**8. Future Perspectives**

AN is a particularly hard-to-treat population, and pharmacological trials in AN often suffer from a high dropout rate. People with AN have reported specific concerns around pharmacological interventions, such as fears around drug-instigating weight gain [185]. However, patients also report wanting medication to alleviate anxiety, eating disorder thoughts, poor concentration and sleep problems [185]. A recent survey conducted on 200 participants with eating disorders (*n* = 105 with AN) investigated views on psychedelic drugs as a treatment for eating disorders [186]. Approximately half of the participants expressed interest in participating in psychedelic interventional research in the context of various concerns. The concerns were mitigated when the participants were informed that esketamine was licensed for the treatment of treatment-resistant depression. Importantly, this survey highlighted important methodological considerations, including the need for collaboration with service users and those with lived experience in the design of trials. The participants emphasised the need for a safe, professional and controlled environment during the dosing, a good rapport with the research team, trust in the trial and trial team and the provision of psychoeducation about psychedelic drugs. They also emphasised the need for psychological preparation before the session and an assessment of the "set". Importantly, a third of the overall group reported that they would never take part in such research. Thus, establishing an ongoing dialogue with service users will be an essential consideration in the design of clinical trials.

Overall, it is apparent that future studies should first aim to establish a safety profile of ketamine for AN through well-controlled feasibility and pilot studies. The outcome measures should be agreed upon with service users. Investigational studies of neuromodulation (e.g., transcranial magnetic stimulation and deep brain stimulation) in severe-enduring AN have found proximal improvements in depression, with improvements in eating disorder psychopathology and weight taking 12–18 months to emerge [187–189]. Therefore, whilst the BMI is often the metric of success in interventional trials in AN, for patients with severe-enduring AN where weight gain is slow, other metrics of improvement such as

depression scores, social connectedness and quality of life should be considered, and long follow-up periods should be implemented. Given the hypothesised role of ketamine in providing a window of neuroplasticity, it will be essential that ketamine is combined with psychotherapy in future trials. Whilst the antidepressant effects of ketamine are transient, there is emerging evidence that psychotherapies (such as CBT) can extend the duration of antidepressant effects [190]. Additionally, the experiential components of ketamine may facilitate the therapeutic bond between patient and clinician [160], which is known to be a predictor of response to treatments [191].

Ketamine-assisted therapy generally follows a three-stage process: (1) preparation, where the patient and client discuss the mindset going into the experience, treatment goals and expectations and set intentions; (2) dosing, where patients are given the ketamine administration; and (3) integration, where the ketamine experience is reflected upon, and insights/lessons gained during the experience are integrated into the self. In the treatment of AN, it may be useful to combine specific therapeutic strategies with ketamine, such as compassion-based meditation exercises, yoga, cognitive bias modifications and exposure therapies. Similarly, specific therapeutic approaches may work well with ketamine, such as compassion-focused therapy, the Maudsley Model of Anorexia Treatment for Adults (MANTRA), family-based interventions and other psychotherapies. However, it is important to note that a "one size fits all" approach is unlikely to be successful, and treatments should be tailored to the individual.
