Active metabolites of JWH-018 may contribute to effects of K2/Spice, etc.

A recent paper from Brents et al. (PubMed) presents the data that we’ve been hearing about for the past several months. I think leigh of the Neurodynamics blog (see posts on THC and cannabimimetic/JWH-018 pharmacology), may have been the first to report seeing these data at a meeting and then I ran across them at CPDD this past June.
As many of you are fully aware by now, the past couple years has witnessed the emergence of broad popular use of “synthetic marijuana” or cannabimimetic products. They have been retailed widely as small (usually 3g) packets of various plant materials sprayed with a growing list of synthetic drugs which all seem to have full agonist properties at the endocannabinoid 1 receptor subtype (CB₁). A series created by J. W. Huffman have been commonly reported, thus you will see reference to the compounds themselves, JWH-018, JWH-073, JWH-081, etc.

Public health concern has been expressed given that these products can cause dependence similar to that of delta9-THC, are involved in acute-intoxication traummatic incidents and are reported in online forums (see comment threads to the linked blog posts for example) to a lot of weird and scary (for cannabis-experienced users) subjective effects. Abel Pharmboy and I have found the web search traffic to our first posts on K2/Spice, JWH-018, etc to be unrelenting. The DEA took action, placing five of the more commonly identified synthetic cannabinoids on Schedule I, making the products containing them illegal to sell in the headshops, cigar shops and convenience stores that had been providing these products.
Brents and colleagues have examined the pharmacological properties of 6 metabolites of JWH-018 that have previously been reported to occur in the urine of users in “appreciable amounts”. To quickly overview, many recreational and therapeutic drugs (not to mention a host of other exogenous compounds that you ingest) are broken down in the body prior to elimination in urine or feces. They are metabolically altered from the parent drug to one or more metabolites which may have pharmacological activity similar to the parent drug, activity that differs from the parent drug or be essentially inactive. Understanding the effects of a drug, therefore, often can be enhanced by determining whether any metabolites are pharmacologically active.

Figure 2This figure from the paper shows the ability of several compounds to displace radiolabeled CP-55,940 (a selective CB₁ ligand, i.e., it binds to these receptors) using mouse brain membranes. The Ki values are the lowest concentrations of the test compounds which displace the radiolabeled CP compound. The unlabeled CP is the most effective, achieving displacement at the lowest concentration. JWH-018 competes for the receptor at a lower concentration than does THC, which has been previously reported. The interesting thing here is that three metabolites of JWH-018 are approximately equal to THC and two are even more effective.
The paper also reports the effects of the M1 metabolite in vivo. Back before the endocannabinoid receptors were identified around the early 90s there was no direct pharmacological way to determine if a novel compound was likely to be similar to THC. So behavioral pharmacologists (primarily Billy Martin, Jenny Wiley and colleagues at VCU) came up with the Tetrad Test of likely cannabinoid action. These four items were catalepsy, analgesia, hypomotility and hypothermia. The Brents paper reports on two of these effects in mice.

Figure 4

Figure 5
These figures show that THC, JWH-018 and the M1 metabolite all reduce locomotor activity and body temperature in the mouse. More importantly, pretreatment with the antagonist AM-251 reverses these effects, providing evidence that it is a selective pharmacological activity at the CB₁ receptor.
All in all a nice demonstration that at least one, and likely several, of the metabolites of JWH-018 that have been identified in human users are active. They have pharmacological properties similar to the parent compound and therefore may contribute to the overall effects of the drug.
This means that the next steps will be to determine the distribution and elimination of the metabolites. If they don’t get past the blood-brain barrier very well or are very rapidly eliminated from circulation the effects may be unimportant, however some metabolites may last in circulation much longer than the parent. In this latter case, inferences based on the pharmacokinetics of JWH-018 would be an underestimate.
Since there are a host of synthetic cannabinoid compounds being reported in retail products, it will be interesting to see if those result in active metabolites as well.
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Brents LK, Reichard EE, Zimmerman SM, Moran JH, Fantegrossi WE, & Prather PL (2011). Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity. PloS one, 6 (7) PMID: 21755008