Comparison of the Neurotoxic and Seizure-Inducing Effects of Synthetic and Endogenous Cannabinoids with Δ⁹-Tetrahydrocannabinol

Abstract

Introduction: Synthetic cannabinoids (SCs) are commonly found in preparations used as recreational drugs. Although severe adverse health effects are not generally associated with cannabis use, a rising number of studies document seizures and even death after SC use. In this study, a mouse model is used to investigate the hypothesis that SCs are more toxic than D 9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis. Materials and Methods: Beginning with the SCs, JWH-073 and AM-2201, dose-response curves were generated to find the dose of each drug that was similarly efficacious to 50 mg/kg THC. Mice were given daily intraperitoneal (IP) injections of vehicle, 50 mg/kg THC, 30 mg/kg JWH-073, or 1 mg/kg AM-2201 until tolerance to the antinociceptive and hypothermic effects was complete, and then were assessed for spontaneous and antagonist-precipitated withdrawal and potential organ damage. No differences in tolerance were noted, but AM-2201 showed more rearing in the spontaneous and antagonist-precipitated withdrawal phases than either vehicle or the other two drug treatments. Histopathological examination of these mice revealed no drug-induced lesions. In a subsequent set of experiments, various doses of THC, methanandamide (mAEA), and of a variety of SCs (HU-210, CP55940, JWH-073, AM-2201, and PB-22) were given IP, and convulsions and change in body temperature were quantified. Discussion: The treatments yielded varying numbers of convulsions and a range of changes in body temperature. JWH-073 and AM-2201 produced significantly more convulsions than THC, HU-210, mAEA, or cannabidiol (CBD) (the latter two producing none). HU-210, CP55940, JWH-073, and mAEA produced greater hypothermia than THC or CBD. Convulsions and hypothermia induced by several agonists were prevented by pretreatment with a CB 1 antagonist, but not a CB 2 antagonist. Conclusions: In agreement with human studies and case reports, this study found that SCs generally produced more seizures than THC. Of particular significance was the finding that mAEA produced far greater hypothermia than THC (similar to most SCs), but unlike the SCs and THC, produced no seizures.

Cannabigerol (CBG) attenuates mechanical hypersensitivity elicited by chemotherapy‐induced peripheral neuropathy

“…(Lambert et al, 2009; Tékus et al, 2010; van den Wijngaard et al, 2009), SR144528 (10 mg/kg, i.p.) (Breivogel et al, 2020), or T0070907 (10 mg/kg, i.p.) (Khasabova et al, 2019) were administered 30 min prior to CBG treatment.…”

Synthetic cannabinoid JWH-073 alters both acute behavior and in vivo/vitro electrophysiological responses in mice

“…Preclinical studies report that JWH-073 reproduces the typical "tetrad" (hypothermia, analgesia, hypolocomotion, akinesia) effects previously ascertained for 9 -THC (3, 4, 20. 21), as well as neurological effects, are worse than this latter (22). Moreover, JWH-073 facilitates dopamine release in the shell of the nucleus Accumbens and impairs sensorimotor responses in mice (5).…”

Cannabinoid-2 Agonism with AM2301 Mitigates Morphine-Induced Respiratory Depression

“…Cannabinoids and respiration THC (1, 10 mg/kg, i.p., N = 9/group), a mixed CB1R/CB2R agonist, doses were chosen based on published reports. [31][32][33] THC was compared with vehicle and was significant for a factor of dose (F[2,52] = 4.245, p = 0.0196). THC 1, p > 0.9999 under both conditions, and 10 mg/kg, p = 0.4098, did not significantly decrease frequency of respirations, or BPM, under the 0% CO 2 condition ( Fig.…”