![]() The diverse conditions under which insensitivity is observed and heterogeneity in its presentation imply that it is multifactorial. However, the most appropriate ways of conceptualizing this insensitivity remains unclear and sometimes controversial. Given the key role that insensitivity to adverse consequences plays in the presentation, diagnosis, and impacts of persistent drug use, as well as evidence that the eventual recognition and appraisal of these adverse consequences contributes to decisions to reduce or cease use, it is not surprising that it has been of intense interest. It is shared with other problematic behaviors such as problem gambling that impose real and significant costs on individuals and the community. Insensitivity to adverse consequences is not limited to drug use. It is responsible for a large part of the human toll of addiction, contributing directly to the detriments in health and well-being suffered by individuals, and imposing substantial burdens upon families and communities. The apparent insensitivity of drug taking to its adverse consequences is among the most pernicious features of addiction. ![]() Given this evidence for controlled drug use, Pickard and Ahmed asked why do these individuals choose to use despite the portent of negative consequences from that use? They began by considering evidence that people with problematic drug use can frequently control their behavior and can choose to abstain under many circumstances. In 2016, Pickard and Ahmed posed the ‘puzzle of choice’. ![]() We describe these pathways, their characteristics, brain cellular and circuit substrates, and we highlight their relevance to different pathways to self- and treatment-guided behavior change. These pathways are dynamic, not linear, with multiple possible trajectories between them, and each is sufficient to produce persistence. A cognitive pathway for recognition of adverse consequences, a motivational pathway for valuation of these consequences, and a behavioral pathway for responding to these adverse consequences. Here we review evidence that there are at least three pathways to persistent use despite the negative consequences of that use. However, the most appropriate ways of conceptualizing persistence in the face of adverse consequences remain unclear. Eventual recognition and appraisal of these adverse consequences is central to decisions to reduce or cease use. The persistence of drug taking despite its adverse consequences plays a central role in the presentation, diagnosis, and impacts of addiction.
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