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.     

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.     

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.     

Subjective responses to alcohol: a paradigm shift may be brewing

Background: The meta‐analysis by Quinn and Fromme (2011 ) is reviewed and integrated into the larger field. Guidelines for future research are presented. Results: With results of the meta‐analysis along with those of a recent comprehensive prospective study by our group ( King et al., 2011 ), there is a call to the field to specify terms and integrate theoretical frameworks to advance our knowledge and improve comparisons across trials. Conclusions: The meta‐analysis is both timely and thorough and will provide clinical researchers with important information to move the field forward.     

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.     

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.     

Role of GABRA2 in moderating subjective responses to alcohol

Background: Human twin studies have shown that certain responses to alcohol, including subjective perceptions, are genetically influenced. Previous studies have provided evidence that a low level of response to alcohol predicts future alcohol use disorders in humans. Recent genetic studies suggest an association between alcohol dependence and genetic variation in the γ‐aminobutyric acid A (GABA_A) receptor α2 subunit gene (GABRA2). Based on a haplotypic association of alcohol dependence with GABRA2, we investigated whether GABRA2 alleles are associated with the subjective responses to clamped alcohol concentration. Methods: One hundred and ten healthy social drinkers (53 men) underwent the alcohol clamp. Fifteen minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 50 ± 5 mg/dl for 165 minutes. Subjective physiologic responses to alcohol and stimulant and sedative effects of alcohol were measured repeatedly during the alcohol clamp. Because aldehyde dehydrogenase 2 (ALDH2) has been shown to have a great impact on the subjective responses to alcohol, we divided subjects by ALDH2 genotype for further analyses. To examine the role of genetic variation in GABRA2, 7 single nucleotide polymorphisms (SNPs) that were informative in association studies were included as factors in the analysis. Results: Among these 7 SNPs, 3 SNPs (rs279869, rs279858, and rs279837) located in the middle of the GABRA2 gene showed significant associations with subjective effects of alcohol. Subjects with 1 or 2 copies of the more common allele showed greater subjective responses to alcohol than did individuals homozygous for the alcohol dependence–associated allele regardless of ALDH2 genotype. Conclusions: These findings confirm and extend the observation that the GABRA2 alleles affect the subjective responses to alcohol, and suggest that the genetic variations in GABRA2 might play a role in the risk of alcohol use disorders by moderating the subjective effects of alcohol.     

The biphasic effects of alcohol: comparisons of subjective and objective measures of stimulation, sedation, and physical activity

BACKGROUND: Alcohol produces biphasic effects of both stimulation and sedation. Sensitivity to these effects may increase the risk for the development of alcoholism. Alcohol-induced changes in stimulation and sedation are commonly assessed with self-report questionnaires in human research and with physical activity monitoring in animal research. However, little is known about the effects of alcohol on physical activity or the relationship between physical activity and subjective self-report measures of stimulation and sedation following alcohol consumption in humans. METHODS: Thirty healthy men and women (n = 15 each) from 21 to 38 years old completed daily measurements of physical activity and self-reports of stimulation and sedation following alcohol or placebo consumption. Across each of the four experimental days, all participants consumed a placebo, 0.4, 0.6, or 0.8 g/kg dose of 95% alcohol in a counterbalanced order. Breath alcohol concentrations, physical activity levels, and self-reported stimulation and sedation were measured at baseline and on the ascending and descending limbs of the breath alcohol concentration (BrAC) curve. RESULTS: All alcohol doses increased physical activity, but these increases were time- and dose-dependent. Increases in physical activity lasted across both ascending and descending limbs of the BrAC curve. Following the 0.6 g/kg dose, both physical activity and self-reported stimulation increased during the ascending BrAC. Separate analyses of self-reported sedation scores indicated that alcohol consumption also increased sedation for the 0.6 and 0.8 g/kg doses. Physical activity was not significantly correlated with either self-reported stimulation or sedation at any time point. CONCLUSIONS: These findings suggest that assessments of subjectively measured stimulation and sedation and objectively measured physical activity each assess unique aspects of the effects of alcohol. Used simultaneously, these measures may be useful for examining underlying mechanisms of the effects of alcohol on behavior.     

Saccadic eye movements are associated with a family history of alcoholism at baseline and after exposure to alcohol

OBJECTIVE: To evaluate the influence of family history of alcoholism (FHA) on the response of saccadic eye movements to alcohol. METHOD: Saccadic performance was evaluated in 54 healthy adult subjects with a FHA (family history-positive) and 49 controls (family history-negative). Alcohol and placebo sessions were presented in counterbalanced order. Alcohol was administered intravenously to achieve and maintain a target breath alcohol concentration of 60 mg/100 ml (60%) for 160 min in each subject. During each session, saccadic eye movement testing was performed at baseline (before infusion of alcohol) and twice during the steady-state target breath alcohol concentration. The saccadic testing elicited visually guided saccades (VGS) and antisaccades (AS). Saccadic latency and velocity and the percentage of AS errors were quantified and analyzed using multivariate analysis of variance. RESULTS: The family history-positive and family history-negative groups showed an overall difference at baseline in AS and VGS latencies and velocities in the alcohol and placebo sessions ( p= 0.006). Alcohol delayed saccades such that AS and VGS latencies increased (p = 0.0001) and slowed the execution of saccades such that peak velocities decreased ( p = 0.0002). The percentage of AS errors decreased after alcohol administration, but no significant effect of alcohol (alcohol versus placebo session) was observed (p = 0.1). Latency of AS saccades demonstrated a significant overall FHA effect (p = 0.02) and a significant interaction between FHA and response to alcohol over time (p = 0.02). CONCLUSIONS: Differences in operational characteristics of the saccadic control system are associated with FHA in adult social drinkers, both at baseline and when the brain is exposed to ethanol at 60 mg/100 ml.     

Serum 6-beta-naltrexol levels are related to alcohol responses in heavy drinkers

BACKGROUND: There is strong evidence for the role of the endogenous opioid system in alcohol reinforcement and consumption; however, recent human laboratory studies and clinical trials have reported mixed effects of naltrexone (a nonselective opioid antagonist) on alcohol-related behaviors. This paper reports a secondary data analysis of a human laboratory study that examines the relationship between serum levels of 6-beta-naltrexol, the major, biologically active metabolite of naltrexone, and subjective effects of alcohol. METHODS: The study used a within-subjects design to examine the effects of naltrexone (0, 50, and 100 mg/day) on subjective responses to alcohol (none, moderate, and high dose) in heavy drinkers (n = 23). Each subject received three doses of naltrexone in random order; each naltrexone dose was administered over an 8 day period on an inpatient unit, with a 1 week outpatient washout between doses. After stabilization at each of the naltrexone doses, subjects participated in three alcohol challenge sessions (none, moderate, and high dose) in random order; thus, each subject participated in a total of nine alcohol administration sessions. RESULTS: Doubling the naltrexone dose (50 vs. 100 mg/day) doubled the mean serum 6-beta-naltrexol levels. At each naltrexone dose, there was a 4-fold range in 6-beta-naltrexol levels across subjects. Before alcohol administration, higher 6-beta-naltrexol levels were associated with higher ratings of sedation. After high-dose alcohol administration, higher 6-beta-naltrexol levels were associated with significantly lower ratings of liking and best effects. CONCLUSIONS: These findings provide further evidence of the involvement of the opioid system in the modulation of alcohol effects and suggest that serum 6-beta-naltrexol concentrations may be important in predicting therapeutic response to naltrexone.     

Behavioral Effects and Pharmacokinetics of Low-Dose Intravenous Alcohol in Humans

Alcohol has physiological effects on the human central nervous system at blood alcohol concentrations (BACs) as low as 9 mg/dl. It is unknown, however, if humans can perceive the effects of such low doses of alcohol. Furthermore, low BACs can be difficult to measure. The purpose of this experiment was to: (1) assess the ability of humans to perceive subjective effects of low BACs; (2) measure behavioral effects of low BACs on a psychomotor performance task; and (3) test the sensitivity and accuracy of the transdermal alcohol sensor (TAS) for measuring low BACs from skin. Five men and seven women were administered single-blind intravenous infusions of ethyl alcohol in 5% dextrose/water to achieve peak BACs of 0,10,20, and 40 mg/dl. Subjective intoxication scales and a computer administered continuous performance task (CPT) were used to assess alcohol effects. BACs were estimated from skin, blood, and breath. The only alcohol-induced sensation significantly increased during the alcohol infusions was anesthesia measured by the Alcohol Sensation Scale on the descending limb of the BAC curve. The subjective positive-reinforcing stimulant and mood effects of alcohol were not reported until subjects were administered the 40 mg/dl alcohol infusion. Other measures of subjective intoxication and sedation, and the CPT were unaffected by the alcohol infusions. The TAS provided a noninvasive method for estimating BACs that was comparable with estimates obtained from blood and breath, although delayed in time.     

Predictors and outcomes of variability in subjective alcohol intoxication among college students: an event-level analysis across 4 years

Background: Individual differences in subjective alcohol intoxication, as measured by laboratory‐based alcohol challenge, have been identified as a phenotypic risk factor for alcohol use disorders. Further, recent evidence indicates that subjective alcohol response is also associated with event‐level physiological consequences among college students, including blackouts and hangovers. Methods: The current investigation tested predictors of and outcomes associated with subjective intoxication in the natural drinking environment. In a preliminary laboratory alcohol‐challenge study (n = 53), we developed a brief measure of subjective alcohol intoxication for use in event‐level research. Participating students in the principal study (n = 1,867; 63% women; 54% Caucasian) completed 30 days of Web‐based self‐monitoring in each of the 4 college years. Results: In the principal study, generalized estimating equation analyses revealed that both lighter drinking and a family history of alcohol problems predicted greater subjective intoxication after accounting for estimated blood alcohol concentration (eBAC). Moreover, greater subjective intoxication during a given drinking episode was associated with negative alcohol‐related consequences, illicit drug use, and unsafe sex, and at higher eBACs, was associated with aggression, sex, and property crime. Students who on average experienced greater subjective intoxication were also more likely to experience negative consequences and engage in illicit drug use, sex, unsafe sex, and aggression. Conclusions: These findings suggest that both within‐person variability and between‐person individual differences in subjective intoxication may be risk factors for adverse drinking outcomes at the event level. Intervention efforts aimed at reducing problems associated with collegiate drinking may benefit from consideration both of who experiences greater subjective intoxication and of the situations in which they are more likely to do so.     

Amphetamine self-administration in light and moderate drinkers

Background: Light and moderate drinkers respond differently to the effects of abused drugs, including stimulants such as amphetamine. The purpose of this study was to determine whether light and moderate drinkers differ in their sensitivity to the reinforcing and subjective effects of d‐amphetamine. We hypothesized that moderate drinkers (i.e., participants that reported consuming at least seven alcohol‐containing beverages per week) would be more sensitive to the reinforcing and positive subject‐rated effects of d‐amphetamine than light drinkers. Methods: Data from four studies that employed similar d‐amphetamine self‐administration procedures and subject‐rated drug‐effect measures were included in the analysis. Light (n = 17) and moderate (n = 16) drinkers sampled placebo, low (8 to 10 mg), and high (16 to 20 mg) doses of oral d‐amphetamine administered in eight capsules. Following sampling sessions, participants worked for a maximum of eight capsules, each containing 12.5% of the previously sampled dose, on a modified progressive‐ratio schedule of reinforcement. Results: Both active doses of d‐amphetamine functioned as a reinforcer in the moderate drinkers, while only the high dose did so in the light drinkers. The moderate drinkers worked for significantly more capsules that contained the high dose of d‐amphetamine than did the light drinkers. d‐Amphetamine produced prototypical stimulant‐like subjective effects (e.g., dose‐dependent increases in ratings of Good Effects; Like Drug and Willing to Take Again). Moderate drinkers reported significantly greater subjective effects than the light drinkers. Conclusion: These results are consistent with those from previous laboratory experiments and suggest that moderate alcohol consumption may increase vulnerability to the abuse‐related effects of stimulants.     

Expanding the Utility of the Biphasic Alcohol Effects Scale (BAES) and Initial Psychometric Support for the Brief-BAES (B-BAES)

Background:  The utility of one of the most widely used subjective alcohol assessment tools, the Biphasic Alcohol Effects Scale (BAES) has been somewhat limited based on lack of psychometric studies in large and diverse samples, a range of alcohol doses, the length of the measure, and the original instructional set which precluded baseline measurement and disclosed to subjects that they received alcohol.
Methods:  The current study investigated the factor structure of the BAES with a modified instructional set at pre-drink baseline and after consumption of various doses of alcohol, in a sample of 190 men and women, heavy and light social drinkers. This study tested the psychometric properties of a brief version of the BAES (Brief-BAES or B-BAES).
Results:  Results demonstrated robust support of the stimulant and sedative constructs across all conditions, and demonstrated strong psychometric support for the 6-item B-BAES.
Discussion:  This is the first comprehensive study to expand the utility of the BAES by instructional set, baseline measurement, at various alcohol doses, and by drinking history and sex. In addition, the introduction of the B-BAES may further increase the utility of this scale, particularly in paradigms with repeated measurement or time constraints.