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

The new synthetic cannabinoids on the block

Since approximately 2007, quinoline cannabinoid derivatives have been evaluated for cannabinoid receptor affinity.  A few studies have demonstrated a handful of compounds with the quinoline structure to be highly selective for the CB2 receptor over the CB1 receptor.

PB-22 and 5F-PB-22 are two emerging synthetic cannabinoid substances of this quinoline class.  They have been analytically confirmed as adulterants in herbal incense blends in the USA.

PB-22’s chemical name is 1-pentyl-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C23H22N2O2 and formula weight is 358.4 g/mol.  The chemical structure features an indole group, a pentyl alkyl chain, a carbonyl group and a 8-hydroxyquinoline moiety.

5F-PB-22’s chemical name is 1-(5-fluoropentyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C23H21FN2O2 and formula weight is 376.4 g/mol.  It features the same chemical structure as PB-22 with the exception of a single fluorine atom at the terminal carbon of the pentyl chain.

BB-22’s chemical name is 1-(cyclohexylmethyl)-8-quinolinyl ester-1H-indole-3-carboxylic acid.  Its molecular formula is C25H24N2O2 and formula weight is 384.5 g/mol.  It features the same chemical structure as PB-22 with the exception of the replacement of the pentyl alkyl chain with a cyclohexylmethyl moiety.

I am currently in the midwest traveling, so I thought I would look up these substances and see if they are controlled at the state level.  They are not controlled in any of the several midwestern states as schedule I drugs.  They are also not included in the updated list of controlled compounds in the legislation pending in any midwestern state.  In fact, I do not know of any location in the USA (state and/or federal) in which they are controlled explicitly.  It would also prove difficult to make these an analog case as they are significantly different (my scientific opinion) than JWH-018 or other controlled synthetic cannabinoids.   It is also of importance that these substances have no published in vitro or animal modeling data regarding their pharmacological activity at the receptor. 

Goodbye UR-144 and XLR-11.  Welcome the next wave of synthetic cannabinoids…the quinoline derivatives.  Meet the new boss, same as the old boss - more unknown than the preceding generations.

PS. Note reference 4 – not only the quinoline derivatives are listed, but also isoquinoline, quinoxaline, and quinazoline derivaties exist as well.

The cat and mouse games will continue!

References

1.    C Manera, V Benetti, MP Castelli et al. Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists. J Med Chem (2006) 49(20):  5947-5957.  PMID:  17004710

2.    C Manera, MG Cascio, V Benetti et al. New 1,8-naphthyridine and quinoline derivatives as CB2 selective agonists. Bioorg Med Chem Lett (2007) 17(23): 6505-6510.  PMID: 17942307

3.    R Saari, JC Torma, T Nevalainen. Microwave-assisted synthesis of quinoline, isoquinoline, quinoxaline and quinazoline derivatives as CB2 receptor agonists. Bioorg Med Chem (2011) 19(2): 939-950. PMID: 21215643

4.    PG Baraldi, G Saponaro, AR Moorman et al. 7-Oxo-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamides as selective CB(2) cannabinoid receptor ligands: structural investigations around a novel class of full agonists. J Med Chem (2012) 55(14): 6608-6623.  PMID 22738271

The comfort zone

As a scientist, I am all too familiar with my comfort zone.  You know, that area that we like to exist within, the one that feels good, is "normal" and relatively stress free...

Well, I had to step outside that zone today.  In a big way.  I generally exist in a little lab bubble with my drugs, my instrumentation and my work only exiting for a court room appearance or client education on forensic toxicology...it's a relatively stress and anxiety free environment (at least most of the time unless there is a malfunctioning mass spec to troubleshoot at 4 pm on a Friday afternoon or a troublesome attorney relentlessly badgering you on the witness stand) .

Cue Imperial Death March...

And you know what? I stepped outside it and I was fine. I excelled.  And that feels really good, not only professionally, but also personally.  This is the way we continually improve as when we are out of our element, we learn the most about ourselves.  And after-all, isn't that what Science is at its core?

Cue Superman March...

Onward and upward.

Cheers.  

Folks, TV shows ain't the real world.

Hey folks, TV shows ain't the real world!

Something for your amusement.  I had posted this a while back on my personal Facebook account.  It is a screen shot of a mass spectrum used in the TV show, NCIS.  Please look at the text.  Hold back laughter.

Sorry for the clarity - the lighting in the room wasn't the greatest.

Even though it doesn't really make sense, I still want this mass spec! The sample that was analyzed was gastric contents of a decedent. It identifies "chicken stock", coffee, and cocoa! Also it identified some random water, "protein", and of course a mass spectrometerist's favorite, sodium! Maybe that's what makes up the "chicken stock"?  One good thing is that the chemical formula displayed for coffee is actually caffeine and the one displayed for cocoa is theobromine, so at least that makes a tiny bit of sense and they got water's formula and sodium correct too. 

People, I hate these TV shows...

Analogue or not an analogue: that is the question!

A beginning dialogue on this subject...this will set the stage for further discussions.

The Analogue Enforcement Act (AEA) was added to the Controlled Substances Act (CSA) of 1970 in 1986. It defines the term “controlled substance analogue” as a substance which:

1.   The chemical structure of which is substantially similar to the chemical structure of a controlled substance in schedule I or II; AND

2.   Which has a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the nervous system of a controlled substance in schedule I or II; OR

3.   With respect to a particular person, which such person represents or intends to have a stimulant, depressant, or hallucinogenic effect on the central nervous system that is substantially similar to or greater than the stimulant, depressant, or hallucinogenic effect on the central nervous system of a controlled substance in schedule I or II.

It is noted that the AEA only applies to a substance if it is intended for human consumption.

The AEA was essentially established to allow the Drug Enforcement Administration (DEA) to criminally prosecute cases involving so-called derivatives or “analogues” even though the specific substances are not explicitly scheduled under the CSA.  It is a way to control the tweaks and minor changes made by manufacturers of so-called “designer drugs” to circumvent the CSA and stay within the confines of the law or stay “legal”.  It is like the DEA's safety net that they can throw out and ensnare any rogue substances that are not scheduled. But this is not a black/white situation – it is more of a “gray area” as the use of the term “substantially similar” is very vague, obviously open for interpretation, and very, very, very unscientific.

There are various organizations/committees that are discussing this topic at length. One of these committees is the Advisory Committee for the Evaluation of Controlled Substance Analogs (ACECSA). Their website is http://www.druganalogs.org. This group primarily consists of forensic and academic chemists, toxicologists, pharmacologists and other scientists. Another committee is the Scientific Working Group for the Analysis of Seized Drugs.  Their website is http://www.swgdrug.org. This group primarily consists of federal, state, military, and even international chemists.  The DEA maintains a heavy presence on this committee.

Currently, cases involving the determination of a controlled substance analogue involve dueling chemists, toxicologists and pharmacologist as there is no consensus in the scientific community regarding what exactly is a controlled substance analogue.  Typically, the prosecuting attorneys will have consultation and testimony from the DEA chemists or toxicologists/pharmacologists while the defense will have consultation and testimony from chemists and toxicologists/pharmacologists from other entities.  The decision boils down to opinion vs. opinion.

There have been a couple of landmark cases regarding the AEA.  The first was a district court case in Colorado (USA vs. Damon S. Forbes et al. in 1992) that involved the determination of alphaethyltryptamine (AET) as an analogue of controlled substances, dimethyltryptamine (DMT) and diethyltryptamine (DET).  Ultimately it was determined that AET is not an analogue of DMT or DET as AET is a primary amine while DMT/DET are tertiary amines AND AET cannot be synthesized from DMT/DET AND the pharmacological effects of AET are not similar enough to DMT/DET.  The court also ruled that the definition of ‘substantially similar’ in the AEA was “void for vagueness” and therefore unconstitutional. 

The second case was heard by the US 8^th judicial circuit court of appeals (USA vs. Washam in 2002) and involved the determination of 1,4-butanediol as an analogue of gamma-hydroxybutyrate (GHB).  In the end, it was ruled that 1,4-butanediol was substantially similar to GHB because they were “both linear compounds containing four carbons and that there is only  difference between the substances on one side of their molecules” AND 1,4-butanediol is biotransformed in the human body to GHB, therefore if ingested, it would produce substantially the same pharmacological effects.

So, let us consider the substances Pyrovalerone, MDPV, and Alpha-PVP.

Pyrovalerone is a psychoactive substance that has been shown to be a norepinephrine and dopamine reuptake inhibitor, also known as an NDRI.  Pyrovalerone and other related pyrrolidino ketone compounds were patented in the United States on April 18, 1967.  It is a schedule V substance according to the CSA of 1970 and has been prescribed for the treatment of chronic fatigue or lethargy and as an anorectic drug for weight loss (even though it is rarely prescribed in the USA). Its IUPAC (International Union of Pure and Applied Chemistry) name is 1-(4-methylphenyl)-2-(1-pyrrolidinyl)-1-pentanone. Its molecular formula is C₁₆H₂₃NO and it has a molecular weight equal to 245.3 g/mol. Synonyms for pyrovalerone are Centroton, Thymergix, Valerophenone, and O-2371.

MDPV is a psychoactive substance that has been shown to be a norepinephrine and dopamine transporter inhibitor.  MDPV is an acronym for the name 3,4-methylenedioxypyrovalerone.  MDPV and other related methylendioxyphenylpyrrolidino-alkanones were patented in the United States on November 11, 1969.  It is a schedule I substance according to the CSA of 1970 and has no medical record of use in the United States.  Its IUPAC name is 1-(1,3-benzodioxol-5-yl)-2-(1-pyrrolidinyl)-1-pentanone. Its molecular formula is C₁₆H₂₁NO₃ and it has a molecular weight equal to 275.3 g/mol.  This compound was among the first substances detected in so-called “bath salts” products that were (and still are) available for sale over the Internet and in smokeshopes, headshops, and convenience stores.

Alpha-PVP is a substance that has an unknown mechanism of action and pharmacological effects. No published data is available regarding direct evidence of its pharmacology.  Its metabolism and excretion patterns in rat urine have been studied. Alpha-PVP was included in the document in which pyrovalerone and other related pyrrolidino ketone compounds were patented on April 18, 1967.  It is currently unscheduled in the United States’ CSA of 1970.  Its IUPAC name is 2-(1-pyrrolidinyl)-1-pentanone.  Its molecular formula is C₁₅H₂₁NO and it has a molecular weight equal to 231.3 g/mol.  Synonyms for alpha-PVP are alpha-pyrrolidinopentiophenone, α-PVP, PVP, O-2387, and Desmethylpyrovalerone.  After MDPV became emergency scheduled by the Federal government, this compound was used as a replacement substance and became very prevalent in the USA in “bath salt” products.

The chemical structures of these substances are:

Chemical structures of 3 related compounds

The DEA maintains that Alpha-PVP is a controlled substance analogue of MDPV.  There are cases still in litigation resulting from Operation Log Jam (July 2012) specifically about Alpha-PVP as an analogue. I have spoken to several (too many too count) scientists who think otherwise, but again, this just shows that opinions vary.

We won’t discuss these substances right now, but Operation Log Jam also included cases of the synthetic cannabinoids UR-144 and XLR-11.  The DEA maintains that UR-144 and XLR-11 are controlled substance analogues of JWH-018.

So, as a scientist, how would you determine what “substantially similar” means?

Should one consider 2D chemical structure or 3D chemical structure or both? What about shared functional groups? How much of a difference is significant? Methyl or ethyl group?  Is a compound containing a naphthoyl group substantially different from one that contains a tetramethylcyclopropyl group (as in the case of JWH-018 vs. UR-144)?  Is an exotic moiety like a methylenedioxyl group too significant of a difference (as in the case of MDPV vs. Alpha-PVP)? At what point is a change “too much” to be considered “similar”? Does synthetic pathway matter?  Do patents matter?

Is the use of structure activity relationships (SAR) valid when determining “substantially similar” pharmacological effects? Or should one rely solely on in vivo or in vitro data? Animal models?

Is it even possible to do this?  Is this type of legislation flawed?

All of these questions need answers but finding those answers will be a long journey.

Any thoughts on this one?

 

References

1.       Controlled Substances Act of 1970

2.      Controlled Substance Analogue Enforcement Act of 1986

3.      C Heron, J Costentin, J Bonnet.  Evidence that pure uptake inhibitors including cocaine interact slowly with the dopamine neuronal carrier.  Eur J Pharmacol. 264: 391-398 (1994).

4.      PC Meltzer, D Butler, JR Deschamps et al.  1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovalerone) analogs.  A promising class of monoamine uptake inhibitors.  J Med Chem. 49 (4) 1420-1432 (2006).

5.      LD Simmler, TA Buser, M Donzelli et al.  Pharmacological characterization of designer cathinones in vitro.  British Journal of Pharmacology. 168 (2) 458-470 (2013).

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15.   Alpha-Pyrrolidinovalerophenone (α-PVP) Analogue Status.  December 2011, Drug Enforcement Administration, Drug and Chemical Evaluation Section.  1-7