Daniel I Brierley1,2, James Samuels1, Marnie Duncan3, Benjamin J Whalley2, Claire M Williams4. 1. School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK. 2. School of Chemistry, Food and Nutritional Sciences, and Pharmacy, University of Reading, Reading, UK. 3. GW Pharmaceuticals Ltd, Cambridge, UK. 4. School of Psychology and Clinical Language Sciences, University of Reading, Reading, UK. claire.williams@reading.ac.uk.
Abstract
RATIONALE: Anticipatory nausea (AN) is a poorly controlled side effect experienced by chemotherapy patients. Currently, pharmacotherapy is restricted to benzodiazepine anxiolytics, which have limited efficacy, have significant sedative effects and induce dependency. The non-psychoactive phytocannabinoid, cannabidiolic acid (CBDA), has shown considerable efficacy in pre-clinical AN models, however determination of its neuromotor tolerability profile is crucial to justify clinical investigation. Provisional evidence for appetite-stimulating properties also requires detailed investigation. OBJECTIVES: This study aims to assess the tolerability of CBDA in locomotor activity, motor coordination and muscular strength tests, and additionally for ability to modulate feeding behaviours. METHODS: Male Lister Hooded rats administered CBDA (0.05-5 mg/kg; p.o.) were assessed in habituated open field (for locomotor activity), static beam and grip strength tests. A further study investigated whether these CBDA doses modulated normal feeding behaviour. Finally, evidence of anxiolytic-like effects in the habituated open field prompted testing of 5 mg/kg CBDA for anxiolytic-like activity in unhabituated open field, light/dark box and novelty-suppressed feeding (NSF) tests. RESULTS: CBDA had no adverse effects upon performance in any neuromotor tolerability test, however anxiolytic-like behaviour was observed in the habituated open field. Normal feeding behaviours were unaffected by any dose. CBDA (5 mg/kg) abolished the increased feeding latency in the NSF test induced by the 5-HT1AR antagonist, WAY-100,635, indicative of anxiolytic-like effects, but had no effect on anxiety-like behaviour in the novel open field or light/dark box. CONCLUSIONS: CBDA is very well tolerated and devoid of the sedative side effect profile of benzodiazepines, justifying its clinical investigation as a novel AN treatment.
RATIONALE: Anticipatory nausea (AN) is a poorly controlled side effect experienced by chemotherapy patients. Currently, pharmacotherapy is restricted to benzodiazepine anxiolytics, which have limited efficacy, have significant sedative effects and induce dependency. The non-psychoactive phytocannabinoid, cannabidiolic acid (CBDA), has shown considerable efficacy in pre-clinical AN models, however determination of its neuromotor tolerability profile is crucial to justify clinical investigation. Provisional evidence for appetite-stimulating properties also requires detailed investigation. OBJECTIVES: This study aims to assess the tolerability of CBDA in locomotor activity, motor coordination and muscular strength tests, and additionally for ability to modulate feeding behaviours. METHODS: Male Lister Hooded rats administered CBDA (0.05-5 mg/kg; p.o.) were assessed in habituated open field (for locomotor activity), static beam and grip strength tests. A further study investigated whether these CBDA doses modulated normal feeding behaviour. Finally, evidence of anxiolytic-like effects in the habituated open field prompted testing of 5 mg/kg CBDA for anxiolytic-like activity in unhabituated open field, light/dark box and novelty-suppressed feeding (NSF) tests. RESULTS:CBDA had no adverse effects upon performance in any neuromotor tolerability test, however anxiolytic-like behaviour was observed in the habituated open field. Normal feeding behaviours were unaffected by any dose. CBDA (5 mg/kg) abolished the increased feeding latency in the NSF test induced by the 5-HT1AR antagonist, WAY-100,635, indicative of anxiolytic-like effects, but had no effect on anxiety-like behaviour in the novel open field or light/dark box. CONCLUSIONS:CBDA is very well tolerated and devoid of the sedative side effect profile of benzodiazepines, justifying its clinical investigation as a novel AN treatment.
Authors: Mark G Kris; Paul J Hesketh; Mark R Somerfield; Petra Feyer; Rebecca Clark-Snow; James M Koeller; Gary R Morrow; Lawrence W Chinnery; Maurice J Chesney; Richard J Gralla; Steven M Grunberg Journal: J Clin Oncol Date: 2006-05-22 Impact factor: 44.544
Authors: Jane T Hickok; Joseph A Roscoe; Gary R Morrow; David K King; James N Atkins; Tom R Fitch Journal: Cancer Date: 2003-06-01 Impact factor: 6.860
Authors: D Bolognini; E M Rock; N L Cluny; M G Cascio; C L Limebeer; M Duncan; C G Stott; F A Javid; L A Parker; R G Pertwee Journal: Br J Pharmacol Date: 2013-03 Impact factor: 8.739
Authors: R M Navari; R R Reinhardt; R J Gralla; M G Kris; P J Hesketh; A Khojasteh; H Kindler; T H Grote; K Pendergrass; S M Grunberg; A D Carides; B J Gertz Journal: N Engl J Med Date: 1999-01-21 Impact factor: 91.245
Authors: Erin M Rock; Cheryl L Limebeer; Gavin N Petrie; Lauren A Williams; Raphael Mechoulam; Linda A Parker Journal: Psychopharmacology (Berl) Date: 2017-04-20 Impact factor: 4.530
Authors: Daniel I Brierley; Joe R Harman; Natasha Giallourou; Emma Leishman; Anna Emily Roashan; Ben A D Mellows; Heather B Bradshaw; Jonathan R Swann; Ketan Patel; Benjamin J Whalley; Claire M Williams Journal: J Cachexia Sarcopenia Muscle Date: 2019-04-29 Impact factor: 12.910
Authors: Daniel I Brierley; James Samuels; Marnie Duncan; Benjamin J Whalley; Claire M Williams Journal: Psychopharmacology (Berl) Date: 2016-08-09 Impact factor: 4.530