*7.2. Side Effects and Safety Concerns*

There are specific safety concerns when investigating pharmacological interventions for AN. Liver enzyme abnormalities, such as elevations in liver transaminases, are associated with a lower body mass index (BMI) and hypoglycaemia [175]. Repeated high doses of ketamine and prolonged ketamine abuse have been associated with hepatotoxicity and liver injury [176]. Whilst this causal pathway is not fully understood, it may be related to lipid peroxidation (oxidative damage) [177]. Liver function tests are therefore a necessary precursor to ketamine treatment in AN.

Moreover, upper and lower urinary tract dysfunctions are present in approximately 20–40% of recreational ketamine users [178–180], which tend to be discontinued following the cessation of ketamine use. There is a dose–response relationship between ketamine use and the probability of lower urinary tract symptoms, meaning that long-term usage may be a concern. This is a particular concern, as renal complications have been observed in patients with AN [181]. Thus, patients should be asked about polydipsia, haematuria, incontinence and pelvic pain; indicators of renal function in the blood (e.g., albumin to a creatinine ratio and glomerular filtration rate) should be monitored, and abnormalities would warrant the cessation of ketamine.

Cardiac complications/abnormalities are a notable feature of AN. For example, hypokaemia can be a consequence in patients who use self-induced vomiting as a compensatory behaviour to manage weight gain. This, in turn, can lead to prolonged QT intervals, markers of arrhythmias. Other cardiac complications include bradycardia/tachycardia, congestive heart failure and hypotension. Ketamine administration is associated with transient increases in the blood pressure and heart rate. The use of psychostimulants (e.g., amphetamines, methylphenidate, modafinil and armodafinil) should not be permitted, as they increase blood pressure. Moreover, patients on concomitant monoamine oxidase inhibitors (MAOIs) should have their blood pressure monitored closely, since MAOI usage has been reported to increase blood pressure [182]. Completing an ECG and measuring electrolytes prior to treatment may be recommended. Recent cardiovascular events or clinically significant cardiovascular conditions are also a specific contraindication of ketamine.

Other identified key side effects of ketamine include transient dissociative states, sedation, nausea and vomiting, dysgeusia (alterations in taste) and hypoesthesia (changes in touching sensation). Dissociation is more common in people with comorbid PTSD, which is likely due to it already being a feature of the disorder. Patients with comorbid PTSD should therefore be closely monitored, and studies should administer the Clinician Administered Dissociative States Scale (CADSS [183]) to investigate the incidence of dissociation in AN following ketamine treatment. The "setting" of the room should promote feelings of calm and relaxation, minimising bright lights and too many stimuli, and encouraging patients to focus on music and pleasant thoughts.

Psychosis may be a contraindication for ketamine; ketamine can induce psychotic episodes in people that have schizophrenia [184]. Sedation is more of a risk if patients are on opioids or benzodiazepines; thus, this should be considered when patients are screened for treatment. Nausea, vomiting and dysgeusia may be specific concerns in the context of AN, since they have the potential to be triggers. This will need to be examined closely in future research, although the aforementioned studies conducted so far have not indicated any of the above to be particular concerns.
