Ketamine abuse potential and use disorder

Ketamine is a phencyclidine (PCP) derivative and a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor that has long been used as an anaesthetic in humans and veterinary medicine. Beyond anaesthesia, subanaesthetic doses produce rapid antidepressant effects and have been trialled for treatment-resistant depression, bipolar disorder, anxiety and chronic pain. At the same time, ketamine produces dissociative and reinforcing psychological effects and carries documented neurological, hepatic, renal and other peripheral toxicities, which have contributed to growing recreational use and public-health concerns. Liu and colleagues set out to review the epidemiology, pharmacology, neurochemistry and treatment of ketamine abuse, with particular focus on brain circuitry implicated in reinforcing effects. The paper synthesises findings from human epidemiological surveys, clinical reports, neuroimaging and biochemical studies, and animal models (for example self-administration and conditioned place preference paradigms) to characterise harms, mechanisms and therapeutic approaches reported in the literature.

The extracted text does not provide a formal Methods section or a described literature-search strategy; the paper is presented as a narrative review. Evidence cited in the review includes population surveys and surveillance data, clinical case reports and emergency-department series, controlled human studies (including pharmacological and imaging work), animal experiments (self-administration, conditioned place preference, cognitive and neurochemical assays), and some small clinical intervention studies and historical psychotherapy reports. Key types of experimental approaches discussed are animal self-administration (SA) and conditioned place preference (CPP) models to assess reinforcing and motivational properties, pharmacological manipulations and receptor/ signalling assays (for example studies of dopamine, GABA, NMDA and glycogen synthase kinase-3β, GSK-3β), and human neuroimaging (BOLD/phMRI) studies examining task-related and resting responses after ketamine. Treatment evidence summarised ranges from symptomatic medical management of peripheral toxicity to pharmacological attempts (eg lamotrigine) and ketamine-assisted psychotherapy (historical and recent studies). Because no systematic inclusion/exclusion criteria or search dates are reported in the extracted text, the review appears to be selective and descriptive rather than a systematic meta-analysis.

Epidemiology and social harms: Survey and surveillance data indicate substantial and growing non-medical ketamine use in multiple regions. A US survey in 2006 estimated about 2.3 million people had used ketamine in their lifetime. The number of ketamine-related deaths in the UK rose tenfold between 1999 and 2008. In Australia, 40% of party drug users reported ketamine use in one survey. Regional increases were reported in Asia: Malaysia saw almost a four-fold rise in users from 2006 to 2012, and mainland China and Hong Kong have experienced marked increases, including over 2,000 cases reported in Hong Kong in 2013–2014 and an increase in the proportion of ketamine users among registered drug users from 21.5% in 2001 to 40% in 2009. In response to rising harms, China changed ketamine’s status from a class II to class I psychotropic drug. Traffic safety and sexual risk: Recreational use has been linked to driving under the influence and risky sexual behaviour. Examples include ketamine being the third most common illicit drug found among drivers tested in Shanghai, 36% of 122 partygoers in a Scottish survey admitting to driving after ketamine use, and 9% of drivers in fatal crashes in Hong Kong testing positive for ketamine. The authors link these harms to impaired executive function, attention and memory, and to reports that ketamine can enhance sexual experience and thus may increase risk of drug-facilitated sexual assault. Psychological and physiological effects: Pharmacokinetics reported in the review list a plasma half-life of 2–4 hours and a distribution half-life of 7–11 minutes. Common administration routes are intravenous, intramuscular, intranasal (predominant in recreational use), and smoking. Low recreational doses produce relaxation or ‘‘K-land’’ while higher doses produce profound dissociation or a ‘‘K-hole’’. Acute administration impairs verbal working and episodic memory in healthy volunteers and chronic users show deficits correlated with estimated lifetime use, particularly in verbal learning and spatial memory. High doses can evoke transient hallucinations and schizophrenia-like positive and negative symptoms. Systemic effects include cardiovascular stimulation (increased heart rate and blood pressure), and chronic use is associated with urinary tract symptoms (suprapubic pain, dysuria, haematuria) with radiological and cystoscopic changes (reduced bladder volume, wall thickening, mucosal inflammation), renal epithelial alterations and, in severe cases, surgical interventions. Liver pathology is also reported in humans and in animals subjected to prolonged exposure, with suggested mitochondrial dysfunction as one mechanism. Reinforcement and addictive behaviours: Preclinical data show ketamine increases dopamine efflux and inhibits dopamine uptake in the nucleus accumbens. Self-administration paradigms consistently demonstrate ketamine reinforcement in monkeys, rats and dogs, and conditioned place preference is induced in rodents; female rats showed higher CPP scores than males in at least one report. Withdrawal-related symptoms in humans and animals include fatigue, poor appetite, drowsiness, craving, anxiety, sleep problems and dysphoria, and chronic administration increased immobility in the forced swim test in mice. Neurochemical mechanisms: Ketamine’s reinforcing and cognitive effects are linked to interactions among glutamate (via NMDA antagonism), GABAergic circuits, and dopamine pathways. One hypothesised mechanism is blockade of NMDA receptors on GABA interneurons in the thalamic reticular nucleus, causing disinhibition of dopaminergic neurons and increased dopamine release. Increases in dopamine D1 and D2 receptors in prefrontal cortex and striatum are described, and D2/3 receptor availability has been correlated with psychopathological changes after subanaesthetic ketamine in volunteers. GSK-3β signalling is implicated: decreased p‑GSK-3β activity has been associated with ketamine-induced apoptosis in developing animals, GSK-3β activation with motor and cognitive abnormalities, and GSK-3β blockade reduced ketamine self-administration and cue-induced reinstatement in rats. Paradoxically, acute ketamine increased plasma p‑GSK-3β in patients with major depressive disorder in a clinical report. Neuroimaging studies report altered activation patterns after ketamine: impaired working and episodic memory with changes in cingulate, striatum and frontal cortex; increased BOLD signal in frontal, hippocampal and thalamic regions; reduced posterior cingulate and medial prefrontal deactivation during working memory tasks; and links between perceptual distortions and paracentral lobule activity. Animal pharmacology work suggests roles for nicotinic receptors, GABAA and GABAB receptors, hippocampal dopamine D1/D5 and AMPA receptors in memory effects, and some contexts show a protective effect of ketamine against electroconvulsive-shock-induced memory impairment via reduced neuroinflammation and soluble Aβ. Treatment approaches and evidence: No specific pharmacological antidote for peripheral ketamine toxicity is identified. Symptomatic treatments reported to have usefulness include antibiotics, non-steroidal anti-inflammatory drugs, steroids and anticholinergics; severe urological damage has at times required urinary diversion or nephrectomy. Abstinence is associated with partial recovery of organ damage; in animal models, abstinence combined with environmental enrichment enhanced recovery compared with isolation. Attempts to modulate glutamatergic transmission include a report of lamotrigine (a glutamate-release inhibitor) reducing both frequency and daily dose in a chronic user, but evidence is limited. Behavioural and cognitive interventions are described as mainstream treatments for compulsive drug-taking. Historical and contemporary work on ketamine psychedelic therapy (KPT) is summarised: trials from the 1950s–1960s and a ten-year review suggested benefits for alcoholism, a two-year follow-up reported reduced relapse in heroin addiction after high-dose intramuscular ketamine, repeated KPT sessions were more effective than a single session, and a recent single subanaesthetic infusion reduced cue-induced craving and promoted motivation to quit in cocaine-dependent patients. The authors note that results are sometimes conflicting and mechanisms are not well understood.

Liu and colleagues interpret the literature as presenting a dual picture: ketamine has important and rapid antidepressant properties that have stimulated clinical interest, but the same pharmacological profile confers reinforcing potential and organ toxicities that complicate therapeutic use. They position the findings relative to earlier work by emphasising convergent evidence from animal models, human imaging and biochemical studies linking NMDA antagonism, dopaminergic disinhibition and downstream signalling pathways (including GSK-3β) to both beneficial and adverse behavioural effects. Key limitations acknowledged in the extracted text include the absence of a specific, universally effective treatment for peripheral toxicity and the presence of conflicting or limited data on interventions for addiction. The authors note that mechanistic understanding remains incomplete and that many therapeutic reports (for example lamotrigine or ketamine psychotherapy) derive from small, historical or uncontrolled studies. Clinical implications discussed are cautious: while ketamine may hold promise as an antidepressant and as an adjunct in addiction treatment in some contexts, its reinforcing and toxic effects pose a major challenge and warrant careful further study. The review highlights the need for innovative research into mechanisms and treatments for ketamine abuse and for rigorous investigation of the safety profile and long-term risks if ketamine is to be used more widely in psychiatry.

The discovery of ketamine’s rapid antidepressant effects has opened new avenues for understanding and treating mood disorders, but the drug’s significant reinforcing properties and peripheral and central toxicities complicate its therapeutic application. Recent mechanistic work has begun to implicate NMDA receptor actions, GSK-3β signalling and inflammatory mediators in ketamine’s harmful effects. The authors conclude that further research is needed to elucidate mechanisms and develop effective treatments for ketamine abuse, and that much greater investigation is required before ketamine can be considered a safe antidepressant option for broader clinical use.