Dataset Information

THC and CBD blood and brain concentrations following daily administration to adolescent primates.

ABSTRACT:

Background

Cannabis availability with high concentrations of ?-9-tetrahydrocannabinol (THC) and a range of THC to cannabidiol (CBD) ratios has increased in parallel with a rise in daily cannabis consumption by adolescents. Unanswered questions in adolescents include: 1) whether THC blood concentrations and THC metabolites remain stable or change with prolonged daily dosing, 2) whether CBD modulates THC pharmacokinetic properties and alters THC accumulation in brain, 3) whether blood THC levels reflect brain concentrations.

Methods

In adolescent squirrel monkeys (Saimiri boliviensis), we determined whether a four-month regimen of daily THC (1 mg/kg) or CBD (3 mg/kg) + THC (1 mg/kg) administration (IM) affects THC, THC metabolites, and CBD concentrations in blood or brain.

Results

Blood THC concentrations, THC metabolites and CBD remained stable during chronic treatment. 24 h after the final THC or CBD + THC injection, blood THC and CBD concentrations remained relatively high (THC: 6.0-11 ng/mL; CBD: 9.7-19 ng/mL). THC concentrations in cerebellum and occipital cortex were approximately twice those in blood 24 h after the last dose and did not significantly differ in subjects given THC or CBD + THC.

Conclusions

In adolescent monkeys, blood levels of THC, its metabolites or CBD remain stable after daily dosing for four months. Our model suggests that any pharmacological interactions between CBD and THC are unlikely to result from CBD modulation of THC pharmacokinetics. Finally, detection of relatively high brain THC concentrations 24 h after the final dose of THC suggests that the prolonged actions of THC may contribute to persistent cognitive and psychomotor disruption after THC- or cannabis-induced euphoria wane.

SUBMITTER: Withey SL

PROVIDER: S-EPMC7371526 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

THC and CBD blood and brain concentrations following daily administration to adolescent primates.

Withey S L SL Bergman J J Huestis M A MA George S R SR Madras B K BK

Drug and alcohol dependence 20200618

<h4>Background</h4>Cannabis availability with high concentrations of Δ-9-tetrahydrocannabinol (THC) and a range of THC to cannabidiol (CBD) ratios has increased in parallel with a rise in daily cannabis consumption by adolescents. Unanswered questions in adolescents include: 1) whether THC blood concentrations and THC metabolites remain stable or change with prolonged daily dosing, 2) whether CBD modulates THC pharmacokinetic properties and alters THC accumulation in brain, 3) whether blood THC ...[more]

PMID: 32593153

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Project description:Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces desensitization and downregulation of cannabinoid type 1 receptors (CB₁Rs) in the brain, but the magnitude of these adaptations varies among regions. CB₁Rs in the striatum and its output regions exhibit the least magnitude and slowest development of desensitization and downregulation. The molecular mechanisms that confer these region-dependent differences are not known. The stable transcription factor, ΔFosB, is induced in the striatum following repeated THC administration and could regulate CB₁Rs. To directly compare the regional profile of ΔFosB induction and CB₁R desensitization and downregulation, mice were treated with THC (10 mg/kg) or vehicle for 13.5 days. CP55,940-stimulated [(35)S]GTPγS autoradiography and immunohistochemistry were performed to measure CB₁R desensitization and downregulation, respectively, and ΔFosB expression was measured by immunoblot. Significant CB₁R desensitization and downregulation occurred in the prefrontal cortex, lateral amygdala and hippocampus; desensitization was found in the basomedial amygdala and no changes were seen in remaining regions. ΔFosB was induced in the prefrontal cortex, caudate-putamen, nucleus accumbens and lateral amygdala. An inverse regional relationship between ΔFosB expression and CB₁R desensitization was found, such that regions with the greatest ΔFosB induction did not exhibit CB₁R desensitization and areas without ΔFosB induction had the greatest desensitization, with remaining regions exhibiting intermediate levels of both. Dual immunohistochemistry in the striatum showed both CB₁R co-localization with ΔFosB in cells and CB₁R puncta surrounding ΔFosB-positive cells. THC-induced expression of ΔFosB was absent in the striatum of CB₁R knockout mice. These data suggest that transcriptional targets of ΔFosB might inhibit CB₁R desensitization and/or that ΔFosB induction could be limited by CB₁R desensitization.

Project description:BACKGROUND: Significant interest has emerged in the therapeutic and interactive effects of different cannabinoids. Cannabidiol (CBD) has been shown to have anxiolytic and antipsychotic effects with high doses administered orally. We report a series of studies conducted to determine the vaporisation efficiency of high doses of CBD, alone and in combination with ?9-tetrahydrocannabinol (THC), to achieve faster onset effects in experimental and clinical trials and emulate smoked cannabis. METHODS: Purified THC and CBD (40 mg/ml and 100 mg/ml respectively) were loaded onto a liquid absorbing pad in a Volcano vaporiser, vaporised and the vapours quantitatively analysed. Preliminary studies determined 200 mg CBD to be the highest dose effectively vaporised at 230 ° C, yielding an availability of approximately 40% in the vapour phase. Six confirmatory studies examined the quantity of each compound delivered when 200 mg or 4 mg CBD was loaded together with 8 mg of THC. RESULTS: THC showed 55% availability when vaporised alone or with low dose CBD, while large variation in the availability of high dose CBD impacted upon the availability of THC when co-administered, with each compound affecting the vaporisation efficiency of the other in a dynamic and dose-dependent manner. We describe optimised protocols that enable delivery of 160 mg CBD through vaporisation. CONCLUSIONS: While THC administration by vaporisation is increasingly adopted in experimental studies, often with oral predosing with CBD to examine interactive effects, no studies to date have reported the administration of CBD by vaporisation. We report the detailed methodology aimed at optimising the efficiency of delivery of therapeutic doses of CBD, alone and in combination with THC, by vaporisation. These protocols provide a technical advance that may inform methodology for clinical trials in humans, especially for examining interactions between THC and CBD and for therapeutic applications of CBD. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24109245.

Dataset Information

THC and CBD blood and brain concentrations following daily administration to adolescent primates.

Background

Methods

Results

Conclusions

Publications

THC and CBD blood and brain concentrations following daily administration to adolescent primates.

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