The goal of this paper is to both understand and depathologize clinically significant mental distress related to criminalized contact with psychoactive biotic substances by employing a framework known as critical political ecology of health and disease from the subdiscipline of medical geography. The political ecology of disease framework joins disease ecology with the power-calculus of political economy and calls for situating health-related phenomena in their broad social and economic context, demonstrating how large-scale global processes are at work at the local level, and giving due attention to historical analysis in understanding the relevant human-environment relations. Critical approaches to the political ecology of health and disease have the potential to incorporate ever-broadening social, political, economic, and cultural factors to challenge traditional causes, definitions, and sociomedical understandings of disease. Inspired by the patient-centered medical diagnosis critiques in medical geography, this paper will use a critical political ecology of disease approach to challenge certain prevailing sociomedical interpretations of disease, or more specifically, mental disorder, found in the field of substance abuse diagnostics and the related American punitive public policy regimes of substance abuse prevention and control, with regards to the use of biotic substances. It will do this by first critically interrogating the concept of "substances" and grounding them in an ecological context, reviewing the history of both the development of modern substance control laws and modern substance abuse diagnostics, and understanding the biogeographic dimensions of such approaches. It closes with proposing a non-criminalizing public health approach for regulating human close contact with psychoactive substances using the example of cannabis use.