Synthetic Cannabinoids and Life Threatening Coagulopathy

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.

Brodifacoum

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.








 

JWH Compounds Make the NEJM

JWH-018

AMB-FUBINACA

Synthetic cannabinoids have been a problem for over a decade.  There have been sensational news reports that typically occur as a result of aggressive and disorganized behavior when users are acutely intoxicated.  When these compounds initially started to appear on the scene, regulators were far behind the curve.  Some of the first forms were sold in head shops, wrapped in paper and labelled "Not For Human Consumption."  They went by names like K2, Spice, and Plant Food.  They are typically applied to shredded plant material so that they can be smoked.   The chemical structures of these compounds do not resemble typical cannabinoids and the synthesis is relatively straightforward.  That has facilitated black market production.  Apart from easy availability the other draw was that users could take these compounds and not have to worry about standard drug testing protocols in the work place.  The word on the street was that the synthetics were undetectable by typical urine toxicology and that was accurate.  Apart from isolated aggressive incidents there were also deaths associated with their use.  There were some epidemics that clustered in communities and eventually (like most drug epidemics) the sale of the compounds was prohibited and some head shop operators were prosecuted.

From the standpoint of addiction practice, many of these compounds create a dangerous situation for the patient and a dilemma for treatment facilities.  They are highly addictive to some people and unless there is some familiarity with the concept of delirium producing drugs causing addiction, it may not be clear why anyone would continue to use them.  Many people are amnestic for what occurred when they were under the influence.  In some cases they develop life threatening conditions as a result of use and crave the drug when they are being acutely treated for the medical complications.  Another abused drug with this kind of dissociative profile is dextromethorphan.  When used in high doses it leads to delirium and hallucinations and can be highly addictive.


The JWH designation represents the organic chemist John W. Huffman who synthesized the series of compounds as cannabinoid receptor agonists.  The goal of the research was to produce pharmacological probes to study cannabinoid receptors.  He is a coauthor on 30 papers in Medline.  There are several articles in the popular press including several that include his opinion about his original research being used to produce compounds for sale as street intoxicants.     JWH compounds have been in the medical literature since about 2005.  PubChem contains structural information on 281 JWH compounds, 367 protein targets, and 706 bioassays.  PubChem also allows the user to generate 2D and 3D structural similarity comparisons and bioactivity analyses - for example activity at the CB-1 and CB-2 receptor.  As the JWH compounds and other synthetics have evolved they follow a familiar pattern of the development of classes of addictive compounds - subsequent syntheses have increasing activity at the target receptor.

There are other classes of synthetic cannabinoids in addition to the JWH compounds including UR-144, AKB4, AB-CHMINACA, AB-FUBINAC and others.  There are also a number of psychedelic phenethylamines 2C-B, 2C-I, 3C-E, 3C-I, and 2C-P that are often sold as equivalent drugs.  There are obviously no guarantees that purchases from non-medical sources results in the desired chemical or effect.  There is a also a class of synthetic cathinines referred to as Bath Salts, that are structurally similar to amphetamines and are often sold as mephedrone, MDPV, or methylone.  The total number of synthetics and the requirement of relatively sophisticated analysis for detection (gas or liquid chromatography-mass spectrometry) frequently leaves the acute care or addiction physician depending on history alone about what was ingested.

The New England Journal of Medicine has a general review of the issue in the January 19, 2017 edition (1).  Full text of the article is available online.  The article details the current number of new psychoactive compounds as 540 with 177 identified synthetic cannabinoids in 2014.  They have an illustrated timeline of the evolution of these compounds from 2010 to 2016.  The most interesting aspect of the timeline is the evolution of a 50 fold increase in drug potency from JWH-018 in about 2010 to AMB-FUBINACA in 2016.

They also provide an analysis of a mini epidemic of AMB-FUBINACA use in Brooklyn that occurred in 2016.  Of the 33 people exposed - 18 required transport to medical facilities.  An index case is described with features of a blank stare and unresponsiveness 13/15 on the Glasgow Coma Scale.  He had episodic groaning and slowed movement of his extremities.  The term "zombielike" was used as a descriptor but in psychiatry that term is used so frequently by patients and untrained observers that it lacks meaning. The patient was sweating and had normal vital signs with the exception of tachypnea with a respiratory rate of 21.  Screening labs, toxicology, and ECG were all normal.  He recovered in about 9 hours and was discharged.  The authors recovered the original herbal product labelled "AK-47 24 Karat Gold"  and sent that as well as biological samples (blood and urine) from 8 other users for analysis.

The samples were analyzed with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS).  AMB-FUBINACA was confirmed as the compound in the original packet of material.  The de-esterified product rather than the parent compound was confirmed in the blood and urine of the patients with serum concentrations from 66 to 636 ng/ml.  

In the discussion the authors point out the potency increase with these synthetic compounds.  They illustrate the attractiveness to drug dealers and users - about $3800 of AMB-FUBINACA can produce about a half million dollars worth of product containing about 64 mg of the original compound sprayed over shredded plant material.  That is strong incentive for getting this drug out on the street.  They also discuss the role of inter-agency collaboration in identifying novel intoxicants during similar mini-epidemics.  In this case the entire timeline from case to molecular identification was 17 days.  In many toxicology cases that I have been involved with, it often takes that long to learn that the lab you are using is not able do the necessary analysis.

Treating patients addicted to these compounds will be a challenge in the foreseeable future.  People who changed to synthetics just to escape drug testing in the workplace have ended up addicted to these compounds.  The psychoactive side effects of the compounds frequently results in a downward spiral of job loss, loss of relationships, and social isolation that goes along with the preoccupation of using the drug.  Explaining to the patient and their family that this is a potentially life-threatening addiction is not necessarily a deterrent to further use and fatal outcomes are possible.  Understanding the motivation for using a drug that has never been tested in humans, can result in the loss of days or an entire weekend, and can result in toxidromes that directly or indirectly lead to fatal outcome may be another sign that this is a neurobiologically mediated process that bypasses rational thought.

Prevention would seem like it is the best approach but American society remains fascinated by intoxicants and Americans have plenty of money to spend on these drugs.  Like most political arguments the common sense approach of a better plan for living is lost between the poles of liberalized drug use and prohibition.  I hope that the people at highest risk for using these drugs can learn to avoid them without exposure.          


George Dawson, MD, DFAPA




References:


1. Adams AJ, Banister SD, Irizarry L, Trecki J, Schwartz M, Gerona R. "Zombie"Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York. N Engl J Med. 2017 Jan 19;376(3):235-242. doi: 10.1056/NEJMoa1610300. PubMed PMID:27973993. (free full text online).


Attribution:

Molecular structures at the  top of this post are generated from NLM PubChem interface and are public domain.


Additional Analyses Available from PubChem:

I ran two analyses for 281 and 279 JWH compounds.  Additional information is available if you run the analysis for yourself.

Supplementary:

I encountered some stories on the Internet about the chemists who originally synthesized these compounds in the course of their professional careers.  Some of them have felt badly about the morbidity and mortality associated with their use as street drugs.  Others have pointed out that they were not intended for human use and not tested in humans and therefore nobody should be using them.  Keeping in mind the profit motive suggested by the NEJM article and the incentives for gaming the system by finding compounds that are not on the Schedule of Controlled Substances, I don't think that there should be any question that the sellers and buyers of these drugs are responsible for the outcomes.

Some Arguments on Drug Tolerance and Prohibition

I have extensive experience treating people with alcohol and drug use problems.  I am always amazed at the lack of knowledge about addiction and alcoholism in the general public and how that impacts public policy.  As a result I occasionally get involved in public forums to argue a few points.  As a matter of disclosure I am thoroughly independent and vowed not to vote for any major party candidates a long time ago.  That doesn't prevent people from sending me heated e-mails accusing me of either being a Democrat or a Republican.  Of course you can also be attacked for being a independent and being too much of an elitist to not accept the fact that only major party candidates can be elected.  I have never found that to be a compelling argument.  My latest post to the quoted excerpt follows.  You can read the entire sequence of posts by clicking the link at the bottom.  There are obvious limitations to engaging in this exercise and that should be evident by reading the exchange right up to the last post where I get the expected shot for being a psychiatrist.  Tiresome isn't it?

“Come again...Politicians are pushing for legalization?  Politicians have been spewing the “war on drugs” “tough on crime” protecting the “fabric of society” bullshit for the last 40-plus years.”

Sorry – I try just to stay to the facts.  If you read the actual history of drug use in this country we swing from periods of prohibition to drug tolerance.  We are currently swinging into a period of drug tolerance and I fully expect to see drugs legalized in some way or another in most states.  So I really don’t have a stake in this fight either way.  So you can lighten up.  I am not “on your side” but I can predict with certainty that it will happen.  You can Google “politicians who support drug legalization” as well as I can.  As more of them get on board you will hear an escalation in rhetoric on how they will tax and control it.

You can put any type of spin on it you want – more freedom, freedom from the war on drugs, ability to generate more taxes, ability to treat any problem you might have with medical marijuana, you name it – history shows the outcome will be the same.  If you are still serious about legalizing heroin and coca like you previously stated that experiment has already been done and the outcome will be the same.  That experiment is being done right now with diverted legal opioids (the source of synthetic heroin) and according to the CDC we are in about year ten of an opioid epidemic that is killing more people in many states than motor vehicle accidents – about 15,000 people a year.  If you consider that the drugs typically called synthetic heroin on the street are usually pharmaceuticals with known safe doses, that also illustrates the nature of the problem.  If you think that nobody will be looking for synthetic marijuana if marijuana is legalized – I know that is false per my previous post.  No matter how free you are to smoke marijuana, there are very few employers I know of that will tolerate it at work and none if you are in a job where your decision making can lead to substantial liability. 

The problem with the “war on drugs” and excessive incarceration of people with drug charges in many ways parallels the excessive incarceration of the mentally ill because we have a health care system that is politically managed.  The politicians realized a long time ago that you can save health care costs by incarcerating the mentally ill instead of treating them in medical settings.  It may not have been a conscious decision up front but they have done little to stop it after it was clearly underway.  The three largest mental hospitals in the US right now are county jails.  Addicts in many cases are treated even more poorly if they are incarcerated because they do not get medically supervised detoxification and go through acute withdrawal.

In any “war” somebody has to be blamed and denied resources.  I prefer Musto’s analysis of the US tending to blame other countries for our drug problems:  “That analysis avoids the painful and awkward realization that the use of dangerous drugs may be an integral part of American society.”  That is reminiscent of Mexico’s Past President Vincente Fox pointing out that Mexico’s problem with cartel violence is fueled by America’s massive appetite for drugs supplying the money.  On that basis he was a proponent of the legalization and control of marijuana argument.  That doesn’t address the massive appetite for drugs problem.

The problem with the politics of addictive drugs is that people generally don’t know much about addiction.  There is a significant portion of the population that is vulnerable and the only thing it takes in increased availability for them to start having significant problems.

So good luck with the new temporary American dream of increased access to intoxicants and enjoy it while you can.  Depending on exactly what gets legalized – I would predict that would be the next 20 – 40 years.  That is the usual time it takes to complete a cycle.

Minnesota Politics and Issues Forum

George Dawson, MD, DFAPA

David F. Musto.  The American Disease: Origins of Narcotic Control.  Third Edition.  New York, Oxford University Press, 1999: p 298.  

Additional Clinical Note 1: A couple of graphs from my other blog that show alcohol use patterns over time are available on my other blog for the United States and the United Kingdom.  Graphs of opioid consumption over the past decade by the UN drug control agency shows a linear increase in consumption and production.

Additional Clinical Note 2:  If you had the patience to follow the political thread you probably notice the marijuana advocate trying to tell me that I was saying there was an epidemic of synthetic marijuana abuse that occurred with the legalization of marijuana.  My argument was simply that marijuana users if they are screened for THC at work will switch to synthetic marijuana in order to avoid positive toxicology screens and job loss.  Now in the February 5, 2014 edition of JAMA a report from the CDC it turns out that there was an "outbreak" of synthetic marijuana use in Colorado in August and September that involved about 200 people.  There was a similar outbreak in Georgia in August of 2013.  In addition  to the medical characteristics I would encourage the CDC to collect data on how many people were smoking marijuana to avoid toxicology testing and how many people were unable to stop smoking marijuana in order to achieve that same goal. I sent the CDC a note on how to refine their methodology. 

Supplementary Material Note 1:  My response from the CDC.