JWH018, a common constituent of 'Spice' herbal blends, is a potent and efficacious cannabinoid CB₁ receptor agonist

Background and purpose: 'Spice' is an herbal blend primarily marketed in Europe as a mild hallucinogen with prominent cannabis-like effects and as a legal alternative to cannabis. However, a recent report identified a number of synthetic additives in samples of 'Spice'. One of these, the indole derivative JWH018, is a ligand for the cannabinoid receptor 1 (CB₁) cannabinoid receptor and inhibits cAMP production in CB₁ receptor-expressing CHO cells. Other effects of JWH018 on CB₁ receptor-mediated signalling are not known, particularly in neurons. Here we have evaluated the signalling pathways activated by JWH018 at CB₁ receptors. Experimental approach: We investigated the effects of JWH018 on neurotransmission in cultured autaptic hippocampal neurons. We further analysed its activation of ERK1/2 mitogen activated protein kinase (MAPK) and internalization of CB₁ receptors in HEK293 cells stably expressing this receptor. Key results: In cultured autaptic hippocampal neurons, JWH018 potently inhibited excitatory postsynaptic currents (IC₅₀ = 14.9 nM) in a concentration- and CB₁ receptor-dependent manner. Furthermore, it increased ERK1/2 MAPK phosphorylation (EC₅₀ = 4.4 nM). We also found that JWH018 potently induced rapid and robust CB₁ receptor internalization (EC₅₀ = 2.8 nM; t_1/2 = 17.3 min). Conclusions and implications: JWH018, a prominent component of several herbal preparations marketed for their psychoactivity, is a potent and effective CB₁ receptor agonist that activates multiple CB₁ receptor signalling pathways. Thus, it is likely that the subjective effects of 'Spice' are due to activation of cannabinoid CB ₁ receptors by JWH018, added to this herbal preparation.