Oral efficacy of Δ(9)-tetrahydrocannabinol and cannabidiol in a mouse neuropathic pain model

Neuropharmacology. 2021 May 15:189:108529. doi: 10.1016/j.neuropharm.2021.108529. Epub 2021 Mar 16.


The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have synergistic analgesic efficacy in animal models of neuropathic pain when injected systemically. However, the relevance of this preclinical synergy to clinical neuropathic pain studies is unclear because many of the latter use oral administration. We therefore examined the oral effectiveness of these phytocannabinoids and their interactions in a mouse chronic constriction injury (CCI) model of neuropathic pain. THC produced a dose-dependent reduction in mechanical and cold allodynia, but also induced side-effects with similar potency. CBD also reduced allodynia, albeit with lower potency than THC, but did not produce cannabinoid-like side-effects at any dose tested. Combination THC:CBD produced a dose-dependent reduction in allodynia, however, it displayed little to no synergy. Combination THC:CBD produced substantial, synergistic side-effects which increased with the proportion of CBD. These findings demonstrate that oral THC and CBD, alone and in combination, have analgesic efficacy in an animal neuropathic pain model. Unlike prior systemic injection studies, combination THC:CBD lacks analgesic synergy when delivered orally. Furthermore, both THC and combination THC:CBD display a relatively poor therapeutic window when delivered orally. This suggests that CBD provides a safer, albeit lower efficacy, oral treatment for nerve injury induced neuropathic pain than THC-containing preparations. This article is part of the special issue on 'Cannabinoids'.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Analgesics, Non-Narcotic / administration & dosage*
  • Animals
  • Cannabidiol / administration & dosage*
  • Dose-Response Relationship, Drug
  • Dronabinol / administration & dosage*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuralgia / drug therapy*
  • Neuralgia / physiopathology*
  • Neuralgia / psychology
  • Psychotropic Drugs / administration & dosage*
  • Sciatic Neuropathy / drug therapy
  • Sciatic Neuropathy / physiopathology
  • Sciatic Neuropathy / psychology
  • Treatment Outcome


  • Analgesics, Non-Narcotic
  • Psychotropic Drugs
  • Cannabidiol
  • Dronabinol