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

Br J Pharmacol. 2010 Jun;160(3):585-93. doi: 10.1111/j.1476-5381.2009.00582.x. Epub 2010 Jan 22.


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 (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.

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 CB(1) receptors in HEK293 cells stably expressing this receptor.

Key results: 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 ERK1/2 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(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 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cannabinoids / pharmacology*
  • Cell Culture Techniques
  • Cell Line, Transformed
  • Dose-Response Relationship, Drug
  • Excitatory Postsynaptic Potentials / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hallucinogens / pharmacology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiology
  • Humans
  • Indoles / pharmacology*
  • Mice
  • Mice, Inbred Strains
  • Naphthalenes / pharmacology*
  • Neurons / metabolism
  • Neurons / physiology
  • Phosphorylation / drug effects
  • Plant Preparations / pharmacology*
  • Receptor, Cannabinoid, CB1 / agonists*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Signal Transduction / drug effects
  • Synaptic Transmission / drug effects


  • Cannabinoids
  • Hallucinogens
  • Indoles
  • Naphthalenes
  • Plant Preparations
  • Receptor, Cannabinoid, CB1
  • Extracellular Signal-Regulated MAP Kinases
  • 1-pentyl-3-(1-naphthoyl)indole