ASPET 2014: XLR-11 synthetic cannabinoid associated with nephrotoxicity

This is an overview of a presentation in Symposium 491. Scientists versus Street Chemists: The Toxicity of Designer Marijuana Wed, Apr 30, 9:30 AM – 12:00 PM at Experimental Biology 2014.

Wed, Apr 30, 10:45 – 11:10 AM Clinical and unexplained idiosyncratic toxicity of K2 exposure by G. Buser of the Oregon Health Authority.

One potential health consequence of the use of synthetic cannabinoids is acute kidney injury (AKI) or nephrotoxicity. There have been Case Reports published and there are more cases described in the MMWR report of the US CDC.

Buser indicated that in Oregon the index case for her agency’s attention was a 17 yo male who reported to the emergency department where he was found to have abnormal kidney function. He had been smoking a synthetic cannabis product. With such a finding, there are a number of questions: Is it a contaminant? Possibly a toxic solvent used to prepare the product? Toxic constituents of the plant material used for a given product? A hot spot in the product that resulted in an unusually high dose?

This thinking triggered an investigation around the state of OR, in which medical facilities, officers and other public health authorities were queried for cases of unexplained nephrotoxicity in young adults. Buser identified several additional cases in which it appeared from case histories that the smoking of synthetic cannabis products were involved. The author then attempted to secure the clinical course, case histories and any clinical samples collected.

She ended up with 9 cases collected between May-Oct 2012, all male with a median age of 18. Due to the variability in the cases, the onset from last smoking to symptoms was 2 weeks to 30 minutes although Buser cautioned that the case histories derived from friend or the user might not be that reliable.

Affected individuals (also see the above links) tend to suffer from nausea, vomiting and abdominal/flank/back pain. Buser said that in the OR cases, the individuals tended to wait anywhere from 12 hrs to a day after the start of their symptoms, thinking that it would resolve by itself.

The cases typically featured abnormal clinical chemistry (BUN, serum creatinine), proteinuria and kidney biopsies were found to confirm both acute tubular nephritis and interstitial nephritis.

The study interviewed 6 of 9 cases, all were habitual marijuana smokers, had obtained their synthetic cannabis over the counter from convenience stores or head shops and they reported 5 different product brand names. The team was able to secure 2 of the products for testing.

One of the more frustrating issues for a study like this is that the patients reported to Emergency services of some sort a long time after last exposure to synthetic cannabis. So there is a good deal of uncertainty about being able to detect any of the known agents. Nevertheless, one invidual was positive for (1-(5-fluoropentyl)-1H-indol-3-yl)(2,2,3,3-tetramethylcyclopropyl) methanone (XLR-11). No other known cannabimimetics were found. This individual happened to be one (of the two) for whom they were able to secure and analyze a sample of the product he had used. It was also positive for XLR-11.

XLR-11 was found in four of the five product samples and four of six patient’s specimens in the WY report as well.

It appears to be the case that no other cannabimimetic compounds have been reported in association with acute kidney injury. Obviously, the data are thin and in many cases of AKI, there are no analyses of the product and timing may be such that clinical sample would be negative anyway.

Still, there is enough of a smoking gun here to recommend some preclinical studies on the nephrotoxic effects of XLR-11, as mentioned by Buser.

Buser ended up by observing that in three of the cases there were other people smoking the same product with the affected individual. It was speculated that perhaps there was a hot spot, perhaps those individuals smoked more or perhaps they had an individul liability. With respect to the latter, she noted that two brother pairs were represented in the affected sample. This might point to shared genetic liability for these adverse effects of XLR-11 consumption.

One major takeaway from the presentation is that a specific synthetic cannabinoid might have specific risks for kidney injury. A second major takeaway is that we know far too little about this phenomenon, both from a mechanistic perspective and an epidemiological one. Efforts from public health officials such as Buser can enhance awareness and therefore detection of human cases.