Self-reported paranoia during laboratory “binge” cocaine self-administration in humans

Abstract

Cocaine-induced paranoia (CIP) has been extensively studied by retrospective interviews; however, only limited efforts have been made to further characterize CIP by human laboratory methods. We examined CIP in 28 healthy cocaine-dependent volunteers, who participated in 2-h, intravenous cocaine self-administration sessions at 8, 16, and 32 mg/70 kg doses, including 18 in a placebo-controlled design. Self-reports of paranoia showed significant main effects of cocaine dose (p = 0.0002) and time (p = 0.0003), and were statistically distinguishable from placebo at the two highest doses (16 and 32 mg). These effects were accounted for by a subgroup of vulnerable subjects in whom self-reports were consistent across dose and test–retest sessions. Subjects with CIP did not differ from those without CIP with respect to demographic, cocaine use, or cocaine self-administration variables. In conclusion, self-reports of CIP in the human lab are frequently endorsed, dose-dependent, and though variable between subjects, reproducible within subjects. Such methods may facilitate our understanding of the vulnerability to CIP in humans.

Introduction

Cocaine use can induce a range of transient psychotic experiences (Brady et al., 1991, Cubells et al., 2005), and cocaine-induced paranoia (CIP) is one of the most common symptoms associated with cocaine intoxication. Paranoia refers to an irrational belief that someone or something may cause harm to oneself, despite the fact that no such threat exists or that the perceived fear is out of proportion to the situation. As many as 50–80% of cocaine-dependent individuals endorse CIP during ‘street’ use of the drug (Bartlett et al., 1997, Brady et al., 1991, Cubells et al., 2005, Kalayasiri et al., in press, Rosse et al., 1994, Satel et al., 1991). CIP occurs almost invariably as a time-limited effect of cocaine (Brady et al., 1991, Satel et al., 1991) and resolves with sobriety. The positive symptoms of stimulant-induced psychosis, including paranoia, are indistinguishable from those seen in other primary psychoses, making it a valuable investigational model for idiopathic psychoses (e.g., schizophrenia). In addition, an understanding of CIP may have implications for understanding cocaine reward and aversion. For example, the clinical efficacy of disulfiram (i.e., Antabuse) in non-alcohol-dependent cocaine abusers (Carroll et al., 2004) has been hypothesized to result from its ability to increase the aversive effects (i.e., paranoia) associated with cocaine, thereby discouraging continued drug use. In this regard, an improved understanding of the vulnerability to CIP and its underlying neurobiology may facilitate medication development efforts for cocaine dependence.

Studies of CIP have most commonly relied upon retrospective self-report data obtained by interview (Bartlett et al., 1997, Brady et al., 1991, Cubells et al., 2005, Kalayasiri et al., in press, Rosse et al., 1994, Satel et al., 1991). In contrast, relatively few studies have examined CIP in a controlled experimental setting (Angrist, 1990, Addiction Research Center (ARC), Muntaner et al., 1989, Sherer et al., 1988). The first laboratory demonstration of paranoid ideation occurred in a single subject administered intravenous cocaine (2 g) over a 12-h period (Addiction Research Center, NIDA). Subsequently, Sherer and colleagues reported evidence of “suspiciousness” in cocaine users (n = 8) during a 4-h, continuous, intravenous (but not single bolus) administration of the drug as assessed by staff observations (Sherer et al., 1988). In contrast, Muntaner et al. (1989) found bolus cocaine injections (10–40 mg) capable of producing increases in self-reported ‘suspiciousness’ among chronic users of the drug (n = 8). With these limited exceptions (3 studies, N = 17 subjects), however, the vast majority of studies examining cocaine-induced subjective effects in the human laboratory (Cascella et al., 1994, Fischman and Schuster, 1982, Fischman et al., 1985, Foltin and Fischman, 1991, Foltin and Haney, 2004, Foltin et al., 2003, Kumor et al., 1989, Nagoshi et al., 1992, Van Dyke et al., 1978, Van Dyke et al., 1982, Ward et al., 1997a, Ward et al., 1997b), including studies examining the effects of anti-psychotic medications on cocaine administration (Evans et al., 2001, Gawin et al., 1996, Sherer et al., 1989) do not comment on the phenomenon.

Our group has recently developed a human laboratory paradigm of self-regulated cocaine administration under a fixed-ratio (FR1) schedule (Sughondhabirom et al., 2005). In that pilot study, we observed a modest and statistically significant effect of cocaine on visual analog scale (VAS) self-ratings of paranoia when compared to administration of placebo. However, the limited number of subjects (n = 8) and the modest levels of paranoia precluded addressing questions about potential dose–response relationships and other factors that might account for vulnerability to the trait. Therefore, the current study focused on examining and characterizing CIP in an expanded sample (N = 28) of cocaine users, who as part of several ongoing studies were allowed to self-administer cocaine in our laboratory “binge” self-administration paradigm.