Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT 1A receptor-mediated suppression of nausea and anxiety in rats

Br J Pharmacol. 2018 Jan;175(1):100-112. doi: 10.1111/bph.14073. Epub 2017 Dec 5.


Background and purpose: The aim of this study was to compare the abilities of cannabidiolic acid methyl ester (HU-580) and cannabidiolic acid (CBDA) to enhance 5-HT1A receptor activation in vitro and produce 5-HT1A -mediated reductions in nausea and anxiety in vivo.

Experimental approach: We investigated the effects of HU-580 and CBDA on (i) activation by 8-hydroxy-2-(di-n-propylamino)tetralin of human 5-HT1A receptors in CHO cell membranes, using [35 S]-GTPγS binding assays, (ii) gaping by rats in acute and anticipatory nausea models, and (iii) stress-induced anxiety-like behaviour, as indicated by exit time from the light compartment of a light-dark box of rats subjected 24 h earlier to six tone-paired foot shocks.

Key results: HU-580 and CBDA increased the Emax of 8-hydroxy-2-(di-n-propylamino) tetralin in vitro at 0.01-10 and 0.1-10 nM, respectively, and reduced signs of (i) acute nausea at 0.1 and 1 μg·kg-1 i.p. and at 1 μg·kg-1 i.p., respectively, and (ii) anticipatory nausea at 0.01 and 0.1 μg·kg-1 , and at 0.1 μg·kg-1 i.p. respectively. At 0.01 μg·kg-1 , HU-580, but not CBDA, increased the time foot-shocked rats spent in the light compartment of a light-dark box. The anti-nausea and anti-anxiety effects of 0.01 or 0.1 μg·kg-1 HU-580 were opposed by the 5-HT1A antagonist, WAY100635 (0.1 mg·kg-1 i.p.).

Conclusions and implications: HU-580 is more potent than CBDA at enhancing 5-HT1A receptor activation, and inhibiting signs of acute and anticipatory nausea, and anxiety. Consequently, HU-580 is a potential medicine for treating some nausea and anxiety disorders and possibly other disorders ameliorated by enhancement of 5-HT1A receptor activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Anxiety Agents / chemistry
  • Anti-Anxiety Agents / therapeutic use
  • Antiemetics / chemistry
  • Antiemetics / therapeutic use
  • Anxiety / drug therapy*
  • Anxiety / physiopathology
  • CHO Cells
  • Cannabinoids / chemistry
  • Cannabinoids / therapeutic use*
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Humans
  • Male
  • Nausea / drug therapy*
  • Nausea / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / physiology*
  • Serotonin 5-HT1 Receptor Agonists / chemistry
  • Serotonin 5-HT1 Receptor Agonists / therapeutic use*


  • Anti-Anxiety Agents
  • Antiemetics
  • Cannabinoids
  • HTR1A protein, human
  • Serotonin 5-HT1 Receptor Agonists
  • Receptor, Serotonin, 5-HT1A
  • cannabidiolic acid