, Volume 232, Issue 24, pp 4445–4454 | Cite as

Effect of combined doses of Δ9-tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) on acute and anticipatory nausea using rat (Sprague- Dawley) models of conditioned gaping

  • Erin M. RockEmail author
  • Cheryl L. Limebeer
  • Linda A. Parker
Original Investigation



Δ9-Tetrahydrocannabinol (THC) and cannabidiolic acid (CBDA) found in cannabis both reduce the distressing symptom of nausea, but their combined effects are not understood.


The potential of combined doses of THC and CBDA to reduce acute nausea and anticipatory nausea in rodent models was assessed.

Materials and methods

For acute nausea, the potential of cannabinoid pretreatment(s) to reduce LiCl-induced nausea paired with saccharin was evaluated in a subsequent drug free taste reactivity test, followed by a taste avoidance test. For anticipatory nausea, the potential of the cannabinoid pretreatment(s) to reduce the expression of LiCl-induced contextually elicited conditioned gaping was evaluated.


Combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) reduced acute nausea. Higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses also reduced acute nausea. THC (10 mg/kg) interfered with conditioned taste avoidance, an effect attenuated by CBDA (10 μg/kg). On the other hand, combined subthreshold doses of THC (0.01 and 0.1 mg/kg) and CBDA (0.01 and 0.1 μg/kg) did not suppress contextually elicited conditioned gaping in a test for anticipatory nausea. However, higher doses of THC (1.0, 10 mg/kg) or CBDA (1.0, 10 μg/kg) alone, as well as these combined doses, also reduced anticipatory nausea. Only at the highest dose (10 mg/kg) did THC impair locomotor activity, but CBDA did not at any dose.


Combined subthreshold doses of THC:CBDA are particularly effective as a treatment for acute nausea. At higher doses, CBDA may attenuate THC-induced interference with learning.


CBDA THC Acute nausea Anticipatory nausea Locomotor activity Conditioned taste avoidance 



This work was supported by a Natural Sciences and Engineering Research Council of Canada (NSERC) Engage Grant (EGP #470199-14) to LAP in partnership with Prairie Plant Systems Inc, as well as grants to LAP from NSERC (92056) and Canadian Institute of Health Research (137122).


  1. Aapro MS, Molassiotis A, Olver I (2005) Anticipatory nausea and vomiting. Support Care Cancer 13:117–121. doi: 10.1007/s00520-004-0745-8 CrossRefPubMedGoogle Scholar
  2. Bolognini D, Rock EM, Cluny NL, Cascio MG, Limebeer CL, Duncan M, Stott CG, Javid FA, Parker LA, Pertwee RG (2013) Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Br J Pharmacol 168:1456–1470. doi: 10.1111/bph.12043 PubMedCentralCrossRefPubMedGoogle Scholar
  3. Bornheim LM, Correia MA (1990) Selective inactivation of mouse liver cytochrome P-450IIIA by cannabidiol. Mol Pharmacol 38(3):319–326PubMedGoogle Scholar
  4. Bornheim LM, Correia MA (1991) Purification and characterization of the major hepatic cannabinoid hydroxylase in the mouse: a possible member of the cytochrome P-450IIC subfamily. Mol Pharmacol 40(2):228–234PubMedGoogle Scholar
  5. Breslin PA, Spector AC, Grill HJ (1992) A quantitative comparison of taste reactivity behaviors to sucrose before and after lithium chloride pairings: a unidimensional account of palatability. Behav Neurosci 106:820–836CrossRefPubMedGoogle Scholar
  6. Elwood C, Devauchelle P, Elliott J, Freiche V, German AJ, Gualtieri M et al (2010) Emesis in dogs: a review. J Small Anim Pract 51:4–22. doi: 10.1111/j.1748-5827.2009.00820.x, Review CrossRefPubMedGoogle Scholar
  7. Englund A, Morrison PD, Nottage J, Hague D, Kane F, Bonaccorso S, Stone JM, Reichenberg A, Brenneisen R, Holt D, Feilding A, Walker L, Murray RM, Kapur S (2013) Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol 27:19–27. doi: 10.1177/0269881112460109 CrossRefPubMedGoogle Scholar
  8. Foubert J, Vaessen G (2005) Nausea: the neglected symptom? Eur J Oncol Nurs 9:21–32. doi: 10.1016/j.ejon.2004.03.006 CrossRefPubMedGoogle Scholar
  9. Grill HJ, Norgren R (1978) The taste reactivity test. I. Mimetic responses to gustatory stimuli in neurologically normal rats. Brain Res 143:263–279CrossRefPubMedGoogle Scholar
  10. Hesketh PJ, Van Belle S, Aapro M, Tattersall FD, Naylor RJ, Hargreaves R, Carides AD, Evans JK, Horgan KJ (2003) Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur J Cancer 39:1074–1080CrossRefPubMedGoogle Scholar
  11. Hindocha C, Freeman TP, Schafer G, Gardener C, Das RK, Morgan CJ, Curran HV (2015) Acute effects of delta-9-tetrahydrocannabinol, cannabidiol and their combination on facial emotion recognition: a randomised, double-blind, placebo-controlled study in cannabis users. Eur Neuropsychopharmacol 25:325–334. doi: 10.1016/j.euroneuro.2014.11.014 PubMedCentralCrossRefPubMedGoogle Scholar
  12. Jordan K, Kasper C, Schmoll HJ (2005) Chemotherapy-induced nausea and vomiting: current and new standards in the antiemetic prophylaxis and treatment. Eur J Cancer 41:199–205. doi: 10.1016/j.ejca.2004.09.026 CrossRefPubMedGoogle Scholar
  13. Katsidoni V, Kastellakis A, Panagis G (2013) Biphasic effects of Delta9-tetrahydrocannabinol on brain stimulation reward and motor activity. Int J Neuropsychopharmacol 16:2273–2284. doi: 10.1017/S1461145713000709 CrossRefPubMedGoogle Scholar
  14. Klein C, Karanges E, Spiro A, Wong A, Spencer J, Huynh T, Gunasekaran N, Karl T, Long LE, Huang XF, Liu K, Arnold JC, McGregor IS (2011) Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology (Berlin) 218(2):443–457CrossRefGoogle Scholar
  15. Limebeer CL, Parker LA (2000) The antiemetic drug ondansetron interferes with lithium-induced conditioned rejection reactions, but not lithium-induced taste avoidance in rats. J Exp Psychol Anim Behav Process 26:371–384CrossRefPubMedGoogle Scholar
  16. Limebeer CL, Parker LA (2003) The 5-HT1A agonist 8-OH-DPAT dose-dependently interferes with the establishment and the expression of lithium-induced conditioned rejection reactions in rats. Psychopharmacology (Berlin) 166:120–126. doi: 10.1007/s00213-002-1309-6 Google Scholar
  17. Limebeer CL, Hall G, Parker LA (2006) Exposure to a lithium-paired context elicits gaping in rats: a model of anticipatory nausea. Physiol Behav 88:398–403. doi: 10.1016/j.physbeh.2006.04.014 CrossRefPubMedGoogle Scholar
  18. Limebeer CL, Krohn JP, Cross-Mellor S, Litt DE, Ossenkopp KP, Parker LA (2008) Exposure to a context previously associated with nausea elicits conditioned gaping in rats: a model of anticipatory nausea. Behav Brain Res 187:33–40. doi: 10.1016/j.bbr.2007.08.024 CrossRefPubMedGoogle Scholar
  19. Limebeer CL, Vemuri VK, Bedard H, Lang ST, Ossenkopp KP, Makriyannis A, Parker LA (2010) Inverse agonism of cannabinoid CB1 receptors potentiates LiCl-induced nausea in the conditioned gaping model in rats. Br J Pharmacol 161:336–349. doi: 10.1111/j.1476-5381.2010.00885.x PubMedCentralCrossRefPubMedGoogle Scholar
  20. Malik IA, Khan WA, Qazilbash M, Ata E, Butt A, Khan MA (1995) Clinical efficacy of lorazepam in prophylaxis of anticipatory, acute, and delayed nausea and vomiting induced by high doses of cisplatin. A prospective randomized trial. Am J Clin Oncol 18:170–175CrossRefPubMedGoogle Scholar
  21. Malone DT, Jongejan D, Taylor DA (2009) Cannabidiol reverses the reduction in social interaction produced by low dose Delta(9)-tetrahydrocannabinol in rats. Pharmacol Biochem Behav 93:91–96. doi: 10.1016/j.pbb.2009.04.010 CrossRefPubMedGoogle Scholar
  22. Morrow GR, Roscoe JA, Hynes HE, Flynn PJ, Pierce HI, Burish T (1998a) Progress in reducing anticipatory nausea and vomiting: a study of community practice. Support Care Cancer 6:46–50CrossRefPubMedGoogle Scholar
  23. Morrow GR, Roscoe JA, Kirshner JJ, Hynes HE, Rosenbluth RJ (1998b) Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer 6:244–247CrossRefPubMedGoogle Scholar
  24. Nesse RM, Carli T, Curtis GC, Kleinman PD (1980) Pretreatment nausea in cancer chemotherapy: a conditioned response? Psychosom Med 42:33–36CrossRefPubMedGoogle Scholar
  25. Parker LA (1995) Rewarding drugs produce taste avoidance, but not taste aversion. Neurosci Biobehav Rev 19:143–157CrossRefPubMedGoogle Scholar
  26. Parker LA (2014) Conditioned flavor avoidance and conditioned gaping: rat models of conditioned nausea. Eur J Pharmacol 722:122–133. doi: 10.1016/j.ejphar.2013.09.070 CrossRefPubMedGoogle Scholar
  27. Parker LA, Mechoulam R (2003) Cannabinoid agonists and antagonists modulate lithium-induced conditioned gaping in rats. Integr Physiol Behav Sci 38:133–145CrossRefPubMedGoogle Scholar
  28. Parker LA, Mechoulam R, Schlievert C, Abbott L, Fudge ML, Burton P (2003) Effects of cannabinoids on lithium-induced conditioned rejection reactions in a rat model of nausea. Psychopharmacology (Berlin) 166:156–162. doi: 10.1007/s00213-002-1329-2 Google Scholar
  29. Parker LA, Kwiatkowska M, Burton P, Mechoulam R (2004) Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew). Psychopharmacology (Berlin) 171:156–161. doi: 10.1007/s00213-003-1571-2 CrossRefGoogle Scholar
  30. Pavlov IP (1927) Conditioned reflexes: an investigation of the physiological activity of the cerebral cortex. Oxford University Press, OxfordGoogle Scholar
  31. Poli-Bigelli S, Rodrigues-Pereira J, Carides AD, Julie Ma G, Eldridge K, Hipple A, Evans JK, Horgan KJ, Lawson F, Aprepitant Protocol 054 Study Group (2003) Addition of the neurokinin 1 receptor antagonist aprepitant to standard antiemetic therapy improves control of chemotherapy-induced nausea and vomiting. Results from a randomized, double-blind, placebo-controlled trial in Latin America. Cancer 97:3090–3098. doi: 10.1002/cncr.11433 CrossRefPubMedGoogle Scholar
  32. Potter DJ, Clark P, Brown MB (2008) Potency of delta 9-THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci 53:90–94. doi: 10.1111/j.1556-4029.2007.00603.x CrossRefPubMedGoogle Scholar
  33. Razavi D, Delvaux N, Farvacques C, De Brier F, Van Heer C, Kaufman L, Derde MP, Beauduin M, Piccart M (1993) Prevention of adjustment disorders and anticipatory nausea secondary to adjuvant chemotherapy: a double-blind, placebo-controlled study assessing the usefulness of alprazolam. J Clin Oncol 11:1384–1390PubMedGoogle Scholar
  34. Reid MJ, Bornheim LM (2001) Cannabinoid-induced alterations in brain disposition of drugs of abuse. Biochem Pharmacol 61(11):1357–1367CrossRefPubMedGoogle Scholar
  35. Rock EM, Parker LA (2013a) Effect of low doses of cannabidiolic acid and ondansetron on LiCl-induced conditioned gaping (a model of nausea-induced behaviour) in rats. Br J Pharmacol 169:685–692. doi: 10.1111/bph.12162 PubMedCentralCrossRefPubMedGoogle Scholar
  36. Rock EM, Parker LA (2013b) Suppression of lithium chloride-induced conditioned gaping (a model of nausea-induced behaviour) in rats (using the taste reactivity test) with metoclopramide is enhanced by cannabidiolic acid. Pharmacol Biochem Behav 111:84–89. doi: 10.1016/j.pbb.2013.08.012 CrossRefPubMedGoogle Scholar
  37. Rock EM, Parker LA (2015) Synergy between cannabidiol, cannabidiolic acid, and Delta(9)-tetrahydrocannabinol in the regulation of emesis in the Suncus murinus (house musk shrew). Behav Neurosci 129:368–370. doi: 10.1037/bne0000057 CrossRefPubMedGoogle Scholar
  38. Rock EM, Limebeer CL, Mechoulam R, Piomelli D, Parker LA (2008) The effect of cannabidiol and URB597 on conditioned gaping (a model of nausea) elicited by a lithium-paired context in the rat. Psychopharmacology (Berlin) 196:389–395. doi: 10.1007/s00213-007-0970-1 CrossRefGoogle Scholar
  39. Rock EM, Bolognini D, Limebeer CL, Cascio MG, Anavi-Goffer S, Fletcher PJ, Mechoulam R, Pertwee RG, Parker LA (2012) Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. Br J Pharmacol 165:2620–2634. doi: 10.1111/j.1476-5381.2011.01621.x PubMedCentralCrossRefPubMedGoogle Scholar
  40. Rock EM, Kopstick RL, Limebeer CL, Parker LA (2013) Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus. Br J Pharmacol 170:641–648. doi: 10.1111/bph.12316 PubMedCentralCrossRefPubMedGoogle Scholar
  41. Rock EM, Limebeer CL, Navaratnam R, Sticht MA, Bonner N, Engeland K, Downey R, Morris H, Jackson M, Parker LA (2014a) A comparison of cannabidiolic acid with other treatments for anticipatory nausea using a rat model of contextually elicited conditioned gaping. Psychopharmacology (Berlin) 231:3207–3215. doi: 10.1007/s00213-014-3498-1 CrossRefGoogle Scholar
  42. Rock EM, Limebeer CL, Parker LA (2014b) Anticipatory nausea in animal models: a review of potential novel therapeutic treatments. Exp Brain Res 232:2511–2534. doi: 10.1007/s00221-014-3942-9 CrossRefPubMedGoogle Scholar
  43. Russo E, Guy GW (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 66:234–246. doi: 10.1016/j.mehy.2005.08.026 CrossRefPubMedGoogle Scholar
  44. Sharkey KA, Darmani NA, Parker LA (2014) Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol 722:134–146. doi: 10.1016/j.ejphar.2013.09.068 CrossRefPubMedGoogle Scholar
  45. Sotelo C, Cholley B, El Mestikawy S, Gozlan H, Hamon M (1990) Direct immunohistochemical evidence of the existence of 5-HT1A autoreceptors on serotoninergic neurons in the midbrain raphe nuclei. Eur J Neurosci 2:1144–1154CrossRefPubMedGoogle Scholar
  46. Taffe MA, Creehan KM, Vandewater SA (2015) Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Delta(9) -tetrahydrocannabinol in Sprague–Dawley rats. Br J Pharmacol 172:1783–1791. doi: 10.1111/bph.13024 CrossRefPubMedGoogle Scholar
  47. Thamm DH, Vail DM (2007) Aftershocks of cancer chemotherapy: managing adverse effects. J Am Anim Hosp Assoc 43:1–7. doi: 10.5326/43.6.toc CrossRefPubMedGoogle Scholar
  48. Tomiyasu H, Takahashi M, Fujino Y, Ohno K, Tsujimoto H (2010) Gastrointestinal and hematologic adverse events after administration of vincristine, cyclophosphamide, and doxorubicin in dogs with lymphoma that underwent a combination multidrug chemotherapy protocol. J Vet Med Sci 72:1391–1397CrossRefPubMedGoogle Scholar
  49. Travers JB, Norgren R (1986) Electromyographic analysis of the ingestion and rejection of sapid stimuli in the rat. Behav Neurosci 100:544–555CrossRefPubMedGoogle Scholar
  50. Vann RE, Gamage TF, Warner JA, Marshall EM, Taylor NL, Martin BR, Wiley JL (2008) Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9)-tetrahydrocannabinol. Drug Alcohol Depend 94:191–198. doi: 10.1016/j.drugalcdep.2007.11.017 PubMedCentralCrossRefPubMedGoogle Scholar
  51. Varvel SA, Wiley JL, Yang R, Bridgen DT, Long K, Lichtman AH, Martin BR (2006) Interactions between THC and cannabidiol in mouse models of cannabinoid activity. Psychopharmacology (Berlin) 186:226–234. doi: 10.1007/s00213-006-0356-9 CrossRefGoogle Scholar
  52. Verge D, Daval G, Patey A, Gozlan H, el Mestikawy S, Hamon M (1985) Presynaptic 5-HT autoreceptors on serotonergic cell bodies and/or dendrites but not terminals are of the 5-HT1A subtype. Eur J Pharmacol 113:463–464CrossRefPubMedGoogle Scholar
  53. Wright MJ Jr, Vandewater SA, Taffe MA (2013) Cannabidiol attenuates deficits of visuospatial associative memory induced by Delta(9) tetrahydrocannabinol. Br J Pharmacol 170:1365–1373. doi: 10.1111/bph.12199 PubMedCentralCrossRefPubMedGoogle Scholar
  54. Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982) Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects. Psychopharmacology (Berlin) 76:245–250CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Erin M. Rock
    • 1
    Email author
  • Cheryl L. Limebeer
    • 1
  • Linda A. Parker
    • 1
  1. 1.Department of Psychology and Collaborative Neuroscience ProgramUniversity of GuelphGuelphCanada

Personalised recommendations