Cannabidiol potentiates Δ9-tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinetics during acute and chronic treatment in adolescent rats
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The interactions between Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) during chronic treatment, and at equivalent doses, are not well characterised in animal models.
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.
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.
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.
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.
KeywordsTHC Cannabidiol Cannabis Adolescent Anxiety Reward Pharmacokinetics
Supported by research grants from the Australian Research Council (ISM) and National Health and Medical Research Council (TK, ISM and JCA).
- 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 35:764–774PubMedCrossRefGoogle 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:e5844PubMedCrossRefGoogle Scholar
- Guilani D, Ferrari F, Ottani A (2000) The cannabinoid agonist HU 210 modifies rat behavioural responses to novelty and stress. Pharmacol Res 41:47–53Google 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 52:1079–1087PubMedCrossRefGoogle 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 1188:157–164PubMedCrossRefGoogle Scholar
- Hollister LE, Gillespie H (1975) Interactions in man of delta9-tetrahydrocannabinol, H-cannabinol and cannabidiol. Clin Pharmacol 18:329–338Google Scholar
- Mechoulam R (1986) The pharmacohistory of Cannabis sativa. In: Mechoulam R (ed) Cannabinoids as therapeutic agents. CRC, Boca Raton, p 19Google 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 27:799–810PubMedCrossRefGoogle Scholar
- Pertwee RG (2004) The pharmacology and therapeutic potential of cannabidiol. In: Marzo VD (ed) Cannabinoids. Kluwer/Plenum, New York, p 51Google 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, TotowaGoogle 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 33:1113–1126PubMedCrossRefGoogle Scholar
- Robson P (2005) Human studies of cannabinoids and medicinal cannabis. In: Pertwee RG (ed) Cannabinoids. Handbook of experimental pharmacology. Springer, Heidelberg, p 37Google Scholar