A Prospective 5-Year Re-examination of Alcohol Response in Heavy Drinkers Progressing in Alcohol Use Disorder

In the paper

“In brief, the LD largely continued with low-risk drinking. While they consumed alcohol more frequently over time, binge drinking and alcohol problems were rare, and they formed one low-risk trajectory group(34).”

What the sources say

• Not checked yetcites [34] King, 2014, Alcohol challenge responses predict future alcohol use disorder symptoms: A 6-year prospective study, Biol Psychiatry source

In the paper

“BrAC peak levels at 60 minutes were slightly higher at initial testing in the HD vs. LD (94 vs. 85 mg/dl, respectively, p<.001) but at re-examination there were no differences [89 vs. 85 mg/dl, p=.126].”

In the paper

“For the HD subgroups, there was a subgroup x phase interaction for stimulation such that the high AUD subgroup persisted with heightened stimulation at re-examination and the intermediate group persisted at intermediate levels, but the low AUD subgroup showed a reduction in stimulation over time.”

In the paper

“Within-subject associations of each alcohol response between initial and re-examination phases were positive and significant [stimulation (r=.30, p<.001), liking (r=.26, p<.001), wanting (r= .30, p<.001), sedation (r=.42, p<.0001), and cortisol (r= .18, p<.05)].”

In the paper

“HD also had lower sensitivity to sedation (Fig 3A) and cortisol response versus LD (Fig 3B).”

In the paper

“the majority of persons in this subgroup either maintaining heightened stimulation or increasing further at re-examination, with only 2 of 9 high AUD individuals showing a lessening of response.”

In the paper

“The AUD subgroups did not differ on alcohol sedation or cortisol response (Fig 3A, 3B).”

In the paper

“At the declining limb, stimulating and rewarding responses were lower in magnitude than at the earlier time points but heightened responses remained in HD, particularly for wanting in the high AUD subgroup.”

In the paper

“Light drinkers largely continued low-risk drinking and rare AUD symptoms over time with an overall protective alcohol response “footprint”: persistently low sensitivity to alcohol stimulation and reward and high sensitivity to alcohol sedative and stress hormone effects.”

In the paper

“Finally, the results did not support sensitization theory, as heavy drinkers with progressive AUD subjects maintained but did not further increase their already heightened sensitivity to stimulation.”

In the paper

“Alcohol response differences between these groups observed at initial testing remained 5–6 years later, with greater alcohol stimulating and rewarding effects and lower sedation and cortisol excretion in heavy drinkers.”

In the paper

“Human studies in this area have been limited to retrospective patient reports(23), post mortem brain tissue methods(24), or cross-sectional laboratory paradigms(2, 3, 25–29), none of which directly measure alcohol responses in the same individuals over time.”

What the sources say

• Not checked yetcites [23] Edwards, 1976, Alcohol dependence: Provisional description of a clinical syndrome, Br Med J source
• Not checked yetcites [24] Hutchison, 2008, The incentive salience of alcohol: Translating the effects of genetic variant in CNR1, Arch Gen Psychiatry source
• Not checked yetcites [2] Corbin, 2013, Early subjective response and acquired tolerance as predictors of alcohol use and related problems in a clinical sample, Alcohol Clin Exp Res source
• Not checked yetcites [3] Morean, 2008, Subjective alcohol effects and drinking behavior: The relative influence of early response and acquired tolerance, Addict Behav source
• Not checked yetcites [25] Ostafin, 2010, Testing the incentive-sensitization theory with at-risk drinkers: Wanting, liking, and alcohol consumption, Psychol Addict Behav source
• Not checked yetcites [26] Hobbs, 2005, Dissociation of wanting and liking for alcohol in humans: A test of the incentive-sensitisation theory, Psychopharmacology (Berl) source
• Not checked yetcites [27] Newlin, 1991, Chronic tolerance and sensitization to alcohol in sons of alcoholics, Alcohol Clin Exp Res source
• Not checked yetcites [28] Schuckit, 1996, An 8-year follow-up of 450 sons of alcoholic and control subjects, Arch Gen Psychiatry source
• Not checked yetcites [29] King, 2011, Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking, Arch Gen Psychiatry source

In the paper

“Tolerance, a diagnostic criteria for AUD from DSM-III (1980) to DSM-5 (2013)(8), implies that attenuation of subjective alcohol responses over time plays a key role in the development of addiction.”

What the sources say

• Not checked yetcites [2] Corbin, 2013, Early subjective response and acquired tolerance as predictors of alcohol use and related problems in a clinical sample, Alcohol Clin Exp Res source
• Not checked yetcites [3] Morean, 2008, Subjective alcohol effects and drinking behavior: The relative influence of early response and acquired tolerance, Addict Behav source
• Not checked yetcites [4] Schuckit, 2008, Clinical implications of tolerance to alcohol in nondependent young drinkers, Am J Drug Alcohol Abuse source
• Not checked yetcites [5] Matson, 2014, Selectively bred crossed high-alcohol-preferring mice drink to intoxication and develop functional tolerance, but not locomotor sensitization during free-choice ethanol access, Alcohol Clin Exp Res source
• Not checked yetcites [6] Tabakoff, 1988, Tolerance and the etiology of alcoholism: Hypothesis and mechanism, Alcohol Clin Exp Res source
• Not checked yetcites [7] Ramsay, 1997, Biological consequences of drug administration: Implications for acute and chronic tolerance, Psychol Rev source
• Not checked yetcites [8] 2013

In the paper

“which may not sensitize over time.”

What the sources say

• Not checked yetcites [16] Robinson, 1993, The neural basis of drug craving: An incentive-sensitization theory of addiction, Brain Res Brain Res Rev source
• Not checked yetcites [17] Robinson, 2001, Incentive-sensitization and addiction, Addiction source

In the paper

“The present study provided the first comprehensive repeated evaluation of alcohol responses in at-risk drinkers to test these neurobiological theories of AUD progression.”

In the paper

“In contrast, the sensitization theory asserts that greater stimulant effects over time underlie addictive processes(9), based on rodent data showing that stimulant-like and locomotor alcohol responses increase after repeated exposures(10, 11).”

What the sources say

• Not checked yetcites [9] Wise, 1987, A psychomotor stimulant theory of addiction, Psychol Rev source

In the paper

“Finally, allostatic theory asserts heightened brain reward sensitivity and positive reinforcement characterize the early stages of addiction(18), but reward insensitivity and negative reinforcement underlie the later and more severe stages(18–20).”

What the sources say

• Not checked yetcites [18] Koob, 2001, Drug addiction, dysregulation of reward, and allostasis, Neuropsychopharmacology source

In the paper

“but reward insensitivity and negative reinforcement underlie the later and more severe stages(18–20).”

What the sources say

• Not checked yetcites [18] Koob, 2001, Drug addiction, dysregulation of reward, and allostasis, Neuropsychopharmacology source
• Not checked yetcites [19] Volkow, 2010, Addiction: Decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain’s control circuit, Bioessays source
• Not checked yetcites [20] Koob, 2008, Addiction and the brain antireward system, Annu Rev Psychol source

In the paper

“The incentive-sensitization theory of addiction(16, 17) also emphasizes sensitization process, but specifies that repeated use of a drug produces neuroadapations that sensitize motivational reward to drugs and associated drug stimuli (i.e.., processes of “wanting”) distinct from the neurocircuitry mediating hedonic reward (liking) which may not sensitize over time.”

What the sources say

• Not checked yetcites [16] Robinson, 1993, The neural basis of drug craving: An incentive-sensitization theory of addiction, Brain Res Brain Res Rev source
• Not checked yetcites [17] Robinson, 2001, Incentive-sensitization and addiction, Addiction source

In the paper

“At the 5-year follow-up, 187 individuals (98.4%) continued to participate, and telephone re-screening was conducted to determine eligibility for re-examination.”

In the paper

“From this eligible subject pool, 156 (88% of those eligible, 83% of the original sample) returned to participate in re-examination sessions.”

In the paper

“To reduce alcohol expectancy, the Alternative Substance Paradigm(51) was used: participants were informed that their allocated beverage might contain a stimulant, sedative, alcohol, or a placebo, or a combination of these substances.”

What the sources say

• Not checked yetcites [51] Conrad, 2012, Alternative substance paradigm: Effectiveness of beverage blinding and effects on acute alcohol responses, Exp Clin Psychopharmacol source

In the paper

“The instructions asked for current mood state at each time point and did not reveal that alcohol was ingested (60).”

What the sources say

• Not checked yetcites [60] Rueger, 2009, Expanding the utility of the Biphasic Alcohol Effects Scale (BAES) and initial psychometric support for the Brief-BAES (B-BAES), Alcohol Clin Exp Res source

In the paper

“Samples were stored at −20°C and later assayed for levels of the stress hormone cortisol by high sensitivity enzyme immunoassay at the University of Chicago CRC Core Laboratory. The inter- and intra-assay coefficients of variation at initial testing were 6.88% and 7.12%, respectively, and at re-examination were 6.60% and 7.99%, respectively.”

In the paper

“Participants were interviewed to confirm compliance with 3-hour abstinence from food, caffeine, and smoking.”

In the paper

“The CSDP is a within-subject, double-blind, randomized-order study of responses to alcohol and placebo beverages in 190 young adult non-alcohol dependent drinkers.”

In the paper

“Most participants (95%, 178/187) remained eligible: they were current drinkers with no major medical or psychiatric contraindications.”

In the paper

“All analyses controlled for peak BrAC levels at each testing phase.”

In the paper

“Urine samples were collected prior to one session, chosen randomly, for toxicology in all participants, and prior to each session for women to verify non-pregnancy.”

In the paper

“Since FH is as a potential risk factor for development of alcohol problems(64), analyses were repeated including FH as a covariate with FH coded by 2 dummy variables: FH positive vs. negative, and FH not sure vs. negative.”

What the sources say

• Not checked yetcites [64] Goodwin, 1973, Alcohol problems in adoptees raised apart from alcoholic biological parents, Arch Gen Psychiatry source

In the paper

“Our previously published results showed that compared with light drinkers, heavy drinkers exhibited both higher alcohol sensitivity, in terms of subjective stimulation and reward (liking and wanting)(29), as well as lower sensitivity, in terms of subjective sedation(29), and salivary cortisol reactivity(29, 32).”

What the sources say

• Not checked yetcites [29] King, 2011, Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking, Arch Gen Psychiatry source
• Not checked yetcites [32] King, 2006, Attenuated cortisol response to alcohol in heavy social drinkers, Int J Psychophysiol source

In the paper

“Participants completed measures before and after ingesting a blinded beverage that contained either 0.8 g/kg alcohol or placebo administered in random order at each phase.”

In the paper

“Upon arrival, the participant completed self-report measures and engaged in objective breath tests to confirm compliance with recent alcohol abstinence.”

In the paper

“The few published test-retest studies of alcohol responses have included only brief between-session intervals with a focus on measurement reliability(30, 31).”

What the sources say

• Not checked yetcites [30] Mundt, 1997, Individual differences in alcohol responsivity: Physiological, psychomotor and subjective response domains, J Stud Alcohol source
• Not checked yetcites [31] Wilson, 1987, One-month repeatability of alcohol metabolism, sensitivity and acute tolerance, J Stud Alcohol source

In the paper

“The DSM-IV criteria are similar to those in DSM-5(8, 62) with the former including an item for alcohol-related legal problems that has since been dropped and excluding the DSM-5 item for craving that had not yet been developed.”

What the sources say

• Not checked yetcites [8] 2013
• Not checked yetcites [62] Hasin, 2013, DSM-5 criteria for substance use disorders: Recommendations and rationale, Am J Psychiatry source

In the paper

“All these aforementioned effects remained after controlling for covariates and other risk factors, such as FH, and group differences were largely apparent on the rising and declining limbs as well as at peak BrAC.”

In the paper

“The findings may have relevance to medication development, as altering euphoric and pleasurable effects of alcohol would be important targets for novel treatments and are hypothesized to underlie in part the efficacy of opioid receptor antagonists, including naltrexone and nalmefene(67–76).”

What the sources say

• Not checked yetcites [67] Anton, 2006, Combined pharmacotherapies and behavioral interventions for alcohol dependence: The COMBINE study: A randomized controlled trial, JAMA source
• Not checked yetcites [68] Drobes, 2004, Effects of naltrexone and nalmefene on subjective response to alcohol among non-treatment-seeking alcoholics and social drinkers, Alcohol Clin Exp Res source
• Not checked yetcites [69] Garbutt, 1999, Pharmacological treatment of alcohol dependence: A review of the evidence, JAMA source
• Not checked yetcites [70] Mason, 1999, A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence, Arch Gen Psychiatry source
• Not checked yetcites [71] Swift, 1995, Effect of naltrexone on human alcohol consumption, J Clin Psychiatry
• Not checked yetcites [72] Volpicelli, 1995, Effect of naltrexone on alcohol “high” in alcoholics, Am J Psychiatry source
• Not checked yetcites [73] King, 1997, Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence, Psychopharmacology (Berl) source
• Not checked yetcites [74] Swift, 1994, Naltrexone-induced alterations in human ethanol intoxication, Am J Psychiatry source
• Not checked yetcites [75] Anton, 2004, Naltrexone effects on alcohol consumption in a clinical laboratory paradigm: Temporal effects of drinking, Psychopharmacology (Berl) source
• Not checked yetcites [76] Ray, 2007, Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response: A double-blind placebo-controlled study, Arch Gen Psychiatry source

In the paper

“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.”

In the paper

“Limitations included that the reexamination interval may not have been sufficient to observe the extent of neuroadaptative responses to alcohol(18)”

What the sources say

• Not checked yetcites [18] Koob, 2001, Drug addiction, dysregulation of reward, and allostasis, Neuropsychopharmacology source

In the paper

“Koob and colleagues have coined the later stage of addiction as “the dark side of addiction”(65) because it is characterized by development of reward insensitivity and drinking behaviors related to negative reinforcement.”

What the sources say

• Not checked yetcites [65] Koob, 2005, Plasticity of reward neurocircuitry and the ’dark side’ of drug addiction, Nat Neurosci source

In the paper

“Further, trajectory analyses resulted in unequal subgroup sample sizes”

In the paper

“beverages were consumed over short interval to capture direct alcohol effects and minimize variability but this may not translate to typical drinking situations.”

In the paper

“Thus, while the present study includes one of the largest samples to date and the only investigation of alcohol responses over time, replication will be a necessary next step to assure confidence in the main findings.”

In the paper

“participants under age 21 were not enrolled due to legal restrictions of alcohol administration in the U.S. precluding study of alcohol responses in earlier developmental periods.”

In the paper

“However, heavy drinkers have also shown reduced alcohol-related stimulation and ventral striatal brain activation relative to social drinkers(82).”

What the sources say

• Not checked yetcites [82] Gilman, 2012, Subjective and neural responses to intravenous alcohol in young adults with light and heavy drinking patterns, Neuropsychopharmacology source

In the paper

“The results support prior work showing high alcohol-induced stimulation, reward, and craving in heavy drinkers or alcoholics(33, 79, 80) as well as low alcohol-induced sedation and cortisol in other at-risk drinkers(81).”

What the sources say

• Not checked yetcites [33] Roche, 2014, Acute alcohol response phenotype in heavy social drinkers is robust and reproducible, Alcohol Clin Exp Res source
• Not checked yetcites [79] Ray, 2013, Subjective response to alcohol among alcohol-dependent individuals: Effects of the mu-opioid (OPRM1) gene and alcohol severity, Alcohol Clin Exp Res source
• Not checked yetcites [80] Thomas, 2004, Following alcohol consumption, nontreatment-seeking alcoholics report greater stimulation but similar sedation compared with social drinkers, J Stud Alcohol source
• Not checked yetcites [81] Schuckit, 1994, Low level of response to alcohol as a predictor of future alcoholism, Am J Psychiatry source