Skip to main content
SpringerLink
Log in

Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

The interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models.

Objectives

The aim of this study is to examine whether the behavioural effects of THC, and blood and brain THC levels are affected by pre-treatment with equivalent CBD doses.

Methods

Adolescent rats were treated with ascending daily THC doses over 21 days (1 then 3 then 10 mg/kg). Some rats were given equivalent CBD doses 20 min prior to each THC injection to allow examination of possible antagonistic effects of CBD. During dosing, rats were assessed for THC and CBD/THC effects on anxiety-like behaviour, social interaction and place conditioning. At the end of dosing, blood and brain levels of THC, and CB1 and 5-HT1A receptor binding were assessed.

Results

CBD potentiated an inhibition of body weight gain caused by chronic THC, and mildly augmented the anxiogenic effects, locomotor suppressant effects and decreased social interaction seen with THC. A trend towards place preference was observed in adolescent rats given CBD/THC but not those given THC alone. With both acute and chronic administration, CBD pre-treatment potentiated blood and brain THC levels, and lowered levels of THC metabolites (THC-COOH and 11-OH-THC). CBD co-administration did not alter the THC-induced decreases in CB1 receptor binding and no drug effects on 5-HT1A receptor binding were observed.

Conclusions

CBD can potentiate the psychoactive and physiological effects of THC in rats, most likely by delaying the metabolism and elimination of THC through an action on the CYP450 enzymes that metabolise both drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alves FH, Crestani CC, Gomes FV, Guimaraes FS, Correa FM, Resstel LB (2010) Cannabidiol injected into the bed nucleus of the stria terminalis modulates baroreflex activity through 5-HT1A receptors. Pharmacol Res 62:228–236

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, Nosarti C, O'Connel CM, Seal M, Allen P, Mehta MA, Stone JM, Tunstall N, Giampietro V, Kapur S, Murray RM, Zuardi AW, Crippa JA, Atkan Z, McGuire PK (2010) Opposite effect of delta9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology 35:764–774

    Article  PubMed  CAS  Google Scholar 

  • Bornheim LM, Correia MA (1989) Effect of cannabidiol on cytochrome P-450 isoenzymes. Biochem Pharmacol 38:2789–2794

    Article  PubMed  CAS  Google Scholar 

  • Bornheim LM, Correia MA (1990) Selective inactivation of mouse liver cytochrome P-450IIIA by cannabidiol. Mol Pharmacol 38:319–326

    PubMed  CAS  Google Scholar 

  • 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 40:228–234

    PubMed  CAS  Google Scholar 

  • Bornheim LM, Kim K, Beatrice J, Perotti Y, Benet L (1995) Effect of cannabidiol pretreatment on the kinetic of tetrahydrocannabinol metabolites in mouse brain. Drug Metab Dispos 23:825–831

    PubMed  CAS  Google Scholar 

  • Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Vogt LJ, Sim-Selley LJ (1999) Chronic delta9-tetrahydrocannabinol treatment produces a time-dependent loss of cannabinoid receptors and cannabinoid receptor-activated G proteins in rat brain. J Neurochem 73:2447–2459

    Article  PubMed  CAS  Google Scholar 

  • Campos AC, Guimaraes FS (2008) Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology (Berl) 199:223–230

    Article  CAS  Google Scholar 

  • Dalton GD, Smith FL, Smith PA, Dewey WL (2005) Chronic delta9-tetrahydrocannabinol treatment produces antinociceptive tolerance in mice without altering protein kinase A activity in mouse brain and spinal cord. Biochem Pharmacol 70:152–160

    Article  PubMed  CAS  Google Scholar 

  • Deveaux V, Cadoudal T, Ichigotani Y, Teixeira-Clerc F, Louvet A, Manin S, Nhieu JT, Belot MP, Zimmer A, Even P, Cani PD, Knauf C, Burcelin R, Bertola A, Le Marchand-Brustel Y, Gual P, Mallat A, Lotersztajn S (2009) Cannabinoid CB2 receptor potentiates obesity-associated inflammation, insulin resistance and hepatic steatosis. PLoS ONE 4:e5844

    Article  PubMed  Google Scholar 

  • Di Forti M, Morgan C, Dazzan P, Pariante C, Mondelli V, Marques TR, Handley R, Luzi S, Russo M, Paparelli A, Butt A, Stilo SA, Wiffen B, Powell J, Murray RM (2009) High-potency cannabis and the risk of psychosis. Br J Psychiatry 195:488–491

    Article  PubMed  Google Scholar 

  • Fernandes M, Warning N, Christ W, Hill R (1973) Interactions of several cannabinoids with the hepatic drug metabolizing system. Biochem Pharmacol 22:2981–2987

    Article  PubMed  CAS  Google Scholar 

  • Fernandes M, Schabarek A, Cooper H, Hill R (1974) Modification of delta9-THC actions by cannabinol and cannabidiol in the rat. Psychopharmacologia 38:329–338

    Article  PubMed  CAS  Google Scholar 

  • Genn RF, Tucci S, Marco EM, Viveros MP, File SE (2004) Unconditioned and conditioned anxiogenic effects of the cannabinoid receptor agonist CP 55,940 in the social interaction test. Pharmacol Biochem Behav 77:567–573

    Article  PubMed  CAS  Google Scholar 

  • Gomes FV, Resstel LB, Guimaraes FS (2011) The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology (Berl) 213:465–473

    Article  CAS  Google Scholar 

  • Guilani D, Ferrari F, Ottani A (2000) The cannabinoid agonist HU 210 modifies rat behavioural responses to novelty and stress. Pharmacol Res 41:47–53

    Google Scholar 

  • Guimaraes FS, Chiaretti TM, Graeff FG, Zuardi AW (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559

    Article  CAS  Google Scholar 

  • Gunasekaran N, Long L, Arnold JC, McGregor IS (2009) Reintoxication: the release of fat-stored delta-9-tetrahydrocannabinol (THC) into blood is enhanced by food deprivation or ACTH exposure. British Journal of Pharmacology 158:1330–1337

    Article  PubMed  CAS  Google Scholar 

  • Han M, Huang XF, du Bois TM, Deng C (2009) The effects of antipsychotic drugs administration on 5-HT1A receptor expression in the limbic system of the rat brain. Neuroscience 164:1754–1763

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu A-X, Fujioka M, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M (2007) Repeated treatment with cannabidiol but not delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology 52:1079–1087

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa K, Mishima K, Hazekawa M, Sano K, Irie K, Orito K, Egawa T, Kitamura Y, Uchida N, Nishimura R, Egashira N, Iwasaki K, Fujiwara M (2008) Cannabidiol potentiates pharmacological effects of delta9-tetrahydrocannabinol via a CB1 receptor-dependent mechanism. Brain Res 1188:157–164

    Article  PubMed  CAS  Google Scholar 

  • Hollister LE, Gillespie H (1975) Interactions in man of delta9-tetrahydrocannabinol, H-cannabinol and cannabidiol. Clin Pharmacol 18:329–338

    Google Scholar 

  • Ignatowska-Jankowska B, Jankowski MM, Swiergiel AH (2011) Cannabidiol decreases body weight gain in rats: involvement of CB2 receptors. Neurosci Lett 490:82–84

    Article  PubMed  CAS  Google Scholar 

  • Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–527

    Article  PubMed  CAS  Google Scholar 

  • Jones G, Pertwee RG (1972) A metabolic interaction in vivo between cannabidiol and 1-tetrahydrocannabinol. Br J Pharmacol 45:375–377

    PubMed  CAS  Google Scholar 

  • Karniol IG, Carlini EA (1973) Pharmacological interaction between cannabidiol and delta9-tetrahydrocannabinol. Psychopharmacologia 33:53–70

    Article  PubMed  CAS  Google Scholar 

  • Karniol IG, Shirakawa I, Kasinaki N, Carlini EA (1974) Cannabidiol interferes with the effects of delta9-tetrahydrocannabinol in man. Eur J Pharmacol 28:172–177

    Article  PubMed  CAS  Google Scholar 

  • Karschner EL, Darwin WD, McMahon RP, Liu F, Wright S, Goodwin RS, Huestis MA (2011a) Subjective and physiological effects after controlled Sativex and oral THC administration. Clin Pharmacol Ther 89:400–407

    Article  PubMed  CAS  Google Scholar 

  • Karschner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA (2011b) Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem 57:66–75

    Article  PubMed  CAS  Google Scholar 

  • Kmietowicz Z (2010) Cannabis based drug is licensed for spasticity in patients with MS. BMJ 340:c3363

    Article  PubMed  Google Scholar 

  • Long LE, Chesworth R, Huang XF, McGregor IS, Arnold JC, Karl T (2010) A behavioural comparison of acute and chronic delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. Int J Neuropsychopharmacol 13:861–876

    Article  PubMed  CAS  Google Scholar 

  • Mallet PE, Beninger PJ (1998) Delta9-tetrahydrocannabinol, but not the endogenous cannabinoid receptor ligand anandamide, produces conditioned place avoidance. Life Sci 62:2431–2434

    Article  PubMed  CAS  Google Scholar 

  • Malone DT, Jongejan D, Taylor DA (2009) Cannabidiol reverses the reduction in social interaction produced by low dose of delta9-tetrahydrocannabinol in rats. Pharmacol Biochem Behav 93:91–96

    Article  PubMed  CAS  Google Scholar 

  • McGregor IS, Issakidis CN, Prior G (1996) Aversive effects of the synthetic cannabinoid CP 55,940 in rats. Pharmacol Biochem Behav 53:657–664

    Article  PubMed  CAS  Google Scholar 

  • McLaren J, Swift W, Dillon P, Allsop S (2008) Cannabis potency and contamination: a review of the literature. Addiction 103:1100–1109

    Article  PubMed  Google Scholar 

  • Mechoulam R (1986) The pharmacohistory of Cannabis sativa. In: Mechoulam R (ed) Cannabinoids as therapeutic agents. CRC, Boca Raton, p 19

    Google Scholar 

  • Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M (2005) Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 36:1071–1076

    Article  CAS  Google Scholar 

  • Moreira FA, Aguiar DC, Guimaraes FS (2006) Anxiolytic-like effect of cannabidiol in the rat Vogel conflict test. Prog Neuropsychopharmacol Biol Psychiatry 30:1466–1471

    Article  PubMed  CAS  Google Scholar 

  • Morgan CJ, Curran HV (2008) Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry 192:306–307

    Article  PubMed  Google Scholar 

  • Morgan CJ, Freeman TP, Schafer GL, Curran HV (2010a) Cannabidiol attenuates the appetitive effects of delta(9)-tetrahydrocannabinol in humans smoking their chosen cannabis. Neuropsychopharmacology 35:1879–1885

    Article  PubMed  CAS  Google Scholar 

  • Morgan CJ, Schafer G, Freeman TP, Curran HV (2010b) Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study. Br J Psychiatry 197:285–290

    Article  PubMed  Google Scholar 

  • Nadulski T, Pragst F, Weinberg G, Roser P, Schnelle M, Fronk EM, Stadelmann AM (2005) Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of delta9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract. Ther Drug Monit 27:799–810

    Article  PubMed  CAS  Google Scholar 

  • Onaivi ES, Green MR, Martin BR (1990) Pharmacological effects of cannabinoids in the elevated plus-maze. J Pharmacol Exp Ther 253:1002–1009

    PubMed  CAS  Google Scholar 

  • Oviedo A, Glowa J, Herkenham M (1993) Chronic cannabinoid administration alters cannabinoid receptor binding in rat brain: a quantitative autoradiographic study. Brain Res 616:293–302

    Article  PubMed  CAS  Google Scholar 

  • Parker LA, Burton P, Sorge RE, Yakiwchuk C, Mechoulam R (2004) Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats. Psychopharmacology (Berl) 175:360–366

    Article  CAS  Google Scholar 

  • Pertwee RG (2004) The pharmacology and therapeutic potential of cannabidiol. In: Marzo VD (ed) Cannabinoids. Kluwer/Plenum, New York, p 51

    Google Scholar 

  • Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199–215

    Article  PubMed  CAS  Google Scholar 

  • Pertwee RG, Thomas A (2007) Therapeutic applications for agents that act at CB1 and CB2 receptor. In: Reggio PH (ed) The cannabinoid receptors. Humana, Totowa

    Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Quinn HR, Matsumoto I, Callaghan PD, Long LE, Arnold JC, Gunasekaran N, Thompson MR, Dawson B, Mallet PE, Kashem MA, Matsuda-Matsumoto H, Iwazaki T, McGregor IS (2008) Adolescent rats find repeated delta(9)-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure. Neuropsychopharmacology 33:1113–1126

    Article  PubMed  Google Scholar 

  • Reid MJ, Bornheim LM (2001) Cannabinoid-induced alterations in brain disposition of drugs of abuse. Biochem Pharmacol 61:1357–1367

    Article  PubMed  CAS  Google Scholar 

  • Resstel LB, Tavares RF, Lisboa SF, Joca SR, Correa FM, Guimaraes FS (2009) 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol 156:181–188

    Article  PubMed  CAS  Google Scholar 

  • Robson P (2005) Human studies of cannabinoids and medicinal cannabis. In: Pertwee RG (ed) Cannabinoids. Handbook of experimental pharmacology. Springer, Heidelberg, p 37

    Google Scholar 

  • Russo E, Guy GW (2006) A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 66:234–246

    Article  PubMed  CAS  Google Scholar 

  • Sjoden PO, Jarbe TU, Henriksson BG (1973) Influence of tetrahydrocannabinols (delta8-THC and delta9-THC) on body weight, food, and water intake in rats. Pharmacol Biochem Behav 1:395–399

    Article  PubMed  CAS  Google Scholar 

  • South T, Huang XF (2008) Temporal and site-specific brain alterations in CB1 receptor binding in high fat diet-induced obesity in C57Bl/6 mice. J Neuroendocrinol 20:1288–1294

    Article  PubMed  CAS  Google Scholar 

  • Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24:417–463

    Article  PubMed  CAS  Google Scholar 

  • Teixeira D, Pestana D, Faria A, Calhau C, Azevedo I, Monteiro R (2010) Modulation of adipocyte biology by delta(9)-tetrahydrocannabinol. Obesity (Silver Spring) 18:2077–2085

    Article  Google Scholar 

  • Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 (Berl) 186:226–234

    Article  CAS  Google Scholar 

  • Zanelati TV, Biojone C, Moreira FA, Guimaraes FS, Joca SR (2010) Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. Br J Pharmacol 159:122–128

    Article  PubMed  CAS  Google Scholar 

  • Zavitsanou K, Wang H, Dalton VS, Nguyen V (2010) Cannabinoid administration increases 5HT1A receptor binding and mRNA expression in the hippocampus of adult but not adolescent rats. Neuroscience 169:315–324

    Article  PubMed  CAS  Google Scholar 

  • Zuardi AW, Finkelfarb E, Bueno OF, Musty RE, Karniol IG (1981) Characteristics of the stimulus produced by the mixture of cannabidiol with delta9-tetrahydrocannabinol. Arch Int Pharmacodyn Thér 249:137–146

    PubMed  CAS  Google Scholar 

  • Zuardi AW, Shirakawa I, Finkelfarb E, Karniol IG (1982) Action of cannabidiol on the anxiety and other effects produced by delta9-THC in normal subjects. Psychopharmacology (Berl) 76:245–250

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported by research grants from the Australian Research Council (ISM) and National Health and Medical Research Council (TK, ISM and JCA).

Author information

Authors and Affiliations

  1. Schools of Psychology and Department of Pharmacology, University of Sydney, Brennan MacCullum Building, Sydney, NSW, 2006, Australia

    Charlotte Klein, Emily Karanges, Adena Spiro, Alexander Wong, Jarrah Spencer, Thanh Huynh, Nathan Gunasekaran, Jonathon C. Arnold & Iain S. McGregor

  2. Neuroscience Research Australia, University of New South Wales, Hospital Road, Randwick, NSW, 2031, Australia

    Tim Karl & Leonora E. Long

  3. Centre for Translational Neuroscience, University of Wollongong, Northfield Avenue, Wollongong, NSW, 2522, Australia

    Xu-Feng Huang & Kelly Liu

Authors
  1. Charlotte Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emily Karanges
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adena Spiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alexander Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jarrah Spencer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thanh Huynh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nathan Gunasekaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tim Karl
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Leonora E. Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xu-Feng Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kelly Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jonathon C. Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Iain S. McGregor
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Iain S. McGregor.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klein, C., Karanges, E., Spiro, A. et al. Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats. Psychopharmacology 218, 443–457 (2011). https://doi.org/10.1007/s00213-011-2342-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2342-0

Keywords

Search

Navigation