The CDC has posted a MMWR report on the 2019 spate of serious lung injuries reported as a consequence of vaping. The first culprit to hit the news was vitamin E, it turns out this is not a unique factor after all.

Schier and colleagues report: No consistent e-cigarette product, substance, or additive has been identified in all cases, nor has any one product or substance been conclusively linked to pulmonary disease in patients. authors identified lipids within alveolar macrophages from the three bronchoalveolar lavage (BAL) specimens stained with oil red O. All five patients reported using marijuana oils or concentrates in e-cigarettes, and three also reported using nicotine (3). In a report describing the clinical course and outcomes of six patients from Utah, health care providers described the potential diagnostic utility of identification of lipid-laden macrophages from BAL specimens (4). Among the 53 cases from Illinois and Wisconsin, however, the pathologic findings were heterogeneous. Whereas almost half (24/53) of these patients underwent BAL, seven reports described the use of oil red O stain that identified lipid-laden macrophages

Perrine and colleagues report: Among 514 patients with information on substances used in e-cigarettes, or vaping products, in the 3 months* preceding symptom onset, 76.9% reported using THC-containing products, and 56.8% reported using nicotine-containing products; 36.0% reported exclusive use of THC-containing products, and 16.0% reported exclusive use of nicotine-containing products. *erratum for the original which says “30 days”.

It’s frustrating that the takeaway message so far is that nobody knows if there even is a unique cause or set of causes for the recent spate of lung injuries. We certainly don’t know the cause. We probably don’t even know if the injuries *are* recently occurring or have always been a consequence of vape device use that simply wasn’t connected to the e-cigarette device use. We know how long it took to recognize that cannabis was causing a hyperemesis syndrome, after all.

My suspicion at the start was that it wasn’t anything to do with cannabinoids, specifically. This reported diversity would appear to confirm that. It always seemed more likely to me that if there was a unique cause that appeared to be associated with cannabis vape cartridges that this is a classic case of a third variable. Perhaps a new vehicle constituent or an extraction method that was being used only, or primarily, with cannabis vape preparation. Well, clearly even that is not the case since there seem to be some nicotine-only users who have experienced lung injury.

Keep your eye on PubMed for updates on this health crisis.

Schier JG, Meiman JG, Layden J, et al. Severe Pulmonary Disease Associated with Electronic-Cigarette–Product Use — Interim Guidance. MMWR Morb Mortal Wkly Rep 2019;68:787–790. DOI: http://dx.doi.org/10.15585/mmwr.mm6836e2external icon

Perrine CG, Pickens CM, Boehmer TK, et al. Characteristics of a Multistate Outbreak of Lung Injury Associated with E-cigarette Use, or Vaping — United States, 2019. MMWR Morb Mortal Wkly Rep 2019;68:860–864. DOI: http://dx.doi.org/10.15585/mmwr.mm6839e1

Erratum: Vol. 68, No. 39. MMWR Morb Mortal Wkly Rep 2019;68:900. DOI: http://dx.doi.org/10.15585/mmwr.mm6840a5

XLR-11_structureA 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.