To drink (moderately) or not to drink by Erik Skovenborg

“Throughout the history of humanity, alcoholic beverages have been widely used for their pleasing taste and their mood-altering effects. However, the use of alcohol has evoked strong opposition, because of the potential for abuse and the adverse effects on safety and health”. Dr. Charles S. Lieber, a distinguished scientist and pioneer in the field of alcohol effects on the liver, outlined this classic dilemma in his editorial “To drink (moderately) or not to drink” (1). “It could be argued that these adverse effects (alcoholic liver disease) were cause by relatively large amounts of alcohol, and that there was no evidence that moderate intake was detrimental to health. This position was encouraged in recent years by the observation between moderate alcohol intake a decreased incidence of coronary heart disease, with the implication that, when used in moderation, alcohol might in fact be beneficial.”
The evidence base present in 1984 was reviewed by Michael M. Marmot (2). “Of six case-control studies reviewed from England and the USA, all show an inverse association between CHD and alcohol consumption which persists after control for other risk factors. Longitudinal studies, in Japanese-Americans, white American men and women, British civil servants, Puerto Ricans, Yugoslavs and Australians, all show moderate drinkers to have a lower CHD risk than abstainers. Abstainers are likely to differ from moderate drinkers in a number of ways. To date it has not proved possible to show that any of these differences account for the higher CHD risk of abstainers.”
“These data are consistent with a protective effect of moderate alcohol consumption—but give little clue as to what ‘moderate’ means,” Marmot observed. “From other data, we know that in France, a country with a low rate of CHD, the mean yearly alcohol consumption of people aged 15 and over is 22.3 litres. This corresponds to the startling figure of 49 g alcohol per adult per day, or approximately six drinks per day.” Dr Genevieve Knupfer (who made influential contributions to ideas and methods relating to drinking survey research) suggested this definition of light drinking: “By ‘light drinking’, we mean something like “usually two drinks a day” (between 4 and 6 times a week), occasionally as much as four drinks in one day, but not more often than three times a month, and never more (3).
Alcohol and all-cause mortality
The association between alcohol Intake and risk of all-cause mortality should be of crucial importance to anyone considering whether to drink (moderately) or not to drink. A recent systematic review and meta-analysis of 107 cohort studies involving more than 4.8 million participants by Zhao et al. (4). In models adjusting for potential confounding effects of sampling variation, former drinker bias, and other prespecified study-level quality criteria, the meta-analysis of all 107 included studies found no significantly reduced risk of all-cause mortality among occasional (>0 to <1.3 g of ethanol per day; relative risk [RR], 0.96; 95%CI, 0.86-1.06; P = .41) or low-volume drinkers (1.3-24.0 g per day; RR, 0.93; P = .07) compared with lifetime nondrinkers. There was a significantly increased risk of all-cause mortality among female drinkers who drank 25 or more grams per day and among male drinkers who drank 45 or more grams per day.
The results from this mount of evidence should not worry the moderate drinker and fall in line with the conclusion reached by Lieber back in 1984 (1): “Obviously, the “threshold” for toxicity may depend on the congener content of the beverage, body size, and various other factors (such as drinking pattern and genetic disposition); consequently, considerable variation in individual responses to alcohol exist. At present, one’s past capacity to keep consumption within socially and medically acceptable bounds is probably the most useful guide in deciding, for a given person, whether to drink (moderately) or not to drink.”
The risk starts from the first drop
While Lieber found “no compelling reason for the moderate drinker to change a lifestyle and eliminate a pleasurable and possibly beneficial habit”, WHO begs to differ (5). “We cannot talk about a so-called safe level of alcohol use. It doesn’t matter how much you drink – the risk to the drinker’s health starts from the first drop of any alcoholic beverage. The only thing that we can say for sure is that the more you drink, the more harmful it is – or, in other words, the less you drink, the safer it is,” explains Dr Carina Ferreira-Borges, Regional Advisor for Alcohol and Illicit Drugs in the WHO Regional Office for Europe. “To identify a “safe” level of alcohol consumption, valid scientific evidence would need to demonstrate that at and below a certain level, there is no risk of illness or injury associated with alcohol consumption. The new WHO statement clarifies: currently available evidence cannot indicate the existence of a threshold at which the carcinogenic effects of alcohol “switch on” and start to manifest in the human body.” According to the experience of Lieber (1) “Arguments for or against control of intake have evoked powerful emotional responses, which tend to cloud the scientific assessment of whether to drink or not to drink.” The call for a scientifically proven safe level with zero risk is neither possible for intake of alcohol nor for other human activities like riding a bicycle or flying to Mallorca.
WHO Technical Report Series 841
The fog that clouds WHO’s scientific assessment of moderate alcohol intake is neither new nor evidence based. Actually the evidence was sufficient for a WHO Technical Committee on cardiovascular disease which reported in 1994, to conclude that the consumption of 30 g of alcohol a day is associated with lover cardiovascular risk and that the validity of e U-shaped relationship of mortality to alcohol consumption could no longer be doubted (6). However, a few months later (November 1, 1994), the World Health Organization said in a report that even moderate alcohol consumption is harmful to a person’s health, contradicting some medical theories that suggest moderate drinking can stave-off cardiovascular diseases (7). Hans Emblad, director of WHO’s Program of Substance Abuse, said that there is no minimum threshold below which alcohol can be consumed without any risk, and assertions that moderate alcohol consumption can be good for health, are wrong. Scientific studies show that only very low consumption, of the order of one drink every other day, is liable to reduce the risk of cardiovascular diseases compared with total abstinence. “There is no indication that higher consumption has a similar effect, whereas above two drinks per day this risk certainly increases,” Emblad said. WHO agrees that low levels of drinking have a protective effect on a very limited part of the population, mainly males above 35 years of age and post-menopausal women.
Conceptual and methodological challenges
“Teetotallers may differ from moderate drinkers in ways other than alcohol”, Lieber observed in his editorial (1). The J-shaped/U-shaped alcohol-coronary heart disease association has been examined intensely for conceptual and methodological challenges that may bring the validity of the J-shaped curve into question. Among the methodological flaws suggested are bias in self-reported alcohol consumption with misclassification of alcohol intake; confounding bias; alcohol consumption being linked to certain socio-economic and lifestyle characteristics known to affect cardio-vascular events; the sick quitters’ fallacy leading to a reverse causality bias; residual confounding bias, and the question whether drinking pattern and/or type of alcohol may influence the J-shaped association (8). An important epidemiologic principle is that weak associations can often be explained by one or more confounding variables.

1. Misclassification of abstainers. The “Sick quitters” fallacy leading to a reverse causality bias was proposed as explanation for the U-shaped curve by Shaper et al. in 1988 (9). In a report of 23 years’ observation of the 12,000 male British doctors (10), overall mortality during the past decade of the study (1991-2001) was significantly higher in the 239 recent ex-drinkers (men who had been current drinkers in 1978) than in the neverdrinkers or current drinkers, while the mortality of long-term ex-drinkers (men who were exdrinkers in 1978 as well) was similar to that of never-drinkers. Thus the effect of “reverse causality,” that is, a tendency for some drinkers who have developed a life-threatening disease to become ex-drinkers because of the disease, seems to wear off within a decade.
2. Confounding by SES (Socio Economic Status). Socioeconomic position is relevant to behaviors, exposures and susceptibilities that may influence health, such as education, social support, financial resources or the knowledge, awareness and determination required to actively follow a healthy lifestyle or consult a physician if needed.
3. Confounding by lifestyle factors. Many lifestyle risk factors for CHD have been identified, e.g. smoking, obesity, physical inactivity and poor diet quality, and the lifestyle factors may act as confounding factors in studies of alcohol and CHD.
4. Aspects of drinking patterns. Many cohort studies examining the effects of alcohol lack information on drinking patterns with regard to frequency of drinking (regular moderate versus binge drinking), beverage type (wine, beer or spirits) and drinking with or without meals.
   May drinking (moderately) play a role as positive lifestyle factor?
   With no randomized, controlled trials in view for the foreseeable future, we are left with evidence from high quality observational studies like the study by Li et al. (11) using data from the Nurses’ Health Study (1980-2014; n=78 865) and the Health Professionals Follow-up Study (1986-2014, n=44 354).
   1) The issue of the “Sick quitters” fallacy was addressed by assessing alcohol consumption every 4 years during up to 34 years of follow-up.
   2) Confounding by SES was addressed by the study of 2 homogeneous cohorts of educated participants (nurses and male health professionals) with favourable socioeconomic positions.
   3) Confounding by lifestyle factors was addressed by assessing diet every 4 years; physical activity levels were investigated and updated every 2 years; body weight and smoking habits were self-reported and updated every 2 years.
   4) Biennial questionnaires were used to collect information on potential confounders such as age, ethnicity, multivitamin use, regular aspirin use, postmenopausal hormone use (NHS only), and the presence or absence of a family history of diabetes mellitus, cancer, or myocardial infarction.
   Li et al. defined 5 low-risk lifestyle factors as never smoking, body mass index of 18.5 to 24.9 kg/m2, ≥30 min/d of moderate to vigorous physical activity, moderate alcohol intake (5-15 g/d for women, 5-30 g/d for men), and a high diet quality score (upper 40%), and estimated hazard ratios for the association of total lifestyle score (0–5 scale) with mortality. The authors estimated that the life expectancy at age 50 years was 29.0 years (95% CI, 28.3-29.8) for women and 25.5 years (95% CI, 24.7-26.2) for men who adopted zero low-risk lifestyle factors. In contrast, for those who adopted all 5 low-risk factors, they projected a life expectancy at age 50 years of 43.1 years (95% CI, 41.3-44.9) for women and 37.6 years (95% CI, 35.8-39.4) for men. The projected life expectancy at age 50 years was on average 14.0 years (95% CI, 11.8-16.2) longer among female Americans with 5 low-risk factors compared with those with zero low-risk factors; for men, the difference was 12.2 years (95% CI, 10.1-14.2).
   Is zero alcohol optimal?
   “We strongly believe that less is better. If you reach the point of zero, from the health point of view that is optimal”, Hans Emblad told at the WHO news conference in 1994, giving birth to the “No safe level of alcohol use” WHO mantra (7). Emblad said that moderate consumption of wine “may reduce” coronary disease for a very few, but said that it offers no health benefits to most people. “There are other ways of reducing the risk of cardiovascular disease,” he said. “Avoid smoking, engage in physical activity, eat less fats. Those already taking these precautions are unlikely to reduce their risk still further with light drinking.” To answer the question if less is always better and zero alcohol is optimal, let us return to the study by Li et al. (11).
   As expected, increased exercise, not smoking or a reduced amount of smoking if a smoker, a healthy dietary pattern, moderate alcohol intake, and optimal body weight were all associated with longer life expectancy. In a sensitivity analysis using a low-risk score without moderate alcohol intake, the projected life expectancy at age 50 years was on average only 11.4 years (95% CI, 9.5-13.3) longer among female Americans with 4 low-risk factors compared with those with zero low-risk factors; for men, the difference was 10.0 years (95% CI, 9.2-10.9) Accordingly the life expectancy for nurses taking all the precautions recommended by Hans Emblad increased from 11.4 years to 14.0 years by drinking moderately, while the life expectancy for male health professionals with 4 low-risk lifestyle factors increased from 10.0 years to 12.2 years when moderate drinking was added as the 5th lifestyle factor. For the US nurses and health professionals zero alcohol was associated with a reduced life expectancy.
   Evidence based health policy or White Hat Bias?
   A significant volume of consistent evidence suggests that a healthy lifestyle may indeed include a regular, light to moderate consumption of alcohol. To praise the beneficial effects of non-smoking, regular exercise, a normal weight and a Mediterranean-style diet while at the same time dismiss similar beneficial effects of a moderate, regular alcohol intake observed in exactly the same type of studies is hardly an example of rational reasoning by dispassionate scientists but rather a result of “White Hat Bias” ─ defined as bias leading to distortion of research-based information in the service of what may be perceived as “righteous ends” (12).
   The question of whether moderate alcohol consumption may be considered a healthy lifestyle behavior that is inversely associated with risk for myocardial infarction (MI) / coronary heart disease / coronary heart disease mortality / all-cause mortality in individuals on a par with normal weight, regular exercise, a healthy diet and no smoking has so far (from 1973 to 2024) been examined in 69 observational cohort studies. The studies are listed below according to publication year. There is little heterogeneity between the studies and the large majority of results found moderate alcohol intake associated with decreased all-cause mortality and longer expected survival time including the segment of study participants with the highest score of healthy lifestyle habits.
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