Third, a greater understanding of the relationship between alcohol consumption and adverse outcomes is hampered by the use of weak study designs. In particular, most of the underlying evidence, even if exposure and outcomes are measured properly, is based on non-experimental studies (e.g. case-control or cohort studies). There are limitations to such study designs, as is clearly indicated by the recent failures to confirm the protective effect of various antioxidants on mortality which had been found in observational studies. In contrast to the observational studies the intervention trials with placebo control groups showed no protective effect, and even some indication of a detrimental effect [238]. This is a limitation that is unlikely to be overcome, however, because long-term intervention trials with alcohol are problematic for a number of reasons, and long-term placebo control groups are impossible. Thus, plausible mechanisms from experimental and clinical studies remain an essential aspect of interpreting epidemiologic findings and such studies warrant further development. As has been argued before [46], one way to settle the question concerning a true causal impact of alcohol would be to
