JWH018, a common constituent of Spice herbal blends, is a potent and efficacious cannabinoid CB receptor agonist.
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 (CB(1)) cannabinoid receptor and inhibits cAMP production in CB(1) receptor-expressing CHO cells. Other effects of JWH018 on CB(1) receptor-mediated signalling are not known, particularly in neurons. Here we have evaluated the signalling pathways activated by JWH018 at CB(1) receptors. We investigated the effects of JWH018 on neurotransmission in cultured autaptic hippocampal neurons. We further analysed its activation of ERK12 mitogen activated protein kinase (MAPK) and internalization of CB(1) receptors in HEK293 cells stably expressing this receptor. In cultured autaptic hippocampal neurons, JWH018 potently inhibited excitatory postsynaptic currents (IC(50) 14.9 nM) in a concentration- and CB(1) receptor-dependent manner. Furthermore, it increased ERK12 MAPK phosphorylation (EC(50) 4.4 nM). We also found that JWH018 potently induced rapid and robust CB(1) receptor internalization (EC(50) 2.8 nM t(12) 17.3 min). JWH018, a prominent component of several herbal preparations marketed for their psychoactivity, is a potent and effective CB(1) receptor agonist that activates multiple CB(1) 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.