Interactions between cannabidiol and Δ 9-THC following acute and repeated dosing: Rebound hyperactivity, sensorimotor gating and epigenetic and neuroadaptive changes in the mesolimbic pathway

Eur Neuropsychopharmacol. 2017 Feb;27(2):132-145. doi: 10.1016/j.euroneuro.2016.12.004. Epub 2016 Dec 31.


The evidence base for the use of medical cannabis preparations containing specific ratios of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) is limited. While there is abundant data on acute interactions between CBD and THC, few studies have assessed the impact of their repeated co-administration. We previously reported that CBD inhibited or potentiated the acute effects of THC dependent on the measure being examined at a 1:1 CBD:THC dose ratio. Further, CBD decreased THC effects on brain regions involved in memory, anxiety and body temperature regulation. Here we extend on these finding by examining over 15 days of treatment whether CBD modulated the repeated effects of THC on behaviour and neuroadaption markers in the mesolimbic dopamine pathway. After acute locomotor suppression, repeated THC caused rebound locomotor hyperactivity that was modestly inhibited by CBD. CBD also slightly reduced the acute effects of THC on sensorimotor gating. These subtle effects were found at a 1:1 CBD:THC dose ratio but were not accentuated by a 5:1 dose ratio. CBD did not alter the trajectory of enduring THC-induced anxiety nor tolerance to the pharmacological effects of THC. There was no evidence of CBD potentiating the behavioural effects of THC. However we demonstrated for the first time that repeated co-administration of CBD and THC increased histone 3 acetylation (H3K9/14ac) in the VTA and ΔFosB expression in the nucleus accumbens. These changes suggest that while CBD may have protective effects acutely, its long-term molecular actions on the brain are more complex and may be supradditive.

Keywords: Behaviour; Cannabidiol; Epigenetic; Mesolimbic pathway; Neuroadaption; THC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Anxiety / chemically induced
  • Anxiety / drug therapy
  • Body Temperature / drug effects
  • Cannabidiol / pharmacology*
  • Cannabinoid Receptor Agonists / pharmacology*
  • Dopamine / metabolism
  • Dose-Response Relationship, Drug
  • Dronabinol / pharmacology*
  • Drug Interactions
  • Epigenesis, Genetic / drug effects
  • Histones / metabolism
  • Male
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism
  • Sensory Gating / drug effects
  • Time Factors
  • Ventral Tegmental Area / cytology
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / metabolism


  • Cannabinoid Receptor Agonists
  • Fosb protein, mouse
  • Histones
  • Proto-Oncogene Proteins c-fos
  • Cannabidiol
  • Dronabinol
  • Dopamine