While causation cannot be proved with any degree of certainty in human subject research, pairs of twins discordant for cannabis exposure afford one elegant framework for disproving causation (35; 36) as illustrated in Figure 2. We use the example of the association between cannabis use and use of hard drugs. The classical twin design capitalizes on differences between identical or monozygotic (MZ) twins, who share all their segregating genes and fraternal or dizygotic (DZ) twins who only share 50% of them. It is also assumed that both MZ and DZ twins reared together are equally matched for familial environment (the equal environments assumption) (37). As all MZ twin pairs, including those discordant for cannabis use, are perfectly correlated for their segregating genes and for familial environment, any residual association between cannabis exposure and, say, subsequent hard drug use, within the pairs of discordant twins, can be attributed to non-familial sources, such as individual-specific environments and causal processes (Figure 2). Only those pairs of twins where one twin uses cannabis but the other does not are selected. Within these discordant pairs,
