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The self-medication hypothesis emphasizes the role of distressing affect as the primary motivator for the compulsive use that leads to substance dependence. The model also postulates that there will be psychopharmacological specificity between symptom presentation and the primary drug of dependence. In this review, the self-medication hypothesis is examined in relation to the development and chronicity of heroin dependence. It is argued that if self-medication has a role in engendering and extending substance dependence, it should be apparent in the use of a drug that carries such overwhelming personal risk. The psychopathology seen among adult users is certainly consistent with the model. More importantly, however, are the extraordinarily high levels of childhood trauma and psychopathology that occur typically well before the initiation of heroin use. In contrast, the postulate of drug specificity appears less supported by the polydrug use patterns typical of heroin users, and does not appear to be a necessary corollary of the model.