, Volume 236, Issue 9, pp 2569–2577 | Cite as

Influence of phendimetrazine maintenance on the reinforcing, subjective, performance, and physiological effects of intranasal cocaine

  • William W. StoopsEmail author
  • Justin C. Strickland
  • Joseph L. AlcornIII
  • Lon R. Hays
  • Abner O. Rayapati
  • Joshua A. Lile
  • Craig R. Rush
Original Investigation



No pharmacotherapies are approved for cocaine use disorder. Phendimetrazine, a prodrug of the monoamine-releaser phenmetrazine, attenuates the reinforcing effects of cocaine in preclinical models, has minimal abuse potential, and is safe when combined with cocaine.


This study determined the influence of phendimetrazine maintenance on the reinforcing effects of cocaine (i.e., choice to self-administer cocaine), along with the subjective, performance, and physiological effects of cocaine. We hypothesized that phendimetrazine would attenuate the reinforcing effects of cocaine.


Twenty-nine subjects with cocaine use disorder completed this within-subject, inpatient study. The subjects were maintained on placebo and 210 mg phendimetrazine in a counterbalanced order. After at least 7 days of maintenance on the target dose, the subjects completed experimental sessions in which the effects of single doses of 0, 20, 40, and 80 mg of intranasal cocaine were determined.


Cocaine functioned as a reinforcer, producing significant dose-related increases in self-administration. Cocaine increased prototypic effects (e.g., ratings of stimulated and blood pressure). Phendimetrazine attenuated ratings on a select set of subjective outcomes (e.g., ratings of talkative/friendly), but failed to reduce the reinforcing effects of cocaine or a majority of positive subjective cocaine effects. Phendimetrazine increased heart rate, indicating a physiologically active dose was tested, but heart rate increases were not clinically significant.


These results indicate that although phendimetrazine can safely be combined with cocaine, it does not attenuate the abuse-related effects of cocaine. It is unlikely, then, that phendimetrazine will be an effective standalone treatment for cocaine use disorder.


Humans Self-administration Behavioral economic demand Pharmacotherapy Phendimetrazine Cocaine 



The authors gratefully acknowledge the staff of the University of Kentucky Laboratory of Human Behavioral Pharmacology for the technical assistance, the staff of the University of Kentucky Center for Clinical and Translational Science Clinical Research Services Core for the medical assistance, and the University of Kentucky Investigative Drug Service for the preparation of study medications. This study complied with all laws of the United States of America.

Funding information

The authors gratefully acknowledge research support from the National Institute on Drug Abuse (R01DA036553; T32DA035200) and from the National Center for Advancing Translational Sciences (UL1TR001998) of the National Institutes of Health as well as grant 1247392 from the National Science Foundation. These funding agencies had no role in study design, data collection or analysis, or preparation and submission of the manuscript.

Compliance with ethical standards

This study complied with all relevant local, national and international ethical standards. All subjects provided sober, written consent prior to participation.

Conflict of interest

The authors declare that they have no conflicts of interest.


The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the National Science Foundation.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Behavioral ScienceUniversity of Kentucky College of MedicineLexingtonUSA
  2. 2.Department of PsychiatryUniversity of Kentucky College of MedicineLexingtonUSA
  3. 3.Department of PsychologyUniversity of Kentucky College of Arts and SciencesLexingtonUSA
  4. 4.Center on Drug and Alcohol ResearchUniversity of Kentucky College of MedicineLexingtonUSA

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