Ketamine Misuse Research Articles

Adolescent administration of ketamine impairs excitatory synapse formation onto parvalbumin-positive GABAergic interneurons in mouse prefrontal cortex

Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, induces deficits in cognition and information processing following chronic abuse. Adolescent ketamine misuse represents a significant global public health issue; however, the neurodevelopmental mechanisms underlying this phenomenon remain largely elusive. This study investigated the long-term effects of sub-chronic ketamine (Ket) administration on the medial prefrontal cortex (mPFC) and associated behaviors. In this study, Ket administration during early adolescence displayed a reduced density of excitatory synapses on parvalbumin (PV) neurons persisting into adulthood. However, the synaptic development of excitatory pyramidal neurons was not affected by ketamine administration. Furthermore, the adult Ket group exhibited hyperexcitability and impaired socialization and working memory compared to the saline (Sal) administration group. These results strongly suggest that sub-chronic ketamine administration during adolescence results in functional deficits that persist into adulthood. Bioinformatic analysis indicated that the gene co-expression module1 (M1) decreased expression after ketamine exposure, which is crucial for synapse development in inhibitory neurons during adolescence. Collectively, these findings demonstrate that sub-chronic ketamine administration irreversibly impairs synaptic development, offering insights into potential new therapeutic strategies.

The impact of scheduling ketamine as an internationally controlled substance on anaesthesia care in Sub-Saharan Africa: a case study and key informant interviews

BackgroundAccess to anaesthesia and surgical care is a major problem for people living in Sub-Saharan Africa. In this region, ketamine is critical for the provision of anaesthesia care. However, efforts to control ketamine internationally as a controlled substance may significantly impact its accessibility. This research therefore aims to estimate the importance of ketamine for anaesthesia and surgical care in Sub-Saharan Africa and assess the potential impact on access to ketamine if it were to be scheduled.MethodsThis research is a mixed-methods study, comprising of a cross-sectional survey at the hospital level in Rwanda, and key informant interviews with experts on anaesthesia care in Sub-Saharan Africa. Data on availability of four anaesthetic agents were collected from hospitals (n = 54) in Rwanda. Semi-structured interviews with 10 key informants were conducted, collecting information on the importance of ketamine, the potential impact of scheduling ketamine internationally, and opinions on misuse of ketamine. Interviews were transcribed verbatim and analysed using a thematic analysis approach.ResultsThe survey conducted in Rwanda found that availability of ketamine and propofol was comparable at around 80%, while thiopental and inhalational agents were available at only about half of the hospitals. Significant barriers impeding access to anaesthesia care were identified, including a general lack of attention given to the specialty by governments, a shortage of anaesthesiologists and migration of trained anaesthesiologists, and a scarcity of medicines and equipment. Ketamine was described as critical for the provision of anaesthesia care as a consequence of these barriers. Misuse of ketamine was not believed to be an issue by the informants.ConclusionKetamine is critical for the provision of anaesthesia care in Sub-Saharan Africa, and its scheduling would have a significantly negative impact on its availability for anaesthesia care.

Drug dependence and prescribing ketamine for treatment-resistant depression in Australia and New Zealand.

Ketamine is a restricted and regulated medication in Australia and New Zealand, which has implications when considering treatment for patients with treatment-resistant depression and a history of illicit drug use, abuse or dependence. Regulations governing prescription of ketamine for treatment-resistant depression vary between jurisdictions in Australia and New Zealand, though most restrict use in those with drug dependence. There is substantial variation in definitions of drug dependence used in each jurisdiction, and between the legal and clinical definitions, with the latter specified in the current International Classification of Diseases, Eleventh Revision and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This paper reviews the literature assessing the risk of ketamine misuse and dependence in patients with a history of illicit drug use, abuse or dependence and presents recommendations for psychiatrists who prescribe ketamine in such patients with treatment-resistant depression.

Ketamine abuse Another side of the miracle drug

Ketamine is a " dissociative anaesthetic " with fast analgesic and amnesic properties that has been used since more than 40 years. Today, ketamine abuse has become a public health concern. We report the case of a 23-year-old patient who came to the Casablanca Addictology Centre asking for help with ketamine abuse. At the interview the patient presented depressive symptoms and had already made 3 suicide attempts, the last one dating from two months ago. Mr J. started his consumption of psychoactive substances during adolescence (age 14) by experimentation, the first substance was tobacco followed by crack, alcohol and ketamine. The ketamine dependency started one year ago, with 2 grams of ketamine snorted per occasion (twice a week). The reported psychoactive effects of ketamine ranged from dissociation and depersonalisation to psychotic experiences. The patient has never made a withdrawal attempt. Given the increasing therapeutic importance of ketamine, our aim was to highlight the other side of the problem, the significant risk of ketamine abuse. Thus, in this article we tried to review the history of ketamine, its growing role as a "dance drug", as well as the specifics of the management of ketamine misuse. In conclusion, the clinicians must stay vigilant, however this should not be a deterrent to appropriate prescribing.

Ketamine misuse: an update for primary care.

Ketamine misuse: an update for primary care.

Ketamine plus Alcohol: What We Know and What We Can Expect about This.

Drug abuse has become a public health concern. The misuse of ketamine, a psychedelic substance, has increased worldwide. In addition, the co-abuse with alcohol is frequently identified among misusers. Considering that ketamine and alcohol share several pharmacological targets, we hypothesize that the consumption of both psychoactive substances may synergically intensify the toxicological consequences, both under the effect of drugs available in body systems and during withdrawal. The aim of this review is to examine the toxicological mechanisms related to ketamine plus ethanol co-abuse, as well the consequences on cardiorespiratory, digestive, urinary, and central nervous systems. Furthermore, we provide a comprehensive discussion about the probable sites of shared molecular mechanisms that may elicit additional hazardous effects. Finally, we highlight the gaps of knowledge in this area, which deserves further research.

Non-parenteral Ketamine for Depression: A Practical Discussion on Addiction Potential and Recommendations for Judicious Prescribing.

Intravenous (IV) ketamine is increasingly used off-label at subanesthetic doses for its rapid antidepressant effect, and intranasal (IN) esketamine has been recently approved in several countries for treating depression. The clinical utility of these treatments is limited by a paucity of publicly funded IV ketamine and IN esketamine programs and cost barriers to private treatment programs, as well as the drug cost for IN esketamine itself, which makes generic ketamine alternatives an attractive option. Though evidence is limited, use of non-parenteral racemic ketamine formulations (oral, sublingual, and IN) may offer more realistic access in less rigidly supervised settings, both for acute and maintenance treatment in select cases. However, the psychiatric literature has repeatedly cautioned on the addictive potential of ketamine and raised caution for both less supervised and longer-term use of ketamine. To date, these concerns have not been discussed in view of available evidence, nor have they been discussed within a broader clinical context. This paper examines the available relevant literature and suggests that ketamine misuse risks appear not dissimilar to those of other well-established and commonly prescribed agents with abuse potential, such as stimulants or benzodiazepines. As such, ketamine prescribing should be considered in a similar risk/benefit context to balance patient access and need for treatment with concern for potential substance misuse. Our consortium of mood disorder specialists with significant ketamine prescribing experience considers prescribing of non-parenteral ketamine a reasonable clinical treatment option in select cases of treatment-resistant depression. This paper outlines where this may be appropriate and makes practical recommendations for clinicians in judicious prescribing of non-parenteral ketamine.

Increasing Prevalence of Ketamine in Drivers in New York City Including the Identification of 2-Fluoro-Deschloroketamine.

Ketamine is a dissociative anesthetic used in veterinary and human medicine since the 1970s. Its clinical use has expanded to control of seizures, by pre-hospital emergency medical services (EMS), and is finding new purpose as an analgesic alternative and antidepressant. Ketamine brings hope for effective management of chronic pain in the absence of opioids and decreasing suicidal ideations; however, its persistence as a recreational drug for its hallucinogenic properties remains. In the wake of expanding medicinal purposes, the diversity of New York City's population was explored to better understand its misuse. This retrospective study looks at the prevalence of ketamine in driver fatalities over a period of 18 years (2003-2020) and cases involving suspected driving under the influence of drugs (DUID) over a period of 6 years (2015-2020). Ketamine was identified in 6 driver fatalities and in 47 DUID cases. None of the driver fatalities were suspected of ketamine misuse, due to administration either in hospital or by EMS. In the DUID cases, an increasing trend was observed over the 6-year study period with 100% (n = 47) of the cases confirmed as non-hospital/non-EMS administered ketamine. Of the DUID cases, 94% were male with the majority between the age of 21 and 39 years (85%) and were predominantly Hispanic (36%) and Asian (34%). Blood concentrations of ketamine ranged from 27 to >2000 ng/mL with polydrug use prevalent. The most common drug classes detected in addition to ketamine were cannabinoids (38%), ethanol (32%), benzodiazepines (26%), cocaine (19%) and amphetamines/3,4-methylenedioxymethamphetamine (15%). In 2019, 2-fluoro-deschloroketamine was identified in two cases for the first time. Despite its increased acceptance for mental health disorders, ketamine's persistence and misuse as a recreational drug remains and should continue to be monitored by relevant toxicological, clinical and law enforcement communities along with emerging illicit ketamine analogs.

Effects of early ketamine exposure on cerebral gray matter volume and functional connectivity

Ketamine has been used for medical purposes, most typically as an anesthetic, and recent studies support its use in the treatment of depression. However, ketamine tends to be abused by adolescents and young adults. In the current study, we examined the effects of early ketamine exposure on brain structure and function. We employed MRI to assess the effects of ketamine abuse on cerebral gray matter volume (GMV) and functional connectivity (FC) in 34 users and 19 non-users, employing covariates. Ketamine users were categorized as adolescent-onset and adult-onset based on when they were first exposed to ketamine. Imaging data were processed by published routines in SPM and AFNI. The results revealed lower GMV in the left precuneus in ketamine users, with a larger decrease in the adolescent-onset group. The results from a seed-based correlation analysis show that both ketamine groups had higher functional connectivity between left precuneus (seed) and right precuneus than the control group. Compared to controls, ketamine users showed decreased GMV in the right insula, left inferior parietal lobule, left dorsolateral prefrontal cortex/superior frontal gyrus, and left medial orbitofrontal cortex. These preliminary results characterize the effects of ketamine misuse on brain structure and function and highlight the influence of earlier exposure to ketamine on the development of the brain. The precuneus, a structure of central importance to cerebral functional organization, may be particularly vulnerable to the influences of early ketamine exposure. How these structural and functional brain changes may relate to the cognitive and affective deficits remains to be determined with a large cohort of participants.

Striatal functional connectivity in chronic ketamine users: a pilot study

ABSTRACT Background: The striatum supports motivated behavior and impulse control. Altered striatal activation and connectivity has been observed in link with impulse control dysfunction in individuals with drug addiction. Objectives: We examined how resting state functional connectivity (rsFC) of the striatum is altered as a result of chronic ketamine misuse. Methods: Thirty-six ketamine users (10 women) and 20 healthy controls (9 women) completed an assessment with the Barratt Impulsiveness Scale (BIS-11) and magnetic resonance imaging. In SPM we examined voxel-wise connectivities of the caudate, pallidum, putamen, and ventral striatum in ketamine users (versus healthy controls) and in association with BIS-11 score and duration of use, all at a corrected threshold. Results: Compared to controls, ketamine users showed higher connectivity between caudate and dorsal anterior cingulate cortex and between pallidum and bilateral cerebellum. In ketamine users, putamen showed higher connectivity with the left orbitofrontal cortex (OFC) in association with both BIS-11 score and months of ketamine use. Mediation analyses suggest that the connectivity z score mediated the relationship between impulsivity and duration of use. Conclusions: These preliminary findings highlighted altered striatal connectivity in chronic ketamine users, and the potential role of putamen OFC connectivity in supporting the correlation between impulsivity and duration of ketamine use. If replicated in a larger sample, these findings may represent neural markers of ketamine misuse.

Ketamine abusers referring to emergency departments in northern Italy: a cross- sectional study.

Ketamine is an essential medicine used as an anesthetic in low and middle-income countries and in veterinary medicine. Recreational use is widespread throughout the world, especially owing to its lower price compared to other substances. In Western countries its use has been mainly linked to subpopulations of young people who use drugs recreationally. Ketamine misuse is associated with amnesia, dependence, dissociation, lower urinary tract dysfunction and poor impulse control. Regular ketamine use is associated with abdominal pains. The aims of this study are to analyze characteristics and main symptoms of ketamine abusers attending emergency departments (EDs) in the metropolitan area of Bologna, Emilia-Romagna Region, northern Italy. We identified 74 records of ketamine-related visits: 30% female; 22% non-natives; mean age 25.6 years. Forty-two percent reported ketamine use alone, 46% reported the use of other illegal substance (cocaine 19%, heroin 18%), 26% alcohol misuse. The most common reported symptoms were neurological (soporous state 18%, agitation 14%, confusion 7%, panic attacks 7%, mydriasis 7%, tremors 7%), gastro-intestinal (abdominal pain 15%, vomiting 11%), urological (6.8%) and cardiac (palpitations 5%, chest pain 5%). Complications secondary to falls and cuts (7%) were the most frequent trauma complications. We highlight a significant number of visits regarding suicide attempts (10%) and overdose (4%). The results highlight a particular population of problematic ketamine users identified using the hospital's ICT system. In particular, poly-drug users who consume ketamine in combination with heroin or cocaine presenting to the ED represent a specific target for targeted prevention projects on non-lethal overdoses and suicide attempts.

Risks Associated with Misuse of Ketamine as a Rapid-Acting Antidepressant.

Major depression is a serious psychiatric disorder and remains a leading cause of disability worldwide. Conventional antidepressants take at least several weeks to achieve a therapeutic response and this lag period has hindered their ability to attain beneficial effects in depressed individuals at high risk of suicide. The non-competitive N-methyl-D-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in both rodents and humans. The emergence of ketamine as a fast-acting antidepressant provides promising new insights into the development of a rapid treatment response in patients with clinical depression. However, its safety and toxicity remain a concern. In this review, we focus on the limitations of ketamine, including neurotoxicity, cognitive dysfunction, adverse events associated with mental status, psychotomimetic effects, cardiovascular events, and uropathic effects. Studies have shown that its safety and tolerability profiles are generally good at low doses and with short-term treatment in depressed patients. The adverse events associated with ketamine usually occur with very high doses that are administered for prolonged periods of time and can be relieved by cessation. The antidepressant actions of its two enantiomers, S-ketamine (esketamine) and R-ketamine, are also discussed. R-ketamine has greater antidepressant actions than S-ketamine, without ketamine-related side-effects. Future treatment strategies should consider using R-ketamine for the treatment of depressed patients to decrease the risk of adverse events associated with long-term ketamine use.

SY23-4 * BRAIN IMAGING STUDY ON KETAMINE ABUSERS

Ketamine had been used as an anesthetic for a long time. In recent years, unfortunately, ketamine has become an abusive drug in many parts of the world including Taiwan. However, there are only few neuroimaging studies on possible damages induced by ketamine in the brains. A recent study reported brain damages on chronic ketamine abusers by MRI study and showed atrophy over several regions. Also white matter changes were found in bilateral frontal and left temporo-parietal cortices. Another study was conducted on healthy subjects received ketamine challenge and revealed decreases brain functional connectivity of Default Mode Network. Despite some progress in identifying changes in behavior and brain function following heavy ketamine use; our current understanding of the effects of ketamine on the brain is poor. Specifically, we conduct a two-year study with 30 ketamine users being recruited. We will characterize behavioral performance, changes of brain structural and activities in ketamine users, as compared the healthy controls. The potential findings will extend the literature in addiction neuroscience and provide critical information facilitating research and treatment of ketamine misuse.

La kétamine dans le traitement du trouble dépressif aigu sévère

Depression is a frequent, severe and expensive illness. Approximately 20% of depressive episodes are resistant to classic antidepressants. Glutamatergic antagonists, in particular ketamine, established a new, rapid and robust therapeutic approach in resistant depression.The main results in the literature show a rapid and robust antidepressant effect of ketamine, with infra-anesthesic posology (0.5mg/kg) administered in intravenous way. Positive effects are observed on depressive symptoms, suicidal thoughts, and there is a potential synergic action when used in the induction of anesthesia for electroconvulsive therapy. However, effects only last shortly. Side effects are mostly reversible and of mild intensity, no severe consequences were reported.Limits are the lack of power of the included studies, due to small sample sizes, and the scarcity of studies. Misuse of ketamine is an important issue to be taken into account, and few data about ketamine addiction potential and its long-term effects are published at the moment.

Ketamine for chronic noncancer pain

Ketamine misuse and abuse is on the increase. This review focuses on recent studies on ketamine toxicity in recreational users and possible implications for the use of ketamine in chronic pain therapy. Urological toxicity, hepatotoxicity and cognitive deficits are all reported as adverse effects of the recreational use of ketamine. Urological toxicity and hepatotoxicity have been reported as adverse effects of ketamine in pain therapy. These findings may have implications for the clinical use of ketamine in chronic noncancer pain conditions. Until safety issues are resolved, it is suggested that chronic pain treatment involving higher doses and repeated exposure to ketamine be restricted to the context of randomized, controlled trials or clinical audits.

Performance characteristics of ELISAs for monitoring ketamine exposure

Background Growing misuse of ketamine necessitates the development of high throughput testing approaches. Two commercial enzyme-linked immunosorbent assays (ELISA) for ketamine have recently become available and were adapted for this development. Method The newly available ketamine ELISA reagents were examined to better understand their cross-reacting, calibration and other performance characteristics. ELISA apparent analyte concentrations were also correlated against ketamine concentrations as determined by GC-MS to examine the relationship between these 2 parameters. Result Both adapting ketamine as the targeted analyte, reagent from International Diagnostic Systems (IDS) also responded very significantly to the metabolites of ketamine (norketamine and dehydronorketamine), while the NEOGEN reagent responded very specifically to ketamine. Conclusion NEOGEN ELISA test data exhibit better correlation with the ketamine concentration as determined by GC-MS. It can be more reliably used as the preliminary test method in the 2-step approach now routinely adapted in workplace drug testing programs. Using 100 ng/ml ketamine as the GC-MS cutoff, the corresponding ELISA cutoff value is approximately 110–120 ng/ml. With significantly higher responses to ketamine metabolites, IDS reagent can detect specimens with much lower ketamine/metabolites concentrations and can better meet other testing requirements.

Misuse of Ketamine: Report of two Cases

Two patients were referred to our hospital from different private hospitals, within a period of 2-months, following complications arising from ketamine anaesthesia. Our assessment revealed obvious cases of misuse of ketamine hydrochloride as a sole anaesthetic. The cases are presented to highlight various forms of misuse of ketamine in the hands of non-anaesthetists. (Nig J Surg Res 2001; 3: 175 – 180) KEY WORDS: Ketamine, Misuse

Misuse of ketamine in Sweden

Misuse of ketamine in Sweden