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

<jats:p><jats:bold>Background and purpose: </jats:bold> ‘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<jats:sub>1</jats:sub>) cannabinoid receptor and inhibits cAMP production in CB<jats:sub>1</jats:sub> receptor‐expressing CHO cells. Other effects of JWH018 on CB<jats:sub>1</jats:sub> receptor‐mediated signalling are not known, particularly in neurons. Here we have evaluated the signalling pathways activated by JWH018 at CB<jats:sub>1</jats:sub> receptors.</jats:p><jats:p><jats:bold>Experimental approach: </jats:bold> 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 CB<jats:sub>1</jats:sub> receptors in HEK293 cells stably expressing this receptor.</jats:p><jats:p><jats:bold>Key results: </jats:bold> In cultured autaptic hippocampal neurons, JWH018 potently inhibited excitatory postsynaptic currents (<jats:italic>IC</jats:italic><jats:sub>50</jats:sub>= 14.9 nM) in a concentration‐ and CB<jats:sub>1</jats:sub> receptor‐dependent manner. Furthermore, it increased ERK1/2 MAPK phosphorylation (<jats:italic>EC</jats:italic><jats:sub>50</jats:sub>= 4.4 nM). We also found that JWH018 potently induced rapid and robust CB<jats:sub>1</jats:sub> receptor internalization (<jats:italic>EC</jats:italic><jats:sub>50</jats:sub>= 2.8 nM; <jats:italic>t</jats:italic><jats:sub>1/2</jats:sub>= 17.3 min).</jats:p><jats:p><jats:bold>Conclusions and implications: </jats:bold> JWH018, a prominent component of several herbal preparations marketed for their psychoactivity, is a potent and effective CB<jats:sub>1</jats:sub> receptor agonist that activates multiple CB<jats:sub>1</jats:sub> receptor signalling pathways. Thus, it is likely that the subjective effects of ‘Spice’ are due to activation of cannabinoid CB<jats:sub>1</jats:sub> receptors by JWH018, added to this herbal preparation.</jats:p>