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

Abstract

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 receptormediated 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; t1/2 = 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 CB1 receptors by JWH018, added to this herbal preparation.

Effect of synthetic cannabinoids on spontaneous neuronal activity: Evaluation using Ca 2+ spiking and multi-electrode arrays

“…This study confirmed that synthetic cannabinoids identified as CB 1 (Table 1). Low neuronal density appears to be common with the most relevant studies (Shen et al, 2007).…”

Emergence of New Classes of Recreational Drugs—Synthetic Cannabinoids and Cathinones

“…These substances include either THC or THC-like compounds, and were originally developed for potential medicinal purposes and to study cannabinoid receptor pharmacology. [16][17][18][19][20] SC products first emerged in Europe in 2004 as "Spice," and in the U.S. in 2008 as "K2." Today, SC products are distributed worldwide under countless trade names, such as "Aztec Gold," "Black Mamba," "Cloud 9," and "Mad Hatter" (Table 1).…”

“…Today, SC products are distributed worldwide under countless trade names, such as "Aztec Gold," "Black Mamba," "Cloud 9," and "Mad Hatter" (Table 1). [16][17][18][19][20] These products are generally marked with disingenuous labels such as "not for human consumption" or "herbal incense" and often packaged in colorful wrappers designed to appeal to teens, young adults, and first-time drug users. 11 They are often inhaled via a pipe or rolled into a cigarette.…”

“…[17][18][19][20][25][26][27] Studies in adults have linked SCs to other cardiovascular, psychiatric, and neurological signs and symptoms (Table 2). [17][18][19][20][21][26][27][28] There has also been a case report of severe rhabdomyolysis associated with SC use. 29 Recently, SCs have been associated with acute kidney injury (AKI) (acute tubular injury and acute interstitial nephritis) in young, previously healthy patients without preexisting renal disease.…”

Cannabis and Its Derivatives: Review of Medical Use

“…Despite legal curtailment, cannabis is still used by 10% to 15% of patients with multiple sclerosis 43 and noncancer types of chronic pain 44 for both analgesia and psychological detachment. Various well-designed, randomized, placebo-controlled trials have shown that smoked cannabis can relieve peripheral, 45 posttraumatic, 46 and HIV-induced 47,48 neuropathic pain.…”