic psychedelics are the focus of recent attention as novel fastacting pharmacotherapies for depression and related disorders, especially in the context of
psychotherapy [1–7]. The emerging clinical data (Box 1) support the robust, rapid, and sustained
therapeutic efficacy of these diverse compounds in treatment-resistant depression (TRD) and
major depressive disorder (MDD), and intranasal esketamine was approved by the FDA for
TRD in 2019.
Dysregulation of neural plasticity is implicated in the pathophysiology of depression (Box 2),
consistent with synaptic weakening, neuronal atrophy, and loss of connectivity in vulnerable
brain regions, particularly the prefrontal cortex (PFC) and hippocampus (HPC) (panel 1 in
Figure 1, Key figure) [8–12]. This review integrates preclinical and clinical data from molecular,
electrophysiological, neuroimaging, and behavioral studies which support the hypothesis that
ketamine and classical psychedelics, including psilocybin, LSD, and DMT, all modulate glutamatergic neurotransmission, synaptic remodeling, and network activity within circuits implicated in mood
disorders [7,9,10,13–20]. The growing literature suggests that these compounds share key downstream neurobiological mechanisms related to facilitating adaptive neuroplasticity at multiple levels
(synaptic plasticity, structural plasticity, and behavioral plasticity).
Via their primary receptor targets, ketamine and psychedelics can both upregulate glutamate
release and excitatory neuronal activity [21–33], brain-derived neurotrophic factor (BDNF)
and mammalian target of rapamycin (mTOR) signaling [18,20,29,32,34–38], the expression
of synaptic proteins [22,23,25,35,39–43], and long-term frontocortical structural plasticity
[22,25,32,37,44–48], predominantly in the PFC (Figure 1, panels 2–9). This is thought to reverse
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Ketamine and psychedelics engage
mechanisms rapidly and appear to induce long-lasting structural adaptations
that sustain therapeutic activity without
the need for chronic dosing.
Neuroplasticity substrates serve as
potential targets for clinical intervention and drug development related to
mental ill-health.
1
Djavad Mowafaghian Centre for Brain
Health and Department of Psychiatry,
University of British Columbia,
Vancouver, BC, Canada
*Correspondence:
lily.aleksandrova@ubc.ca
(L.R. Aleksandrova) and
aphillips@psych.ubc.ca (A.G. Phillips).
https://doi.org/10.1016/j.tips.2021.08.003
© 2021 Elsevier Ltd. All rights reserved.
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Box 1. Clinical efficacy of ketamine and psychedelics
The discovery that a single subanesthetic dose of ketamine elicits robust rapid and sustained antidepressant effects in patients with TRD [54] has been replicated numerous times, and there is additional evidence for improved neurocognitive
function (outside the window of acute psychotomimetic effects) and therapeutic utility in suicidal ideation, PTSD, and
substance use disorders [5,6,16,17,89,90]. Importantly, intranasal esketamine was approved by the FDA for TRD and
MDD in 2019 and 2020, while around the same time psilocybin received an FDA breakthrough therapy designation for
the same indications. Psilocybin and LSD are under active investigation in Phase I–II trials, and several meta-analyses of
ketamine and psychedelic clinical trials were recently conducted [1,3,7,16,17]. Despite current limitations (e.g., few
studies, small sample sizes, unblinding, expectancy, etc.) [1,98], the emerging data on the therapeutic effects of
psychedelics in the context of depression are extremely encouraging.
Briefly, accumulating clinical data indicate the safety, efficacy, and tolerability of ketamine, psilocybin, and ayahuasca in the
treatment of treatment-resistant and recurrent MDD [7,16,72,95,99]. In addition to studies in MDD that are underway,
modern randomized controlled trials (RCTs) have investigated LSD for its anxiolytic properties [3,7]. Despite important
methodological limitations, historical data also support the utility of LSD in the treatment of unipolar mood disorders [7].
One meta-analysis evaluated 12 double-blind placebo-controlled RCTs of the clinical effects of classical serotonergic
psychedelics, predominantly psilocybin and LSD, on mood and symptoms of depression in healthy (n = 124) and clinical
populations (n = 133) [1]. In MDD patients, significant effect sizes in favor of psychedelics compared with placebo were
reported for acute (3 h to 1 day after treatment), medium (2–7 days, peak effect), and longer-term (16–60 days) outcomes,
indicating robust, rapid, and sustained reductions in depressive symptoms and increased quality of life [1]. Acute mood
outcomes in healthy volunteers were also significantly improved with psychedelic treatment; however, long-term data
are lacking [1].
Interestingly, although the antidepressant effects of a single ketamine dose last for an average of ~1 week, the sustained
antidepressant/anxiolytic effects of psilocybin are detectable up to 6 months after administration [7,16,95], which may be
due to neuroplasticity-related mechanisms and/or synergistic effects of drug treatment and psychotherapy (Box 3). The
rapid and sustained antidepressant effects after only 1–3 treatment dose(s)/session(s) of ketamine and psychedelics stand
in stark contrast to the delayed onset of action of traditional antidepressants that require weeks of continuous drug intake,
and the complete lack of efficacy in TRD populations.
stress-induced structural and functional deficits in depression, presumably by rewiring of pathological corticolimbic circuitry (Figure 1, panel 10), which may underlie the sustained treatmentinduced behavioral adaptations (e.g., stress coping, emotional processing, and cognition) and
reductions in clinical symptoms [8,10,17,22–24,31,34–37,48–53]. Despite current gaps in
knowledge, this neuroplasticity framework provides an overarching perspective on the neurobiological mechanisms underlying the rapid and sustained therapeutic efficacy of ketamine and
classical psychedelics following single/infrequent dosing. We highlight key molecular events
that serve as crucial mediators of rapid/sustained antidepressant response, and thus represent
targets for future drug development, while emphasizing where further research is needed.
Ketamine and its glutamatergic mechanism of action
Ketamine has remarkable fast-acting antidepressant effects, particularly in TRD patients who
have failed multiple traditional monoamine antidepressants, and has only mild and transient
acute psychotomimetic effects [5,6,17,54]. Preclinical studies have given rise to two major,
non-mutually exclusive models of the mechanism of action of ketamine as an NMDAR antagonist,
novel antidepressant, and neuroplasticity-inducing agent (Figure 1, panel 2a,b) [13,21,35,55–58].
According to the 'disinhibition' hypothesis, low sub-anesthetic doses of ketamine, a noncompetitive, open-channel antagonist, preferentially block NMDARs on gamma-aminobutyric
acid (GABAergic) inhibitory interneurons, resulting in disinhibition of excitatory pyramidal neurons
in the PFC, increased glutamate release, and sustained activation of AMPAR and key
synaptogenic signaling pathways (discussed later) [13,21,28,55,58]. Under the 'direct inhibition'
hypothesis, antagonism of NMDARs directly on pyramidal neurons by ketamine at rest blocks
tonic NMDAR activation by ambient or spontaneously released glutamate, which in turn reduces
suppression of eukaryotic elongation factor 2 (eEF2)-mediated protein synthesis and engages
similar downstream synaptogenic cascades [13,35,55–57].
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Glossary
Behavioral plasticity: functional
changes/adaptations in behavior in
response to changes in environmental
conditions/experiences, such as during
learning, which contribute to effective
coping, survival, and well-being.
Brain-derived neurotrophic factor
(BDNF): a major brain neurotropic
factor that has roles in neuronal survival
and growth, as well as in different
aspects of neuroplasticity and learning/
memory via the high-affinity receptor
TrkB. BDNF is a key mediator of stress
resilience, depression susceptibility, and
antidepressant response.
Classical serotonergic
psychedelics: a class of psychoactive
drugs, also referred to as classical
hallucinogens, that include psilocybin
(the active ingredient of psychedelic or
‘magic’ mushrooms), lysergic acid
diethylamide (LSD, synthetic ergot
derivative), and N,N-dimethyltryptamine
(DMT, active ingredient in ayahuasca),
and which alter perception, mood, and
cognition, primarily through serotonin
receptor activation, and exhibit
therapeutic potential for conditions such
as depression, anxiety, PTSD, and
substance use disorders.
Glutamate: the major excitatory
neurotransmitter in the nervous system;
it is involved in neuroplasticity, learning/
memory, cognition, mood, stress
responses, homeostatic processes, and
excitotoxicity. Glutamate-gated
ionotropic receptors include α-amino-3hydroxy-5-methyl-4-isoxazole propionic
acid receptors (AMPAR) and NMDARs
which mediate fast excitatory
neurotransmission and the induction of
long-term synaptic plasticity, respectively.
Ketamine: a non-selective,
open-channel, glutamate N-methyl-Daspartate receptor (NMDAR) antagonist
and dissociative anesthetic. Low,
subanesthetic doses have robust, rapid,
and sustained antidepressant effects in
treatment-resistant depression (TRD)
and major depressive disorder (MDD).
Recent studies support the
pro-cognitive effects of ketamine in
depression and its therapeutic efficacy
for suicidal ideation, bipolar disorder,
post-traumatic stress disorder (PTSD),
and substance use disorders.
Mammalian target of rapamycin
(mTOR): a nutrient-sensitive serine/
threonine protein kinase and a key
regulator of cell growth that has central
roles in physiology, metabolism, aging,
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Box 2. Neuroplasticity theory of depression and antidepressant response
The monoamine hypothesis of depression has recently been superseded, and attention is shifting towards other promising
treatment targets, especially those related to dysregulation of neural/synaptic plasticity and dysfunction in glutamatergic
systems [8,10–12,16,79]. In major depressive disorder (MDD) and preclinical models of depression, chronic stress and
sustained elevations of circulating glucocorticoids are thought to exert neurotoxic effects, particularly within the PFC
and HPC [8,10,12,16,79]. Specific stress-induced synaptic, morphological, and functional deficits include loss of long-term
potentiation (LTP) and/or facilitation of long-term depression (LTD), impaired brain-derived neurotrophic factor (BDNF) and
mammalian target of rapamycin (mTOR) signaling, and decreased neurogenesis, synaptogenesis, and dendritic complexity,
eventually leading to neuronal atrophy, dysfunction in corticolimbic circuits, and the development/exacerbation of depressive-like phenotypes in rodent models [8,10,17,20,79]. This is consistent with structural and functional findings in MDD
reflecting hypofunction, progressive grey matter volume loss, and reduced functional connectivity in the PFC, HPC, and associated networks, decreased levels of neurotrophic factors such as BDNF, downregulation of synaptic proteins and genes,
and various cognitive deficits in subjects with depression [8,10,12,16,20,79]. In particular, impairments in attention, episodic
memory, and executive function, as well as the core symptoms of emotional dysregulation, rigid, negative thinking, and
anhedonia, could be mediated by impaired synaptic plasticity processes and loss of connectivity between key brain regions
that are particularly vulnerable to stress [8,10,12,16,79]. When neuroplasticity is compromised, pathologic and/or beneficial
circuits cannot be appropriately modulated, ultimately leading to inflexible and maladaptive cognitive/behavioral responses,
including compromised learning, emotional processing, and stress coping [8,50].
Notably, neuroplasticity across the brain is not uniformly impaired in MDD or indiscriminately enhanced following ketamine
and classical psychedelics (Box 3). The medial PFC is thought to serve as the primary site for the therapeutic action of novel
fast-acting antidepressants [8,16,79], where region-specific differences in the relative expression of different receptor
subtypes steer effects towards a select subpopulations of neurons, particularly pyramidal cells in layer 5 [14,66]. Because
the mPFC innervates many subcortical brain areas implicated in depressive symptomatology, including other parts of the
PFC, limbic structures (HPC and amygdala), nucleus accumbens, dorsal raphe, and hypothalamus, modulation of
frontocortical function in depression has a far-reaching impact on brain function and symptom reduction [8–12]. Finally,
the broad therapeutic potential of neuroplasticity-based pharmacotherapies for conditions that share common neural
circuitry pathology or display high comorbidity with depression, including bipolar disorder, anxiety, post-traumatic stress
disorder (PTSD), substance use disorders, and neurodegenerative diseases, is gaining prominence [16,50,79].
Accordingly, sustained modulation of glutamatergic neurotransmission in pyramidal neurons of the
PFC and HPC has emerged as a promising therapeutic target for depression and related disorders
[5,8,13,55,58]. These opposing/dual actions of ketamine, via direct inhibition of NMDARs, thereby
enhancing AMPAR function indirectly, and effectively shifting the local excitation–inhibition balance
by targeting pyramidal or GABAergic neurons, appear to serve as crucial triggers of adaptive neural
plasticity and antidepressant response [5,8,13,21,35,55–59]. Importantly, these effects of
ketamine are somewhat unique in its drug class because other NMDAR antagonists have failed
to consistently show robust and/or long-lasting antidepressant effects, presumably owing to key
differences in their pharmacological properties (e.g., receptor affinity, trapping, state-dependency,
subtype, subcellular location, and intracellular consequences) [5,13,14,55]. Several NMDARindependent mechanisms of ketamine, such as the active metabolite (2R,6R)-hydroxynorketamine
(HNK), metabotropic glutamate mGluR2 receptors, and opioid receptor signaling, are beyond the
scope of this review [23,60,61].
and disease. mTOR signaling regulates
activity-dependent translation of
synaptic proteins, neural plasticity, and
antidepressant response.
Neural plasticity: also known as
neuroplasticity, this underlies the ability
of the nervous system to change in
response to intrinsic or extrinsic stimuli
by reorganizing its activity, structure,
functions, or connections. It plays an
essential role in the capacity of the brain
to sense, assess, and store information,
guide behavior, and adapt to a dynamic
environment. This construct has recently
emerged as a promising target for the
treatment of various neuropsychiatric
disorders.
Serotonin (5-HT): a monoamine
neurotransmitter implicated in the
regulation of mood, cognition,
neuroplasticity, reward, learning, etc. It
acts through a variety of serotonin
receptors, that are almost exclusively G
protein-coupled receptors (GPCRs),
and which couple to various downstream signaling cascades. Of particular
importance is 5-HT2AR, the canonical
hallucinogenic receptor.
Structural plasticity: physical modifications of axonal/dendritic branches,
spine morphology, and synaptic
numbers that mediate sustained adaptations to environmental stimuli such as
learning events or pathophysiological
processes (e.g., synaptogenesis vs.
synaptic atrophy).
Synaptic plasticity: neural activitydependent changes in the efficacy of
synaptic transmission at glutamatergic
synapses. In particular, these changes
manifest as long-term potentiation (LTP)
and long-term depression (LTD), which
are thought to represent the cellular
substrates of learning and memory in the
brain.
Psychedelics and their serotonergic mechanism of action
Although classical psychedelics, such as psilocybin (and its active metabolite psilocin), LSD, and
DMT, each exhibit unique and complex pharmacological profiles, they share affinity for serotonin
(5-HT) G protein-coupled receptors (GPCRs) [18,62–64]. The hallucinogenic and potentially
therapeutic effects of these compounds are predominantly attributed to their partial agonist activity
at serotonin 2A receptors (5-HT2ARs) [17,18,62–65], with recent animal studies casting some
doubt [31,48]. Although ubiquitous, 5-HT2ARs are highly enriched in apical dendrites of cortical
layer 5 pyramidal neurons (the principal output neurons of the medial PFC), and largely increase
their firing rate upon activation (Figure 1, panel 3a,b) [29,66]. In humans, cortical 5-HT2AR
occupancy correlates with psychedelic-induced subjective effects, including acute increases in
dissociation and positive mood, while pretreatment with the non-selective 5HT2AR antagonist
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Key figure
Neuroplasticity as a convergent mechanism for ketamine and classical
psychedelics
Trends in Pharmacological Sciences
Figure 1. Dysregulation of neural plasticity is implicated in depression, consistent with the observed synaptic weakening,
neuronal atrophy, and loss of connectivity in vulnerable brain regions (panel 1, far left). Accumulating evidence indicates
that ketamine (KET) and classical psychedelics (CPs) share key downstream neurobiological mechanisms related to
neuroplasticity, including modulation of excitatory glutamatergic transmission, dendritic spine remodeling, and frontocorticolimbic network activity. Specifically, KET acts via N-methyl-D-aspartate receptor (NMDAR) antagonism on inhibitory interneurons
(INs) (disinhibition hypothesis, 2a) and on pyramidal neurons (PNs) (direct inhibition hypothesis, 2b), whereas CPs are thought to
predominantly activate serotonin 5-HT2A receptors within PNs (3a,b), particularly within layer 5 of the medial prefrontal cortex
(mPFC). Through their specific receptor actions, ketamine and psychedelics can both induce a burst of glutamate release and
sustained α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation (4) in excitatory PNs. This in
turn potentiates brain-derived neurotrophic factor-tropomyosin receptor kinase B (BDNF-TrkB) (5) and mammalian target of
rapamycin (mTOR) (6) signaling, thus upregulating the expression of neuroplasticity-related genes (7) and protein synthesis
(e.g., via eukaryotic elongation factor 2, eEF2) of synaptic components (8), which triggers an amplification mechanism and
ultimately drives rapid and long-lasting local synaptogenesis (9). These effects are thought to reverse stress-induced structural
and functional deficits in depression by promoting synaptic homeostasis and adaptive rewiring of pathological neural
corticolimbic circuitry, and these effects presumably contribute to the remarkable clinical efficacy of these diverse compounds
(10, far right). Figure created with BioRender.com.
ketanserin blocks the acute subjective effects [67,68]. Similarly, blocking 5-HT2ARs in animals
eliminates many, but not all, of the molecular, synaptic, and behavioral effects of these compounds
[31,32,36,37,48].
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Preclinical studies also implicate 5-HT1A receptors, which are densely expressed in midbrain,
limbic, and cortical regions, as well as in serotonergic neurons of the dorsal and median raphe
nuclei, where they act as somatodendritic autoreceptors [65]. The dual effects of psychedelics
on 5-HT2AR (excitatory, coupling to Gq) and 5-HT1AR (inhibitory, coupling to Gi/o) signaling
may be key in mediating their unique, circuit-specific effects on neuronal excitability and synaptic
remodeling, thereby ultimately contributing to their antidepressant/anxiolytic effects [14,16,62].
Importantly, serotonergic psychedelics show biased agonist activity at 5-HT2AR [62,64]. Unlike
serotonin, they are linked to preferential activation of non-canonical β2-arrestin-mediated signaling,
where β-arrestin acts as a key molecular scaffold linking the receptor to unique downstream transducers [62,64], although the exact mechanisms and their clinical implications are under
investigation.
Convergent downstream neuroplasticity mechanisms
PFC glutamate release and excitatory activity
Ketamine
Systemic antidepressant doses of ketamine have been shown to induce elevations in extracellular
corticostriatal glutamate levels and firing rates of pyramidal neurons in the medial PFC in vivo
(Figure 1, panel 4) [5,12,14,16,27,33,55,58]. This is consistent with the disinhibition framework
of ketamine action, where blocking NMDAR on GABAergic interneurons leads to a decrease in
inhibitory drive and a subsequent enhancement of pyramidal neuron excitability and activitydependent glutamate release [5,12,21–28,55,58,59]. Ketamine enhances evoked excitatory
postsynaptic potentials/currents (EPSPs/EPSCs) in mPFC layer V pyramidal neurons, and
AMPAR blockade prevents the synaptic and behavioral effects of ketamine in rodents [21–26].
Simultaneously, consistent with the direct inhibition hypothesis, ketamine inhibits spontaneous
NMDAR-mediated field EPSPs (fEPSPs) and miniature EPSCs (mEPSCs) [35,56]. Preclinical
studies on the antidepressant effects of ketamine, its metabolite (2R,6R)-HNK, and mGluR antagonists also implicate mGluR2 receptors which importantly function as inhibitory presynaptic
autoreceptors that modulate glutamate release [60]. In humans, increases in cortical glutamate,
metabolic activity, and high-frequency electroencephalography (EEG) oscillations may serve as
markers of clinical response to ketamine [15,17,23,58]. It is worth noting that studies utilizing
techniques with higher temporal resolution have reported that antidepressant doses of ketamine
increase, have no effect on, or decrease glutamate release in the PFC and/or other regions,
introducing some controversy to the field [69].
Psychedelics
Although preliminary, converging biochemical and electrophysiological evidence supports a similar glutamatergic mechanism in classical psychedelic action. Activating postsynaptic 5-HT2ARs
on pyramidal cells, particularly those in layer 5 of the PFC, is generally associated with an
increased frequency of spontaneous and evoked EPSP/EPSC responses [29–32,66,70].
Consistent with this, LSD (systemic or intra-PFC) and the related psychedelic compound 2,5dimethoxy-4-iodoamphetamine (DOI) can elevate frontocortical asynchronous glutamate release
in vitro and in vivo in a time-dependent manner (4 minutes to at least 1 h after systemic LSD),
leading to subsequent activation of postsynaptic AMPARs (Figure 1, panel 4) [29,30,36,46].
Importantly, this effect is blocked by antagonists of 5-HT2AR, AMPAR, and NR2B subunitcontaining NMDARs [19,29,30,66,70], as well as by mGluR2 modulators, implicating a
5-HT2A–mGluR2 receptor complex in psychedelic drug action [71]. Repeated LSD treatment
potentiated AMPAR and 5-HT2AR synaptic responses in vivo and increased the burst firing activity
of rodent mPFC pyramidal neurons, whose optogenetic inhibition eliminated the prosocial effects
of LSD [36]. Multimodal neuroimaging studies in animals and humans suggest that classical
psychedelics induce a hypermetabolic state, especially in frontocortical regions, which may
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correlate with their downstream effects and therapeutic efficacy [16,29,30,72]; however, direct
measurements of glutamate levels in humans are scarce [73].
BDNF and mTOR signaling pathways
Ketamine
Ketamine induces an increase in BDNF translation and release in the rodent PFC and HPC, although
this effect is highly dose-dependent and region-specific [20,24,34,57]. Preclinical research confirms
that BDNF is required for the antidepressant and synaptogenic effects of ketamine (Figure 1, panel
5), and ketamine lacks antidepressant-like effects in BDNF knockout mice [24,34,35,74]. Following
ketamine administration, sustained activation of postsynaptic AMPARs triggers activity-dependent
synaptic release of BDNF and activation of its surface receptor, tropomyosin receptor kinase B
(TrkB), as well as of two major downstream signaling cascades, mitogen-activated protein kinase
(MEK)-extracellular regulated protein kinases (ERK) and protein kinase B (Akt), which are both involved in cell survival and growth and converge onto mTOR activation (Figure 1, panel 6)
[12,20,24,34,35]. Accordingly, mTOR is consistently implicated in the mechanism of action
of ketamine, and a significant time-dependent increase in mTOR phosphorylation and function
in the PFC is observed following ketamine administration, while local pharmacological inhibition
of mTOR eliminates the synaptic and antidepressant effects of ketamine [12,22,24,25,34,75]. Clinical trials of ketamine efficacy for treatment of TRD and MDD confirm increased BDNF serum
levels post-administration (2–24 h) in responders compared with non-responders, effects
which correlate positively with antidepressant response and prefrontal connectivity changes
[12,76,77]. A preliminary human study reported that coadministration of the mTOR inhibitor
rapamycin does not block the antidepressant effects of ketamine but in fact extends their duration; however, insufficient dosing and the potent peripheral anti-inflammatory actions and
poor brain penetrance of rapamycin may account for this paradoxical effect [78].
Psychedelics
Classical psychedelics, acting via 5-HT2AR, are associated with glutamate release and sustained
AMPAR signaling in the PFC, which in turn engages key synaptogenic signaling cascades, particularly BDNF and mTOR, as seen with ketamine (Figure 1, panels 6,7) [15,18,29,32,36–38].
Consistent with the known, close bidirectional interaction between serotonin and BDNF
function, 5-HT2AR activation is linked to neuroplasticity and neurotrophins via several possible
mechanisms including non-canonical β2-arrestin-mediated signaling, ERK, Akt-mTOR,
phosphoinositide 3-kinase (PI3K), NMDARs, and kalirin-7 [62,64,79,80]. Specifically, acute or
repeated administration of various classical psychedelics, including LSD, DOI, and DMT, is
associated with increases in BDNF levels/function and Akt-mTOR activation in the PFC or HPC
[15,18,32,36–38,52]. Accordingly, inhibition of either 5-HT2AR, AMPAR, BDNF-TrkB, or mTOR
signaling consistently abolishes the structural and behavioral effects of psychedelics (discussed
later) [32,36,37,52]. Furthermore, intact mTOR complex 1 (mTORC1) function in glutamatergic
excitatory but not GABAergic inhibitory neurons mediates the prosocial effects of repeated LSD
administration in mice [36]. Human research on this topic is still sparse; although the preliminary
preclinical [32,38] and clinical [81] data are encouraging, they indicate a complex relationship
between psychedelic treatment and BDNF levels, dependent on the treatment protocol (compound,
dose, frequency, etc.) and outcome measure (e.g., levels in serum vs. different brain regions),
warranting further investigation.
Gene expression and protein synthesis
Ketamine
The sustained activation of AMPAR, BDNF, and mTOR signaling following a single antidepressant
dose of ketamine triggers an amplification mechanism which drives the gene expression, eEF2934
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mediated protein synthesis, and subcellular trafficking of several key components of the
excitatory synapse and glutamate signaling-related neuroplasticity genes/protein (Figure 1,
panels 7,8) [8,12,15,17,20,22,23,25,26,35,56,57]. These include AMPAR subunits (GluR1,2),
postsynaptic density protein 95 (PSD95), synapsin 1, the immediate-early genes cFos (marker
of neuronal activity) and Arc (activity-dependent cytoskeleton associated protein), reelin
(glycoprotein involved in neuronal cell–cell interactions), and Homer1a (regulator of glutamatergic
synapse homeostasis), as well as of mTOR and BDNF themselves, in the PFC and HPC
[8,12,15,17,20,22,23,25,26,35,56,57]. With a few exceptions (e.g., increased serum BDNF levels),
ketamine regulation of neuroplasticity-related genes/proteins remains to be confirmed in the
context of clinical depression.
Psychedelics
Similarly, acute administration of classical psychedelics, particularly LSD, DOI and psilocybin
(or psilocin), is associated with dose- and time-dependent upregulation of various genes/proteins
related to synaptic plasticity, predominantly in cortical regions (Figure 1, panels 7,8) [15,16,62,70].
Psychedelic transcriptional targets are wide-ranging and include cFos, Arc, and BDNF, as well as
early growth response factors EGR1/2, β-arrestin 2, serum glucocorticoid kinase (Sgk), neuronderived orphan receptor 1 (Nor1), Ania3 (Homer1 transcript), Iκβ-α (NF-κB inhibitor), mitogenactivated protein kinase phosphatase 1 (Mkp1), core/enhancer binding protein b (C/EBP-b),
dual-specificity phosphatase 1 (DUSP1), Period1 and others [39–43,62,82,83]. All these genes
are linked to different aspects of synaptic function and neural plasticity, and many act as activitydependent enzymes or transcription factors that are involved in regulating LTP expression/
maintenance, structural plasticity, and long-term memory formation [15,16,70]. Pharmacological
inhibition or genetic deletion of 5-HT2AR or mGluR2 blocks many of these transcriptional effects
[39,41–43,82,83]. The EGR family of immediate early genes/transcription factors, which regulate
neuronal activity and synaptic plasticity under both physiological and pathological conditions, is
the most highly validated gene target of psychedelics in the rodent brain [40–43,62,82]. The only
study to investigate the effects of LSD on acute gene expression in healthy subjects focused solely
on EGR1–3 and failed to detect significant changes in mRNA levels in whole blood samples up to
24 h after administration [84].
Long-term structural plasticity
Ketamine
The ability of ketamine to drive cortical structural plasticity in rodents, including increasing
dendritic complexity, spine number/density, and synaptic strength in the PFC/HPC for up to
2 weeks, is well established (Figure 1, panel 9) [10,12,22,23,25,44–46,85]. An elegant study
utilizing in vivo two-photon imaging and a new optogenetic tool (photoactivatable Rac1)
recently showed that ketamine reverses chronic stress-induced cortical synaptic deficits in
mice, and that selective deletion of these new synapses blocks its sustained antidepressantlike effects at 2–7 days [45]. Another seminal study, utilizing two-photon imaging of mPFC
brain slices and two-photon glutamate uncaging, found that ketamine increased the likelihood
of dendritic synaptogenesis (termed 'synaptic potential') following a local burst of glutamate
efflux in layer 5 pyramidal neurons – from 20–25% under control conditions to 50% at 2 h
post-injection, with effects at 4 h but not at 12 h [46]. Thus, ketamine rapidly triggers a transient
window of enhanced plasticity and implicates mPFC dopaminergic signaling in the glutamateevoked long-term structural effects of ketamine [46,85]. These findings support a causal
relationship between ketamine-induced cortical glutamate release, dendritic spine remodeling,
and therapeutic response [8,45,85]. Notably, ketamine is reported to elicit structural plasticity
beyond pyramidal neurons, namely in mouse mesencephalic and human iPSC-derived
dopaminergic (DA) neurons [86].
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Psychedelics. Recent studies demonstrate a similar ability of classical psychedelics to induce
structural plasticity within cells/circuits of interest (Figure 1, panel 9) [32,37,47,48,87]. Seminal
work by Olson and colleagues indicates that acute (15 minutes to 6 h) or sustained (24–72 h) psychedelic treatment with therapeutically relevant concentrations of LSD, DMT, psilocin, and/or DOI
can induce robust and persistent growth of dendritic spines and increases in synapse number
and function (measured on day 3) in vitro using cultured cortical neurons and/or in vivo using
both vertebrate and invertebrate models [32,37]. Notably, LSD was significantly more potent
than other psychedelics and ketamine [32,37]. Blocking AMPA or mTORC1 during either the
drug stimulation or growth periods, and blocking TrkB during the initial stimulation period,
prevented neuronal growth in vitro [32,37]. In rats, a single dose of DMT causes a significant
increase in dendritic spinogenesis and excitatory neurotransmission in cortical pyramidal neurons
in vivo at 24 h after treatment [32], as reported previously for ketamine [22]. A single dose of psilocybin increased the presynaptic marker synaptic vesicle protein 2A (SV2A) in the pig PFC/HPC
at 1–7 days after administration, potentially reflecting sustained synaptogenesis [47]. Chronic
two-photon microscopy for longitudinal imaging of apical dendritic spines in vivo recently confirmed that a single antidepressant dose of psilocybin increases spine density/size in mouse
frontocortical pyramidal neurons [48]. Importantly, this effect is observed within 24 h, persists
for at least 1 month, and is not fully blocked by partial (~30%) 5-HT2AR inhibition using ketanserin
pretreatment [48]. Although data are largely lacking and the clinical significance remains unclear,
psilocybin may modulate adult neurogenesis (the generation of newly born neurons) in the mouse
dentate gyrus in a dose-dependent, biphasic manner; however, others found no changes in
neurogenesis following acute or repeated LSD/DOI administration [87].
Behavioral plasticity and antidepressant efficacy
Ketamine
Numerous studies have replicated the positive effects of ketamine in rodent models of depression
or in antidepressant screens [9,22–24,34,35,49]. Systemic intraperitoneal (i.p.) injection of ketamine (most commonly 10 mg/kg) significantly reduces forced swim test (FST) immobility in naïve
animals as early as 30 minutes after administration, and this persists for an average of 7 days
[23,24,34,35,49]. In addition, ketamine effectively reversed stress-induced depressive-like behaviors at 24 h post-injection, including abnormal stress-coping in the FST and anhedonia, in rodents exposed to chronic mild stress (CMS) [22,23]. The robust, rapid, and sustained
antidepressant-like effects of ketamine in animals mirror its clinical efficacy in patients with
depression, thus allowing the underlying neurobiological mechanisms to be probed [5,6,16,17].
As mentioned, preliminary data have provided causal evidence linking ketamine-induced
spinogenesis in the PFC and its antidepressant-like activity in the mouse tail suspension test
(TST) [45]. Although the data are limited, ketamine appears to facilitate fear extinction [75].
Importantly, outside the window of acute psychotomimetic effects, antidepressant doses of
ketamine exert pro-cognitive effects in both rodent models and patients with depression, reversing
the deficits in executive function as well as learning and memory, further supporting neuroplasticitydriven improvements in depression symptomology [8,27,49,88–90].
Psychedelics
Preclinical studies evaluating the antidepressant-like effects of psychedelics are limited, but
generally support the therapeutic potential observed clinically [17,31,36,48,51–53]. Several compounds, including DMT (single high dose or chronic, intermittent low doses), LSD, and psilocybin,
exert antidepressant-like effects in the FST in rats [51–53]. Repeated but not acute LSD treatment
enhanced social behavior in mice via 5-HT2AR, AMPAR, and mTOR signaling in excitatory mPFC
neurons, supporting the neuroplasticity theory and the potential usefulness of psychedelics
in treating social deficits, as in depression [36]. Notably, this study found no antidepressant/
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anxiolytic-like effects of LSD in the FST, SPT, or the novelty-suppressed feeding test in naïve mice
[36]. By contrast, LSD and psilocybin produced a sustained FST antidepressant-like effect in the
Wistar-Kyoto model of depression at 5 weeks after a single dose, whereas the effects of ketamine
were only transient [53]. Repeated LSD treatment also reversed the deficits in active avoidance
learning in the olfactory bulbectomy model of depression, without affecting control rats [91].
In two separate studies, a single psilocybin injection reversed the hedonic and active avoidance
deficits in mice subjected to chronic stress, accompanied by a strengthening of excitatory neurotransmission in the HPC or mPFC [31,48]. In these studies, partial (~30%) 5-HT2AR antagonism
using low-dose ketanserin was only sufficient to block the psilocybin-induced psychotomimetic
(i.e., head-twitch) but not synaptic or antidepressant-like responses, possibly implicating
5-HT2AR-independent mechanisms [31,48]. Although limited, preclinical studies also suggest
that psychedelics can enhance the acquisition of associative learning with both aversive or
appetitive unconditioned stimuli [17,91,92], while also facilitating the extinction of fear memory
[51,52,87]. Finally, psilocybin enhances measures of motivation and attention in poor-performing
rats, as does ketamine [88]. Clinical implications of these findings may include treatment of
cognitive deficits, depression, PTSD, and related conditions.
Synaptic plasticity (LTP, LTD) and current gaps in knowledge
Long-term potentiation (LTP) and long-term depression (LTD), the major forms of synaptic
plasticity at glutamatergic synapses, involve activity-dependent changes in synaptic strength
that are thought to represent the cellular substrates of learning and memory in the brain [93].
Importantly, the balance in LTP/LTD is perturbed in depression, and this may contribute to
the observed synaptic deficits [8,10,11,49]. Although there are different induction mechanisms
for LTP/LTD (e.g., NMDAR, mGluR), their expression predominantly involves changes in postsynaptic AMPAR expression density and/or function, leading to synaptic strengthening
or weakening, respectively [93]. Activity-dependent synaptic plasticity is correlated with
bidirectional changes in AMPAR expression and dendritic spines (i.e., increases with LTP
vs. decreases with LTD) [93].
Whereas the molecular, structural, and behavioral effects of ketamine and psychedelics are
of considerable interest, the effects of these drugs on the induction, maintenance, and decay
of LTP/LTD are rarely studied, with the exception of our own studies [10,49]. Interestingly,
we found that a single low dose of ketamine, or of its metabolite HNK, rescued the dorsal
hippocampal LTP deficit observed in the Wistar-Kyoto (WKY) rat model of stress susceptibility
and depression, at 3.5 h but not at 30 minutes post-injection, with subsequent synaptic
strengthening at 24 h [49]. Furthermore, WKY rats exhibited impaired hippocampus-dependent
long-term spatial memory compared to control rats, which was effectively restored by ketamine/
HNK, consistent with their positive effects on LTP [49]. These findings support ketamine-induced
reversal of HPC-dependent cognitive deficits which are key features of clinical depression
[8,10,49,89,90]. However, the effects of ketamine on LTP/LTD in other regions implicated
in depression and/or other animal models remain unclear, highlighting the need for future
investigation. Preliminary human evidence suggests that low-dose ketamine enhances
visual sensory evoked potential LTP in patients with MDD at 3–4 h post-administration
[94]. Because serotonin is known to modulate synaptic plasticity [80], and ketamine may
restore LTP in the context of depression [10,49,94], determining how ketamine and classical psychedelics affect region-specific synaptic plasticity processes is of great importance.
Incorporating synaptic plasticity into the current framework of ketamine/psychedelic drug
action may serve to bridge understanding of their molecular and cellular effects with knowledge related to neural circuit functioning and structural plasticity, underscoring the urgent
need for further studies.
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Concluding remarks and future perspectives
Outstanding questions
Through their respective primary receptor targets (NMDAR and 5-HT2AR), ketamine and psychedelics are associated with acute increases in cortical glutamate release and sustained activation
of excitatory neurotransmission in pyramidal neurons, predominantly within the PFC (Figure 1),
effects which represent crucial first steps of convergence [21–33]. Recurrent frontocortical
network activity has long been implicated in the dissociative/hallucinogenic effects of these
drugs (i.e., distortions in higher-level perceptual and cognitive function) [29], and are now thought
to play important roles in triggering the long-lasting state of enhanced neural plasticity in
corticolimbic circuits [14,16,18,30]. Ketamine and classical psychedelics crucially activate
two synaptogenic signaling pathways, namely BDNF and mTOR, which orchestrate, in part,
the rapid and sustained facilitation of synaptic, structural, and functional neuronal remodeling,
and this may mediate their clinical efficacy (Figure 1, panel 10) [18,20,29,32,34–38]. The
treatment response to traditional antidepressants (e.g., selective serotonin reuptake inhibitors,
SSRIs) also involves BDNF and possibly mTOR, mechanisms which, unlike with novel fastacting antidepressants, take several days to weeks to be engaged [20,25,58]. Downstream
effects of ketamine and classical psychedelics include upregulation of transcription and translation of synaptic proteins within the PFC/HPC [22,23,25,35,39–43], and long-lasting changes in
synaptic function and morphology in pyramidal neurons [22,25,32,37,44–48]. Based on these
findings, ketamine and classical psychedelics are thought to facilitate structural plasticity and
neuronal growth in frontocortical-limbic circuits, which may counteract the synaptic deficits,
neuronal atrophy, and loss of network connectivity that are associated with chronic stress or
clinical depression (Figure 1) [8,10–12,50]. Importantly, these changes in key neural circuits are
correlated with enduring therapeutic outcomes at the cognitive and behavioral levels that are
essential for improvement of coping strategies and alleviation of depression symptomology
[8,10,16,17,23,24,32,35–37,45,49,50,53,89,90]
How do ketamine/psychedelics affect
synaptic plasticity (LTP and LTD)? Do
psychedelics affect region-specific
AMPAR synaptic levels?
In summary, clinical research has inspired tremendous interest in identifying the mechanisms
mediating the efficacy of ketamine and classical psychedelics in treating depression and related
disorders, moving beyond the outdated monoamine theory. Importantly, these effects are
hypothesized to mediate the rapid (within hours) and sustained (week to months) therapeutic
activity of these unique molecules following single/infrequent administration, especially in the
context of psychotherapy (Box 3) [7,14–16,50,72,85,95]. The duration of therapeutic effects
observed following psilocybin (up to 6 months) is much longer than with ketamine (average of 1
week), which seems to correlate well with their time-dependent effects on PFC spine density
[37,44–46,48,85]. Taken together, these discoveries indicate that ketamine and classical psychedelics share a common neurobiological mechanism that involves complex interactions between
glutamate, serotonin, and region-specific synaptic homeostasis. Notably, the muscarinic receptor antagonist scopolamine, the NMDA receptor partial agonist GLYX-13 (i.e., rapastinel), and
mGluR2/3 antagonists, which all possess some ketamine-like antidepressant activity in animal
models, appear to engage similar convergent downstream mechanisms related to neuroplasticity
[5,8,12,50,58].
Given major challenges in translating these findings to the human brain, the causal link between
drug-induced neuroplasticity and therapeutic efficacy has yet to be established in clinical settings.
Several methods can be utilized in humans to examine potential biomarkers related to neural
plasticity, including EEG, functional [e.g., positron emission tomography (PET), functional
magnetic resonance imaging (fMRI), and auditory/visual evoked potentials] and structural
[e.g., diffusion tensor imaging (DTI), voxel-based morphometry (VBM)] imaging techniques, as
well as non-invasive brain stimulation (NIBS) [e.g., transcranial magnetic simulation (TMS) and
repetitive sensory stimulation] [96,97]. Currently, TMS [96,97] and novel PET ligands such as
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How do these compounds affect
cognition, learning/memory, behavioral
flexibility, anxiety, and depression-like
behaviors in different animal models?
What are the optimal treatment protocols
(compound, dose, frequency, etc.) to
maximize neuroplasticity/treatment
response? What is the duration of
the therapeutic window of enhanced
neuroplasticity post-treatment?
Are there sex-specific differences in
neuroplasticity-related mechanisms?
How do other mechanisms (e.g.,
monoamine signaling, network activity,
neuroendocrine and anti-inflammatory
effects) contribute to the clinical actions
of these compounds? Is 5-HT2AR activation the predominant mechanism of
action of classical psychedelics?
Do ketamine and psychedelics engage
a summative therapeutic response by
acting at various molecular targets,
while limiting adverse effects and
excessive action at a single target
(‘magic shotgun’ vs. ‘magic bullet’
approach)?
Are the acute dissociative/hallucinogenic
effects necessary for long-lasting
therapeutic efficacy? Do they correlate with the magnitude/duration of
treatment response? Is administration of repeated, sub-hallucinogenic
doses ('microdosing') sufficient to trigger neuroplasticity/therapeutic effects?
Do non-hallucinogenic analogs that are
capable of promoting neuroplasticity
represent promising novel pharmacotherapies?
Can neuroplastic effects and neurotrophin levels be reliably studied in
humans in vivo to establish a causal link
between potential biomarkers and longlasting symptom improvements? Can
valid biomarkers related to human
neuroplasticity be developed?
Are there additive or synergistic
effects with psychotherapy and
lifestyle interventions (e.g., exercise,
social support, diet)?
Trends in Pharmacological Sciences
Box 3. Adaptive neuroplasticity and the effects of psychotherapy
Neuroplasticity in depression and related conditions is not uniformly impaired across the brain, and neuroplasticity
changes may be adaptive or maladaptive depending on the brain region, context, and functional consequences.
In MDD, regional differences in stress-induced synaptic/structural plasticity lead to progressive frontocortical
hypofunction/atrophy and loss of top-down inhibitory control, accompanied by hyperactivity/hypertrophy in downstream
regions such as the amygdala, hypothalamic–pituitary–adrenal axis (HPA) axis, and the ventral tegmental area–nucleus
accumbens (VTA-NAc) dopamine system, which may underlie different depression-related symptoms (e.g., cognitive, stress,
anxiety, aversive and anhedonic responses) [8,16,79]. Accordingly, indiscriminate enhancement of neuroplasticity may
not be beneficial, whereas successful treatment of depression may involve region-specific reversal of pathological circuit
dysfunction, in which the mPFC has a far-reaching impact on brain function and symptom reduction [8].
Can ketamine and psychedelics treat
other
neuropsychiatric
disorders
involving abnormalities in neuroplasticity
and glutamatergic homeostasis?
Psychedelic-assisted psychotherapy for depression and other psychiatric disorders has recently demonstrated unprecedented efficacy in clinical trials [1,3,7,16,17]. This strategy, as recently applied to ketamine treatment [4], is not only safer
but may also potentiate therapeutic effects via converging drug- and experience-dependent neuroplasticity mechanisms
[1,17]. The window of heightened neuroplasticity with ketamine/psychedelics offers an important opportunity for psychotherapeutic interventions, and there is preliminary evidence of synergistic effects and the potential for adaptive rewiring of
beneficial/pathological circuits [65,98]. Because the transient drug-induced neuroplastic state is susceptible to environmental inputs, concomitant therapy may steer towards therapeutically relevant new neural connections [14]. Conversely,
combining a neuroplasticity-inducing agent with stress, adversity, or pre-existing psychopathology may promote negative
neuroplasticity, thus strengthening pathological network activity and/or maladaptive learning of negative associations [8].
Accordingly, the use of psychedelics to treat neuropsychiatric disorders should proceed with caution. Fortunately, in the
context of psychotherapy (i.e., with proper screening, preparation, supervision, integration, and follow-up), ketamine/psychedelics appear to promote the perception and extinction of negative thought/behavioral patterns, as well as the
reframing and recontextualization of emotional experiences/memories or trauma, which, in conjunction with synaptogenesis and long-lasting network adaptations, may ultimately lead to enhanced cognitive/behavioral flexibility, thus enabling
the acquisition new coping strategies [2,8,17,50,100]. In depression, rigid, negative, and maladaptive thought/behavioral
patterns may be gradually replaced by improved cognitive control, emotional processing, and stress coping, whereas in
PTSD or substance use disorders, extinguishing fear/trauma or drug-cue memories, respectively, would be the desired
functional outcomes [2,8,17,50,100]. Importantly, the pharmacology-assisted therapy approach represents a potential
paradigm shift in psychiatry, and the concepts of 'set and setting' may tap into important determinants of treatment outcomes related to adaptive neuroplasticity and symptom reduction [4,17,62], warranting further investigation.
Box 4. Key experimental variables and research considerations
In the context of the neuroplasticity hypothesis of ketamine/psychedelic drug action, key experimental variables include the
compound, dose, and frequency of administration. Compounds differ substantially in terms of potency, plasma half-lives,
and duration of therapeutic activity, therefore the dose and frequency of administration are crucial for maximizing efficacy
while minimizing side effects [62,63]. Pharmacokinetic studies suggest that therapeutically relevant doses of ketamine [0.5
mg/kg, intravenously (i.v.) in humans, and ~10 mg/kg, i.p. in rodents] and DMT (~10 mg/kg, i.p. in rodents) yield similar concentrations in the body (~10 μM) [13,23,37,52]. Ketamine has a plasma half-life of 1–3 h, and antidepressant effects are observed within hours and are maintained for an average of 1 week following a single dose in rodents and patients with
depression [6,9,17,99]. By contrast, DMT has a very short half-life (15 min) and, although its therapeutic activity is less well
established, its duration of action can be dramatically prolonged by continuous infusion or coadministration of monoamine
oxidase inhibitors (e.g., ayahuasca) [50]. Owing to its unique receptor kinetics, LSD is significantly more potent and has a longer half-life (3–5 h), and clinically relevant doses [~200 μg, orally (p.o.) in humans, and ~0.1–0.2 mg/kg i.p. in rodents] lead to
peak plasma concentrations in the low nanomolar range [1,62,63]. Psilocybin (~0.2 mg/kg, p.o. in humans, and ~1 mg/kg, i.
p. in rodents) is metabolized into psilocin, an active metabolite with a shorter half-life (~1—3 h), but the therapeutic effects of
psilocybin-assisted therapy can be extremely long-lasting (up to 6 months) [1–3,62,95]. Although the clinical literature most
commonly involves a single administration of ketamine/psychedelics, repeated ketamine infusions effectively sustain the
antidepressant response in rodents and humans [99].
Preliminary studies suggest that psychedelics may be significantly more potent/long-lasting than ketamine in promoting
structural plasticity [37,44–46,48,85], consistent with their more enduring clinical effects [7,16,95]. The time between
dosing and testing is another important factor, and thus therapeutically relevant functional/behavioral outcomes should
be assayed at various timepoints after drug administration, in particular following a ‘growth’ period that allows
neuroplasticity mechanisms to be fully engaged, and at longer intervals to determine the timecourse of the effects
[17,37]. Finally, in animals as in humans, set (mindset, i.e., internal context) and setting (environment, i.e., external context)
are likely to modulate the long-term functional outcomes of psychedelic and ketamine treatment [17,53,62]. Experiences
prior to (e.g., naïve vs. depressive-like state) and subsequent to (e.g., negative vs. positive reinforcement) treatment with a
neuroplasticity-inducing agent may be crucial in steering the effects towards adaptive plasticity and enduring therapeutic effects.
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SV2A [47] represent particularly promising research avenues to study, and in the case of NIBS
modify, long-lasting neuronal function in the human brain. Finally, based on current understanding
of key experimental variables and research considerations (Box 4), future studies should address
current gaps in knowledge (see Outstanding questions), while further refining neuroplasticity
theories of depression and antidepressant response. Ultimately, the evolving framework of ketamine and psychedelic drug action can provide several promising neuroplasticity-related substrates
for clinical intervention that may serve as potential targets for development of next-generation
pharmacotherapies for various neuropsychiatric disorders.
Acknowledgments
This work was supported by grants from the Canadian Institutes of Health Research (to A.G.P.).
Declaration of interests
L.A. reports receiving consulting fees from Resilience Biosciences Inc., Psygen Labs Inc., and MindCure Health Inc. A.G.P.
holds shares in Resilience Biosciences Inc. and declares two patents related to a peptide blocker of AMPAR endocytosis and
hippocampal LTD, as well as to the use of D-govadine to enhance dopamine function in the prefrontal cortex.
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