The beat goes on with synthetic cannabinoids...

There have been many reports lately about hospitalizations, illnesses, "overdoses", and even a few deaths surrounding synthetic cannabinoid compounds in the media.

Spike Max herbal incense blend via ForensicToxGuy (2013)

This blend is not associated with the outbreaks discussed here.

Here is an outbreak in Mississippi. As of today, there have been 473 reports of synthetic cannabinoid hospital visits in Mississippi.

Here is an outbreak in Alabama. From March 15 to April 20, 2015 - 462 patients were seen in the hospital for synthetic cannabinoid related matters. Of those patients, 96 were admitted to the hospital. 2 fatalities resulted.

Here is an outbreak in New York as reported by CNN. Reports were that more than 160 people visited the hospital with synthetic cannabinoid issues over the course of 9 days (as of April 18).

That equates to 1,095 people located in three states traveling to the hospital after consuming a synthetic cannabinoid product in approximately one month

All had been quiet on the specific identification of drug involved or associated with these outbreaks.

Today, the New York Times reported via Dr. Mark Ryan of the Louisiana Poison Center that "a large portion of cases appear to involve a form called mab-chminaca". I can only assume these cases that Dr. Ryan speaks of are from Louisiana and not the other states. I wouldn't doubt that MAB-CHMINACA is at play in the next states to the east as well (Mississippi and Alabama). I do know that this cannabinoid substance is out there in the wild now and has been for quite a bit of time.

MAB-CHMINACA was discussed briefly here in October 2014 when, oddly enough, the state of Louisiana moved to classify it as a Schedule I controlled substance.

As you can see from taking a quick look at the chemical structures, these new synthetic cannabinoids are all quite similar. Add in fluorinated derivatives for AB-PINACA, ABICA, ADB-PINACA, and ADBICA too.

How about some newer CHMINACA derivatives?

 

 

Want a new FUBINACA derivative or two?

 

 

 



The chemical diversity in structure of these compounds is amazing. Take a bit of substance A and mix it with this bit from substance B and add it all together with this group from substance C. Voila! We have new alphabet soup compound D!

As I've said before, they are a diverse chemical grab bag o' unknown pharmacological and toxicological profile. We have absolutely no pharmacological or toxicological data on most of the compounds listed above.

None.

We do not know if they truly act on CB1 and CB2. It is surmised that they do.

We do not know if they act on other receptors or mediate other effects downstream. It is thought they don't. But who knows.

We do not know longterm (chronic) effects. And we won't for quite a while.

This guy knows more than we do...

Image courtesy of Wikipedia (2015)

All kidding aside, synthetic cannabinoids have been and will continue to be a major issue in the United States. They are public health nightmares. These recent hospitalizations are not surprising to me and should not be surprising to anyone that knows any science at all. They are the norm. The vast majority of people using these substances and products are essentially consuming substances of unknown identity with unknown pharmacological and toxicological effects in unknown combinations at unknown dosages. That is reckless. That is dangerous.

I have no answers here on what to do about these cat-and-mouse games that seem to spur on this chemical diversity over time.

Is MAB-CHMINACA really to blame for these hospitalizations? Maybe. Maybe not.

Are there other compounds out there being consumed that may be contributing to these hospitalizations? As you can see from the structures presented above, yes, there are many other compounds out there at the moment. I wouldn't be surprised to hear that some other CHMINACA or FUBINACA compounds were also associated with these outbreaks.

"And the beat goes on, the beat goes on...
Drums keep pounding a rhythm to the brain."




* Jon Snow image can be found here at Wikipedia.
http://en.wikipedia.org/wiki/Jon_Snow_(Game_of_Thrones)#/media/File:Jon_Snow-Kit_Harington.jpg

*All chemical structure images were created by ForensicToxGuy in ChemDraw

Flakka in Meme

The latest media hysteria I've seen about Flakka includes a man who believed he was God, had sexual relations with a tree, and assaulted a law enforcement officer.

All of these recent Flakka headlines are reminiscent of the MDPV-zombie days of 2010-2013. I figured we could combat some of this recent silliness in media reports with some silliness of our own.

Who fed these puppies some Flakka?

Here's Johnny! On Flakka. Looking back at the Shining, it makes a little more sense...

Wonder if Darth Vader knew the Emperor was on Flakka?

Of course, we all knew Charlie Sheen was on Flakka. Winning!

ALL THE FLAKKA!

Say Flakka again. Say Flakka again. I dare you. I double dare you motherfucker. Say Flakka one more goddamn time!

 

Research Ryan wants to invite you over for some cuddling and some Flakka.

 

We wants it...we needs it. Must have the Flakka. They stole it from us. Sneaky little hobbittses. Wicked, tricksy, false!

Get off my lawn with that flakka!

Even Grumpy Cat weighs in on Flakka.

And finally, beware of those drop bears on Flakka. When you least expect it...

On Flakka, Gravel, and Alpha-PVP

Flakka. Gravel.

No, it’s not a “new drug”.

Flakka and Gravel are generic terms that have been used to describe what is most likely the substituted cathinone, alpha-pyrrolidinopentiophenone, also known as alpha-PVP, PVP, or alpha-pyrrovalerophenone. It is most closely structurally related to the substances, prolintane (beta-ketone difference) and pyrovalerone (methyl group difference)

 

I covered alpha-PVP back in January 2014 here when "gravel" was a hot-topic in the media.

But, now we know more about alpha-PVP's pharmacology than we did even just over a year ago. Dr. Michael Taffe has covered these updates on alpha-PVP very well on his lab's blog, which can be found here. The Taffe Laboratory's site is also here.

Dr. Leon Gussow over at The Poison Review has also covered Flakka.

Because alpha-PVP is a rather important compound in my work in postmortem toxicology and has been associated with fatalities in the USA, I keep a list of all relevant papers/abstracts, etc. for the substance. This list is updated to April 2015.

1. H. Koppe, G. Ludwig, K. Zeile (1967) α-Pyrrolidino Ketones. United States Patent No. 3,314,970. Washington, D.C.: U.S. Patent and Trademark Office.

2. G. Gardos and J.O. Cole (1971) Evaluation of pyrovalerone in chronically fatigued volunteers. Current Therapeutic Research, Clinical and Experimental, 13: 631-635.

3. P.C. Meltzer, D. Butler, J.R. Deschamps, B.K. Madras (2006) 1-(4-methylphenyl)-2-pyrrolidin-1-yl-pentan-1-one (pyrovarlerone) analogs. A promising class of monoamine uptake inhibitors. Journal of Medicinal Chemistry, 49: 1420-1432.

4. L.R. Watterson and M. Foster Olive (2014) Synthetic cathinones and their rewarding and reinforcing effects in rodents. Advances in Neuroscience (Hindawi), 4: 209875

5. A.Kaizaki, S. Tanaka, S. Numazawa (2014) New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron. The Journal of Toxicological Sciences, 39: 1-6.

6. K.G. Shanks, T. Dahn, G. Behonick, A. Terrell (2012) Analysis of first and second generation legal highs for synthetic cannabinoids and synthetic stimulants by ultra-performance liquid chromatography and time of flight mass spectrometry. Journal of Analytical Toxicology, 36: 360-371.

7. L.R. Watterson, B.T. Burrows, R.D. Hernandez, K.N. Moore, M. Grabenauer, J.A. Marusich, M.F. Olive (2014) Effects of α-pyrrolidinopentiophenone and 4-methyl-N-ethylcathinone, two synthetic cathinones commonly found in second-generation “bath salts”, on intracranial self-stimulation thresholds in rats. International Journal of Neuropsychopharmacology, 18.

8. J.A. Marusich, K.R. Antonazzo, J.L. Wiley, B.E. Blough, J.S. Partilla, M.H. Baumann (2014) Pharmacology of novel synthetic stimulants structurally related to the“bath salts” constituent, 3,4-methylenedioxypyrovarlerone (MDPV). Neuropharmacology, 87: 206-213.

9. J.E. Naylor, K.B. Freeman, B.E. Blough, W.L. Wooverton, S.L. Huskinson (2015) Discriminative-stimulus effects of second generation synthetic cathinones in methamphetamine-trained rats. Drug and Alcohol Dependence, 149: 280-284.

10. C. Sauer, F.T. Peters, C. Haas, M.R. Meyer, G. Fritschi, H.H. Mauer (2009) New designer drug alpha-pyrrolidinovalerophenone (PVP): studies on its metabolism and toxicological detection in rat urine using gas chromatographic/mass spectrometric techniques. Journal of Mass Spectrometry, 44: 952-964.

11. E. Tyrkko, A. Pelander, R.A. Ketola, I. Ojanpera (2013) In silico and in vitro metabolism studies support identification of designer drugs in human urine by liquid chromatography/quadrupole-time-of-flight mass spectrometry. Analytical and Bioanalytical Chemistry, 405: 6697-6709.

12. V. Uralets, S. Rana, S. Morgan, W. Ross (2014) Testing for designer stimulants: metabolic profiles of 16 synthetic cathinones excreted free in human urine. Journal of Analytical Toxicology, 38: 233-241.

13. Drug Enforcement Administration, Department of Justice (2014) Schedules of controlled substances: temporary placement of 10 synthetic cathinones into Schedule I. Final order. Federal Register, 79: 12938-12943.

14. A.M. Leffler, P.B. Smith, A. de Armas, F.L. Dorman (2014) The analytical investigation of synthetic street drugs containing cathinone analogs. Forensic Science International, 234: 50-56.

15. F. Dragogna, L. Oldani, M. Buoli, A.C. Altamura (2014) A case of severe psychosis induced by novel recreational drugs. F1000Research,3: 21.

16. J.L. Knoy, B.L. Peterson, F.J. Couper (2014) Suspected impaired driving case involvingα-ppyrrolidinovalerophenone, methylone, and ethylone. Journal of Analytical Toxicology, 38: 615-617.

17. L.J. Marinetti and H.M. Antonides (2013) Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results. Journal of Analytical Toxicology, 37: 135-146.

18. L.L. Richards-Waugh, K.M. Bailey, D.J. Clay, M.A. Gebhardt, C.L. Newsome-Sparks, H.E. Mahmoud, S.E. Venuti, J.C. Kraner (2013) Deaths involving the recreational use of α-PVP (α-pyrrolidinopentiophenone). K16. Proceedings of the American Academy of Forensic Sciences. http://www.aafs.org/sites/default/files/pdf/ProceedingsWashingtonDC2013.pdf

19. K.G. Shanks, G.S. Behonick, A.R. Terrell (2013) Detection of Alpha-PVP in Postmortem Blood Casework by UPLC/MS/MS. P12. Proceedings of the Society of Forensic Toxicologists

http://soft-tox.org/files/meeting_abstracts/SOFT_2013_meeting_abstracts.pdf

20. K.W. Simonsen, H.M. Edvardsen, G. Thelander, I. Ojanpera, S. Thordardottir, L.V. Andersen, P. Krikku, V. Vindenes, D. Christoffersen, G.J. Delaveris, J. Frost (2015) Fatal poisoning in drug addicts in the Nordic countries in 2012. Forensic Science International, 248: 172-180.

21. H. Nagai, K. Saka, M. Nakajima, H. Maeda, R. Kuroda, A. Igarashi, T. Tsujimura-Ito, A. Nara, M. Komori, K. Yoshida (2014) Sudden death after sustained restraint following self-administration of the designer drug α-pyrrolidinovalerophenone. International Journal of Cardiology, 172: 263-265.

22. K. Sellors, A. Jones, B. Chan (2014) Death due to intravenous use ofα-pyrrolidinopentiophenone. Medical Journal of Australia, 201: 601-603.

23. M. Skykutera, M. Cychowska, E. Bloch-Boguslawska (2015) A fatal case of pentedrone and α-pyrrolidinovalerphenone poisoning. Journal of Analytical Toxicology. Manuscript in Press.

If you know of a paper or abstract that includes alpha-PVP that I have missed, please send it to me or leave the citation in the comments and I can add it to the list.

Case Report - Synthetic Cannabinoid-Induced Mania / And Other Thoughts

Synthetic cannabis-induced mania
Mehmet Fatih Ustundag, Esra Ozhan Ibis, Atakan Yucel, and Halil Ozcan
Case Rep Psychiatry (2015) doi: 10.1155/2015/210930
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369931/

This case was reported out of the Department of Psychiatry and the Department of Child and Adolescent Psychiatry, Ataturk University in Erzurum, Turkey.

The authors present a case of an 18 year old male who was admitted to an outpatient psychiatric clinic by family.

The brother of the patient noticed drastic change in behavior over the last few months including:

§  Increase self-talking

§  Increase in self-laughing

§  Increase in spending money

§  Increase in interest in religion

§  Lack of need for sleep.

§  Belief that he was an angel, a demon, and a prophet

After admittance to the clinic, the patient’s mood was irritable and euphoric. No hallucinations were observed, but “mystical and grandiose delusions” were observed. I’m guessing that is the angel, demon, and prophet part.

No history of psychiatric or mental conditions was noted by his family. He did have a more recent drug use issue, including volatile substances, cannabis powder, and “synthetic cannabis”, starting about 4 years prior to this admittance. The “synthetic cannabis” use started approximately 6 months prior to this episode. There were no remarkable findings during physical and neurological examinations. A urine drug screen for cocaine, cannabis, opioids, amphetamines, and benzodiazepines was negative. He was diagnosed with substance-induced bipolar disorder and was treated with olanzapine, valproic acid, quetiapine, and lorazepam.

The “mystical and grandiose delusions” were still observed on day 15 of the admittance. By the 30^th day, these delusions had significantly decreased and he was discharged. According to the authors, his psychiatric condition “was stable in the first month of follow up with current treatment”.

On followup, the patient stated he had been using synthetic cannabinoid products “in the previous 6 months, several times per week” and consumed the substances via the smoking route of administration.

The authors conclude that this is the first case of manic episode with psychotic symptoms induced by synthetic cannabinoids published in literature.

Overall, a decent case report, but lacking one thing.

Analytical confirmation of substance.

In fact, the only mention of toxicology is a urine drug screen for cocaine, cannabis, opioids, amphetamines, and benzodiazepines. No blood analysis was attempted. No analysis for synthetic cannabinoids was attempted. We’ve known for years now that a standard urine drug screen will not detect synthetic cannabinoids and the authors even mention this in the paper.

This is my main issue with case reports such as these. I completely understand that not all laboratories (especially hospitals) are set up to do confirmation of new psychoactive substances such as synthetic cannabinoids or substituted cathinones or NBOMe hallucinogens via mass spectrometry. But, to not even attempt this analytical confirmation AND then take the time and effort to publish this case as mania induced by a very specific cause - “synthetic cannabinoids” - is negligent at worst and sloppy at best.  If you are going to publish the paper as a case report (whether it’s a death caused by x substance or symptoms caused by y substance), then attempt confirmation of drug in urine, or more preferably blood (that's an argument for another time). To not do so is shoddy science. In a similar vein - we would not publish a case report as death associated with x substance without at least detecting the substance in some sort of biological specimen such as blood, liver, brain, kidney, urine, vitreous humor, etc.

For this described case, how do we know that the patient was using or had been using a synthetic cannabinoid product? Other than anecdotal reports from family during his admission to the clinic and from the patient after the fact, we do not know. That is hardly evidence that should make a case report. We have no true empirical evidence. As a forensic toxicologist, I’d love to find out what specific substance or combination of substances led to this induced mania/bipolar disorder in an ordinarily “normal” individual. “Synthetic cannabinoids” are a vast array of substances with diverse chemical structures and quite possibly diverse pharmacological and toxicological effects. As I like to say, they are a chemical grab bag o’ fun.

That leads to my final question: how and why do these reports keep getting published? Why are the manuscript reviewers and journal editors not questioning the lack of analytical confirmation? Why are we as toxicologists and chemists and generally as scientists not questioning this type of work?

Happy Easter!

Ecstasy tablets or candy?

 

Candy!

Happy Easter all!