Effect of rate of administration on subjective and physiological effects of intravenous cocaine in humans

https://doi.org/10.1016/j.drugalcdep.2005.08.004Get rights and content

Abstract

The rate hypothesis of psychoactive drug action holds that the faster a drug reaches the brain and starts to act, the greater its reinforcing effects and abuse liability. A previous human study using a single cocaine dose confirmed the rate hypothesis for subjective responses, but found no rate effect on cardiovascular responses. We evaluated the rate hypothesis in 17 experienced cocaine users (7 [all men] provided complete data; 6 participated in only 1–2 sessions) by administering IV cocaine at each of three doses (10, 25, 50 mg) and injection durations (10, 30, 60 s) in a double-blind, placebo-controlled, escalating dose design. Heart rate, blood pressure, and positive (e.g., rush, high) and negative (e.g., feel bad, anxious) subjective effects (100-mm visual analogue scales) were measured for 1 h after dosing. Peak change from baseline, time to peak, and area under the time–response curve were evaluated with repeated measures mixed linear regression analyses, allowing use of data from all sessions for all subjects, including non-completers. Both dose (mg) and infusion rate (mg/s) significantly influenced most subjective and cardiovascular variables. Analysis of the interaction suggested that dose had a stronger impact than rate. Rate had a stronger influence on positive subjective effects than on negative subjective effects or cardiovascular variables. These findings provide support for the rate hypothesis as it applies to both subjective and cardiovascular effects of IV cocaine administration in humans.

Introduction

The “rate hypothesis” holds that the rewarding effect and abuse liability of a psychoactive drug are related to its rate of onset of effect, i.e., the faster a drug exerts its psychoactive effects the more rewarding the drug effect (de Wit et al., 1992, Gorelick, 1998). This hypothesis is thought to explain the differential abuse liability of various drugs within the same pharmacological class (e.g., faster onset diazepam versus slower onset oxazepam) (Griffiths et al., 1984) and of the same drug (or drug class) taken by rapid onset versus slow onset routes of administration (e.g., IV heroin versus oral methadone, smoked versus transdermal nicotine, and smoked or IV versus oral cocaine) or in standard versus slow release formulations (Kollins et al., 1998, Mumford et al., 1995). This hypothesis forms part of the rationale for substitution therapy of drug addiction based on slow onset, long acting agonists with less abuse liability, e.g., oral methadone for IV heroin addiction and transdermal nicotine for smoked tobacco addiction. However, there is limited direct experimental evidence for this hypothesis with regard to cocaine (Gorelick, 1998) or other abused psychoactive drugs, e.g., sedative-hypnotics (de Wit et al., 1992, de Wit et al., 1993, Kato et al., 1987), nicotine (Wakasa et al., 1995).

Four IV cocaine self-administration studies in monkeys had results consistent with the rate hypothesis. Two studies found increased rates of responding to obtain cocaine reinforcement with faster IV infusion rates (Balster and Schuster, 1973, Panlilio et al., 1998). A third study found that faster infusion rates were associated with more injections per session on a progressive ratio schedule (Woolverton and Wang, 2004). The fourth study found an inverse relationship between the minimum reinforcing dose of cocaine and injection speed, i.e., the faster the injection speed, the lower the minimum reinforcing dose, a relationship which also held for pentobarbital (Kato et al., 1987). In contrast, three studies in rats found no increase in IV cocaine or amphetamine self-administration over 3–20-fold increases in infusion rate (Crombag et al., 2003, Liu et al., 2005, Pickens et al., 1969).

We are aware of only two relevant studies in humans. One unpublished study (available in abstract only) administered two IV cocaine doses (16 or 32 mg) at each of two infusion durations (60 or 600 s) in mixed order to six experienced cocaine users, generating infusion rates of 0.03–0.53 mg/s (Fischman and Schuster, 1984). Shorter infusion durations produced greater heart rate increases and stronger subjective effects on some, but not all, measures. Results were not presented separately by dose. A second study administered a single dose of IV cocaine (30 mg/70 kg) at three infusion durations (2, 15, 60 s) to 12 experienced cocaine users, generating infusion rates of 15, 2, and 0.5 mg/s (assuming a 70 kg subject) (Abreu et al., 2001). There were significant duration (rate)-dependent effects on psychological measures (e.g., “like”, “rush”, “high” measured by visual analogue scales), but no significant effect on cardiovascular measures, such as heart rate and blood pressure.

Cocaine effects are robustly dose-dependent, with dose moderating the influence of other variables. For example, the effect of delay of reinforcement on cocaine self-administration in rhesus monkeys is less at higher cocaine doses than at lower doses (Beardsley and Balster, 1993). Thus, it is possible that cocaine dose might moderate the influence of infusion rate. We are aware of two monkey studies that compared the effect of infusion rate at different cocaine doses. One study found less of a rate effect at the higher cocaine dose (400 mg/kg) than at the lower dose (200 mg/kg) (Balster and Schuster, 1973), consistent with a moderating influence of dose on rate. Another study found a similar effect of rate across a range of cocaine doses (0.1–1.0 mg/kg/injection) (Woolverton and Wang, 2004). Of the two prior human studies, one used two cocaine doses but did not report findings by dose (Fischman and Schuster, 1984); the other used only one cocaine dose (Abreu et al., 2001) and so could not address this issue.

We present here a study comparing the effect in experienced cocaine users of varying the rate of intravenous cocaine administration on subjective and physiological parameters. We employed both different infusion durations and different cocaine doses, thus providing the ability to compare the effects of dose and rate. Based on a previous monkey study (Balster and Schuster, 1973), we hypothesized that cocaine dose would have a moderating influence on the rate effects.

Section snippets

Subjects

Non-treatment-seeking, adult (21–40 years of age), experienced cocaine users were recruited through advertisements and word of mouth. Subjects received a comprehensive medical and psychological evaluation, including medical and drug use history, physical examination, complete blood count, blood chemistries, serologic tests for syphilis and hepatitis B, urinalysis, 16-lead EEG, 12-lead ECG with 3-min rhythm strip, 24-h ambulatory monitoring of ECG and blood pressure, echocardiogram, exercise

Subjects

Forty-three subjects enrolled in the study, of whom 17 completed at least one drug administration session. The remaining 26 subjects were disqualified for medical (22) or behavioral (4) reasons prior to any drug administration. Seven subjects completed all 10 sessions; four subjects completed 3–9 sessions. The 10 non-completing subjects were discharged from the study for a variety of medical reasons, including cardiovascular (5), hepatic (2), neurologic (1), metabolic (1), and other (1). There

Discussion

This study found the expected dose-dependent subjective and cardiovascular effects of cocaine, comparable in magnitude to those reported in previous studies administering IV cocaine at similar doses (10–12.5, 20–25, 40–50 mg) and infusion durations (10–60 s) (Abreu et al., 2001, Jones et al., 1999, Preston et al., 1992, Preston et al., 1993, Smith et al., 2001), e.g., increases of 30–50 mm on VAS measures of positive subjective effects after a 50 mg cocaine dose. This study also found a modest but

Acknowledgments

This research was supported by NIDA intramural funds. We thank Jennifer Schroeder for help with statistical analysis.

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