Context Excessive consumption of alcohol is a major problem in the United States and abroad. Despite many years of study, it is unclear why some individuals drink alcohol excessively while others do not. It has been postulated that either lower or greater acute responses to alcohol, or both, depending on the limb of the breath alcohol concentration curve, contribute to propensity for alcohol misuse. Objective To prospectively assess the relationship of acute alcohol responses to future binge drinking. Design Within-subject, double-blind, placebo-controlled, multidose laboratory alcohol challenge study with intensive follow-up. Each participant completed 3 randomized sessions examining responses to a high (0.8 g/kg) and low (0.4 g/kg) alcohol dose and placebo, followed by quarterly assessments for 2 years examining drinking behaviors and alcohol diagnoses. Setting Participants recruited from the community. Participants High-risk heavy social drinkers aged 21 to 35 years who habitually engage in weekly binge drinking (n=104) and light drinker controls (n=86). Intervention We conducted 570 laboratory sessions with a subsequent 99.1% follow-up (1506 of 1520). Main Outcome Measures Biphasic Alcohol Effects Scale, Drug Effects Questionnaire, cortisol response, Time-line Follow-Back, Drinker Inventory of Consequences–Recent, and DSM-IV alcohol abuse and dependence. Results Alcohol produced greater stimulant and rewarding (liking and wanting) responses and lower sedative and cortisol responses in heavy vs light drinkers. Among the heavy drinkers, greater positive effects and lower sedative effects after alcohol consumption predicted increased binge drinking frequency during follow-up. In turn, greater frequency of binge drinking during follow-up was associated with greater likelihood of meeting diagnostic criteria for alcohol abuse and dependence. Conclusions The widely held low level response theory and differentiator model should be revised: in high-risk drinkers, stimulant and rewarding alcohol responses even at peak breath alcohol concentrations are important predictors of future alcohol problems. Trial Registration clinicaltrials.gov Identifier: NCT00961792

Background Propensity for alcohol misuse may be linked to an individuals’ response to alcohol. This study examined the role of alcohol response phenotypes to future drinking problems. Methods One hundred four young heavy social drinkers participated in a within-subject, double-blind, placebo-controlled laboratory alcohol challenge study with 6-year follow-up. Participants were examined for subjective responses before and after receiving an intoxicating dose of alcohol (.8 g/kg) or a placebo beverage, given in random order. Follow-up was conducted in 5 waves over 6 years after the sessions to assess drinking behaviors and alcohol use disorder (AUD) symptoms. Retention was high with 98% (509 of 520) of possible follow-ups completed. Results Greater sensitivity to alcohol, in terms of stimulation and rewarding effects (like, want more) and lower sensitivity to alcohol sedation predicted greater number of AUD symptoms through 6 years of follow-up. Cluster analyses revealed that for half the sample, increasing levels of stimulation and liking were predictors of more AUD symptoms with the other half divided between those showing like and want more and want more alone as significant predictors. Conclusions The findings extend previous findings and offer new empirical insights into the propensity for excessive drinking and alcohol problems. Heightened alcohol stimulation and reward sensitivity robustly predicted more alcohol use disorder symptoms over time associated with greater binge-drinking frequency. These drinking problems were maintained and progressed as these participants were entering their third decade of life, a developmental interval when continued alcohol misuse becomes more deviant.

--We conclude that (1) this community-based exercise training program improved fitness but not heart disease risk factors among sedentary, healthy older adults; (2) home-based exercise was as effective as group exercise in producing these changes; (3) lower-intensity exercise training was as effective as higher-intensity exercise training in the home setting; and (4) the exercise programs were relatively safe.

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 stimulantlike effects of ethanol (p Ͻ 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 Ͻ 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.Key Words: Alcohol Response, Heavy Drinker, Risk for Alcoholism, Biphasic Alcohol Effects Scale, Cortisol. H EAVY ETHANOL DRINKING among young adultsis a serious problem in this country (Chou and Pickering, 1992), and the consequences of this excessive use, both financial and personal, are widespread. The cost of ethanol-related health care, loss of productivity, crime, and accidents totals more than $148 million annually in the United States alone (Harwood et al., 1999). Approximately 30% of all accidents are connected to ethanol use, and excessive ethanol use contributes to many chronic and life-threatening illnesses, including gastrointestinal, liver, and cardiovascular disease ("Tenth Special Report to Congress on Alcohol and Health," 2000). Data indicate that those who start drinking before the age of 14 years are 12 times more likely to be injured in accidents while under the influence of ethanol than those who start drinking after age 21 (Hingson et al., 2000). Early-onset alcohol drinking is also strongly associated with lifetime alcohol problems (Chou and Pickering, 1992). Understanding the factors that contribute to the escalation and maintenance of excessive ethanol drinking is crucial to improve prevention, public education, and early intervention strategies. At this time, it is still unclear why some individuals abuse ethanol and others do not.One potential source of vulnerability to developing alcohol use problems is the quality and magnitude of acute subjective responses to alcohol (Fischman and Foltin, 1991). For instance, individuals who experience greater stimulant-like effects from an acute dose of ethanol also report greater drug liking and euphoria and have greater behavioral preference for ethanol (over placebo) compared with those individuals who experience mos...

We investigated specific subjective effects of naltrexone pretreatment or placebo during various intervals on the breath alcohol level (BAL) curve in nonalcoholic volunteers. Fifteen high-risk (social drinkers with an alcoholic father) and 14 low-risk (no alcoholic relatives in at least two generations) subjects were tested in a double-blind placebo-controlled study of the effects of 50 mg oral naltrexone on response to a moderate dose of alcohol. Dependent measures included subjective stimulation and sedation subscales from the Biphasic Alcohol Effects Scale (BAES) and mood subscales from the Profile of Mood States (POMS). At rising BALs, high-risk subjects showed a naltrexone-related attenuation of BAES stimulation. This effect was not evident in low-risk subjects, who directionally showed the opposite effect, although nonsignificant. For both groups, there were no significant naltrexone-related effects for BAES sedation; however, naltrexone did affect several POMS scales on alcohol response, such as decreased vigor, and increased fatigue, tension, and confusion. Confusion was significantly elevated for the high-risk group during rising BALs of the naltrexone session. The results suggest a differential response to naltrexone, based on paternal history of alcoholism and level of stimulation experienced during alcohol drinking.

Writing Committee for the REMAP-CAP Investigators IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONSThe immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURESThe primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11...

Rationale The Drug Effects Questionnaire (DEQ) is widely used in studies of acute subjective response (SR) to a variety of substances, but the format of the DEQ varies widely across studies, and details of its psychometric properties are lacking. Thus, the field would benefit from demonstrating the reliability and validity of the DEQ for use across multiple substances. Objective The current study evaluated the psychometric properties of several variations of DEQ items, which assessed the extent to which participants (1) feel any substance effect(s), (2) feel high, (3) like the effects, (4) dislike the effects, and (5) want more of the substance using 100mm Visual Analog Scales. Methods DEQ data from three placebo-controlled studies were analyzed to examine SR to amphetamine, nicotine, and alcohol. We evaluated the internal structure of the DEQ for use with each substance as well as relationships between scale items, measures of similar constructs, and substance-related behaviors. Results Results provided preliminary psychometric support for items assessing each DEQ construct (FEEL, HIGH, DISLIKE, LIKE, and MORE). Conclusions Based on the study results, we identify several common limitations of extant variants of the DEQ and recommend an improved version of the measure. The simplicity and brevity of the DEQ combined with its promising psychometric properties support its use in future SR research across a variety of substances.

Background The main neurobiological theories of the development of addiction, including tolerance, sensitization, incentive-sensitization, and allostasis have not been tested in longitudinal human alcohol response research. To address this issue, we conducted the first controlled prospective investigation of subjective and neuroendocrine responses to alcohol measured over a five year interval in at-risk young adult heavy drinkers and light drinker controls. Methods Participants were 156 individuals, 86 heavy drinkers (HD) and 70 light drinkers (LD), undergoing an initial oral alcohol challenge testing (0.8 g/kg alcohol vs. placebo) and an identical re-examination testing 5–6 years later. Alcohol use disorder (AUD) symptoms and drinking behaviors were assessed in the interim follow-up period. Results At reexamination, HD continued to exhibit higher sensitivity on alcohol’s stimulating and rewarding effects with lower sensitivity to sedative effects and cortisol reactivity, relative to LD. In HD with high AUD symptom trajectories over follow-up, heightened alcohol stimulation and reward persisted at reexamination. HD with low AUD symptoms showed reduced alcohol stimulation over time and lower reward throughout compared with the HD with high and intermediate AUD symptoms. Conclusions Results support the early stage phase of the allostasis model, with persistently heightened reward sensitivity and stimulation in heavy drinkers exhibiting AUD progression in early mid-adulthood. While there are multiple pathways to development of a disorder as complex as AUD, maintenance of alcohol stimulatory and rewarding effects may play an important role in the continuation and progression of alcohol addiction.