Evaluation of repeated or acute treatment with cannabidiol (CBD), cannabidiolic acid (CBDA) or CBDA methyl ester (HU-580
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ORIGINAL INVESTIGATION
Evaluation of repeated or acute treatment with cannabidiol (CBD), cannabidiolic acid (CBDA) or CBDA methyl ester (HU-580) on nausea and/or vomiting in rats and shrews Erin M. Rock 1 & Megan T. Sullivan 1 & Stephen A. Collins 1 & Hannah Goodman 1 & Cheryl L. Limebeer 1 & Raphael Mechoulam 2 & Linda A. Parker 1 Received: 5 March 2020 / Accepted: 18 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale When acutely administered intraperitoneally, the non-psychoactive cannabinoid cannabidiol (CBD), its acidic precursor cannabidiolic acid (CBDA) and a stable methyl ester of CBDA (HU-580) reduce lithium chloride (LiCl)–induced conditioned gaping in male rats (a selective preclinical model of acute nausea) via activation of the serotonin 1A (5-HT1A) receptor. Objectives To utilise these compounds to manage nausea in the clinic, we must determine if their effectiveness is maintained when injected subcutaneously (s.c) and when repeatedly administered. First, we compared the effectiveness of each of these compounds to reduce conditioned gaping following repeated (7-day) and acute (1-day) pretreatments and whether these antinausea effects were mediated by the 5-HT1A receptor. Next, we assessed whether the effectiveness of these compounds can be maintained when administered prior to each of 4 conditioning trials (once per week). We also evaluated the ability of repeated CBD (7 days) to reduce LiCl-induced vomiting in Suncus murinus. Finally, we examined whether acute CBD was equally effective in male and female rats. Results Both acute and repeated (7 day) s.c. administrations of CBD (5 mg/kg), CBDA (1 μg/kg) and HU-580 (1 μg/kg) similarly reduced LiCl-induced conditioned gaping, and these effects were blocked by 5HT1A receptor antagonism. When administered over 4 weekly conditioning trials, the anti-nausea effectiveness of each of these compounds was also maintained. Repeated CBD (5 mg/kg, s.c.) maintained its anti-emetic efficacy in S. murinus. Acute CBD (5 and 20 mg/kg, s.c.) administration reduced LiCl-induced conditioned gaping similarly in male and female rats. Conclusion When administered repeatedly (7 days), CBD, CBDA and HU-580 did not lose efficacy in reducing nausea and continued to act via agonism of the 5-HT1A receptor. When administered across 4 weekly conditioning trials, they maintained their effectiveness in reducing LiCl-induced nausea. Repeated CBD also reduced vomiting in shrews. Finally, CBD’s anti-nausea effects were similar in male and female rats. This suggests that these cannabinoids may be useful anti-nausea and anti-emetic treatments for chronic conditions, without the development of tolerance. Keywords Cannabidiol . Cannabidiolic acid . HU-580 . Conditioned gaping . 5-HT1A . Repeated
Abbreviations Serotonin 1A 5-HT1A ANOVA Analysis of variance CBD Cannabidiol
* Linda A. Parker [email protected] 1
Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON N1G2W1, Canada
2
Institute of Drug Resear
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