Do initial responses to drugs predict future use or abuse?

Abstract

Individuals vary in their initial reactions to drugs of abuse in ways that may contribute to the likelihood of subsequent drug use. In humans, most drugs of abuse produce positive subjective states such as euphoria and feelings of well-being, which may facilitate repeated use. In nonhumans, many drugs initially increase locomotor activity and produce discriminative stimulus effects, both of which have been considered to be models of human stimulant and subjective states. Both humans and nonhumans vary in their sensitivity to early acute drug effects in ways that may predict future use or self-administration, and some of these variations appear to be genetic in origin. However, it is not known exactly how the initial responses to drugs in either humans or nonhumans relate to subsequent use or abuse. In humans, positive effects of drugs facilitate continued use of a drug while negative effects discourage use, and in nonhumans, greater genetic risk for drug intake is predicted by reduced sensitivity to drug aversive effects; but whether these initial responses affect escalation of drug use, and the development of dependence is currently unknown. Although early use of a drug is a necessary step in the progression to abuse and dependence, other variables may be of greater importance in the transition from use to abuse. Alternatively, the same variables that predict initial acute drug effects and early use may significantly contribute to continued use, escalation and dependence. Here we review the existing evidence for relations between initial direct drug effects, early use, and continued use. Ultimately, these relations can only be determined from systematic longitudinal studies with comprehensive assessments from early drug responses to progression of problem drug use. In parallel, additional investigation of initial responses in animal models as predictors of drug use will shed light on the underlying mechanisms.

Introduction

Most drugs of abuse produce subjective feelings of well-being and euphoria in humans, which are thought to contribute to the drug's potential to be used or abused (de Wit and Griffiths, 1991, Fischman and Foltin, 1991). Indeed, drug-induced changes in mood or subjective state have long been the primary indicator of abuse potential used by the Food and Drug Administration (FDA) to assess the likelihood of abuse for new medications (Jasinski, 1991; FDA guidelines in Balster and Bigelow, 2003, Carter and Griffiths, 2009). Drugs that produce euphoria are more likely to be abused than drugs that fail to produce euphoria, and individuals who report experiencing more positive effects from a drug are more likely to use the drug again. However, the extent to which either the quality or magnitude of responses to the first few exposures to a drug are indicators of the individual's likelihood of continued use, or in the longer term to abuse or dependence, remains to be determined. The full clinical manifestation of drug dependence results from dynamic changes that occur only after repeated administration of the drug, including alterations related to learning, tolerance, cognitive function, stress, sensitization and complex neuroadaptations underlying these phenomena (Everitt et al., 2008). Thus, the relationship between early subjective responses and fully developed dependence is at best indirect (Wagner and Anthony, 2002). Yet, there is evidence that an individual's initial responses to drugs may constitute one factor contributing to the risk for future abuse or dependence. This is of particular interest because of the possibility that genetic factors may influence these initial responses, and thus impart vulnerability to future use.