by the formal consideration of potential site differences in all statistical analyses. As discussed above, the degree of exposure to the various substances was not characterized uniformly across studies, which limits, for instance, the interpretation of the widespread alcohol effects and whether alcohol represents a greater source of toxicity than the other substances examined. It should be emphasized, however, that this study examined brain volumetric associations with dependence and not with total lifetime substance use. A beneficial outcome of this first study of the Addiction Working Group will be to raise awareness of the data needed to estimate the relation between brain volume and total exposure and, more generally, of the utility of uniform phenotypic data for data pooling. Greater consideration of how data may be used in international collaborations may influence the collection of data in future studies, which will increase their impact beyond their primary research focus. The PhenX Toolkit (https://www.phenxtoolkit.org/), for example, provides an extensive catalog of standardized measures expressly intended to facilitate secondary cross-study comparisons. Finally, co-occurring substance use limits the interpretation of the findings. Pervasive recreational substance use is a general issue for all studies of human substance dependence. For example, it is likely epidemiologically
