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Ketamine plus Alcohol: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by NATALIA HARUMI CORREA KOBAYASHI.

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.

  • ketamine
  • alcohol
  • drug abuse
  • addiction
  • toxicological effects

1. Introduction

Drug abuse is an ancient human practice, which involves genetic and environmental factors, as well as a great complexity of neuronal circuitry [1]. Currently, the use of psychoactive substances has become a worldwide concern and public health issue, due to health risks and social problems [2,3][2][3]. In general, such involvement in drug misuse occurs early in life. On a global scale, it is estimated that 1 among 20 individuals, ranging from 15 to 64 years old, have already consumed any recreational substance to achieve altered states of consciousness [4,5][4][5].
Of note, ethanol consists of the most widely consumed psychoactive substance [6]. According to the World Health Organization (2014), the harmful use of ethanol is responsible for about 5.9% of deaths in the world, as a consequence of traffic accidents, social interaction problems, domestic violence, crimes, public disorder, and chronic health problems [7,8,9][7][8][9]. Moreover, the consumption of alcohol is a factor that can lead to the consumption of additional psychoactive drugs, such as methylenedioxymethamphetamine (MDMA), methamphetamine, lysergic acid diethylamide (LSD), gamma-hydroxybutyrate (GHB), and especially ketamine, which has been in evidence among drug abusers [10].
Ketamine has been used for non-therapeutic purposes, especially as a “club drug”, being referred to as “Key”, “Special K”, “angel dust”, “K”, or “Kit Kat” [11]. Ketamine is commonly misused by intranasal route, inhaled, or smoked [12]. When administered in liquid form, users inject it into the body or mix it in alcoholic drinks for oral route [13].
It is noteworthy that both psychoactive drugs share several mechanisms of action on the central nervous system (CNS). Primarily, ethanol evokes non-competitive inhibition of N-methyl-D-aspartate (NMDA) receptors [14,15,16][14][15][16]. Ketamine also acts through an NMDA open-channel blockade mechanism [17,18][17][18]. Although both drugs act equally on the same receptor, it is unclear whether ketamine can modify the molecular effects of alcohol on NMDA receptor [14,19][14][19]. Thus, we ask whether co-exposure to these substances could imply a synergistic toxicological effect mediated by the NMDA pathway, intensifying toxicological responses.
Several and robust preclinical and clinical studies have described the hazardous effects elicited by alcohol consumption, even after long-lasting withdrawal [20,21,22,23][20][21][22][23]. On the other side, ketamine non-medical purpose use has been described in only a few studies in the last decades [12,24,25,26][12][24][25][26]. Unfortunately, studies that have researched the consequences of ethanol plus ketamine concomitant exposure in body systems are scarce. 

2. Epidemiological Features of Ethanol plus Ketamine Consumption

According to the 2018 Global Report on Alcohol and Health published by the World Health Organization (WHO), young adults, ranging from 20 to 39 years old, are the main consumers of alcohol [7]. In 2010, a survey reported that male alcohol intake was higher than that of females, with a consumption of around 19.4 L/year. In contrast, women consume about 7 L/year [27], but such a pattern of global alcohol consumption has been modified, since women have augmented alcohol drinking over the years in amounts that are increasingly closer to men [28]. Of particular interest is the co-ingestion of alcohol with other drugs by abusers [2,10,13][2][10][13]. Ketamine consists of a dissociative anesthetic applied to sedation and analgesia procedures and some psychiatry conditions [29,30,31][29][30][31]. Although there are few epidemiological data on the non-medical use of ketamine, it has been reported that ketamine misuse started in the 1970s [32]. It is used primarily in the United States, but nowadays the recreational use has spread worldwide [33]. Thus, ketamine is included as a new psychoactive substance (NPS) in drug-abuse criteria [11,31,34][11][31][34]. Currently, the Asian continent is emerging as a major geographic region that consumes this substance; ketamine is ranked as the first choice for misused drug among young abusers in Hong Kong. In Western countries, ketamine misuse is around 1–2% [35]. However, the recreational use of this drug has also increased in United Kingdom, Australia, and China [13]. In a French survey between 2012 and 2017, ketamine misuse was prevalent in 67% of NPSs detected [34]. From this information, wit can be suggested that ketamine recreational use is not restricted to some countries; on the contrary, such psychoactive substance is overspread worldwide. The concomitant use of ethanol plus ketamine has been described. In an emergency department of Bologna (Italy), alcohol was present with 25% of ketamine recreational misusers admitted to emergency care [36]. In accordance, the abuser’s co-ingestion percentage was around 39–98% in the preceding 12 months [37,38][37][38]. Unfortunately, both studies failed to link the negative symptoms to the possible synergism of toxicological effects of both drugs users were exposed to. However, a more prevalent association was found in controlled studies with volunteers recruited at party scenes, of which at least 65% of ketamine users also consume alcohol [24,39,40][24][39][40]. A wide survey reported that alcohol is present at a percentual of 98% of ketamine abusers, in a co-administration pattern or not [38]. Actually, all of these findings suggest the close relationship between ketamine and alcohol consumption.

Fatal Outcomes

A positive relationship between recreational drugs plus alcohol and fatal or non-fatal overdose has been postulated [41,42,43][41][42][43]. In a wide Australian survey (2000–2019), ketamine self-administration as contributory to death was investigated [44]. In Darke and colleagues’ study [44], ethanol was present in a over a quarter (27.3%) of ketamine-related deaths. Previously, in the United Kingdom (1993–2006), alcohol was present in almost 50% of postmortem analyses from ketamine-related deaths [45]. Such few reports highlight the occurrence of polydrug use among addicts, in which alcohol consumption is prevalent. Of note, the limitation of the studies that clearly establish the contribution of each drug to a fatal outcome is obvious, since ketamine and alcohol are commonly associated with the use of other psychoactive drugs [44].

3. Potential Pharmacological Interactions between Ketamine and Ethanol Use

The context of interaction between ethanol and ketamine is considerably complex. In fact, ethanol is the most consumed psychoactive drug worldwide, and it is culturally and legally accepted in most countries, with it mainly being linked to recreational contexts [96][46]. The broad variation in patterns of dose, frequency, and intermittence of consumption increases the complexity of analysis, since such patterns (i.e., acute effects vs. chronic consumption) induce opposite outcomes [6,7,8,9][6][7][8][9]. Ketamine, on the other hand, presents its use primarily linked to a medical context, as a sedative analgesic and general anesthetic, and more recently being proposed for affective disorders treatment [189,190][47][48]. However, ketamine has become popular as a recreational drug, used acutely or in a binge pattern; orally, inhaled, or injected; and alone or associated with alcoholic beverages or stimulants [191][49]. Each of these paradigms must be examined to identify potential synergistic points and risks related to this combination [11,12,13][11][12][13]. Pharmacokinetically, interactions between ethanol plus ketamine consumption are reasonable through competition for the CYP3A4 metabolic enzyme [192,193][50][51]. Although such an enzyme is not the primary route for alcohol metabolism, the consumption of a large amount of ethanol, as occurs in binge drinking pattern, elicits a metabolic enzymes saturation phenomenon, which may reduce ketamine metabolism, increasing ketamine bioavailability. On the other hand, ethanol chronic consumption induces CYP3A4 expression, increasing ketamine biotransformation and consequently reducing bioavailability. Therefore, investigations are necessary to elucidate the consequences of these interactions and their clinical relevance. As highlighted in thies reviewe contents, systemic toxicity of both drugs is another point that deserves attention. Interestingly, both ethanol and ketamine present coincidental or synergistic deleterious effects on cardiorespiratory, hepatic, and urinary tracts [46,51,55,56,57,58,60,62,64,67,71,82,83][52][53][54][55][56][57][58][59][60][61][62][63][64]. Some of these damages are linked to concurrent pharmacological mechanisms on glutamatergic, noradrenergic, and cholinergic pathways’ modulation, resulting in biliary motility impairment, tachycardia, respiratory disability, and intraglomerular pressure. The ability to modulate ion channels, mitochondrial function, and oxidative metabolism interference is also common to both drugs, frequently triggering cell dysfunctions [194][65]. Ionic dysregulation is correlated with pulmonary edema, cardiac arrhythmias, and urinary dysfunction [195][66]. Mitochondrial dysfunction is associated with pro-oxidant effects that are related to inflammation, cell injury, apoptosis, and fibrosis in different systems [196,197][67][68]. Such harmful mechanisms shared by ethanol and ketamine use highlight the potential risk of this association that requires further investigation. In CNS, the harmful potential effects of both of these drugs are mainly related to the concomitant ability to modulate glutamatergic and GABAergic pathways [198][69]. Different manifestations and symptoms may emerge, depending on the pattern of use (under effect of the drugs) or abstinence symptoms’ consequences. Considering that binge consumption consists of the main pattern among misusers, both ketamine and ethanol display a reduction of glutamatergic activity on NMDA receptors [198][69]. Additionally, ethanol potentiates GABAa receptors’ activity. Therefore, interference in formation of LTP processes, as well as reduced production of BDNF and Bcl-2, has been observed, impairing neuroplasticity and memory consolidation [199][70]. Accessory mechanisms such as the modulation of dopaminergic, serotonergic, cholinergic, and pathways, among other things, also may be shared by the drugs per se [19,65,96,108,158,159,160,181][19][46][71][72][73][74][75][76]. Considering that the isolated use of these substances, according to dose, induces distinct levels of cognition and perception disturbance, also identifying molecular synergistic potential, theoretically, the co-use may aggravate outcomes; this deserves further studies to be properly proved. In an abstinence context, ketamine and ethanol also share deleterious mechanisms, involving overspread glutamatergic excitotoxicity, resulting in oxidative stress, mitochondrial dysfunction, neuroinflammation, and cell death induction [200,201][77][78]. These hazardous processes have been associated with genesis and poor outcomes of several CNS diseases, such as depression and anxiety [108,146,147,148,150][72][79][80][81][82]. Once again, the severity of manifestations might be influenced by dose, frequency, and intermittence of use, but the correlation between isolated use of ketamine or ethanol vs. anxiogenic or depressive-like behavior manifestation has already been demonstrated [25,202][25][83]. Based on all convergent targets divided by ethanol and ketamine use, which we have highlighted above in the present review, the probable risk of potentiation of CNS disorders in co-use circumstances is imminent and deserves further research.

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