Subjective response to alcohol (SR) refers to an individual's unique experience of the pharmacological effects of alcohol and is a putative risk factor for the development of alcoholism. Subjective effects include both stimulating experiences typically occurring during the beginning of a drinking episode as breath alcohol content (BAC) rises and sedative effects, which are more prevalent later in a drinking episode as BAC wanes. The combined influence of hedonic and aversive subjective experiences over the course of a drinking session are strong predictors of alcohol consumption and drinking consequences. There is also mounting evidence for consideration of SR as an endophenotype with some studies suggesting that it accounts for a significant proportion of genetic risk for the development of alcohol use disorder.
Theoretical models
Low Level of Response Model The Low Level of Response Model proposes that individuals who are less sensitive to the effects of alcohol are at greater risk for developing alcohol use disorder. One explanation for this phenomenon is that the experiences of elevated intoxication constitutes a feedback mechanism, which prompts drinking cessation. Low-level responders need to consume more alcohol than high responders to achieve a similar level of intoxication and experience the aversive effects of alcohol; consequently, these individuals must consume more alcohol to trigger the negative feedback loop. Escalating alcohol consumption may ultimately contribute to the development of tolerance, which further dampens sensitivity to alcohol's unpleasant effects. Notably, there is no population-level demarcation separating low from high responders and so level of response is arbitrarily defined (generally in terciles) within a given sample. Early studies compared SR in individuals (mostly males) with (FH+) and without (FH-) a family history of alcohol dependence in order to demonstrate that individual differences in SR could be considered genetically linked determinants of alcohol use disorder. Non-placebo controlled studies conducted by Schuckit and colleagues found that FH+ males experienced less of the aversive effects of alcohol as compared to FH- males matched on key demographic and body mass variables. Furthermore, FH+ young males and their fathers showed similar SR after reaching peak BAC, suggesting that SR is a heritable risk factor for the development of alcohol use disorder. Schuckit's placebo-controlled studies generally reported lower SR among FH+, as compared to FH-, subjects along declining BAC, with differences more evident among men than women. Additional studies found that FH+ subjects who experienced low-level of response were more than 4 times as likely to meet criteria for alcohol use disorder at 10-year follow-up as compared to FH- subjects who reported the same SR pattern. Subsequent follow-up studies conducted primarily by Schuckit's group established that low-level of response is a genetically linked risk factor for alcohol use disorder, which is not better explained by robust confounding factors such as age of first drink, current alcohol use and impulsivity. A 1992 meta-analysis further buttressed the Low Level of Response Model by reporting that sons of alcoholics exhibited lower responses to alcohol on both the ascending and descending limbs of the BAC curve. Importantly, differences in SR by family history were significant only in the alcohol condition and not the placebo condition, suggesting that SRs observed in the alcohol condition could be attributed to the pharmacological effects of alcohol, rather than to a confounding factor. A 2011 meta-analysis revealed that FH+ individuals reported lower SR in comparison to FH- individuals across both limbs of intoxication, consistent with the Low Level of Response Model. These findings were more robust along the descending limb of the BAC curve where sedative effects of alcohol are more prevalent and among males who comprised the overwhelming majority of participants in early SR studies. Critics noted that studies supporting the Low Level of Response Model only accounted for the negatively valenced sedative effects of alcohol and that while decreased sensitivity to aversive effects of alcohol would likely lead to increased drinking frequency and severity, the subjective effects of alcohol are, in actuality, quite varied. For example, it is widely accepted that the rewarding properties of alcohol are reinforcing. Yet, according to the Low Level of Response Model, reduced sensitivity to these rewarding effects is an indicator of problematic drinking. To that end, critics have noted that in Schuckit's seminal SR study, FH+ males experienced more "energy" than FH- males along rising BAC, suggesting that heightened sensitivity to the stimulating effects of alcohol may convey risk for developing alcohol problems. Another study found that FH+ subjects reported experiencing less intoxication than FH- subjects in response to a placebo drink, indicating that alcohol expectancies may account for differences in risk more so than SR. That is, individuals at greatest risk for developing alcohol use disorder may expect alcohol to be more enjoyable and less aversive than low-risk individuals.
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