Abuse potential of oral phendimetrazine in cocaine-dependent individuals

Stoops, William W.; Bolin, B. Levi; Sites, Jeremy P.; Rush, Craig R.

doi:10.1016/j.drugalcdep.2015.07.574

Cited by 2 publications

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“…Although increasing face validity does not guarantee enhanced predictive validity, and validation of any behavioral model is a gradual and ongoing process, the effects of several drugs on cocaine self-administration in this model have demonstrated good concordance with clinical data (Czoty et al, 2011, 2013; Gould et al, 2011). Regarding PDM, although clinical trials have not been conducted, recent findings suggest that oral PDM produces only minimal increases in positive subjective measures in cocaine users (Stoops et al, 2015). Taken together, the data provide support for testing the effectiveness of PDM in patients with cocaine use disorder.…”

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Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys

et al. 2016

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Chronic treatment with the monoamine releaser d-amphetamine has been consistently shown to decrease cocaine self-administration in laboratory studies and clinical trials. However, the abuse potential of d-amphetamine is an obstacle to widespread clinical use. Approaches are needed that exploit the efficacy of the agonist approach but avoid the abuse potential associated with dopamine releasers. The present study assessed the effectiveness of chronic oral administration of phendimetrazine (PDM), a pro-drug for the monoamine releaser phenmetrazine, to decrease cocaine self-administration in four rhesus monkeys. Each day, monkeys pressed a lever to receive food pellets under a 50-response fixed-ratio schedule of reinforcement and self-administered cocaine (0.005-0.56 mg/kg per injection, i.v.) under a progressive-ratio (PR) schedule in the evening. After completing a cocaine self-administration dose-response curve, sessions were suspended and PDM was administered (1.0-9.0 mg/kg, p.o., b.i.d.). Cocaine self-administration was assessed using the PR schedule once every 7 days while food-maintained responding was studied daily. When a persistent decrease in self-administration was observed, the cocaine dose-effect curve was re-determined. Daily PDM treatment decreased cocaine self-administration by 30-90% across monkeys for at least 4 weeks. In two monkeys, effects were completely selective for cocaine. Tolerance developed to initial decreases in food-maintained the third monkey, and in the fourth fluctuations were observed that were lower in magnitude than effects on cocaine self-administration. Cocaine dose-effect curves were shifted down and/or rightward in three monkeys. These data provide further support for the use of agonist medications for cocaine abuse, and indicate that the promising effects of d-amphetamine extend to a more clinically viable pharmacotherapy.

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confidence: 99%

Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys

et al. 2016

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Safety and tolerability of intranasal cocaine during phendimetrazine maintenance

et al. 2016

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Rationale Phendimetrazine appears to have limited abuse potential and reduces cocaine self-administration in preclinical studies. No human studies have evaluated the safety and tolerability of cocaine in combination with phendimetrazine, which is a necessary next step in evaluating the efficacy of phendimetrazine for treating cocaine use disorder. Objectives This study determined the safety and tolerability of acute cocaine doses during chronic phendimetrazine treatment. Methods Ten subjects completed this within-subjects, placebo-controlled, inpatient study. Subjects were maintained on ascending oral phendimetrazine doses (0, 70, 140 and 210 mg/day). After at least 7 maintenance days at each dose, subjects received ascending doses of intranasal cocaine (0, 10, 20, 40 and 80 mg), separated by 90 minutes, within one session. Results Cocaine produced prototypical cardiovascular and subject-rated effects (e.g., increased blood pressure and ratings of like drug). The cardiovascular effects of cocaine alone were not clinically significant for an acute drug response (e.g., average heart rate did not approach tachycardia, 100 beats/minute). Phendimetrazine enhanced peak heart rate following placebo and low cocaine doses, but these effects were also not clinically significant. Phendimetrazine was otherwise devoid of effects alone and did not alter the subject-rated effects of cocaine or hypothetical demand for cocaine on a purchase task. Conclusions Cocaine was safe and well tolerated during maintenance on a three-fold range of phendimetrazine doses. Given this safety profile, the reduced abuse potential of phendimetrazine and promising preclinical research, future human laboratory studies and possibly clinical trials should evaluate the efficacy of phendimetrazine for reducing cocaine use.

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Abuse potential of oral phendimetrazine in cocaine-dependent individuals

Cited by 2 publications

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Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys

Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys

Safety and tolerability of intranasal cocaine during phendimetrazine maintenance

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