LAUSR

ABSTRACT Benzphetamine is a Schedule III anorectic agent that is a prodrug for d‐amphetamine and d‐methamphetamine and may have utility as an “agonist” medication for cocaine use disorder treatment. This study evaluated the pharmacokinetic‐pharmacodynamic profile of benzphetamine using a drug discrimination procedure in rhesus monkeys. The potency and time course of cocaine‐like discriminative stimulus effects were compared for benzphetamine (10–18 mg/kg, intramuscular (IM)) and d‐amphetamine (0.032–0.32 mg/kg, IM) in monkeys (n = 3–4) trained to discriminate IM cocaine (0.32 mg/kg) from saline in a two‐key food‐reinforced discrimination procedure. Parallel pharmacokinetic studies in the same monkeys determined plasma benzphetamine, d‐methamphetamine and/or d‐amphetamine levels for correlation with behavioral effects. d‐Amphetamine produced dose‐dependent, time‐dependent, and full cocaine‐like effects, i.e. ≥ 90% cocaine‐appropriate responding, in all monkeys without altering response rates. The time course of d‐amphetamine's cocaine‐like discriminative stimulus effects correlated with plasma d‐amphetamine levels. Benzphetamine was 180‐fold less potent than d‐amphetamine and produced full cocaine‐like effects in only 2 of 4 monkeys while significantly decreasing response rates. Benzphetamine administration increased plasma d‐methamphetamine (peak at 100 min) and d‐amphetamine (peak at 24 h) levels, but the time course of behavioral effects did not correlate with increased levels of benzphetamine, d‐methamphetamine or d‐amphetamine. These results suggest that benzphetamine yields d‐amphetamine and d‐methamphetamine as active metabolites in rhesus monkeys, but generation of these metabolites is not sufficient to account for benzphetamine behavioral effects. The incomplete cocaine substitution profile and protracted d‐amphetamine plasma levels suggest that benzphetamine may still warrant further evaluation as a candidate pharmacotherapy for cocaine use disorder treatment. HIGHLIGHTSd‐Amphetamine produced full cocaine‐like stimulus effects in all monkeys.A clockwise hysteresis loop related d‐amphetamine behavioral effects and levels.Benzphetamine produced full cocaine‐like stimulus effects in 2 of 4 monkeys.Benzphetamine produced sequential d‐methamphetamine and d‐amphetamine plasma levels.Benzphetamine behavioral effects did not correlate with metabolite levels.