Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal

Neuroscience. 2013 Sep 17:248:637-54. doi: 10.1016/j.neuroscience.2013.04.034. Epub 2013 Apr 24.


Withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. For many opiate addicts, achieving abstinence may be further complicated by poly-drug use and co-morbid mental disorders. Research over the past decade has shed light on the influence of endocannabinoids (ECs) on the opioid system. Evidence from both animal and clinical studies point toward an interaction between these two systems, and suggest that targeting the EC system may provide novel interventions for managing opiate dependence and withdrawal. This review will summarize the literature surrounding the molecular effects of cannabinoids and opioids on the locus coeruleus-norepinephrine system, a key circuit implicated in the negative sequelae of opiate addiction. A consideration of the trends and effects of marijuana use in those seeking treatment to abstain from opiates in the clinical setting will also be presented. In summary, the present review details how cannabinoid-opioid interactions may inform novel interventions in the management of opiate dependence and withdrawal.

Keywords: 2-AG; 2-arachidonoylglycerol; AC; CB1r; CREB; CRF; EC; HPA; LC; MMT; MOR; NAc; NTS; PGi; PKA; UDS; adenylyl cyclase; cAMP response element binding protein; cannabinoid type 1 receptors; clinical; corticotropin releasing factor; endocannabinoid; hypothalamic–pituitary–adrenal; locus coeruleus; marijuana; methadone maintenance treatment; mu-opioid receptor; norepinephrine; nucleus accumbens; nucleus of the solitary tract; paragigantocellularis; protein kinase-A; stress; urinary drug screen.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Cannabinoids / pharmacology*
  • Cannabinoids / therapeutic use
  • Drug Interactions
  • Endocannabinoids / physiology*
  • Humans
  • Locus Coeruleus / drug effects
  • Locus Coeruleus / physiology
  • Norepinephrine / physiology
  • Opioid-Related Disorders / physiopathology*
  • Signal Transduction / physiology
  • Substance Withdrawal Syndrome / physiopathology*
  • Synapses / physiology


  • Analgesics, Opioid
  • Cannabinoids
  • Endocannabinoids
  • Norepinephrine