Neurocognitive Functioning and Treatment Outcome Following Detoxification Among Asian Alcohol-Dependent Inpatients.

BACKGROUND: The prevalence of alcohol use disorders in Asia is increasing and relapse among treated populations remains the norm, not the exception. The extent to which cognitive impairment influences clinical outcome remains unclear, with research dominated by studies of Caucasian populations. OBJECTIVES: This study examines behavioral and self-reported cognitive functioning in detoxified alcohol-dependent (AD) patients in Singapore and its association with outcome. METHODS: The cognitive performance of 30 recently-detoxified AD inpatients and 30 demographically-matched controls was compared using visuospatial memory, working memory, set-shifting, planning and reflection impulsivity tests of the CANTAB®, and self-reported dysexecutive symptoms and everyday cognitive difficulties. Patients' alcohol use and self-reported cognitive functioning were reassessed 3-months post-discharge. RESULTS: Compared to matched controls, AD inpatients exhibited significantly poorer fluid intelligence, visuospatial memory, working memory, set-shifting flexibility and planning/organization, but not reflection impulsivity. In support of Western studies, a significant proportion (three-quarters) were "clinically impaired" on subtests. Significant reductions were observed in alcohol units, frequency and dependency scores at follow-up, though improvements in self-reported cognitive functioning were limited to abstainers. Baseline cognitive performance did not differentiate those who had abstained from alcohol and relapsed at follow-up. CONCLUSIONS/IMPORTANCE: Memory and executive functioning impairments were evident among Asian AD patients alongside self-reported cognitive difficulties, thus cognitively demanding psychological interventions may have limited impact during early detoxification. Future studies can build on these findings, with larger samples and measurement of moderating and mediating factors to extend our understanding of how cognitive impairment influences outcome.

The alcohol-preferring (P) and high-alcohol-drinking (HAD) rats--animal models of alcoholism.

The objective of this article is to review the literature on the utility of using the selectively bred alcohol-preferring (P) and high-alcohol-drinking (HAD) lines of rats in studies examining high alcohol drinking in adults and adolescents, craving-like behavior, and the co-abuse of alcohol with other drugs. The P line of rats meets all of the originally proposed criteria for a suitable animal model of alcoholism. In addition, the P rat exhibits high alcohol-seeking behavior, demonstrates an alcohol deprivation effect (ADE) under relapse drinking conditions, consumes amounts of ethanol during adolescence equivalent to those consumed in adulthood, and co-abuses ethanol and nicotine. The P line also exhibits excessive binge-like alcohol drinking, attaining blood alcohol concentrations (BACs) of 200 mg% on a daily basis. The HAD replicate lines of rats have not been as extensively studied as the P rats. The HAD1,2 rats satisfy several of the criteria for an animal model of alcoholism, e.g., these rats will voluntarily consume ethanol in a free-choice situation to produce BACs between 50 and 200 mg%. The HAD1,2 rats also exhibit an ADE under repeated relapse conditions, and will demonstrate similar levels of ethanol intake during adolescence as seen in adults. Overall, the P and HAD1,2 rats have characteristics attributed to an early onset alcoholic, and can be used to study various aspects of alcohol use disorders.

Metabolic products of [2-(13) C]ethanol in the rat brain after chronic ethanol exposure.

Most ingested ethanol is metabolized in the liver to acetaldehyde and then to acetate, which can be oxidized by the brain. This project assessed whether chronic exposure to alcohol can increase cerebral oxidation of acetate. Through metabolism, acetate may contribute to long-term adaptation to drinking. Two groups of adult male Sprague-Dawley rats were studied, one treated with ethanol vapor and the other given room air. After 3 weeks the rats received an intravenous infusion of [2-(13) C]ethanol via a lateral tail vein for 2 h. As the liver converts ethanol to [2-(13) C]acetate, some of the acetate enters the brain. Through oxidation the (13) C is incorporated into the metabolic intermediate α-ketoglutarate, which is converted to glutamate (Glu), glutamine (Gln), and GABA. These were observed by magnetic resonance spectroscopy and found to be (13) C-labeled primarily through the consumption of ethanol-derived acetate. Brain Gln, Glu, and, GABA (13) C enrichments, normalized to (13) C-acetate enrichments in the plasma, were higher in the chronically treated rats than in the ethanol-naïve rats, suggesting increased cerebral uptake and oxidation of circulating acetate. Chronic ethanol exposure increased incorporation of systemically derived acetate into brain Gln, Glu, and GABA, key neurochemicals linked to brain energy metabolism and neurotransmission. The liver converts ethanol to acetate, which may contribute to long-term adaptation to drinking. Astroglia oxidize acetate and generate neurochemicals, while neurons and glia may also oxidize ethanol. When (13) C-ethanol is administered intravenously, (13) C-glutamine, glutamate, and GABA, normalized to (13) C-acetate, were higher in chronic ethanol-exposed rats than in control rats, suggesting that ethanol exposure increases cerebral oxidation of circulating acetate.

Using electronic health records data to assess comorbidities of substance use and psychiatric diagnoses and treatment settings among adults.

OBJECTIVE: To examine prevalences of substance use disorders (SUD) and comprehensive patterns of comorbidities among psychiatric patients ages 18-64 years (N = 40,099) in an electronic health records (EHR) database. METHOD: DSM-IV diagnoses among psychiatric patients in a large university system were systematically captured: SUD, anxiety (AD), mood (MD), personality (PD), adjustment, childhood-onset, cognitive/dementia, dissociative, eating, factitious, impulse-control, psychotic (schizophrenic), sexual/gender identity, sleep, and somatoform diagnoses. Comorbidities and treatment types among patients with a SUD were examined. RESULTS: Among all patients, 24.9% (n = 9984) had a SUD, with blacks (35.2%) and Hispanics (32.9%) showing the highest prevalence. Among patients with a SUD, MD was prevalent across all age groups (50.2-56.6%). Patients aged 18-24 years had elevated odds of comorbid PD, adjustment, childhood-onset, impulse-control, psychotic, and eating diagnoses. Females had more PD, AD, MD, eating, and somatoform diagnoses, while males had more childhood-onset, impulse-control, and psychotic diagnoses. Blacks had greater odds than whites of psychotic and cognitive/dementia diagnoses, while whites exhibited elevated odds of PA, AD, MD, childhood-onset, eating, somatoform, and sleep diagnoses. Women, blacks, and Native American/multiple-race adults had elevated odds of using inpatient treatment; men, blacks, and Hispanics had increased odds of using psychiatric emergency care. Comorbid MD, PD, adjustment, somatoform, psychotic, or cognitive/dementia diagnoses increased inpatient treatment. CONCLUSION: Patients with a SUD, especially minority members, use more inpatient or psychiatric emergency care than those without. Findings provide evidence for research on understudied diagnoses and underserved populations in the real-world clinical settings.

Episodic heavy drinking, problem drinking and injuries - results of the WHO/NIAAA collaborative emergency room study in South Korea.

Alcohol is the 5th leading risk factor to the global disease burden and disability and about half of the global alcohol burden was attributable to injuries. Despite a large body of evidence documenting the associations between alcohol and injuries, data from Asian countries including South Korea are sparse. The aim of this study was to investigate the associations between episodic heavy past-year drinking, problem drinking symptomatic of alcohol dependence and alcohol-related and intentional injuries. Data from 1989 injured patients recruited for the WHO/NIAAA Collaborative Study on Alcohol and Injury in South Korea were analyzed with respect to the prevalence rates and associations between injuries and frequency of past-year episodic heavy drinking and problem drinking. In estimating the odds ratios (ORs) and the associated 95% confidence intervals between alcohol intake and injuries multivariable logistic models were employed to adjust for sociodemographic characteristics and selected drinking variables. All analyses were conducted using the SAS 9.2 software. Findings of this study were consistent with prior studies that the risk of alcohol-related or intentional injury was positively associated with the frequency of episodic heavy drinking. The magnitudes of the associations were larger with frequent consumption of 5+ drinks (OR=4.0 approximately) than with frequent consumption of 12+ drinks (OR=3.1). Strong associations were also noted between RAPS4-assessed alcohol dependence and alcohol-related and intentional injuries. Further, the prevalence of intentional injury and its association with alcohol increased sharply once the acute alcohol intake exceeded 90 ml. Our results were consistent with prior studies that episodic heavy consumption, acute intoxication and problem drinking are pervasive among emergency room patients. Results of our study also lent support for administering a single-item screener querying consumption of 5+ drinks at a sitting in the past 12 months as a triage tool in Korea.

Behavioral profiling of multiple pairs of rats selectively bred for high and low alcohol intake using the MCSF test.

Genetic aspects of alcoholism have been modeled using rats selectively bred for extremes of alcohol preference and voluntary alcohol intake. These lines show similar alcohol drinking phenotypes but have different genetic and environmental backgrounds and may therefore display diverse behavioral traits as seen in human alcoholics. The multivariate concentric square field™ (MCSF) test is designed to provoke exploration and behaviors associated with risk assessment, risk taking and shelter seeking in a novel environment. The aim was to use the MCSF to characterize behavioral profiles in rat lines from selective breeding programs in the United States (P/NP, HAD1/LAD1, HAD2/LAD2), Italy (sP/sNP) and Finland (AA/ANA). The open field and elevated plus maze tests were used as reference tests. There were substantial differences within some of the pairs of selectively bred rat lines as well as between all alcohol-preferring rats. The most pronounced differences within the pairs of lines were between AA and ANA rats and between sP and sNP rats followed by intermediate differences between P and NP rats and minor differences comparing HAD and LAD rats. Among all preferring lines, P, HAD1 and HAD2 rats shared similar behavioral profiles, while AA and sP rats were quite different from each other and the others. No single trait appeared to form a common 'pathway' associated with a high alcohol drinking phenotype among all of the alcohol-preferring lines of rats. The marked behavioral differences found in the different alcohol-preferring lines may mimic the heterogeneity observed among human alcoholic subtypes.

Treatment use and barriers among adolescents with prescription opioid use disorders.

BACKGROUND: This study examined national trends, patterns, correlates, and barriers to substance abuse treatment use by adolescents aged 12-17 years who met at least one of the past-year criteria for prescription opioid abuse or dependence (N=1788). METHODS: Data were from the 2005-2008 National Surveys of Drug Use and Health (NSDUH). Past-year substance use disorders, major depression, and treatment use were assessed by audio computer-assisted self-interviewing. RESULTS: About 17% of adolescents with opioid dependence (n=434) and 16% of those with opioid abuse (n=355) used any substance abuse treatment in the past year compared with 9% of subthreshold users, i.e., adolescents who reported 1-2 prescription opioid dependence criteria but no abuse criteria (n=999). Only 4.2% of adolescents with opioid dependence, 0.5% of those with abuse, and 0.6% of subthreshold users reported a perceived need for treatment of nonmedical opioid use. Self-help groups and outpatient rehabilitation were the most commonly used sources of treatment. Few black adolescents used treatment (medical settings, 3.3%; self-help groups, 1.7%) or reported a need for treatment (1.8%). Talking to parents/guardians about dangers of substance use increased the odds of treatment use. Barriers to treatment use included "wasn't ready to stop substance use," "didn't want others to find out," and "could handle the problem without treatment." CONCLUSIONS: Adolescents with prescription opioid use disorders markedly underutilize treatment. Non-financial barriers are pervasive, including stigma and a lack of perceived treatment need.

Genetic propensities to increase ethanol intake in response to stress: studies with selectively bred swim test susceptible (SUS), alcohol-preferring (P), and non-preferring (NP) lines of rats.

RATIONALE: Swim test susceptible (SUS) rats selectively bred for reduced struggling in the forced swim test (FST) following stress show high voluntary ethanol intake like alcohol-preferring (P) rats selectively bred for ethanol preference. It is unknown whether stress enhances drinking in SUS rats or FST behavior in P and non-preferring (NP) rats. OBJECTIVES: The aim of this study was to assess the response to stress in male SUS, Sprague-Dawley (SD), P, and NP rats on 10% ethanol drinking and FST behavior. METHODS: In experiment 1, SUS and SD rats had limited access to ethanol and water following white noise, rehousing, and forced swim stress. In experiment 2, P and NP rats received footshock, white noise, restraint, or no stress prior to the FST. Rats then had continuous access to ethanol and water, and the effects of weekly exposures to stress were measured. RESULTS: SUS rats drank more ethanol (M = 2.98 g/kg) than SD rats (M = 1.26 g/kg) at baseline. Stress produced sustained increases (~33% of baseline) in ethanol intake in SUS rats. NP rats spent twice as much time immobile as P rats in the FST. Stress did not alter FST behavior in P or NP rats. Only footshock produced an increase (~29%) in ethanol intake in P rats. CONCLUSIONS: Selection for stress-induced depressive-like behavior in SUS rats is associated with enhanced stress-induced ethanol drinking. However, the selection for alcohol preference is not associated with stress-induced depressive-like behavior but is associated with footshock stress-induced ethanol drinking. In these experiments, relationships among stress, depressive-like behavior, and alcohol preference were not symmetrical.

Alcohol research: past, present, and future.

Created forty years ago, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) has played a major role in the great strides made in the understanding, treatment, prevention, and public acceptance of alcohol-use disorders. Throughout most of U.S. history "habitual drunkenness" was viewed as a problem of moral degeneracy or character flaw inherent in the individual. However, the wealth of scientific evidence amassed throughout NIAAA's history has established alcoholism as a medical condition, that is, as a disease for which affected individuals should feel no shame or be treated with disdain. We look at the developments in alcohol epidemiology, typology, etiology, prevention, and treatment research over the past 40 years. We also discuss how NIAAA addresses alcohol disorders from a life-course framework, affecting all stages of the lifespan, from fetus through child, adolescent, and young adult, to midlife/senior adult, with each stage involving different risks, consequences, prevention efforts, and treatment strategies.

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.

Effects of sazetidine-A, a selective alpha4beta2 nicotinic acetylcholine receptor desensitizing agent on alcohol and nicotine self-administration in selectively bred alcohol-preferring (P) rats.

RATIONALE: Manipulations of nicotinic cholinergic receptors have been shown to influence both alcohol and nicotine intake. Sazetidine-A [6-(5(((S)-azetidine-2-yl)methoxy)pyridine-3-yl)hex-5-yn-1-ol] is a novel compound that potently and selectively desensitizes alpha4beta2 nicotinic receptors with only modest receptor activation. OBJECTIVES: The goal of the present study was to examine the effects of sazetidine-A on alcohol and nicotine self-administration in alcohol-preferring (P) rats. METHODS: P rats were given the choice of water or alcohol. Once stable baselines were established, the acute (0, 0.1, 0.3, 1, and 3 mg/kg, s.c.) and chronic (3 mg/kg for 10 days) effects of sazetidine-A on alcohol intake were assessed. Naltrexone (2.5 mg/kg) served as a positive control. The effect of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on saccharin (0.2%) preference was also assessed. In addition, the acute effects of sazetidine-A (3 mg/kg) and naltrexone (4 mg/kg) on alcohol intake after alcohol deprivation were evaluated. In another experiment, the effects of sazetidine-A (0, 1, or 3 mg/kg) on i.v. nicotine self-administration in P and NP rats were assessed. RESULTS: Sazetidine-A caused a dose-dependent reduction in alcohol intake. Chronic sazetidine-A also effectively reduced alcohol intake until the seventh day of treatment, when partial tolerance appeared to develop. In the post-deprivation study, sazetidine-A significantly reduced alcohol intake and preference. Sazetidine-A at 3 mg/kg significantly reduced nicotine self-administration in both lines. CONCLUSIONS: Sazetidine-A significantly reduced alcohol and nicotine intake in P rats that self-administer higher levels of both drugs. Sazetidine-A may hold promise for the treatment of alcohol and nicotine addiction.

Gender differences in the relationship of internalizing and externalizing psychopathology to alcohol dependence: likelihood, expression and course.

OBJECTIVE: To determine whether internalizing and externalizing psychopathology were differentially associated with alcohol dependence in men and women. METHODS: Four categories of lifetime psychopathology were examined: neither internalizing nor externalizing (NINE), internalizing only (IO), externalizing only (EO) and both internalizing and externalizing (BIE). Multivariate models assessed gender differences in the adjusted associations of these categories with the odds of lifetime alcohol dependence in a representative sample of 43,093 U.S. adults 18 and older and with clinical course and expression in a subsample of 4781 lifetime alcoholics. RESULTS: The excess odds of lifetime alcohol dependence associated with IO, EO and BIE were significantly greater for women than men, OR=2.6, 8.8 and 10.7 versus 1.9, 4.0 and 6.5, respectively. Regardless of gender, the ORs were significantly higher for EO than IO and for BIE than EO. Gender differences in the expression and course of alcoholism were most pronounced for the categories of NINE and IO, with men having greater consumption, dependence severity and treatment but less familial alcoholism. Gender variation in the association of psychopathology with the expression and course of alcoholism was most evident in the BIE category, where the associations were stronger for women. Lifetime externalizing psychopathology was associated with an increased likelihood of treatment utilization, especially among women. CONCLUSIONS: Findings highlight the need to increase alcoholism screening, prevention and intervention among women with psychopathology, especially externalizing. The greater numbers of internalizing than externalizing alcoholics emphasize the need to treat symptoms of depression and anxiety in alcohol treatment settings.

Alterations in brain glucose utilization accompanying elevations in blood ethanol and acetate concentrations in the rat.

BACKGROUND: Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. METHODS: Rats were infused with solutions of sodium acetate, ethanol, or saline containing (13)C-2-glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs' cycle, acyl-coenzyme A (CoA) compounds, and amino acids. RESULTS: Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol-infused animals. Peak blood BAcC increased to 12 mM in acetate-infused animals. Both ethanol and acetate infused animals had a lower uptake of (13)C-glucose into the brain compared to controls and the concentration of brain (13)C-glucose-6-phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl-CoA and somewhat lower levels of free Mg(2+) in ethanol-treated animals compared to saline controls. In acetate-infused animals the concentrations of brain lactate, alpha-ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD(+)]/[NADH] was lower, the free mitochondrial [NAD(+)]/[NADH] and [CoQ]/[CoQH(2)] were oxidized and the DeltaG' of ATP lowered by acetate infusion from -61.4 kJ to -59.9 kJ/mol. CONCLUSIONS: Animals with elevated levels of blood ethanol or acetate had decreased (13)C-glucose uptake into the brain. In acetate-infused animals elevated BAcC were associated with a decrease in (13)C-glucose phosphorylation. The co-ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in DeltaG' of ATP was similar to administration of uncoupling agents indicating that the metabolism of acetate in brain caused the mitochondrial voltage dependent pore to form.

A critical evaluation of influence of ethanol and diet on salsolinol enantiomers in humans and rats.

BACKGROUND: (R/S)-Salsolinol (SAL), a condensation product of dopamine (DA) with acetaldehyde, has been speculated to have a role in the etiology of alcoholism. Earlier studies have shown the presence of SAL in biological fluids and postmortem brains from both alcoholics and nonalcoholics. However, the involvement of SAL in alcoholism has been controversial over several decades, since the reported SAL levels and their changes after ethanol exposure were not consistent, possibly due to inadequate analytical procedures and confounding factors such as diet and genetic predisposition. Using a newly developed mass spectrometric method to analyze SAL stereoisomers, we evaluated the contribution of ethanol, diet, and genetic background to SAL levels as well as its enantiomeric distribution. METHODS: Simultaneous measurement of SAL enantiomers and DA were achieved by high performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). Plasma samples were collected from human subjects before and after banana (a food rich in SAL) intake, and during ethanol infusion. Rat plasma and brain samples were collected at various time points after the administration of SAL or banana by gavage. The brain parts including nucleus accumbens (NAC) and striatum (STR) were obtained from alcohol-non-preferring (NP) or alcohol-preferring (P) rats as well as P-rats which had a free access to ethanol (P-EtOH). RESULTS: Plasma SAL levels were increased significantly after banana intake in humans. Consistently, administration of banana to rats also resulted in a drastic increase of plasma SAL levels, whereas brain SAL levels remained unaltered. Acute ethanol infusion did not change SAL levels or R/S ratio in plasma from healthy humans. The levels of both SAL isomers and DA were significantly lower in the NAC of P rats in comparison to NP rats. The SAL levels in NAC of P rats remained unchanged after chronic free-choice ethanol drinking. There were decreasing trends of SAL in STR and DA in both brain regions. No changes in enantiomeric ratio were observed after acute or chronic ethanol exposure. CONCLUSIONS: SAL from dietary sources is the major contributor to plasma SAL levels. No significant changes of SAL plasma levels or enantiomeric distribution after acute or chronic ethanol exposure suggest that SAL may not be a biomarker for ethanol drinking. Significantly lower SAL and DA levels observed in NAC of P rats may be associated with innate alcohol preference.

Intravenous ethanol infusions can mimic the time course of breath alcohol concentrations following oral alcohol administration in healthy volunteers.

BACKGROUND: Our previous studies have used intravenous (IV) clamping methods to demonstrate that family history positive (FHP) subjects exhibit a greater initial response to alcohol than family history negative (FHN) subjects. These results differ from other studies of family history of alcoholism (FHA) influences, most of which have used an oral alcohol challenge, suggesting that the route of administration may influence both the response to alcohol and FHA-related differences in response. To examine this possibility, one approach would be to directly compare responses following oral and IV alcohol administration in the same subjects. There is, however, a 3- to 4-fold variance, between- and within-subjects, in the breath alcohol concentrations (BrACs) following oral alcohol administration. Thus, our objective was to characterize the between-subject variability in the time course of BrACs following oral alcohol administration in healthy volunteers and to develop an IV infusion method to mimic the BrAC-time course attained following oral alcohol in the same subject. METHODS: This was a 2-session study in young adult, healthy, nondependent drinkers. In the first session, subjects ingested an oral dose of alcohol, based on total body water, to achieve a target peak BrAC of 80 mg%. In the second session, subjects received an IV infusion of ethanol designed to achieve the same BrAC time course as that achieved in the first session. The individualized infusion-rate profile was precomputed using a physiologically-based pharmacokinetic (PBPK) model for alcohol with model parameters adjusted to the individual's physiology. The peak BrACs (C(max)), times of peak BrAC (T(max)), and the areas under the BrAC vs. time curve (AUC) were compared between sessions to assess how closely the BrAC exposure during the IV infusion session mimicked the exposure following oral alcohol. RESULTS: The time course of BrACs following oral alcohol administration showed a high degree of between-subject variability. Mean C(max), T(max), and AUC did not differ by gender, indicating that calculation of oral doses based on total body water results in comparable BrAC-time courses, on average, for females and males. The IV infusion driven BrAC-time profiles demonstrated good fidelity to the BrAC-time curves resulting from oral alcohol: the mean %difference in C(max) and AUC were both 11%, while the mean %difference for T(max) was 27%. This degree of variability is less than half that seen across individuals following oral alcohol administration, which was substantial [coefficient of variation (%CV) ranging from 22 to 52%]. CONCLUSIONS: Despite the use of standardized doses and controlled experimental conditions, there was substantial between-subject variability in the BrAC time course following oral administration of alcohol. The PBPK-model-based infusion method can mimic the BrACs attained with oral alcohol for individual subjects. This method provides a platform to evaluate effects attributable to the route of administration on the response to alcohol, as well as the influence of determinants such as family history of alcoholism on the alcohol response.