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 PURPOSECannabis is a recreational drug leading to intoxication, following stimulation of cannabinoid CB 1 receptors. However, more recently, herbs mixed with synthetic cannabinoids sometimes known as 'Spice' and 'Black Mamba' have been increasingly used, and their high CB 1 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 CB 1 receptor antagonists can block cannabimimetic effects in animals and humans, the aim of this study was to determine whether CB 1 receptor antagonism could reverse physical cannabimimetic effects. EXPERIMENTAL APPROACHCannabimimetic effects, measured by the hypothermic response following sedation and hypomotility, were induced by the synthetic CB 1 receptor agonist CB-13 (1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone) in Biozzi Antibody High mice. The CB 1 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 RESULTSIn this study, the CNS-related cannabimimetic effects, as measured by the hypothermic effect, induced by the CB 1 receptor agonist were therapeutically treated and were rapidly reversed by the CB 1 receptor antagonist/inverse agonist. There was also a subjective reversal of visually evident sedation. CONCLUSIONS AND IMPLICATIONSCannabinoid 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 offtarget influences of the synthetic cannabinoids or non-cannabinoids within the recreational drug mixture. In animals, cannabimimetic effects have been associated with a tetrad of behavioural effects including catalepsy, analgesia, lack of locomotor activity and thermoregulation, mediated mainly by THC within cannabis and by CB 1 receptors expressed within the CNS (Zimmer et al., 1999;Varvel et al., 2005;Croxford et al., 2008). These behavioural effects induced by THC and synthetic cannabinoids can be blocked by CB 1 receptor antagonists (Varvel et al., 2005;Marshell et al., 2014). Likewise, behavioural and physiological effects of cannabis can be blocked by CB 1 receptor antagonists/inverse agonists in humans (Huestis et al., 2007). Therefore, receptor blockade could act as an antidote to limit potentially life-threatening intoxication.Although there are claims that inverse agonists of CB 1 receptors can reverse cannabimimetic effects of synthetic cannabinoids (Taffe et al., 2015), on closer analysis, it is evident that these antagonists/inverse agonists are typically applied before the cannabinoid agonist. Therefore, it is an inhibition of the development of cannabimimetic effects rather than a reversal of established cannabimimet...

Cannabinoid1 (CB-1) receptor antagonists: a molecular approach to treating acute cannabinoid overdose

“…CB-1 antagonists have also been shown to reverse the pharmacological effects of cannabinoids. For example, the CB-1 antagonist AM-251 has been reported to reverse the hypothermia induced by the SC, CB13 (Pryce and Baker 2017). In this study (Fig.…”

“…Converging lines of evidence, including compelling clinical data, have shown that cannabinoid (CB-1) receptors mediate the principal psychopharmacological actions of both Δ 9 -tetrahydrocannabinol (THC) (the main psychoactive component in cannabis) and synthetic cannabinoids (SCs) that are likely to precipitate an ED visit (Huestis, et al 2001;Baskfield et al 2004;Zimmer et al 1999;Sain et al 2009;Pryce and Baker 2017;Marshell et al 2014;Zuurman et al 2010;Klumpers et al 2012). The identification of CB-1 receptors in 1990 (Matsuda et al 1990) and an emerging literature describing the role of endocannabinoids (e.g., anandamide) in multiple physiological processes (reviewed in Howlett et al 2002;Pertwee et al 2010) led to the development of selective, high affinity CB-1 receptor antagonists.…”

Discovery of High-Affinity Cannabinoid Receptors Ligands through a 3D-QSAR Ushered by Scaffold-Hopping Analysis

“…The chemical structures of the 312 CB 1 receptor ligands, and of the 187 CB 2 receptor ligands were selected from the literature that reports the experimental K i values, primarily involving assays where isolated CB 1 and/or CB 2 receptors were incubated with a predetermined fixed concentration of radiolabeled cannabinoid ([ 3 H] CP 55,490) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 56 , 57 ]. The binding affinity data of the selected dataset were converted into their negative decimal logarithm p K i (p K i = −log K i ).…”

“…The models were created using a set of 312 CB 1 receptor ligands, and 187 CB 2 receptor ligands. Details of all the compounds having experimentally determined K i values were retrieved from the literature (i.e., anandamide analogues, benzoyl/alkoyl-indoles, cyclohexylphenols, dibenzopyrans, indazole derivatives, indazole-carboxylates, indazole-carboxamides, indole-carboxylates, indole-carboxamides, naphthoyl-benzimidazoles, naphthoyl-indazoles, naphthoyl-indoles, naphthoyl-naphthalenes, naphthoyl-pyrroles and phenylacetyl-indoles) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Figure 1 details the structures of some example of CB 1 and CB 2 ligands.…”

New ways of dealing with new psychoactive substances

“…For example, increasing evidence suggests that CB 1 antagonists can reverse cannabinoid intoxication. 3 If and when CB 1 antagonists are approved for this indication, RIDR could record the clinical circumstances in which they are used and the outcomes.…”