Riley Blanton

Introduction. Substance use disorder (SUD), a chronic brain disorder, affects millions worldwide and has various etiologies.¹ No cure exists for SUD and relapse rates remain high despite psychosocial interventions and limited pharmacological therapies intended for symptom management.¹ A pharmacologic agent with higher efficacy is essential in future efforts towards SUD treatment.¹ The mesolimbic reward system is vital in the pathogenesis of SUD.² Its components – the ventral tegmental area (VTA) and nucleus accumbens (NAc) – show modifications when exposed to certain substances.² All drugs of abuse directly or indirectly increase dopamine release in the NAc.² In long term cocaine use, the GluA2 subunit – which confers calcium impermeability at AMPA receptors – was removed from VTA synapses, allowing increased excitability in these neurons.³ This change is described as induction of long-term potentiation (LTP) and inhibition of long-term depression (LTD).^1,4 High relapse rates can be attributed to the initiation of place preference (PP) and craving incubation (CI).^1,5,6 PP is positive reinforcement conditioning that associates an environment with a rewarding stimulus.^1,5 CI is the increase in intensity of cravings that develops over a period of drug abstinence and withdrawal.⁶  Methods. Ketamine, an NMDA receptor antagonist and dissociative anesthetic, is implicated in the treatment for SUD due to its high efficacy against treatment-resistant depression, which has a similar pathophysiology.^3,5 Ketamine exerts most of its effects on the VTA and NAc.³ Several studies utilizing rodent models subjected to SUD were used in the analysis of ketamine’s relationship with SUD.^3,5,6,7,8 Some were observed for self-administration of substances via lever pushing and nose-pokes while others had their brains injected directly with ketamine and examined for electrophysiological properties.^3,5,6,7 Most notably, a human clinical trial was performed on cocaine dependent subjects.⁸ The subjects were admitted, began mindfulness-based relapse prevention (MBRP), and received one ketamine or midazolam infusion.⁸ Over 5 weeks, subjects attended 2 MBRP sessions weekly and were assessed for relapse and craving reduction over 6 months.⁸  Results. Ketamine was shown to reduce dopamine release and inhibit LTP in the NAc, induce LTP in the VTA, and block formation of PP.^3,5,6,7 The clinical trial showed a decrease in craving intensity and increased time between relapse when given ketamine.⁸  Conclusion. A better treatment option is vital in SUD therapy.¹ Ketamine shows promising results in mouse and human studies by altering neuronal components in the SUD pathway that contribute to relapse and should be considered for SUD therapy in the future.^3,4,8

1. Volkow ND, Michaelides M, Baler R. The Neuroscience of Drug Reward and Addiction. Physiol Rev. Oct 1 2019;99(4):2115-2140. doi:10.1152/physrev.00014.2018
2. Cooper S, Robison AJ, Mazei-Robison MS. Reward Circuitry in Addiction. Neurotherapeutics. Jul 2017;14(3):687-697. doi:10.1007/s13311-017-0525-z
3. Skiteva O, Yao N, Chergui K. Ketamine induces opposite changes in AMPA receptor calcium permeability in the ventral tegmental area and nucleus accumbens. Transl Psychiatry. Oct 14 2021;11(1):530. doi:10.1038/s41398-021-01658-3
4. Yao N, Skiteva O, Zhang X, Svenningsson P, Chergui K. Ketamine and its metabolite (2R,6R)-hydroxynorketamine induce lasting alterations in glutamatergic synaptic plasticity in the mesolimbic circuit. Mol Psychiatry. Oct 2018;23(10):2066-2077. doi:10.1038/mp.2017.239
5. Witkin JM, Kranzler J, Kaniecki K, et al. R-(-)-ketamine modifies behavioral effects of morphine predicting efficacy as a novel therapy for opioid use disorder(1). Pharmacol Biochem Behav. Jul 2020;194:172927. doi:10.1016/j.pbb.2020.172927
6. Wang J, Ishikawa M, Yang Y, et al. Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. J Neurosci. May 2 2018;38(18):4316-4328. doi:10.1523/JNEUROSCI.3291-17.2018
7. Rezvani AH, Tizabi Y, Slade S, Getachew B, Levin ED. Sub-anesthetic doses of ketamine attenuate nicotine self-administration in rats. Neurosci Lett. Mar 6 2018;668:98-102. doi:10.1016/j.neulet.2018.01.022
8. Dakwar E, Nunes EV, Hart CL et al. A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial, The American Journal of Psychiatry. 2019;176(11):923-930.