Tolerance to ketamine can develop in patients undergoing ketamine therapy for mental health conditions. Tolerance refers to a decrease in response to a drug after repeated use, necessitating higher doses to achieve the same therapeutic effects. The exact mechanisms underlying ketamine tolerance are not fully understood. Still, it is thought to involve changes in N-methyl-D-aspartate (NMDA) receptor function and expression and adaptations in other neurotransmitter systems.

Prolonged or repeated use of ketamine can lead to the development of tolerance, which may result in reduced treatment efficacy. This can be particularly problematic for patients with treatment-resistant depression or other mental health conditions who rely on ketamine’s rapid and robust antidepressant effects. Tolerance development may increase the frequency or dosage of ketamine administration, potentially increasing the risk of side effects and dependence.

Several strategies may help manage or mitigate ketamine tolerance, including drug holidays (periods of abstinence), alternating ketamine with other treatments, or utilizing adjunctive medications to enhance ketamine’s effects. However, more research is needed to understand the long-term consequences of ketamine tolerance and to develop effective strategies for managing it in clinical practice.

It is important to note that individual responses to ketamine therapy can vary, and not all patients will develop tolerance. The risk of tolerance development may be influenced by factors such as dose, frequency of administration, and individual differences in genetics and metabolism.

Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101(5), 774-778. Retrieved from

Short, B., Fong, J., Galvez, V., Shelker, W., & Loo, C. K. (2018). Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry, 5(1), 65-78. Retrieved from

Williams, N. R., Heifets, B. D., Bentzley, B. S., & Schatzberg, A. F. (2018). Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Molecular psychiatry, 23(12), 2229-2230. Retrieved from

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