Pharmacokinetics of oral and intravenous cannabidiol and its antidepressant-like effects in chronic mild stress mouse model

Environ Toxicol Pharmacol. 2019 Aug;70:103202. doi: 10.1016/j.etap.2019.103202. Epub 2019 May 30.

Abstract

Cannabidiol (CBD) exhibits significant efficacy in mental and inflammatory diseases. Several studies have recently reported on the rapid antidepressant-like effects of CBD, suggesting that CBD is a potential anti-depressant or anti-stress drug. However, CBD is mainly administered orally or by inhalation with poor bioavailability, resulting in high costs. We aim to explore the efficacy of long-term periodic administration of CBD in chronic mild stress (CMS) via two routes and its pharmacokinetics. We treated ICR mice with CBD administered orally and intravenously and then determined the kinetic constants. A single bolus intravenous injection of CBD resulted in a half-life of 3.9 h, mean residence time of 3.3 h, and oral bioavailability of about 8.6%. The antidepressant-like effects of periodically administered CBD on the chronic mild stress mouse model are evaluated. Results demonstrated that such treatment at a high dose of 100 mg/kg CBD (p.o.) or a low dose of 10 mg/kg CBD (i.v.), elicited significant antidepressant-like behavioral effects in forced swim test, following increased mRNA expression of brain-derived neurotrophic factor (BDNF) and synaptophysin in the prefrontal cortex and the hippocampus. Our findings are expected to provide a reference for the development of intravenous antidepressant formulations of CBD.

Keywords: CBD; CMS; Cannabidiol; Depression; Pharmacokinetics.

MeSH terms

  • Administration, Intravenous
  • Administration, Oral
  • Animals
  • Antidepressive Agents / administration & dosage*
  • Antidepressive Agents / blood
  • Antidepressive Agents / pharmacokinetics*
  • Behavior, Animal / drug effects
  • Brain-Derived Neurotrophic Factor / genetics
  • Calcium-Binding Proteins / genetics
  • Cannabidiol / administration & dosage*
  • Cannabidiol / blood
  • Cannabidiol / pharmacokinetics*
  • Disease Models, Animal
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Male
  • Mice, Inbred ICR
  • Microfilament Proteins / genetics
  • Prefrontal Cortex / drug effects
  • Prefrontal Cortex / metabolism
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / genetics
  • Synaptophysin / genetics

Substances

  • Aif1 protein, rat
  • Antidepressive Agents
  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • Calcium-Binding Proteins
  • Microfilament Proteins
  • Synaptophysin
  • Cannabidiol