Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers

BACKGROUND: Recent studies have implicated central nicotinic cholinergic receptor systems in the reinforcing properties of alcohol. In laboratory animals, mecamylamine, a central nicotinic receptor antagonist, reduces the consumption of and preference for alcohol. This study investigated the effect of mecamylamine on the subjective responses to alcohol in humans. It was hypothesized that mecamylamine (7.5 and 15 mg) would attenuate the stimulant-like subjective effects of alcohol (0.8 g/kg) and decrease the self-reported desire to consume additional alcohol beverages. METHODS: Fourteen male and 13 female nonsmokers participated in 6 laboratory sessions. During each session, subjects received, in randomized order under double-blinded conditions, a capsule containing mecamylamine (7.5 or 15 mg) or placebo followed by a beverage containing alcohol (0.8 g/kg) or placebo. Physiologic and subjective-effect measures were taken at 30-min intervals for 2 hr after beverage consumption. RESULTS: Mecamylamine attenuated the stimulant and euphoric effects of alcohol and reduced the self-reported desire to consume additional alcohol beverages. This effect was most pronounced in men, even though women exhibited greater physiologic reactions to mecamylamine. CONCLUSIONS: These findings suggest that nicotinic cholinergic receptors are involved in mediating some of the stimulant-like effects of alcohol.     

Effects of stress and alcohol on subjective state in humans

BACKGROUND: There is increasing evidence that stress and hypothalamic-pituitary-adrenal axis activation interact with drugs of abuse and influence drug-taking behaviors. Both studies with laboratory animals and survey data with alcohol users suggest that acute or chronic stressful events increase alcohol intake. One mechanism for the increase in alcohol intake may be that stress alters the subjective effects produced by the drug in ways that enhance the reinforcing properties of alcohol. Therefore, in this study we determined whether an acute social stressor alters subjective responses to ethanol in humans. The stressor was a modified version of the Trier Social Stress Test, an arithmetic task that increases cortisol levels. METHODS: Twenty male volunteers participated in two laboratory sessions, in which they performed the Trier Social Stress Test on one session and no task on the other session, immediately before consuming a beverage that contained ethanol (0.8 g/kg in juice) or placebo (juice alone). Eleven subjects received ethanol on both sessions, and nine subjects received placebo on both sessions. Primary dependent measures were self-report questionnaires of mood states. Salivary levels of cortisol were obtained to confirm the effectiveness of the stress procedure. RESULTS: Stress alone produced stimulant-like subjective effects. In the group who received ethanol, stress increased sedative-like effects and decreased stimulant-like effects. CONCLUSIONS: At this relatively high dose of ethanol, stress increased sedative effects of alcohol and did not increase desire for more alcohol. It is possible that in some individuals, the increased sedative effects after stress may increase the likelihood of consuming more alcohol. The effects of stress on consumption at this, or lower, doses of alcohol remain to be determined.     

Ethanol impairs saccadic and smooth pursuit eye movements without producing self-reports of sedation

It has been suggested that eye movements provide a sensitive tool to assess the sedative-like properties of drugs. However, the relationship between sedative-like subjective effects and impairment in eye movements is not clear. For example, it is not clear whether drugs with stimulant-like effects can also impair eye movements. This study evaluated whether ethanol, a drug with both sedative-like and stimulant-like properties, impairs eye movements, and whether the impairment observed after ethanol is related to its sedative properties. Twenty healthy men and women, aged 21 to 35, consumed beverages containing placebo or ethanol (0.4 or 0.8 g/kg) on three separate laboratory sessions, in randomized order. Eye movement and psychomotor and subjective responses were assessed before and at regular intervals for 3 hr after ingestion of the beverage. Subjects were divided post hoc into two groups, based on their sedative-like or stimulant-like subjective responses to ethanol. Nine subjects reported increases in sedative-like effects after ethanol and 11 reported decreases in sedative-like effects, and increases in stimulant-like effects, after alcohol. Despite their distinctly different subjective responses to ethanol, the groups did not differ in the magnitude, time-course or quality of responses on the eye movement measures. In both groups, ethanol decreased peak saccadic eye velocity and smooth pursuit gain. These results demonstrate the dissociation between impairment in eye movements and subjective feelings of sedation after ethanol, and show that eye movements can be impaired even when subjects are reporting stimulant-like effects. The findings suggest that impaired eye movements are not a nonselective index of sedation, but may be related to specific drug actions on brain regions involved in generating these eye movements.     

Individual Differences in the Biphasic Effects of Ethanol

Ethanol exerts both stimulant-like and sedative-like subjective and behavioral effects in humans depending on the dose, the time after ingestion and, we will argue, also on the individual taking the drug. This study assessed stimulant-like and sedative-like subjective and behavioral effects of ethanol during the ascending and descending limbs of the blood alcohol curve across a range of doses in nonproblem social drinkers. Forty-nine healthy men and women, 21 to 35 years old, consumed a beverage containing placebo or ethanol (0.2, 0.4, or 0.8 g/kg) on four separate laboratory sessions, in randomized order and under double-blind conditions. Subjective and behavioral responses were assessed before and at regular intervals for 3 hr after ingestion of the beverage. The lowest dose of ethanol (0.2 g/kg) only produced negligible subjective effects compared to placebo. The moderate dose (0.4 g/kg) increased sedative-like effects 90 min after ethanol ingestion but did not increase ratings of stimulant effects at any time. The highest dose (0.8 g/kg) increased ratings of both stimulant- and sedative-like effects during the ascending limb and produced only sedative-like effects during the descending limb. Closer examination of the data revealed that individual differences in response to the highest dose of ethanol accounted for this unexpected pattern of results: about half of the subjects reported stimulant-like effects on the ascending limb and sedative-like effects on the descending limb after 0.8 g/kg ethanol, whereas the other half did not report stimulant-like effects at any time after administration of ethanol. These results challenge the simple assumption that ethanol has biphasic subjective effects across both dose and time, and extend previous findings demonstrating individual differences in response to ethanol.     

Effects of acute social stress on alcohol consumption in healthy subjects

BACKGROUND: There has been renewed interest in interactions between stress and use of drugs and alcohol. Although there is evidence that stress increases drug use in human drug users and in laboratory animals, the processes by which stress affects drug-motivated behavior are not understood. Here we examined the effects of an acute social stressor (performing a mental arithmetic task in front of an audience) on consumption of ethanol or placebo beverages in healthy social drinkers. METHODS: Thirty-seven men and women, ages 21-35, were randomly assigned to a placebo (n = 15) or ethanol group (n = 22). Subjects participated in two sessions, one with stress (Trier Social Stress Test) the other without stress. In each session, immediately after the stress or no-stress period, subjects consumed the first dose (placebo or 0.3 g/kg of ethanol for men or 0.2 g/kg for women). Then, subjects were allowed to choose up to six more beverages (0.1 g/kg each for the ethanol group or placebo beverages for the placebo group). Measures included percentage of beverage consumed, salivary cortisol level, heart rate, blood pressure, and subjective ratings of mood and drug effect. RESULTS: Subjects in both the placebo and ethanol groups consumed significantly more of their beverages after stress, compared to no stress. Stress increased anxiety, uneasiness, and produced some stimulant-like effects and, in the ethanol group, it dampened some of the acute subjective effects of ethanol. The direct physiologic and mood effects of the stress were fairly short-lived. CONCLUSIONS: It is concluded that acute stress may produce a modest increase in alcohol consumption in healthy, nonproblem social drinkers but that this increase is not directly related to the pharmacological effects of the drug. Nonpharmacological factors may include expectancies, thirst, or nonspecific facilitation of ongoing behaviors.     

Individual differences in responses to ethanol and d-amphetamine: a within-subject study

BACKGROUND: In some individuals, ethanol (EtOH) produces marked stimulant-like subjective effects resembling those of stimulant drugs, like d-amphetamine (AMP). In this study, we examined the neurochemical basis of these individual differences by examining the same subjects' responses to both EtOH and AMP. A positive correlation between subjects' responses to the two drugs may suggest that AMP and EtOH produce their stimulant-like subjective effects by a shared mechanism. METHODS: Twenty-seven volunteers (17 male, 10 female), aged 21-35, received beverages or capsules containing EtOH 0.8 g/kg, AMP 10 or 20 mg, or placebo on four separate sessions in random order and under double-blind conditions. Various self-reported and objective drug effects were measured, including measures sensitive to subjective and cognitive stimulant-like effects. RESULTS: EtOH and AMP produced their prototypical subjective and behavioral effects, including increased ratings of stimulant-like subjective effects, increased heart rate and blood pressure, and improved vigilance performance after AMP and increased ratings of sedative-like subjective effects, increased heart rate and blood pressure, and impaired vigilance performance after EtOH. Consistent with previous reports, there was substantial intersubject variability in subjective responses to EtOH: some subjects reported primarily stimulant-like effects, whereas others reported primarily sedative-like effects. To examine the relationship between these responses to EtOH and subjects' responses to AMP, correlations were examined between effects of EtOH and AMP. For all subjects together, there was a significant positive correlation between responses to EtOH and 20 mg AMP on the ARCI A scale (a measure of stimulant-like subjective effects; r = 0.41, p < 0.05). Among only those subjects who reported primarily stimulant-like effects from EtOH, the correlation between EtOH and AMP was 0.64 (p < 0.05). CONCLUSIONS: Subjects who experience pronounced stimulant-like effects from EtOH also report greater stimulant effects from AMP, suggesting that these effects may be mediated through similar mechanisms. These correlations between the drugs' effects were not observed on other measures, such as DSST or vigilance task performance or heart rate. This may indicate that these other effects are mediated by separate mechanisms. The study illustrates a novel approach to studying the neurochemical basis of drug effects.     

Biphasic alcohol response differs in heavy versus light drinkers

BACKGROUND: Most studies of risk factors for alcohol-related problems have focused on biological family history as a primary risk factor. However, other factors, such as early-age heavy drinking, are also risk factors for sustained or progressive heavy consumption. Little is currently known about the mechanisms underlying binge or heavy drinking. METHODS: This study examined the acute subjective and objective effects of ethanol in heavy drinkers versus light drinkers. Thirty-four subjects participated in this within-subjects study consisting of three early-evening testing sessions in which subjects consumed a beverage containing either 0.8 or 0.4 g/kg ethanol or placebo. RESULTS: Compared with lighter drinkers, heavy drinkers were more sensitive to the positive stimulant-like effects of ethanol (p < 0.05), especially during the increasing limb of the blood alcohol curve. Heavy drinkers also showed less sedation and cortisol response after alcohol than the light drinkers (p < 0.05). CONCLUSIONS: The results indicate that young adult binge drinkers show a biphasic alcohol response, with heightened sensitivity to stimulant-like alcohol effects and greater tolerance to sedative alcohol effects compared with their light-drinking counterparts.     

Subjective and objective responses to ethanol in moderate/heavy and light social drinkers

BACKGROUND: Individuals who drink heavily are at an increased risk for adverse consequences of drinking and progression of their drinking habits to abuse or dependence. Therefore, it is important to delineate factors associated with their heavy drinking. METHODS: We examined individual differences in subjective and objective responses to ethanol associated with level of consumption by reanalyzing data from the nine heaviest and nine lightest social drinkers from each of two independently collected subject samples: Holdstock and de Wit (1998) and King et al. (1997). The light drinkers in both samples consumed five or less alcoholic drinks per week, whereas the moderate/heavy drinkers consumed eight or more drinks per week with frequent binge episodes. Acute subjective and objective responses to ethanol (0.6 or 0.8 g/kg) or placebo were compared in the two groups at baseline and during rising and falling blood alcohol concentrations. RESULTS: Moderate/heavy drinkers reported greater stimulant-like and fewer sedative-like and aversive subjective effects after ethanol than did lighter drinkers. These differences occurred in the absence of any group differences in breath alcohol levels, performance effects, or neuroendocrine changes or in overall reports of feeling any drug effects. CONCLUSIONS: These data indicate that habitual moderate/heavy ethanol use was associated with greater stimulant-like effects after an acute dose of alcohol. This finding is consistent with the idea (Newlin and Thomson, 1990, 1999) that individuals who experience greater stimulant-like effects during the ascending limb and lesser sedative-like effects on the descending limb of the blood alcohol concentration curve may be at greater risk for developing ethanol use disorders. Although we cannot determine the causality of this association, sensitivity to the stimulant effects of ethanol may play an important role in the continuation of heavy ethanol use and the increased risk of negative consequences from this use.     

Individual Differences in Behavioral and Subjective Responses to Alcohol

The reinforcing properties and subjective effects of alcohol were assessed in 29 normal volunteers using a seven-session choice procedure. On the first four sessions, subjects sampled an alcohol (0.5 g/kg) and a placebo beverage twice each. On three subsequent choice sessions, subjects chose the drink they preferred. The number of times they chose alcohol was the measure of its reinforcing properties. On all sessions subjects completed mood questionnaires before and several times after consuming the beverage. Other dependent measures during the experiment included a cognitive performance task, drug liking and identification questionnaires, and breathalyzer alcohol determinations. Demographic and personality data also were obtained. Approximately one-third of the subjects chose the alcohol-containing beverage on all three choice sessions, one-third alternated in their choices of alcohol and placebo, and one-third consistently chose the placebo. When the subjective effects of alcohol (determined during sampling sessions) were compared across the three choice groups, qualitative differences in response to alcohol were observed. For example, alcohol increased elation and vigor scores in the consistent choosers of alcohol, whereas it decreased scores on these measures in the consistent placebo choosers. Consistent alcohol choosers did not differ from placebo choosers in gender or age but they reported more marijuana use and slightly more alcohol use outside the laboratory. They also scored higher on certain measures of arousal and depression, on the Sensation Seeking Scale and on the Psychopathic State Inventory. The results are discussed in terms of individual differences in vulnerability to excessive use of alcohol.     

Alcohol choice and amphetamine effects in light and moderate drinkers

BACKGROUND: The results of previously published reports suggest that light and moderate drinkers respond differently to the effects of commonly abused sedatives (e.g., diazepam or ethanol). The purpose of this experiment was to determine whether light and moderate drinkers respond differentially to the effects of ethanol and d-amphetamine. METHODS: In the first phase of this experiment, volunteers (eight light drinkers and eight moderate drinkers) randomly sampled 0.5 g/kg of ethanol and placebo across two separate sessions. In the second phase, volunteers completed three sessions in which they chose either ethanol or placebo. In the third phase, volunteers received 0, 5, 10, and 15 mg of d-amphetamine. Each dose was tested twice. After drug administration in each phase, volunteers completed a battery of subject-rated, performance, and physiologic measures periodically for 5 hr. RESULTS: Ethanol produced prototypical subject-rated effects (e.g., increased ratings on the Alcohol Sensation Scale), but it was chosen over placebo infrequently. Light and moderate drinkers did not differ in terms of the self-reported or reinforcing effects of ethanol. d-Amphetamine produced prototypical subject-rated stimulant-like effects (e.g., dose-dependent increases in ratings of High and Rush). Moderate drinkers reported significantly greater drug effects than light drinkers. Responses to ethanol reliably predicted subsequent responses to d-amphetamine on several measures. CONCLUSIONS: The results of this experiment suggest that even moderate ethanol use may increase an individual's vulnerability to abuse drugs. Future studies should determine whether light and moderate drinkers respond differentially to other commonly abused drugs (e.g., opioids) and whether behavioral responses to ethanol also predict responses to these compounds.     

Mecamylamine and ethanol preference in healthy volunteers

BACKGROUND: Recent evidence suggests that some of the behavioral effects of alcohol may be mediated through actions on nicotinic acetylcholine receptors. Mecamylamine, a nicotinic acetylcholine receptor antagonist, reduces alcohol preference and consumption in alcohol-preferring rats, and in humans, mecamylamine dampens some of the subjective, or mood-altering, effects of alcohol. This experiment was designed to investigate the effects of mecamylamine on consumption of alcohol in healthy social drinkers. METHODS: Healthy volunteers (12 men, 12 women) participated in a choice procedure in which they chose between an alcoholic beverage and money (low, medium, or high amounts) after pretreatment with mecamylamine (7.5 or 15 mg) or placebo. Outcome measures were the number of alcoholic beverages consumed and the subjective effects of alcohol. RESULTS: Mecamylamine (15 mg) decreased blood alcohol levels (BALs) after a small fixed dose of alcohol (0.2 g/kg). Even when the lower BALs were taken into account, mecamylamine reduced ratings of stimulation after alcohol (Addiction Research Center Inventory A scale). Mecamylamine did not significantly reduce choice for alcohol versus money. However, there was a tendency for the drug to decrease alcohol choice among participants who reported the greatest stimulant-like effects from alcohol. CONCLUSION: These results provide only limited support for the idea that nicotinic acetylcholine receptors are involved in the rewarding effects of alcohol.     

Alcohol dose-dependent increases in smoking urge in light smokers

BACKGROUND: The current study assessed dose-dependent effects of alcohol compared with placebo on ratings of urge to smoke in light smokers. METHODS: Sixteen nonalcoholic social drinker-smokers were tested individually in three separate early evening sessions where they received a placebo (with 1% ethanol as a taste mask), a low-dose (0.4 g/kg) alcoholic beverage, or high-dose (0.8 g/kg) alcoholic beverage administered in random order. Participants refrained from smoking 2 hr before and throughout the entire early evening experimental sessions. Two subfactors of the Brief Questionnaire of Smoking Urges, BQSU; (factor 1, urge to smoke for stimulation; factor 2, urge to smoke to relieve negative mood and withdrawal) were assessed at baseline and again at rising and declining portions of the blood alcohol curve. RESULTS: Both the high and low doses of alcohol significantly increased BQSU factor 1 scores during the rising and declining blood alcohol concentration (BAC) limbs (p < 0.05). Comparisons across doses during both limbs revealed that the high dose significantly increased factor 1 smoking urge compared with the low dose and placebo beverage (p < 0.05, high > low = placebo). Alcohol tended to increase factor 2 scores throughout the BAC curve, but levels were not as increased as factor 1 scores. Finally, there was no significant association between participants' smoking levels and smoking urge ratings during the high- and low-dose sessions. CONCLUSIONS: The results support a dose-dependent alcohol-induced increase in smoking urge in cigarette-deprived light smokers. These smoking urge increases were apparent during the rising limb of the BAC and maintained throughout the declining limb. Smoking urge increases were greater for positive reinforcing effects than for negative reinforcing effects.     

Lack of effects of ethanol pretreatment on the abuse liability of nitrous oxide in light and moderate drinkers

Aims. To determine effects of ethanol-use history and ethanol pretreatment on abuse liability of nitrous oxide (N ₂O).
Design. Placebo-controlled, double-blind, cross-over design evaluating effects of N ₂O, 0% (100% O ₂, placebo) and 30% (in O ₂), in the presence of three doses of ethanol: 0 g/kg (placebo), 0.35 g/kg and 0.7 g/kg.
Setting. Subjects sat in a reclining chair in a hospital laboratory.
Participants. Eight healthy light drinkers (one drink or less/week) and eight healthy moderate drinkers (seven or more drinks/week) with no history of drug dependence completed the study.
Intervention. On three sessions (1, 3, 5) subjects drank a beverage that contained one of the three ethanol doses, then sampled for 10 minute each 0% and 30% N ₂O. During choice sessions (2, 4, 6), subjects received the same ethanol dose as in the previous session, then chose six times, once every 5 min, between 0% and 30% N ₂O.
Measurements. Subjective (self-reported) drug effects, reinforcing effects of N ₂O as assessed by choice, and psychomotor effects were measured.
Findings. Choice of N ₂O did not differ between light (mean = 3.4 choices) and moderate (mean = 3.2 choices) drinkers and was not influenced by ethanol dose (0 g/kg: 3.3 choices, 0.35 g/kg: 3.5 choices, 0.7 g/kg: 3.1 choices). Subjective effects of N ₂O also did not depend on ethanol-use history or ethanol dose. N ₂O liking and desire to inhale the drug again were positively correlated with N ₂O choice.
Conclusions. Ethanol pretreatment and ethanol-use history had no effect on the abuse liability of N ₂O as assessed in the present study.     

Alcohol effects on cerebral blood flow in subjects with low and high responses to alcohol

Background: Although there are multiple indications that alcohol can alter many physiological brain functions, including cerebral blood flow (CBF), studies of the latter have generally used small‐ or modest‐sized samples. Few investigations have yet evaluated how CBF changes after alcohol relate to subsets of subjects with elevated alcoholism risks, such as those with lower levels of response (LR) to alcohol. This study used arterial spin labeling (ASL) after alcohol administration to evaluate a large sample of healthy young men and women with low and high alcohol responses, and, thus, varying risks for alcohol use disorders (AUD). Methods: Healthy young adult social drinkers with low and high LR (N = 88, 50% women) matched on demography and drinking histories were imaged with whole‐brain resting ASL ～1 hour after ingesting ～3 drinks of ethanol and after a placebo beverage (i.e., 178 ASL sessions). The relationships of CBF changes from placebo to alcohol for subjects with low and high LR were evaluated. Results: CBF increased after alcohol when compared to placebo in 5 frontal brain regions. Despite identical blood alcohol concentrations, these increases with alcohol were less prominent in individuals who required more drinks to experience alcohol‐related effects (i.e., had a lower LR to alcohol). The LR group differences remained significant after covarying for recent drinking quantities. Conclusions: The results confirm that alcohol intake is associated with acute increases in CBF, particularly in frontal regions. Less intense CBF changes were seen in subjects with a genetically influenced characteristic, a low LR to alcohol, that relates to the future risk of heavy drinking and alcohol problems.     

Differences in Alcohol Expectancy Between Aggressive and Nonaggressive Social Drinkers

Previous reports have shown that drinkers with aggressive personalities not only hold the strongest beliefs that alcohol facilitates aggressive behavior, but they also display the greatest increases in laboratory aggression after receiving alcohol. Given that several studies have demonstrated that a portion of the behavioral and subjective effects of alcohol are due to psychological expectancy, this study explored whether aggressive drinkers have elevated intoxication expectancies from laboratory beverages with unknown alcohol content. The rates of aggressive responses emitted in a money subtraction aggression model under baseline conditions were used to select an aggressive group and a nonaggressive group, each with five male and five female participants. Subjects then ingested and rated each of three placebo (1 ml alcohol) beverages administered hourly during a subsequent laboratory visit, and rated a series of three 0.35 g/kg of alcohol beverages the following day. Whereas nonaggressive subjects clearly discriminated the relative alcohol content of alcohol and placebo drinks, aggressive subjects gave progressively elevated shot equivalent ratings to placebo drinks, similar to their ratings of alcohol doses. However, despite similar self-reported drinking histories, aggressive subjects reported anticipating only half the intoxication from the alcohol doses (and in fact achieved a lower peak breath alcohol concentration) than was expected by nonaggressive subjects.     

Healthy subjects with a family history of alcoholism show increased stimulative subjective effects of alcohol

Background: Research has shown that subjects with a family history positive (FHP) of alcoholism are at increased risk for alcoholism and that this group reacts differently to alcohol than family history negative (FHN) subjects. These different levels of sensitivity may make FHP persons more likely to consume alcohol. Here, we tested the hypothesis that subjects FHP for type 1 alcoholism (according to Cloninger) are more sensitive than control subjects to the stimulative, properties of alcohol following a single moderate dose of alcohol. Methods: Fifty‐one healthy men and women (22 FHP and 29 FHN) participated in 2 laboratory sessions, in which they consumed a beverage containing ethanol (0.6 g/kg in juice) or placebo (juice alone) in a randomized order. Primary dependent measures were self‐report questionnaires of mood states. Results: Subjects with family history of type 1 alcoholism showed increased stimulative responses and an elevated positive mood state after ethanol compared to controls. Conclusions: At this moderate dose, ethanol increased stimulative subjective responses in individuals who were “family history positive.” This enhanced sensitivity could motivate to exaggerated drinking and thereby increase the risk for developing alcoholism.     

Alterations in ethyl alcohol pharmacokinetics during oral consumption of malt liquor beverages in African Americans

Background: Malt liquor (ML) beverages have become increasingly popular among urban minority groups, due partly to their inexpensive price and targeted advertising. We hypothesized that nonfermented by‐products contained in ML beverages will alter the pharmacokinetics (PK) and pharmacodynamic (PD) effects of its ethanol content. In addition, we determined the effect of alcohol dehydrogenase (ADH) genotypes on the PK following consumption of ML beverages. Methods: The study was conducted in 31 healthy adult African‐American social drinkers, mean ± SD age of 22.3 ± 1.3 years, and weight of 70.7 ± 10.9 kg. Participants were administered ethanol, in randomized order, 2‐weeks apart, in the form of oral ML beverage (6%v/v), or isocaloric solution of diet soda–ethanol (DS–Etoh) beverage (6%v/v). During each session the beverage was consumed over 4 minutes and breath alcohol concentrations (BrAC) as well as subjective and behavioral effects of ethanol were evaluated over 180 minutes. Pharmacokinetic parameters of ethanol were calculated using Michaelis–Menten elimination kinetics. The effect of ML and ADH genotype on PK was evaluated using the Wilcoxon rank‐sum test and the Wilcoxon signed rank test, respectively. Results: Results show a slower mean rate of absorption, K_a, (0.12 vs. 0.15 min^?1, p = 0.03) and a longer time to reach maximum concentration, T_max, (28 vs. 23 minute, p < 0.01) for the ML compared with DS–Etoh beverage. The ML beverage resulted in a larger area under the BrAC–time curve compared with DS–Etoh beverage (8.4 vs. 6.8 min g/dl, p = 0.02). There was no difference in the subjective PD effects between the 2 beverages. Conclusion: Results show that exposure to ethanol following the consumption of ML beverages is different compared to that following nonmalt beverages in African‐Americans. These differences may be related to nonfermented by‐products present in commercially available ML products. These PK differences do not appear to result in significant perceived alcohol PD changes, nor are they related to ADH genotype.     

Effects of aripiprazole on subjective and physiological responses to alcohol

Background:  Aripiprazole is an atypical antipsychotic with partial agonist activity at D₂ receptors, which could reduce the reinforcing effects of alcohol. The present study examined whether aripiprazole modifies the behavioral and physiological effects of a moderate dose of alcohol in a group of social drinkers.
Methods:  Eighteen healthy subjects (9 men; mean age = 27.6 years) completed a double-blind, within-subject study with 3 experimental sessions in a randomized sequence, during which they received no medication, aripiprazole 2.5 mg, or aripiprazole 10 mg on the day prior to the laboratory session. During the session, subjects consumed alcohol that was served as three standardized drinks (i.e., a total of 0.8 g/kg for men and 0.7 g/kg for women). Breath alcohol concentration (BrAC), heart rate, blood pressure, static ataxia, and subjective effects were measured regularly throughout the laboratory sessions.
Results:  Alcohol consumption produced physiological and subjective responses that were consistent with the literature on its effects. Pre-treatment with aripiprazole was generally well tolerated, with tiredness being the most commonly reported adverse event. The medication was associated with modest physiological effects. It also significantly and dose-dependently increased the sedative effects of alcohol and, to a lesser degree, decreased the euphoric effects of alcohol.
Conclusions:  These findings require replication in a larger subject sample that includes heavy drinkers and in a study that employs a placebo session. Based on its capacity to increase the sedative effects and decrease the euphoric effects of alcohol, aripiprazole could be of value in the treatment of heavy drinking.     

Combined Scopolamine and Ethanol Treatment Results in a Locomotor Stimulant Response Suggestive of Synergism That is Not Blocked by Dopamine Receptor Antagonists

Background: Muscarinic acetylcholine receptors (mAChRs) are well positioned to mediate ethanol’s stimulant effects. To investigate this possibility, we examined the effects of scopolamine, a receptor subtype nonselective mAChR antagonist, on ethanol‐induced stimulation in genotypes highly sensitive to this effect of ethanol. We also investigated whether the dopamine D1‐like receptor antagonist, SCH‐23390 or the dopamine D2‐like receptor antagonist, haloperidol, could block the extreme stimulant response found following co‐administration of scopolamine and ethanol. Methods: Scopolamine (0, 0.0625, 0.125, 0.25, or 0.5 mg/kg) was given 10 minutes prior to saline or ethanol (0.75 to 2 g/kg) to female FAST (Experiment I) or DBA/2J (Experiment II) mice that were then tested for locomotion for 30 minutes. In Experiments III and IV, respectively, SCH‐23390 (0, 0.015, or 0.03 mg/kg) was given 10 minutes prior, and haloperidol (0, 0.08, or 0.16 mg/kg) was given 2 minutes prior, to scopolamine (0 or 0.5 mg/kg), followed 10 minutes later by saline or ethanol (1.5 g/kg) and female DBA/2J mice were tested for locomotion for 30 minutes. Results: FAST and DBA/2J mice displayed a robust enhancement of the locomotor effects of ethanol following pretreatment with scopolamine that was suggestive of synergism. SCH‐23390 had no effect on the response to the scopolamine + ethanol drug combination, nor did it attenuate ethanol‐ or scopolamine‐induced locomotor activity. Haloperidol, while attenuating the effects of ethanol, was not able to block the effects of scopolamine or the robust response to the scopolamine‐ethanol drug combination. Conclusions: These results suggest that while muscarinic receptor antagonism robustly enhances acute locomotor stimulation to ethanol, dopamine receptors are not involved in the super‐additive interaction of scopolamine and ethanol treatment. They also suggest that in addition to cautions regarding the use of alcohol when scopolamine is clinically prescribed due to enhanced sedative effects, enhanced stimulation may also be a concern.     

Influence of i.v. haloperidol on ventricular repolarization and monophasic action potential duration in anesthetized dogs

INTRODUCTION: i.v. haloperidol is used commonly for sedation in critically ill patients. However, i.v. haloperidol has been shown to cause the life-threatening ventricular tachyarrhythmia torsades de pointes. Mechanisms by which haloperidol causes torsades de pointes have not been widely investigated in controlled studies. STUDY OBJECTIVES: To determine the effects of i.v. haloperidol on electrophysiologic parameters known to promote torsades de pointes. INTERVENTIONS: Monophasic action potential catheters were guided under fluoroscopy into the right and left ventricles of 14 chloralose-anesthetized dogs (haloperidol, nine dogs; placebo, five dogs). Effective refractory period (ERP), action potential duration at 90% repolarization (APD90), and QTc interval measurements were performed at baseline and after each of four doses of haloperidol (0.15, 0.5, 2.0, and 3.0 mg/kg) or placebo at three different pacing cycle lengths (450, 300, and 250 ms). MEASUREMENTS AND RESULTS: i.v. haloperidol significantly prolonged left and right ventricular ERP by a magnitude of 12 to 20% at all pacing cycle lengths. ERP values in the placebo group did not change significantly from pretreatment values in either ventricle. Haloperidol significantly prolonged left ventricular APD90 at a pacing cycle length of 300 ms. The effects of haloperidol on right ventricular APD90 approached significance at a cycle length of 450 ms. Overall, haloperidol prolonged APD90 by 7 to 11%, with less consistent and more variable effects than those for the ERP. APD90 was not significantly altered in the placebo groups. Haloperidol produced significant prolongation in QTc intervals. The electrophysiologic effects of haloperidol were related to dose, with a plateau reached at the 0.5 mg/kg dose for ERP measurements and at the 2 mg/kg dose for the APD90 and QTc interval measurements. CONCLUSIONS: i.v. haloperidol prolongs ventricular ERP and APD90 in intact canine hearts. These electrophysiologic effects are likely associated with the clinical torsades de pointes-inducing actions of i.v. haloperidol in critically ill patients.