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Δ9-Tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development.

ABSTRACT: Many developmental disorders are thought to arise from an interaction between genetic and environmental risk factors. The Hedgehog (HH) signaling pathway regulates myriad developmental processes, and pathway inhibition is associated with birth defects, including holoprosencephaly (HPE). Cannabinoids are HH pathway inhibitors, but little is known of their effects on HH-dependent processes in mammalian embryos, and their mechanism of action is unclear. We report that the psychoactive cannabinoid Δ9-tetrahydrocannabinol (THC) induces two hallmark HH loss-of-function phenotypes (HPE and ventral neural tube patterning defects) in Cdon mutant mice, which have a subthreshold deficit in HH signaling. THC therefore acts as a 'conditional teratogen', dependent on a complementary but insufficient genetic insult. In vitro findings indicate that THC is a direct inhibitor of the essential HH signal transducer smoothened. The canonical THC receptor, cannabinoid receptor-type 1, is not required for THC to inhibit HH signaling. Cannabis consumption during pregnancy may contribute to a combination of risk factors underlying specific developmental disorders. These findings therefore have significant public health relevance.

SUBMITTER: Lo HF

PROVIDER: S-EPMC8513605 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Δ9-Tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development.

Lo Hsiao-Fan HF Hong Mingi M Szutorisz Henrietta H Hurd Yasmin L YL Krauss Robert S RS

Development (Cambridge, England) 20211005 19

Many developmental disorders are thought to arise from an interaction between genetic and environmental risk factors. The Hedgehog (HH) signaling pathway regulates myriad developmental processes, and pathway inhibition is associated with birth defects, including holoprosencephaly (HPE). Cannabinoids are HH pathway inhibitors, but little is known of their effects on HH-dependent processes in mammalian embryos, and their mechanism of action is unclear. We report that the psychoactive cannabinoid Δ ...[more]

PMID: 34610637

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Project description:Delta-9-tetrahydrocannabinol (Δ9-THC) is a naturally occurring psychoactive compound derived from the hemp plant Cannabis sativa. In 2015, EFSA established an acute reference dose (ARfD) of 1 μg/kg body weight (bw) for Δ9-THC and assessed acute dietary exposure from milk and dairy products. This resulted at the most 3% and 13% of the ARfD for adults and toddlers, respectively. Following the European Commission Recommendation 2016/2115 on the monitoring of the presence of Δ9-THC in food and the issuing of a new mandate, EFSA assessed the acute human exposure to Δ9-THC. 'Standard' food categories were used as proxies for consumption of hemp and hemp-based products. Twelve independent scenarios based on single food categories were considered and acute exposure was assessed for consumption days only for all age groups excluding infants. Occurrence data for Total-Δ9-THC (588 samples in total) were used for this assessment up to the highest reliable percentile for each food category. The EFSA ARfD of 1 μg/kg bw was exceeded in the adult high consumers of most considered hemp and hemp-containing products, under the lower-bound (LB) and upper-bound (UB) scenario. At the UB, acute exposure in adult high consumers was estimated based on the highest reliable percentile of occurrence, for Hemp seeds (P95, up to 9 μg/kg bw), Hemp oil (P95, up to 21 μg/kg bw), Tea (Infusion) (P95, up to 208 μg/kg bw), Breakfast cereals (P50, up to 1.3 μg/kg bw), Pasta (Raw) (P75, up to 6.4 μg/kg bw), Bread and rolls (P75, up to 1.3 μg/kg bw), Bread and rolls from hemp flour (P90, up to 4.1 μg/kg bw), Cereal bars (P50, up to 0.3 μg/kg bw), Fine bakery wares (P75, up to 5.1 μg/kg bw), Chocolate (Cocoa) products (P75, up to 1.1 μg/kg bw), Energy drinks (P75, up to 0.2 μg/kg bw), Dietary supplements (P75, up to 9.9 μg/kg bw), Beer and beer-like beverages (P90, up to 41 μg/kg bw). The use of proxies for the consumption of hemp and hemp-containing products, the limited number of occurrence data and the analytical limitations in the quantification of Δ9-THC represent the most important sources of uncertainty. Overall, exposure estimates presented in this report are expected to represent an overestimation of acute exposure to Δ9-THC in the EU.

Project description:ImportanceControlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations.ObjectiveTo compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg).Design, setting, and participantsThis randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week.InterventionsBrownies containing (1) no cannabis extract (ie, placebo); (2) Δ9-THC-dominant extract (20 mg Δ9-THC with no CBD); and (3) CBD-dominant extract (20 mg Δ9-THC + 640 mg CBD) were administered to participants 30 minutes prior to administering a cytochrome P450 (CYP) probe drug cocktail, which consisted of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam.Main outcomes and measuresChange-from-baseline plasma concentrations for Δ9-THC or Δ9-THC metabolites and scores for subjective drug effects, cognitive and psychomotor performance, and vital signs. The area under the plasma vs concentration vs time curve (AUC) and maximum plasma concentration (Cmax) were determined.ResultsThe participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean [SD] day since last cannabis use, 86 [66] days). The CYP cocktail + placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail + Δ9-THC, CYP cocktail + Δ9-THC + CBD produced a higher Cmax and area under the plasma concentration vs time curve for Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH. The CYP cocktail + Δ9-THC + CBD increased self-reported anxiety, sedation, and memory difficulty, increased heart rate, and produced a more pronounced impairment of cognitive and psychomotor performance compared with both CYP cocktail + Δ9-THC and CYP cocktail + placebo.Conclusions and relevanceIn this randomized clinical trial of oral Δ9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a Δ9-THC-dominant cannabis extract at the same Δ9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of Δ9-THC. CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoid-cannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision-making regarding the therapeutic and nontherapeutic use of cannabis products.Trial registrationclinicaltrials.gov Identifier: NCT04201197.

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Δ9-Tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development.

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Δ9-Tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development.

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