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.
Abstract
“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.”
Authors: Bashkim Kadriu,Maximillian Greenwald, Ioline D. Henter, Jessica R. Gilbert, Christoph Kraus, Lawrence T. Park & Carlos A. Zarate Jr
Notes
This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health‘
Summary
The glutamatergic modulator ketamine has created a blueprint for studying novel neurons.
Ketamine is an antidepressant that induces mild, transient psychoactive effects at subanesthetic doses. However, a recent study found that 50% of participants experienced SP-like psychoactive effects and 80% reported “feeling strange, weird or bizarre”. Ketamine’s psychoactive effects are well documented, but psilocybin and DMT are far more commonly used in antidepressant trials and therapeutic ceremonies than ketamine. Furthermore, more research has examined the therapeutic relevance of psychoactive effects with regard to SPs than ketamine. In studies of SP therapy, participants who reported mystical experiences had greater depressive symptom reductions. In addition, in an open-label study, participants who reported a 5-Dimensional Altered States of Consciousness Rating Scale subscale had greater depressive symptom reductions. Therapeutic insights are not reported in qualitative studies of ketamine treatment, but may help explain the prolonged antidepressant effects associated with SPs.
Research suggests that the therapeutic setting during which SPs are administered may affect the subjective experiences and efficacy associated with these compounds. Although there is some evidence that the setting in which ketamine infusions take place influences subjective experience and outcome, the connection between psychoactive impact and antidepressant efficacy remains unclear.
Ketamine and SPs may both produce rapid neuroplastic effects by stimulating 5-HT2A receptors, which in turn triggers glutamate-dependent increases in pyramidal neuron activity in the PFC, thus modulating prefrontal network activity. This increase in cortical excitatory signaling may be the origin of the psychoactive effects of these agents. In this model, high AMPA throughput would trigger BDNF release and mTOR signaling, strengthening certain synapses and causing new synapses to form.
Figure Legends
Ketamine and serotonergic psychedelics act at glutamatergic synapses through different mechanisms, but both cause increased glutamate release and AMPA potentiation, which in turn triggers BDNF release and increased expression of diverse proteins acting at glutamatergic synapses.