The PPARγ Agonist Pioglitazone Fails to Alter the Abuse Potential of Heroin, But Does Reduce Heroin Craving and Anxiety

ABSTRACT

Possibly through its effects on glia, the peroxisome proliferator-activated gamma receptor (PPARγ) agonist pioglitazone (PIO) has been shown to alter the effects of heroin in preclinical models. Until now, these results have not been assessed in humans. Heroin-dependent participants were randomized to either active (45 mg, n = 14) or placebo (0 mg, n = 16) PIO maintenance for the duration of the three-week study. After stabilization on buprenorphine (8 mg), participants began a two-week testing period. On the first to fourth test days, participants could self-administer drug or money by making verbal choices for either option. On the fifth day, active heroin and money were administered and participants could work to receive heroin or money using a progressive ratio choice procedure. Test days 6–10 were identical to test days 1–5 with the exception that, during one of the test weeks, placebo was available on the first four days, and during the other week heroin was available. PIO failed to alter the reinforcing or positive subjective effects of heroin, but it did reduce heroin craving and overall anxiety. Although we were unable to replicate the robust effects found in preclinical models, these data provide an indication of drug effects that deserves further exploration.

KEYWORDS:

• Abuse potential
• glia
• heroin
• opioids
• pioglitazone

Acknowledgments

The medical assistance of Janet Murray and Claudia Tindall, along with the technical assistance of Rachel Luba, Jonathan Vogelman, Andrew Segoshi, and Brian Wade, is gratefully acknowledged.

Disclosure statement

Drs. Comer, Mogali, and Manubay have received compensation (in the form of partial salary support) from studies supported by Alkermes, Braeburn Pharmaceuticals, Cerecor Inc., Endo Pharmaceuticals, Indivior PLC/Reckitt-Benckiser Pharmaceuticals, Johnson & Johnson Pharmaceutical Research & Development, MediciNova, Omeros, and Schering-Plough Corporation. In addition, Dr. Comer has served as a consultant to the following companies: Analgesic Solutions, AstraZeneca, BioDelivery Sciences International, Cephalon, Clinilabs, Daiichi Sankyo, Egalet, Endo, Inflexxion, Innovative Science Solutions, Janssen, KemPharm, King, Lightlake (now Opiant), Neuromed, Pfizer, and Salix. Dr. Bisaga served as an unpaid consultant to Alkermes and received an honorarium from Indivior for an unbranded educational activity.

Additional information

Funding

Financial support for this study was provided by the National Institute on Drug Abuse grant R01DA031022 to SDC and AB. Additional support for the manuscript preparation was provided by grant K01DA030446 to JDJ. Study medication (pioglitazone) was provided by the OMEROS Corporation. The authors would like to thank the National Institute on Drug Abuse and the OMEROS Corporation for supporting this research. Only the authors are responsible for the content and preparation of this manuscript. The funding source played no role in the collection, analysis, and interpretation of data, in the writing of the article, or in the decision to submit it for publication.