**9. Conclusions**

The current treatment options for AN show limited efficacy, and addressing severeenduring cases presents a particular challenge to clinicians and researchers. This review gave an overview of a conceptual rationale for the use of ketamine in the treatment of AN. Ketamine has proven to be an effective treatment for a range of psychiatric disorders, including depression, anxiety disorders, addiction and PTSD. Relatedly, it was recently licensed for treatment-resistant depression as a nasal spray esketamine device. In AN, there are several compelling reasons for its application, which were discussed. Ketamine may promote neuroplasticity, neurogenesis and hippocampal volume, and mitigate neuroinflammation. As a rapid antidepressant, ketamine may also reduce depression in patients with AN, which may be a barrier to treatment. In combination with therapies, it may also promote cognitive flexibility, openness, open-mindedness and detachment from the self whilst also promoting a therapeutic bond. However, there are specific safety concerns that require consideration in the treatment of AN with ketamine, and future studies designed in collaboration with service users are warranted in order to establish its efficacy, acceptability and safety.

**Author Contributions:** Conceptualisation, J.L.K. and H.H.; validation, J.L.K., H.H., J.T., M.F.J. and C.K.; writing—original draft preparation, J.L.K.; writing—review and editing, J.L.K., H.H., J.T., M.F.J. and C.K.; visualisation, J.L.K. and supervision, H.H. and J.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** J.K. acknowledges financial support from a Medical Research Council (MRC) funded Doctoral Training Partnership stipend (ref: MR/N013700/1). H.H. and J.T. acknowledge salary support from the National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre (BRC) for Mental Health. M.J. is an Honorary Consultant at South London and Maudsley NHS Foundation Trust (SLaM) supported by the NIHR, BRC and SLaM.

**Acknowledgments:** The figure in this manuscript were created using Biorender.com, accessed on 15 September 2021.

**Conflicts of Interest:** M.J. has, within the last year, received honoraria for speaking from Janssen, Lundbeck, EMS, Neurocentrx and Daiichi Sankyo. M.J. also received the Wellcome Innovator award to study the first in-human, randomised, double-blinded, placebo-controlled study to investigate the safety and tolerability, PK and PD of oral ketamine in HV. C.K. has previously received salary

support from the Lundbeck Foundation, NIHR, Novo Nordisk UK Research Foundation and Marie Curie Fellowship. H.H. has received a consulting honorarium from COMPASS pathways.
