Ketamine is an incredibly versatile drug that can act as an anesthetic, analgesic, antidepressant, and psychedelic, depending on the dose and clinical context. It can provide pain relief and clinical sedation but may also produce dissociative and perceptual effects, ranging from altered sensations of time and space to feelings of derealization and depersonalization.1
These psychoactive effects can put restraints on patient acceptance and generally limit the use of ketamine in pain management. As a result, an important question is whether ketamine’s analgesic and psychedelic effects arise from the same underlying neural mechanisms or if they represent distinct pharmacological processes. Understanding this relationship could help guide the development of treatments that retain analgesic efficacy while minimizing unwanted psychological effects.2
A randomized, double-blind crossover trial of 20 healthy male volunteers administered increasing intravenous doses of either S-ketamine or racemic ketamine over a 3-hour period. Throughout the experiment, researchers measured pain sensitivity using a pressure pain threshold test and assessed psychedelic effects using the Bowdle questionnaire, which is known to evaluate changes in perception such as altered body image, distorted surroundings, and the perception of time. Blood samples were also collected at regular intervals to measure plasma concentrations of ketamine and its primary metabolite, norketamine.1
The researchers then used population pharmacokinetic-pharmacodynamic modeling to examine the relationship between ketamine concentrations in the blood and both analgesic and psychedelic effects over time. Several in-depth mathematical models were developed to estimate the potency, onset, and offset of ketamine’s effects on pain relief and altered perception while accounting for individual variability between participants. Additionally, the analysis investigated whether norketamine contributed to or modified ketamine’s effects1
The pharmacodynamic modeling showed that ketamine’s analgesic and dissociative effects were best explained by a single model with shared parameters. The researchers found no significant differences in potency or onset/offset times between pain relief, as measured by pressure pain threshold, and dissociation, as measured by changes in external perception. Similarly, there were no meaningful differences between S-ketamine and racemic ketamine. Interestingly, adding S-norketamine, a ketamine metabolite, significantly improved the model fit, suggesting it influences ketamine’s effects, whereas R-ketamine and R-norketamine appeared to contribute little to either analgesia or dissociation.1
Overall, the results suggest that ketamine-induced analgesia and dissociation are closely linked and may arise from common underlying mechanisms. The similar concentration-effect relationships and time courses for the two outcomes indicate that the same pharmacological processes may drive both the analgesic and psychedelic effects of ketamine. These findings contrast with some previous studies that reported little association between ketamine’s analgesic and dissociative effects, but it may be the case that those studies used much higher ketamine doses and less detailed pharmacokinetic analyses.3-5 This study suggests that ketamine’s analgesic and psychedelic effects may not be easily separable.
Remarkably similar potency and time-course parameters for pain relief and altered perception have been found between the analgesic and psychedelic effects of ketamine, supporting an association between the two. While the results suggest that ketamine-induced analgesia and dissociation may arise from interconnected neural processes, perhaps from the thalamus and/or limbic system, further research can help determine whether a direct functional dependency exists between the brain networks underlying these effects.
References
- Olofsen, E., Kamp, J., Henthorn, T.K., et al. Ketamine Psychedelic and Antinociceptive Effects are Connected. Anesthesiology 2022; 136:792–801. https://doi.org/10.1097/aln.0000000000004176
- Mashour, G.A., Ketamine Analgesia and Psychedelia: Can We Dissociate Dissociation? Anesthesiology. 2022;136(5):675-677. https://doi.org/10.1097/aln.0000000000004172
- Gitlin, J., Chamadia, S., Locascio, J. J., Ethridge, B. R., Pedemonte, J.C., Hahm, E.Y., Ibala, R., Mekonnen, J., Colon, K.M., Qu, J., Akeju, O., Dissociative and Analgesic Properties of Ketamine are Independent. Anesthesiology 2020; 133:1021–8
- Jonkman, K., van der Schrier, R., van Velzen, M., Aarts, L., Olofsen, E., Sarton, E., Niesters, M., Dahan, A., Differential Role of Nitric Oxide in the Psychedelic Symptoms Induced by Racemic Ketamine and Esketamine in Human Volunteers. Br J Anaesth 2018; 120:1009–18
- Hahm, E.Y., Chamadia, S., Locascio, J.J., Pedemonte, J.C., Gitlin, J., Mekonnen, J., Ibala, R., Ethridge, B.R., Colon, K.M., Qu, J., Akeju, O. Dissociative and Analgesic Properties of Ketamine are Independent and Unaltered by Sevoflurane General Anesthesia. Pain Rep 2021; 6:e936. https://doi.org/10.1097/pr9.0000000000000936