Effects of Phendimetrazine Treatment on Cocaine vs Food Choice and Extended-Access Cocaine Consumption in Rhesus Monkeys

Abstract

There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).

Effects of the dopamine/norepinephrine releaser phenmetrazine on cocaine self-administration and cocaine-primed reinstatement in rats

“…The present results with phenmetrazine provide proof-of-concept data to support the evaluation of its pro-drug, the Schedule III compound PDM. As described above (see Introduction) PDM, which has been used clinically anorectic for over 50 years, can attenuate the reinforcing effects of cocaine in monkeys under multiple experimental conditions and possesses low abuse liability (Jain et al 1979; Corwin et al 1987; Banks et al 2013a,c). PDM is therefore a promising candidate to provide the selective attenuation of cocaine self-administration observed with monoamine releasers without the high abuse liability inherent in Schedule II drugs.…”

“…When taken orally, PDM is metabolized in the liver to phenmetrazine, an amphetamine-like releaser of dopamine and norepinephrine (Rothman et al 2002; Negus et al 2009; Banks et al 2013b). Orderly pharmacokinetics and behavioral effects have been observed over several weeks of repeated intravenous and chronic oral administration, respectively, of PDM (Banks et al 2013a,b,c), suggesting a consistent metabolism of PDM to phenmetrazine over long-term treatment. Importantly, parenterally administered phenmetrazine has cocaine-like discriminative stimulus effects (Negus 2009; Banks et al 2011) and can decrease cocaine self-administration in monkeys at doses that do not alter food-maintained responding (e.g.…”

Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter

“…These compounds thus represent yet another atypical class of releaser. Phenmetrazine has been studied in animal models as a potential therapeutic for stimulant use, both directly and via a clinically approved compound phendimetrazine which acts as a pro-drug for phenmetrazine (Negus et al, 2009; Banks et al, 2013a; 2013b; 2013c). Human laboratory experiments using phendimetrazine are under way.…”

“…There is promising pre-clinical and clinical evidence for efficacy of the DAT substrates d -amphetamine, d -phenmetrazine and sustained-release d -methamphetamine (Negus et al, 2009; Banks et al, 2013a; 2013c; Phillips et al, 2014), making a strong case for further work on this group of medications. Prodrug formulations of d -amphetamine (lisdexamfetamine) and phenmetrazine (phendimetrazine), for which abuse has not been reported, are especially promising.…”

Agonist Medications for the Treatment of Cocaine Use Disorder

“…Thus, effects of amphetamine can be mimicked by other dopamine-selective releasers such as phenmetrazine or methamphetamine, but not by serotonin-selective releasers such as fenfluramine. Second, prodrugs for amphetamine and phenmetrazine can also decrease cocaine choice (Banks et al, 2013a;Banks et al, 2013b). For example, lisdexamfetamine is a Schedule II prodrug for amphetamine that produces an amphetaminelike reduction in cocaine choice [Banks ML, Hutsell BA, Blough BE, Poklis JL, Negus SS (submitted).…”