Cannabidiol prevents amphetamine relapse and modulates D1- and D2-receptor levels in mesocorticolimbic brain areas of rats

Eur Neuropsychopharmacol. 2021 Sep;50:23-33. doi: 10.1016/j.euroneuro.2021.04.008. Epub 2021 May 2.


Amphetamine (AMPH) is an addictive psychostimulant highly used worldwide and its consumption is related to neurotoxic effects. Currently, there is no pharmacotherapy approved for treating AMPH or other psychostimulant drug addiction. Different studies have shown promising properties of cannabidiol (CBD) for treating many neurological and psychiatric diseases, and recently, CBD is being considered a potential strategy for the treatment of drug addiction disorders. Thus, we investigated possible CBD beneficial effects on relapse symptoms following AMPH re-exposure considering drug relapse is the most difficult clinical factor to control during addiction treatment. Rats received d,l-AMPH (4 mg/kg, i.p.) or vehicle in the conditioned place preference (CPP) paradigm (8 days), when each experimental group was re-assigned to receive CBD at two different doses (5 or 10 mg/kg, i.p) or control, for 5 days. Subsequently, animals were re-exposed to AMPH-CPP (4 mg/kg, i.p.) for 3 additional days to assess relapse behavior. Besides locomotor and anxiety-like behaviors, dopaminergic molecular parameters were quantified in both prefrontal cortex and ventral striatum. Regarding molecular levels, CBD modulated at basal levels the dopaminergic targets (D1R, D2R, DAT, and TH) in the assessed brain areas, preventing AMPH relapse and decreasing anxiety-like behavior per se and in AMPH-CPP animals. The current findings give evidence about CBD-induced AMPH-relapse prevention, which may be linked to dopaminergic mesocorticolimbic system modulation. Although future and clinical studies are needed, our outcomes show that CBD may be a useful alternative to prevent AMPH relapse.

Keywords: Addiction; Anxiety; Cannabinoid; Dopaminergic system; Psychostimulant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology
  • Amphetamine-Related Disorders* / therapy
  • Animals
  • Brain / metabolism
  • Cannabidiol* / pharmacology
  • Central Nervous System Stimulants* / pharmacology
  • Dopamine
  • Rats
  • Rats, Wistar
  • Receptors, Dopamine D2 / metabolism
  • Recurrence


  • Central Nervous System Stimulants
  • Receptors, Dopamine D2
  • Cannabidiol
  • Amphetamine
  • Dopamine