Cannabidiol Interferes with Establishment of Δ9-Tetrahydrocannabinol-Induced Nausea Through a 5-HT1A Mechanism

Cannabis Cannabinoid Res. 2022 Feb;7(1):58-64. doi: 10.1089/can.2020.0083. Epub 2020 Dec 21.


Introduction: Cannabinoid hyperemesis syndrome (CHS) is characterized by intense nausea and vomiting brought on by the use of high-dose Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis. Cannabidiol (CBD), a nonpsychotropic compound found in cannabis, has been shown to interfere with some acute aversive effects of THC. In this study, we evaluated if CBD would interfere with THC-induced nausea through a 5-HT1A receptor mechanism as it has been shown to interfere with nausea produced by lithium chloride (LiCl). Since CHS has been attributed to a dysregulated stress response, we also evaluated if CBD would interfere with THC-induced increase in corticosterone (CORT). Materials and Methods: The potential of CBD (5 mg/kg, ip) to suppress THC-induced conditioned gaping (a measure of nausea) was evaluated in rats, as well as the potential of the 5-HT1A receptor antagonist, WAY-100635 (WAY; 0.1 mg/kg, ip), to reverse the suppression of THC-induced conditioned gaping by CBD. Last, the effect of CBD (5 mg/kg, ip) on THC-induced increase in serum CORT concentration was evaluated. Results: Pretreatment with CBD (5 mg/kg, ip) interfered with the establishment of THC-induced conditioned gaping (p=0.007, relative to vehicle [VEH] pretreatment), and this was reversed by pretreatment with 0.1 mg/kg WAY. This dose of WAY had no effect on gaping on its own. THC (10 mg/kg, ip) significantly increased serum CORT compared with VEH-treated rats (p=0.04). CBD (5 mg/kg, ip) pretreatment reversed the THC-induced increase in CORT. Conclusions: CBD attenuated THC-induced nausea as well as THC-induced elevation in CORT. The attenuation of THC-induced conditioned gaping by CBD was mediated by its action on 5-HT1A receptors, similar to that of LiCl-induced nausea.

Keywords: 5-HT1A receptor; cannabidiol; cannabinoid hyperemesis; corticosterone; nausea; Δ9-tetrahydrocannabinol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiemetics* / pharmacology
  • Cannabidiol* / pharmacology
  • Cannabinoid Receptor Agonists / adverse effects
  • Cannabinoids* / adverse effects
  • Cannabis*
  • Dronabinol / pharmacology
  • Lithium Chloride / adverse effects
  • Nausea / chemically induced
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / therapeutic use
  • Serotonin / adverse effects
  • Vomiting / chemically induced


  • Antiemetics
  • Cannabinoid Receptor Agonists
  • Cannabinoids
  • Receptor, Serotonin, 5-HT1A
  • Cannabidiol
  • Serotonin
  • Dronabinol
  • Lithium Chloride

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