CPDD 2014: The XLR-11 synthetic cannabinoid is looking nastier by the day

A session on synthetic cannabinoids at the Experimental Biology meeting in April included a talk on nephrotoxicity consequent to use of synthetic cannabinoid products. I covered it in a post. As with a prior report of Cases in Wyoming, the scientist from Oregon reported being able to identify XLR-11 in two of the cases presented. There is not much available on PubMed at the moment regarding the effects of this cannabimimetic. (The XLR-11 structure at the right is courtesy of “meodipt” who submitted it to the Wikipedia page for free use.)

New data presented by Michael Gatch at the recent meeting of the College on Problems of Drug Dependence in San Juan, PR (lovely venue, btw) caught my eye because of an unusual property of XLR-11. Previously, Gatch has looked at a lengthy series of synthetic cathione (“bath salt”) drugs in mouse locomotor and rat drug-discrimination assays. This new work is similar, save for the different drug class, so if you want some background reading, that prior paper would be a good complement.

The key, for me, was the drug-discrimination data. This is an assay in which animals are trained to discriminate saline from a reference drug, in this case good old Δ⁹Tetrahydrocannabinol (THC). In essence the rat is reinforced for responding on one lever if it has received saline just prior to the operant session and on the other lever if it has received THC. Then, on critical test days, you can substitute a dose of some other drug and determine the extent to which the rat responds on the drug-paired versus saline-paired lever. As I’ve mentioned before, this seems imprecise to the newcomer since seemingly any intoxicant would be scored as “drug” to a rat. Not so. They are actually highly specific in categorizing drugs of similar pharmacological activity.

The interesting thing in the presentation by Gatch was that he showed time-course with bins of about 5 minutes after the start of the session. One drug, XLR-11, popped out as having rapid onset of activity (i.e., full THC responding at 5 min when it takes maybe 10 or 15 for this to occur for THC itself) and a short duration of action (THC-lever responding disappeared after about 15 minutes). I say it popped out because out of a series of cannabimimetic drugs he presented, this one was the only one to have this profile (to my recollection).

This is interesting because in a general sense this tells me two things. First, this is the profile of a drug that is going to engender rapid on/off subjective effects and therefore very likely frequent re-dosing. From a comparative perspective this sounds like enhanced abuse liability to me…i.e., better chances of causing addiction.

The second aspect only hit me when I recalled that XLR-11 was the compound associated with nephrotoxicity. Now, admittedly, it may be the case that XLR-11 itself has a pyrolosis product produced during the smoking of plant matter containing it. But it also strikes me that this rapid on/off pharmacological profile might lead to recreational users simply using more of the products containing this compound than they ever would of products containing some longer acting synthetic cannabinoid. And that might get us back to thinking about what is contained in the various plants used in the products being sold to users.