Kratom into Schedule I

I’m sure you’ve heard by now that the DEA has filed a notice of intent to temporarily place kratom (active substances, mitragynine and 7-hydroxymitragynine) into Schedule I of the Controlled Substances Act.

What is kratom and why does the DEA think it needs to be banned?

Mitragyna speciosa is an tree that grows in Southeast Asia (primarily Thailand and Malaysia) and is known as kratom and biak-biak. The plant is in the Rubiaceae family, which famously includes the genera Coffea (caffeine). The leaves of the kratom tree contain many alkaloids, but the two primary ones are mitragynine (66% of total content) and 7-hydroxymitragynine (2% of total content). These two alkaloids are mu (μ) opioid receptor agonists similar to morphine and therefore, would exhibit similar pharmacological effects such as analgesia, sedation, central nervous system depression, and respiratory depression) From a potency aspect, mitragynine is considered to be 4 times less potent than morphine, while 7-hydroxymitragynine is said to be 10-20 times more potent. In lower dosages, kratom is said to have a cocaine-like (stimulant) effects.

 

 

 

Chemical structures drawn by ForensicToxGuy (2016)

Because of the opioid pharmacological activity, the kratom plant has been used for its medicinal properties (without the supervision of a physician or medical professional) in the management of chronic pain and treatment for opioid dependence/withdrawal. It has also been used as a recreational substance of abuse.  The raw leaf of the plant can be chewed or boiled into a tea. Kratom has been used for decades in Thai cultural traditions in this form. More recently it has been found in the form of capsules/pills, powders, and concentrated extracts.

Up until this notice of intent, the plant was considered a “drug and chemical of concern”, which is another name for the DEA’s watchlist of emerging substances. On February 28, 2014 and June 15, 2014 the US Food and Drug Administration (FDA) announced an import alert for kratom and issued multiple guidances that detailing that any shipments containing Mitragyna speciosa were to be seized without physical examination, especially those deemed dietary supplements and bulk dietary ingredients.

Data from the National Forensic Laboratory Information System (NFLIS) over 2012-2015 shows that mitragynine seizures in solid dose evidence has been relatively low. There were no reports of mitragynine in 2012. In 2013-2014, there were 181 and 137 detections of mitragynine respectively. The only data for 2015 available is through the midyear report and it listed 93 detections of mitragynine. To put this in perspective, propoxyphene (Darvon, Darvocet), a drug that was removed from the US market in 2010-2011, had 208 (2013), 143, (2014), and 53 (2015-midyear) detections reported in NFLIS.

Data from the CDC and National Poison Data System shows that from January 2010-December 2015 total 660 phone calls related to kratom exposure – 73.8% of calls reported intentional exposure to kratom and 90.2% reported ingestion of the substance.

Data from toxicology laboratories and coroner/medicalexaminer offices report a growing number of positive detections of mitragynine and/or 7-hydroxymitragynine.  There were 31 positive results reported from August 2012-July 2013; 274 positive results from July 2013-May 2014; 555 positive results from December 2014-March 2016. It is important to point out that without further case context, we cannot state much more about the toxicology results or detections of mitragynine other than they were simply detected in a biological fluid - the detections could have been associated with cause of death or they could have merely been incidental findings in postmortem toxicology; they could also be simple detection in probationary urine drug testing or even findings in urine drug testing for physicians prescribing medications and testing their patient's urine. for prescribed drug/illicit substance use. The Federal Register Notice of Intent states that 15 deaths have been associated with kratom from 2014-2016 – many of which have included the use of other central nervous system depressants or other drugs. Most notably, there were a cluster of nine deaths in Sweden associated with kratom use (Krypton brand) that was contaminated with the potent O-desmethyltramadol (active metabolite of the drug tramadol).

Because of these reasons, the DEA feels that scheduling kratom is necessary to avoid an imminent hazard to public safety. I look forward to observing the outcome of this action. I’m not so sure that the DEA has thought this one through completely. There has already been a petition created via the WhiteHouse.gov website - at the time of typing this sentence, there have been 49,965 signatures (100,000 signatures are needed) acquired in about 4 days. The American Kratom Association has also banded together for a Kratom March on Washington DC on September 13, 2016.

Some References of Interest

1.      Federal Register. Schedules of Controlled Substances: Temporary Placement of Mitragynine and 7-hydroxymitragynine Into Schedule I. Notice of Intent. August 31, 2016.

https://www.federalregister.gov/articles/2016/08/31/2016-20803/schedules-of-controlled-substances-temporary-placement-of-mitragynine-and-7-hydroxymitragynine-into

2.     Kroll. Forbes. The DEA is placing kratom and mitragynine into Schedule I. August 30, 2016.

http://www.forbes.com/sites/davidkroll/2016/08/30/dea-to-place-kratom-mitragynine-on-schedule-i-premature-move-may-compromise-research-benefits/#7462be6c7924

3.     Boodman. STAT News. DEA will ban chemicals contained in kratom, a popular herbal supplement. August 30, 2016.

https://www.statnews.com/2016/08/30/kratom-ban-dea-schedule-1/

4.     Anson. DEA Banning All Sales of Kratom. August 30, 2016. http://www.painnewsnetwork.org/stories/2016/8/30/dea-to-ban-all-sales-of-kratom

5.     Main. Newsweek. DEA to list kratom as Schedule I, effectively outlawing herbal supplement. September 1, 2016.

http://www.newsweek.com/dea-list-kratom-schedule-i-effectively-outlawing-herbal-supplement-495144

6.     Adkins et al. Mitragyna Speciosa, a psychoactive tree from southeast Asia with opioid activity. Current Topics in Medicinal Chemistry. PMID 21050173.

7.     National Forensic Laboratory Information System. http://www.deadiversion.usdoj.gov/nflis/index.html

8.    Anwar et al. Notes from the field. Kratom (Mitragyna speciosa) exposures reported to poison centers – US, 2010-2015. MMWR Morb Mortal Wkly Rep. PMID 27466822.

9.     Holler et al. (2011) A drug toxicity death involving propylhexdrine and mitragynine. Journal of Analytical Toxicology. PMID 21218704.

10.  Kronstrand et al. (2011) Unintentional fatal intoxications with mitragynine and O-desmethyltramadol from the herbal blend Krypton. Journal of Analytical Toxicology. PMID 21513619.

11.  Rosenbaum et al. (2012) Here today, gone tomorrow…and back again? A review of herbal marijuana laternatives (K2, Spice), synthetic cathinones (bath salts), kratom, Salvia divinorum, methoxetamine, and piperazines. Journal of Medical Toxicology. PMID 22271566.

12.  Neerman et al. (2013) A drug fatality involving Kratom. Journal of Forensic Science. PMID 23082895.

13.  Karinen et al. (2014) An accidental poisoning with mitragynine. Forensic Science International. PMID 25453780.

Wait for the tox...

News broke the other day about a "face eater" and unprovoked attack that ended in two deaths in Florida. Of course the media jumped all over the possible drug angle. They've asked, could it be flakka? Some have said, yes, he was high on flakka.

Of course they did.

But let's wait for the toxicology analyses to come back. At this point, I seriously doubt any toxicology tests (outside of routine drug screens) have been completed. I'm sure tests will be run for cathinones such as MDPV and alpha-PVP (the supposed ingredient in flakka). Probably NBOMe hallucinogens as well. I'm sure an extensive and comprehensive toxicological analysis will be undertaken.

But, that takes time - this ain't CSI or NCIS.

Let's wait. Not speculate.

Remember the other famous (or infamous) "face eater" Rudy Eugene? Yeah, he wasn't on bath salts. And the media got that wrong from the initial reporting.

So again, let's just wait until the toxicology is reported.

But, if you do want to read more about alpha-PVP, gravel, or flakka, see these links:

5/26/15: Another day, another flakka story
4/14/15: On Flakka, Gravel, and Alpha-PVP
4/25/14: Gravel again
4/24/14: C'mon media, you have to do better...
1/29/2014: Gravel: human sacrifice, dogs and cats living together...mass hysteria?

It was only a matter of time...

News reports out of Arizona (12News) state that the DEA has raided a synthetic cannabinoid manufacturing laboratory.

Well, that's not news. It's happened quite a bit over the last several years.

Oh wait...

These folks were mixing synthetic cannabinoids with fentanyl.

This definitely is a way to cause serious harm.

It was only a matter of time.

According to the news report, they manufacturers were preparing the fentanyl and synthetic cannabinoid product in a cement mixer.

Yikes.

If I was in possession of a synthetic cannabinoid containing product in the state of Arizona, I'd throw it away. Now.

To all the people that come into contact with these substances (whether user, law enforcement, first responder, hospital staff, forensic chemists, etc.), be safe.

Officials prepare for the next big drug? It's U-47700.

Here is an article about the possible emergence of the opioid research chemical U-47700 in Iowa.

One quote to which you should pay attention...

"Weber says the new drug contains fentanyl which is a powerful medication."

No.

No.

No.

Though they may be found together in illicitly produced products, U-47700 is not Fentanyl. Fentanyl is not U-47700.

They are two different compounds each with its own distinct chemical structure.

Let's make sure to accurately describe the situation.

W-18 is now controlled in Canada.

Health Canada has controlled W-18.

Link is here.

Though, they still say it is an opioid drug and it is 100 times more potent than fentanyl, which we know is not accurate.

Health Canada needs to do better. People, internally and externally, look to the organization for accurate information.

More on W-18's pharmacology

Another update on Twitter by Dr. Bryan Roth from Roth Lab at UNC - Chapel Hill...

W18 predicted by SEA only H3 histamine activity. No predicted opioid activities

— BryanRoth(@zenbrainest) May 21, 2016

@drugmonkeyblog we will post all data this week on bioarchivxas getting lots of media requests for info

— BryanRoth(@zenbrainest) May 21, 2016

So, no predicted opioid activities again. Only histamine H3 receptor activity. And data will be posted on Bioarchivx sometime this coming week!

Ain't social media great?

W-18 Associated Fatality Reported in Calgary

It was reported today in the Calgary Herald that a 35 year old man was found deceased at a Calgary hotel on March 7, 2016. The death was believed to be drug-related at the time. Law enforcement found drugs, paraphernalia, and a naloxone kit (albeit unusued) on the scene.

The Herald reports that the individual had "heroin, W-18, and 3-methylfentanyl" in his system when he died.

The article gives some "fast facts on W-18". They include:

"The drug is said by police  to be 100 times more potent than fentanyl."

My thoughts?

First, I'm glad I'm not a forensic pathologist. And cause and manner of death is obviously the pathologist's responsibility. It is her call to make.

Second, from a toxicology perspective, I'd be more focused on 3-methylfentanyl (known potent mu opioid receptor agonist) and heroin (prodrug for 6-acetylmorphine and morphine) than the W-18 (at this point). Especially considering what we know about W-18 - that the 10,000 times more potent than morphine and 100 times more potent than fentanyl trope comes from a mouse model writhing assay - and what we officially unofficially know about W-18 - not an opioid receptor agonist.

Interesting article. Still we should be very, very careful on how we talk about W-18. Hysteria and hyperbole is not the way to go. Talk about what we do know. Talk about what we do not know. But misrepresenting facts in not ok. The headline of the article only includes W-18. That is misrepresenting the situation at hand. This is a death that was associated with all three compounds.


Reference:

Medical examiner confirms city's first fatal W-18 overdose

W-18 Pharmacology Update

From the last post on W-18, we should remember that other than the mouse writing assay data, we know nothing about the pharmacology of the substance. NOTHING.

 

Chemical structure of W-18

Well, that's changed a bit. At least officially unofficially.

Dr. Brian Roth (@zenbrainest) of Roth Lab in the Department of Pharmacology at the University of North Carolina - Chapel Hill tweeted a few days ago that they had preliminary information on W-18 via the NIMH Psychoactive Drug Screening Program.

Regarding W-18 and possible activity at mu opioid receptors...

@rgcjk @forensictoxguy We have no evidence for mu receptor activity....

— BryanRoth (@zenbrainest) May 11, 2016

And what about activity at kappa and delta opioid receptors?

@andcunningham @rgcjk @forensictoxguy No activity there. Compound seems quite toxic (unknown target) which is problematic for some assays.

— BryanRoth (@zenbrainest) May 11, 2016

And toxicity at what cells?

@drugmonkeyblog @andcunningham @rgcjk @forensictoxguy HEK cells though I wouldn't be surprised if others also toxic

— BryanRoth(@zenbrainest) May 11, 2016

So, there you have it. Officially unofficially W-18 has no activity at the mu, kappa, or delta opioid receptors.

DEA Schedules AH-7921

On April 14, 2016, the US DEA placed the opioid research chemical AH-7921 into Schedule I of the Controlled Substances Act. This move surprised me because I hadn't heard anything about it, but it's expected.

You can find the DEA final order here.

Now, with this substance scheduled, will U-47700 be considered a Controlled Substance Analog under the Analog Enforcement Act?

I'm sure it will be.

What do we know about W-18?

“W18 drug is 10,000 times stronger than morphine: Calgary police warning”

“Police warn against deadly new street drug W-18”

“Alberta health official warns of deadly new street drug”

“W-18, a drug 100 times more potent than fentanyl, is now in B.C.”

“Albertans left in the dark about police seizure of deadly new street drug”

“ER doctors warned about massive seizure of suspected W-18, 100 times more powerful than fentanyl”

“A toxic drug, more powerful than fentanyl, hits the streets in Alberta”

Those are some recent headlines regarding a newly emerged drug named W-18 in North America. The substance is supposedly 10,000 times more potent than morphine or 100 times more potent than fentanyl as a central nervous system depressant.

Counterfeit Oxycodone tablets containing fentanyl

Image taken from CBC News

http://www.cbc.ca/news/canada/saskatoon/w18-overdose-saskatchewan-alberta-1.3549043

W-18 is a compound in a series of 32 substances (named W-1 to W-32) that were first synthesized in academic research by Edward Knaus, Brent Warran, and Theodore Ondrus at the University of Alberta in 1981. These W-series compounds are covered under US patent 4468403A (August 28, 1984). The chemical name for W-18 is 4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide and it has a chemical formula C₁₉H₂₀ClN₃O₄S. Molecular weight is 421.9 g/mol.

Chemical structure of W-18

Image drawn by ForensicToxGuy (2016)

W-18 was detected in counterfeit tablets sold as fentanyl in Calgary, Alberta, Canada in August 2015. W-18 was also identified as the constituent in four kilograms of powder in a drug seizure in Edmonton, Alberta, Canada in December 2015; purity of the powder substance was reported to be 90% by Canadian authorities. In 2016, a Florida man was found to be in possession of 2.5 pounds of a powder containing W-18.

Despite media reports and quotes from law enforcement officials, the pharmacological profile for W-18 is not established at this time.  We have no data on absorption, distribution, metabolism, or excretion of the substance. We do not know on what specific receptors W-18 acts. We know nothing about receptor binding affinities. We know nothing of the acute effects of the substance. The only piece of pharmacological data that exists for W-18 was acquired via the mouse phenylquinone (PQ) writhing assay. In that test, W-18 had an IC₅₀ equal to 3.7 ng/kg and 50% inhibition. In the same test, morphine’s IC₅₀ was equal to 38,000 ng/kg and 50% inhibition. It very important to note that the PQ writhing assay is a general or non-specific test in which many compounds not considered to be analgesics, including sympathomimetics and central nervous system stimulants, protect mice against the PQ-induced writhing. The assay results should not be interpreted in any way that insinuates W-18 is approximately 10,000 times more potent than morphine as a central nervous system depressant.  We currently have no pharmacological data to support that W-18 has any activity at the opioid receptors: mu (µ), kappa (κ), or delta (δ).

W-18 is not considered a controlled substance in the United States, though it may be considered a controlled substance analog under the Analog Enforcement Act. It was made illegal in Sweden in January 2016. In Canada, the government has proposed making W-18 a Schedule I controlled substance, but it currently remains uncontrolled. In clinical and postmortem toxicology, there have been no analytically confirmed W-18 associated presentations to the hospital or fatalities reported.

As with any other newly emerging psychoactive substance, many claims are made about the compound itself. Many of the headlines are meant to grab attention and readership with hysteria about the new “super potent” or “scary” drug of the day. We should guard ourselves against that sort of hyperbole. But, even though we have no data to support the supposed extreme potency of W-18, let’s not fall into the trap that it isn’t potentially dangerous. We do not have data that shows its lack of potency. This extreme lack of knowledge about the compound makes the drug potentially dangerous.

 

References

Knaus, E.E., Warren, B.K., and Ondrus, T.A. (1984) Analgesic substituted piperidylidene-2-sulfon(cyan)amide derivatives. 399,994. http://www.google.com/patents/US4468403

Brittain, R.T., Lehrer, D.N., Spencer, P.S.J. (1963) Phenylquinone Writhing Test: Interpretation of Data. Nature, 200, 895-896.

Lum, Z-A. (2016) W-18 drug is 10,000 times stronger than morphine: Calgary police warning. http://www.huffingtonpost.ca/2016/01/29/w18-calgary-police_n_9114152.html

Desjardins, L. (2016) Police warn against deadly new street drug W-18. http://www.rcinet.ca/en/2016/04/21/police-warn-against-powerful-deadly-new-drug-w-18/

Zakreski, D. (2016) Alberta health official warns of deadly new street drug. http://www.cbc.ca/news/canada/saskatoon/w18-overdose-saskatchewan-alberta-1.3549043

Eagland, N. (2016) W-18, a drug 100 times more potent than fentanyl, is now in B.C. http://vancouversun.com/health/local-health/w-18-a-drug-100-times-more-potent-than-fentanyl-is-now-in-b-c

Howlett, K. (2016) Albertans left in the dark about police seizure of deadly new street drug. http://www.theglobeandmail.com/news/alberta/alberta-police-seize-drug-100-times-more-deadly-than-fentanyl/article29692152/

Southwick, R. (2016) ER doctors warned about massive seizure of suspected W-18, 100 times more powerful than fentanyl. http://calgaryherald.com/news/crime/er-doctors-warned-about-massive-seizure-of-suspected-w-18-100-times-more-powerful-than-fentanyl

Markusoff, J. (2016) A toxic drug, more powerful than fentanyl, hits the streets in Alberta.

http://www.macleans.ca/?dpsfa_article=a-toxic-drug-more-powerful-than-fentanyl-hits-the-streets-in-alberta

Russell, A. (2016) What we know about W-18, a drug ‘100 times more powerful than fentanyl’. http://globalnews.ca/news/2495761/what-we-know-about-w-18-a-drug-100-times-more-powerful-than-fentanyl/

McMahon, P. (2016) Broward man who smuggled synthetic heroin also had new lethanl, but legal, street drug. http://www.sun-sentinel.com/local/broward/fl-fentanyl-broward-sentencing-20160318-story.html

Consultation - Proposal regarding the scheduling of W-18 under the Controlled Drugs and Substances Act and its Regulations". Health Canada. Canadian Government. http://www.hc-sc.gc.ca/hc-ps/consult/w-18-eng.php

Gonçalves, Jacqueline (13 February 2016). "Notice to interested parties — Proposal regarding the scheduling of W-18 under the Controlled Drugs and Substances Act and its regulations". Canada Gazette (Government of Canada) 150 (7). http://gazette.gc.ca/rp-pr/p1/2016/2016-02-13/html/notice-avis-eng.php#nl3

Currrent Mood

 

 

Fentanyl analogs and opioid research chemicals...

It seems as if they are everywhere folks.

FtG

Thoughts on Meldonium and Sharapova

As you've probably seen by now, professional tennis player Maria Sharapova had a positive urine test for Meldonium/Mildronate - a Russian substance used to treat angina and myocardial infarction.

I won't rehash what Meldonium/Mildronate is, how it seems to work in the body, or why it was added to the WADA banned list as this has been done several times very well over the past couple of days.

Maria Sharapova and Meldonium: What ban can the tennis star expect?

Vox.com - Five things to know about meldonium, the drug Maria Sharapova has used for 10 years

Forbes.com - Banned drug Sharapova took was first patented as an animal growth promoter

Forbes.com - Meldonium isn't FDA approved. How could a US doctor have prescribed it to Sharapova?

Vox.com - Maria Sharapova's meldonium doping scandal explained

CNN.com - Kremlin hits back in Maria Sharapova scandal

Sharapova claims she has taken the substance for about the last ten years for medical issues. And I don't care. The substance wasn't explicitly banned by WADA until January 2016. Consumption of the substance was not against the rules. Any substance not banned is fair game for use.

After the January 2016 ban? Sure. She's a knuckleheaded cheater who was found with a banned substance in her urine. No sympathy from me on that one. None at all. She claims neither she nor any of her teammates looked at the newly updated banned substance list. There are reports that she was actually warned five separate times that the substance was to be banned in the upcoming year. Five times! Another knucklehead move. She could have filed for a therapeutic use exemption, but she did not. Sharapova has no one to blame but herself (for using the substance AND getting caught with it in her system after the banned date).

On the other hand, I've said this before - maybe we should allow doping in all professional sports? It is entertainment, right? Push the human body as far as it can go, and if performance enhancing substances expand a person's abilities, then maybe we should. Maybe? Someone recently said, if we were to allow this to occur, then wouldn't all sports become a "nuclear arms race"?

Professional sports already is an arms race. If you don't believe that, well, you're sadly mistaken.

Better living through chemistry as they like to say.

Case Report: GHB in a Sexual Assault

Newly published is a case report in Forensic Science International describing a truly horrible and deplorable situation in which a six year old female child was brutally sexually assaulted over the course of approximately nine months by her uncle. The child died.

It is an important case report. But, it is very difficult to read.

The paper is available behind a paywall via Science Direct here.

The uncle obtained GHB liquid over the Internet and was able to synthesize GHB salt from GBL with instructions acquired over the Internet. About nine months into the assaults, the uncle mixed GHB into some spaghetti with Bolognese sauce and later some apple juice. The child became sedated and unconscious. After about four hours and several heinous sexual assaults, the child stopped breathing. The uncle tried to resuscitate her, but was unsuccessful.

Toxicological analysis of the postmortem cardiac blood (1.5 mcg/mL), bile (2.92 mcg/mL), vitreous humor (5.8 mcg/mL), liver (100 mg/kg), kidney (125 mg/kg), and brain (110 mg/kg). Cause of death was ruled as GHB intoxication.

While we think that GHB is rarely used in drug facilitated sexual assaults (DFSA) in present day, this case is an important reminder that GHB is still utilized and should always be considered in DFSA casework and included in the scope of analysis in any toxicology analyses.

Reference

L.M. Mehling, S.S. Johansen, X. Wang, E. Doberentz, B. Madea, and C. Hess (2016) Drug Facilitated Sexual Assault with Lethal Outcome: GHB Intoxication in a Six-Year-Old Girl. Forensic Science International, Volume 259, e25-e31.

What is Ayahuasca?

Ayahuasca is a word from the Quechua language which means “vine of the souls”. More commonly ayahuasca is used in reference to a traditional “brew” made from various Central and South American plants including the perennial shrubs Psychotria viridis, Mimosa hostilis, and Peganum harmal, the perennial tree Acacia confusa, and/or the Banisteriopsis caapi vine. This brew is used in various spiritual ceremonies and most often in the ancient healing traditions of shamanism.

B. caapi vine, photo taken from Erowid.org

https://www.erowid.org/plants/show_image.php?i=banisteriopsis/banisteriopsis_caapi18.jpg

 So, why are these specific plants used?  Let’s look at chemistry and pharmacology.

P. viridis berries and leaves, photo taken from Erowid.org

https://www.erowid.org/plants/show_image.php?i=psychotria/psychotria_viridis_berry__i2003e0105_disp.jpg

P. viridis and the root bark of M. hostilis contain an alkaloid called N,N-Dimethyltryptamine, otherwise known as DMT. From a chemical structure perspective, DMT is very similar to the neurotransmitter 5-HT (serotonin). DMT is considered a psychedelic tryptamine and its mechanism of action is thought to be via partial 5-HT2A receptor agonism, but much is unknown still to this day. In the human body, DMT is readily degraded in the stomach and small intestine by the enzyme monoamine oxidase A (MAO-A). And for this reason, DMT’s effects are highly dependent on dose and route of administration. Use of the substance can range from mild psychedelic experiences to powerful hallucinations. It is important to note that DMT is also a trace endogenous compound in the human body.

 

To counteract this degradation of DMT by MAO-A, something else must be added to the brew. This is where P. harmal, A. confusa, and B. caapi enter the picture. They contain various substances called harmala alkaloids, with the primary ones being harmine, harmaline, and tetrahydroharmine. Harmine and harmaline act as selective reversible inhibitors of the enzyme monoamine oxidase A, so they are monoamine oxidase inhibitors or MAOIs. These inhibitors bind reversibly to MAO-A, thereby inhibiting the degradation of neurotransmitters and other substances, which has the overall effect of potentiating and prolonging the activity of the substances, i.e. substances are able to enter the blood without being rapidly metabolized. Tetrahydroharmine is considered a weak serotonin reuptake inhibitor, so while it has no MAOI activity, it does allow for some accumulation of serotonin in the neuronal synaptic cleft.

 

Positive user described effects of DMT include euphoria, hallucinations, and perceptual distortions. Ego softening/loss (loss of all reality or what is truthful/apparent) has been described. Feelings of love and empathy and acceptance have also been documented. Many users have described the drug effects as profoundly life-changing and spiritual. Some have reported understanding his/her ultimate purpose on Earth or the true nature of the universe. Others have used the term spiritual awakening to describe the drug’s effects.

Adverse effects include hypertension, tachycardia, nausea, diarrhea, body aches, fear, and paranoia. Vomiting is also an adverse effect, but is sometimes considered to be an essential part of the spiritual experience as it represents the release of negative energy and emotions.

Ayahuasca brew, photo taken from Erowid.org

https://www.erowid.org/chemicals/show_image.php?i=ayahuasca/ayahuasca__i2006e0454_disp.jpg

 Alexander and Ann Shulgin devote one chapter to ayahuasca and another chapter to DMT in their book on tryptamines, TiHKAL (Tryptamines I Have Known And Loved), The Continuation. As with their other book, PiHKAL, I highly recommend TiHKAL as a source of information on the psychedelic and hallucinogenic tryptamines.
Some user reports from TiHKAL regarding the effects of DMT were:

20 mg intramuscularly: I begin to see patterns on the wall that were continuously moving. They were transparent, and were not colored. After a short period these patterns became the heads of animals, a fox, a snake, a dragon. Then kaleidoscopic images appeared to me in my inner eye, fantastically beautiful and colored

50 mg intramuscularly: I feel strange, everything is blurry. I want my mother, I am afraid of fainting, I can’t breathe.

60 mg intramuscularly: I don’t like this feeling – I am not myself. I saw such strange dreams a while ago. Strange creatures, dwarfs or something; they were black and moved about. Now I feel as if I am not alive. My left hand is numb. As if my heart would not beat, as if I had no body, no nothing. All I feel are my left hand and stomach. I don’t like to be without thoughts.

60 mg smoked: Slightly threatening patterns – no insight – slight sense of cruelty and sharpness between us, but enjoying. His face, as before with MDA, demonic but pleasantly so. He said he saw my face as a mask. He asked me to let him see my teeth. I laughed – aware that laughter was slightly not funny. Heavy massive intoxication. Time extension extraordinary. What seemed like 2 hours was 30 minutes.

100 mg smoked: As I exhaled I became terribly afraid, my hear very rapid and strong, palms sweating. A terrible sense of dread and doom filled me – I knew what was happening, I knew I couldn’t stop it, but it was so devastating; I was being destroyed – all that was familiar, all reference points, all identity – all viciously shattered in a few seconds. I couldn’t even mourn the loss – there was no one left to do the mourning. Up, up, out, out, eyes close, I am at the speed of light, expanding, expanding, expanding, faster and faster until I have become so large that I no longer exist – my speed is so great that everything has come to a stop – here I gave upon the universe.

 

Ayahuasca Invitation by Alex Grey (2001)

http://alexgrey.com/art/paintings/soul/adam-and-eve/

 

While ayahuasca use and intoxication is reported in the media every so often, there has been one true report in clinical toxicology literature regarding DMT intoxication. Paterson et al. report the case of a 42 year old male who was brought to the hospital by law enforcement. He was found exhibiting disinhibited behavior, disorganized thought process, and delusions of reference. Testing in the hospital revealed elevated creatinine kinase indicative of rhabdomyolysis. Over the course of three weeks, the male was treated with quetiapine, divalproex sodium, gabapentin, and hydroxyzine for psychosis, impulsivity, anxiety, and sleep disturbances. The patient admitted to recent repeated use of DMT and marijuana.

One report in postmortem toxicology regarding ayahuasca involved DMT and its 5-methoxy derivative. Sklerov et al. reported a case of a 25 year old male who was found dead the morning after consuming an ayahuasca preparation. No anatomical cause of death could be determined at autopsy. Heart blood was subjected to toxicological analyses and was positive for DMT (0.02 mgL), 5-Methoxy-DMT (1.88 mg/L), tetrahydroharmine (0.38 mg/L), harmaline (0.07 mg/L), and harmine (0.17 mg/L). The cause and manner of death was determined to be accidental hallucinogenic amine intoxication.

DMT is considered a federally controlled Schedule I substance in the USA. The legality of ayahuasca has been at conflict in a few court decisions since 2004. In 2004, the US Supreme Court lifted a stay and allowed a UDV church to use ayahuasca in service. In 2005-2006, the Supreme Court heard arguments and ultimately ruled that under the 1993 Religious Freedom Restoration Act (RFRA), the government must allow the same UDV church to import and consume ayahuasca for religious ceremonies. In 2008, three Brazilian churches filed suit to gain legal status to import ayahuasca. The judge ruled in favor of the churches. In 2009, a federal judge issued a permanent injunction which barred the government from prohibiting or penalizing the use of ayahuasca as a sacrament.

Selected References of Interest

Tittarelli, R., Mannocchi, G., Pantano, F., Romolo, F.S. (2015) Recreational use, analysis, and toxicity of tryptamines. Curr Neuropharmacol, 13, 26-46.

Liester, M.B., Prickett, J.I. (2012) Hypotheses regarding the mechanisms of ayahuasca in the treatment of addictions. J Psychoactive Drugs, 44, 200-208.

Araujo, A.M., Carvalho, F., Bastos Mde, L., Guedes de Pinho, P., Carvalho, M. (2015) The hallucinogenic world of tryptamines: an updated review. Arch Toxicol, 89, 1151-1173.

Sklerov, J., Levine, B., Moore, K.A., King, T., Fowler, D. (2005) A fatal intoxication following the ingestion of 5-methoxy-N,N-dimethyltryptamine in an ayahuasca preparation. J Anal Tox, 29, 838-841.

Paterson, N.E., Darby, W.C., Sandhu, P.S. (2015) N,N-Dimethyltryptamine-Induced Psychosis. Clin Neuropharmacol, 38, 141-143.

  



Synthetic Cannabinoids (SCRAs): A 2.5 Minute Primer

What are synthetic cannabinoid receptor agonists and how do they work in the body?

Synthetic cannabinoid receptor agonists (also called SCRAs or synthetic cannabinoids) are laboratory developed chemicals that bind to the cannabinoid receptors 1 and 2 (CB₁ and CB₂) in the body. CB₁ receptors are primarily located in the central nervous system (the brain and spinal cord) and are responsible for mediating the psychoactive effects of cannabis. The CB₂ receptors are primarily located in the peripheral nervous system, as well as the spleen and immune system, and are thought to be involved in pain perception mediation and immunosuppression. While delta-9-tetrahydrocannabinol (THC), the primary psychoactive component found in marijuana, is a partial agonist of both the CB₁ and CB₂ receptors, SCRAs are considered to act as full agonists of the same receptors.

Are these substances the same as marijuana?

No. The media loves to use the words synthetic marijuana or synthetic weed or synthetic pot to describe SCRA containing products. This description could not be further from reality. SCRAs and related products are not marijuana. 

From where did these compounds originate?

Many compounds have originated in academic research on new drug targets and the cannabinoid receptor systems. The JWH series (JWH-018, JWH-019, JWH-122, etc.) of SCRAs were developed at Clemson University under Dr. John W. Huffman. AM-2201 was developed at Northeastern University under Alexandros Makriyannis. Another SCRA, UR-144, was developed by Abbott Labs. XLR-11, a 5-fluorinated derivative of UR-144, was covered under an Abbott Labs patent, but never synthesized. The indazole carboxamide ADB-FUBINACA was synthesized by Pfizer as a possible therapeutic drug. Some compounds on the market today have no formal academic or industry history and are the product of clandestine chemists using rational drug design.

Are these chemicals considered “controlled substances” in the USA?

In the USA, SCRAs have been sold as ingredients in herbal incense, herbal potpourri, or smoking blends since approximately 2009 and have become popular as a cannabis alternative. The powders are also available via the Internet. Throughout the last several years in the USA, various waves of legislation have been passed by the Federal government classifying several synthetic cannabinoids as Schedule I controlled substances. Schedule I controlled substances are those substances that are considered to have a high potential for abuse, a potential for severe psychological or physical dependence, and have no currently accepted medical use in the USA. These substances are illegal to possess, manufacture, and distribute. As this legislation is enacted, manufacturers and vendors of these substances and resulting mass-produced retail products vary the active ingredient(s) to now uncontrolled (and quasi-legal) substances. Currently there are twenty four (24) synthetic cannabinoids explicitly controlled by the Federal government as Schedule I controlled substances.

These are:

5F-PB-22, AB-CHMINACA, AB-FUBINACA, AB-PINACA, ADB-PINACA, AKB48/APINACA, AM694, AM2201, CP-47,497, CP-47,497-C8 homologue, JWH-018/AM678, JWH-019, JWH-073, JWH-081, JWH-122, JWH-200, JWH-203, JWH-398, PB-22, RCS-4/SR-19, RCS-8/SR-18, THJ-2201, UR-144, and XLR-11

Each state in the USA has its own controlled substance laws. As there is considerable variation in inter-state laws – some states have blanket bans on chemical structure classes and other states only explicitly list substances by name while other states use a combinatorial approach – please consult those specific laws for a list of scheduled substances.

How are these products made?

Common plant material, such as marshmallow leaf, mullein, or damiana can be easily purchased over the internet in bulk and used as the base for the herbal incense product. The drug material can also be purchased over the Internet and is then dissolved in acetone or high proof ethanol and sprayed on the plant material. The plant material is dried and packaged for distribution. The laboratories in which these products are made do not possess stringent quality assurance/quality control (QA/QC) policies, so there tends to be much cross contamination of product as well as intra-product variation in actual synthetic cannabinoids used. Also, due to the lack of QA/QC procedures, there may be ‘hot spots’ of drug in certain section of the plant material, which essentially means that the drug is not uniformly applied to the substrate leading to extreme variation in dosages across a batch of product.

How are these substances or products consumed?

The plant material products can be rolled up in a cigarette or joint and smoked like tobacco or marijuana. The chemical powder can also be smoked. SCRAs are also available in liquid form for vaping via electronic cigarettes (e-cigarettes).

What are some commonly reported effects of these substances?

Common cognitive and psychomotor effects attributed to SCRAs include poor coordination, instability, slowed movements, sedation, sway, balance issues, slowed or slurred speech, agitation, irritability, delusions, paranoia, hallucinations, and psychosis. Other adverse effects that have been observed include nausea, vomiting, tachycardia, hypertension, hyperthermia, and acute kidney injury. Several fatalities have occurred after use of these substances. As with any drug, effects seem to be very dose-dependent. Lower doses will elicit the more common effects while larger doses or repeated dosing will lead to the more exaggerated adverse effects.

What are a forensic toxicologist’s thoughts on SCRAs?

In the laboratory, we’ve been dealing with synthetic cannabinoids for approximately the last 6 years. In 2009-2010, there were only 1-2 synthetic cannabinoids detected in casework. Via different forces on the market (in my opinion, not the only factor, but primarily legislation) the market exploded in sheer number of compounds and continues to change with the ever-evolving controlled substance laws. The USA has legislated itself into a public health nightmare. By continually outlawing substances, we have allowed compounds with completely unknown pharmacological and toxicological profile to find their way to the grey-market. We are only seeing the beginnings of this nightmare through mass hospitalizations and outbreaks of illnesses (and a noted increase in phone calls to poison centers) after use of synthetic cannabinoid-containing products. The vast majority of people using these substances and products are consuming substances of unknown identity with unknown pharmacological and toxicological profiles in unknown combinations at unknown dosages. This is reckless behavior. This is dangerous behavior. It will result in serious adverse health effects for the individual.

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 synthetic cannabinoid compound D! I’ve coined the phrase “diverse chemical grab bag o’ death” to describe these substances. We know very little of the true acute effects of individual synthetic cannabinoids. We know nothing of the long-term or chronic effects of synthetic cannabinoid use (and we will not for quite some time). We do not know if they act on other receptors or mediate other effects downstream. It is thought that they do not, but who knows. And therein is the important part of this - we know nothing about these compounds. Nothing. And that is what makes them dangerous.