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

Serena Deiana, Akihito Watanabe, Yuki Yamasaki, Naoki Amada, Marlene Arthur, Shona Fleming, Hilary Woodcock, Patricia Dorward, Barbara Pigliacampo, Steve Close, Bettina Platt, Gernot Riedel

Research output: Contribution to journalArticle

99 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)859-873
Number of pages15
JournalPsychopharmacology
Volume219
Issue number3
Early online date28 Jul 2011
DOIs
Publication statusPublished - Feb 2012

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Cannabidiol
Oral Administration
Pharmacokinetics
Brain
Cannabis
Cannabinoids
Calcium Carbonate
Constipation
Rheumatic Diseases
Nervous System Diseases
Intraocular Pressure
Neurodegenerative Diseases
Malaria
Vomiting
Anxiety
tetrahydrocannabivarin 9
cannabigerol
Therapeutics
Research
Pharmaceutical Preparations

Keywords

  • phytocannabinoids
  • systemic administration
  • bioavailability
  • area under curve
  • elimination half-life
  • pharmacokinetic
  • pharmacodynamic
  • rats
  • mice

Cite this

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. / Deiana, Serena; Watanabe, Akihito; Yamasaki, Yuki; Amada, Naoki; Arthur, Marlene; Fleming, Shona; Woodcock, Hilary; Dorward, Patricia; Pigliacampo, Barbara; Close, Steve; Platt, Bettina; Riedel, Gernot.

In: Psychopharmacology, Vol. 219, No. 3, 02.2012, p. 859-873.

Research output: Contribution to journalArticle

Deiana, Serena ; Watanabe, Akihito ; Yamasaki, Yuki ; Amada, Naoki ; Arthur, Marlene ; Fleming, Shona ; Woodcock, Hilary ; Dorward, Patricia ; Pigliacampo, Barbara ; Close, Steve ; Platt, Bettina ; Riedel, Gernot. / 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. In: Psychopharmacology. 2012 ; Vol. 219, No. 3. pp. 859-873.
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abstract = "RationalePhytocannabinoids 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 methodsWe 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.ResultsAll 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.ConclusionsThese 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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author = "Serena Deiana and Akihito Watanabe and Yuki Yamasaki and Naoki Amada and Marlene Arthur and Shona Fleming and Hilary Woodcock and Patricia Dorward and Barbara Pigliacampo and Steve Close and Bettina Platt and Gernot Riedel",
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T1 - 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

AU - Deiana, Serena

AU - Watanabe, Akihito

AU - Yamasaki, Yuki

AU - Amada, Naoki

AU - Arthur, Marlene

AU - Fleming, Shona

AU - Woodcock, Hilary

AU - Dorward, Patricia

AU - Pigliacampo, Barbara

AU - Close, Steve

AU - Platt, Bettina

AU - Riedel, Gernot

PY - 2012/2

Y1 - 2012/2

N2 - RationalePhytocannabinoids 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 methodsWe 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.ResultsAll 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.ConclusionsThese 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.

AB - RationalePhytocannabinoids 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 methodsWe 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.ResultsAll 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.ConclusionsThese 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.

KW - phytocannabinoids

KW - systemic administration

KW - bioavailability

KW - area under curve

KW - elimination half-life

KW - pharmacokinetic

KW - pharmacodynamic

KW - rats

KW - mice

U2 - 10.1007/s00213-011-2415-0

DO - 10.1007/s00213-011-2415-0

M3 - Article

VL - 219

SP - 859

EP - 873

JO - Psychopharmacology

JF - Psychopharmacology

SN - 0033-3158

IS - 3

ER -