Mechanisms of Action
Ketamine is a NMDA receptor antagonist. NMDA and AMPA are the two main neuroreceptors activated by the neurotransmitter glutamate.
As an NMDA receptor antagonist, ketamine blocks the NMDA receptor which prevents the transmission of glutamate (Rush et al., 2022; Kohtala, 2021). These neurological processes increase neuroplasticity, neurogenesis, and neural connectivity (Rush et al., 2022).
Ketamine's effects on the NMDA receptors inhibit the depolarization of the post-synaptic neuron, affecting that cell's ability to fire; sensory input to higher areas of the central nervous system involved in memory, learning, and emotional response are also affected (Drug Science and Small Pharma, n.d.). With time, the action of ketamine on the NMDR decreases the size of the post-synaptic response, while also leading to strengthening and increased efficacy of neural connections, as well as reconfiguration of important regions of the brain involved in certain mental health symptoms (Drug Science and Small Pharma, n.d.; Kohtala, 2021).
Ketamine is also known to have effects on a number of other systems, such as the μ-opioid, dopamine, serotonin, acetylcholine, GABA, cannabinoid, nitric oxide, and sigma systems (Kolp et al., 2014). Though these other pathways have been thought to potentially play a role in ketamine's beneficial effects on mental health conditions, their effects are largely theoretical or unexplained. In mouse models, for example, ketamine has been shown to enhance and preserve the rescue of lost synapses, which may promote sustained remission of depression and explain some of its neuroplastic effects (Moda-Sava et al., 2019). Interactions between ketamine and the gut microbiota have also been implicated in its antidepressant effects (Hua et al., 2022).
Learn More
Read Slipping into a K-Hole to learn more about the mechanisms of action of ketamine, including its dissociative effects.
References
Drug Science and Small Pharma. Ketamine Part 2 - Pharmacology. Retrieved September 7 from https://mindmedicineaustralia.org.au/wp-content/uploads/Ketamine-Pharmacology.pdf
Hua, H., Huang, C., Liu, H., Xu, X., Wu, Z., Liu, C., . . . Yang, C. (2022). Depression and antidepressant effects of ketamine and its metabolites: The pivotal role of gut microbiota. Neuropharmacology, 220, 109272. https://doi.org/10.1016/j.neuropharm.2022.109272
Kohtala, S. (2021). Ketamine-50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms. Pharmacol Rep, 73(2), 323-345. https://doi.org/10.1007/s43440- 021-00232-4
Kolp, E., Friedman, H. L., Krupitsky, E., Jansen, K., Sylvester, M., Young, M. S., & Kolp, A. (2014). Ketamine psychedelic psychotherapy: Focus on its pharmacology, phenomenology, and clinical applications. International Journal of Transpersonal Studies, 33(2), 84-140. https://doi.org/10.24972/ijts.2014.33.2.84
Moda-Sava, R. N., Murdock, M. H., Parekh, P. K., Fetcho, R. N., Huang, B. S., Huynh, T. N., . . . Liston, C. (2019). Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science, 364(6436). https://doi.org/10.1126/science.aat8078
Rush, B., Marcus, O., Shore, R., Cunningham, L., Thomson, N., & Rideout, K. (2022). Psychedelic medicine: A rapid review of therapeutic applications and implications for future research. Homewood Research Institute. https://hriresearch.com/research/exploratory- research/research-reports/