EXPLORING THE NEUROBIOLOGICAL AND PSYCHOLOGICAL MECHANISMS OF KETAMINE IN PROBLEMATIC GAMBLING: A MECHANISTIC STUDY
Authors: Krecké *Joy , Ottewill Jessica , Statton Sarah , Depla Simon , Fraser Flora , Shaw Alex D , Morgan Celia 
Published: February 2025

Abstract

Background
Ketamine, an NMDA-receptor antagonist approved for depression treatment, exhibits a wide spectrum of applicability in psychiatric disorders. With established efficacy in addressing substance addictions1, ketamine's potential could extend to encompass behavioural addictions such as gambling disorder.

Aims & Objectives
We explored the impact of ketamine on gambling cue reactivity, craving, cognition, and mood in individuals at risk of gambling disorder, aiming to assess its potential in non-clinical populations before considering its application as a treatment. Further, we aimed to investigate the neurobiological mechanisms of ketamine, focusing on enhanced visual long-term potentiation2 (LTP) measured using electroencephalogram (EEG). We examined potential psychological mechanisms of ketamine by focalising on maladaptive memory destabilisation and subjective experience.

Method
A total of 39 participants were recruited, with 22 participants included in the EEG sub-arm. Participants were recruited from the community and scored at least a low risk of developing gambling disorder. On the study day, participants were randomised to receive either a single-dose sublingual ketamine (100mg) or placebo lozenge following an established memory destabilisation procedure3. EEG recordings were collected in two sessions, at screening and at two hours post drug administration on the study day, using a 64-channel EEG system. See Figure 1 for study design and outcomes.

Results
No significant effect of drug was found on any of the cue reactivity, craving, gambling-related and mood measures. However, ketamine significantly increased LTP in our study and all subjective effect measures were significantly higher in the ketamine condition when compared to the placebo group.

Discussion & Conclusion
Despite increased synaptic plasticity and notable subjective effects in the ketamine group, reactivity to gambling cues, gambling and mood measures remained unaffected. We suggest that the enhanced-LTP model of ketamine could have broader implications for various mental health disorders. Nonetheless, limitations such as low drug dose, no psychotherapy and likely inclusion of ‘non-problematic’ gamblers in our study may have contributed to not observing changes in gambling and mood measures. Additional analyses are currently being conducted, and resting state EEG measurements as well as plasma concentrations of ketamine and metabolites will be reported.
References
1.Ezquerra-Romano, I.I., Lawn, W., Krupitsky, E. and Morgan, C.J.A., 2018. Ketamine for the treatment of addiction: evidence and potential mechanisms. Neuropharmacology, 142, pp.72-82.
2.Sumner, R.L., McMillan, R., Spriggs, M.J., Campbell, D., Malpas, G., Maxwell, E., Deng, C., Hay, J., Ponton, R., Kirk, I.J. and Sundram, F., 2020. Ketamine enhances visual sensory evoked potential long-term potentiation in patients with major depressive disorder. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 5(1), pp.45-55.
3.Das, R.K., Gale, G., Walsh, K., Hennessy, V.E., Iskandar, G., Mordecai, L.A., Brandner, B., Kindt, M., Curran, H.V. and Kamboj, S.K., 2019. Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nature communications, 10(1), p.5187.