Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC

Hložek, Tomáš; Uttl, Libor; Kadeřábek, L.; Balı́ková, Marie; Lhotková, Eva; Horsley, Rachel Rutter; Nováková, Pavlína; Šíchová, Klára; Štefková, Kristýna; Tylš, Filip; Kuchař, Martin; Páleníček, Tomáš

doi:10.1016/j.euroneuro.2017.10.037

Cited by 185 publications

(180 citation statements)

References 68 publications

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“…Third, females had higher blood levels of the major active metabolite, 11-OH-THC, relative to males (Tseng et al 2004; Wiley and Burston 2014). Fourth, inhibition of THC metabolism by CBD observed in the present study has been reported previously in rats (Britch et al 2017; Klein et al 2011; Hložek et al 2017), mice (Varvel et al 2006), and humans (Nadulski et al 2005). The present results therefore suggest that these four findings are reliable.…”

Section: Discussionsupporting

confidence: 88%

“…One possible mechanism underlying this drug interaction is inhibition of THC metabolism by CBD: consistently higher blood levels of THC during the chronic THC treatment period would result in greater CB 1 receptor down-regulation and/or desensitization, two known mechanisms of cannabinoid tolerance in rats (Sim-Selley 2003; Burston et al 2010) and in humans (Villares 2007). Although CBD significantly increased blood levels of THC only in female rats, this sex difference was likely due to the single time point assessed after completion of THC dose-effect curve determination, since CBD has been shown previously to increase blood and brain levels of THC in male rats, at 0.5–1 h post-injection (Klein et al 2011; Hložek et al 2017). In the present study, repeated CBD treatment also increased blood levels of CBN, an active metabolite, in chronic THC-treated rats of both sexes.…”

Section: Discussionmentioning

confidence: 96%

“…CBD is a potent inhibitor of hepatic drug metabolism via inhibition of multiple cytochrome P450 (CYP) isozymes (Bornheim and Grillo 1998; Jiang et al 2013; Narimatsu et al 1990; Watanabe et al 2007; Yamaori et al 2010; 2011). Both animal (Britch et al 2017; Bornheim et al 1995; Klein et al 2011; Hložek et al 2017) and human (Nadulski et al 2005) studies have demonstrated that CBD inhibits hydroxylation of THC to its primary psychoactive metabolite, 11-hydroxy-tetrahydrocannabinol (11-OH-THC). However, this pharmacokinetic mechanism alone cannot explain enhancement of some THC effects but suppression of other THC effects by CBD.…”

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confidence: 99%

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Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol

Greene

Wiley

et al. 2018

Psychopharmacology

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Rationale Humans typically self-administer cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) together repeatedly (as in cannabis, cannabis extract, or Sativex®) to relieve pain. It has been suggested that one benefit of the drug combination may be decreased tolerance development. Objective The present study compared the development of tolerance to the antinociceptive effects of THC given alone versus combined with CBD, in rats. Methods THC dose-effect curves on tail withdrawal and paw pressure tests were obtained before and after twice-daily treatment with vehicle or CBD (10 mg/kg), plus vehicle or THC (3.6 mg/kg females; 9.3 mg/kg males) for 4 days. Results On the first day, THC was more potent in females than males on both nociceptive tests. From pre- to post-chronic (Day 1 to Day 6), THC potency on the tail withdrawal test decreased more in females than males, and rats that had been treated with CBD+THC repeatedly showed greater rightward/downward shifts of the THC dose-effect curve than rats that had been treated with THC alone. Analysis of blood samples taken after Day 6 testing showed that serum THC levels were higher in CBD+THC-treated females than in vehicle+THC-treated females, and THC’s active metabolite 11-OH-THC and its inactive metabolite THC-COOH were lower in CBD+THC-treated rats than in vehicle+THC-treated rats of both sexes. CBD also increased serum levels of the active metabolite cannabinol in both sexes. Conclusion The decrease in THC’s antinociceptive effects after repeated CBD exposure may be due to CBD-induced inhibition of THC metabolism, and/or antagonism of THC effects that emerges with repeated CBD treatment.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

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Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol

Greene

Wiley

et al. 2018

Psychopharmacology

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“…In this study, AUC 0– ∞ and C max following oral administration of CBD oil were similar to the results of previously published studies [26, 27, 30, 36]. The present results demonstrated that the novel CBD-NE formulation improved the bioavailability of CBD (AUC 0– ∞ /dose) by approximately 65%, although this change was not significant.…”

Section: Discussionsupporting

confidence: 81%

Development of a Novel Nanoemulsion Formulation to Improve Intestinal Absorption of Cannabidiol

Nakano

Tajima

Sugiyama

et al. 2019

Med Cannabis Cannabinoids

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Background: Cannabidiol (CBD) is highly lipophilic, and its oral bioavailability is known to be very low in humans. In this study, we developed a novel nanoemulsion preparation of CBD (CBD-NE) to improve the poor solubility and absorption of CBD. The pharmacokinetic profiles of CBD in rats were evaluated after oral administrations of CBD oil and CBD-NE, and the effect of bile secretion on CBD absorption was also evaluated. Methods: The CBD-NE formulation developed in this study consisted of vitamin E acetate, ethanol, Tween-20, and distilled water (1.7/3.8/70/24.5, w/w%). A CBD oil formulation (CBD oil, control) 100 mg/kg or CBD-NE 50 mg/kg was orally administered to rats, and the blood samples were collected over time. Moreover, the CBD oil or CBD-NE was orally administered to bile-fistulated rats, and the pharmacokinetic profiles of CBD were also evaluated. CBD concentrations in plasma were measured using LC-MS/MS. Results: The particle size of CBD-NE was 35.3 ± 11.8 nm. Mean T_max of CBD-NE was shortened significantly by the factor of 3 (from 8.00 to 2.40 h, p < 0.001) and AUC_0–_∞/dose increased by 65% (from 0.272 ± 0.045 to 0.448 ± 0.087 h L/kg) compared with CBD oil. AUC_0–_∞/dose and C_max/dose after oral administration of CBD oil were significantly reduced by the factor of 27 and 23 (p < 0.05 and p < 0.01), respectively, in bile-fistulated rats compared with the untreated rats. In contrast, all pharmacokinetic parameters after oral administration of CBD-NE were not significantly different between the untreated and bile-fistulated rats. Therefore, these results demonstrated that conventional CBD oil formulation but not CBD-NE requires bile-mediated micelle formation. Conclusions: The novel NE formulation developed in this study successfully improved the absorption of CBD regardless of bile secretion. The newly developed oral CBD-NE preparation could be useful to achieve a more stable and quicker onset of action by CBD.

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“…Thus, studying the effects of THC in the presence of other phytocannabinoids is important for modeling cannabis use. Current animal models typically use the intravenous route for drug delivery; even though, the most common route of recreational cannabis use is inhalation [13], and the pharmacokinetics of cannabinoids vary considerably depending on administration route [14][15][16]. For example, intravenous THC administration produces adverse effects in humans, likely related to high dosing and faster infusion rates [17].…”

Section: Introductionmentioning

confidence: 99%

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

Freels

Baxter-Potter

Lugo

et al. 2019

Preprint

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Recent trends in cannabis legalization have increased the necessity to better understand the effects of cannabis use. Animal models involving traditional cannabinoid self-administration approaches have been notoriously difficult to establish and differences in the drug employed and its route of administration have limited the translational value of preclinical studies. To address this challenge in the field, we have developed a novel method of cannabis self-administration using response-contingent delivery of vaporized ∆9-tetrahydrocannabinol-rich (CANTHC) or cannabidiol-rich (CANCBD) complete cannabis extracts. Male Sprague Dawley rats were trained to nosepoke for discrete puffs of CANTHC, CANCBD, or vehicle (VEH) in daily one-hour sessions. Cannabis vapor reinforcement resulted in strong discrimination between active and inactive operanda. CANTHC maintained higher response rates under fixed ratio schedules and higher break points under progressive ratio schedules compared to CANCBD or VEH, and the number of vapor deliveries positively correlated with plasma THC concentrations. Moreover, metabolic phenotyping studies revealed alterations in locomotor activity, energy expenditure, and daily food intake that are consistent with effects in human cannabis users. Furthermore, both cannabis regimens produced ecologically relevant brain concentrations of THC and CBD and CANTHC administration decreased hippocampal CB1 receptor binding. Removal of CANTHC reinforcement (but not CANCBD) resulted in a robust extinction burst and an increase in cue-induced cannabis-seeking behavior relative to VEH. These data indicate that volitional exposure to THC-rich cannabis vapor has bona fide reinforcing properties and collectively support the utility of the vapor self-administration model for the preclinical assessment of volitional cannabis intake and cannabis-seeking behaviors. Cannabis vapor self-administration

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Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC

Cited by 185 publications

References 68 publications

Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol

Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol

Development of a Novel Nanoemulsion Formulation to Improve Intestinal Absorption of Cannabidiol

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

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Pharmacokinetic and behavioural profile of THC, CBD, and THC+CBD combination after pulmonary, oral, and subcutaneous administration in rats and confirmation of conversion in vivo of CBD to THC

Cited by 185 publications

References 68 publications

Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol

Cannabidiol modulation of antinociceptive tolerance to Δ9-tetrahydrocannabinol

Development of a Novel Nano­emulsion Formulation to Improve Intestinal Absorption of Cannabidiol

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

Contact Info

Product

Resources

About

Development of a Novel Nanoemulsion Formulation to Improve Intestinal Absorption of Cannabidiol