Abuse Potential of Oral Phendimetrazine in Cocaine-dependent Individuals

Abstract

Objectives Phendimetrazine is a prodrug for the monoamine releaser phenmetrazine, a drug with known abuse potential. Preclinical studies suggest that phendimetrazine has limited abuse potential and may have promise as an agonist-like replacement therapy for cocaine dependence. This study evaluated the abuse potential of phendimetrazine in humans. Methods Nine cocaine-dependent individuals (N = 9) were enrolled to investigate the abuse potential of phendimetrazine and d-amphetamine using a double blind, placebo-controlled, within-subject design. Subjective and cardiovascular effects of oral phendimetrazine (35, 70, and 105 mg), d-amphetamine (10, 20, and 30 mg), and placebo were assessed in quasi-random order across eight sessions lasting approximately eight hours each. Results d-Amphetamine (20 and 30 mg) significantly increased cardiovascular measures in a time- and dose-related manner but phendimetrazine did not systematically alter cardiovascular measures. Although d-amphetamine and phendimetrazine significantly increased ratings indicative of abuse potential (e.g., drug liking) and stimulant-like effects relative to placebo, these increases were generally small in magnitude, with phendimetrazine producing significant effects on fewer abuse-related measures and at fewer time points than d-amphetamine. Conclusions These preliminary findings suggest that oral phendimetrazine and d-amphetamine may have limited abuse potential in cocaine-dependent individuals. These findings collectively emphasize that the clinical utility of medications to treat cocaine-use disorders should be weighed carefully against their potential for abuse and diversion, with careful attention paid to evaluating abuse potential in a clinically relevant population of interest. Future studies are needed to further elucidate the potential utility of phendimetrazine as an agonist-like replacement therapy for cocaine dependence.

The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine

“…Human self-administration studies (Greenwald et al, 2010; Rush et al, 2010) and clinical trials (Mooney et al, 2009) show that amphetamine treatment decreases cocaine intake. Similar to amphetamine, phenmetrazine acts as a monoamine reverse transport releaser, however in contrast to amphetamine, phenmetrazine when given orally in the form of its prodrug phendimetrazine has relatively low abuse liability (Bolin et al, 2016). Moreover, heart rate measures in human cocaine users have shown that phendimetrazine is safe and tolerable across a threefold span of doses alone and when combined with cocaine (Bolin et al, 2016; Stoops et al, 2016).…”

“…We chose to study the mGluR2/3 agonist, LY379268, given the fact that mGluR2/3 receptors are altered following cocaine self-administration. We also chose to study the monoamine releaser, phenmetrazine, given its ability to increase dopamine tone in a manner similar to amphetamine combined with the fact that in the clinic it can be administered orally via its prodrug, phendimetrazine, which exhibits relatively low abuse potential compared to other proposed agonist therapies like amphetamine (Bolin et al, 2016). Finally, we chose to investigate the combined effects of these compounds given increasing interest in the ability of combination therapy to reduce self-administration to a greater extent than monotherapy in addition to the fact that these drugs have been proposed to reduce cocaine self-administration, in part, through distinct mechanisms.…”

Effects of acute buspirone administration on inhibitory control and sexual discounting in cocaine users

“…No medications are currently approved to treat cocaine use disorder, and most candidate pharmacotherapies have demonstrated limited impact on drug‐taking behavior (see reviews by Czoty, Stoops, & Rush, ; Kampman, ; Karila et al, ). Those with demonstrated efficacy have a perceived increased potential for abuse and diversion, limiting their adoption (Bolin, Stoops, Sites, & Rush, ). Identifying novel effective pharmacological treatments that would be more readily adopted is a clear research priority given the negative economic and public health consequences of continued cocaine use.…”

Evaluation of the Reinforcing Strength of Phendimetrazine Using a Progressive-Ratio Schedule of Reinforcement in Rhesus Monkeys

“…JPET/2020/264952.R1 13 cocaine ("stimulant" and "talkative/friendly"), it does not attenuate most of the positive subjective effects (e.g., "euphoric," "high" or "like drug") or the reinforcing effects of cocaine (Bolin et al 2016;Stoops et al 2019). The clinical implication of these results is that despite the ability to reduce cocaine self-administration in laboratory animals, the potential for abuse may limit the clinical potential of PDM; our goal was to determine whether that abuse potential was lower than cocaine.…”