Cocaine abuse versus cocaine dependence: Cocaine self-administration and pharmacodynamic response in the human laboratory

https://doi.org/10.1016/j.drugalcdep.2009.07.011Get rights and content

Abstract

Cocaine has high abuse liability but only a subset of individuals who experiment with it develop dependence. The DSM-IV (APA. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-R. American Psychiatric Association, Washington, DC, 2000) provides criteria for diagnosing cocaine abuse and cocaine dependence as distinct disorders- the latter characterized by additional symptoms related to loss of control over drug use. In this study, two groups of cocaine users (n = 8/group), matched on demographic factors and length of cocaine use history and meeting criteria for either cocaine abuse (CocAb) or cocaine dependence (CocDep), were compared on (1) measures related to impulsivity and sensation seeking, (2) response to experimenter-administered cocaine (0, 12.5, 25 and 50 mg/70 kg, i.v.), and (3) cocaine self-administration using a Relapse Choice and a Progressive Ratio Procedure (0, 12.5 and 25 mg/70 kg, i.v.). Groups did not differ on impulsivity or sensation seeking scores. After experimenter-administered cocaine, the CocAb group reported feeling more suspicious and observers rated them significantly higher on unpleasant effects (e.g., irritability, difficulty concentrating). In contrast, the CocDep group reported significantly greater desire for cocaine, which was sustained over the course of the study, and gave higher street value estimates for cocaine (p < 0.05). While cocaine self-administration was dose-related and generally comparable across the two procedures, the CocDep users chose to take significantly more cocaine than the CocAb users. These data suggest that, while regular long-term users of cocaine with cocaine abuse or dependence diagnoses cannot be distinguished by trait measures related to impulsivity, they do exhibit significant differences with regard to cocaine-directed behavior and response to cocaine administration.

Introduction

Epidemiological data show that the susceptibility to drug dependence is not a uniform risk—as individuals who have access to drugs do not always experiment, individuals who experiment do not always proceed to regular use, and individuals who use regularly do not always advance to compulsive use, even with a drug like cocaine, which is associated with very high abuse liability (e.g., Brady and Griffiths, 1976, Stafford et al., 1998). In a retrospective twin-registry study on the transition from drug use to dependence, cocaine was identified as possessing the highest probability of leading from regular use to abuse or dependence among the range of illicit drugs examined (Tsuang et al., 1999). Cocaine has also been characterized as having a more “explosive” risk for the development of drug dependence, that is, the risk of advancing to dependence occurs faster after initial experimentation compared to other drugs such as marijuana and alcohol for which the transition to dependence occurs more slowly (Wagner and Anthony, 2002).

Numerous factors are believed to contribute to the relative vulnerability to the development of drug dependence, including genetic predisposition (Kendler et al., 2000, Nestler, 2000), biological responses to drug exposure (Robinson and Berridge, 1993, Koob and Le Moal, 2000, Lyvers, 2000), and a wide range of environmental, developmental and social factors (e.g., Dusenbury et al., 1992, Kendler et al., 1999, Brook et al., 2000, Friedman and Glassman, 2000). The concept of this transition from drug abuse to drug dependence was described by a former Director of the National Institute on Drug Abuse as turning on the “switch” (Leshner, 1997). Popularization of the metaphorical “switch” provided a useful conceptual framework particularly for the lay audience, and, importantly, spurred efforts to elucidate neuroadaptive changes that may mediate compulsive drug-taking behaviors.

While non-human models lend readily themselves to explore causative factors in the development of drug dependence (e.g., quantification of the relative rate of developing tolerance or sensitization), parallel controlled examination of similar phenomena in humans is more challenging. Studies requiring purposeful induction of the transition to addiction or dependence are precluded by ethical constraints. Alternatively, longitudinal studies examining the trajectory of drug experimentation to dependence require years to complete, and retrospective analyses require large groups of subjects and employ correlational techniques. An alternative strategy is to conduct controlled evaluations in which subjects, who are susceptible and presently drug dependent, are compared to others who, despite a comparable duration of drug use, have not developed drug dependence.

One defining feature that differentiates dependent individuals from abusers without dependence is their apparent “loss of control” over their drug use. That is, drug-dependent individuals whose use is frequent and compulsive, thus leading to negative consequences, are considered to have a loss of control, while sporadic users who maintain a regular use pattern without escalation are categorized dissimilarly. Indeed, “loss of control” has been used interchangeably with the term addiction and applied to conditions of excessive drug use (Jaffe, 1990), and even more widely investigated as a defining construct in alcoholism (Jellinek, 1960, Kahler et al., 1995). This concept has made its way into the treatment and recovery community on a broad scale in self-help groups based upon the 12-step ideology in which participants are encouraged to admit that they are helpless or powerless over their drug use. This construct has been operationalized and incorporated into widely used diagnostic criteria for drug dependence. Specifically, the “loss of control” construct is reflected in the DSM-IV dependence criteria (APA, 2000), whereby (1) “the substance is often taken in larger amounts or over a longer period than was intended,” and (2) “there is a persistent desire or unsuccessful efforts to cut down or control substance use.” In contrast to this clinical viewpoint, a behavior analyst might argue that the problem of compulsive drug use or drug dependence is not due to the loss of control, but rather due to the exquisite control that the drug (as a reinforcer) or the environmental context associated with drug use (as a conditioned reinforcer or discriminative stimulus) has come to exert over the individual's behavior and the concomitant relative decline in the value of alternative reinforcers (e.g., food, activities, social experiences), see for example (Johanson et al., 1976). The dependence criterion from the DSM-IV “important social, occupational, or recreational activities are given up or reduced because of substance use” is a diagnostic parallel that reflects this relative decline in reinforcing value of alternative reinforcers.

Despite intensive clinical research efforts directed toward understanding cocaine abuse and dependence and identifying effective treatments over the past two decades, surprisingly few studies have sought to evaluate directly factors that may differentiate individuals who intensify their use to a state of dependence compared to those who sustain regular, but controlled, patterns of use and remain in the diagnostic category of “abuse.” To examine differences between cocaine abusers with and without cocaine dependence with respect to their response to cocaine, drug-directed behaviors, or factors that may confer risk or resiliency to drug-taking and relapse in the laboratory, this study capitalized upon paradigms designed to assess drug-seeking behavior that have been developed and widely explored with non-human and, to a lesser extent, human subjects. Human self-administration studies have examined the influence of pharmacological factors (e.g., Fischman et al., 1990, Foltin and Fischman, 1994) and environmental factors (Griffiths et al., 1974, Silverman et al., 1994) on drug self-administration. To our knowledge, this paradigm has not been applied to study individual differences in the vulnerability to cocaine dependence, differences between groups who vary in their drug use characteristics, or the influence of environmental and pharmacological factors on cocaine-seeking behavior in dependent and non-dependent drug users.

The present study compared individuals meeting DSM-IV criteria for cocaine dependence to those meeting diagnostic criteria for cocaine abuse, but not dependence. As dependence can occur soon after initiation of drug use or after extended experimentation, it was important that the diagnosis of individuals meeting criteria only for cocaine abuse not be attributable to recent initiation of cocaine use (i.e., a lack of opportunity to develop dependence because of a short history of drug use). Thus, in addition to matching on basic demographic characteristics, groups were also matched on the duration of cocaine exposure (i.e., years of use) as a proxy for the opportunity to develop dependence. This controlled laboratory evaluation sought to compare individuals who report a loss of control over their cocaine use in the natural environment to those who exhibit regular but controlled use (as distinguished by frequency of reported cocaine use and DSM-IV diagnosis) on trait characteristics (e.g., impulsivity and sensation seeking), pharmacodynamic response to cocaine and on cocaine self-administration behaviors in the presence and absence of alternative reinforcers.

Section snippets

Subjects

Subjects were healthy adult male and female volunteers recruited through local newspaper advertisements and word-of-mouth. All subjects were determined to be in good health following medical history, physical examination, electrocardiogram (ECG), laboratory tests and were without psychiatric disorders other than their drug abuse according to a structured psychiatric interview (SCID, Structured Clinical Interview for Diagnosis, DSM-IV; Spitzer and Williams, 1986). Subjects were excluded if they

Recruitment

The results from the subject enrollment process are illustrated in the upper portion of Table 1. One hundred and ninety people completed an initial in-person assessment. Out of the 190 subjects screened 132 were disqualified for reasons unrelated to the SCID interview outcome [i.e., failure to meet the cocaine criteria, medical problems (e.g., abnormal EKG, hypertension), seeking treatment, lost interest in the study, or lost to follow-up]. Fifty-eight subjects met all preliminary study

Discussion

This study examined differences between individuals with lengthy histories of cocaine use on their pharmacodynamic response to cocaine, their cocaine self-administration behavior under multiple conditions, and baseline characteristics related to impulsivity and sensation seeking. Two groups of current users, those meeting DSM-IV criteria for cocaine dependence and those meeting only criteria for cocaine abuse were compared. The groups did not differ significantly with regard to their reported

Conflicts of interest

All the authors declare that they have no conflicts of interest to report that could inappropriately influence, or be perceived to influence, this work.

Role of funding source

This work was supported by grants from the National Institute on Drug Abuse (NIDA), R0114653 (SLW) and T320007209 (ECD); NIDA had no further role in study design; in the collection, analysis and interpretation of the data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors

Dr. Walsh secured funding for the project. Drs. Walsh, Donny and Bigelow participated in the design the study. Dr. Walsh and Mr. Nuzzo undertook the statistical analysis. Dr. Umbricht provided medical support and supervised dosing sessions. Dr. Walsh wrote the manuscript. All authors have contributed to and approve the final version of the manuscript.

Acknowledgements

The authors would like to thank the following staff members who contributed to this project: John Yingling for technical assistance, Abby Yuscavage, Lisa Notes, Abigail Robarts, Victoria Casselton, Anthony Fluty and the Residential Nursing Staff for research support, and Jeff McCagh, Pharm. D. for pharmacy support.

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