Safety and tolerability of intranasal cocaine during phendimetrazine maintenance

Abstract

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.

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

“…Interestingly, similar to LY379268, phenmetrazine administration does not reduce food maintained responding in animals (Czoty et al, 2015). It should be noted that a recent study in human cocaine abusers showed that phendimetrazine did not reduce hypothetical demand for cocaine or the subject-rated effects of sampled cocaine (Stoops et al, 2016) in an experimental setting. Comparing the effects of phenmetrazine in rodents under a PR schedule of reinforcement in the current study with lack of effects of phendimetrazine on hypothetical demand for cocaine in human cocaine users is difficult.…”

“…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). …”

“…Comparing the effects of phenmetrazine in rodents under a PR schedule of reinforcement in the current study with lack of effects of phendimetrazine on hypothetical demand for cocaine in human cocaine users is difficult. However, Stoops et al (2016) noted that differences in phendimetrazine efficacy between animal models and their study in humans could be attributed to reductions that are specific to the reinforcing effects of cocaine among other factors.…”

Comparing exponential and exponentiated models of drug demand in cocaine users.

“…Our findings are not meant to be critical of previous studies or to target researchers that used replacement to account for zero consumption values. In fact, we have used these replacement methods when presented with this problem, not realizing the profound influence they might have on demand outcomes (Stoops et al, 2016; Strickland et al, 2016). We hope instead that this report encourages the adoption of an alternative approach to help improve the validity, generalizability, and clinical utility of demand curve measurement.…”

Behavioral economic demand as a unifying language for addiction science: Promoting collaboration and integration of animal and human models.

“…A considerable body of work has evaluated putative and approved pharmacotherapies for substance use disorder by applying demand methods in animal and human models (Bentzley & Aston-Jones, 2017; Bentzley et al, 2014; Bujarski, MacKillop, & Ray, 2012; Stoops et al, 2019; Stoops et al, 2016). Despite this diversity of studies, the only compounds that have been evaluated in both animal subjects and human participants for the same indication are FDA-approved pharmacotherapies for tobacco cessation: the monoamine transport inhibitor bupropion and the nicotinic partial agonist varenicline.…”