Smoking and Reactions to Alcohol

by National Institute of Health

(Page 2 of 2)

In an important series of investigations, Schuckit and colleagues have shown that when compared with control participants, young adult males with family histories of alcoholism exhibit diminished reactions to a standardized dose of alcohol. Those reactions included the subjects' subjective ratings of alcohol effects and their degree of body-sway compared with a baseline measurement taken before testing. Although this work has been criticized on a number of methodological grounds, Schuckit has completed a followup study showing that a low response to alcohol's effects when originally tested predicts an increased risk of alcohol dependence at followup. As we discuss below, these findings may provide one important clue as to how the association between smoking and alcohol dependence may arise. Schuckit has hypothesized that one subgroup of alcoholics may inherit a diminished reactivity to alcohol and because they experience less intoxication, less body-sway, or other similar effects after consuming a specified amount of alcohol, they are able to drink more heavily before becoming impaired and, thus, are more likely to progress to more harmful levels of alcohol use.

Shortly before the 1981 questionnaire survey of the Australian twin panel, researchers initiated an alcohol challenge study in which 206 young adult male and female twin pairs were tested with a challenge dose of alcohol. Schuckit hypothesized that the alcohol reactivity measures that he was using were, at least in part, genetically determined. The Australian Alcohol Challenge Twin Study (AACTS) confirmed significant evidence for genetic effects on bodysway increase and subjective intoxication rating after drinking alcohol, with a combined measure of alcohol reactivity (based on both body-sway and intoxication) showing 60 percent heritability.

The Australian study differed in important respects from the studies conducted by Schuckit. First, the Australian study did not attempt to recruit people with positive family histories of alcoholism. Second, the study did not use the exclusionary criteria considered standard in contemporary research (people with histories of alcohol problems at baseline were not excluded). As a consequence of this (and probably unique for this type of research), people with and without family histories of alcoholism and people who were light or heavy drinkers, or who had problems with alcohol, participated in this study in approximately the same proportions as would be observed for the general population of Australians of this age group. In other words, participants (at least the men) broadly represented all twins of their age group from the Australian twin panel, showing few significant differences from those twins who did not participate. Twins who participated in the original 1981 Australian twin study who could be located also were included in the 1992 diagnostic interview followup survey. Similar to the research conducted by Schuckit, even when drinking history and alcohol problems reported at the time of the original challenge study were controlled for, people with histories of alcohol dependence at interview followup had significantly lower scores on the alcohol reactivity measure at baseline.

Furthermore, people, at least men, who reported not having histories of alcohol dependence but who were at higher-than-average genetic risk, because they were monozygotic co-twins of alcohol-dependent participants, showed the same diminished responses to alcohol in the challenge study. And nondependent people at intermediate genetic risk who had dizygotic co-twins with histories of alcohol dependence had scores that fell between the two former high-risk groups and the control group. For reasons not yet understood, comparable associations were not observed in women.

Consistent with Schuckit's research, findings from the AACTS suggest that men who inherit a low reactivity to alcohol have an increased risk of alcohol dependence. Currently, we do not know which genes are involved in this reduced reactivity to alcohol. Genetic variations (polymorphisms) in a key enzyme involved in alcohol metabolism (alcohol dehydrogenase) at two genes called ADH2 and ADH3 did not predict differences in alcohol reactivity, even though the ADH2 gene variant (allele) predicted diminished alcohol-dependence risk in men from this sample. However, analyses of the relationship between smoking history and alcohol challenge performance produced important further insights. Men and women who were current smokers at the time of the alcohol challenge study rated themselves as significantly less intoxicated than did nonsmokers or former smokers despite receiving the same amount of alcohol. This relationship persisted in women, even when a history of heavy drinking was controlled for, and also was observed in men at the second post-alcohol assessment. Furthermore, in women, researchers found a highly significant genetic correlation between smoking status and selfreport of intoxication after the alcohol challenge. In men, the familial association between smoking status and post-alcohol intoxication appeared to be largely attributable to similar alcohol-relevant experiences between twins. Because of the small sample sizes, however, we cannot exclude the possibility that a genetic correlation existed in the men.

Thus, either acute or chronic crosstolerance effects may exist between smoking and alcohol or some similar interaction that leads to diminished response to alcohol in those who smoke. Alternatively, common genetic mechanisms may lead to the increased probability that a person will become

a regular smoker and to reduced propensity for intoxication after a given dose of alcohol. These effects appear to be much stronger in women than in men, consistent with the much stronger association between smoking and alcohol problems in women.

Several limitations of the original AACTS make it difficult to determine whether the study results show a direct interaction between smoking and alcohol use or common underlying genetic mechanisms. Participants in the study were allowed to smoke if they so wished, but their smoking during the experimental session was not documented. Consequently, we were unable to separate the effects of smoking histories from smoking during the challenge session. Furthermore, because the study used a quasi-random sampling scheme and because monozygotic twin pairs exhibit a high concordance for regular smoking, few smoking discordant pairs (where only one twin smoked) participated in the protocol. Researchers are currently addressing these issues more directly in ongoing challenge studies using separate and joint administration of nicotine and alcohol to adult nonsmokers and smokers.

Conclusions

For many years both clinicians and researchers have acknowledged the strong comorbidity between smoking and alcohol dependence. This issue cannot be explained simply in terms of shared individual risk factors. Genetic approaches are likely to play an important role in helping to document the biological mechanisms underlying this association. The experimental finding that smokers appear to experience less intoxication after a challenge dose of alcohol than do nonsmokers, combined with evidence that low reactivity to alcohol predicts increased long-term risk of alcohol dependence, suggests that further experimental studies of nicotine-alcohol interactions using genetically informative approaches should be a research priority.

About the Author

NIH is the nation's medical research agency - making important medical discoveries that improve health and save lives. The National Institutes of Health (NIH), a part of the U.S. Department of Health and Human Services, is the primary Federal agency for conducting and supporting medical research.