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      Notes from the Field: Outbreak of Severe Illness Linked to the Vitamin K Antagonist Brodifacoum and Use of Synthetic Cannabinoids — Illinois, March–April 2018

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          Abstract

          Synthetic cannabinoids, also known as K2 and spice, are heterogeneous psychoactive compounds identified as substances of abuse ( 1 , 2 ). On March 22, 2018, the Illinois Department of Public Health was notified by the Illinois Poison Center of four patients seen in emergency departments (EDs) during the preceding 2 weeks with unexplained bleeding and high international normalized ratios (INRs; range from 5 to >20 [normal <1.1]), indicating a clotting disorder, and reported synthetic cannabinoid use during the previous 3 days. None reported taking prescription anticoagulants or exposure to anticoagulant rodenticides. An investigation by the Illinois Department of Public Health, the Illinois Poison Center, CDC, local health departments, and law enforcement agencies was initiated to identify additional cases, ascertain epidemiologic links among patients, and implement control measures. Requests for information regarding patients with serious bleeding and an elevated INR without a definitive etiology identified on or after February 1, 2018, were issued to Illinois EDs, emergency medical services, health care providers, local health departments, and coroners through Epi-X,* state and local health alert systems, and electronic distribution lists. Syndromic surveillance queries were developed by the Illinois Department of Public Health and implemented to identify patients evaluated at EDs and urgent care centers. Seven press releases encouraged anyone with a serious reaction after using synthetic cannabinoids to seek immediate medical attention. Based on clinical signs and symptoms (unexplained bleeding, prolonged high INR values, and response to fresh frozen plasma and high doses of vitamin K), exposure to a long-acting vitamin K antagonist was suspected. Case definitions were developed based on signs and symptoms, synthetic cannabinoid exposure, and laboratory findings (Box). Data concerning signs and symptoms; synthetic cannabinoid use, brand, and location of purchase; and exposure to rodenticides, prescription anticoagulants, and illicit drugs were collected through patient interviews, medical chart abstraction, and Illinois Poison Center consultations. Blood samples were tested for presence of anticoagulants by high-performance liquid chromatography–tandem mass spectrometry (NMS Laboratories, Willow Grove, Pennsylvania). BOX Case definitions for unexplained bleeding after use of synthetic cannabinoids — Illinois, 2018 Clinical criteria Bruising, nosebleeds, bleeding gums, bleeding disproportionate to injury, vomiting blood, coughing up blood, blood in urine or stool, or excessively heavy menstrual bleeding. Laboratory criteria Elevated international normalized ratios (INRs; ≥2.0) or abnormal coagulation profile (e.g., prothrombin time in absence of INR values) for which there is no other clinical explanation, or Detection of a long-acting anticoagulant (e.g., brodifacoum) in blood, serum, plasma, or urine, as determined by reference laboratory testing. Case classification Suspected case One or more of the clinical criteria listed above in a patient, without an alternative explanation, and with reported use of synthetic cannabinoids or unknown drugs, or with some suspicion of previous or current drug use or exposure. Probable case One or more of the clinical criteria listed above in a patient with reported use of synthetic cannabinoids in the 3 months preceding illness onset (by patient, proxy, medical record, or health care provider), and laboratory evidence of coagulopathy as measured by meeting the first laboratory criterion listed above, or One or more of the clinical criteria listed above, and meeting both laboratory criteria listed above, with no other explanation of results. Confirmed case One or more of the clinical criteria listed above in a patient, with reported use of synthetic cannabinoids in the 3 months preceding illness onset (by patient, proxy, medical record, or health care provider), and meeting the second laboratory criterion listed above. As of April 25, 2018, a total of 155 cases (76 confirmed and 79 probable) had been identified; four (2.6%) patients died from major bleeding events. Median patient age was 32 years (range = 18–65 years), 115 (74%) were male, 81 (52%) were non-Hispanic white, 147 (95%) were hospitalized, and eight (5%) were treated in an ED only. The most frequently reported sign was hematuria (125; 81%); all patients reported bleeding from at least one site. INRs were elevated in all patients. All 81 (52%) analyzed clinical specimens from patients with a confirmed or probable case were positive for brodifacoum, a long-acting vitamin K antagonist used in rodenticides. Although cases clustered in two geographic areas (the Chicago area and seven neighboring counties in central Illinois), no single product source has been identified. Law enforcement is investigating the synthetic cannabinoid distribution network. Thirty-eight patients have been identified in eight other states, and CDC is conducting a multistate investigation ( 3 ). Product testing is ongoing in Illinois; some products in other states have tested positive for brodifacoum ( 4 ). Currently, the reason why brodifacoum was present in the synthetic cannabinoids is not known. In 2017, 26 synthetic cannabinoids were listed as Schedule I substances under the Controlled Substances Act ( 5 ). However, they are often marketed as alternatives to marijuana or labeled as not for human consumption ( 5 , 6 ). They remain available for purchase, are relatively inexpensive, and are sometimes favored over marijuana because they are not detected in routine drug testing ( 2 , 6 ). The synthetic cannabinoid supply chain is unregulated, resulting in variable product compositions ( 2 ). Given the various compounds and unclear provenance, use of these products can result in unpredictable health effects ( 1 ). Stronger public messaging is needed and should target persons at risk. Engaging substance abuse services and community coalitions might improve outreach. Health care providers should consider vitamin K-dependent coagulopathy in patients with unexplained bleeding and reported or suspected synthetic cannabinoid use.

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          Synthetic cannabinoids: epidemiology, pharmacodynamics, and clinical implications.

          Synthetic cannabinoids (SC) are a heterogeneous group of compounds developed to probe the endogenous cannabinoid system or as potential therapeutics. Clandestine laboratories subsequently utilized published data to develop SC variations marketed as abusable designer drugs. In the early 2000s, SC became popular as "legal highs" under brand names such as Spice and K2, in part due to their ability to escape detection by standard cannabinoid screening tests. The majority of SC detected in herbal products have greater binding affinity to the cannabinoid CB1 receptor than does Δ(9)-tetrahydrocannabinol (THC), the primary psychoactive compound in the cannabis plant, and greater affinity at the CB1 than the CB2 receptor. In vitro and animal in vivo studies show SC pharmacological effects 2-100 times more potent than THC, including analgesic, anti-seizure, weight-loss, anti-inflammatory, and anti-cancer growth effects. SC produce physiological and psychoactive effects similar to THC, but with greater intensity, resulting in medical and psychiatric emergencies. Human adverse effects include nausea and vomiting, shortness of breath or depressed breathing, hypertension, tachycardia, chest pain, muscle twitches, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and cognitive impairment. Long-term or residual effects are unknown. Due to these public health consequences, many SC are classified as controlled substances. However, frequent structural modification by clandestine laboratories results in a stream of novel SC that may not be legally controlled or detectable by routine laboratory tests.
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            Synthetic Cannabinoids.

            Synthetic cannabinoids (SCBs), also known under the brand names of "Spice," "K2," "herbal incense," "Cloud 9," "Mojo" and many others, are becoming a large public health concern due not only to their increasing use but also to their unpredictable toxicity and abuse potential. There are many types of SCBs, each having a unique binding affinity for cannabinoid receptors. Although both Δ-tetrahydrocannabinol (THC) and SCBs stimulate the same receptors, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), studies have shown that SCBs are associated with higher rates of toxicity and hospital admissions than is natural cannabis. This is likely due to SCBs being direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Furthermore, the different chemical structures of SCBs found in Spice or K2 may interact in unpredictable ways to elicit previously unknown, and the commercial products may have unknown contaminants. The largest group of users is men in their 20s who participate in polydrug use. The most common reported toxicities with SCB use based on studies using Texas Poison Control records are tachycardia, agitation and irritability, drowsiness, hallucinations, delusions, hypertension, nausea, confusion, dizziness, vertigo and chest pain. Acute kidney injury has also been strongly associated with SCB use. Treatment mostly involves symptom management and supportive care. More research is needed to identify which contaminants are typically found in synthetic marijuana and to understand the interactions between different SBCs to better predict adverse health outcomes.
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              Acute Poisonings from Synthetic Cannabinoids — 50 U.S. Toxicology Investigators Consortium Registry Sites, 2010–2015

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                Author and article information

                Journal
                MMWR Morb Mortal Wkly Rep
                MMWR Morb. Mortal. Wkly. Rep
                WR
                Morbidity and Mortality Weekly Report
                Centers for Disease Control and Prevention
                0149-2195
                1545-861X
                01 June 2018
                01 June 2018
                : 67
                : 21
                : 607-608
                Affiliations
                Epidemic Intelligence Service, CDC; Communicable Disease Control Section, Illinois Department of Public Health; Illinois Poison Center, Illinois Health and Hospital Association, Chicago, Illinois; Division of State and Local Readiness, Office of Public Health Preparedness and Response, CDC; Council of State and Territorial Epidemiologists Applied Epidemiology Fellowship; Peoria City/County Health Department, Illinois; Tazewell County Health Department, Tremont, Illinois; City of Chicago Department of Public Health, Illinois; Division of Environmental Health Science and Practice, National Center for Environmental Health, CDC; Geospatial Research Analysis and Services Program, National Center for Environmental Health/Agency for Toxic Substances and Disease Registry, CDC; Emory University School of Medicine, Atlanta, Georgia; Division of Laboratory Sciences, National Center for Environmental Health, CDC.
                Author notes
                Corresponding author: Erin Moritz, emoritz@ 123456cdc.gov , 217-782-2016.
                Article
                mm6721a4
                10.15585/mmwr.mm6721a4
                6038901
                29851941
                e43fd281-bd57-4681-be7e-30c1778fbb01

                All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated.

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