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JWH-018 is a synthetic cannabinoid found in several versions of the herbal mixture “Spice.” Illicit use of this synthetic cannabinoid centers on its psychoactive effects which mimic those of Δ9-THC in cannabis. While considerably more potent than similar amounts of cannabis, JWH-018 also presents significant challenges for detection by typical Δ9-THC testing assays. In July 2009, the US Drug Enforcement Agency (DEA) listed JWH-018 on its Drugs and Chemicals of Concern list. In addition to reported seizures of Spice in Ohio and Florida, several states have passed legislative action restricting the sale or possession of JWH-018 including Alabama, Arkansas, Georgia, Kansas, Kentucky, North Dakota, and Tennessee.
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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 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.
Marijuana (Cannabis sativa L.) is the most commonly abused drug in the United States1, with a similar tendency worldwide2. In the last few years its use for recreational and medical purposes has become legal in an increasing number of countries3. Particularly, in the United States marijuana use is illegal under federal law, nevertheless, it has been legalized by individual state laws for non-medical use in 8 states and is allowed for medical use by another 29 states4. A primary component of marijuana, Δ9-tetrahydrocannabinol (∆9-THC)5, mediates a psychoactive effect on the nervous system via cannabinoid receptor 1 (CB1R), for which it has a low binding affinity (Ki = 39.5 nM)6. However, in recent years, strains of herbal cannabis with an increased CB1R potency have appeared: one example is sinsemilla, a female non-pollinated cannabis plant in which the content of ∆9-THC has been raised from 3.96% in 1995 to 12.3% in 20141. This recent shift in the generation of high-potency cannabis plant material has led to an increasing demand for cannabis-related treatments and emergency department admissions stemming from acute anxiety, psychosis or cognitive impairment7,8,9.
The advent of synthetic cannabinoids (SCs), a type of new recreational drug commonly known on the market as “Spice” created additional challenges. Since 2008 SCs have led to increased public awareness as the most rapidly growing group of new “legal highs”, with the ability to escape detection by standard cannabinoid screening tests. Once some substances have become regulated, novel analogues have emerged on the market to satisfy demand; and the speed of production is outpacing lawmakers’ attempts to ban them10. Most SCs act as full agonists at CB1R, with a much higher binding affinity (JWH-018, Ki = 9 nM; CP 47,497, Ki = 2.2 nM; HU210, Ki = 0.06 nM) compared to ∆9-THC6, 11. SCs can not only permeate the blood–brain barrier, but they also accumulate in CB1R-rich areas of the brain12, 13. Recently, the number of users displaying pathological behaviors after consuming SCs has dramatically increased; symptoms include anxiety, agitation, tachycardia, cardiotoxicity and seizures or status epilepticus14, 15. Deaths after SC use have also been documented: SCs were reported in 2014 to have killed 25 people and sickened more than 700 in northern Russia16. Controlled studies on humans to examine the action of cannabinoid ligands are difficult, and human data on induction, pharmacokinetics and adverse effects are therefore limited to case studies on users after voluntary drug consumption17, 18. At the same time, rapid analogue development and the growing popularity of SCs impose a strong demand for evaluation of their pharmacology and toxicology to reveal the mechanism of action and to facilitate future development of a drug-specific therapy for intoxication.
Here, we report, for the first time, that acute administration of a natural (∆9-THC, 10 mg/kg) or synthetic (JWH-018, 2.5 mg/kg) cannabinoid triggered electrographic seizures in mice, recorded by electroencephalography (EEG) and videography. We further show that cannabinoid-induced seizures were completely prevented by pretreatment of the animals with AM-251 (5 mg/kg), a CB1R-selective antagonist. Our data imply that even single use of cannabinoids may result in significant adverse neurological and physical effects and negatively affect human health. Finally, based on our results, AM-251 has a strong therapeutic potential for the suppression of toxic symptoms induced by cannabinoid abuse, although the human safety need to be established in controlled clinical trials.
Cannabinoids induce electrographic seizures
We administered ∆9-THC (10 mg/kg) or JWH-018 (2.5 mg/kg), intraperitoneally to two independent groups of mice and recorded video, EEG, electromyogram (EMG) and locomotor activity (LMA). Shortly after administration, we observed a significant decrease in LMA and EMG activity that coincided with low-intensity behavioral seizures. Several minutes after cannabinoid administration, the EEG trace resembled non-rapid eye movement sleep (Fig. 1A,B). However, detailed inspection of a magnified view (Fig. 1A,B inset) revealed the presence of electrographic seizures in the form of frequent EEG seizure spikes. The average onset latency of electrographic/behavioral seizures was shorter after JWH-018 (5.4 ± 0.6 min; p < 0.05) compared to ∆9-THC administration (11.1 ± 2.5 min) (Fig. 1A,B). Electrographic seizures were apparent for 256 ± 15.3 minutes after ∆9-THC; however, after JWH-018 administration they persisted for longer (344 ± 12 min; p < 0.001) and were observed in all tested animals (Fig. 2A). Seizure spike quantification analysis revealed significantly more frequent spikes after JWH-018 (25.1 ± 3.1 spikes/min; p < 0.001) compared to ∆9-THC administration (12.3 ± 1.4 spikes/min) (Fig. 2B). Isolated EEG seizure spikes were still observed in both groups 4 h after administration (Suppl. Figure 1A,C); on the next day, the effect was diminished and no electrographic seizures could be detected (Suppl.
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