Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive–compulsive behaviour

Abstract

Rationale

Phytocannabinoids are useful therapeutics for multiple applications including treatments of constipation, malaria, rheumatism, alleviation of intraocular pressure, emesis, anxiety and some neurological and neurodegenerative disorders. Consistent with these medicinal properties, extracted cannabinoids have recently gained much interest in research, and some are currently in advanced stages of clinical testing. Other constituents of Cannabis sativa, the hemp plant, however, remain relatively unexplored in vivo. These include cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG).

Objectives and methods

We here determined pharmacokinetic profiles of the above phytocannabinoids after acute single-dose intraperitoneal and oral administration in mice and rats. The pharmacodynamic–pharmacokinetic relationship of CBD (120 mg/kg, ip and oral) was further assessed using a marble burying test in mice.

Results

All phytocannabinoids readily penetrated the blood–brain barrier and solutol, despite producing moderate behavioural anomalies, led to higher brain penetration than cremophor after oral, but not intraperitoneal exposure. In mice, cremophor-based intraperitoneal administration always attained higher plasma and brain concentrations, independent of substance given. In rats, oral administration offered higher brain concentrations for CBD (120 mg/kg) and CBDV (60 mg/kg), but not for Δ9-THCV (30 mg/kg) and CBG (120 mg/kg), for which the intraperitoneal route was more effective. CBD inhibited obsessive–compulsive behaviour in a time-dependent manner matching its pharmacokinetic profile.

Conclusions

These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.

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Acknowledgements

This work was partly supported by a collaboration between GW Pharmaceuticals and Otsuka Pharma. Furthermore, and we are indebted to Drs. T Kikuchi for comments on an earlier draft of this manuscript.

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Correspondence to Gernot Riedel.

Electronic supplementary material

Supplementary Fig. 1

HPLC spectra of compounds used in this study. Purity was above 95%. a CBD; b CBDV; c Δ9-THCV; d CBG (JPEG 47 kb)

Supplementary Fig. 2

Pharmacokinetic comparison of CBD dissolved in solutol or chremophor and injected into rat. Administration routes included intraperitoneal (a, b) and oral (c, d) routes. CBD (120 mg/kg) was administered at time point 0 and tissue harvested at six time points within 24 h post-dosing. Drug levels are shown in top row (a and c) as log 10 of plasma concentration (C P) and in b and d as log 10 of brain concentration (C B). Mean ± SEM. (JPEG 73 kb)

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Deiana, S., Watanabe, A., Yamasaki, Y. et al. Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ9-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive–compulsive behaviour. Psychopharmacology 219, 859–873 (2012). https://doi.org/10.1007/s00213-011-2415-0

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Keywords

  • Phytocannabinoids
  • Systemic administration
  • Bioavailability
  • Area under curve
  • Elimination half-life
  • Pharmacokinetic
  • Pharmacodynamic
  • Rats
  • Mice