Pharmacokinetics of Cannabidiol, Cannabidiolic Acid, Δ9-Tetrahydrocannabinol, Tetrahydrocannabinolic Acid and Related Metabolites in Canine Serum After Dosing With Three Oral Forms of Hemp Extract

Abstract

Cannabidiol (CBD)-rich hemp extract use is increasing in veterinary medicine with little examination of serum cannabinoids. Many products contain small amounts of Δ9-tetrahydrocannabinol (THC), and precursor carboxylic acid forms of CBD and THC known as cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA). Examination of the pharmacokinetics of CBD, CBDA, THC, and THCA on three oral forms of CBD-rich hemp extract that contained near equal amounts of CBD and CBDA, and minor amounts (<0.3% by weight) of THC and THCA in dogs was performed. In addition, we assess the metabolized psychoactive component of THC, 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and CBD metabolites 7-hydroxycannabidiol (7-OH-CBD) and 7-nor-7-carboxycannabidiol (7-COOH-CBD) to better understand the pharmacokinetic differences between three formulations regarding THC and CBD, and their metabolism. Six purpose-bred female beagles were utilized for study purposes, each having an initial 7-point, 24-h pharmacokinetic study performed using a dose of 2 mg/kg body weight of CBD/CBDA (~1 mg/kg CBD and ~1 mg/kg CBDA). Dogs were then dosed every 12 h for 2 weeks and had further serum analyses at weeks 1 and 2, 6 h after the morning dose to assess serum cannabinoids. Serum was analyzed for each cannabinoid or cannabinoid metabolite using liquid chromatography and tandem mass spectroscopy (LC-MS/MS). Regardless of the form provided (1, 2, or 3) the 24-h pharmacokinetics for CBD, CBDA, and THCA were similar, with only Form 2 generating enough data above the lower limit of quantitation to assess pharmacokinetics of THC. CBDA and THCA concentrations were 2- to 3-fold higher than CBD and THC concentrations, respectively. The 1- and 2-week steady-state concentrations were not significantly different between the two oils or the soft chew forms. CBDA concentrations were statistically higher with Form 2 than the other forms, showing superior absorption/retention of CBDA. Furthermore, Form 1 showed less THCA retention than either the soft chew Form 3 or Form 2 at weeks 1 and 2. THC was below the quantitation limit of the assay for nearly all samples. Overall, these findings suggest CBDA and THCA are absorbed or eliminated differently than CBD or THC, respectively, and that a partial lecithin base provides superior absorption and/or retention of CBDA and THCA.

Pharmacokinetics and effects on arachidonic acid metabolism of low doses of cannabidiol following oral administration to horses

“…In humans, elimination is rapid with reported elimination half‐lives of 1.09 and 1.97 hr following oral administration of 10 and 20 mg, respectively 29,30 and 2.95 and 3.21 hr following oral ingestion of 10‐mg lipid capsules 31,32 . In dogs, while the elimination half‐life is longer (3.8–4.4 hr) 28 ; than that reported for humans, it is shorter than for horses. Elimination appears to be dose independent over the range of doses administered in the current study as evidenced by a similar elimination half‐life at each dose.…”

“…This is in agreement with what is reported in the current study primary metabolites found in blood and urine in horses are 7‐COOH CBD and 7‐OH CBD. Although detectable, Wakshlag and colleagues 28 reported that 7‐OH CBD concentrations were below the LOQ in blood. Similarly, in the current study, concentrations of this metabolite were low in blood at all times post drug administration with the carboxylated metabolite (7‐COOH CBD) predominating.…”

Feeding Cannabidiol (CBD)-Containing Treats Did Not Affect Canine Daily Voluntary Activity

“…The tendency for dogs in the HIGH CBD treatment to be less active than CON dogs in the p.m. may indicate that CBD exerted some sedative or calming effect on the dogs. However, this potential sedative effect was expected to be observed in the a.m., as previous pharmacokinetic reports have shown a half-life for CBD of 1–4 h ( 35 , 51 , 52 , 57 ). As this effect was not observed during the a.m. sessions, exercise periods, or overall daily activity, these collective results do not support a sedative or calming effect of CBD in dogs.…”

Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations

“…Many have been puzzled by the high bioavailability of CBDA in humans following the oral ingestion of CBD-dominant cannabis-derived nutraceutical oils 5 , 55 – 57 . Our results suggest that the oral administration of such cannabis extracts provides a natural vehicle to enhance plasma CBDA concentrations due to cannabinoid-cannabinoid interactions at the drug efflux transporter BCRP.…”