Dataset Information

Natural (?⁹-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB₁ receptor.

ABSTRACT: Natural cannabinoids and their synthetic substitutes are the most widely used recreational drugs. Numerous clinical cases describe acute toxic symptoms and neurological consequences following inhalation of the mixture of synthetic cannabinoids known as "Spice." Here we report that an intraperitoneal administration of the natural cannabinoid ?⁹-tetrahydrocannabinol (10?mg/kg), one of the main constituent of marijuana, or the synthetic cannabinoid JWH-018 (2.5?mg/kg) triggered electrographic seizures in mice, recorded by electroencephalography and videography. Administration of JWH-018 (1.5, 2.5 and 5?mg/kg) increased seizure spikes dose-dependently. Pretreatment of mice with AM-251 (5?mg/kg), a cannabinoid receptor 1-selective antagonist, completely prevented cannabinoid-induced seizures. These data imply that abuse of cannabinoids can be dangerous and represents an emerging public health threat. Additionally, our data strongly suggest that AM-251 could be used as a crucial prophylactic therapy for cannabinoid-induced seizures or similar life-threatening conditions.

SUBMITTER: Malyshevskaya O

PROVIDER: S-EPMC5585372 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Natural (∆9-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB1 receptor.

Malyshevskaya Olga O Aritake Kosuke K Kaushik Mahesh K MK Uchiyama Nahoko N Cherasse Yoan Y Kikura-Hanajiri Ruri R Urade Yoshihiro Y

Scientific reports 20170905 1

Natural cannabinoids and their synthetic substitutes are the most widely used recreational drugs. Numerous clinical cases describe acute toxic symptoms and neurological consequences following inhalation of the mixture of synthetic cannabinoids known as "Spice." Here we report that an intraperitoneal administration of the natural cannabinoid Δ9-tetrahydrocannabinol (10 mg/kg), one of the main constituent of marijuana, or the synthetic cannabinoid JWH-018 (2.5 mg/kg) triggered electrogr ...[more]

PMID: 28874764

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Project description:Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for ?(9)-tetrahydrocannabinol (?(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of ?(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the ?(9)-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective ?(9)-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor-binding assay suggests multiple CB1R-SCB binding sites.

Project description:Introduction: Synthetic cannabinoid mixtures have been easily accessible for years, leading to the belief that these products were natural and harmless, which contributed to their popularity. Nevertheless, there are many reports of users ending up in hospital due to severe side effects such as tachycardia, aggression, and psychosis. Controlled studies on the effects of synthetic cannabinoids on human performance are lacking. In the present study, we assessed the safety pharmacology of the synthetic cannabinoid JWH-018 after acute administration. Methods: Seventeen healthy cannabis-experienced participants took part in this placebo-controlled, crossover study. Participants inhaled the vapor of JWH-018 (doses ranged between 2 and 6.2 mg) and were subsequently monitored for 12 h, during which vital signs, cognitive performance, and subjective experience were measured. Subjective high scores showed that there is a large variability in the subjective experience of participants. Therefore, a mixed analysis of variance, with "Responder" (i.e., subjective high score >2) as a between-subjects factor and "Drug" as a within-subjects factor (placebo and JWH-018), was used. Results: Serum concentrations of JWH-018 were significantly higher in the responders. Overall, JWH-018 increased heart rate within the first hour and significantly impaired critical tracking and memory performance. Responders to JWH-018 performed more poorly in tests measuring reaction time and showed increased levels of confusion, amnesia, dissociation, derealization, and depersonalization and increased drug liking after JWH-018. Conclusion: JWH-018 administration produced large variability in drug concentrations and subjective experience. Fluctuations in drug delivery probably contributed to the variation in response. JWH-018's impairing effects on cognition and subjective measures were mainly demonstrated in participants who experienced a subjective intoxication of the drug. Lack of control over drug delivery may increase the risk of overdosing in synthetic cannabinoid users.

Dataset Information

Natural (?⁹-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB₁ receptor.

Publications

Natural (∆<sup>9</sup>-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB<sub>1</sub> receptor.

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Natural (?9-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB1 receptor.

Publications

Natural (∆<sup>9</sup>-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB<sub>1</sub> receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Natural (?⁹-THC) and synthetic (JWH-018) cannabinoids induce seizures by acting through the cannabinoid CB₁ receptor.