Just when I thought that renal failure was the only unexpected complication of synthetic cannabinoids - it turns out they can also cause bleeding or more specifically Vitamin K dependent antagonist coagulopathy. The basic mechanism of action is noted in the above diagram on the action of warfarin on Vitamin K dependent mechanisms that can lead to an anticoagulated state. Warfarin and similar Vitamin K antagonists block the function of the vitamin K epoxide reductase complex. That blocks the recycling of Vitamin K epoxide and eventual depletion of Vitamin K. That is turn leads to no gamma carboxylation of Vitamin K dependent coagulation factors (depicted here as descarboxy prothrombin being converted to prothrombin (Factor II), but factors VII, IX, and X are also involved).
The anticoagulated state can be used therapeutically to prevent embolic strokes or recurrent pulmonary emboli, but warfarin has a very narrow therapeutic index and it needs to be monitored closely in patients who are also watching their diet and drug interactions to prevent excessive anticoagulation and bleeding that can be fatal. The warfarin effect can be reversed by Vitamin K administration.
The CDC issued an outbreak alert last month about an outbreak that occurred in the midwest - largely Illinois about unexplained bleeding. The time frame where this was noted was the previous year. People were presenting to emergency departments with unexplained bleeding ( no exposure to anticoagulants or anticoagulant containing rat poison and no medical explanation for the bleeding). In their Clinical Action Alert they explain the symptoms of coagulopathy including bleeding from the gums, nose, gastrointestinal tract, genitourinary tract, excessive bruising, unexplained abdominal of flank pain, mental status change, feeling faint, and collapse. There were a total of two fatalities at the time of the alert and medical evaluation and treatment with Vitamin K and fresh frozen plasma suggested that the toxicity was due to brodifacoum a long acting Vitamin K antagonist found in rat poison.
Ninety four people were involved through April 5, 2018. Since that time the Illinois web site following this outbreak reports 164 cases including 4 deaths since March 2018. They name a few of the brands commonly sold including K2, Spice, Black Mamba, Bombay Blue, Genie, and Zohai but emphasize that there are a large number of these compounds as listed in a previous post on this blog. As previously noted, synthetic cannabinoids are basically highly concentrated organic chemical that are sprayed in plant material to facilitate smoking. When I checked the medical literature to see if these cases were written up and specific biochemical analyses done - I found the only reference brodifacoum was a study done (1) that looked at the results of applications to areas around marijuana growing operations. Anticoagulant based rodenticides are apparently used to prevent damage to the crop and are described as being used extensively. This study looked at marijuana growers on California and the relationship to wildlife species. In this case a threatened species the northern spotted owl was necropsied and it was demonstrated that the liver and blood contained high concentrations of brodifacoum. The authors point out a basic ecological principle that if the target of the rodenticide is rodent - it will be concentrated to higher levels in the predators higher in the food chain. The alarming situation here is the fact that dead wildlife from rodenticide poisoning have been found around 22% of 41 marijuana growers in 3 California counties.
The message from the CDC and the Illinois Department of Public Health (IDPH) was clear. Be aware of the problem, recognize coaglopathies, and be prepared to intervene. The IDPH advises consumers to watch for bleeding and bruising if they have used these compounds and if it occurs to seek emergency assistance. The CDC discusses the high cost of Vitamin K therapy and possible shortages, the need to warn post op patients not to use these compounds, and concern that some of the affected patients may be plasma donors.
Addiction docs and acute care psychiatrists need to have a higher index of suspicion, especially in settings where people are admitted rapidly for detoxification and stabilization and if the patient gives a history of synthetic cannabinoid use. The commonest current coagulopathy in those settings is probably alcohol related and that is relatively rare.
Additional concerns would include the possibilities that the rodenticide could be sprayed on some cannabis plants and be ingested or smoked by people who believe they are using cannabis. An associated concern is that the contaminated synthetic material was considered plant waste from cannabis products and just used as a carrier for the synthetic cannabinoids. That is a potential reason why the synthetics were contaminated with brodifacoum in the first place.
As far as I know there have been no reports of the problem in cannabis smokers who were not using synthetic cannabinoids.
The authors of reference 1 point out that since cannabis is not regulated as an agricultural product there are no regulations about what can be applied to it when it is grown. It seems like another disadvantage of a laissez-faire approach to drug regulation.
Coagulopathy is just another in a long list of reasons to stay away from synthetic cannabinoids and to beware of other toxic effects from street drugs. There has always been some concern over what chemicals and biologicals end up in smoked or ingested cannabis. Rodenticide should be added to that list until it is effectively ruled out by sampling and testing of the products being sold.
George Dawson, MD, DFAPA
References:
1: Franklin AB, Carlson PC, Rex A, Rockweit JT, Garza D, Culhane E, Volker SF,Dusek RJ, Shearn-Bochsler VI, Gabriel MW, Horak KE. Grass is not always greener: rodenticide exposure of a threatened species near marijuana growing operations. BMC Res Notes. 2018 Feb 2;11(1):94. doi: 10.1186/s13104-018-3206-z. PubMed PMID: 29391058;
2: Brodifacoum on ToxNet.
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3: Minnesota Department of Health. Health Advisory: Significant Bleeding Associated with Contaminated Synthetic Cannabinoids. April 5, 2018.
4: Minnesota Department of Health. Health Advisory Network. See additional links.
Graphics:
1: Mechanism of warfarin slide at the top is from Visiscience slides online per their user agreement.
2: Brodifacoum chemical structure from PubChem.
