Ketamine

"Ketamine is closely related to the internationally controlled drug phencyclidine (also known as PCP or ‘angel dust’) which is listed in Schedule II of the 1971 Convention (see section 2.7.2).

"Phencyclidine was investigated as an intravenous anaesthetic in the 1950s but was later withdrawn due to undesired hallucinogenic and delirium effects.³⁴ Following the withdrawal of phencyclidine, ketamine was synthesized as an anaesthetic in 1962, patented in 1963 in Belgium and three years later in the United States. In the early 1970s, ketamine was marketed as a medical alternative to phencyclidine.

"The use of ketamine as a new psychoactive substance dates back to the 1980s and 1990s. At the international level, ketamine was subject to a series of risk assessments. The Expert Committee on Drug Dependence of the WHO pre-reviewed ketamine in 2003 and conducted a critical review in 2006. After reviewing the information contained before it, the Committee concluded that 'this information was not sufficient to warrant scheduling'.³⁵ It also requested an updated version of the critical review to be presented at the next meeting of the Committee which was held in 2012. At that meeting, the Committee decided that 'bringing ketamine under international control is not appropriate.'³⁶ At the level of European Union, in 2000, growing concern over the use of ketamine as a NPS prompted a risk assessment in the framework of the joint action on new synthetic drugs.³⁷ The European Commission concluded that it was not appropriate to introduce control measures and recommended further monitoring of the use of ketamine."

"The non-negligible non-medical use of ketamine started to emerge in the United States of America in the 1980s, in connection with the rave dance scene, and in Western Europe in the 1990s. Hard data from that period are available only for North America and Western Europe, although the non-medical use of ketamine at alternative dance parties on beaches in Goa, India, in that early period has also been reported.¹¹¹ 

"Surveys conducted in Western Europe in the early 1990s suggest that ketamine was used in relatively high doses,^{112, 113} often in private settings,¹¹⁴ by recreational users wanting to experience the psychedelic effects of the drug rather than its stimulant effects as a dance drug.¹¹⁵ Towards the end of the 1990s, ketamine may have acquired a bad reputation on the European dance scene as a result of it being sold as “ecstasy”, leading to it being used inadvertently¹¹⁶ and having effects that were potentially markedly different from users’ expectations. 

"In the early 2000s, while the use of ketamine was lower than the use of internationally controlled drugs in Europe and was decreasing among young people in the United States,¹¹⁷ a surge in ketamine use was occurring in East and South-East Asia. Also in connection with the dance scene,¹¹⁸ the non-medical use of the substance in Asia was initially documented in China in 1997.¹¹⁹ From the early 2000s, such use was also documented in Hong Kong, China, Taiwan Province of China,¹²⁰ Macao, China, and Malaysia.¹²¹ 

"Indicators of ketamine availability rose sharply in that period and the popularity of ketamine in Hong Kong, China, increased so steeply that within three years of the introduction of the substance on the illicit market, it became the first drug of choice among people under 21 years of age.^{122, 123, 124} In Taiwan Province of China, the popularity of ketamine soared in the early 2000s;¹²⁵ in a series of surveys among middle- and high-school students in the early 2000s, ketamine was one of the most commonly used drugs, along with “ecstasy”.^{126, 127} By 2014, 222,000 people, or more than 15 per cent of all registered drug users in China, were officially registered by the police as users of ketamine.¹²⁸ The non-medical use of ketamine was placing a health burden on Chinese society, as described in a study on ketamine cystitis published in 2015.¹²⁹"

"Ketamine and phencyclidine have similar modes of action, affecting a range of central neurotransmitters. Ketamine is frequently sold as ‘ecstasy’ in illicit ATS [Amphetamine-Type Stimulants] markets. Street names for ketamine include ‘K’, ‘special K’, ‘kit kat’, ‘tac’, ‘tic’, ‘cat valium’, ‘cat tranquilizer’, ‘vitamin K’, ‘ket’, ‘super K’.³⁸
"Pharmaceutical preparations of ketamine are usually found in liquid form, but powder and capsules are also available. The powder prepared by evaporation of the original solution is often nasally insufflated (‘bumping’), smoked or swallowed."

"Prevalence of past-12 month use of ketamine (another “club drug”) among 12th grade students has been below 2% for the past decade and in 2022 stood at 1.2%. This “club drug” was added to the survey in 2000. It showed little change in its usage levels through 2002. Since then use has declined in all grades. Because of the very low levels of use of this drug by 2011, questions about its use were dropped from the questionnaires administered to 8th and 10th graders."

"The quantity of ketamine seized and reported to the EU Early Warning System on new psychoactive substances has varied over time, but has remained at relatively high levels in recent years, suggesting that this drug is likely to be consistently available in some national drug markets and may have become an established drug of choice in some settings. Ketamine is commonly snorted, but can also be injected, and has been linked to various dose-dependent acute and chronic harms, including neurological and cardiovascular toxicity, mental health problems, such as depression, and urological complications, such as bladder damage from intensive use or the presence of adulterants. Ketamine may also be added to other drug mixtures, including MDMA powders and tablets, although 2021 data from drug checking services show that these are generally less adulterated than other illicit drugs. It can also be found in mixtures sold as ‘pink cocaine’ or ‘tucibi’, which are more likely to contain ketamine and other synthetic drugs, such as amphetamines or MDMA, but less likely to contain the synthetic drug 2C-B. As noted elsewhere in the 2023 European Drug Report, people using mixtures of drugs may be unaware of the substances they are consuming, and drug interaction effects can expose them to elevated health risks. While the numbers of clients entering treatment for problems related to ketamine use remain low overall, some EU Member States have seen increases and there is a strong case for improving the monitoring of both the use of this drug and the extent to which it is associated with negative health outcomes."

"The use of hallucinogens was similar for college and noncollege young adults in 2022, for use in the past 12 months (5.0 vs. 8.5%), LSD (1.4% vs. 2.9%), hallucinogens other than LSD (4.6% vs. 7.2% ), MDMA (ecstasy, Molly) (1.7% vs. 2.0%), and ketamine (0.4% vs. 0.9%; Table/Figure 77)."

"Ecstasy

"The trend in the proportion of 16 to 59 year olds using ecstasy in the last year has been relatively flat throughout the lifetime of the survey, fluctuating between one and two per cent (Figure 1.6). The proportion of last year ecstasy users aged 16 to 59 in the 2018/19 survey (1.6%) was similar to the 2017/18 CSEW (1.7%).

"Among 16 to 24 year olds, the trend shows greater fluctuation between years. Following a generally downward trend from the start of the times series, there was an increase in last year use among this age group between the 2011/12 (3.3%) and 2018/19 (4.7%) surveys. Whilst estimated levels of use have fluctuated between 4.3 and 5.4 per cent in recent years, prevalence of ecstasy use among 16-24 year olds remain below its peak of 6.8 per cent estimated from the 2001/02 survey.

"Other drugs

"The information below presents findings on some of the less commonly used drugs. These can be found in Appendix Table 1.02. Due to the lower number of people using these drugs, even small changes in prevalence can be statistically significant. Changes from one year to the next should be interpreted with caution and greater attention paid to the medium and longer-term trends in these drugs.

"• Use of amphetamines decreased among both 16 to 59 and 16 to 24 year olds. For those aged 16 to 59, prevalence of amphetamine use has followed a general downward trend since a high of 3.3 per cent in 1996 to 0.6 per cent in 2018/19. Use of amphetamines followed a similar trend for those aged 16 to 24, falling from a high of 11.7 per cent in 1996 to 1.0 per cent in 2018/19.

"• Ketamine use has increased from a decade ago across both age groups. For adults aged 16 to 59, use of ketamine has fluctuated in the last decade, with the latest estimate at 0.8 per cent, an increase compared with 2008/09 (0.5%). Use among adults aged 16 to 24 also showed a lot of variation in the last decade, although there was a general increase from 1.9 per cent in 2008/09 to 2.9 per cent in 2018/19, with a particularly large rise between 2016/17 and 2017/18 (1.3% to 3.1% respectively).

"• Nitrous oxide continued to be the second most used drug among 16 to 24 year olds, with 8.7% having used it, a similar proportion (8.8%) to last year’s survey. This equates to around 552,000 young adults who used nitrous oxide in the last year. Use of new psychoactive substances among 16 to 24 year olds in the 2018/19 survey was also at a similar proportion to last year’s survey (1.4% and 1.2% respectively)."

"In 2022, generally very low levels of ketamine residues in municipal wastewater were reported by 15 cities, with the highest mass loads being detected in cities in Denmark, Spain, Italy and Portugal (see the figure Ketamine residues in wastewater in selected European cities, 2022, below)."

"There is increasing interest in the use of ketamine as an adjunct to treatment of AUD and management of AWS. There were three studies that showed the benefit of using ketamine as an adjunctive treatment to conventional first-line therapies in patients with severe AWS. Ketamine was added to the medication regimen when AWS was refractory to BZD or after clinical signs of delirium tremens (DT). IV ketamine was administered in variable doses ranging from 0.15 to 0.75 mg/kg/h. Ketamine therapy led to a decrease in BZD dose requirements, early resolution of AWS and DT, and decreased duration of ICU stay and intubation time. No AWS complications such as seizures, hallucinations, or delirium tremens were reported after initiation of ketamine (13). The administration of ketamine in AWS was generally safe without any serious adverse effects except oversedation noted in two participants among all the three studies (13, 14). Oversedation was managed by ketamine dose reduction and there was no reported use of any additional treatment modalities. This adverse effect could be explained by either due to the primary known effect of ketamine or due to sedation potentiation by BZD’s administration.

"Despite encouraging results after ketamine initiation in AWS, one of several potential confounders was the use of other medications such as phenobarbital and propofol. In all studies, ketamine was initiated late in AWS management depending on the BZD refractory status of AWS or development of DT. It is possible that the efficacy of ketamine may be greater if it were used as a first line or adjunct to BZD before large doses of BZD or other GABA agonists are used. These limitations make it difficult to determine the true efficacy and situation in which ketamine may be used in AWS.

"We also found seven studies that assessed the efficacy and safety of ketamine for AUD. While the study design, rigor, and target population varied across studies, all studies that examined alcohol outcomes showed greater alcohol abstinence rates in both short-term (21 days) and long-term (1 year) intervals compared to control conditions (43, 44, 46). Ketamine was administered in subanesthetic doses in variable frequency and routes. The highest dose administered was a single dose ketamine 2.5 mg/kg IM (43). Subsequent studies used lower doses – single ketamine 0.35 mg/kg IV infusion, ketamine 0.5 mg/kg IV once weekly for 4 weeks, single ketamine 0.71 mg/kg, three weekly ketamine 0.8 mg/kg IV infusions. Severe adverse effects like euphoria, tachycardia, hypertension, and low mood were reported in 6.3% (3/96) of participants in the Grabski et al. study and affected their normal activities of daily living. Two out of the three participants with severe adverse effects withdrew from the study due to medication intolerability. In addition to ketamine, most studies included adjunctive psychotherapy which may have contributed to outcomes, raising important questions about the frequency, timing, and type of psychotherapy that might help to optimally improve AUD-related outcomes.

"While ketamine did show an improvement in abstinence rates, the longevity of this effect was variable as there was return to alcohol consumption. However, all studies showed ketamine administration produced longer periods of abstinence and reduction in alcohol consumption and cravings, which suggests that ketamine impacts drinking outcomes beyond the direct pharmacologic effects. Furthermore, due to its anti-depressant properties, ketamine may be useful for managing depression that may arise during the abstinence periods."

• "Among young adults (aged 15 to 34), recent national surveys show last year prevalence estimates for both LSD and hallucinogenic mushrooms equal to or less than 1 %. Exceptions for hallucinogenic mushrooms include Czechia (2.7 % in 2021), Finland (2.0 % in 2018), the Netherlands (1.9 % in 2021), Estonia (1.6 % in 2018, 16–34), Denmark (1.5 % in 2021), Spain (1.1 % in 2022) and Germany (1.1 % in 2021). Exceptions for LSD include Ireland (2.4 % in 2019), Finland (2.0 % in 2018), Estonia (1.7 % in 2018, 16–34), Latvia (1.4 % in 2020), Norway (1.3 % in 2021) and the Netherlands (1.2 % in 2021).
• "Among respondents to the European Web Survey on Drugs, 20 % of those who had used drugs within the last 12 months had used LSD, while 13 % had used ketamine.
• "Recent estimates of last year prevalence of ketamine use among young adults (15–34) range from 0.4 % in Denmark (2021, 16–34) to 0.8 % in Romania (2019). The Netherlands reported that ketamine use has increased among young people in nightlife settings.
• "In 2022, generally very low levels of ketamine residues in municipal wastewater were reported by 15 cities, with the highest mass loads being detected in cities in Denmark, Spain, Italy and Portugal (see the figure Ketamine residues in wastewater in selected European cities, 2022, below)."

"The potential use of ketamine for AUD was first suggested in 1972 (32, 33). Possible hypotheses for ketamine use in AUD include balancing cortical glutamate homeostasis and enhancing neuroplasticity which may facilitate learning and acquiring new skills, especially those that help individuals cope with drinking (29, 34). Acute alcohol exposure stimulates the GABA receptors and inhibits the NMDA-glutamate receptors. Chronic alcohol use decreases the concentration of GABA receptors and upregulates NMDA-glutamate receptors. This new balance of inhibitory and excitatory neurotransmitters requires continued regulation with alcohol. Abrupt cessation of alcohol use causes enhanced signaling of the glutamatergic system manifesting as fear, anxiety, and restlessness resulting in a syndrome of alcohol withdrawal. Additionally, the dysregulation of glutaminergic tone results in individuals experiencing alcohol craving. Ketamine mimics some of the mechanisms of action of alcohol through antagonism of the NMDA receptor which may reduce alcohol cravings. Ketamine additionally upregulates the mu and kappa-opioid receptor. The downstream effects are to enhance dopamine secretion which has been described as a mechanism to address depression. For individuals who have AUD, depression is a common comorbidity and may explain some of the potential effects of ketamine on alcohol use (35, 36). Like any substance use, alcohol use can change the neuronal plasticity and lead to formation of maladaptive memories that contribute to increased drug craving and seeking behavior. This neuronal plasticity is partly modulated by the NMDA-glutamate receptor (glutamatergic system) which can be potentially reversed by the inhibitory action on this receptor by ketamine (37, 38). Ketamine can also serve as a potential adjunct in the management of AWS. Ketamine may serve as an adjunct to benzodiazepines in AWS because it acts as an NMDA antagonist and may help to balance cortical glutamate homeostasis faster with decreased sedation time than with benzodiazepines alone (39)."