Cannabis constituent synergy in a mouse neuropathic pain model

Pain. 2017 Dec;158(12):2452-2460. doi: 10.1097/j.pain.0000000000001051.


Cannabis and its psychoactive constituent Δ9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain, however, this is hampered by their side effects. It has been suggested that co-administration with another major constituent cannabidiol (CBD) might enhance the analgesic actions of THC and minimise its deleterious side effects. We examined the basis for this phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model of neuropathic pain. Acute systemic administration of THC dose-dependently reduced CCI-induced mechanical and cold allodynia, but also produced motor incoordination, catalepsy, and sedation. Cannabidiol produced a lesser dose-dependent reduction in allodynia, but did not produce the cannabinoid side effects. When co-administered in a fixed ratio, THC and CBD produced a biphasic dose-dependent reduction in allodynia. At low doses, the THC:CBD combination displayed a 200-fold increase in anti-allodynic potency, but had lower efficacy compared with that predicted for an additive drug interaction. By contrast, high THC:CBD doses had lower potency, but greater anti-allodynic efficacy compared with that predicted for an additive interaction. Only the high dose THC:CBD anti-allodynia was associated with cannabinoid side effects and these were similar to those of THC alone. Unlike THC, the low dose THC:CBD anti-allodynia was not cannabinoid receptor mediated. These findings demonstrate that CBD synergistically enhances the pain-relieving actions of THC in an animal neuropathic pain model, but has little impact on the THC-induced side effects. This suggests that low dose THC:CBD combination treatment has potential in the treatment of neuropathic pain.

MeSH terms

  • Analgesics / therapeutic use
  • Animals
  • Cannabidiol / therapeutic use*
  • Cannabis
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Dronabinol / therapeutic use*
  • Hyperalgesia / drug therapy*
  • Male
  • Mice, Inbred C57BL
  • Neuralgia / drug therapy*


  • Analgesics
  • Cannabidiol
  • Dronabinol