Prevalence of Ketamine Abuse
Ketamine abuse has been increasing quickly over the last 20 years  [10]. A US survey estimated that there was an increase in self-reported non-medical ketamine use compared to the previous year from 2006 to 2014 (Β = 0.21; P = 0.030) and an increase from 2015 to 2019 (Β = 0.29; P = 0.036), with a peak of 0.9% in late 2019[11]. This strong evidence of ketamine's addictive potential was confirmed by another Australian study including 100 users of recreational ketamine which found that about one in five participants (22%) reported having physical tolerance to ketamine[12]. In Asia, the number of ketamine users almost increased four times in Malaysia between 2006 and 2012 [13]. Ketamine is the second and third most abused drug in Hong Kong and mainland China and Taiwan respectively [14]. It is most commonly consumed by young people [15], ,gay nightclubbers [16] and poly-drug users  [17]. In the case of our patient, the first experience with ketamine was not a result of a medical prescription. MR JH is a young man, who had multiple substance use and who worked in a night club. All these factors may contribute to the initiation of ketamine use.

Pharmacological Properties of Ketamine

Ketamine has a chemical structure composed of two pure optical isomers, the S- and R-ketamine, and each racemate consists of the two isomers in equal parts.   The (S) enantiomer has higher affinity for NMDA [18, p. TUY] and a 4-fold higher anaesthetic potency than the R(-) isomer [19]. The predominant mode of administration of ketamine for recreational use is sniffing, and the intravenous injection is relatively rare [20].

Hashimoto et al 2020 evaluated another physiological indicator of drug reward, the release of dopamine, by measuring the regional uptake of 18F-fallypride, a dopamine receptor ligand that can be displaced by promoting dopamine release. (R)-ketamine preferentially reduced 18F-fallypride uptake in the NAc, while (S)-ketamine seemed to further stimulate dopamine release in the prefrontal cortex and other regions. (S) ketamine is apparently responsible for the reward properties of ketamine [21]. A further study identified a selective activation of mu and kappa opioid receptors by (S)-ketamine in the medial prefrontal cortex (mPFC). These results suggest that the abuse risk of ketamine in humans is principally attributed to the pharmacological effects of its enantiomer (S) [9]. In 2019, the FDA approved the enantiomer S-ketamine, in an intranasal spray (Spravato), for the adjunctive treatment of treatment-resistant depression (TRBD), and in 2020 for the treatment of major depressive disorder with acute suicidal ideation or behavior [22]. In addition, intravenous ketamine is also used off-label as an adjunctive treatment for resistant bipolar depression, although the safety and efficacy of this treatment still await more studies [23].

Although the abuse potential of (R,S)-ketamine is well established in animals, there is limited clinical evidence that both single and repeated administrations of ketamine in controlled clinical conditions have not led to abuse, dependence, misuse and/or gateway behavior in patients with TRD [18].

Symptoms of ketamine abuse
Ketamine's positive reinforcing properties include anesthesia, euphoric and dissociative effects. A low dose is associated with a feeling of relaxation, called "K-land", while a higher dose induces a dream like state, called "K-hole" [24]. Reports of “out-of-body” experiences have been consistently associated with recreational use and abuse of ketamine [25]. These feelings disappear about 2 hours after acute ketamine use [8] . The K-hole experience is known to vary between users [19]. In this case report, snorting was the most mode of administration of ketamine.  The patient felt light, euphoric, had pleasant visual hallucinations and depersonalizing sensations. The most common symptoms of ketamine withdrawal observed are discomfort, fatigue, reduced appetite and energy. As well as sleepiness, craving, panic attacks and dysphoria [3]. And finally, because of the CNS-modulating activity of ketamine, it should be used with caution with other drugs that affect mood and perception, including alcohol, opioids, benzodiazepines and cannabis [19].

Many neurological side effects of ketamine abuse are dose-dependent, although most of them are self-limiting. These effects include hypersalivation, hyperreflexia and transient clonus [26]. Ketamine may also cause vestibular type symptoms including dizziness, nausea and vomiting. The cardiopulmonary toxicity of ketamine is rare, being limited to effects caused by transient sympathetic activation such as tachycardia, hypertension and palpitations. [27]. More recently, cases of cystitis and other lower urinary tract symptoms (e.g. detrusor overactivity) have also been reported in chronic ketamine users [28].

Both clinical and animal studies confirm the liver damage caused by chronic ketamine use. Bile duct dilatation, microscopic bile duct damage and even significant liver fibrosis have been observed in ketamine users [29].  These adverse effects are potentially reversible with abstinence [30].

It is interesting to note that in the recent systematic review of the literature by Walsh ANDal 2021, there were no reports of ketamine use/abuse after ketamine treatment, neither any evidence of transition from medical to non-medical use of ketamine [31].

Treatment of ketamine abuse
There is still no specific guideline in the literature for the management of Ketamine dependency. A recent study, based on the primary pharmacological action of ketamine, reported a significant decrease in the frequency and daily dose of ketamine among a chronic ketamine user who received an administration of lamotrigine, a glutamate release inhibitor [32]. Like other substance use disorders, behavioural and cognitive therapies have also been the main approach to managing compulsive use behaviours in patients with ketamine dependence [8].