An Outbreak of Synthetic Cannabinoid–Associated Coagulopathy in Illinois

Kelkar, Amar H.; Smith, Nichole A.; Martial, Annia; Moole, Harsha; Tarantino, Michael D.; Roberts, Jonathan C.

doi:10.1056/nejmoa1807652

Cited by 71 publications

(57 citation statements)

References 24 publications

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“…Recently, a painless macro-hematuria with altered coagulation was described in association with SC use, though no anticoagulant poisoning panel was performed [47]. Additionally, there were reports about products containing SCs allegedly laced with potent anticoagulant coumarin derivatives like brodifacoum and difenacoum [48,49]. In our case, to verify if the kidney bleedings could have been caused by such contaminants, the analysis of coumarin derivatives including super-warfarintype drugs was performed, but was found negative.…”

Section: Discussionmentioning

confidence: 77%

“…Kidney bleedings have never been previously demonstrated in such contexts, even though the ultrasound appearance of the cases presented by the CDC, which displayed an increase in cortical echogenicity, is consistent with subcapsular hemorrhage. Moreover, in all the cases described by the CDC and by other authors, the victims suffered from nausea, vomiting, and abdominal pain, which were the chief symptoms at presentation [45][46][47][48]. AKI was also described in combination with fatal hepatic failure after the intake of another fluoro-SC, quinolin-8-yl 1-(5-fluoropentyl)-1H-indole-3-carboxylate (5F-PB-22) [38].…”

Section: Discussionmentioning

confidence: 99%

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Four cases of death involving the novel synthetic cannabinoid 5F-Cumyl-PEGACLONE

et al. 2019

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Purpose Cumyl-PEGACLONE was the first synthetic cannabinoid (SC) with a γ-carbolinone core structure detected in forensic casework and, since then, it has dominated the German SC-market. Here the first four cases of death involving its fluorinated analog, 5F-Cumyl-PEGACLONE, a recently emerged γ-carbolinone derived SC, are reported. Methods Complete postmortem examinations were performed. Postmortem samples were screened by immunoassay, gas chromatography mass spectrometry (GC-MS) or liquid chromatography tandem mass spectrometry. For quantification of SCs, the standard addition method was employed. Herbal blends were analyzed by GC-MS. In each case of death, the Toxicological Significance Score (TSS) was assigned to the compound. Results 5F-Cumyl-PEGACLONE was identified at concentrations ranging 0.09-0.45 ng/mL in postmortem femoral blood. In case 1, signs of hypothermia and kidney bleedings were noted. Despite a possible tolerance due to long term SC use, a TSS of 3 was assigned. In case 2, an acute heroin intoxication occurred and a contributory role (TSS = 1) of 5F-Cumyl-PEGACLONE was suggested. In case 3, a prisoner was found dead. GC-MS analysis of herbal blends, retrieved in his cell together with paraphernalia, confirmed the presence of 5F-Cumyl-PEGACLONE and a causative role was deemed probable (TSS = 2). In case 4, the aspiration of gastric content due to a SC-induced coma was observed (TSS = 3). Conclusions 5F-Cumyl-PEGACLONE is an emerging and extremely potent SC which raises serious public health concerns. A comprehensive analysis of circumstantial, clinical, and postmortem findings, as well as an in-depth toxicological analysis is necessary for a valid interpretation and for the assessment of the toxicological significance.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Four cases of death involving the novel synthetic cannabinoid 5F-Cumyl-PEGACLONE

et al. 2019

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“…Importantly, the aforementioned adverse effects associated with SCRA use are not typically observed following cannabis consumption . Cases of coagulopathies following SCRA consumption in the United States have recently been linked to the presence of a potent vitamin K antagonist (brodifacoum [ 9 ]) in certain batches of SCRA‐containing products . At present, it remains unclear if this presence of 9 in certain batches of SCRA‐containing products is deliberate or accidental.…”

Section: Introductionmentioning

confidence: 99%

Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

Alam

Keating

2020

Drug Testing and Analysis

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Synthetic cannabinoid receptor agonists (SCRAs) first appeared on the international recreational drug market in the early 2000s in the form of SCRA‐containing herbal blends. Due to the cannabimimetic effects associated with the consumption of SCRAs, they have acquired an ill‐informed reputation for being cheap, safe, and legal alternatives to illicit cannabis. Possessing high potency and affinity for the human cannabinoid receptor subtype‐1 (CB1) and ‐2 (CB2), it is now understood that the recreational use of SCRAs can have severe adverse health consequences. The major public health problem arising from SCRA use has pressed legislators around the world to employ various control strategies to curb their recreational use. To circumvent legislative control measures, SCRA manufacturers have created a wide range of SCRA analogs that contain, more recently, previously unencountered azaindole, γ‐carbolinone, or carbazole heterocyclic scaffolds. At present, little information is available regarding the chemical syntheses of these newly emerging classes of SCRA, from a clandestine perspective. When compared with previous generations of indole‐ and indazole‐type SCRAs, current research suggests that many of these heterocyclic SCRA analogs maintain high affinity and efficacy at both CB1 and CB2 but largely evade legislative control. This review highlights the importance of continued research in the field of SCRA chemistry and pharmacology, as recreational SCRA use remains a global public health issue and represents a serious control challenge for law enforcement agencies.

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“…A very recent paper described an US area‐endemic incident of synthetic cannabinoids associated with many cases of bleeding. The authors suggested that these synthetic cannabinoids, manufactured specifically for abuse under uncontrolled conditions, may have been purposely contaminated with warfarin‐like anticoagulants to potentiate effects of cannabinoids through inhibition of cytochrome P450 . However, as preparations containing cannabis are not widely marketed as conventional pharmaceutical drugs, safety data pertaining to medical remain insufficient.…”

Section: Introductionmentioning

confidence: 99%

Interaction between warfarin and cannabis

Damkier

Lassen

Christensen

et al. 2018

Basic Clin Pharma Tox

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Delta‐9‐tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug‐drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27‐year‐old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9‐mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increases INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis use.

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An Outbreak of Synthetic Cannabinoid–Associated Coagulopathy in Illinois

Cited by 71 publications

References 24 publications

Four cases of death involving the novel synthetic cannabinoid 5F-Cumyl-PEGACLONE

Four cases of death involving the novel synthetic cannabinoid 5F-Cumyl-PEGACLONE

Adding more “spice” to the pot: A review of the chemistry and pharmacology of newly emerging heterocyclic synthetic cannabinoid receptor agonists

Interaction between warfarin and cannabis

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