Saturday, April 7, 2018

CDC Warning - Vitamin K Dependent Antagonist Coagulopathy Associated With Synthetic Cannabinoid Use

Looks like the issue has spread - which isn't all that surprising. But is frightening.

The Center for Disease Control (CDC) issued a warning regarding the surge in severe bleeding cases associated with synthetic cannabinoid use from Illinois. From March 10 to April 5, 2018, ninety-four (94) people have presented to the hospital with severe bleeding symptoms after exposure to herbal incense/potpourri synthetic cannabinoid products. Eighty nine (89) of the cases are in Illinois, with the remaining five (5) originating in Indiana, Maryland, Missouri, and Wisconsin. There has been positive analytical confirmation of Brodifacoum in at least eighteen (18) individuals, with two (2) fatalities. Brodifacoum has been identified as a constituent in three (3) synthetic cannabinoid products.

Read here and here for previous my updates on this issue as well as a quick explainer as to what Brodifacoum actually is.



If you are on Twitter, check out Dr. Steve Aks (@ERtox) and Cook County Medical Examiner's Office (@CookCountyME) for updates.

Be safe.


References

Outbreak Alert: Potential Life-Threatening Vitamin K Dependent Antagonist Coagulopathy Associated With Synthetic Cannabinoid Use
https://content.govdelivery.com/accounts/USCDC/bulletins/1e6dac3
Accessed: April 7, 2018

Tainted Synthetic Pot Eyed As Cause Of Another Illinois Death As Store Owner Accused Of Selling Substance Held Without Bail
http://www.chicagotribune.com/news/local/breaking/ct-met-fake-pot-poison-cook-county-20180406-story.html
Accessed: April 7, 2018

Bleeding and Coagulopathy Associated with Synthetic Cannabinoid Products
https://dosemakespoison.blogspot.com/2018/03/bleeding-and-coagulopathy-associated.html

Update of an Outbreak of Severe Bleeding Cases / Synthetic Cannabinoid Use
http://dosemakespoison.blogspot.com/2018/04/update-of-outbreak-of-severe-bleeding.html

Tuesday, April 3, 2018

Update of an Outbreak of Severe Bleeding Cases / Synthetic Cannabinoid Use

As I wrote about the other day, there was a mass outbreak of severe bleeding cases associated with synthetic cannabinoid use in Illinois during March. As of March 29, there were 22 reports of vitamin K dependent severe coagulopathy.

Five days later and there have been 56 affected individuals. Symptoms include coughing up blood, blood in the urine, severe bloody nose, and/or bleeding gums. Nine people have tested positive for the vitamin K antagonist Brodifacoum (see my last post for explanation of its effects). Two people have died.

Three people have been arrested in Chicago in connection to selling some herbal incense/potpourri products that (according to police) have detectable amounts of Brodifacoum.

Dump your product if you have any.

Stay safe out there.



References

Bleeding and Coagulopathy Associated with Synthetic Cannabinoid Products
https://dosemakespoison.blogspot.com/2018/03/bleeding-and-coagulopathy-associated.html

Second Death of An Individual Who Used Synthetic Cannabinoids
http://www.dph.illinois.gov/news/second-death-individual-who-used-synthetic-cannabinoids
Accessed April 3, 2018.

3 Chicago Store Clerks Charged With Selling Synthetic Pot Laced With Rat Poison
http://abcnews.go.com/US/chicago-store-clerks-charged-selling-synthetic-pot-laced/story?id=54197525
Accessed April 3, 2018.

Thursday, March 29, 2018

Bleeding and Coagulopathy Associated With Synthetic Cannabinoid Products

There have been warnings out of Chicago over the last couple days regarding users of synthetic cannabinoid products experiencing abnormal bleeding issues especially from the eyes and ears. As of today (Thursday, March 29), there have been 22 reports in the Chicago area since March 7. Vitamin K dependent severe coagulopathy has been observed in several cases which is consistent with exposure to a 4-hydroxycoumarin rodenticide (superwarfarin) such as brodifacoum.

 
Chemical Structure of Brodifacoum
Drawn by Kevin G. Shanks (2018)

A substance such as Brodifacoum inhibits the action of the vitamin K epoxide reductase enzyme. This enzyme inhibition interferes with the recycling of vitamin K epoxide to vitamin K and ultimately results in a steady decrease in blood vitamin K, which is a problem, because vitamin K is a vital part of the synthesis of prothrombin (coagulation factor II). Prothrombin is involved in the blood coagulation cascade, also known as blood clotting.

Low vitamin K means severely impacted blood clotting which can result in profuse bleeding.

Another effect of Brodifacoum is the increase in permeability of blood capillaries, leading to internal hemorrhaging, or when blood leaks from vessels. An individual can bleed internally progressively with time.

Brodifacoum is a highly lipophilic substance and has an extremely slow elimination pathway from the body. Biological half-life of the substance is 20-130 days. LD50 values for mammals are substantially less than 1.0 mg/kg. It is a potent substance with a long duration of action that can result in devastating effects in humans (and animals) - afterall, it's primary (only) use is to kill warfarin-resistant rodents (hence the class name superwarfarins).

Other superwarfarins include Bromadiolone, Coumatetralyl, Difenacoum, Flocoumafen, and Tioclomarol.

This is not the typical media hysteria/hyperbole that we all have grown accustomed to over the years with reporting on drugs. While no specific products have yet been implicated, my advice is that if you are a synthetic cannabinoid user (or know a user) in the Illinois area (including bordering states), discard your supply. Immediately.

Be safe.



References

Outbreak: severe coagulopathy associated with synthetic cannabinoids (K2/Spice)
http://myemail.constantcontact.com/Outbreak--Severe-coagulopathy-associated-with-Synthetic-Cannabinoids---K2-Spice--.html?soid=1100929526407&aid=_6hDV-Frs5Q; Accessed March 29, 2018.

Synthetic pot warning issued after 22 people in Illinois report bleeding from eyes, ears
http://www.chicagotribune.com/news/local/breaking/ct-met-fake-weed-synthetic-cannabis-warning-20180329-story.html; Accessed March 29, 2018.

Illinois health officials warn of synthetic pot after 17 people report of severe bleeding.
http://wgntv.com/2018/03/29/illinois-heath-officials-warn-of-synthetic-pot-after-17-people-report-severe-bleeding/; Accessed March 29, 2018.

IDPH issues warning about synthetic cannabinoids.
http://dph.illinois.gov/news/idph-issues-warning-about-synthetic-cannabinoids; Accessed March 28, 2018.

Friday, March 9, 2018

High Impact Research from JAT

One of my papers from 2014 is listed among the "highly cited articles" in the Journal of Analytical Toxicology. It involves the analytical detection of the synthetic cannabinoid 5F-PB-22 in postmortem toxicology and presentation of four deaths that were associated with its use. You can read it, along with other papers, for free at the link below. Have fun reading!

High-Impact Research from JAT

Wednesday, February 14, 2018

Forensic Toxicology Valentines

Happy Valentine's Day!

Here are a few Valentine's wishes.

Roses are CO red.
Violets are cyanotic blue.
Let's hope you're neither already dead,
Nor hypoxic too.

Postmortem blood is red.
And sometimes blue,
And oftentimes green.
And maybe black too.

Decomposed liver is brown.
Decomposed liver is too.
Decomposed kidney is also brown.
Why is everything brown?

Postmortem blood is red.
It may also be blue,
Though it can be black.
It smells horrible, too.

MDMA and cannabis are Schedule I.
LSD is too.
Do they belong?
Let me ask you.

Sunday, February 11, 2018

NERD and Rihanna - Lemon

NERD and Rihanna’s song Lemon came across my Spotify list last night. The song came out a few months ago but this was my first time ever hearing it.

"Bath salt...bitin’ speakers in the face..."

Yes, the infamous 2012 Causeway Cannibal bath salts attack is referenced here - the attack that was not ever shown to be “bath salt” related, not to mention even drug related at all.

Here’s a link to the song. It's got a nice beat. Enjoy!


Friday, February 9, 2018

Kratom Redux

Kratom is back in the news. 

Long story short...

During the summer of 2016, the DEA moved to place kratom (mitragynine/7-hydroxymitragynine) into Schedule I of the Controlled Substances Act. Almost immediately there was a massive outcry from advocates of the plant, as well as members of Congress, toxicologists, and physicians. I initially wrote about this here. In an unprecedented move, the DEA rescinded their Notice of Intent in Fall 2016. In the Withdrawal, the DEA stated that they would accept public comment on the scheduling of these substances until December 1, 2016 as well as request a scientific/medical evaluation of the substances from the Food and Drug Administration (FDA). During the approximate 2 month comment period, the DEA received around 20,000+ comments, with near 100% having positive comments on the plant.

The FDA has now released their report on Kratom. If you want to read the 164 page document, you can find it here.

I'm not going to go into much here, because other folks have covered it comprehensively.

Nick Wing, a senior reporter with the Huffington Post, covered the FDA report and methodically looked at the case reports where Kratom was associated with cause of death that were covered in the FDA report. You can find his article here.

Dr. David Kroll at Forbes covered it as well and his excellent work can be found here.

Kratom researchers in academia from across the USA and Canada also penned a letter to the DEA and the White House's newly established Opioid Commission. The letter can be found here.

I highly recommend reading the links as they are all spot on.

When the DEA initially moved to schedule Kratom in summer 2016, I said the move was misguided. And farcical. And that the DEA hadn't thought it completely through. 

And after reading the FDA's report, I still believe that.

Tuesday, January 30, 2018

Random Observations on the Opioid Epidemic

Stop treating substance use, dependence, and addiction as a crime.

Listen to doctors and nurses. Listen to medical professionals. Listen to toxicologists.

The answer is not always, "Make it illegal!" or "It needs to be a controlled substance."

Stop throwing drug users in jail. Get those folks who are dependent or addicted the treatment they need.

Increase access to medical treatment for drug dependence/addiction.

Expand methadone and buprenorphine maintenance treatment.

Think about the harm reduction potential of safe injection sites and clean needle programs.

Don't conflate the medical use of pharmaceutical opioids with the misuse of pharmaceutical opioids.

Recognize the need for compassionate pain management.

Legalize medical and recreational cannabis.

Naloxone should be available over the counter everywhere.

Sunday, January 28, 2018

Call for Abstracts and Speakers - MATT 2018

This will be one of the rare times you'll see a work affiliated post on this blog.

I'm chairing the scientific program for the Midwest Association of Toxicology and Therapeutic Drug Monitoring (MATT) meeting. The 2018 meeting will be held in Indianapolis, IN on April 12-13th.

The meeting announcement can be found here. There will be more information coming very soon.

If you have a toxicology topic of interest to present (either poster or oral presentation), please contact me at kshanks@axisfortox.com.



Saturday, January 20, 2018

In the News: Tom Petty

The Los Angeles County, California Medical Examiner/Coroner's Office released Tom Petty's official cause and manner of death yesterday.

The cause of death was "multisystem organ failure due to resuscitated cardiopulmonary arrest due to mixed drug toxicity (fentanyl, oxycodone, temazepam, alprazolam, citalopram, acetylfentanyl, and despropionylfentanyl).

Other conditions listed included coronary artery atherosclerosis and emphysema.

Manner of death was accident.

Tom Petty's family released a statement on social media and his personal website. The statement can be read here.

_______________________________

What were the substances found in his system?

Several central nervous system depressants or related substances and an antidepressant.
Fentanyl is an synthetic opioid typically prescribed as the pharmaceutical medications Duragesic (transdermal), Actiq (oral transmucosal), or Fentora (buccal). Historically, it has been used to treat breakthrough pain and is used in pre-operation procedures as an analgesic and anesthetic. Fentanyl is a mu opioid receptor agonist that is considered to be approximately 100-200 times as potent as morphine as an analgesic. It is metabolized to norfentanyl. The substance is also illicitly manufactured in clandestine laboratories and has been found as a very common adulterant in street heroin and counterfeit tablets over the last few years. Fentanyl is a Schedule II controlled substance in the USA.
Oxycodone is a semisynthetic opioid that is derived from thebaine. Trade names of the  pharmaceutical medication include OxyContin, OxyIR, Roxicodone, Percocet, or Endocet. It is typically used for the relief of moderate to severe pain. It functions as a mu opioid receptor agonist. Oxycodone is metabolized to oxymorphone and noroxycodone. Oxycodone is a Schedule II controlled substance in the USA.
Temazepam is a benzodiazepine routinely prescribed as the brand name Restoril. Chemically, it is a 3-hydroxyl derivative of diazepam (trade name Valium). It is used for the treatment of short term insomnia. It functions as a GABAA receptor agonist. Temazepam is metabolized to the oxazepam. Temazepam is also a metabolite of diazepam. Temazepam is a Schedule IV controlled substance in the USA.
Alprazolam is a potent benzodiazepine prescribed as the brand name Xanax. It is typically used to treat anxiety and panic disorders. Much like temazepam (and other benzodiazepines), it functions as a GABAA receptor agonist. Alprazolam is metabolized to alpha-hydroxyalprazolam. Alprazolam is a Schedule IV controlled substance in the USA.
Citalopram is a drug prescribed as an antidepressant under the brand name Celexa. It functions as a selective serotonin reuptake inhibitor (SSRI) and is approved for treatment of major depressive disorder and is prescribed off-label for a multitude of other conditions including anxiety and panic disorders and obsessive-compulsive disorder. From a chemistry standpoint, citalopram is sold as a racemic mixture of the R and S enantiomers, with the S enantiomer having an antidepressant effect. A medication named Lexapro is sold as only the S enantiomer otherwise known as escitalopram. Citalopram is metabolized to desmethylcitalopram and didesmethylcitalopram. Citalopram is not a controlled substance, but is only available via prescription.
Acetylfentanyl is a synthetic fentanyl derivative that is considered to be about fifteen times more potent than morphine as an analgesic. It is not available as a prescription medication and is a true designer/research chemical substance. It functions as a mu opioid receptor agonist, much like fentanyl and oxycodone. Chemically, acetylfentanyl differs from fentanyl by a replacement of the propionyl group with an acetyl group. Acetylfentanyl has been found in the USA since 2013 and has been detected in street heroin and counterfeit pharmaceutical tablets. It was made a Schedule I controlled substance in the USA in 2015.
Despropionylfentanyl is also known as 4-ANPP. It is a very minor metabolite of fentanyl and is a precursor in the illicit (non-pharmaceutical) synthesis of illicitly manufactured fentanyl and related fentanyl analogs. The substance itself has very little pharmacological activity, but its presence in the human body can be used to aid in determining the source of fentanyl used, e.g. consumption of pharmaceutical fentanyl vs. ingestion of illicitly manufactured fentanyl.
My thoughts?

I won't give many thoughts because I am not privy to the case specifics. I do not know all the details. The only people that know the details are those who investigated his death and formulated the final autopsy report and cause of death certification. Any general comments I make are speculative in nature, but are based on my knowledge and experience in the field.

From a general forensic toxicology standpoint, the real takeaway is that this is a dangerous combination of substances to use concurrently. He was consuming two powerful opioid and two potent benzodiazepines which when used together can create synergistic effects and exaggerated central nervous system depression. Add that situation to an already compromised cardiovascular and respiratory system, and it's a recipe for disaster.  For my own information, I would love to see the full toxicology report with quantitative measures of drug, etc. How much fentanyl was present? How much temazepam and alprazolam were detected? Not that any of that really matters though.

With the detection of acetylfentanyl and despropionylfentanyl, it seems as if Tom Petty was supplementing his pharmaceutical medications with illicitly manufactured substances. Acetylfentanyl is not a pharmaceutical medication anywhere in the world and is only found as a designer opioid/analog meant to skirt the controlled substances act in the USA. Fentanyl does not metabolize to acetylfentanyl. As despropionylfentanyl is a precursor/intermediate used in the illicit (non-pharmaceutical) synthesis of fentanyl, it generally used as a marker for exposure to illicitly manufactured fentanyl. The presence of this substance has also been associated with the use of various fentanyl analogs including acetylfentanyl, acrylfentanyl, and furanylfentanyl. No one knows if the use of illicit opioid was intentional or not. Remember the situation surrounding Prince's death. Multiple pills were found in his residence that looked like pharmaceutical hydrocodone/acetaminophen but turned out to be counterfeit tablets containing fentanyl and the opioid research chemical U-47700.

As a conclusion, I'll say, please do not mix depressant drugs. Do not mix opioids with benzodiazepines. Do not mix either of them with ethanol. Stay safe, folks.

Addendum:

I just saw that the great Dr. David Kroll wrote an article on this matter over at Forbes. Go read his work here. He is one of the best writers on these sorts of topics.

Wednesday, January 3, 2018

Always confirm presumptive results. Always.

Baltimore police raided a grocery store at the beginning of December 2017 and seized 13.2 pounds of what they suspected was morphine and 16.5 pounds of what they suspected was fentanyl. Two individuals faced distribution of fentanyl and other related drug charges and then were held in jail without bail. Other items seized were vials, containers, tubes, capsules, and plastic bags.

Turns out that the drugs were neither morphine nor fentanyl. As reported by the Baltimore Sun, charges have been dropped in the case as the substances were not identified by the crime laboratory as morphine or fentanyl or illicit drugs or controlled substances. The story seems to still be developing and as reported, the police say they will provide more information Thursday (1/4/2018) as to the substance's identity.

Thoughts?

Now, I'm not sure in this case if presumptive field tests were used, but this is a good reminder to always confirm presumptive results prior to making any medical or legal decision. Field tests, color tests, reagent tests, point of care device tests, dipstick tests, laboratory immunoassay tests, and other similar tests are considered presumptive in nature. They are prone to false positive results (and false negative results too). Care must be taken in interpreting a presumptive test and if any important decision is to be made using the result, the result must be confirmed via an alternate more specific confirmatory method such as gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS), which is not prone to false positives (or negatives).

Also, as to what the substance was? Maybe one of the many fentanyl analogs or designer opioids available in the wild these days? That's complete speculation, but if it was an analog, I wouldn't expect the police to drop charges. Maybe flour or sugar? Or some baking powder? This was a corner shop/grocery store after all. Who knows what the substance was. I guess we'll find out when the police let us know.

Stay tuned on this one.

In case you want to read about false positive results for amphetamines by a presumptive immunoassay test, read this (a little ditty...about immunoassays).


References

http://www.baltimoresun.com/news/maryland/crime/bs-md-ci-store-raid-folo-20171206-story.html

http://www.baltimoresun.com/news/maryland/crime/bs-md-ci-fentanyl-charges-dropped-20180103-story.html