Responding to medicinal and non-medicinal ketamine use

Ketamine challenges our consideration of drug benefit and harm and how these two opposing concepts should be balanced by clinicians, policy makers and the public. At a time when ketamine and other related arylcyclohexamines are being investigated as novel treatments for a range of mental health problems, the non-medical use of ketamine is increasing along with associated, often severe, harms. Untangling this apparent contradiction requires sound research, careful monitoring of emerging evidence and a co-ordinated response from health providers.

Derived from phencyclidine and first synthesized in 1962, ketamine has a complex neurochemical profile producing effects including sedation, dissociation, anaesthesia, analgesia and amnesia [1]. Primarily acting as a non-competitive N-methyl-d-aspartate (NMDA) receptor agonist, ketamine is also a weak dopamine D2, 5-HT_2A and μ-opioid agonist and has weak affinity for the serotonin and norepinephrine transporters.

Listed as an essential medicine by the World Health Organization, ketamine is well established in paediatric, emergency and pre-hospital medicine, and also used in veterinary medicine [2, 3]. More recently, ketamine's antidepressant effects have been studied in those with treatment-resistant and major depressive disorders. Intravenous ketamine shows powerful, rapidly acting, but short-lived antidepressant effects [4, 5]. More recently an enantiomer of ketamine, esketamine, has been developed as a nasal preparation and licensed for the management of treatment-resistant depression [6]. A range of other indications are being explored including for the treatment of substance use disorders and post-traumatic stress and there are currently over 1500 clinical trials registered on clinictrials.gov investigating ketamine and related arylcylohexamines [7]. There is genuine excitement among researchers about the potential for ketamine and related compounds working through similar mechanisms to deliver new treatment options for patients. However, as the evidence continues to develop, ‘ketamine clinics’ have been opening in some countries providing off-label ketamine prescriptions for a wide-range of mental-health and ‘lifestyle’ indications for which there is little or no supporting research. It is estimated the United States (US) ketamine clinic market was worth US$3.4 billion in 2023 [8].

Non-medical use of ketamine was first reported in the United States in 1971 and has since spread worldwide with the United Nations Office on Drugs and Crime reporting non-medical ketamine use in 64 countries [9]. Rather than being diverted from legitimate hospital, pharmacy or veterinary supplies, most ketamine used non-medically is produced in clandestine laboratories as a fine crystalline powder that is generally used by nasal insufflation. People using ketamine report desirable effects at lower doses including visual and auditory hallucinations and distortions of time and space, while at higher dose intense dissociation with out of body experiences (often termed the ‘K' hole by people who use ketamine) are combined with dose-related sedation. There are also reports of ketamine being used without medical supervision to self-manage mental health problems, including post-traumatic stress disorder, anxiety and depression. The non-medical use of ketamine is increasing. While it has been an established and popular drug in East Asia for many years, consumption has recently increased in other regions. Global seizures of ketamine have reached record levels with significant increases in East and South-East Asia as well as North America, the Near and Middle East/South-West Asia, Western and Central Europe, Southern Africa and the Caribbean illustrating the geographical diversification of illegal drug markets [9]. In England, over the last 5 years of available data, the estimated prevalence of population use has stayed stable (16–59 year old ~1%, 16–24 year olds ~3%) [10]. Treatment presentations however have tripled over the same period (1140 in 2019 to 3609 in 2023) [11].

Non-medical use of ketamine has increased at a time when the associated harms are becoming clearer. The risk of the acute harms of ketamine toxicity are lower than many other illegal drugs because of the relative preservation of respiratory and swallowing reflexes even in individuals with significant sedation. Most acute ketamine-related harms result from accidents such as falling or drowning because of poor co-ordination, depersonalisation, sedation or assault while in a vulnerable and intoxicated state [12, 13]. Reported harms from persistent non-medical use of ketamine, particularly at higher doses, include psychological dependence with features such as tolerance and non-specific withdrawals including anxiety, tremor, palpitations, sweating and severe drug craving [14]. Cognitive impairment, especially short-term memory problems [14] and hepatotoxicity related to biliary obstruction and choledochal cysts have also been described [15]. Perhaps the most concerning long-term harm relates to ketamine-related urinary tract damage. While the exact mechanisms remain unclear, it is thought to be related to the direct toxic effects of ketamine metabolites excreted in the urine with resultant microvascular damage in the bladder, ischaemia and fibrosis. Symptoms include frequency, urgency, bladder pain, dysuria, incontinence and haematuria [16]. Severity is linked to dose and frequency of use. In advanced cases the ureters may stricture down and the bladder can become fibrotic, leading to urinary tract obstruction, renal failure and the need for surgical intervention. In response, guidelines have been developed in some countries for urological management [17].

The medicinal and non-medicinal use of ketamine raises questions that require urgent responses. As an emerging medicine, where does ketamine fit therapeutically? Better understanding is needed of which health conditions respond to ketamine treatment, the most effective prescribing regimens for these conditions, the likelihood and severity of adverse effects, and the profiles of patients most likely to benefit from treatment. Exciting research is underway to answer these questions, but in some countries the demand for novel treatments, coupled with a desire to meet this demand, has led to ketamine prescribing moving ahead of the scientific and clinical consensus. Clinics promising effective ketamine treatment for indications where weak or no evidence exist raises concern about unintended harms to patients, unethical profiteering and the need for stronger regulatory oversight.

Non-medicinal ketamine use necessitates a different response. Frontline drug treatment staff, who largely work in services focused on other drugs, need to improve their skills in the assessment and treatment of problematic use of ketamine. Standard bio-psycho-social approaches including motivational enhancement and relapse prevention interventions remain the cornerstone of drug treatment approaches, and there is no suggestion that these will not be effective in treating people who use ketamine, but more research is needed to examine this. The urological harms related to persistent ketamine use necessitate that treatment services develop appropriate screening, referral pathways and joint working protocols with urology services. Co-produced harm reduction information for people consuming ketamine need to be developed, particularly targeting higher risk groups including young people, people using the night-time economy and those using ketamine for sexual enhancement. Treatment services, particularly those focusing on opioids, may be less familiar with these groups, less culturally competent and poorer at treatment engagement. Finally, in light of recent reported increases in the prevalence of ketamine use, national and global surveillance systems, including toxicology, seizures by enforcement agencies and health data, must better capture changes in patterns of ketamine supply, use and harm.

As with other medicines with potential for harmful use, a sophisticated approach is needed, which facilitates innovative research and drug development within regulatory frameworks that keep patients safe. At the same time, emerging non-medical use also requires multiple responses including improved treatment engagement, developing ketamine-specific treatment protocols, effective harm reduction interventions and accurate monitoring including international data sharing on emerging non-medicinal use and harm.

Owen Bowden-Jones: Writing—original draft (equal); writing—review and editing (equal). Arun Sahai: Writing—original draft (equal); writing—review and editing (equal). Paul Dargan: Writing—original draft (equal); writing—review and editing (equal).

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