Alcohol Interaction with Cocaine, Methamphetamine, Opioids, Nicotine, Cannabis, and Γ-Hydroxybutyric Acid

biomedicines

Review Alcohol Interaction with Cocaine, Methamphetamine, Opioids, Nicotine, Cannabis, and γ-Hydroxybutyric Acid

Ashok K. Singh

Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA; [email protected]; Tel.: +1-763-234-9655

Received: 9 January 2019; Accepted: 27 February 2019; Published: 7 March 2019

Abstract: Millions of people around the world drink alcoholic beverages to cope with the stress of modern lifestyle. Although moderate alcohol drinking may have some relaxing and euphoric effects, uncontrolled drinking exacerbates the problems associated with alcohol abuse that are exploding in quantity and intensity in the United States and around the world. Recently, mixing of alcohol with other drugs of abuse (such as opioids, cocaine, methamphetamine, nicotine, cannabis, and γ-hydroxybutyric acid) and medications has become an emerging trend, exacerbating the public health concerns. Mixing of alcohol with other drugs may additively or synergistically augment the seriousness of the adverse effects such as the withdrawal symptoms, cardiovascular disorders, liver damage, reproductive abnormalities, and behavioral abnormalities. Despite the seriousness of the situation, possible mechanisms underlying the interactions is not yet understood. This has been one of the key hindrances in developing effective treatments. Therefore, the aim of this article is to review the consequences of alcohol’s interaction with other drugs and decipher the underlying mechanisms.

Keywords: alcohol; addiction; withdrawal; cocaine; methamphetamine (METH); nicotine; marijuana; opioids; γ-aminobutyric acid (GABA)

1. Introduction Ethanol (referred as alcohol hereafter) and other illicit drugs-of-abuse (referred as drug(s) hereafter) such as cocaine, methamphetamine (METH), nicotine, opioids, cannabis, and γ-hydroxybutyric acid (GHBA) continue to be a major public health concern globally. In 2015, the estimated global prevalence among the adult population was 18.4% for daily heavy alcohol use, 15.2% for daily tobacco smoking, 3.8% for cannabis, 0.77% for amphetamine/methamphetamine (METH) use, 0.37% for opioid use, and 0.35% for cocaine use [1]. Europe had the highest prevalence of heavy episodic alcohol use and daily tobacco use. Approximately 6.6% (16 million) of Americans aged 12 or older reported heavy drinking, 22.7% (55 million) reported binge drinking, and 8.1% (19.7 million) reported using drugs within the month prior to the survey [2]. However, drug abusers have historically tended to use more than one drug, a condition known as poly-drug abuse (defined as the concurrent or sequential abuse of more than one drug or type of drug, with dependence upon at least one [3]). Over the past several years, there has been an increasing tendency to combine narcotics, alcohol, sedatives, and/or stimulants [4,5]. Higgins et al. [6] have suggested that a combination of alcohol and other drugs of abuse such as cocaine, nicotine, opioids, or cannabis is popular among drug users, perhaps because of more intense feelings of ‘high’ beyond that perceived with either drug alone or less intense feelings of alcohol’s aversive effects. Their survey of the cocaine-dependent patients showed that more than half of the subjects met criteria for current alcohol dependence, and in more than 50% of the occasions both drugs had been used simultaneously. In forensic studies of Budd et al. [7] and Marzuk et al. [8],

Biomedicines 2019, 7, 16; doi:10.3390/biomedicines7010016 www.mdpi.com/journal/biomedicines Biomedicines 2019, 7, 16x 22 of of 31 cocaine and ethanol were frequently identified in biological samples from fatally injured drivers. cocaine and ethanol were frequently identified in biological samples from fatally injured drivers. Dani and Harris [9] showed that almost 20 million cigarette-smoking Americans, either abuse or were Dani and Harris [9] showed that almost 20 million cigarette-smoking Americans, either abuse or addicted to alcohol. According to Patrick et al. [10], 94% of adults between the ages of 18 and 30 years were addicted to alcohol. According to Patrick et al. [10], 94% of adults between the ages of 18 and have used alcohol in their lifetimes, and 56% have also used marijuana. In general, alcohol is 30 years have used alcohol in their lifetimes, and 56% have also used marijuana. In general, alcohol is commonly co-abused with (i) psycho-stimulants such as METH, cocaine or nicotine, (ii) opioids such commonly co-abused with (i) psycho-stimulants such as METH, cocaine or nicotine, (ii) opioids such as morphine, fentanyl and heroin, (iii) cannabis that is now legal in many states of the United States, as morphine, fentanyl and heroin, (iii) cannabis that is now legal in many states of the United States, and (iv) a potent neuro-inhibitor γ-hydroxybutyric acid (GHBA) [11–13]. The adverse effects of and (iv) a potent neuro-inhibitor γ-hydroxybutyric acid (GHBA) [11–13]. The adverse effects of mixing mixing alcohol with other drugs can be dramatically severe [14,15] that may hinder decision making, alcohol with other drugs can be dramatically severe [14,15] that may hinder decision making, thinking, thinking, and neurocognitive capabilities [16–20]. and neurocognitive capabilities [16–20]. Although mechanisms underlying the alcohol-drug interaction are not fully understood, two Although mechanisms underlying the alcohol-drug interaction are not fully understood, possibilities have been proposed: (i) common mechanisms including pharmacokinetics and two possibilities have been proposed: (i) common mechanisms including pharmacokinetics and pharmacodynamics [21,22] (Section 2) and (ii) specific mechanisms related to individual drug pharmacodynamics [21,22] (Section2) and (ii) specific mechanisms related to individual drug (Section 3). Earlier studies [23] have shown that alcohol increased the risk of heroin-related deaths, (Section3). Earlier studies [ 23] have shown that alcohol increased the risk of heroin-related deaths, not not due to any pharmacokinetic interaction, but due to pharmacodynamic interactions [22,23]. due to any pharmacokinetic interaction, but due to pharmacodynamic interactions [22,23]. Conversely, Conversely, alcohol modulated the effects of anti-inflammatory drugs via pharmacokinetic alcohol modulated the effects of anti-inflammatory drugs via pharmacokinetic interactions [24]. Taken interactions [24]. Taken together, these observations indicate that an understanding of the alcohol- together, these observations indicate that an understanding of the alcohol-drug interaction may be drug interaction may be essential to develop new strategies for treatment of addiction. Therefore, the essential to develop new strategies for treatment of addiction. Therefore, the aim of this review article aim of this review article is to decipher the common and drug-specific mechanisms underlying is to decipher the common and drug-specific mechanisms underlying interaction between alcohol and interaction between alcohol and cocaine, METH, nicotine, opioids, cannabis or GHBA. The overall cocaine, METH, nicotine, opioids, cannabis or GHBA. The overall hypothesis is that alcohol modulates hypothesis is that alcohol modulates the effects of cocaine, METH, nicotine, opioids, cannabis or the effects of cocaine, METH, nicotine, opioids, cannabis or GHBA via a common mechanism involving GHBA via a common mechanism involving pharmacokinetics and pharmacodynamics, and/or drug- pharmacokinetics and pharmacodynamics, and/or drug-specific mechanisms addressed in Sections2 specific mechanisms addressed in Sections 2 and 3, respectively (Figure 1). and3, respectively (Figure1).

Figure 1. Proposed mechanisms for alcohol-drug interaction. NT: neurotransmitter systems and drug: cocaine, METH, nicotine, cannabis, opioids or GHBA. Figure 1. Proposed mechanisms for alcohol-drug interaction. NT: neurotransmitter systems and drug: 2. Commoncocaine, MechanismsMETH, nicotine, of cannabis, the Alcohol-Drug opioids or GHBA. Interactions

2. CommonPeople abusingMechanisms alcohol of the or suffering Alcohol-Drug from alcoholismInteractions tend to use multiple illegal and addictive drugs either sequentially or simultaneously [4,5]. Alcohol interacts with the co-abused drug and, additivelyPeople or abusing synergistically, alcohol or modulate suffering their from effects alcoholi viasm common tend to pharmacokinetic use multiple illegal (interference and addictive with drugsthe drug’s either metabolism) sequentially and or pharmacodynamicsimultaneously [4,5]. (modulation Alcohol interacts of the drug with mechanisms) the co-abused mechanisms drug and, additivelydetailed in or the synergistically, following sub-sections. modulate their effects via common pharmacokinetic (interference with the drug’s metabolism) and pharmacodynamic (modulation of the drug mechanisms) mechanisms detailed2.1. Pharmacokinetic in the following Mechanisms sub-sections. of Alcohol-Drug Interactions Alcohol, when ingested orally, undergoes substantial first-pass metabolism pre-systemically in 2.1. Pharmacokinetic Mechanisms of Alcohol-Drug Interactions stomach and systemically in liver [25]. Alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs)Alcohol, metabolize when ingested alcohol into orally, acetaldehyde undergoes and substantial acetate, respectively first-pass metabolism [25]. In liver, pre-systemically alcohol induces the in stomachcytochrome and P450 systemically enzymes CYP2E1, in liver CYP1A2 [25]. and Alcohol CYP3A4 (ADHdehydrogenases >> CYP2E1 =(ADHs) (CYP1A2 +and CYP3A4)) aldehyde that dehydrogenasesmetabolize alcohol (ALDHs) [26], many metabolize drug and alcohol pharmaceuticals into acetaldehyde [27,28]. Alcohol-induced and acetate, respectively modulation of[25]. these In liver,enzymes alcohol may alsoinduces affect the drug’scytochrome pharmacokinetics P450 enzymes (Figure CYP2E1,2, [ 11]). AccumulationCYP1A2 and ofCYP3A4 acetaldehyde (ADH may >> CYP2E1induce disulfiram-like = (CYP1A2 + CYP3A4)) reaction. Inthat general, metabolize the following alcohol [26], alcohol-drug many drug interactions and pharmaceuticals have been reported [27,28]. (FigureAlcohol-induced2): modulation of these enzymes may also affect the drug’s pharmacokinetics (Figure 2, [11]). Accumulation of acetaldehyde may induce disulfiram-like reaction. In general, the following alcohol-drug interactions have been reported (Figure 2): Biomedicines 2019, 7, 16 3 of 31 i. In the absence of alcohol, drugs are metabolized via liver CYP enzymes and the metabolites are excreted [11,29]. ii. Acute low dose of alcohol exposure in alcohol-naïve subjects is metabolized to acetaldehyde mostly by ADHs, but acute high-dose or chronic alcohol exposure may be metabolized by both ADH and CYP enzymes listed above. CYP enzymes remain induced in alcohol abstinent subjected chronically exposed to alcohol [11]. iii. In alcohol-naïve subjects using alcohol and another drug, acute dose of alcohol may compete with the drug for the same set of CYP enzymes and inhibit a drug’s metabolism. This may enhance the drug’s availability and ensuing increase in the harmful side effects from the drug [29]. iv. In recently abstinent chronic alcohol drinker, many drug-metabolizing CYPs remain induced, thus decreasing the drug’s availability and diminishing its effects for several weeks after drinking ceased. This suggests that a recently abstinent chronic drinker may need higher doses of medications than those required by nondrinkers to achieve therapeutic levels of certain drugs [30]. v. CYP enzymes activated by chronic alcohol consumption transform some drugs into toxic metabolites that can damage the liver or other organs [11].

These observations suggest that the drug and alcohol pharmacokinetics may play an important role on determining consequences of the alcohol-drug interaction. Earlier studies [30,31] have shown that the interaction pharmacokinetics can be predicted based on the metabolic profile of the drug. In general, alcohol exposure may modulate drug accumulation (Cmax and AUC) by modulating their metabolism and excretion. Parker and Laizurs [32] studied effects of alcohol on pharmacokinetics of cocaine administered via oral and intravenous (i.v.) administration (Table1). They showed cocaine area under the curve (AUC0–∞) and benzoylecgonine (BE) AUC0–∞ values were approximately 5.5-fold and 2-fold, respectively, higher after i.v. compared with oral administration. Alcohol exposure significantly increased (3 to 4 folds) oral cocaine systemic bioavailability and peak concentration (Cmax) values, respectively, but alcohol did not affect oral cocaine elimination half-life. The BE AUC0–∞ values were approximately 2.5-fold higher with alcohol cocaine co-administration than with oral cocaine given alone. The mean cocaethylene concentration was 30.9 ± 7.3 ng/mL. Compared with oral cocaine administered alone, alcohol co-administration also reduced the AUC ratio by 40%. Alcohol did not significantly affect the AUC ratios for intravenous cocaine. Similar to the observations of Parker and Laizurs [32], Pan and Hedaya [33] also showed that alcohol exposure increased systemic bioavailability of intraperitoneal administered cocaine.

Table 1. Effects of alcohol on cocaine and benzoylecgonine pharmacokinetic parameters [33].

Oral Cocaine + Intravenous Intravenous Indices Oral Cocaine Alcohol Cocaine Cocaine + Alcohol × × AUC0–α (mg·min/L) 15.0 ± 4.7 * 58.0 ± 10 83.1 ± 4.7 110.3 ± 22.5 CL (L/min) 5.6 ± 1.8 *× 1.6 ± 0.35 1.0 ± 1.8 × 0.74 ± 0.2 × Cmax (ng/mL) 116.0 ± 98 * 331.0 ± 131 2677 ± 98 2885 ± 702

Tmax (min) 83.6 ± 46 99.8 ± 32.5 × T1/2 (min) 85.2 ± 6.6 84.2 ± 9.1 75.0 ± 6.6 * 84.0 ± 8.2 F 0.2 ± 0.05 × 0.7 ± 0.17

CE Cmax (ng/mL) ND 30.9 ± 7.3 ND ND × BE AUC0–α (mg·min/L) 172.0 ± 46 * 410.0 ± 82 375.0 ± 46 407.0 ± 110 × BE/cocaine AUC0–α 11.9 ± 3 * 7.1 ± 1.5 4.9 ± 3 3.7 ± 0.6

AUC: area under the plasma concentration–time curve, CL: clearance, Cmax: maximum concentration, T1/2 elimination half-life, Tmax: time to Cmax, BE: benzoylecgonine. * p < 0.05 compared with intravenous cocaine, × p < 0.05 compared with corresponding alcohol group given by the same route. Biomedicines 2019, 7, 16 4 of 31

The pharmacokinetics of alcohol-cocaine interaction is determined by cocaine’s complex metabolic pathways (Figure2) involving (i) pre first-pass and first-pass metabolism of cocaine toBiomedicines form BE2019 and, 7, x ecogonine methyl ester, (ii) conversion of cocaine to norcocaine by hepatic4 of 31 butyrylcholinesterase and p450 enzymes, and (iii) alcohol mediated formation of cocaethylene and et al. [35] have shown alcohol to be a potent inhibitor of carboxyesterases and butyrylcholinesterase, norcocaethylene [34]. Patrick et al. [35] have shown alcohol to be a potent inhibitor of carboxyesterases resulting in accumulation of cocaine in the body. Parker et al. [32] have shown that alcohol suppressed and butyrylcholinesterase, resulting in accumulation of cocaine in the body. Parker et al. [32] have first pass metabolism and elimination of cocaine. Taken together, these observations suggest that shown that alcohol suppressed first pass metabolism and elimination of cocaine. Taken together, these alcohol exposure may increase cocaine bioavailability and toxicity. observations suggest that alcohol exposure may increase cocaine bioavailability and toxicity.

Figure 2. Effects of alcohol exposure on cocaine metabolism. Figure 2. Effects of alcohol exposure on cocaine metabolism. Alcohol, in addition to interacting with cocaine, also interacts with other drugs, albeit to different degrees.Alcohol, Li et al.in [addition36] have to shown interacting that alcohol with increasedcocaine, al absorptionso interacts and with Cmax otherof METHdrugs, andalbeit its to metabolite, different amphetaminedegrees. Li et (AP)al. [36] without have alteringshown theirthat alcohol elimination. increased They absorption also suggested and thatCmaxan of alcohol-inducedMETH and its increasemetabolite, in amphetamine toxicity of METH (AP) without may be altering due to their pharmacodynamics elimination. They mechanisms. also suggested Adir that an et alcohol- al. [37], Roseinduced et al. increase [38] and inFerguson toxicity of et METH al. [39 ]may have be provided due to pharmacodynamics indirect evidence that mechanisms. alcohol alters Adir distribution et al. [37], andRose metabolism et al. [38] and of Ferguson nicotine, thuset al. altering [39] have its provid toxicity.ed Cannabisindirect evidence and opioids, that alcohol on the otheralters handdistribution poorly respondand metabolism to alcohol of nicotine, exposure. thus Toenne altering et its al. toxicity. [40,41] haveCannabis shown and that opioids, alcohol on increased the other half-lifehand poorly and decreasedrespond to blood alcohol concentrations exposure. Toenne of cannabis et al. but [40,41] did nothave affect shown concentrations that alcohol of increased its metabolites half-life such and as 11-OH-decreased tetrahydrocannabinol blood concentrations (THC) of ca andnnabis 11-nor-9-carboxy but did not affect THC. concentrations Hartman et al. of [42 its] andmetabolites Lukas et such al. [43 as] reported11-OH- tetrahydrocannabinol significant increases in (THC) THC andand cannabidiol 11-nor-9-carbox (CBD)y concentrations,THC. Hartman whileet al. two[42] studiesand Lukas found et noal. change.[43] reported Likely, significant alcohol did increases not modify in THC metabolism and cannabidiol and pharmacokinetics (CBD) concentrations, of opioids. while two studies found no change. Likely, alcohol did not modify metabolism and pharmacokinetics of opioids. 2.2. Pharmacodynamics of Alcohol-Drug Interactions 2.2. PharmacodynamicsPharmacodynamics of Alcohol-Drug defines (i) the Interactions effects of alcohol and drug in body, especially at the target sites,Pharmacodynamics and (ii) how drug combinations defines (i) the influence effects eachof alcoho other’sl and effects drug directly in body, [44 –especially46]. Figure at3 thedescribes target pharmacodynamicsites, and (ii) how drug interactions combinations of alcohol influence (a neuro-inhibitor) each other’s effects with directly neuro-stimulatory [44–46]. Figure drugs 3 describes (such aspharmacodynamic cocaine, METH orinteractions nicotine) of and alcohol neuro-inhibitory (a neuro-inhibitor) drugs (suchwith neuro-st as opioid,imulatory cannabis drugs and (such GHBA). as Incocaine, general, METH the following or nicotine) alcohol-drug and neuro-inhibitory pharmacodynamic drugs interactions(such as opioid, have cannabis been reported: and GHBA). In i.general,The the acute followingneuro-inhibitory alcohol-drugeffects pharmacodynamic of the alcohol, opioids, interactions cannabis have andbeen GHBA reported: are caused via (i) Thedevelopment acute neuro-inhibitory of inhibitory effects postsynaptic of the alcohol, potential opioids, (IPSP). cannabis The acute andneuro-excitatory GHBA are causedeffects via of developmentcocaine, METH, of andinhibitory nicotine postsyna cause developmentptic potential of (IPSP). excitatory The postsynaptic acute neuro-excitatory potential (EPSP) effects [11 of]. cocaine,Therefore, METH, acute and alcohol nicotine exposure cause may development attenuate of the excitatory effects of postsyna neuro-stimulatoryptic potential drugs (EPSP) but [11].augments Therefore, the effectsacute alcohol of neuro-inhibitory exposure may drugsattenuate (Figure the effects4A). As of neuro-stimulatory an example, alcohol drugs cause but − augmentsneuro-inhibition the effects by of inducing neuro-inhibitory Cl influx drugs into (F theigure neurons 4A). As [47 an], example, resulting alcohol in development cause neuro- of inhibitionneural membrane by inducing IPSP [48Cl,-49 influx] that antagonizesinto the neurons the effects [47], ofresulting stimulatory in development drugs, but additively of neural or membranesynergistically IPSP augment [48,49] thethat effects antagonizes of inhibitory the effects drug. of stimulatory drugs, but additively or synergistically augment the effects of inhibitory drug. ii. Chronic alcohol and drug exposure results in in development of tolerance and addiction via a common addiction mechanism (Figure 3). Therefore, chronic alcohol exposure may negatively impact addictive effects of both excitatory and inhibitory drugs. Biomedicines 2019, 7, 16 5 of 31 ii.BiomedicinesChronic 2019 alcohol, 7, x and drug exposure results in in development of tolerance and addiction5 viaof 31 a common addiction mechanism (Figure3). Therefore, chronic alcohol exposure may negatively Biomedicines 2019, 7, x 5 of 31 iii. Figureimpact 4 addictive shows receptor effects of overlap both excitatory in development and inhibitory of alcohol, drugs. nicotine, and psycho-stimulant- (such as cocaine and METH) dependence. The genes listed in Figure 4 have received strong iii.iii. Figure 44 showsshows receptorreceptor overlapoverlap inin developmentdevelopment ofof alcohol,alcohol, nicotine,nicotine, andand psycho-stimulant-psycho-stimulant- statistical and biological (knockout studies) support for association with multiple substances (such as cocaine and METH) dependence.dependence. The The genes genes listed listed in Figure 44 have have receivedreceived strongstrong [50]. The nAChR gene variants such as gene cluster CHRNA5/A3/B4 encoding α3, β4, and α5 statistical andand biologicalbiological (knockout (knockout studies) studies) support support for for association association with with multiple multiple substances substances [50]. nAChR are associated strongly with poly-drug addiction [51–54]. The possible role of nAChR in [50].The nAChRThe nAChR gene variantsgene variants such as such gene as cluster gene CHRNA5/A3/B4cluster CHRNA5/A3/B4 encoding encodingα3, β4, andα3, βα4,5 nAChRand α5 alcohol dependence is further validated by the observation that varenicline, a partial agonist at nAChRare associated are associated strongly strongly with poly-drug with poly-drug addiction ad [diction51–54]. [51–54]. The possible The possi role ofble nAChR role of nAChR in alcohol in α4β2 nAChRs and a full agonist at the α7 nAChR [55] reduced alcohol craving and total alcohol alcoholdependence dependence is further is further validated validated by the observationby the observation that varenicline, that varenicline, a partial a partial agonist agonist at α4β at2 consumption in patients with alcohol use disorders [56,57]. αnAChRs4β2 nAChRs and aand full a agonistfull agonist at the at theα7 α nAChR7 nAChR [55 [55]] reduced reduced alcohol alcohol craving craving and and totaltotal alcoholalcohol consumption in patients with alcohol use disorders [[56,57].56,57].

Figure 3. Proposed interaction between alcohol and Drug. (+): alcohol augments the effects, and (−): Figurealcohol 3. antagonizesProposed interaction the effects. between alcohol and Drug. (+): alcohol augments the effects, and (−): Figure 3. Proposed interaction between alcohol and Drug. (+): alcohol augments the effects, and (−): alcohol antagonizes the effects. alcohol antagonizes the effects.

Figure 4. Overlapping receptor systems involved in nicotine and alcohol or psychostimulant dependence. GeneticFigure and4. Overlapping pharmacological receptor studies systems in both involved humans andin nicotine rodents suggestand alcohol that co-use or psychostimulant of nicotine and dependence. Genetic and pharmacological studies in both humans and rodents suggest that co-use of alcoholFigure or4. psychostimulantsOverlapping receptor is mediated, systems in involved part, by activityin nicotine at overlapping and alcohol substrates. or psychostimulant In particular, nicotine and alcohol or psychostimulants is mediated, in part, by activity at overlapping substrates. cholinergicdependence. and Genetic serotonergic and pharmacological systems underlie studies reward-related in both humans behaviors, and including rodents drug suggest intake, that preference, co-use of In particular, cholinergic and serotonergic systems underlie reward-related behaviors, including drug andnicotine dependence and alcohol to all threeor psychostimul drugs of abuse.ants Commonis mediated, addiction in part, genes by areactivity described at overlapping by Cross et substrates. al [50] and Liintake, and Burmeister preference, [58 and]. Abbreviations: dependence *:to Nicotinic all three Acetylcholine drugs of abuse. Receptors Common (nAChRs) addiction containing genes other are In particular, cholinergic and serotonergic systems underlie reward-related behaviors, including drug subunits,described ANKK1: by Cross ankyrin et al [50] repeat and and Li kinaseand Burmeist domainer 1, CHRN:[58]. Abbreviations: cholinergic receptor *: Nicotinic nicotinic, Acetylcholine C: CHRN, intake, preference, and dependence to all three drugs of abuse. Common addiction genes are D2:Receptors dopamine (nAChRs) receptors, containing Glu: glutamate, other subunits, HTR: 5-hydroxytryptamine ANKK1: ankyrin repeat (serotonine) and kinase receptorts, domain KOR: 1, CHRN: kappa described by Cross et al [50] and Li and Burmeister [58]. Abbreviations: *: Nicotinic Acetylcholine opioidcholinergic receptor, receptor NMDA: nicotinic, N-methyl-D-aspartate, C: CHRN, D2: SLC6A4: dopamine solute carrierreceptors, family Glu: 6 member glutamate, 4. Reproduced HTR: 5- Receptors (nAChRs) containing other subunits, ANKK1: ankyrin repeat and kinase domain 1, CHRN: fromhydroxytryptamine [50] with permission. (serotonine) receptorts, KOR: kappa opioid receptor, NMDA: N-methyl-D- cholinergic receptor nicotinic, C: CHRN, D2: dopamine receptors, Glu: glutamate, HTR: 5- aspartate, SLC6A4: solute carrier family 6 member 4. Reproduced from [50] with permission. Ahydroxytryptamine relatively older study(serotonine) conducted receptorts, by Pan KO andR: kappa Hedaya opioid [33] havereceptor, described NMDA: negative N-methyl-D- effects of aspartate, SLC6A4: solute carrier family 6 member 4. Reproduced from [50] with permission. alcoholA relatively on pharmacodynamics older study conducted of cocaine by by Pan using and indices Hedaya that [33] relate have braindescribed cocaine negative concentrations effects of withalcohol biological on pharmacodynamics functions (Table 2of). cocaine For example, by using E indicesdescribes that relate brain DAbrain concentration cocaine concentrations measured A relatively older study conducted by Pan andmax Hedaya [33] have described negative effects of atwith maximum biological change functions in the(Table brain 2). For cocaine example, concentration Emax describes (δC brain), andDA concentration EC describes measured a cocaine at alcohol on pharmacodynamics of cocaine by using indices thatmax relate brain 50cocaine concentrations concentrationmaximum change that caused in the 50% brain Emax cocaineresponse. concentration Similarly, the cardiac(δCmax), indices and EC assessed50 describes rate constants a cocaine for with biological functions (Table 2). For example, Emax describes brain DA concentration measured at theconcentration direct effects that of caused cocaine 50% on cardiacEmax response. functions. Similarly, An increase the cardiac in Emax indicesindicates assessed augmentation rate constants of DA for maximum change in the brain cocaine concentration (δCmax), and EC50 describes a cocaine releasethe direct at δeffectsCmax cocaine of cocaine concentrations. on cardiac functions. These studies An increase showed in that Emax cocaine indicates + saline augmentation administration of DA concentration that caused 50% Emax response. Similarly, the cardiac indices assessed rate constants for increasedrelease at theδCmax brain cocaine extracellular concentrations. fluid (ECF) These DA andstudies nucleus show accumbensed that cocaine (NAc) + cocaine saline administration concentrations the direct effects of cocaine on cardiac functions. An increase in Emax indicates augmentation of DA increased the brain extracellular fluid (ECF) DA and nucleus accumbens (NAc) cocaine release at δCmax cocaine concentrations. These studies showed that cocaine + saline administration concentrations that peaked within 20–40 min, then gradually declined. Alcohol co-administration increased the brain extracellular fluid (ECF) DA and nucleus accumbens (NAc) cocaine with cocaine caused significantly higher estimate for Emax values (not significant) but significantly concentrations that peaked within 20–40 min, then gradually declined. Alcohol co-administration with cocaine caused significantly higher estimate for Emax values (not significant) but significantly Biomedicines 2019, 7, 16 6 of 31 that peaked within 20–40 min, then gradually declined. Alcohol co-administration with cocaine caused significantly higher estimate for Emax values (not significant) but significantly lower IC50 values (Table2). This suggests that alcohol exerts a direct stimulatory effect on the brain DA system in cocaine administered subjects. Unlike the neurological effects, the cardiovascular parameters were not different after cocaine + normal saline and cocaine + alcohol administration. This suggests that the same brain ECF cocaine concentration produced higher neurochemical response after co-administration of alcohol, causing more intense and longer lasting euphoric effects. This stronger response may be caused by the pharmacologically active metabolite cocaethylene [59].

Table 2. Pharmacodynamic parameters deﬁning the effects of alcohol on Cocaine’s adverse effects in Wistar Rats (Mean ± SE, n = 8) [33].

Pharmacodynamic Parameters Cocaine (ip) a + Normal Saline Cocaine (ip) a + Alcohol (po) A. Neurochemical

Emax (% of baseline) 850 ± 200 1550 ± 640 EC50 (ng/mL) 3400 ± 580 2000 ± 650 N 1.23 ± 0.17 2.31 ± 0.29 b B. Cardiovascular

kin (% of baseline/min) 23.8 ± 5.1 36.0 ± 13.0 −1 Kout (min ) 0.218 ± 0.047 0.31 ± 0.11 Imax 0.304 ± 0.033 0.307 ± 0.035 IC50 (mg/mL) 6700 ± 2100 5600 ± 710 Rmax (% of baseline) 146 ± 6.9 148 ± 8.9 N 3.0 ± 1.5 3.6 ± 1.9 a: Cocaine dose, 30 mg/kg; alcohol dose, 5 g/kg; b: Signiﬁcantly different from the cocaine+normal saline treatment group (p < 0.05). Abbreviations: Emax: ECF DA concentration measured at maximum change in brain ECF cocaine concentration, EC50: brain ECF cocaine concentration causing 50% Emax response, n: sigmoidicity factor, kin: apparent 0-order rate constant for response production, kout: 1st-order rate constant for response dissipation, Imax: the maximum inhibition factor producing the response, IC50: cocaine concentration that produces 50% effect, and Rmax maximum response.

Robinson et al. [60] have demonstrated that an antiepileptic drug, levetiracetam (LEV) that is a potent inhibitor of Glu-induced neuro-excitation, differentially modulated the effects of cocaine and alcohol. LEV pretreatment attenuated the development of locomotor sensitization to repeated alcohol exposure but enhanced both acute locomotor stimulation by cocaine and development of locomotor sensitization following repeated exposure. Although a possible mechanism underlying the ability of LEV to differentially modulate the effects of alcohol and cocaine is not fully understood, studies have proposed that the two substances may act at different sites of Gluergic neurotransmission in the mesocorticolimbic circuitry: alcohol and cocaine modulating Gluergic activities in VTA and NAc, respectively [61]. Acute cocaine administration stimulated Glu release in NAc, but not in VTA [62], while acute alcohol increased the ﬁring rate of DAergic VTA neurons [63]. These differences may explain in part why LEV blocks the development of locomotor sensitization to alcohol but not to cocaine, despite observations that increased Gluergic sensitivity of DAergic VTA neurons is an early triggering event in sensitization to both cocaine and alcohol [64]. Taken together, these observations suggest that the neuro-inhibitory and neuro-excitatory substances may cause acute effects by diverse mechanisms, but chronic addictive effects via a common mechanism. Alcohol may augment the acute effects of neuro-inhibitory but attenuate the acute effects of neuro-excitatory drug. However, alcohol may augment the addictive effects of both groups of drugs.

3. Speciﬁc Alcohol-Drug Interactions As discussed earlier, the brain neurotransmitter (NTs) systems including, but not limited to, endogenous opioids (eOPs), DA, GABA, glutamate (Glu), glycine (Gly), serotonin (5-HT), excitatory amino acids (EAAs) and their respective receptors play important roles in rewards, aversive effects and Biomedicines 2019, 7, 16 7 of 31 addictive effects of alcohol and other drugs [65]. In drug-free situations, all NTs interact with each other (positively (+) or negatively (-) as shown in Table3) and maintain a NT balance. Depending on the type of substance (alcohol, cocaine, METH, nicotine, opioids, cannabis, and GHBA), different groups of NTs have been suggested as direct targets. For example, GABA and Glu are key targets of alcohol that simultaneously increases inhibitory neurotransmission through GABA and reduces excitatory neurotransmission through Glu [66]. Unlike alcohol, DA and ACh are direct targets for amphetamine and nicotine, respectively. Amphetamine directly increases the DA level in the synaptic cleft [67], whereas nicotine mimics psychopharmacological effects of ACh and modulates DA release [68,69]. In addition to the direct effects, addictive substances can also modulate other NTs through indirect pathways. For example, alcohol’s direct effect on the striatum Glu may modulate, GABAergic activity in the NAc. Direct and indirect mechanisms both may play an important role in alcohol-Drug interactions.

Table 3. Positive (+) or negative (-) interactions among six neurotransmitter systems in the brain. Abbreviations are shown in the text [70].

NTs Glu GABA 5-HT DA NA ACh Glu + + + - + GABA - - - - - 5-HT + - + + - DA - - - + - NA - - - + - ACh + + + + +

An interactive mechanistic diagram showing possible roles of the brain NT and receptor systems in different brain regions are shown in Figure5A. The details are discussed in the ﬁgure legend. As shown in Figure5B, a direct alcohol-induced activation of hypothalamus OP ergic neurons may indirectly modulate GABAergic neurons followed by modulation of DAergic neurons. This may modulate the effects of amphetamine that acts by directly activating DAergic neurons. Thus, direct and indirect effects of alcohol may modulate effects of co-administered drug. The following paragraph includes a brief discussion of the overall mechanism of action of alcohol. Acute alcohol exposure, in addition to activating the alcohol metabolizing enzymes such as alcohol dehydrogenase (ADH), acetaldehyde dehydrogenase (ALDH) and microsomal P450 enzymes, also causes a psychotropic depression of the CNS, leading to various behavioral and biological alterations [25,26]. Alcohol-induced depression is causally related to (i) direct increase in GABAergic activities, (ii) direct decrease in Gluergic activities and associated decrease the intracellular concentration 2+ of calcium ions (Ca ), and (iii) indirect modulation of DAergic, 5HTergic and AChergic activities [71–73]. All processes, except the DAergic activity, may be negatively regulated by acute alcohol exposure [74]. In contrast, chronic alcohol use causes tolerance and addiction by (i) down-regulating GABA receptors and phosphorylation of ERK which is regulated by GABA receptors, and (ii) activating Glu receptors in the hippocampus that is involved in seizures development during alcohol withdrawal [74–76]. Chronic alcohol abuse may also prevent activation of the memory circuit and the explicit memory supported by the hippocampus [77]. Alcohol withdrawal in addicted subjects decreases GABAR but increases GluR activities, resulting in strong neuro-stimulation (red arrows). Figure5B shows multiple neurotransmitters and neuromodulators that collectively mediate the reward-proﬁle of alcohol [78]. In general, alcohol directly modulated OPergic, GABAergic and Gluergic, and indirectly modulated DAergic, 5-HTergic and cholinergic (AChergic) presynaptic neurons, thus modulating the release of neurotransmitters and ensuing modulation of postsynaptic neurons. Binding of neurotransmitters to the postsynaptic receptors release may modulate respective behavioral traits. Biomedicines 2019, 7, 16 8 of 31 Biomedicines 2019, 7, x 8 of 31

(A) (B)

Figure 5.5. ((AA)) Possible roles ofof GluGluergicergic,, GABAergic andand ACh AChergicergic neuronsneurons in in regulation regulation of ventral

tegmental areaarea (VTA) (VTA) DA DAergicergicneuron neuron excitability. excitability. Opioid Opioid (OP) receptors(OP) receptors are not are shown not inshown this diagram). in this

Thediagram). presynaptic The presynaptic DAergic neurons DAergic (1) neurons express (1) GABA expressBR, DAR1, GABA mGluR2/3BR, DAR1, mGluR2/3 and nicotinic and ( αnicotinic7 and α4 (βα2)7 receptorsand α4β2) thus receptors the neuronal thus the activity neuronal is modulated activity is bymodulated Glu, GABA, by Glu, ACh GABA, and nicotine, ACh and and nicotine, (2) received and

signals(2) received form excitatorysignals form Glu excitatoryergic neurons Glu releasingergic neurons Glu, releasing excitatory Glu, Cholin excitatoryergic neurons Cholin releasingergic neurons ACh,

andreleasing inhibitory ACh, GABA and inhibitoryergic neurons GABA releasingergic neurons GABA. releasing The released GABA. NTs bindThe released to their respective NTs bind receptors to their onrespective DAergic neuronsreceptors and on elicit DA excitatoryergic neurons (depolarization) and elicit excitatory or inhibitory (depolarization) (hyperpolarization) or inhibitory response.

The(hyperpolarization) Gluergic neurons response. also express The mGluR2/3, Gluergic neurons AChR, also GABA expressBR andmGluR2/3, DAR1receptors, AChR, GABA thusB theR and neuronal DAR1

activityreceptors, is modulatedthus the neuronal by Glu, GABA activity and is ACh. modulated The GABA byergic Glu,interneurons GABA and receive ACh. receptors The GABA signalsergic frominterneurons GABAergic receiveand receptors Cholinergic signalsefferent. from (B GABA) Interactionergic and of Cholin OPergicergicneurons efferent. (endorphin(B) Interactionergic ofneurons OPergic

releaseneurons endorphin, (endorphin a MORergic neurons agonist, whilerelease dynorphin endorphin,ergic aneurons MOR agonist, release dynorphin, while dynorphin a KOR agonist)ergic neurons with

GABAreleaseergic dynorphin,interneurons a KOR and agonist) DAergic neurons.with GABA Theergic DA interneuronsergic neurons fromand DA theergic VTA neurons. project toThe ANc DA andergic are under tonic inhibition by GABA interneurons that are under direct inhibition by endorphin neurons from the VTA project to ANcergic and are under tonic inhibition by GABAergic interneurons thatergic neurons from the hypothalamus Therefore, stimulation of endorphin release in VTA inhibits GABA are under direct inhibition by endorphinergic neurons from the hypothalamus Therefore, stimulationergic interneurons and ensuing disinhibition of the DA neurons, leading to increased DA release in of endorphin release in VTA inhibits GABAergic interneuronsergic and ensuing disinhibition of the DAergic NAc.neurons, Acute leading alcohol to stimulatesincreased endorphinDA release andin NAc. met-enkephalin Acute alcohol release, stimulates leading endorphin to an increase and in met- DA release,enkephalin while release, chronic leading alcohol to stimulates an increase dynorphin in DA release, release while that couldchronic attenuate alcohol DAstimulates release indynorphin the NAc. α Abbreviations:release that could DA: dopamine,attenuate DA DAR: release DA receptors, in the NAc. DAT: DAAbbreviations: transporter, Glu:DA: glutamate,dopamine, andDAR:7 andDA α β receptors,4 2: nicotinic DAT: receptors. DA transpor Theter, VTA Glu: DA ergicglutamate,neurons and receive α7 and signals α4β from2: nicotinic Gluergic receptors.(releases excitatoryThe VTA neurotransmitter, Glu), Cholinergic (releases excitatory NT, Ach), and GABA interneurons (releases DAergic neurons receive signals from Gluergic (releases excitatory neurotransmitter, Glu), Cholinergic inhibitory neurotransmitter, GABA) that receive signals from GABA (releases GABA) and Cholin (releases excitatory NT, Ach), and GABA interneurons (releases inhibitoryergic neurotransmitter, GABA)ergic (releases ACh) neurons. Binding of GABA to its receptors on. GABAergic afferent neurons releases GABA that receive signals from GABAergic (releases GABA) and Cholinergic (releases ACh) neurons. Binding inhibits GABA interneurons, thus activating the DAergic neurons. Symbol-i: the sites of actions for alcohol, of GABA to its receptors on. GABAergic afferent neurons releases GABA inhibits GABA interneurons, symbol-ii: the site of action for cocaine, and symbol-iii: the site of action for nicotine. thus activating the DAergic neurons. Symbol-i: the sites of actions for alcohol, symbol-ii: the site of Theseaction for observations cocaine, and suggestsymbol-iii: that the acute site of andaction chronic for nicotine. alcohol exposure may target different sets of the CNS NTs and, therefore, differently modulate the effects of excitatory and inhibitory drug. AcuteThese alcohol observations exposure, suggest due to itsthat depressive acute and effects,chronic may alcohol augment exposure the may effects target of neuro-inhibitory different sets of drugsthe CNS (cannabis NTs and, or therefore, GHBA), differently but suppress modulate the effects the effects of neuro-stimulatory of excitatory and drugs inhibitory (cocaine, drug. METH Acute andalcohol nicotine). exposure, However, due to chronicits depressive alcohol effects, exposure may may augment augment the theeffects neuro-stimulatory of neuro-inhibitory drugs drugs but suppressing(cannabis orneuro-inhibitory GHBA), but suppress Drugs. Interactionthe effects ofof alcoholneuro-stimulatory with other drugs drugs are (cocaine, discussed METH below. and nicotine). However, chronic alcohol exposure may augment the neuro-stimulatory drugs but 3.1.suppressing Alcohol-Cocaine neuro-inhibitory Interaction Drugs. Interaction of alcohol with other drugs are discussed below.

3.1. Alcohol-CocaineCocaine is a powerful Interaction addictive, psychoactive, stimulant drug illegally available on the streets as a ﬁne, white powder. Whatever the form, cocaine acts as a strong stimulant substance that can (i) provideCocaine a rapid-onsetis a powerful of addictive, rewarding psychoactive, high, (ii) speed stimulant up various drug physiologic illegally available processes on via the its streets CNS effects,as a fine, and white (iii) inﬂuencepowder. Whatever both short- the and form, long-term cocaine mental acts as health. a strong Acevedo-Rodriguez stimulant substance et al. that [79 can] have (i) shownprovide that a rapid-onset cocaine, at of concentrations rewarding high, around (ii) sp 0.5eedµM up that various is readily physiologic achievable processes in cocaine via abusers,its CNS inhibitedeffects, and the (iii) DA influence transporter both (DAT)-mediated short- and long-t uptakeerm ofmental DA. Athealth. concentration Acevedo-Rodriguez around 4 µM, et cocaineal. [79] inhibitedhave shown nAChRs that cocaine, and altered at concentrations DA release [80 ].around At cocaine 0.5 µM level that≥20 isµ M,readily its anesthetic achievable effect in cocaine may be abusers, inhibited the DA transporter (DAT)-mediated uptake of DA. At concentration around 4 µM, cocaine inhibited nAChRs and altered DA release [80]. At cocaine level ≥20 µM, its anesthetic effect BiomedicinesBiomedicines 20192019,, 77,, 16x 99 of 3131 Biomedicines 2019, 7, x 9 of 31 may be triggered (Figure 6). This suggests that the mechanistic effects shown in Figure 6 may triggeredmaycontribute be triggered (Figure to the cocaine-induced6 ).(Figure This suggests 6). This increases that suggests the mechanisticthe that ratio the of phasicmechanistic effects to shown tonic effects DA in Figurerelease shown6 andmay in thus contributeFigure potentially 6 may to thecontributeenhances cocaine-induced its to reinforcingthe cocaine-induced increases abilities the [81]. ratioincreases of phasic the ratio to tonic of phasic DA release to tonic and DA thus release potentially and thus enhances potentially its reinforcingenhances its abilities reinforcing [81]. abilities [81].

Figure 6. Diagram showing that cocaine may inhibit DAT-mediated DA uptake and DA release via FigurenAChRs 6. andDiagram Na+ channels showing in that a dose-dependent cocaine may inhibit manner DAT-mediated . DA uptake and DA release via nAChRs and Na+ channelschannels in in a a dose-dependent dose-dependent manner manner.. Epidemiological studies have shown that, compared to the control subject (cocaine free), the prevalenceEpidemiological of alcohol studiesuse was have havefound shown shown89% higher that, that, compar am comparedonged cocaine to tothe dependents the control control subject [82,83], subject (cocaine possibly (cocaine free), due free), the to theprevalencethe prevalenceperception of alcohol of of alcohol higher use use increase was was found found of reward89% 89% higher higher effects amongam whenong cocainecocaine alcohol dependents dependents and cocaine [82 [82,83], ,were83], possibly co-administered possibly due due to the to perceptionthecompared perception ofto higher either of higher increase drug increase administered of reward of reward effects alone wheneffe [cts84–86]. alcohol when In andalcohol a study cocaine and conducted werecocaine co-administered were on rats, co-administered intravenous compared tocomparedinjections either drug ofto cocaine administeredeither drugincreased administered alone alcohol [84–86 ].drinking, Inalone a study [84–86]. suggesting conducted In a thatstudy on rats,cocaine conducted intravenous potentiated on injections rats, alcohol intravenous of seeking cocaine increasedinjections[87]. A preclinical alcoholof cocaine drinking, study increased has suggesting shown alcohol a that drinking, higher cocaine susceptibility suggesting potentiated that of alcohol thecocaine reinforcing seeking potentiated [87 ].effects A preclinicalalcohol of cocaine seeking study in has[87].selectively shown A preclinical abred higher alcohol susceptibilitystudy preferring has shown of the(P) areinforcing ratshigher compared susceptibility effects to of its cocaine outbred of the in selectivelyreinforcingWister rats, bred effects suggesting alcohol of cocaine preferring a higher in (P)selectivelysensitivity rats compared bredof alcoholics alcohol to its outbred preferringto the Wisterreinforcing (P) rats, rats suggesting effectscompared of cocaine a to higher its outbred [88] sensitivity Similarly, Wister of alcoholics rats,it has suggesting been to the revealed reinforcing a higher that effectssensitivitygenetically of cocaine of predisposed alcoholics [88] Similarly, tosubjects the reinforcing it for has alcohol been effects revealed dependen of cocaine thatce have genetically [88] a higher Similarly, predisposed rate toit hasbe cocaine subjectsbeen revealed dependents for alcohol that dependencegenetically[89]. This predisposedsuggests have a higher that subjects alcohol rate to forbe and alcohol cocaine cocaine, dependen dependents whence haveco-administered, [89]. Thisa higher suggests rate potentiateto that be alcoholcocaine the anddependents effects cocaine, of when[89].individual This co-administered, drugs.suggests Different that potentiate alcohol aspect the ofand effects interaction cocaine, of individual betweenwhen drugs.co-administered, alcohol Different and cocaine aspect potentiate exposure of interaction the are effects shown between ofin alcoholindividualFigure 7 and and drugs. cocaine described Different exposure below. aspect are shown of interaction in Figure 7between and described alcohol below. and cocaine exposure are shown in FigureCocaine 7 and described andand alcoholalcohol below. co-administrationco-administration generates a uniqueunique metabolite,metabolite, cocaethylenecocaethylene that isis equipotentequipotentCocaine in and inhibition alcohol ofco-administration bindingbinding to the dopaminegenerates aand unique serotoninseroto metabolite,nin reuptake cocaethylene complex [90,91]. [that90,91 is]. CocaethyleneequipotentCocaethylene in may mayinhibition be be less less anxiogenic ofanxiogenic binding and andto morethe more reinforcingdopamine reinforcing [and92 [92,93],,93 seroto], but but itnin is it more reuptakeis more lethal lethal complex than than cocaine cocaine[90,91]. [94] ConcurrentCocaethylene[94] Concurrent use may of use cocaine be of less cocaine andanxiogenic alcoholand alcohol and has been morehas been associated reinforcing associated with [92,93], with greater butgreater risk it is of riskmore sudden of lethalsudden death than death than cocaine afterthan cocaine[94]after Concurrent cocaine alone alone [95 use]. Cocaethylene[95]. of cocaine Cocaethylene and has alcohol been has been detectedhas been dete inassociatedcted wastewater, in wastewater, with an greater observation an observationrisk of sudden that has that death been has usedbeenthan asafterused evidence cocaineas evidence of alone cocaine [95].of and cocaineCocaethylene alcohol and co-abuse alcoholhas been in urbanco-abu detected area.se in In wastewater,urban addition, area. cocaethylene an In observation addition, concentrations thatcocaethylene has been in wastewaterusedconcentrations as evidence was in signiﬁcantly wastewaterof cocaine higher wasand significantly duringalcohol weekends co-abu higherse compared induring urban weekends toarea. weekdays, In comparedaddition, further tococaethylene suggesting weekdays, a higherconcentrationsfurtherco-abuse suggesting in of wastewater cocainea higher and co-abuse was alcohol significantly of [ 96cocaine]. and higher alcohol during [96]. weekends compared to weekdays, further suggesting a higher co-abuse of cocaine and alcohol [96].

Figure 7. Effects of alcohol exposure on cocaine’s pharmacokinetics, cardiovascular function, CNSFigure functions 7. Effects and of prenatalalcohol effects.exposure on cocaine’s pharmacokinetics, cardiovascular function, CNS Figurefunctions 7. Effectsand prenatal of alcohol effects. exposure on cocaine’s pharmacokinetics, cardiovascular function, CNS Alcoholfunctions administrationand prenatal effects. has been shown to increase the plasma concentration of cocaine [97], leadingAlcohol to an increaseadministration in cocaethylene has been concentration shown to increa in plasmase the andplasma decrease concentration in benzoylecgonine of cocaine renal[97], excretionleadingAlcohol to[ an98 ]. increaseadministration Although in cocaethylene alcohol has been ingestion concentration shown did to notincrea in alter plasmase cocainethe andplasma half-life,decrease concentration itin signiﬁcantly benzoylecgonine of cocaine increased renal[97], leadingexcretion to [98].an increase Although in cocaethylene alcohol ingestion concentration did not inalter plasma cocaine and half-life,decrease init significantlybenzoylecgonine increased renal excretion [98]. Although alcohol ingestion did not alter cocaine half-life, it significantly increased Biomedicines 2019, 7, 16 10 of 31

Biomedicines 2019, 7, x 10 of 31 cocaethylene’s half-life [99], thus increasing the exposure to cocaethylene’s deteriorating toxic effects. cocaethylene’s half-life [99], thus increasing the exposure to cocaethylene’s deteriorating toxic effects. Cocaine and alcohol co-exposure also has deleterious effects on cardiovascular and endocrine systems Cocaine and alcohol co-exposure also has deleterious effects on cardiovascular and endocrine as evidenced by an increase in heart rate, systolic blood pressure, cortisol, and prolactin concentrations, systems as evidenced by an increase in heart rate, systolic blood pressure, cortisol, and prolactin and cerebral blood perfusion [100]. It has been shown that cerebral hypo-perfusion was more common concentrations, and cerebral blood perfusion [100]. It has been shown that cerebral hypo-perfusion among individuals taking cocaine and alcohol together compared to individuals taking cocaine or was more common among individuals taking cocaine and alcohol together compared to individuals alcohol alone [101,102]. taking cocaine or alcohol alone [101,102]. Several indices of neuropsychological performances such as intelligence, memory, verbal learning Several indices of neuropsychological performances such as intelligence, memory, verbal learning were found to be negatively affected by the concurrent intake of cocaine and alcohol compared to were found to be negatively affected by the concurrent intake of cocaine and alcohol compared to either either drug administered alone [103,104]. The sense of pleasure and euphoria increased in co-abuse of drug administered alone [103,104]. The sense of pleasure and euphoria increased in co-abuse of alcohol alcohol and cocaine and consequently elevated the risk of dependence and toxicity [105]. Alcohol and and cocaine and consequently elevated the risk of dependence and toxicity [105]. Alcohol and cocaine cocaine co-exposure increased extracellular DA concentration in the NAc, a region involved in the co-exposure increased extracellular DA concentration in the NAc, a region involved in the rewarding rewarding and reinforcing effects of drugs of abuse [106–108], compared to either drug administered and reinforcing effects of drugs of abuse [106–108], compared to either drug administered alone in rats alone in rats [109]. One recent study has demonstrated a signiﬁcant interaction in prenatal co-exposure [109]. One recent study has demonstrated a significant interaction in prenatal co-exposure of cocaine of cocaine and alcohol on cortical thickness in youths prenatally exposed to these drugs [110,111]. and alcohol on cortical thickness in youths prenatally exposed to these drugs [110,111]. 3.2. Alcohol-Methamphetamine Interactions 3.2. Alcohol-Methamphetamine Interactions METH’s main mechanism of action is its ability to increase in neuronal release of DA into the NAc,METH’s an effect main mediated mechanism via alterations of action in is both its ability the DAT to increase and the vesicularin neuronal monoamine release of transporter-2 DA into the (VMAT-2)NAc, an effect [112 ].mediated In addition, via alterations METH phosphorylates in both the DAT DAT and via proteinthe vesicular kinase monoamine C leads to internalization transporter-2 (VMAT-2)of DAT, thus [112]. impairing In addition, the normal METH function phosphorylates of DAT [ 113DAT]. Concurrentvia protein kinase with reuptake C leads inhibition,to internalization METH ofalso DAT, induces thus DA impairing efﬂux into the the normal synapse function (Figure of8). DAT [113]. Concurrent with reuptake inhibition, METH also induces DA efflux into the synapse (Figure 8).

Figure 8. Mechanism of action of METH on DA neurot neurotransmission.ransmission. [113. 1: Methamphetamine Methamphetamine (MA) (MA) inhibits DA reuptake, 2: MA MA phosphorylates phosphorylates DAT DAT resulting in its internalization, 3: MA MA inhibits inhibits DA’s DA’s synaptosomal uptake via vesicular monoamine- transporter 2 (VMAT-2), 4: intracellular uptake of MA reverse transports DA via DAT into the synaptic cleft,cleft, 5: MA diffuses diffuses into the the synaptosome synaptosome impairing DA storage. Alcohol and METH, often used together, cause co-morbid disorder [113,114]. Approximately Alcohol and METH, often used together, cause co-morbid disorder [113,114]. Approximately 77% of people diagnosed with amphetamine dependence also have an alcohol use disorder [115,116]. 77% of people diagnosed with amphetamine dependence also have an alcohol use disorder [115,116]. Within the population of METH users, alcohol consumption increases the probability of METH use by Within the population of METH users, alcohol consumption increases the probability of METH use four-fold [117–119]. Figure9 shows possible effects of concurrent alcohol and METH exposure. METH by four-fold [117–119]. Figure 9 shows possible effects of concurrent alcohol and METH exposure. abusers frequently use alcohol to have a higher level of euphoric effects. But, alcohol may inhibit METH METH abusers frequently use alcohol to have a higher level of euphoric effects. But, alcohol may metabolism, resulting in higher blood METH concentration, with an increase in its stimulating effects inhibit METH metabolism, resulting in higher blood METH concentration, with an increase in its on brain and heart, resulting in signiﬁcant negative effects on mood, performance, and physiological stimulating effects on brain and heart, resulting in significant negative effects on mood, performance, behaviors [120]. Co-exposure to alcohol and METH also resulted in (i) synergistic depletions of DAT, and physiological behaviors [120]. Co-exposure to alcohol and METH also resulted in (i) synergistic SERT, and DA and 5HT content, and (ii) increase in LPS and COX-2 in rats [118,121]. This suggests that depletions of DAT, SERT, and DA and 5HT content, and (ii) increase in LPS and COX-2 in rats prior alcohol drinking may also increase the inﬂammatory mediators, thus enhancing neurotoxicity. [118,121]. This suggests that prior alcohol drinking may also increase the inflammatory mediators, thus enhancing neurotoxicity. Biomedicines 2019, 7, x 11 of 31

Biomedicines 20192019,, 77,, 16x 1111 of of 31

Figure 9. Effects of METH exposure on alcohol’s pharmacokinetics, cardiovascular function, CNS Figurefunctions 9. Effectsand prenatal of METH effects. exposure on alcohol’s pharmacokinetics, cardiovascular function, CNS functionsFigure 9. andEffects prenatal of METH effects. exposure on alcohol’s pharmacokinetics, cardiovascular function, CNS functionsMendelson and et prenatal al. [122] effects. in humans and Wells et al. [123] in mouse have shown that in utero exposureMendelson of a combination et al. [122] in of humans alcohol and and Wells METH et al. may [123 ]cause in mouse greater have toxicity shown in that offspring in utero exposurethan either of aalcohol combinationMendelson or METH. of alcoholet This al. [122]interaction and METHin humans may may be causeand due Wells greaterto th eet increased toxicity al. [123] in production offspringin mouse than haveof reactive either shown alcohol oxygen that or in species METH. utero Thisexposure(ROS) interaction that of a altercombination may besignal due tooftransduction, thealcohol increased and METH productionand/or mayoxidative of cause reactive greaterstress-induced oxygen toxicity species in (ROS)damageoffspring that tothan alter cellular signaleither transduction,alcoholmacromolecules or METH. and/or like This oxidative lipids, interaction proteins, stress-induced may and be dueDNA, damage to ththee to increasedlatter cellular leading macromolecules production to altered of reactive likegene lipids, expression oxygen proteins, species [123]. and DNA,(ROS)This may thethat latterbe altercausally leading signal torelated altered transduction, to gene the expressiondevelopment and/or [123 oxidative].of Thiscardiac may stress-inducedcytotoxicity be causally related associated damage to the with developmentto adversecellular ofmacromoleculescardiovascular cardiac cytotoxicity effects. like associatedlipids, Andez-Lopez proteins, with adverse andet al. DNA, cardiovascular[124] the have latter shown effects. leading that, Andez-Lopez to inaltered addition gene et al. to expression [124 alcohol-METH] have shown [123]. that,Thiscombination, inmay addition be causallythe to alcohol-METH3,4-Methylenedioxy-methamphetamine related to combination,the development the 3,4-Methylenedioxy-methamphetamine of cardiac (Ecstasy) cytotoxicity and alcohol associated combination with (Ecstasy) adverse also and alcoholcardiovascularaugmented combination euphoria effects. also and Andez-Lopez augmented wellbeing euphoria than et al. Ecstasy and[124] wellbeing haveor alcohol shown than alone. Ecstasythat, Subjects in or addition alcohol may alone. tofeel alcohol-METH euphoric Subjects mayand feelcombination,less euphoricsedated and andthe lessmight3,4-Methylenedioxy-methamphetamine sedated have andthe feeling might haveof doing the feeling better, of but doing(Ecstasy) actual better, performance and but alcohol actual ability performance combination continues ability also to continuesaugmentedbe impaired to euphoria beby impairedthe effect and by of wellbeing thealcohol. effect ofthan alcohol. Ecstasy or alcohol alone. Subjects may feel euphoric and less sedated and might have the feeling of doing better, but actual performance ability continues to 3.3. Nicotine be3.3. impaired Nicotine by the effect of alcohol. Nicotine is a highly addictive substance of tobacco, acting via binding to the nicotinic acetylcholine Nicotine is a highly addictive substance of tobacco, acting via binding to the nicotinic (ACh)3.3. Nicotine receptors or nAChRs that respond to the neurotransmitter ACh. Nicotine addiction is mediated acetylcholine (ACh) receptors or nAChRs that respond to the neurotransmitter ACh. Nicotine through nAChR expressed on most neurons in the brain. Tolu and Eddine [125] showed that addictionNicotine is mediated is a highly through addictive nAChR expressedsubstance onof motobacco,st neurons acting in the via brain. binding Tolu andto the Eddine nicotinic [125] nAChR-mediated activation of GABA neurons in the VTA plays a crucial role in the control of acetylcholineshowed that nAChR-mediated(ACh) receptors activationor nAChRs of thatGABA respond neurons to inthe the neurotransmitter VTA plays a crucial ACh. role Nicotine in the nicotine-elicited DAergic activity (Figure 10). DA and GABA make a concerted effort to generate addictioncontrol of is nicotine-elicited mediated through DA nAChRergic activity expressed (Figure on 10).most DA neurons and GA in theBA brain. make Tolu a concerted and Eddine effort [125] to reinforcing actions of nicotine through DAergic neurons. Therefore, GABAergic neurons may be a showedgenerate thatreinforcing nAChR-mediated actions of nicotineactivation through of GABA DA neuronsergic neurons. in the Therefore, VTA plays GABA a crucialergic neurons role in may the potential drug development target for cessation of drug development. controlbe a potential of nicotine-elicited drug development DAergic target activity for cessation(Figure 10). of drugDA anddevelopment. GABA make a concerted effort to generate reinforcing actions of nicotine through DAergic neurons. Therefore, GABAergic neurons may be a potential drug development target for cessation of drug development.

Figure 10. A schematic representation of the AChergic signaling in VTA and afferents. The DAergic Figure 10. A schematic representation of the AChergic signaling in VTA and afferents. The DAergic output neuron contains high-afﬁnity b2-nAChRs that are inhibited by GABA releasing from GABAergic output neuron contains high-affinity b2-nAChRs that are inhibited by GABA releasing from GABAergic interneurons containing high-afﬁnity b2-nAChRs. GABAergic, Gluergic, and AChergic projections arrive Figureinterneurons 10. A containingschematic representationhigh-affinity b2-nAChRs. of the ACh GABAergic signalingergic, Glu ergicin VTA, and andACh afferents.ergic projections The DAarriveergic from the ventral pallidum (VP), the laterodorsal tegmental nucleus and LDTg/PPTg pontine tegmental outputfrom the neuron ventral contains pallidum high-affi (VP),nity the b2-nAChRs laterodorsal that aretegmental inhibite dnucleus by GABA and releasing LDTg/PPTg from GABA pontineergic nuclei, respectively. DAergic neurons release DA in the NAc, which show biochemical alterations after interneurons containing high-affinity b2-nAChRs. GABAergic, Gluergic, and AChergic projections arrive alcohol exposure. from the ventral pallidum (VP), the laterodorsal tegmental nucleus and LDTg/PPTg pontine Biomedicines 2019, 7, x 12 of 31

tegmental nuclei, respectively. DAergic neurons release DA in the NAc, which show biochemical Biomedicines 2019, 7, 16 12 of 31 alterations after alcohol exposure.

AlcoholAlcohol and and cigarette cigarette smoking smoking is is the the most most common common practice practice globally globally that that may may be be most most costly costly in in termsterms of of health health and and societal societal costs costs [ 126[126–128].–128]. Nicotine Nicotine dependents dependents may may have have a a high high tendency tendency to to be be alcoholalcohol dependents dependents [ 129[129].]. It It has has been been reported reported that that more more than than 80% 80% of of chronic chronic alcohol alcohol users users are are also also smokerssmokers [ 130[130–132].–132]. In In a a preclinical preclinical study, study, rats rats chronically chronically co-exposed co-exposed to to alcohol alcohol and and nicotine nicotine showed showed higherhigher nicotine nicotine self-administration self-administration as as compared compared to to drug drug self-administered self-administered alone alone [ 133[133].]. The The overall overall effectseffects of of alcohol-nicotine alcohol-nicotine interaction interaction are are shown shown in in Figure Figure 11 11..

FigureFigure 11. 11.Effects Effects of of alcohol alcohol exposure exposure on on nicotine’s nicotine’s pharmacokinetics, pharmacokinetics, cardiovascular cardiovascular function, function, CNS CNS functionsfunctions and and prenatal prenatal effects. effects.

Blomqvist et al. [134,135] have proposed that alcohol modulates the reinforcing effects of nicotine Blomqvist et al. [134,135] have proposed that alcohol modulates the reinforcing effects of by directly interacting with the nAChRs, β2 and β4 [136,137]. Lüscher and Malenka [138] have shown nicotine by directly interacting with the nAChRs, β2 and β4 [136,137]. Lüscher and Malenka [138] that chronic nicotine exposure triggers a conformational change in β4 nAChRs that initiates various have shown that chronic nicotine exposure triggers a conformational change in β4 nAChRs that forms of synaptic plasticity and modify the VTA-DA neuron’s responses to alcohol and alcohol drinking initiates various forms of synaptic plasticity and modify the VTA-DA neuron’s responses to alcohol behaviors. Norbinaltorphamine (norBNI), a KOR antagonist, robustly increased alcohol and nicotine and alcohol drinking behaviors. Norbinaltorphamine (norBNI), a KOR antagonist, robustly increased self-administration in adult male rats but not in female rats [139,140]. Taken together, these ﬁndings alcohol and nicotine self-administration in adult male rats but not in female rats [139,140]. Taken suggest that nicotine, from either tobacco or e-cigarette use, may increase the vulnerability of teenage together, these findings suggest that nicotine, from either tobacco or e-cigarette use, may increase the boys to alcohol abuse. vulnerability of teenage boys to alcohol abuse. 3.4. Alcohol-Opioid Interactions 3.4. Alcohol-Opioid Interactions Opioids, addictive substances derived from the poppy seedpod, occurs as (i) a natural drug such as Opioids, addictive substances derived from the poppy seedpod, occurs as (i) a natural drug such opium, morphine and codeine, and (ii) a synthetic drug such as dilaudid, demerol, oxycodone, vicodin, as opium, morphine and codeine, and (ii) a synthetic drug such as dilaudid, demerol, oxycodone, fentanyl, methadone or heroin. Opioids are commonly used analgesic agent with potential for abuse vicodin, fentanyl, methadone or heroin. Opioids are commonly used analgesic agent with potential as street drug [141,142]. In body, the opioid drugs compete with the receptors for endogenous opioid for abuse as street drug [141,142]. In body, the opioid drugs compete with the receptors for peptides (eOP) such as β-endorphin, enkephalins, and dynorphins released by selective OPergic neurons. endogenous opioid peptides (eOP) such as β-endorphin, enkephalins, and dynorphins released by The eOPs, nOPs and sOPs bind to three families of opioid receptors (OPRs): µ (MOR), δ (DOR), and selective OPergic neurons. The eOPs, nOPs and sOPs bind to three families of opioid receptors (OPRs): κ (KOR) with differing affinities [143]. The three OP receptors (OPRs) are widely distributed in the µ (MOR), δ (DOR), and κ (KOR) with differing affinities [143]. The three OP receptors (OPRs) are brain regions involved in pain modulation, reward, stress responses, and autonomic control [144]. OPRs widely distributed in the brain regions involved in pain modulation, reward, stress responses, and selectively interact with G-proteins (composed of two subunits, Gαi, αs or αo and βγ subunits) and autonomic control [144]. OPRs selectively interact with G-proteins (composed of two subunits, Gαi, form MOR-Gαiβγ for β-endorphin and endomorphin 1, DOR-Gαoβγ for enkephalins, and KOR-Gαsβγ αs or αo and βγ subunits) and form MOR-Gαiβγ for β-endorphin and endomorphin 1, DOR-Gαoβγ for dynorphin and endomorphin 2 [145]. The OPR-G protein complex (such as MOR-Gαiβγ), upon for enkephalins, and KOR-Gαsβγ for dynorphin and endomorphin 2 [145]. The OPR-G protein binding to an eOP or a sOP, dissociates into MOR-Gαi subunit and βγ subunits. MOR-Gαi subunit complex (such as MOR-Gαiβγ), upon binding to an eOP or a sOP, dissociates into MOR-Gαi subunit directly inhibits adenylyl cyclase (AC) that reduces cAMP formation and activates inwardly rectifying K+ and βγ subunits. MOR-Gαi subunit directly inhibits adenylyl cyclase (AC) that reduces cAMP channels (GIRK+), causing neuro-inhibition and ensuing analgesic response [146]. The βγ dimer directly formation and activates inwardly rectifying K+ channels (GIRK+), causing neuro-inhibition and inhibits voltage-dependent Ca2+ channels [147]. Taken together, these changes block the presynaptic ensuing analgesic response [146]. The βγ dimer directly inhibits voltage-dependent Ca2+ channels signal from activating postsynaptic terminal, thus causing analgesia. Biomedicines 2019, 7, x 13 of 31

Biomedicines 2019, 7, 16 13 of 31 [147]. Taken together, these changes block the presynaptic signal from activating postsynaptic terminal, thus causing analgesia. AcuteAcute alcohol alcohol exposure exposure has has been been shown shown to to potent potentiateiate the opioid-induced increase increase in analgesia andand CNS CNS depression, depression, leading leading to toserious serious side side effect effectss including including respiratory respiratory distress, distress, coma, coma,and death and [148,149].death [148 Chronic,149]. Chronic alcohol alcohol exposure exposure may develop may develop coaddiction coaddiction when when addiction addiction to one to onedrug drug (such (such as anas opioid) an opioid) enhances enhances craving craving for another for another such such as alcohol as alcohol [150–155]. [150–155 A ].Canadian A Canadian study study has shown has shown that approximatelythat approximately 82% 82%of apparent of apparent opioid-related opioid-related deaths deaths from from 2016 2016 to to2017 2017 also also involved involved one one or or more more typetype of of non-opioid non-opioid substances substances including including alcohol alcohol [148]. [148]. Polettini Polettini et et al. al. [156] [156] have have shown shown that that heroin, heroin, a a dangerousdangerous illegal opioid,opioid, cancan interactinteract with with alcohol alcohol and and produce produce a sensationa sensation of of greater greater pleasure pleasure than than the thetwo two individually, individually, while while at the at samethe same time time inhibiting inhibiting the respiratorythe respiratory system. system. In addition, In addition, alcohol alcohol may mayexacerbate exacerbate the neuronal the neuronal situation bysituation inhibiting by heroin inhibiting metabolism heroin (pharmacokinetic metabolism (pharmacokinetic mechanism) [157]. mechanism)Despite the seriousness[157]. Despite of the the alcohol-opioid seriousness interaction,of the alcohol-opioid the underlying interaction, mechanisms the areunderlying not fully mechanismsunderstood. are Therefore, not fully the understood. aim of proceeding Therefore, sub-sections the aim of are pr tooceeding discuss combinedsub-sections effects are to of discuss alcohol combinedand opioid effects on analgesia, of alcohol CNS and inhibition opioid on and analgesia, addiction. CNS inhibition and addiction. FigureFigure 1212 showsshows signaling signaling pathways pathways for for analgesic analgesic effects effects of opioids of opioids and effects and ofeffects alcohol of drinkingalcohol drinkingon it. In on addition it. In addition to the OPRs, to the type-2 OPRs, G-protein type-2 G-protein coupled coupled inwardly inwardly rectifying rectifying potassium potassium (GIRK2) (GIRK2)channels channels are also implicatedare also implicated in analgesic in actionanalgesic of opioid action drugs of opioid (Figure drugs 16) [158(Figure]. This 16) hypothesis [158]. This is hypothesissupported byis supported the observations by the observations that the analgesic that th effectse analgesic of opioids effects were of opioids absent were in GIRK2 absent null-mutant in GIRK2 null-mutantmice [159,160 mice] or by [159,160] OPR antagonist or by OPR [161 ].antagonist Alcohol exposure [161]. Alcohol augments exposure the opioid’s augments analgesic the responseopioid’s analgesicby co-activating response both by co-activating OPR and GIRK2 both channelOPR and activations GIRK2 channel [161,162 activations]. Unlike [161,162]. the opioid-induced Unlike the opioid-inducedanalgesia, the NMDAR-mediated analgesia, the NMDAR-mediated analgesia may occuranalgesia independently may occur of independently GIRK2 channels of areGIRK2 not channelsmodulated are by not alcohol modulated exposure by alcohol [162]. exposure [162].

Figure 12. Signal pathways mediating opioid-induced analgesia. Opioids distinctively activates MOR, DOR, and KOR, that leads to G protein activation. The activated G protein activates the GIRK Figure 12. Signal pathways mediatingi/o opioid-induced analgesia. Opioidsi/o distinctively activates MOR, channel and inhibits the function of adenylyl cyclase and calcium channels. Alcohol activates the GIRK DOR, and KOR, that leads to Gi/o protein activation. The activated Gi/o protein activates the GIRK channel directly and modulates the functions of other target molecules. Non-steroid anti-inﬂammatory channel and inhibits the function of adenylyl cyclase and calcium channels. Alcohol activates the drugs (NSAIDs) induce analgesia in a GIRK channel independent fashion. In weaver mutant mice, GIRK channel directly and modulates the functions of other target molecules. Non-steroid anti- GIRK channel activation either by G protein or by alcohol is impaired, and both opioid- and inflammatory drugs (NSAIDs) induce i/oanalgesia in a GIRK channel independent fashion. In weaver alcohol-induced analgesia is reduced, whereas NSAIDs normally induce analgesia. mutant mice, GIRK channel activation either by Gi/o protein or by alcohol is impaired, and both opioid-Kranzler and et alcohol-induced al. [163] and Zhanganalgesia et is al. reduced, [164]have whereas shown NSAIDs that normally the A118G induce variant analgesia. of the MOR1 (OPRM1) gene may be an obvious candidate mediating alcohol-induced analgesia. A118G carriers Kranzler et al. [163] and Zhang et al. [164] have shown that the A118G variant of the MOR1 experience attenuated pain sensitivity that may alter analgesic responses to alcohol [141]. The A118G (OPRM1) gene may be an obvious candidate mediating alcohol-induced analgesia. A118G carriers or val158met polymorphism of the catechol-O-methyl-transferase (COMT) gene could be a possible experience attenuated pain sensitivity that may alter analgesic responses to alcohol [141]. The A118G link between alcohol’s analgesia and reinforcement activities [165,166]. The val158met carrier exhibit or val158met polymorphism of the catechol-O-methyl-transferase (COMT) gene could be a possible higher COMT levels, lower DA neurotransmission, elevated activation of the MORs [167,168], link between alcohol’s analgesia andergic reinforcement activities [165,166]. The val158met carrier exhibit and suppressed MOR NT response to pain [169]. higher COMT levels, lower DAergic neurotransmission, elevated activation of the MORs [167,168], and suppressed MOR NT response to pain [169]. Biomedicines 2019, 7, 16 14 of 31 Biomedicines 2019, 7, x 14 of 31

Possible CNS mechanisms underlying the the addictiv addictivee effects effects of opioids alone or in combination with alcohol are hypothesized in Figure 13.13. Acute Acute alcohol alcohol exposure exposure causes causes reinforcing reinforcing (euphoria, red font) andand weakweak analgesia,analgesia, while while acute acute opioid opioid exposure exposure (blue (blue font) font) causes causes strong strong analgesia analgesia (Figure (Figure 13A red font). Acute alcohol activates DA neurons, thus releasing endogenous opioids (eOPs) that 13A red font). Acute alcohol activates DAergicergic neurons, thus releasing endogenous opioids (eOPs) that inhibits GABA activity either by directly binding to the OPRs or via inhibiting Glu release from inhibits GABAergicergic activity either by directly binding to the OPRs or via inhibiting Glu release from the Glu neurons [170]. A decrease in GABA disinhibits postsynaptic DA neurons resulting in the Gluergicergic neurons [170]. A decrease in GABA disinhibits postsynaptic DAINTINT neurons resulting in an increasean increase in DA in DA release release in inNAc NAc causing causing reinforcing reinforcing and and pleasure pleasure effects. effects. However, However, acute acute exposure exposure to synthetic opioids such as morphine morphine directly activates OPR-signaling, resulting in potent activation of cAMP signaling and ensuing analgesia, with weaker reinforcing [[171].171]. A B

Figure 13. Possible mechanisms underlying the reinforcing and analgesic effects of alcohol exposure. (A) Figure 13. Possible mechanisms underlying the reinforcing and analgesic effects of alcohol exposure. Acute alcohol exposure induces eOP release but inhibits Glu release from Gluergic neurons, resulting in (A) Acute alcohol exposure induces eOP release but inhibits Glu release from Gluergic neurons, suppression of GABAergic neurons. Downregulation of GABAergic neurons disinhibits DAergic neurons, resulting inin ansuppression increase in of DA GABA releaseergic and neurons. ensuing Downregulation reinforcement. Opioid of GABA exposureergic neurons induces disinhibits analgesia DAergic neurons, resulting in an increase in DA release and ensuing reinforcement. Opioid exposure via cAMP/CREB signaling. (B) In addicted subjects consuming alcohol, OPergic, Gluergic and GABAergic induces analgesia via cAMP/CREB signaling. (B) In addicted subjects consuming alcohol, OPergic, neurons respond like the non-addicted subjects, but DAergic neurons and the analgesic pathway are less Gluresponsive.ergic and GABA Cumulatively,ergic neurons addicted respond subjects like drinkingthe non-addicted alcohol exhibited subjects, poor but opioid-inducedDAergic neurons analgesia and the analgesic pathway are less responsive. Cumulatively, addicted subjects drinking alcohol exhibited and euphoria. (C) Alcohol abstinence in addicted subjects result in hyperactivity of Gluergic but poor opioid-induced analgesia and euphoria. (C) Alcohol abstinence in addicted subjects result in downregulation of GABAergic neurons, causing neuronal excitation and the withdrawal symptoms. hyperactivityAlcohol resumption of Glu restoresergic but opioid’sdownregulation analgesic potencyof GABA butergic to neurons, a lesser degree,causing but neuronal eOP release excitation is restored. and the withdrawal symptoms. Alcohol resumption restores opioid’s analgesic potency but to a lesser degree,The addictive but eOP release effects is of restored. alcohol and opioids are mediated by a common addiction pathway (Figure 13B) [172–174]. In alcoholic subjects, alcohol exposure reduces release of eOPs from OPergic neurons,The butaddictive activates effects Glu releaseof alcohol from and Glu ergicopioidsneurons, are mediated resulting inby ana increasecommon in addiction GABAergic pathwayactivity (Figure13B)and GABA release.[172–174]. As In shown alcoholic in Figure subjects, 13C, alco alcoholhol exposure withdrawal reduces causes release further of increase eOPs from in Glu OPergicergic neurons,activity and but decreaseactivates in Glu GABA releaseergic fromactivity. Glu Thisergic neurons, results in resulting ampliﬁcation in an increase of the withdrawal in GABAergic symptoms. activity andAlcohol GABA resumption release. As establishes shown in homeostasis Figure 13C, by alcohol increasing withdrawal GABAergic causesactivity, further while increase Gluergic in activityGluergic activityremains and elevated. decrease in GABAergic activity. This results in amplification of the withdrawal symptoms. AlcoholTaken resumption together, theseestablishes observations homeostasis indicate by that increasing alcohol and GABA opioidergic drugsactivity, have while numerous Gluergic common activity remainsbehavioral elevated. effects, including sedation, motor depression, and rewarding experiences, possibly related to the effectsTaken of together, alcohol administrationthese observations on release indicate of eOP that peptides alcohol [175 and,176 opioid]. An increasedrugs have of eOP numerous peptides commonincrease alcoholbehavioral consumption effects, thatincluding is blocked sedation, by nonselective motor depression, opioid antagonists and rewarding such as naloxoneexperiences, and possiblynaltrexone related [177,178 to]. the Possible effects adverse of alcohol effects administra of alcoholtion on opioidson release are shownof eOP in peptides Figure 14 [175,176].. An increase of eOP peptides increase alcohol consumption that is blocked by nonselective opioid antagonists such as naloxone and naltrexone [177,178]. Possible adverse effects of alcohol on opioids are shown in Figure 14. Biomedicines 2019, 7, x 15 of 31 Biomedicines 2019,, 7,, x 16 1515 of of 31 31

Figure 14. Effects of Alcohol exposure on opioid’s pharmacokinetics, cardiovascular function, CNS Figure 14. Effects of Alcohol exposure on opioid’s pharmacokinetics, cardiovascular function, Figurefunctions 14. and Effects prenatal of Alcohol effects. exposure on opioid’s pharmacokinetics, cardiovascular function, CNS CNS functions and prenatal effects. functions and prenatal effects. 3.5. Alcohol-Cannabis Interactions 3.5. Alcohol-Cannabis Interactions Δ∆9-Tetrahydrocannabinol-Tetrahydrocannabinol (THC), (THC), the the main main psychoacti psychoactiveve component of cannabis [179], [179], elicits its 9 acuteΔ effects -Tetrahydrocannabinol via the endocannabinoid (THC), (eCB)the main typetype psychoacti 11 (CB(CB11) receptorve component (CB1R) [180]. [of180 cannabis]. THC THC has[179], been elicits linked its acuteto the effectsrewarding via the aspects endocannabinoid and cognitive (eCB) impairments type 1 (CB of 1cannabis ) receptor (Figure (CB1R) 15).15 [180].). 2-Arachidonoylglycerol 2-Arachidonoylglycerol THC has been linked to(2-AG), the rewarding produced aspects by diacylglyceroldiacylglycerol and cognitive lipase impairments (DAGL)(DAGL) ininof DAcannabisDAergicergic VTAVTA (Figure neurons 15). 2-Arachidonoylglycerol[181], [181], acts on CBCB1Rs on ergic 1 (2-AG),nearby Gluproducedergic andand by GABA GABA diacylglycerolergicergic terminals.terminals. lipase CB CB(DAGL)1Rs1Rs robustly robustly in DA inhibit inhibit VTA GABA GABA neurons inputs inputs [181], onto onto acts VTA VTA on CBDA DARs cells. cells. on ergic ergic 1 nearbyCB1RsRs are areGlu also andlocalized GABA on Glu terminals.ergic terminalsterminals CB Rs synapsing synapsing robustly oninhibit on VTA VTA GABA DA DA neurons neurons inputs where whereonto VTA eCBs DA mediate cells. CBretrograde1Rs are also suppressionsuppression localized of onof excitation. Gluexcitaergiction. terminals Thus, Thus, eCBs synapsingeCBs ﬁne-tune fine-tune theon activityVTA the DA activity of neurons the mesolimbic of wherethe mesolimbic DAeCBs projections mediate DA retrogradeprojectionsthrough modulating suppressionthrough bothmodulating of excitatory excita tion.both and Thus,excitatory inhibitory eCBs and signalingfine-tune inhibitory [182the]. activitysignaling THC exposure of [182].the disrupts mesolimbicTHC exposure the eCBDA projectionsdisruptsretrograde the signalingthrough eCB retrograde systemmodulating andsignaling producesboth system excitatory complex, and producesand diverse inhibitory andcomplex, potentially signaling diverse long-term [182]. and potentially THC effects exposure on long- the disruptstermDAergic effectssystem the oneCB includingthe retrograde DAergic increase system signaling inincluding nerve system ﬁring increase and and produces DAin nerve release complex, firing in response and diverse DA to releaseand acute potentially THC. in response However, long- to ergic termacuteDAergic effects THC.blunting However,on the may DA beDA associatedergic system blunting including with may long-term be increase associated use in [ 183nerve with,184 long-termfiring]. and use DA [183,184] release in. response to acute THC. However, DAergic blunting may be associated with long-term use [183,184].

Figure 15. Schematic description the endocannabinoid receptor signaling. Endogenous endocannabinoids, Figure 15. Schematic description the endocannabinoid receptor signaling. Endogenous N-arachidonoy-lethanolamine (anandamide or AEA) and 2-arachido-noylglycerol (2-AG) released by the Figureendocannabinoids, 15. Schematic N-arachidonoy-lethanolam description the endocannabinoine (anandamideid receptor or AEA)signaling. and Endogenous2-arachido- VTA neurons, bind to CB1 and CB2 receptors on Gluergic and GABAergic neurons, resulting in release endocannabinoids,noylglycerol (2-AG) releasedN-arachidonoy-lethanolam by the VTA neurons,ine bind(anandamide to CB1 and orCB2 AEA) receptors and on 2-arachido-Gluergic and of Glu and GABA, respectively. Glu and GABA bind to their respective receptors on DAergic neurons noylglycerolGABAergic neurons, (2-AG) resulting released in by release the VTA of Glu neur andons, GABA, bind torespectively. CB1 and CB2 Glu receptors and GABA on bind Glu ergicto theirand and induce DA release. Cannabis such as THC compete with ARA and 2-AG for CB1 (AEA >> 2-AG) GABArespectiveergic neurons, receptors resulting on DAergic in neurons release ofand Glu induce and GABA, DA release. respectively. Cannabis Glu such and as GABA THC compete bind to theirwith and CB2 (AEA ≈ 2-AG) receptors and disrupts normal endocannabinoid retrograde signaling from respectiveARA and receptors2-AG for onCB1 DA (AEAergic neurons >> 2-AG) and and induce CB2 DA (AEA release. ≈ 2-AG) Cannabis receptors such asand THC disrupts compete normal with DAergic neurons. ARAendocannabinoid and 2-AG for retrograde CB1 (AEA signaling >> 2-AG) from and DA CB2ergic neurons. (AEA ≈ 2-AG) receptors and disrupts normal endocannabinoid retrograde signaling from DAergic neurons. Biomedicines 2019, 7, x 16 of 31 Biomedicines 2019, 7, 16 16 of 31 Alcohol and cannabis, being neuro-inhibitory agents, share many behavioral abnormalities such as euphoria, analgesia, sedation, hypothermia, cognitive and motor dysfunctions, etc. [185] Alcohol and cannabis, being neuro-inhibitory agents, share many behavioral abnormalities such Therefore, combination of alcohol and marijuana in occasional cannabis users may additively alter as euphoria, analgesia, sedation, hypothermia, cognitive and motor dysfunctions, etc. [185] Therefore, the magnitude of cognitive and motor impairments [186,187]. However, chronic cannabis use may combination of alcohol and marijuana in occasional cannabis users may additively alter the magnitude develop tolerance to the impairing effects of cannabis and/or alcohol. Studies have shown that of cognitive and motor impairments [186,187]. However, chronic cannabis use may develop tolerance approximately 58% of adolescent drinkers also use cannabis [188], contributing to frequent to the impairing effects of cannabis and/or alcohol. Studies have shown that approximately 58% of comorbidity between alcohol and cannabis use disorders [189]. Figure 16 [190] shows 30-day trends adolescent drinkers also use cannabis [188], contributing to frequent comorbidity between alcohol in alcohol and cannabis use prevalence (1976–2011) among high school students. Plots 1 and 2 show and cannabis use disorders [189]. Figure 16[ 190] shows 30-day trends in alcohol and cannabis use percentage of students using alcohol and cannabis, respectively, for the last 30 days, while plots 3 prevalence (1976–2011) among high school students. Plots 1 and 2 show percentage of students using regular cannabis uses accompanied by alcohol use some time and plot 4 shows cannabis use was alcohol and cannabis, respectively, for the last 30 days, while plots 3 regular cannabis uses accompanied almost always associated with alcohol use. by alcohol use some time and plot 4 shows cannabis use was almost always associated with alcohol use.

Figure 16. Prevalence of alcohol and cannabis use among high school students is shown from 1976–2011. Figure 16. Prevalence of alcohol and cannabis use among high school students is shown from 1976– Plots 1 and 2 show percentage of students using alcohol and cannabis, respectively, for last 30 days, 2011. Plots 1 and 2 show percentage of students using alcohol and cannabis, respectively, for last 30 while plots 3 shows regular cannabis use accompanied with alcohol use some time. Plot 4 shows days, while plots 3 shows regular cannabis use accompanied with alcohol use some time. Plot 4 shows the number of students in which cannabis use was almost always associated with alcohol use. [Data the number of students in which cannabis use was almost always associated with alcohol use. [Data from [190] were used in this plot. from [190] were used in this plot. Figure 16 suggests that a sizable proportion of US high school seniors used a combination of alcohol and cannabisFigure 16 in suggests social use that situations. a sizable Alcohol proportion and cannabis of US high use during school adolescence seniors used is ofa concerncombination because of thealcohol introduction and cannabis of drug in combinations social use situations. early may Alco disrupthol healthyand cannabis brain development use during adolescence [191,192]. Studies is of haveconcern shown because that the hippocampusintroduction of (a drug region combinat associatedions with early learning may disrupt and memory healthy formation brain development [193]) may be[191,192]. particularly Studies vulnerable have shown to structural that the damage hippocampus caused (a by region heavy alcoholassociated and/or with cannabis learning use, and especially memory duringformation adolescence. [193]) may Aloi be particularly et al. [194] have vulnerable demonstrated to structural differential damage patterns caused of by dysfunction heavy alcohol associated and/or withcannabis alcohol use, use especially disorder during (AUD) adol andescence. cannabis Aloi use et disorderal. [194] have (CUD) demonstrated symptoms. Elevateddifferential severity patterns of AUDof dysfunction symptoms associated was associated with with alcohol (i) an useincreased disorderamygdala (AUD) response and cannabis to positive use relativedisorder to neutral(CUD) stimulisymptoms. and (ii)Elevated a decreased severityresponses of AUD associated symptoms with behavioral was associated inhibition with and (i) executive an increased attention amygdala during incongruentresponse to andpositive congruent relative trials, to whileneutral elevated stimuli CUD and symptomatology (ii) a decreased wasresponses associated associated with increased with responsesbehavioral ininhibition the posterior and cingulateexecutive cortex, attention precuneus, during andincongruent inferior parietal and congruent lobule for trials, incongruent while relativeelevated to CUD congruent symptomatology and view trials. was This associated suggests with that increased correlates responses of AUD symptomatology in the posterior may cingulate differ fromcortex, those precuneus, of CUD and symptomatology. inferior parietal Therefore, lobule for a combination incongruent of relative AUD and to congruent CUD may additivelyand view trials. cause greaterThis suggests brain damage that thancorrelates AUD orof CUD AUD individually symptomatology as summarized may indiffer Figure from 17. those of CUD symptomatology.Earlier studies Therefore, [195–197 ]a have combination identified of mechanistic AUD and CUD links may between additively the effects cause of greater alcohol brain and damage than AUD or CUD individually as summarized in Figure 17. cannabinoids, both enhanced DA levels in the NAc by activating DAergic neurons in the VTA from which the mesoaccumbal DA-mediated pathway originates. Hungund et al. [198] showed that alcohol −/− did not cause the release of DA in CB1 mice or SR141716A, a selective cannabinoid receptor antagonist, administered wild-type mice. Cohen et al. [199] showed that SR141716A reduced alcohol consumption, possibly via reducing DA release in the NAc in mice. These results strongly suggest that administration of cannabis and alcohol may additively enhance DA release the NAc. Guillot et al. [200] Biomedicines 2019, 7, 16 17 of 31 showed that, among people using cannabis and alcohol, the interplay between social anxiety and coping-oriented motives for using one substance (such as cannabis or alcohol) may pose difficulties in refraining from other substances such as alcohol or tobacco). Therefore, it is important to tailor multi-substanceBiomedicines 2019, 7, treatmentsx to specific needs when a single-substance intervention may not be effective.17 of 31

Figure 17. Effects of alcohol exposure on cannabis’s pharmacokinetics, cardiovascular function, CNS Figure 17. Effects of alcohol exposure on cannabis’s pharmacokinetics, cardiovascular function, CNS functions and prenatal effects. functions and prenatal effects. Although the molecular basis of alcohol-cannabis interaction is not yet known, recent studies have Earlier studies [195–197] have identified mechanistic links between the effects of alcohol and proposed epigenetic mechanisms (nuclear factors, histone modifications, and DNA methylation) to be cannabinoids, both enhanced DA levels in the NAc by activating DAergic neurons in the VTA from which important in determining consequences of the interaction [201–203]. A critical clue for alcohol-cannabis the mesoaccumbal DA-mediated pathway originates. Hungund et al. [198] showed that alcohol did not interaction was provided by the following observation: CB1 receptor knockout mice or those treated cause the release of DA in CB1−/− mice or SR141716A, a selective cannabinoid receptor antagonist, with CB1 antagonist exhibited markedly reduced voluntary alcohol consumption, possibly due to lack administered wild-type mice. Cohen et al. [199] showed that SR141716A reduced alcohol consumption, alcohol-induced DA release in the NAc [204]. Subbanna et al. [205] reported that post-natal alcohol possibly via reducing DA release in the NAc in mice. These results strongly suggest that administration exposure induced neonatal neurodegeneration possibly by enhancing CB1 exon1 activity through of cannabis and alcohol may additively enhance DA release the NAc. Guillot et a.l [200] showed that, upregulated histone H4K8 acetylation and downregulated H3K9 methylation. Another study showed among people using cannabis and alcohol, the interplay between social anxiety and coping-oriented that perinatal alcohol exposure impaired DNA methylation through downregulation of DNA methyl motives for using one substance (such as cannabis or alcohol) may pose difficulties in refraining from transferases DNMT1 and DNMT3A in the neonatal brain and that such deficiencies were absent in other substances such as alcohol or tobacco). Therefore, it is important to tailor multi-substance CB1 receptor null mice [206]. Taken together, these reports suggest the potential of epigenetic overlap treatments to specific needs when a single-substance intervention may not be effective. between alcohol and cannabis activities. Figure 18 summarizes the epigenetic mechanisms of alcohol and Although the molecular basis of alcohol-cannabis interaction is not yet known, recent studies Biomedicinescannabinoid 2019 activity, 7, x and possible overlaps between the two substances at the epigenetic level [20718 ,of208 31]. have proposed epigenetic mechanisms (nuclear factors, histone modifications, and DNA methylation) to be important in determining consequences of the interaction [201–203]. A critical clue for alcohol-cannabis interaction was provided by the following observation: CB1 receptor knockout mice or those treated with CB1 antagonist exhibited markedly reduced voluntary alcohol consumption, possibly due to lack alcohol-induced DA release in the NAc [204]. Subbanna et al. [205] reported that post-natal alcohol exposure induced neonatal neurodegeneration possibly by enhancing CB1 exon1 activity through upregulated histone H4K8 acetylation and downregulated H3K9 methylation. Another study showed that perinatal alcohol exposure impaired DNA methylation through downregulation of DNA methyl transferases DNMT1 and DNMT3A in the neonatal brain and that such deficiencies were absent in CB1 receptor null mice [206]. Taken together, these reports suggest the potential of epigenetic overlap between alcohol and cannabis activities. Figure 18 summarizes the epigenetic mechanisms of alcohol and cannabinoid activity and possible overlaps between the two substances at the epigenetic level. [207,208]. Figure 18. Possible epigenetic mechanisms for alcohol— alcohol—cannabiscannabis interactions. Alcohol and cannabis both modulate modulate CB1 CB1 and and CB2 CB2 receptors, receptors, resulting resulting in activation in activation of the of MAPK the MAPK signaling signaling pathways, pathways, that furtherthat further activates activates (i) nuclear (i) nuclear factors factors CREB CREB and and NF- NF-κB,κ B,(ii) (ii) histone histone modifications, modiﬁcations, and and (iii) (iii) DNA methylation mediated mediated by by the epigenetic enzymes. This This leads leads to to altered altered gene gene expression expression and and cell functionalityfunctionality through through apoptosis, oxidative stress, plasticity or immuno-modulation.

3.6. Alcohol-GHBA Interactions GHB is a natural sedative with the potential to be used as a recreational drug [209,210]. The popularity of GHB as a drug of abuse has grown recently [211]. Alcohol has been shown to enhance the sedative effect of GHB in humans and animals [212,213]. Co-administration of GHB and alcohol induces sedation stronger than the sum of the sedation induced by the individual substances [214], possibly due to a pharmacokinetic interaction resulting in an increased concentration at the site of action (Figure 19).

Figure 19. Pharmacokinetic mechanism of alcohol-GHB interaction. GHB is primarily metabolized to succinic semialdehyde (SSA) by a P450 mediated NAD(P)+-linked oxidation catalyzed by GHB dehydrogenase (GHBD). SSA is further metabolized to succinic acid, a citric acid cycle substrate. In case of alcohol-GHB co-exposure, alcohol competes with GHB for the enzyme’s binding sites, resulting in a decrease in GHB metabolism. However, for exogenously administered GHB, it is unclear whether co- administration with alcohol results in increased GHB or alcohol plasma concentrations.

To understand the effects of alcohol on the pharmacokinetics of GHB, it is important to understand alcohol’s interaction with the metabolic system. Studies have shown that, at lower alcohol concentrations, only about 10% of the consumed alcohol undergoes CYP-mediated first-pass metabolism in liver. Since alcohol and GBH compete for CYP2E1 (GHBD), alcohol, depending on its concentration, reduces GBH degradation and ensuing increase in its blood concentrations [215]. Chronic, heavy alcohol consumption induces the activity of CYP2E1, resulting in a decrease in GHB concentrations. The adverse effects related to GHB ingestion are shown in Figure 20 [216]. Overall adverse effects depend on the variability among users and the inherent variability in street Biomedicines 2019, 7, x 18 of 31

Figure 18. Possible epigenetic mechanisms for alcohol—cannabis interactions. Alcohol and cannabis both modulate CB1 and CB2 receptors, resulting in activation of the MAPK signaling pathways, that further activates (i) nuclear factors CREB and NF-κB, (ii) histone modifications, and (iii) DNA methylation mediated by the epigenetic enzymes. This leads to altered gene expression and cell Biomedicines 2019, 7, 16 18 of 31 functionality through apoptosis, oxidative stress, plasticity or immuno-modulation.

3.6.3.6. Alcohol-GHBA InteractionsInteractions GHBGHB isis a naturala natural sedative sedative with with the potentialthe potential to be usedto be as used a recreational as a recreational drug [209 ,drug210]. The[209,210]. popularity The ofpopularity GHB as aof drug GHB of as abuse a drug has of grownabuse has recently grown [211 rece].ntly Alcohol [211]. has Alcohol been shownhas been to shown enhance to theenhance sedative the effectsedative of GHB effect in of humans GHB in andhumans animals and [animals212,213]. [212,213]. Co-administration Co-administration of GHB and of GHB alcohol and induces alcohol sedation induces strongersedation thanstronger the than sum the of thesum sedation of the sedation induced indu byced the by individual the individual substances substances [214], [214], possibly possibly due todue a pharmacokineticto a pharmacokinetic interaction interaction resulting resulting in an in increased an increased concentration concentration at the at site the of site action of action (Figure (Figure 19). 19).

FigureFigure 19.19. Pharmacokinetic mechanism mechanism of of alcohol-GHB alcohol-GHB inte interaction.raction. GHB GHB is isprimarily primarily metabolized metabolized to tosuccinic succinic semialdehyde semialdehyde (SSA) (SSA) by by a aP450 P450 mediated NAD(P)++-linked-linked oxidation oxidation catalyzed catalyzed by GHBGHB dehydrogenasedehydrogenase (GHBD).(GHBD). SSASSA isis furtherfurther metabolizedmetabolized toto succinicsuccinic acid,acid, aa citriccitric acidacid cyclecycle substrate.substrate. InIn casecase ofof alcohol-GHBalcohol-GHB co-exposure, alcohol competes competes with with GHB GHB for for the the enzyme’s enzyme’s bindin bindingg sites, sites, resulting resulting in in a adecrease decrease in in GHB GHB metabolism. metabolism. However, However, for for exogenously exogenously administered administered GHB, GHB, it is it unclear is unclear whether whether co- co-administrationadministration with with alcohol alcohol results results in incr in increasedeased GHB GHB or alcohol or alcohol plasma plasma concentrations. concentrations.

ToTo understandunderstand the the effects effects of alcoholof alcohol on the on pharmacokinetics the pharmacokinetics of GHB, of it isGHB, important it is toimportant understand to alcohol’sunderstand interaction alcohol’s with interaction the metabolic with the system. metabolic Studies system. have shown Studies that, have at lowershown alcohol that, at concentrations, lower alcohol onlyconcentrations, about 10% ofonly the consumedabout 10% alcohol of the undergoes consumed CYP-mediated alcohol undergoes first-pass metabolismCYP-mediated in liver. first-pass Since alcoholmetabolism and GBHin liver. compete Since foralcohol CYP2E1 and (GHBD),GBH compet alcohol,e for depending CYP2E1 (GHBD), on its concentration, alcohol, depending reduces on GBH its degradationconcentration, and reduces ensuing GBH increase degradation in its blood and concentrations ensuing increase [215]. Chronic, in its blood heavy concentrations alcohol consumption [215]. BiomedicinesinducesChronic, the heavy 2019 activity, 7, alcoholx of CYP2E1, consumption resulting induces in a decrease the acti invity GHB of concentrations. CYP2E1, resulting The adversein a decrease effects in19 related GHBof 31 toconcentrations. GHB ingestion The are adverse shown in effects Figure related 20[ 216 ].to Overall GHB ingestion adverse effectsare shown depend in onFigure the variability20 [216]. Overall among manufacturingusersadverse and effects the inherent [217].depend This variability on makes the in variabilityGHB street a manufacturinghighly among da ngeroususers [217 and ].drug This the to makes inherentconsume. GHB variability aIt highly exhibits dangerous in a steepstreet dosage-responsedrug to consume. curve, It exhibits thus, a steepexceeding dosage-response the intoxicating curve, dose thus, can exceeding result in the severe intoxicating adverse dose effects can occurringresult in severe within adverse 15 minutes effects of occurring ingestion within of GHB 15 [218,219]. minutes of ingestion of GHB [218,219].

Figure 20. 20. EffectsEffects of ofalcohol alcohol exposure exposure on GHBA’s on GHBA’s pharmacokinetics, pharmacokinetics, cardiovascular cardiovascular function, function, CNS functionsCNS functions and prenatal and prenatal effects. effects.

4. Conclusions Co-abuse of alcohol with drugs of abuse (psychostimulants (cocaine, METH and nicotine) and inhibitors (opioids, cannabis and GHBA) and medications) is a serious health problem the society faces today. People abuse multiple drugs possibly due to the perception of potentiated euphoric and pleasure effects and decreased adverse subjective effects. The negative consequences of alcohol and psychostimulant co-abuse may include a decrease in antioxidant enzymes, disruption of learning and memory processes, cerebral hypo-perfusion, neurotransmitters depletion as well as potentiated drug- seeking behavior. As summarized in Figure 21, alcohol activates inhibitory GABAergic and OPergic neurons, but inhibits excitatory Gluergic neurons. Thus, alcohol additively or synergistically augments inhibitory signaling by opioids, cannabis and GHB, but suppresses stimulatory signaling by cocaine, METH and nicotine. Alcohol may also modify the liver CYP enzymes, thus modifying the drugs plasma concentrations. Taken together, alcohol may modify both the pharmacokinetics and pharmacodynamics of co-abused drugs. Therefore, alcohol-drug interaction must be considered when developing alcoholism therapy. Biomedicines 2019, 7, 16 19 of 31

4. Conclusions Co-abuse of alcohol with drugs of abuse (psychostimulants (cocaine, METH and nicotine) and inhibitors (opioids, cannabis and GHBA) and medications) is a serious health problem the society faces today. People abuse multiple drugs possibly due to the perception of potentiated euphoric and pleasure effects and decreased adverse subjective effects. The negative consequences of alcohol and psychostimulant co-abuse may include a decrease in antioxidant enzymes, disruption of learning and memory processes, cerebral hypo-perfusion, neurotransmitters depletion as well as potentiated drug-seeking behavior. As summarized in Figure 21, alcohol activates inhibitory GABAergic and OPergic neurons, but inhibits excitatory Gluergic neurons. Thus, alcohol additively or synergistically augments inhibitory signaling by opioids, cannabis and GHB, but suppresses stimulatory signaling by cocaine, METH and nicotine. Alcohol may also modify the liver CYP enzymes, thus modifying the drugs plasma concentrations. Taken together, alcohol may modify both the pharmacokinetics and pharmacodynamics of co-abused drugs. Therefore, alcohol-drug interaction must be considered when Biomedicines 2019, 7, x 20 of 31 developingBiomedicines alcoholism 2019, 7, x therapy. 20 of 31

Figure 21. Proposed mechanisms underlying alcohol’s interaction with co-abused drugs. Alcohol Figure 21. Proposed mechanisms underlyingFigure alcohol’s 21. Proposedinteraction mechanisms with co-abused underlying drugs. alcohol’sAlcohol interaction with co-abused drugs. Alcohol (referred as alcohol in this article) is rapidly absorbed and distributed. It is metabolized to acetaldehyde (referred as alcohol in this article) is rapidly(referred absorbed as alcohol and distributed. in this article) It is ismetabolized rapidly absorbed to and distributed. It is metabolized to by ADHacetaldehyde and CYP by enzymes, ADH and CYP then enzymes, to acetate then byacetaldehyde toALDH. acetate by In by ALDH. this ADH process, Inand this CYP process, alcohol enzymes, alcohol competes then competes to acet withate by the ALDH. In this process, alcohol competes co-administeredwith the co-administered drugs and suppresses drugs and their suppresses elimination,with their the elimination,co-administered thus increasing thus drugsincreasing the drug’s and suppressesthe plasma drug’s concentration plasmatheir elimination, thus increasing the drug’s plasma

and alteringconcentration its pharmacokinetics and altering its pharmacokinetics (increase in Cmaxconcentration (increaseand AUC, in and C decreasemax altering and AUC, in its CL). pharmacokinetics decrease Chronic in CL). alcohol Chronic (increase exposure in Cmax and AUC, decrease in CL). Chronic activatesalcohol the exposure liver CYP activates enzymes, the resultingliver CYP inenzymes,alcohol a decrease exposureresulting in the activatesin drug’sa decrease the plasma liverin the concentrations,CYP drug’s enzymes, plasma resulting with in a decrease in the drug’s plasma a decreaseconcentrations, in its efficacy. with a decrease Alcohol, in in its addition efficacy.concentrations, Alcoho to alteringl, in addition pharmacokinetics with a to decrease altering in pharmacokinetics its of efficacy. a drug, Alcoho also of alter l,a in itsaddition to altering pharmacokinetics of a drug, also alter its pharmacodynamics by activating GABAergic and OPergic presynaptic neurons (A(+), pharmacodynamicsdrug, also alter its by pharmacodynamics activating GABA byergic activatingand OP GABAergic presynapticergic and OPergic neurons presynaptic (A(+) neurons, but inhibiting (A(+), but inhibiting Gluergic presynaptic neuronsbut (A (-)inhibiting). Post-synoptically, Gluergic presynaptic alcohol activatesneurons GABA(A(-)). APost-synoptically,R − alcohol activates GABAAR Gluergic presynaptic neurons (A(-)). Post-synoptically, alcohol activates GABAAR mediated influx of Cl - mediated influx +of Cl- ions, but inhibits AMPAR-mediated2+ Na+ ions and NMDAR-mediated Ca2+ ions, ions,mediated but inhibits influx AMPAR-mediated of Cl ions, but inhibits Na+ AMPAR-mediatedions and NMDAR-mediated Na ions and NMDAR-mediated Ca2+ ions, resulting Ca in ions, reduced resulting in reduced excitability via IPSP. Thereforresultinge, alcohol in reduced may excitabilityaugment the via effects IPSP. ofTherefor inhibitorye, alcohol may augment the effects of inhibitory excitability via IPSP. Therefore,AP alcohol may augment the effects ofAP inhibitory drugs (opioids, cannabis drugs (opioids, cannabis and GHB) but suppressdrugs the (opioids, effects cannabisof excitatory and drugsGHB) (cocaine,but suppress METH the or effects of excitatory drugs (cocaine, METH or and GHB) but suppress the effects of excitatory drugs (cocaine, METH or nicotine). Chronic alcohol nicotine). Chronic alcohol exposure may have nicotine).opposite effects Chronic not alcohol shown expo in thissure figure. may haveAbbreviations: opposite effects not shown in this figure. Abbreviations: exposure may have opposite effects not shown in this figure. Abbreviations: A positive alcohol effects, + A(+): positive alcohol effects, A(−): negative alcoholA(+): positive effects, alcohol VGSE: effects,voltage-gated A(−(+):): negative sodium alcohol ion (Na effects,+) VGSE: voltage-gated sodium ion (Na ) + A(−): channelsnegative that alcohol may effects,be attenuated VGSE: by voltage-gated alcohol’s channelsIPSP, sodium VGCC: that ion voltage-gatedmay (Na be )attenuated channels calcium thatby alcohol’sion may (Ca be2+ )IPSP, attenuatedchannels VGCC: by voltage-gated calcium ion (Ca2+) channels 2+ - alcohol’sthat IPSP,may VGCC:be attenuated voltage-gated by alcohol’s calcium IPSP, ionthat (Ca GABAmay) channelsAbeR mediatedattenuated that may Clby- channels bealcohol’s attenuated thatIPSP, may by GABA alcohol’s be AR mediated Cl channels that may be − IPSP,additively/synergistically GABAAR mediated Cl activatedchannels by that alcohol’ mayadditively/synergistically bes IPSP, additively/synergistically inhibitory neurot activatedransmitters, activatedby alcohol’ excitatory. bys alcohol’sIPSP, inhibitory neurotransmitters, excitatory. AP IPSP,neurotransmitters, inhibitory neurotransmitters, AP action excitatory.potential. neurotransmitters,neurotransmitters, action potential. potential.

Funding: NO funding. Funding: NO funding.

Conflicts of Interest: The author declares no conflictConflicts of ofinterest. Interest: The author declares no conflict of interest.

Abbreviations Abbreviations

2-AG 2-Arachidonoylglycerol 2-AG 2-Arachidonoylglycerol 5-HT Serotonin 5-HT Serotonin A(+) alcohol’s +ve effects A(+) alcohol’s +ve effects A(−) alcohol’s −ve effects A(−) alcohol’s −ve effects AA arachidonic acid AA arachidonic acid AC adenylyl cyclase AC adenylyl cyclase ACh Acetylcholine ACh Acetylcholine AChergic ACh releasing neurons AChergic ACh releasing neurons Biomedicines 2019, 7, 16 20 of 31

Conﬂicts of Interest: The author declares no conﬂict of interest.

Abbreviations

2-AG 2-Arachidonoylglycerol 5-HT Serotonin

A(+) alcohol’s +ve effects A(−) alcohol’s −ve effects AA arachidonic acid AC adenylyl cyclase ACh Acetylcholine AChergic ACh releasing neurons ADH alcohol dehydrogenase ALDH acetaldehy6de dehydrogenase AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid AUC area under curve AUD alcohol use disorder cAMP cyclic adenosine monophosphate CL clearance Cmax maximum concentration COMT catechol-O-methyl-transferase COX Cyclooxygenase CYP cytochrome P450 DA Dopamine DA dopamine} DAG Diacylglycerol DAGL diacylglycerol lipase DAR1 dopamine receptor 1 DAT dopamine transporter DOR delta OPRs DPDEP D-Pen2, D-Pen5 enkephalin, DOR agonist EAA excitatory amino acids eCB Endocannabinoid eOP endogenous opioids ERK extracellular-signal-regulated kinase GABA γ-aminobutyric acid GABABR GABA B receptor GABAergic GABA releasing neurons GHB γ-hydroxybutyric acid GHBD GHB dehydrogenase GIRK G protein-coupled inwardly-rectifying potassium channels Glu Glutamate Gluergic glutamate releasing neurons Gly Glycine IP3 inositol trisphosphate KOR kappa OPRs LDTg laterodorsal tegmental nucleus LPS Lipopolysaccharide METH Methamphetamine mGluR2/3 metabolic Glu receptors 2/3 MOR mu OPRs NAc nucleus accumbens nAChR nicotinic ACh receptor NAPQI N-acetyl-p-benzoquinone imine Biomedicines 2019, 7, 16 21 of 31

NE Noradrenaline NMDA N-methyl-D-Aspartate receptors OP Opioid OPR opioid receptors OPRM1 A118G variant of the MOR1 PIP2 poly inositol diphosphate pptg pedunculopontine tegmental nucleus SERT serotonin transporter sOP synthetic opioids SSA succinic semialdehyde T elimination half-life THC ∆9-Tetrahydrocannabinol tmax time to Cmax TMU 1,3,7-trimethyluric acid U50488H KOR agonist VGSC voltage gated sodium ion (Na+) channel VGCC voltage gated calcium ion (Ca2+) channel VTA ventral tegmental area α7 and α4β2 nicotinic receptor subtypes

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