**1. Introduction: An Overview of Ketamine**

Ketamine is an n-methyl-D-aspartate (NMDA) receptor antagonist that has traditionally been used for anaesthesia in larger doses [1]. It remains one of the two injectable anaesthetics under the World Health Organisation Model List of Essential Medicines, the other of which is propofol [2]. It is available in two enantiomers: the S(-) and racemic (R-) forms, referred to as esketamine and arketamine. However, when referred to as ketamine, this describes (R,S)-ketamine, which is a 1:1 racemic mixture of S- and R-ketamine enantiomers (see Figure 1 for the molecular structure). S-(Es)ketamine has an approximately four-fold higher affinity for the NMDA receptor site than R-ketamine and is three to four times as potent [3,4]. Moreover, esketamine generally produces fewer psychomimetic effects than R-ketamine. Ketamine can be administered via several routes that have varying bioavailability: intravenous (100%), intramuscular (90–95%), subcutaneous (90–95%), intranasal (30–50%), sublingual (20–30%), transdermal (10–50%) and oral (10–20%) [5]. Estimates of bioavailabilities increase when accounting for the contribution of norketamine; for example, in one study, the bioavailabilities of sublingual and oral ketamine increased from 32% to 54% and 23% to 59%, respectively [6]. Moreover, the area under the curve,

**Citation:** Keeler, J.L.; Treasure, J.; Juruena, M.F.; Kan, C.; Himmerich, H. Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review. *Nutrients* **2021**, *13*, 4158. https:// doi.org/10.3390/nu13114158

Academic Editor: Stefano Erzegovesi

Received: 10 October 2021 Accepted: 18 November 2021 Published: 20 November 2021

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peak plasma concentration and time to peak plasma concentration differ depending on the administration route and dosage (see Table 1).

**Figure 1.** The molecular structure of ketamine, S-ketamine and R-ketamine.

**Table 1.** Single administration of ketamine: selected pharmacokinetic parameters.


Notes: AUC = area under the curve, Cmax = peak plasma concentration, M = mean, SD = standard deviation and tmax = time to peak plasma concentration (adapted from [6]).

Ketamine is rapidly metabolised (the half-life is 2–4 h for racemic ketamine and 5 h for esketamine [5]), mainly by the liver, and is excreted renally through urine and faeces. Its by-products include hydroxyketamine, norketamine, dehydronorketamine and six hydroxynorketamine metabolites [7]. The main metabolic pathway is N-demethylation to an active metabolite norketamine by CYP3A4. There is increasing interest in the metabolites of ketamine. For example, research has demonstrated the importance of the (2S,6S;2R,6R) hydroxynorketamine metabolite for the antidepressant effects of (R,S)-ketamine [7], which is independent of NMDA receptor activity.

The first human dosage of ketamine was in 1964 at the University of Michigan, where it was titrated from a subanaesthetic dose to full anaesthesia [8]. Patient reports of the experiences included feeling "strange" and having "no feeling in their arms or legs" [8]. These experiences contributed to its classification as a "dissociative anaesthetic" by Domino and Corssen [4]. In 1970, ketamine was approved by the Food and Drug Administration (FDA) for use as an anaesthetic in children, adults and the elderly. Four years later, in 1974, ketamine was used for the first time within a psychiatric setting as an adjunct to psychotherapy for depression in Argentina [9]. Since then, advances in the field of ketamine have led to randomised controlled trials investigating its use for the treatment of various psychiatric disorders, including depression [10], anxiety disorders [11], alcohol and substance use disorder [12–14] and post-traumatic stress disorder [15]. Unfortunately, this research was somewhat obscured by ketamine's classification as a class III substance in the US Controlled Substances Act due to it being popular as a recreational drug. However, in 2019, esketamine in intranasal form was licensed to treat treatment-resistant depression in the US and Europe by the FDA and European Medicines Agency (EMA), due to its rapid antidepressant effects.

Factors that contribute to the phenomenology of ketamine treatment include set (person factors) and setting (situational factors), terms introduced by Harvard psychologist Timothy Leary [16]. Set refers to the individual's internal state, such as the psychological preparation and intentions for the experience, as well as intrinsic factors such as mood, psychopathology, personality, fears and wishes [17]. Setting refers to any environmental factors, including the physical, social and cultural environments [18]. Importantly, the nature of the set and setting determine the ketamine experience; optimising both factors is important to minimise the chances of an adverse psychological experience (i.e., a "bad trip"). Set can be optimised by providing patients with "sitters", who help the patient prepare for the ketamine experience, set intentions, support them through the session and aid them in integrating its meaning afterwards. On the other hand, researchers and clinicians often optimise the setting by providing a calm and relaxing environment with minimal stimuli and bright light; an overly clinical or antiseptic environment may increase anxiety (for comprehensive guidelines, see [19]). Additionally, patients may be provided with eye shields and a carefully prepared music playlist and are guided to direct their attention inwards [20].

As aforementioned, the bioavailability of ketamine differs depending on the administration route, although it is unclear how or whether bioavailability is related to therapeutic effects [21]. Regardless, one study found dose-related antidepressant effects across all administration routes tested, including intravenous (IV), intramuscular (IM) and subcutaneous (SC) [22]. In this study, SC administration resulted in the fewest adverse events [22]. By comparison, IM and IV can be painful to administer, and intranasal ketamine can be uncomfortable if administered in the same nostril over 40 min [21]. Oral ketamine produces a bitter taste. However, oral, SC, IM and intranasal ketamine are more convenient than IV ketamine and can be used in everyday clinical care, as the latter requires an anaesthetist to be present for administration [21]. Overall, it is unclear which administration route is optimal within psychiatry, although within the context of treatment-resistant depression, intranasal esketamine alongside an antidepressant seems the most feasible and effective [5].
