2013...errr....2014!

Happy new year folks! Let's ring in the new year right. Be kind. Be safe. Be smart.

Here's to a good start to 2014!

Cheers,

ForensicToxGuy

Krokodil Redux

The Krokodil paper has resurfaced in the American Journal of Medicine. The abstract can be found here.

Comparing this Article in Press to the original accepted manuscript that we discussed, I see a much cleaner and coherent article.  BUT...

Not much has changed between the two versions (old and new).

The only real differences that I see are:

1. The terrible grammar, punctuation and sentence structure that was observed in the accepted manuscript has been corrected. The article in press is a much cleaner version.

2. In the original manuscript, the patient has been injecting [krokodil] for the past two months. Whereas, in the article in press, the patient has been injecting [krokodil] for the past 6-7 months.

3. In the original manuscript, the patient has a history of injecting heroin into the arms and thighs for the past 2 years.  Whereas, in the article in press, the patient has been injecting heroin into the arms and thighs for the past 7-8 years.

4. The last statement in the conclusion section has been removed. The original manuscript read, "All kinds of governmental and non governmental authorities must be aware and on the watch for preventing this devastating and fatal drug addiction from spreading in our society." This is a good change.

5. The article in press adds 2 additional references.  One reference is the paper from Grund et al. (2013) from the International Journal of Drug Policy and the second reference is from Thomas Roche and is a technology web blog posting from 2011 on the subject of krokodil. The Grund paper is truly fantastic - I recommend reading it. I'm not sure we should be referencing blog posts in scientific/medical case reports.


Some things we discussed earlier:

1. Regarding the highly unusual acceptance turnaround.  The manuscript was received on 9/19/13, revised on 9/24/13, accepted for publication on 9/24/13. Still  unusual to me.

2. In the article in press, the drug is described as “flesh eating", which is still not accurate. The drug, desomorphine or its derivatives, does not cause the necrotic effects. 

3. The article in press still states that the drug is spreading rapidly around Europe. There is no scientific evidence to this claim.

4. A TIME article is still cited as a scientific reference. And now a technology blog post is cited as well.

5. Still no mention of toxicology results. In 5 months of treatment, not even a urine drug screen (with confirmation) for opiates/opioids was completed? I would love to see urine/blood drug toxicology. What other things was this patient using? Diacetylmorphine? Fentanyl? Was there codeine present in his urine? Morphine? Also, there are toxicology laboratories in the USA that can and do test for desomorphine. So, it is a misrepresentation to state that chemical analysis is not available.

At the end of the day, I do agree that physicians (and other people) need to be aware of this drug. This article will make people aware, but I still await some real scientific evidence that krokodil is in the USA. Until we see evidence, it is illogical to be here and I remain a skeptic.

Be safe.

Cheers,

ForensicToxGuy

Legislation View - How do we control substituted cathinones in the USA?

As we all know by now, substituted cathinones have been used in products available in smoke shops, gas stations and on the Internet for many years – the research chemical itself can be purchased over the Internet as well. Many of these substances have enactogenic and/or stimulant properties. On the flip-side, we simply do not know the pharmacological properties of many of these substances. Chemicals familiar to the layperson through media stories may be MDPV or Mephedrone.  But these are just two of a humongous number of substituted cathinones in existence. Now, ultimately, when substances such as these become prevalent in society, the various forms of government at the state and Federal levels decide they need to be controlled or banned.

So, how do state governments legislatively control substituted cathinones in the USA? Actually, it is quite easy to do with simple understanding of the general chemical structures of these substances.

Cue a minor amount of chemistry...

Substituted cathinones share the same overall chemical structure, which contain a phenethylamine core structure, an alpha carbon alkyl moiety, and a beta carbon ketone moiety. Specific substitutions can be made at any of the notated sites (R1-R4).

R1 can exist as hydrogen or combination of various alkyl, alkoxy, alkylenedioxy, haloalkyl, or halide moieties.

R2 can exist as hydrogen or any alkyl group.

R3 and R4 can exist as hydrogen, an alkyl moeity, or cyclic structure

Now consulting many of the state laws on this matter, one finds the following:

Any compound, except bupropion or a compound listed under a different schedule, structurally derived from 2-aminopropan-1-one by substitution at the 1-position with either phenyl, naphthyl, or thiophene ring systems, whether or not the compound is further modified:

(A) by substitution in the ring system to any extent with alkyl, alkylenedioxy, alkoxy, haloalkyl, hydroxyl, or halide substituents, whether or not further substituted in the ring system by one or more other univalent substituents;

(B) by substitution at the 3-position with an alkyl substituent

(C) by substitution at the 2-amino nitrogen atom with alkyl, dialkyl, benzyl, or methoxybenzyl groups; or

(D) by inclusion of the 2-amino nitrogen atom in a cyclic structure.

This exact wording or a form of it is used to ban the general class of cathinones in many states, including: Alaska, Arkansas, Colorado, Hawaii, Idaho, Indiana, Iowa, Kansas, Kentucky, Michigan, Minnesota, Nebraska, North Carolina, Ohio, South Carolina, South Dakota, and Tennessee

From memory (and this list isn’t exhaustive as I’m only doing this from recollection and not a reference book), this wording effectively controls the following compounds (and positional isomers):

Alpha-PBP, Alpha-PPP, Alpha-PVP, Benzedrone, Brephedrone, Buphedrone, Butylone, Chlorobuphedrone, Dibutylone, Diethylmethcathinone, Dimethylmethcathinone, Ethedrone, Ethylone, Ethylmethcathinone, Fluorobuphedrone, Fluoroethcathinone, Fluoromethcathinone, MDPBP, MDPPP, MDPV, Mephedrone, Methedrone, Methylone, Methylethcathinone, Naphyrone, N-ethylbuphedrone, Pentedrone, Pentylone.

Bupropion and Diethylpropion (Schedule IV) also fall under this class of drugs, but are typically excepted in the law or scheduled elsewhere.

If you’re goal is to control as many substituted cathinones in one giant swoop of  legislation, then this is a good way to accomplish that goal.  I believe more state governments will use this type of language in future legislation controlling these substances.

Could you do this with synthetic cannabinoids? No, not really.  But, we'll get into that another time.

Cheers,

ForensicToxGuy

"Fair is foul, and foul is fair: Hover through the fog and filthy air."

The CDC has released more information about the Colorado illnesses (221 suspected cases in approximately 1 month) that are linked to synthetic cannabinoids. The full text of the release in MMWR can be found here. Two substances that have been identified in products associated with these cases are ADBICA and ADB-PINACA. They both share a very similar chemical structure with the only difference being that ADBICA contains an indole moiety and ADB-PINACA contains an indazole moiety.  Another note on the newer synthetic cannabinoid terminology that may be helpful for the reader – the 1-amino-3,3-dimethyl-1-oxobutan-2-yl group has become known as ADB and the 1-pentyl-1H-indazole-3-carboxamide group has become known as PINACA.

An interesting feature of these newer synthetic cannabinoids is the ester or amide linkages. These linkages were not included in the earlier waves of cannabinoid compounds (i.e. JWH-018 → AM-2201 → UR-144...) as they contained the simple ketone linkage. The ester linkage is seen in the quinolinyl carboxylate derivative compounds such as PB-22, 5F-PB-22 and BB-22, while the amide linkage is seen the many of these newer substances such as the various ADBs, PINACAs, and FUBINACAs. Regarding these amide-containing cannabinoids (structures referenced in the figure above in red-color and in a previous blog post here), the amide linkage can be very susceptible to hydrolysis reactions. In the case of the two compounds related to the Colorado cases, possible in vivo amide hydrolysis would lead to formation of a carboxylic acid and an amine. Could this amine be active in the body? Possibly.

As a relevant sidenote, the synthetic cannabinoid, NNE1, otherwise known as MN-24, contains the same type of amide linkage but with a naphthoyl moiety. This compound was pre-emptively banned by the New Zealand government in November 2012 due to hypothesized formation of a carcinogenic metabolite - 1-aminonaphthalene.

I'll expound on this at a later date, but I believe we are seeing the signs of the legislation overkill that has been employed by the Federal and various State governments over the past few years. If compounds continue to be controlled in the same manner, then compounds with ever-increasing complexity of chemical structures will continue to emerge. Bleak, yet rooted in reality - I have no doubts that there will be more of these outbreaks.

Double, double, toil and trouble...indeed.

Stay safe,

ForensicToxGuy

 

 

 

Alphabet Soup, or the newer synthetic cannabinoids...

It seems as if the early compounds were the easiest to identify by name as they were series compounds (i.e. JWH-xxx or AM-xxxx).  Now we have what I like to call the alphabet soup compounds…

AB-PINACA, 5F-AB-PINACA, AB-FUBINACA

ADB-PINACA, 5F-ADB-PINACA, ADB-FUBINACA

FUB-PB-22 and FDU-PB-22

THJ and 5F-THJ

………

Here are chemical structures of these compounds:

Now it seems as if we are mixing and matching various structural groups at an increasing rate…indoles, indazoles, hydroxyquinolines, aminoquinolines, hydroxynaphthoyls, isopropyl groups, tert-butyl groups, halogens, alkyl chains…a chemist’s dream.

Also, a nightmare…keep in mind that no one knows what the actual pharmacological or toxicological properties of these drugs are. Do these substances act on only cannabinoid receptor? What downstream effects occur? What are short term and long term effects of use? How are these substances metabolized? What are the prominent metabolites? Do the metabolites have pharmacological activity?

The CDC released case studies through Morbidity and Mortality Weekly Report (MMWR) in February 2013 and November 2013 regarding significant injury and illnesses resulting from use of some synthetic cannabinoid-containing products. The February information included the detection of the cyclopropylindole cannabinoid, XLR-11, and associated it with acute kidney injury in a series of patients in various locations. The November information included the detection of ADB-PINACA in the blood of five patients admitted to the hospital in Georgia.

We’ll see if any of these compounds become prevalent in herbal blends and products. Unfortunately, the truth is that we won’t know about their true prevalence until we see their adverse effects, which may be as presentations to a hospital's emergency department or analyses during postmortem toxicology.  And then, it’s too late.

Be safe out there.

Cheers,

ForensicToxGuy

Krokodil, 7 Days Post-Withdrawal

It’s been seven days since the American Journal of Medicine “krokodil” paper  (referenced here at RetractionWatch) was removed from online viewing. No official reason or explanation (other than a "permission problem") has been given as to why it was withdrawn. 

It is also noted that in the Retraction Watch comments section, Steven M. Marcus (Dr. Marcus from New Jersey Poison Control, I believe) states a group of medical toxicologists associated with poison control centers wrote to the journal about the paper.  

In the meantime, here are some stories from the Huffington Post, Slate, and Columbus Dispatch describing the issues at hand.

Also, here is a Huffington Post article and a New York Daily News article on a new story out of Mexico about a teenager who reportedly injected the drug into her gentitals and had disastrous effects. 

And finally, here is one very odd (and absurd) article from the University of Alabama making a correlation between krokodil usage and The Walking Dead television series…

Ultimately, there is still no toxicological or chemical proof that krokodil is being used in the United States.  And until toxicological or drug chemistry evidence is presented to show us it is here, then I remain skeptical.

Cheers,

ForensicToxGuy

"How doth the little crocodile
Improve his shining tail,
And pour the waters of the Nile
On every golden scale!

How cheerfully he seems to grin,
How neatly spreads his claws,
And welcomes little fishes in
With gently smiling jaws!"

Lewis Carroll, Alices Adventures in Wonderland

EDIT:  added information from Steven Marcus and the medical toxicologists.

Warning! 4-chloroamphetamine (4-CA) being marketed online in pill products

A colleague alerted a group of us to 4-CA, also known as Para-chloroamphetamine (PCA), being sold on the Internet by a high-profile research chemical vendor.

From the Bluelight weblink describing the issue, the products seem to be marketed for customers in the USA and not the UK.

Why should we be worried about 4-CA?

4-CA is a highly neurotoxic substance that destroys serotonergic receptors. For many years, 4-CA has been used in biological research for this reason.

Please do not consume any of these products containing this substance.  I urge anyone who is in possession of one of these products to discard or destroy the product through the proper methods.

Cheers,

ForensicToxGuy

Career Opportunities Galore

Forensic chemistry and toxicology careers routinely become available and are posted on society websites. These career opportunities are available for BS, MS, and PhD scientists and can vary from academic institutions to government laboratories and from private laboratories to consulting work. This is a healthy job-market. Some good resources are:

American Academy of Forensic Sciences - AAFS
(http://www.aafs.org/current-job-openings)

Society of Forensic Toxicologists - SOFT
(http://www.soft-tox.org/employment)

Midwest Association of Forensic Scientists - MAFS
(http://www.mafs.net/employment)

Southwestern Association of Forensic Scientists -SWAFS (http://www.swafs.us/employment.php?c=20)

Northeastern Association of Forensic Scientists - NEAFS (http://www.neafs.org/index.php/employment)

I’ll be posting some interesting opportunities from time-to-time, so be on the look-out for them!

Cheers,

ForensicToxGuy

Krokodil...not so fast, my friends!

The Infamous Krokodil

Well, look at this…

http://www.amjmed.com/article/S0002-9343(13)00879-6/abstract

The krokodil paper that was published online in the American Journal of Medicine has been withdrawn “temporarily” online.  It is definitely an interesting turn of events. Many scientists, including me, had questions when this paper was originally published online.  Let’s go through a very brief list of observations and questions that other scientists (and I)had after review of the originally accepted manuscript:

1.       The manuscript consisted of terrible grammar, punctuation, and sentence structure. Was this manuscript not proofread during review?

2.       The manuscript was received on September 19^th, revised on September 24^th, and accepted for publication on the very same day (September 24^th).  If you consult the calendar, that is 3 business days from receipt of manuscript to revision to acceptance.  Highly unusual! Did the quick turnaround on the manuscript lead to errors during the review process? Was the review process really even effective?

3.       The drug is described as “flesh eating”. This is not accurate and I would expect highly trained physicians to accurately describe a drug and its effects in scientific literature. The drug, desomorphine or its derivatives, does not cause the necrotic effects.  The usage of this sensationalism is merely perpetuating the media hysteria around this drug.

4.       The manuscript states that the drug is spreading rapidly around Europe. There is no scientific evidence to this claim.  And actually, there is no evidence for the drug outside of some Russian countries.

5.       A TIME article is cited as a scientific reference. Since when did an online magazine article become a scientific resource on the emergence of drugs in society?  Is it peer-reviewed? No, I don't think so.

6.       No toxicology, not even a routine urine drug screen, is discussed in the manuscript.  Major flaw!  Was there even an opiate detected in this patient's biological specimens?

7.       The authors conclude that because opiates are prevalent in the USA, krokodil will find its place among drug users.  This is a baseless claim. Krokodil use in the USA is illogical for many reasons, including  the prevalence of cheap heroin, the prescription controls on codeine, the prevalence of other prescription opioids, harm reduction programs such as clean needle programs, as well as the prevalence of treatment programs using methadone and buprenorphine.  That's not to say that some drug user would try to home-brew some krokodil - never say never when it comes to drug users, but it is simply illogical.  And to say anything else is absurd.

I’m sure there will be more to report on this paper withdrawal.

Until then, there is still NO (zero, nil, zilch, nada, none) evidence that supports krokodil is here in the United States.

I'll followup when there is more information available.

Cheers,

ForensicToxGuy

UPDATE

I am finally updating this blog again.  This time I’m going to try to stay with it.  Life happened in the early spring 2013 and I had to step away, but let’s see where this new beginning will take us.

Best regards,

ForensicToxGuy