Research into drug using behaviour has often focused on developing theories to explain why individuals use drugs, yet directly asking an individual why they participate in this behaviour does not necessarily uncover their motivations, or usefully inform strategies which may lead to behavioural change. Khantzian’s theory of self-medication is used to help structure a cross-disciplinary literature search across biopsychosocial domains and also the spiritual domain, for which there is a paucity of empirical research. 12 in-depth case studies are informed by the Biographical Narrative Interpretive Method. There is twin-track analysis of the data employing BNIM panel analysis and Grounded Theory techniques. Findings suggest drugs are used to achieve homeostatic balance in the biopsychosocial domains. Experiences of emptiness also arose in the data. Exploration of these revealed two distinct types of emptiness: ‘deficient’ emptiness and a perceived ‘spiritual’ emptiness. Evidence suggests that drug use can be considered as an attempt to ‘self-medicate’ against the state of deficient emptiness in order to achieve a ‘spiritual homeostasis’.