Alcohol Interactions with Psychostimulants: An Overview of Animal and Human Studies

Alcohol consumption with psychostimulants is very common among drug addicts. There is little known about the possible pharmacological interactions between alcohol and psychostimulants. Among most commonly co-abused psychostimulants with alcohol are methamphetamine, cocaine, 3,4-methylenedioxymethamphetaminen, and nicotine. Co-abuse of alcohol with psychostimulants can lead to several neurophysiological dysfunctions such as decrease in brain antioxidant enzymes, disruption of learning and memory processes, cerebral hypo-perfusion, neurotransmitters depletion as well as potentiation of drug seeking behaviour. Moreover, co-abuse of alcohol and psychostimulants can lead to increase in heart rate, blood pressure, myocardial oxygen consumption and cellular stress, and the risk of developing different types of cancer. Co-abuse of alcohol with psychostimulants during pregnancy can lead to fetal brain abnormalities. Further studies are needed to investigate the pharmacokinetics, pharmacodynamics, and neurochemical changes on co-abuse of alcohol and psychostimulants.


Introduction
Alcohol dependence is considered a major public health problem worldwide [1][2][3][4][5][6]. Alcohol can contribute to a significant number of disabilities due to psychological, medical, injury, or other detrimental effects [7]. These effects can be dramatically severe when alcohol is consumed with other drugs of abuse. Alcohol consumption with other drugs of abuse is very common among drug users. Different pharmacological mechanisms of interactions may occur when alcohol and other psychostimulants are co-abused. It is noteworthy that drugs of abuse have been shown to alter central brain reward circuitry, which can lead addicts to co-abuse because METH might mask the signs of alcohol intoxication, such as sedation and compensated performance, allowing abusers to consume more alcohol with risk of developing alcohol toxicity.
A double blind study was conducted on eight alcohol and METH abusers [37]. The abusers were found to have high myocardial oxygen consumption and increased heart rate ( Figure  2). In this study, the pharmacokinetics of METH did not change significantly, which is possibly due to the limited number of subjects recruited in this study. However, further testing should be done on more subjects to reach more conclusive evidence of the effect of alcohol on METH pharmacokinetics [37]. A recent clinical study conducted on nine volunteers showed an increase in heart rate [36]. Furthermore, findings showed that concurrent consumption of METH and alcohol disrupted learning and discriminating behaviour compared to METH self-administered alone in rats [38]. However, this study did not focus on the effects of alcohol alone which may hinder the conclusion that METH and alcohol co-abuse may disturb the performance compared to METH administered alone. A recent study conducted on rats revealed that concurrent intake of METH and alcohol can lead to synergistic effect in impairment of spatial memory compared to METH administered alone [39]. Interestingly, alcohol administered alone did not cause any changes in spatial memory suggesting the synergistic effects of both drugs on memory. Moreover, this study showed that although alcohol or METH administered alone can induce oxidative stress and impairments in antioxidant enzymes in rats hippocampus, co-abuse of METH and alcohol can cause synergistic effect in impairment and oxidative stress compared to drug administered alone ( Figure 3) [39].
Concurrent exposure to METH and alcohol has also been observed in pregnant women. Indeed, a study demonstrated that more than 40% of pregnant women who abused METH reported using alcohol during their pregnancy [40]. Another study was conducted on 61 participants; 13 of them were exposed prenatally to alcohol, 21 were exposed prenatally to METH, and the remaining 27 control participants were not prenatally exposed to either alcohol or METH [41]. Of the 21 participants in METH group, 18 children were also exposed to alcohol during their fetal life. The results of this study suggest that prenatal exposure to METH and alcohol can cause synergistic striatal structural damage than prenatal exposure to alcohol alone. Damage to the striatal brain region hinders the overall intellectual competence of the affected children [41]. In addition, in a study that found common damage in the fronto-striatal circuit of the prenatally METH exposed group, 15 out of 19 children were exposed to alcohol and METH prenatally ( Figure 4) [42]. It is important to note, however, that these studies could not precisely predict the dosage, frequency, and duration of METH or alcohol exposure during pregnancy, which may hamper our understanding of the pharmacological and neuropathological basis of drugs exposure and their interactions.

Alcohol and cocaine co-abuse
Cocaine can produce different effects on the human body; these effects can last from minutes to hours, based on the route through which cocaine was administered into the body [43]. In the brain, cocaine can affect the reward circuitry by modulating dopamine neurotransmission [44], and acts by preventing the reuptake of dopamine from the synaptic cleft, which leads to prolongation of the pleasurable effects of dopamine [44,45]. Cocaine can produce euphoria, alertness, dependence and tolerance as well as cardiovascular changes [46][47][48][49][50]. Tolerance makes cocaine users increase dosage each time to reach the same level of euphoria that was reached on the first instance of taking the drug. Increasing the doses of cocaine can lead to its side effects and toxicity [51][52][53][54]. It is important to note that the prevalence of alcohol use was found 89% higher among cocaine dependents [55]. This might be due to higher increase of reward effects when alcohol and cocaine co-abused compared to either drug self-administered alone, which have been shown in preclinical studies [56][57][58]. In a study conducted on rats, intravenous injections of cocaine increased alcohol drinking suggesting that cocaine potentiated alcohol seeking [59]. Interestingly, a preclinical study showed a higher genetic susceptibility of the reinforcing effects of cocaine in selectively bred alcohol preferring (P) rats compared to its outbred Wistar rats, which suggests a higher sensitivity of alcoholics to the reinforcing effects of cocaine [60]. Similarly, it has been revealed that genetically predisposed subjects for alcohol dependence have a higher rate to be cocaine dependents [61].
Cocaine co-administered with alcohol can lead to production of cocaethylene, which is more lethal than cocaine itself [62,63]. This cocaethylene can also produce most of the effects that are associated with cocaine [64,65]. Concurrent exposure of alcohol and cocaine may cause more lethality in rats than either drug administered alone, which probably due to the formation of cocaethylene [66]. Interestingly, cocaethylene detection in wastewater has been utilized in recent study as an evidence of co-abuse of cocaine and alcohol in different cities [67]. Cocaethylene levels were found to be significantly higher during weekends compared to weekdays suggesting a higher co-abuse of cocaine and alcohol during weekends [67].
Alcohol has been shown to increase the plasma concentration of cocaine [68]. This is probably mediated through a decrease in the metabolism of cocaine by carboxylesterases, which hydrolyze it to benzoylecgonine and ecgonine methyl ester metabolites [68] (Table 1). Furthermore, it has been demonstrated that alcohol administered with cocaine can lead to increase in cocaethylene concentration in plasma and decrease benzoylecgonine renal excretion ( Figure 1) [69]. It is noteworthy that different routes of drug exposure may produce different peak levels of cocaethylene [70]. For example, oral administration is considered the highest in raising cocaethylene concentration in blood as compared to intravenous route [70]. The inhalation route (i.e., smoking) showed the lowest effect on cocaethylene blood concentration compared to oral and IV routes [70]. Furthermore, cocaine and cocaethylene blood concentrations were obtained following concurrent use of cocaine and alcohol [71]. This study revealed that the concentration of cocaine in plasma was found to be increased by 15% after cocaine and alcohol co-exposure. Moreover, 22% of the absorbed cocaine was converted to cocaethylene. Although, cocaine half-life was not altered significantly by ingestion of alcohol, cocaethylene's half-life was increased in comparison to cocaine's [71]. Increasing the half-life of cocaethylene might impose serious health problem due to increasing body exposure to its deteriorating toxic effects.
Concurrent exposure to cocaine and alcohol has deleterious effects on cardiovascular and endocrine systems. Co-abuse of cocaine and alcohol was found to increase heart rate, systolic blood pressure, cortisol, and prolactin concentrations ( Figure 2) [64,69]. In addition, cerebral blood perfusion was found to be affected by co-exposure to cocaine and alcohol [72,73] (Table 1). It has been shown that cerebral hypo-perfusion was more common among individuals taking cocaine and alcohol compared to individuals taking cocaine or alcohol alone [72,73]. These findings show the significant deleterious effects of the co-abuse of alcohol and cocaine on cardiovascular system that might result in debilitating conditions. Several tests were performed on intelligence, memory, verbal learning and other aspects of neuropsychological performances to explore the effects of co-abuse of alcohol and cocaine [74,75] (Table 1). The resulting neuropsychological performances were found to be negatively affected by the concurrent intake of cocaine and alcohol compared to either drug administered alone ( Figure 3) [74,75]. It has been shown that the sense of pleasure and euphoria increased in co-abuse of alcohol and cocaine and consequently elevated the risk of dependence and toxicity [71,76]. In addition, alcohol was found to significantly potentiate the effect of cocaine in conditioned place preference in rat and invertebrate animal models [56,77]. Moreover, study showed that there is a synergistic effect in self-administration of both alcohol and cocaine in concentrations that did not provoke self-administration to either drug alone [78]. Similarly, a recent study has shown the potentiating effect of cocaine on alcohol seeking and relapse-like alcohol intake in P rats [79]. This might indicate a cross reactivity between alcohol and cocaine on common drug seeking behaviour.
Several studies have shown the involvement of mesolimbic dopaminergic system in reinforcing effects of cocaine [80][81][82][83] and alcohol [84,85]. In fact, alcohol and cocaine coexposure increased extracellular dopamine concentration in the nucleus accumbens, well known brain region involved in the rewarding and reinforcing effects of drugs of abuse [86-89], than either drug administered alone in rats [90] (Table 1). Furthermore, recent findings have demonstrated the critical role of glutamate and its uptake in central brain reward regions in the seeking and reinforcing effects of cocaine [91-93] and alcohol [94][95][96][97]. Further studies are needed for investigating the role of glutamatergic system in alcohol and cocaine co-abuse in brain regions involved in rewarding and reinforcing effects of these drugs.
Alternatively, studies have shown the detrimental effects of prenatal exposure to cocaine such as low birth weight, preterm delivery, and decrease in head circumstance [98][99][100][101]. However, prenatal co-exposure to cocaine and alcohol has not been well studied despite the findings that more than 85% of women who reported using cocaine during pregnancy, also reported concurrent alcohol use [98]. One recent study, however, has demonstrated a significant interaction in prenatal co-exposure of cocaine and alcohol on cortical thickness in youths prenatally exposed to these drugs [102]. Furthermore, it has been shown that prenatal exposure to alcohol increased the rewarding and reinforcing effects of cocaine in rats ( Figure  4) [103].

Alcohol and nicotine co-abuse
Alcohol and nicotine have serious global health problems. Table 1 summarizes different studies of the effects of alcohol and nicotine co-abuse. Nicotine dependents may have high tendency to be alcohol dependents [104]. It has been reported that more than 80% of chronic alcohol users are also smokers [105][106][107]. In a preclinical study, rats chronically co-exposed to alcohol and nicotine showed higher nicotine self-administration as compared to drug selfadministered alone [108]. Although, it has been suggested that nicotine or alcohol consumed alone may have some beneficial effect at low doses, it is clear that co-abuse of these drugs may have negative effects on human health [109].
Nicotine and alcohol activate the mesocorticolimbic dopaminergic system; there is potential synergistic effect in the increase of dopamine release when the drugs are consumed concurrently [110]. Furthermore, studies showed that alcohol and nicotine co-abuse can lead to increase dopaminergic neuronal firings and dopamine release [111][112][113][114][115][116] (Table 1). It is suggested that the synergistic effect of these drugs may influence drug reinforcement to each other and predispose smokers to become alcoholics and vice versa [110,117]. Interestingly, an additive effect on dopamine release in the nucleus accumbens shell was found between alcohol and nicotine in rats [116]. This additive effect on dopamine release was inhibited by mecamylamine pre-treatment, a nicotinic receptor antagonist, suggesting the involvement of nicotinic receptors in the reinforcing effects of alcohol. Importantly, alcohol-induced dopaminergic neurons firing in ventral tegmental area were inhibited in mice lacking nicotinic acetylcholine receptors that contain α6 subunit [118]. Moreover, it has been shown that alcohol and nicotine co-abuse can increase the pleasurable effects of each drug [119] ( Table 1). This may explain some of the pharmacological mechanisms of action involving the co-abuse of nicotine and alcohol in the modulation of dopamine release ( Figure 3).
The risk of developing cancer in general is higher in heavy tobacco smokers and alcohol drinkers [120][121][122][123]. In case-controlled clinical studies that were conducted on European and American subjects, alcohol and tobacco smoking elevated the risk of head and neck cancer in patients addicted to both drugs [124]. The exact mechanism of alcohol and nicotine interaction that results in the development of cancer is not well known and remains controversial. Studies have suggested that alcohol and nicotine co-abuse may produce toxic metabolites such as acetaldehyde, which may contribute to cancer development [125,126]. Other studies have suggested that alcohol and nicotine co-abuse promotes the formation of premalignant lesions (Figure 1) [127][128][129].
The effects of alcohol and nicotine co-abuse on cardiovascular system have been also investigated. Synergistic effects on heart rate and blood pressure were found in healthy human volunteers following alcohol and nicotine exposure [130,131]. Interestingly, the order of self-administering alcohol and nicotine plays a role in their negative interactive effect on cardiovascular system. When self-administration of alcohol was followed by nicotine, a synergistic effect on the increase in left ventricular pressure was revealed, which was alleviated when self-administration of nicotine was followed by alcohol in dogs (Figure 2) [132]. In a study investigated the link between alcohol and nicotine use during pregnancy in more than 14000 previous pregnant mothers, it was found that more than 55% of pregnant alcohol users reported smoking [133]. Alcohol and nicotine exposure during gestational period increased the risk of fetal growth abnormalities more than the exposure to alcohol alone [133][134][135]. Interestingly, in a study conducted on rats, alcohol and nicotine were coadministered to pregnant rats throughout the gestational period [136]. This study showed that offspring prenatally co-exposed to nicotine and alcohol developed rapid increase in nicotine self-administration as compared to controls (Figure 4) [136].

Alcohol and MDMA co-abuse
According to 2001-2002 national epidemiologic survey in United States, the prevalence of alcohol use in MDMA users is more than 95% [137]. MDMA and alcohol exposure in adolescent mice induced physiological and behavioural alteration than either drug administered alone [138]. In fact, recent study has shown that the co-abuse of MDMA and alcohol exacerbated cardiac cellular stress and toxicity through augmented activation of cardiac sympathetic system in adolescent mice ( Figure 2) [139]. MDMA can induce a rapid release of dopamine and serotonin [140]. High consumption of MDMA may result in depletion of serotonin in the brain, resulting in serious psychological consequences [141][142][143][144][145][146][147][148]. MDMA is usually consumed with many drugs such as amphetamine, cocaine, cannabis, and alcohol. Alcohol and MDMA co-abuse is considered the most popular form of MDMA co-abuse [149][150][151][152][153]. Importantly, mice pre-treated with MDMA were found to consume high amount of alcohol compared to control mice [154] (Table 1). Therefore, mice consumed higher amounts of alcohol to reach to the same reward effect that was normally reached at lower doses of alcohol. This study also found that MDMA impaired the dopaminergic pathway. Furthermore, findings revealed that presynaptic modulation of serotonin release in the hippocampus is affected by exposure to both MDMA and alcohol [155]. This study also showed that long term consumption of MDMA and alcohol caused serotonin depletion. The alteration in the serotonergic system might be associated with the psychopathological disturbances observed in MDMA and alcohol co-abusers [155] (Table  1).
It has been found, in a double blind study conducted on nine healthy human volunteers, that MDMA and alcohol co-abuse induced a longer duration of euphoria and feeling well as compared to drug use alone [149]. Therefore, MDMA and alcohol use together can increase the abuse potential more than abusing alcohol or MDMA alone. In a preclinical study, exposure to alcohol during adolescent age in mice increased the reinforcing effects of MDMA [156]. Moreover, exposure to MDMA and alcohol during adolescence potentiated anxiety measures, impaired learning and memory, and decreased striatal dopamine contents during adult life in mice ( Figure 3) [157,158]. Studies have demonstrated an increase in the MDMA plasma concentration by 13% following alcohol intake and a decrease in blood alcohol concentration of about 12% compared to either drug administered alone (Figure 1) [149]. In addition, these studies found that MDMA reversed the subjective sedative effect, which was induced by alcohol consumption.
A recent study aimed to find the effect of MDMA and alcohol co-abuse on learning and memory [159]. In this study, alcohol and MDMA were administered either together or alone to measure their effects on learning and memory in adult mice. Both drugs caused impairment of learning and memory, as the affected mice displayed an imbalance in the interaction of dopamine and serotonin. These findings suggest that the brain in adulthood is very sensitive to MDMA and alcohol damage [159]. However, other study did not demonstrate any additive effect of combining alcohol and MDMA on declarative memory in mice [160] (Figure 3). This might be due to several factors, including the doses used for alcohol and MDMA.
Prenatal exposure to alcohol and MDMA is understudied topic, although pregnant women who reported MDMA use during pregnancy also reported higher alcohol use compared to non MDMA users [161,162]. Importantly, a preclinical study found that prenatal exposure to both alcohol and MDMA impaired working memory, exploratory activity, and neurogenesis in rat's offspring (Figure 4) [163].

Conclusion
Alcohol interaction with drugs of abuse is currently not well understood, however, there are studies that demonstrated numerous side effects, which have occurred with drugs co-abuse. The prevalence of concurrent abuse of alcohol with psychostimulants such as METH, cocaine, nicotine, or MDMA is extremely high. This increase in prevalence of co-abuse of alcohol with psychostimulants is most likely due to potentiated effects on euphoria and pleasure as well as decrease detrimental subjective effects of either alcohol or other drugs of abuse. Co-abuse of alcohol with psychostimulants can lead to serious negative consequences on the brain such as decreasing antioxidant enzymes, disrupting learning and memory processes, cerebral hypo-perfusion, neurotransmitters depletion as well as potentiating drug seeking behaviour. Moreover, co-abuse of alcohol and psychostimulants can lead to increase in heart rate, blood pressure, myocardial oxygen consumption and cellular stress as well as increase in the risk of developing different types of cancer.
Alcohol has been shown to increase the blood concentration of different psychostimulants and its active metabolites. It is suggested that the pharmacokinetics of METH, MDMA, cocaine, and nicotine, might be altered when alcohol is consumed concurrently with these drugs. We suggest here that alcohol metabolism and its metabolites may increase the blood concentration of these drugs of abuse, and consequently elevate the risk of toxicity. Importantly, alcohol co-abuse with psychostimulants during pregnancy can impose critical structural and functional damages in the fetal brains. Further studies are needed to investigate possible pharmacodynamics, pharmacokinetics, and neurochemical basis of coabuse of alcohol and psychostimulants as well as possible therapeutic interventions.     Aspects and effects of alcohol and psychostimulants interactions.

Cocaine metabolism
Alcohol decreased metabolism of cocaine [68]. Alcohol decreased benzoylecgonine renal excretion, and increased in cocaine and cocaethylene blood concentrations [69].

Cardiovascular and endocrine systems
Exposure to cocaine and alcohol increased heart rate, systolic blood pressure, cortisol, and prolactin levels [64,69].

Cerebral blood perfusion
Cerebral hypo-perfusion occurred more in individuals taking cocaine and alcohol than in individuals taking cocaine or alcohol alone [72,73] Neurobehavioral performances Negatively affected by concurrent intake of cocaine and alcohol compared to either drug alone [74,75].

Mesocorticolimbic dopamine system
Increased extracellular dopamine concentration than either drug alone in nucleus accumbens in rats [90] Sense of pleasure and euphoria were found to be improved [71].
Pleasure and drug seeking Increased in the pleasurable effects of each drug [119]. Rats self-administered nicotine more than rats received chronic exposure to either drug alone [108].

Cardiovascular system
Additive effect on heart rate and blood pressure was found in healthy human volunteers [130,131]. Synergistic increase in left ventricular pressure in dogs [132].
Prenatal exposure Showed a multiplicative effect in increasing the risk of head and neck cancer in human [124].
Offspring developed rapid nicotine self-administration and at a higher level in rats [136].

MDMA Cardiovascular system
Exacerbated cardiac cellular stress and toxicity through augmented activation of cardiac sympathetic system in adolescent mice [139].
Blood level MDMA plasma concentration increased following alcohol intake [149].