, Volume 236, Issue 11, pp 3341–3352 | Cite as

Cannabinoid modulation of opioid analgesia and subjective drug effects in healthy humans

  • Shanna BabalonisEmail author
  • Michelle R. Lofwall
  • Paul A. Sloan
  • Paul A. Nuzzo
  • Laura C. Fanucchi
  • Sharon L. Walsh
Original Investigation



Dozens of preclinical studies have reported cannabinoid agonist potentiation of the analgesic effects of μ-opioid agonists.


The aim of this study was to determine if a cannabinoid agonist could potentiate opioid analgesia in humans using several laboratory pain models.


Healthy participants (n = 10) with/out current drug use/pain conditions completed this within-subject, double-blind, placebo-controlled, randomized outpatient study. Nine 8-h sessions were completed during which dronabinol (0, 2.5, 5 mg, p.o.) was administered 1 h before oxycodone (0, 5, 10 mg, p.o.) for a total of 9 test conditions. Outcomes included sensory threshold and tolerance from four experimental pain models (cold pressor, pressure algometer, hot thermode, cold hyperalgesia), along with participant- and observer-rated, performance and physiological effects.


Oxycodone produced miosis (p < 0.05) and analgesic responses (e.g., pressure algometer [p < 0.05]), while dronabinol did not (p > 0.05). Depending on the dose combination, dronabinol attenuated or did not alter oxycodone analgesia; for example, dronabinol (2.5 mg) decreased the analgesic effects of oxycodone (10 mg) on pressure tolerance. Conversely, dronabinol increased oxycodone subjective effects (e.g., drug liking) (p < 0.05); oxycodone (5 mg) ratings of “high” were potentiated by 5 mg dronabinol (p < 0.05; placebo = 1.1 [± 0.7]; 5 mg oxycodone = 4.7 [± 2.2]; 5 mg dronabinol = 9.9 [± 8.4]; 5 mg oxycodone + 5 mg dronabinol = 37.4 [± 11.3]).


This study indicates that dronabinol did not enhance the analgesic effects of oxycodone and increased abuse- and impairment-related subjective effects. These data suggest that dronabinol may not be an effective or appropriate opioid adjuvant; it could potentially increase opioid dose requirements, while increasing psychoactive opioid effects.


Cannabinoid Dronabinol Human Opioid Opioid sparing Pain 



Grants from the National Center for Research Resources and National Center for Advancing of Translational Sciences (KL2TR000116-04 [SB]; UL1TR001998 [UK CTSA]) and the University of Kentucky Center for Clinical and Translation Science provided support for this research. We thank Anne Estrup Olesen (Aalborg University Hospital, Denmark) for feedback on the experimental pain protocols; the staff at the University of Kentucky (UK) Center on Drug and Alcohol Research for research support: Amanda Kopca, Matthew Taylor, and Victoria Vessels; the UK Investigational Pharmacy for preparing study medication; and Dr. Samy-Claude Elayi for patient support.

Author Contributions

Shanna Babalonis, Michelle Lofwall, Paul Sloan, and Sharon Walsh were responsible for the study concept and design. Shanna Babalonis directly supervised the conduct of the study, interviewed and consented the participants, directed the statistical analyses, and wrote the manuscript. Michelle Lofwall and Laura Fanucchi conducted medical interviews and physical examinations and reviewed laboratory results. Michelle Lofwall, Paul Sloan, and Laura Fanucchi provided medical coverage and edited the manuscript. Paul Nuzzo trained the staff, provided technical support services, supervised daily operations, and conducted data analyses. Sharon Walsh, Michelle Lofwall, Paul Sloan, Laura Fanucchi, and Paul Nuzzo provided critical revisions of the manuscript for important intellectual content.


This study was funded by grants from the National Center for Research Resources and National Center for Advancing of Translational Sciences (KL2TR000116-04 [SB]; UL1TR001998 [UK CTSA]).

Compliance with ethical standards

The study was approved by the University of Kentucky Institutional Review Board and was conducted in accordance with the Helsinki guidelines for ethical research. A Certificate of Confidentiality was obtained from the U.S. Food and Drug Administration (FDA).

Conflict of interest

The authors declare that they have no conflict of interest.


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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.Center on Drug and Alcohol ResearchUniversity of Kentucky College of MedicineLexingtonUSA
  3. 3.Department of PsychiatryUniversity of Kentucky College of MedicineLexingtonUSA
  4. 4.Department of AnesthesiologyUniversity of Kentucky College of MedicineLexingtonUSA
  5. 5.Department of Internal MedicineUniversity of Kentucky College of MedicineLexingtonUSA

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