Abstract
BackgroundK2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ9-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R).Methods/Principal FindingsJWH-018, five potential monohydroxylated metabolites (M1–M5), and one carboxy metabolite (M6) were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [3H]CP-55,940, and then for CB1R intrinsic efficacy using an [35S]GTPγS binding assay. JWH-018 and M1–M5 bound CB1Rs with high affinity, exhibiting Ki values that were lower than or equivalent to Δ9-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ9-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ9-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Conclusions/SignificanceUnlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ9-THC, may contribute to the greater prevalence of adverse effects observed with JWH-018-containing products relative to cannabis.
Highlights
In recent years, several products sold as incense in headshops, commonly referred to as ‘‘K2’’ and ‘‘Spice’’, have rapidly emerged as legal substitutes for cannabis due to their cannabimimetic effects when smoked or consumed [1]
JWH-018 has been shown to bind to cannabinoid 1 receptor (CB1R) with high affinity [10], to date, the action of its metabolites at this receptor is unknown
This study importantly demonstrates for the first time that five potential Phase I hydroxylated metabolites of the synthetic cannabinoid JWH-018 bind with high nanomolar affinity to, and very efficaciously activate, CB1Rs in vitro
Summary
Several products sold as incense in headshops, commonly referred to as ‘‘K2’’ and ‘‘Spice’’, have rapidly emerged as legal substitutes for cannabis due to their cannabimimetic effects when smoked or consumed [1]. While smoking or oral consumption of marijuana acutely produces relatively mild and tolerable side effects in most users, such as appetite stimulation and orthostatic hypotension, it very rarely causes the adverse effects observed rather commonly with similar use of K2 products, such as hypertension, agitation, hallucinations, psychoses, seizures and panic attacks [1,4,12,13]. K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from D9-THC, the main psychoactive ingredient in marijuana. The present study proposes that K2’s high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
