We delve into the science behind how ketamine works for depression, particularly its rapid antidepressant effects via complex brain mechanisms. We explore research on its potential long-term benefits when used in a therapeutic setting, especially for treatment-resistant depression. A crucial distinction is made between therapeutic use and long-term heavy unsupervised use, which carries real risks. These risks include cognitive impairment, particularly affecting spatial memory, potential links to psychiatric symptoms, and even structural brain changes. While temporary issues with working memory after a therapeutic session are being studied, research on significant impairments is mixed. The episode emphasizes that therapeutic ketamine is a promising tool, but it is absolutely vital to separate this from the dangers of heavy non-therapeutic use.

These are the papers used in this episode:

Papadopoulos, Z. (2025). Neuropharmacology of Ketamine and Its Use in the Treatment of Major Depressive Disorder: A Review. Cureus, 17(4), e83244. https://doi.org/10.7759/cureus.83244

Harding, R. E., Barton, T., Niepceron, M., Harris, E., Bennett, E., Gent, E., et al. (2025). The landscape of ketamine use disorder: Patient experiences and perspectives on current treatment options. Addiction. Advance online publication. https://doi.org/10.1111/add.70073

Food and Drug Administration. (2023, October 10). FDA warns patients and health care providers about potential risks associated with compounded ketamine products, including oral formulations, for the treatment of psychiatric disorders. https://www.fda.gov/drugs/human-drug-compounding/fda-warns-patients-and-health-care-providers-about-potential-risks-associated-compounded-ketamine

Morgan, C. J. A., Dodds, C. M., Furby, H., Pepper, F., Fam, J., Freeman, T. P., et al. (2014). Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation. Frontiers in Psychiatry, 5, 149. https://doi.org0.3389/fpsyt.2014.00149

Chaves, T. V., Wilffert, B., & Sanchez, Z. M. (2023). Overdoses and deaths related to the use of ketamine and its analogues: a systematic review. The American Journal of Drug and Alcohol Abuse, 49(2), 141–150. https://doi.org/10.1080/00952990.2022.2132506

Chesters, R. A., Pepper, F., Morgan, C., Cooper, J. D., Howes, O. D., Vernon, A. C., & Stone, J. M. (2022). Brain volume in chronic ketamine users – relationship to sub-threshold psychotic symptoms and relevance to schizophrenia. Psychopharmacology, 239(11), 3421–3429. https://doi.org/10.1007/s00213-021-05873-0

Li, C.-C., Wu, S.-T., Cha, T.-L., Sun, G.-H., Yu, D.-S., & Meng, E. (2019). A survey for ketamine abuse and its relation to the lower urinary tract symptoms in Taiwan. Scientific Reports, 9(1), 7240. https://doi.org/10.1038/s41598-019-43746-x

Hung, C.-C., Liu, Y.-H., Huang, C.-C., Chou, C.-Y., Chen, C.-M., Duann, J.-R., et al. (2020). Effects of early ketamine exposure on cerebral gray matter volume and functional connectivity. Scientific Reports, 10(1), 15488. https://doi.org/10.1038/s41598-020-72320-z