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

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Abstract

Rationale

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

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References

  • Banks ML, Blough BE, Fennell TR, Snyder RW, Negus SS (2013a) Role of phenmetrazine as an active metabolite of phendimetrazine: evidence from studies of drug discrimination and pharmacokinetics in rhesus monkeys. Drug Alcohol Depend 130:158–166

    Article  CAS  PubMed  Google Scholar 

  • Banks ML, Blough BE, Fennell TR, Snyder RW, Negus SS (2013b) Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys. Neuropsychopharmacology 38:2698–2707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Banks ML, Blough BE, Negus SS (2013c) Effects of 14-day treatment with the schedule iii anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys. Drug Alcohol Depend 131:204–213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bidwell LC, MacKillop J, Murphy JG, Tidey JW, Colby SM (2012) Latent factor structure of a behavioral economic cigarette demand curve in adolescent smokers. Addict Behav 37:1257–1263

    Article  PubMed  PubMed Central  Google Scholar 

  • Bolin BL, Stoops WW, Sites JP, Rush CR (2016) Abuse potential of oral phendimetrazine in cocaine-dependent individuals: implications for agonist-like replacement therapy. J Addict Med 10:156–165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruner NR, Johnson MW (2014) Demand curves for hypothetical cocaine in cocaine-dependent individuals. Psychopharmacology 231:889–897

    Article  CAS  PubMed  Google Scholar 

  • Bujarski S, MacKillop J, Ray LA (2012) Understanding naltrexone mechanism of action and pharmacogenetics in Asian Americans via behavioral economics: a preliminary study. Exp Clin Psychopharmacol 20:181–190

    Article  PubMed  PubMed Central  Google Scholar 

  • Butler AJ, Rehm J, Fischer B (2017) Health outcomes associated with crack-cocaine use: Systematic review and meta-analyses. Drug Alcohol Depend 80:401–416

    Article  CAS  Google Scholar 

  • Cash JC, Glass CA (2014) Family Practice Guidelines, Third edn. Springer, New York

    Google Scholar 

  • Chait LD, Uhlenhuth EH, Johanson CE (1987) Reinforcing and subjective effects of several anorectics in normal human volunteers. J Pharmacol Exp Ther 242:777–783

    CAS  PubMed  Google Scholar 

  • Comer SD, Ashworth JB, Foltin RW, Johanson CE, Zacny JP, Walsh SL (2008) The role of human drug self-administration procedures in the development of medications. Drug Alcohol Depend 96:1–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Corwin RL, Woolverton WL, Schuster CR, Johanson CE (1987) Anorectics: effects on food intake and self-administration in rhesus monkeys. Alcohol Drug Res 7:351–361

    CAS  PubMed  Google Scholar 

  • Czoty PW, Blough BE, Fennell TR, Snyder RW, Nader MA (2016a) Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys. Neuroscience 324:367–376

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Czoty PW, Stoops WW, Rush CR (2016b) Evaluation of the “pipeline” for development of medications for cocaine use disorder: A review of translational preclinical, human laboratory, and clinical trial research. Pharmacol Rev 68:533–562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • de la Garza R, Johanson CE (1987) Discriminative stimulus properties of intragastrically administered d-amphetamine and pentobarbital in rhesus monkeys. J Pharmacol Exp Ther 243:955–962

    PubMed  Google Scholar 

  • Evans SM, Johanson CE (1987) Amphetamine-like effects of anorectics and related compounds in pigeons. J Pharmacol Exp Ther 241:817–825

    CAS  PubMed  Google Scholar 

  • Foltin RW, Haney M (2004) Intranasal cocaine in humans: Acute tolerance, cardiovascular and subjective effects. Pharmacol Biochem Behav 78:93–101

    Article  CAS  PubMed  Google Scholar 

  • Foltin RW, Haney M, Rubin E, Reed SC, Vadhan N, Balter R, Evans SM (2015) Development of translational preclinical models in substance abuse: Effects of cocaine administration on cocaine choice in humans and non-human primates. Pharmacol Biochem Behav 134:12–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greenwald MK, Lundahl LH, Steinmiller CL (2010) Sustained release d-amphetamine reduces cocaine but not ‘speedball’-seeking in buprenorphine-maintained volunteers: a test of dual-agonist pharmacotherapy for cocaine/heroin polydrug abusers. Neuropsychopharmacology 35:2624–2637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Griffiths RR, Bradford LD, Brady JV (1979) Predicting the abuse liability of drugs with animal drug self-administration procedures: psychomotor stimulants and hallucinogens. In: Thompson T, Dews PB (eds) Advances in behavioral pharmacology, vol 2. Academic Press, New York, pp 164–208

    Google Scholar 

  • Haney M (2009) Self-administration of cocaine, cannabis and heroin in the human laboratory: benefits and pitfalls. Addict Biol 14:9–21

    Article  CAS  PubMed  Google Scholar 

  • Haney M, Spealman R (2008) Controversies in translation research: drug self-administration. Psychopharmacology 199:403–419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Havakuk O, Rezkalla SH, Kloner RA (2017) The cardiovascular effects of cocaine. J Am Coll Cardiol 70:101–113

    Article  CAS  PubMed  Google Scholar 

  • Jalal H, Buchanich JM, Roberts MS, Balmert LC, Zhang K, Burke DS (2018) Changing dynamics of the drug overdose epidemic in the United States from 1979 through 2016. Science 361:eaau1184

    Article  CAS  PubMed  Google Scholar 

  • Koffarnus MN, Franck CT, Stein JS, Bickel WK (2015) A modified exponential behavioral economic demand model to better describe consumption data. Exp Clin Psychopharmacol 23:504–512

    Article  PubMed  PubMed Central  Google Scholar 

  • Mackillop J, Murphy JG, Tidey JW, Kahler CW, Ray LA, Bickel WK (2009) Latent structure of facets of alcohol reinforcement from a behavioral economic demand curve. Psychopharmacology 203:33–40

    Article  CAS  PubMed  Google Scholar 

  • McLeod D, Griffiths RR, Bigelow GE, Yingling J (1982) An automated version of the digit symbol substitution test (DSST). Behav Res Methods Instrum 4:433–436

    Google Scholar 

  • Moeller SJ, Stoops WW (2015) Cocaine choice procedures in animals, humans and treatment seekers: Can we bridge the divide? Pharmacol Biochem Behav 138:133–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Müller OF, Hundt HK, Gosling JA (1975) Availability of phendimetrazine from sustained and non-sustained action formulations. S Afr Med J 49:135–139

    PubMed  Google Scholar 

  • Oliveto AH, Bickel WK, Hughes JR, Shea PJ, Higgins ST, Fenwick JW (1992) Caffeine drug discrimination in humans: acquisition, specificity and correlation with self-reports. J Pharmacol Exp Ther 261:885–894

    CAS  PubMed  Google Scholar 

  • Preston KL, Epstein DH, Cone EJ, Wtsadik AT, Huestis MA, Moolchan ET (2002) Urinary elimination of cocaine metabolites in chronic cocaine users during cessation. J Anal Toxicol 26:393–400

    Article  CAS  PubMed  Google Scholar 

  • Rothman RB, Katsnelson M, Vu N, Partilla JS, Dersch CM, Blough BE, Baumann MH (2002) Interaction of the anorectic medication, phendimetrazine, and its metabolites with monoamine transporters in rat brain. Eur J Pharmacol 447:51–57

    Article  CAS  PubMed  Google Scholar 

  • Rounsaville BJ, Anton SF, Carroll K, Budde D, Prusoff BA, Gawin F (1991) Psychiatric diagnoses of treatment-seeking cocaine abusers. Arch Gen Psychiatry 48:43–51

    Article  CAS  PubMed  Google Scholar 

  • Rush CR, Stoops WW (2012) Agonist replacement therapy for cocaine dependence: A Translational review. Future Med Chem 4:245–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rush CR, Stoops WW, Hays LR, Glaser PEA, Hays LS (2003) Risperidone attenuates the discriminative-stimulus effects of d-amphetamine in humans. J Pharmacol Exp Ther 306:195–204

    Article  CAS  PubMed  Google Scholar 

  • Rush CR, Bolin BL, Rayapati AO, Hays LR, Lile JA (2017) Bupropion-Naltrexone combinations as a pharmacotherapy for cocaine dependence. Presented at the College on Problems of Drug Dependence, Montreal, QC

  • Rush CR, Reynolds AR, Stoops WW, Lile JA, Rayapati AO, Hays LR (2018) Topiramate-Phentermine combinations as a pharmacotherapy for cocaine dependence. Presented at the College on Problems of Drug Dependence, San Diego, CA

  • Schuster CR, Snyder M (1989) NIDA’s medication development program. NIDA Res Monogr 95:64–73

    CAS  PubMed  Google Scholar 

  • Shiels MS, Freedman ND, Thomas D, Berrington de Gonzalez A (2018) Trends in US drug overdose deaths in non-Hispanic black, Hispanic, and non-Hispanic white persons, 2000-2015. Ann Intern Med 168:453–455

    Article  PubMed  Google Scholar 

  • Skinner HA (1982) The drug abuse screening test. Addict Behav 7:363–371

    Article  CAS  PubMed  Google Scholar 

  • Sofuoglu M, DeVito EE, Waters AJ, Carroll KM (2013) Cognitive enhancement as a treatment for drug addictions. Neuropharmacology 64:452–463

    Article  CAS  PubMed  Google Scholar 

  • Stein JS, Koffarnus MN, Snider SE, Quisenberry AJ, Bickel WK (2015) Identification and management of nonsystematic purchase task data: toward best practice. Exp Clin Psychopharmacol 23:377–386

    Article  PubMed  PubMed Central  Google Scholar 

  • Stoops WW, Lile JA, Glaser PE, Hays LR, Rush CR (2012a) Alternative reinforcer response cost impacts cocaine choice in humans. Prog Neuropsychopharm Biol Psychiatry 36:189–193

    Article  CAS  Google Scholar 

  • Stoops WW, Lile JA, Glaser PE, Hays LR, Rush CR (2012b) Influence of acute bupropion pre-treatment on the effects of intranasal cocaine. Addiction 107:1140–1147

    Article  PubMed  PubMed Central  Google Scholar 

  • Stoops WW, Strickland JC, Hays LR, Rayapati AO, Lile JA, Rush CR (2016) Safety and tolerability of intranasal cocaine during phendimetrazine maintenance. Psychopharmacology 233:2055–2063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strickland JC, Lile JA, Rush CR, Stoops WW (2016) Comparing exponential and exponentiated models of drug demand in cocaine users. Exp Clin Psychopharmacol 24:447–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Substance Abuse and Mental Health Services Administration (2018) Key substance use and mental health indicators in the United States: Results from the 2017 National Survey on Drug Use and Health (HHS Publication No. SMA 18-5068, NSDUH Series H-53). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/ on 27 November 2018

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Acknowledgments

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

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.

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Authors and Affiliations

  1. Department of Behavioral Science, University of Kentucky College of Medicine, 1100 Veterans Drive, Medical Behavioral Science Building, Room 140, Lexington, KY, 40536-0086, USA

    William W. Stoops, Joseph L. Alcorn III, Joshua A. Lile & Craig R. Rush

  2. Department of Psychiatry, University of Kentucky College of Medicine, 245 Fountain Court, Lexington, KY, 40509-1810, USA

    William W. Stoops, Lon R. Hays, Abner O. Rayapati, Joshua A. Lile & Craig R. Rush

  3. Department of Psychology, University of Kentucky College of Arts and Sciences, 171 Funkhouser Drive, Lexington, KY, 40506-0044, USA

    William W. Stoops, Justin C. Strickland, Joshua A. Lile & Craig R. Rush

  4. Center on Drug and Alcohol Research, University of Kentucky College of Medicine, 845 Angliana Ave, Lexington, KY, 40508, USA

    William W. Stoops

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  1. William W. Stoops
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  2. Justin C. Strickland
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Correspondence to William W. Stoops.

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

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The authors declare that they have no conflicts of interest.

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Stoops, W.W., Strickland, J.C., Alcorn, J.L. et al. Influence of phendimetrazine maintenance on the reinforcing, subjective, performance, and physiological effects of intranasal cocaine. Psychopharmacology 236, 2569–2577 (2019). https://doi.org/10.1007/s00213-019-05227-x

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