Cannabis use, abuse, and withdrawal: Cannabinergic mechanisms, clinical, and preclinical findings

J Neurochem. 2021 Jun;157(5):1674-1696. doi: 10.1111/jnc.15369. Epub 2021 May 16.


Cannabis sativa is the most widely used illicit drug in the world. Its main psychoactive component is delta-9-tetrahydrocannabinol (THC), one of over 100 phytocannabinoid compounds produced by the cannabis plant. THC is the primary compound that drives cannabis abuse potential and is also used and prescribed medically for therapeutic qualities. Despite its therapeutic potential, a significant subpopulation of frequent cannabis or THC users will develop a drug use syndrome termed cannabis use disorder. Individuals suffering from cannabis use disorder exhibit many of the hallmarks of classical addictions including cravings, tolerance, and withdrawal symptoms. Currently, there are no efficacious treatments for cannabis use disorder or withdrawal symptoms. This makes both clinical and preclinical research on the neurobiological mechanisms of these syndromes ever more pertinent. Indeed, basic research using animal models has provided valuable evidence of the neural molecular and cellular actions of cannabis that mediate its behavioral effects. One of the main components being central action on the cannabinoid type-one receptor and downstream intracellular signaling related to the endogenous cannabinoid system. Back-translational studies have provided insight linking preclinical basic and behavioral biology research to better understand symptoms observed at the clinical level. This narrative review aims to summarize major research elucidating the molecular, cellular, and behavioral manifestations of cannabis/THC use that play a role in cannabis use disorder and withdrawal.

Keywords: CB1; CUD; THC; cannabinoids; endocannabinoids; marijuana; tolerance.

Publication types

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

MeSH terms

  • Animals
  • Dronabinol / pharmacology
  • Drug Tolerance
  • Endocannabinoids*
  • Humans
  • Marijuana Abuse / physiopathology*
  • Marijuana Abuse / psychology
  • Marijuana Smoking / physiopathology*
  • Marijuana Smoking / psychology
  • Receptors, Cannabinoid*
  • Substance Withdrawal Syndrome / physiopathology*
  • Substance Withdrawal Syndrome / psychology


  • Endocannabinoids
  • Receptors, Cannabinoid
  • Dronabinol