Comparison in humans of the potency and pharmacokinetics of intravenously injected cocaethylene and cocaine

Cocaethylene (the ethyl ester of benzoylecgonine) is a product of the interaction between ethanol and cocaine. The results of preclinical studies and of a pilot clinical study have shown cocaethylene to produce pharmacologic effects similar to those of cocaine. However, no information is available concerning the potency and pharmacokinetics of cocaethylene in comparison to those of cocaine in humans. We report the results of a single-blind, crossover study in which six male, healthy, paid volunteers, who were moderate users of cocaine, were intravenously injected with the water soluble fumarate salt of cocaethylene (0.25 mg/kg cocaethylene base) or an equivalent dose of the water soluble hydrochloride salt of cocaine (0.25 mg/kg cocaine base). Each dose was dissolved in normal saline and injected over a 1-min interval. Test sessions were separated by a 1-week interval. The variables measured were: cocaine and cocaethylene plasma concentrations, subjective and cardiovascular effects. The results indicate, that in comparison to cocaine, cocaethylene had a significant smaller elimination rate constant (0.42 versus 0.67 l/h), had a longer elimination half-life (1.68 versus 1.07 h), and induced ratings of high and changes in heart rate that were of lower magnitude (65%, and 43%, respectively). During the period of time that pharmacologic effects were present the plasma concentrations of cocaine and cocaethylene were statistically indistinguishable. This finding supports the conclusion that in humans cocaethylene is less potent than cocaine.     

Concurrent cocaine-ethanol ingestion in humans: pharmacology,physiology, behavior,and the role of cocaethylene

Simultaneous abuse of cocaine and ethanol is a common occurrence. Cocaethylene, the ethyl ester of benzoylecgonine, has been detected in the urine of patients reporting concurrent use of cocaine and ethanol, and high levels have been found in the blood of victims of fatal drug overdose. This placebo-controlled, double-blind study examined the pharmacokinetic, physiologic, and behavioral effects of dual cocaine and ethanol administration in humans (n=6). Cocaethylene was found in the plasma only after administration of both cocaine and ethanol, and appeared to be eliminated more slowly than cocaine. Plasma cocaine concentrations were significantly higher during cocaine/ethanol administration. Euphorigenic effects were both enhanced and prolonged, and heart rate was significantly increased, following cocaine/ethanol administration as compared to administration of cocaine or ethanol alone.     

Comparison of intravenous cocaethylene and cocaine in humans

Rationale: Cocaethylene is a pharmacologically active homolog and metabolite of cocaine, formed by transesterification of cocaine in the presence of ethanol. Here we relate findings from a randomized, placebo-controlled, double-blind study in which we examined the physiological and subjective effects and pharmacokinetics of IV administered cocaethylene in human volunteers using cocaine as a comparator. Methods: Cocaine-dependent participants randomly received one study drug, cocaethylene (0.25 or 0.5 mg/kg), cocaine (0.25 or 0.5 mg/kg), or placebo, during each experimental session which occurred on separate days. Results: Cocaethylene was less potent in elevating heart rate than equivalent doses of cocaine. Similar differences between cocaine and cocaethylene were found for subjective measures (”Cocaine High”, ”Rush”, ”Stimulated” and ”Good Drug Effects”). All active drug conditions produced significant increases in systolic blood pressure relative to placebo, but no significant effect on diastolic blood pressure was observed. Cocaethylene demonstrated a slower clearance, larger volume of distribution and correspondingly longer elimination half-life than cocaine. Conclusion: The findings from this study confirm those of previous studies that show that cocaethylene has pharmacological properties in common with cocaine, but is less potent. Received: 15 July 1999 / Final version: 23 November 1999     

Cocaine and cocaethylene: Effects on extracellular dopamine in the primate

Cocaine and cocaethylene (a psychoactive metabolite of concurrent cocaine and ethanol consumption) were studied in the anesthetized vervet monkey. The ability of each to elevate extracellular DA in the caudate nucleus was assessed using microdialysis probes acutely lowered through chronic guide cannulae. Blood samples were also collected to determine plasma levels of the two drugs. Doses of 1.5 µmol/kg cocaine (equivalent to 0.5 mg/kg cocaine-HC1) and cocaethylene were administered intravenously. Microdialysis and blood samples were collected at 5-min intervals immediately following drug administration. Both drugs caused a maximal four-fold increase in extracellular DA during the 5- to 10-min period following drug administration. This is the first report of cocaine (and cocaethylene) induced alterations in extracellular DA in primates. The abilities of cocaine and cocaethylene to produce euphoria are being compared in ongoing clinical research studies. The potential use of these results for interpreting the neurochemical basis of any differences in those studies is discussed.     

Subjective and cardiovascular effects of cocaethylene in humans

Preclinical studies have shown cocaethylene (the ethyl ester of benzoylecgonine) to produce pharmacologic effects of similar magnitude to those of cocaine. These observations, however, cannot establish whether or not cocaethylene produces cocaine-like subjective effects. We report the results of experiments in which three healthy male, paid volunteers were intravenously injected with the water soluble fumarate salt of cocaethylene in escalating doses. Subjective effects and cardiovascular parameters were the dependent variables. The maximal dose of cocaethylene base administered (0.25 mg/kg) produced subjective effects that were judged as milder and tachycardic effects that were comparable to those produced by the intravenous injection of an equivalent dose (0.25 mg/kg) of cocaine base.     

Ethanol effects on self-administration of alfentanil, cocaine, and nomifensine in rhesus monkeys

 A common form of polydrug use is that of cocaine and ethanol. The identification of an ethanol-cocaine combination product, cocaethylene, with properties in common with cocaine, has led to speculation that this metabolite may contribute to the co-abuse of cocaine and ethanol. In order to determine whether ethanol pretreatments selectively altered cocaine’s reinforcing potency, ethanol pretreatments were given to monkeys trained to press levers and receive IV infusions of several doses of cocaine or alfentanil. In addition, nomifensine, a drug which has a mechanism of action similar to cocaine’s, was evaluated in the presence and absence of ethanol in monkeys with the cocaine baseline history. Ethanol, in doses ranging from 100 to 1780 mg/kg, given 10 min before the 130-min session, had no effect on responding maintained by alfentanil. These doses also had no significant effect on cocaine-maintained responding, although the potency of cocaine as a reinforcer was increased following administration of 1000 mg/kg ethanol in two of the four subjects. The potency of nomifensine as a reinforcer was significantly increased by 1000 mg/kg ethanol, but again, this enhancement was limited to the same two subjects. These data indicate that, in this paradigm, cocaethylene did not selectively modify cocaine’s reinforcing potency, but there appear to be individual differences with respect to ethanol’s ability to stimulate rates of drug-maintained responding. Received: 24 April 1996 / Final version: 7 November 1996     

Differences between adult non-drug users versus alcohol,cocaine and concurrent alcohol and cocaine problem users

Concurrent drug use is a serious public health concern with significant morbidity and mortality associated with the combined use of alcohol and cocaine. Multinomial logistic regression was used to assess differences between non-drug users and alcohol, cocaine and concurrent problem users incorporating data from the 2005 National Survey on Drug Use and Health. Results demonstrated that alcohol and cocaine use is associated with mental health disturbance, other drug use and adverse social consequences. Furthermore, concurrent users were more likely to report cigarette and marijuana use as well as lifetime STDs and arrest for breaking the law. Study results have implications for planning prevention and treatment services differentially for alcohol, cocaine and concurrent users and support the need for more intense resources allocated to the prevention and treatment of the concurrent use of alcohol and cocaine.     

Rapid induction of behavioral and neurochemical tolerance to cocaethylene, a model compound for agonist therapy of cocaine dependence

Rationale: Tolerance to abused drugs may impact on patterns of abuse, and in the case of agonist therapies, may be beneficial in that it reduces the reward value of a given dose of abused drug. Cocaethylene, a psychoactive metabolite resulting from concurrent alcohol and cocaine consumption, was examined because of its use in human research studies of drug reward mechanisms, and its potential as a model compound for an agonist based therapy for cocaine dependence. Objective: Comparisons were made between cocaine and cocaethylene in the acute development of tolerance to the neurochemical and behavioral effects of cocaine. With chronic exposure, tolerance to the behavioral effects of cocaine was examined. Methods: In awake rats with a microdialysis probe in the nucleus accumbens and a jugular catheter, an IV bolus/3-h infusion of cocaine or cocaethylene and a subsequent cocaine challenge was administered while extracellular dopamine and locomotion were monitored. Chronic IV treatment with cocaine, cocaethylene, and a water control was accomplished for 7 days using osmotic minipumps attached to jugular catheters. Animals were then challenged with an IV bolus of cocaine. Results: With acute treatment, the IV bolus of cocaethylene at the beginning of the infusion period resulted in an initial behavioral activation equivalent to that caused by cocaine, after which there was a striking difference in that the cocaethylene group displayed a return to predrug levels of activity, while the cocaine group showed high levels of activity throughout the 3-h period. Both cocaethylene and cocaine resulted in an initial increase in the extracellular concentration of dopamine. However, after that initial increase, levels of dopamine dropped in the cocaethylene group while the cocaine group levels remained elevated. A 1-week infusion of cocaine or cocaethylene resulted in tolerance to the behavioral activating effects of a subsequent cocaine challenge. Conclusions: These results demonstrate a rapid induction of tolerance to the behavioral and neurochemical properties of cocaethylene, resulting in a diminished behavioral response to a cocaine challenge both acutely, and after 7 days. The relevance of these data for the use of cocaethylene as a model compound for an agonist approach to therapy for cocaine dependence is discussed. Received: 22 January 1999 / Final version: 16 April 1999     

A comparison of motivations for use among users of crack cocaine and cocaine powder in a sample of simultaneous cocaine and alcohol users

This study examined the motivations for using cocaine and alcohol comparing those who primarily smoked crack and those who primarily used cocaine powder when using simultaneously with alcohol. Motivations examined included: 1) to cope with a negative affect, 2) enhancement, 3) to be social and 4) to conform. The research design was a cross-sectional study in which clients in treatment for cocaine and alcohol problems completed a self-administered questionnaire about their substance use. Among those who primarily smoked crack or snorted cocaine when also using alcohol (n = 153), there were 93 participants who reported primarily snorting cocaine and 60 participants who primarily reported smoking crack. Bivariate analyses found that those who primarily smoked crack reported lower social motivations to use alcohol and cocaine. When adjusting for other covariates in a multivariate analysis, social motivation was still significantly different between groups. Additionally, those who primarily smoked crack were more likely to be older, report higher cocaine dependence severity, be unemployed and were less likely to have completed some post-secondary education, than those who primarily snorted cocaine. No differences were found in enhancement, coping or conformity motivations between the two groups. These results suggest that simultaneous cocaine and alcohol use may have social importance to those who primarily snort cocaine, but that this importance is less evident to those who smoke crack. Consequently, future studies examining motivations for simultaneous cocaine and alcohol use should distinguish between different routes of cocaine administration.     

Interest for delivery of cocaethylene in a sustained release emulsion vs saline evaluated on behavioral sensitization in naive and cocaine-sensitized mice

Rationale

Repeated administration of psychostimulant elicits behavioral sensitization, characterized by an augmented locomotor response to a subsequent challenge injection. This sensitization is paralleled by neural adaptations. Evidences suggest that the rate at which drugs of abuse are delivered to the brain play a key role in this plasticity. Cocaethylene is a pharmacologically active homolog of cocaine, known to have a pharmacokinetic profile different to that of cocaine.

Objectives

Utilizing locomotor sensitization, we evaluated the consequences of the administration of cocaethylene in a rapid- and slow-onset formulation, in naïve and cocaine-sensitized mice.

Materials and methods

We investigated the development of sensitization after repeated administration of cocaine and cocaethylene and the effects of cocaethylene in animals previously exposed to cocaine. Cocaethylene was dissolved in two vehicles (saline and emulsion).

Results

As observed with cocaine, chronic cocaethylene treatment in saline induced a behavioral sensitization, while in a sustained release emulsion, no behavioral sensitization was observed. Moreover, the expression of the sensitized behavior observed in cocaine-treated mice was reduced or totally abolished after cocaethylene administration in saline and emulsion, respectively. Interestingly, administration of cocaine in mice chronically treated with cocaethylene in saline induced an increase in locomotor activity as compared to control animals. In contrast, no difference was observed after the administration of cocaine in animals chronically treated with cocaethylene in emulsion or control group.

Conclusions

Cocaethylene in a sustained release emulsion blocked locomotor sensitization. These results suggest that cocaethylene, in a specific galenic preparation, such as gum, may be an efficacious harm-reduction alternative to cocaine users.

     

Social reward-conditioned place preference: a model revealing an interaction between cocaine and social context rewards in rats

A recent thrust in drug abuse research is the influence of social interactions on drug effects. Therefore, the present study examined conditioned place preference (CPP) as a model for assessing interactions between drug and social rewards in adolescent rats. Parameters for establishing social reward-CPP were examined, including the number of conditioning sessions/day (1 or 2), the total number of sessions (2, 8, or 16), and the duration of sessions (10 or 30 min). Subsequently, the effects of cocaine or dextromethorphan on social reward-CPP and play behavior were examined. The results demonstrate that social reward-CPP (i.e., preference shift for an environment paired previously with a rat) was similar using either 1 or 2 conditioning sessions/day and either 10 or 30 min sessions; however, social reward-CPP increased as the number of social pairings increased. Additionally, a low dose of cocaine (2 mg/kg, IP) and a low number of social pairings (2 pairings) failed to produce CPP when examined alone, but together produced a robust CPP, demonstrating an interaction between these rewards. The non-rewarding drug, dextromethorphan (30 mg/kg, IP), failed to enhance social reward-CPP, suggesting that drug-enhanced social reward-CPP is specific to rewarding drugs. Surprisingly, there was no relationship between play behaviors and preference shift in drug-naïve animals. Furthermore, cocaine inhibited play behavior despite enhancing social reward-CPP, suggesting that aspects of social interaction other than play behavior likely contribute to social reward. The findings have important implications for understanding the influence of social context on cocaine reward during adolescence.     

Chronic unpredictable stress, but not chronic predictable stress, enhances the sensitivity to the behavioral effects of cocaine in rats

RATIONALE: Chronic unpredictable stress, in which the type and timing of stress exposures are varied, alters protein levels in the mesolimbic DA system in a manner previously shown to be associated with enhanced behavioral responsiveness to cocaine. Chronic exposure to the same or predictable stress (restraint) does not. Thus, we examined the effects of chronic unpredictable and chronic predictable (restraint) stress on the locomotor activating and place conditioning effects to low cocaine doses. OBJECTIVE: To test whether chronic unpredictable stress enhances the sensitivity to the behavioral effects of cocaine. METHODS: Rats were exposed to 10 days of chronic unpredictable stress, of chronic predictable (restraint) stress, or were not stressed. One day following cessation of stress exposure, locomotor activity to cocaine (0 or 7.5 mg/kg) was assessed for 4 consecutive days and corticosterone levels on the last day were determined. In other experiments, the effects of the chronic stress procedures on cocaine (0.5 and 7.5 mg/kg) place conditioning using an unbiased procedure were assessed. RESULTS: Chronic unpredictable, but not chronic predictable, stress transiently increased the locomotor activating effects of cocaine and this was correlated positively with corticosterone levels. Chronic unpredictable, but not chronic predictable, stress also enhanced the place conditioning effects of cocaine: increased place preference was seen with the low dose and a pronounced place aversion occurred with the high dose. CONCLUSIONS: These data demonstrate that chronic unpredictable stress enhances the behavioral effects of cocaine, including its aversive effects, whereas chronic predictable stress (restraint) is without effect.     

Animal model for investigating the anxiogenic effects of self-administered cocaine

Male albino rats were trained to traverse a straight alley for a reward of five intravenous injections of cocaine (0.75 mg/kg/injection in a volume of 0.1 ml/injection delivered over 4 s). Animals were tested one trial per day with the following dependent measures assessed on each trial: start latency, running time, the number of retreats, and the location within the alley where each retreat occurred. While start latencies remained short and stable, running times tended to increase over days. This effect was apparently related to a concomitant increase in the number of retreats occurring in the alley (r=0.896). Retreats tended to occur in very close proximity to the goal box, suggesting that animals working for IV cocaine come to exhibit a from of conflict behavior (i.e., retreats) putatively stemming from the drug's well documented rewarding and anxiogenic properties. Consistent with this hypothesis was the demonstration that diazepam (0.5, 1.0, 2.0 mg/kg IP) pretreatment dose-dependently reduced the incidence of retreat behaviors in the alley. In addition, the rewarding efficacy of the cocaine dosing parameters was subsequently confirmed in the runway subjects by conditioned place preference. The present paradigm, therefore, provides a useful method for investigating the anxiogenic effects of self-administered cocaine in laboratory animals.     

Relationship between the discriminative stimulus effects and plasma concentrations of intramuscular cocaine in rhesus monkeys

The relationship between the discriminative stimulus effects and plasma pharmacokinetics of cocaine was evaluated in six rhesus monkeys trained to discriminate cocaine (0.4 mg/kg, IM) from saline under a FR30 schedule of food presentation. The same monkeys were tested in two procedures. In a cumulative dosing procedure, five cumulative doses of cocaine (0.013–1.3 mg/kg) were administered and discriminative stimulus effects were evaluated 10 min after the administration of each dose. Cocaine plasma concentrations were measured in separate sessions using the same doses and interdose intervals. In a single dosing procedure, the time-courses of the discriminative stimulus effects and plasma concentrations of cocaine were assessed after the administration of cocaine (0.4 mg/kg). A close correspondence between cocaine's discriminative stimulus effects and plasma concentrations was obtained in both procedures. Cocaine was virtually undetectable in plasma at doses that produced saline-appropriate responding (0.013 and 0.04 mg/kg), whereas increasing plasma concentrations were measured at doses that produced primarily cocaine-appropriate responding (0.13 mg/kg or higher). The time-course of the discriminative stimulus effects of cocaine was characterized by a rapid onset (within 1–3 min post-cocaine) and offset (within 20–60 min post-cocaine). Peak plasma levels were obtained at 10 min post-cocaine. No differences in plasma concentrations were found 10 min after the administration of a cumulative versus a single dose of cocaine 0.4 mg/kg (mean, 75.8 and 74.0 ng/ml, respectively). Cocaine plasma concentrations lasted longer than its discriminative stimulus effects. The results of the present study confirm that the cumulative dosing procedure used yields plasma concentrations of cocaine that are similar to the concentrations obtained after single cocaine dosing.In Memoriam: Xavier Lamas, MD, phD; August 26, 1995; Mt. EverestThis work was supported by in part by grants DA 02159, DA 04059, DA 07252 and KO award DA 00101 from the National Institute on Drug Abuse, NIH. Xavier Lamas was supported by a grant from the Ministry of Education and Science of Spain (Formación del Personal Investigador, Subprograma de Perfeccionamiento para Doctores y Tecnólogos). Animals used in this study were maintained in accordance with guidelines of the Committee on Care and Use of Laboratory Animal Resources, National Research Council (Department of Health, Education and Welfare, Publication No. (NIH) 85–23, revised 1985), and the McLean Hospital Institutional Animal Care and Use Committee.     

Comparison of plasma cocaine levels during a "binge" pattern of cocaine administration in male and female rhesus monkeys

Abstract Rationale. Cocaine is often abused in a "binge" pattern, but little is known about changes in plasma cocaine concentrations or cocaine pharmacokinetics during administration of multiple cocaine doses. Moreover, the extent to which gender may influence plasma cocaine levels during a cocaine binge has not been studied in rhesus monkeys. Objectives. To compare the effects of repeated injections of the same dose of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) on plasma cocaine concentrations, cocaine pharmacokinetics and behavioral responses in male and female rhesus monkeys. Methods. Four injections of cocaine (0.4 mg/kg or 0.8 mg/kg, i.v.) were administered at 30-min intervals to five or six male and five or six female rhesus monkeys. Samples for plasma cocaine analysis were collected at 2, 4, 8, 16 and 24 min after the first three injections. After the fourth cocaine injection, additional samples were collected at 10-min intervals over 150 min. Results. Plasma cocaine peaks and nadirs increased monotonically after successive cocaine injections (P<0.0001). Peak plasma cocaine levels measured at 2 min after cocaine administration were higher after 0.8 mg/kg cocaine than after 0.4 mg/kg cocaine (P<0.006). There were no significant gender differences in time to peak plasma cocaine levels (t_max), peak cocaine concentrations (C_max) or half-life (t_1/2; min) at either dose of cocaine. Group average behavioral ratings were similar in males and females after each dose of cocaine. Conclusions. Peak plasma cocaine concentrations increased progressively during low and high dose cocaine binge episodes, and there were no significant gender differences in cocaine pharmacokinetics. These findings demonstrate the feasibility of simulating "binge" patterns of cocaine administration in rhesus monkeys. Electronic Publication     

A critical transition in cocaine self-administration: behavioral and neurobiological implications

Rationale It has long been hypothesized that human as well as animal cocaine users titrate their intake to maintain a specific level of cocaine reward. This hypothesis predicts that the dose–injection function of each subject individually should be a decreasing function, with no initial, gradual ascending limb. Objectives The present study was designed to test this specific prediction. Methods Rats were trained to self-administer cocaine under a continuous reinforcement schedule. After stabilization of cocaine self-administration, all rats were tested with a wide range of i.v. cocaine doses (0.0078–1 mg). To accurately measure the threshold dose of each individual, the pharmacological resolution was set at 0.0078 mg at the four lowest doses. Results As predicted, individual dose–behavior curves are discontinuous at a threshold dose, with a descending limb but no gradual, ascending limb. Below the threshold, there is no evidence for cocaine self-administration; at and above the threshold, the rate of injections spikes to its maximum and then decreases lawfully with the dose, a decrease that reflects cocaine titration. In all individuals, this critical transition occurred over a dose interval of less than 0.008 mg. Conclusions This study suggests that the cumulative effects of cocaine maintained during self-administration are all-or-nothing—a conclusion that confirms the regulation hypothesis of cocaine reward. The neurobehavioral consequences of this specific level of cocaine reward remain to be elucidated.     

Relationship between injection duration, transporter occupancy and reinforcing strength of cocaine

Among drugs that can function as positive reinforcers, slower occupancy of central nervous system sites of action has been associated with diminished reinforcing strength. The present study examined the relative reinforcing strength of cocaine, and the rate of in vivo dopamine transporter binding, as a function of injection duration. Rhesus monkeys (N=5) were allowed to self-administer cocaine under a progressive-ratio schedule with doses injected over different times (10-600 s). An ex vivo dopamine transporter binding assay was used to examine kinetics of in vivo transporter occupancy by cocaine injected over the same times in rats. Cocaine was a weaker reinforcer, and dopamine transporter binding rate decreased, with slower injections. Maximum transporter binding was the same across injection durations. These results support the hypothesis that slower onset of action is associated with a slower transporter occupancy and diminished reinforcing strength. Relative strength as a reinforcer may not be determined by maximum occupancy, at least not exclusively.     

Repeated exposures intensify rather than diminish the rewarding effects of amphetamine,morphine, and cocaine

It is commonly believed that repeated exposures diminish the pleasurable effects of drugs and hence that pleasure must have only a minor role in addiction. In six experiments with rats, repeated exposures to amphetamine, morphine, or cocaine were found to enhance the drug-induced rewarding effect as measured by conditioned place preference. Thus, sensitization to the rewarding effect, rather than tolerance, was obtained. Also, cross-sensitization was obtained; exposures to amphetamine enhanced the rewarding effect of morphine and vice versa; similarly, exposures to morphine enhanced the rewarding effect of cocaine. These findings support a new theory: drugs of abuse are addictive because repeated exposures sensitize the central reward mechanism so that drug taking produces a progressively greater reinforcing effect each time it occurs.     

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.