Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-13, in mice

Abstract

Background and purpose: Cannabis is a recreational drug leading to intoxication, following stimulation of cannabinoid CB₁ receptors. However, more recently, herbs mixed with synthetic cannabinoids sometimes known as 'Spice' and 'Black Mamba' have been increasingly used, and their high CB₁ receptor affinity has led not only to marked intoxication but also life-threatening complications and an increasing number of deaths. Although many studies have indicated that prophylactic treatment with CB₁ receptor antagonists can block cannabimimetic effects in animals and humans, the aim of this study was to determine whether CB₁ receptor antagonism could reverse physical cannabimimetic effects.

Experimental approach: Cannabimimetic effects, measured by the hypothermic response following sedation and hypomotility, were induced by the synthetic CB₁ receptor agonist CB-13 (1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone) in Biozzi Antibody High mice. The CB₁ receptor antagonist/inverse agonist AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) was administered 20 min after the injection of CB-13 and its effects on the cannabimimetic responses were assessed.

Key results: In this study, the CNS-related cannabimimetic effects, as measured by the hypothermic effect, induced by the CB₁ receptor agonist were therapeutically treated and were rapidly reversed by the CB₁ receptor antagonist/inverse agonist. There was also a subjective reversal of visually evident sedation.

Conclusions and implications: Cannabinoid receptor antagonists have been widely used and so may provide an acceptable single-dose antidote to cannabinoid intoxication. This use may save human life, where the life-threatening effects are mediated by cannabinoid receptors and not off-target influences of the synthetic cannabinoids or non-cannabinoids within the recreational drug mixture.

Figure 1

The CB₁ receptor antagonist AM251 reversed the hypothermic effects of the CB₁ receptor agonist CB‐13. Animals (n = 6) were injected i.p. with CB‐13 (5 mg·kg⁻¹) at 0 min, and AM251 (5 mg·kg⁻¹) was injected i.v. at 20 min. Temperature was assessed with a thermocouple placed under the hindlimb. Data shown are the group means ± SD. *P<0.05, significantly different from baseline values.