by Jeff Lapoint

July, 2010. 3:14 am.

“Jeff, I got a liddle case for ya”, said the voice of Lou (named changed), the very New York C-SPI from the Poison Center. “917-555-. . .” He continued to rattle off a phone number. “Dude, give me more than that”, I begged. I was a new fellow, and if I didn’t get to at least perform a brief review of whatever he was calling about before I returned the call, I was going to look like a complete idiot . . .again. “40’s male took some powder from the internet. Starting seizing. Unstable in the ER now. Wife has the packet and label – JWH-018, or something . . .”

Chemical name or something that sounded like one in hand, I tried to fully wake up as I scoured the index of my Goldfrank’s Toxicologic Emergencies. JWH 00-something. Wasn’t there. Shit. Same result after a power search of the online version. Nothing. Finally, a desperate site wide search on Access Emergency Medicine. Nada. Oh man, have to check the secondary textbook.

The use of the secondary text, or “Wikipedia” as the kids call it now, was a risky proposition. Acceptable only in the most dire of circumstances it was the new fellow’s Hail Mary. Thankfully, there was a small entry. JWH-018 was a synthetic cannabinoid, a research chemical designed to study cannabinoid receptors. There was almost no information on toxicity in humans, just a handful of European cases.

8 years and four scores of cases later we are still essentially in the same position that I was that night during my first month of fellowship. We still struggle to deal with a patient poisoned with an unknown dose of an unfamiliar or uncertain (and possibly contaminated) substance under the mantle of “synthetic cannabinoid”.

What is a cannabinoid?

Cannabinoids are chemicals that bind to cannabinoid receptors. They can be plant based such as tetrahydrocannabinol (THC) and cannabidiol (CBD) which are found in marijuana. They can also be synthetic (such as the JWH compounds) or endogenous. Being a cannabinoid has nothing to do with structural resemblance to THC but only involves binding and interactions with cannabinoid receptors.

The original definition of a cannabinoid was a compound that was structurally similar to THC because at the time this was the only known substance that interacted with the cannabinoid receptors. If we time travel to 1960, this would be the correct definition. Today, after the better part of 60 years of cannabinoid research and the discovery of hundreds of diverse chemicals that interact with cannabinoid receptors, the term cannabinoid does not require structural similarity to THC.1

Most of us in toxicology had no reason to follow cannabinoid research since the 1960’s. So when the synthetic cannabinoids burst onto the scene in the late 2000’s with newfound toxicologic relevance, some looked at their structure and mistakenly thought new nomenclature was needed. Thus, Synthetic Cannabinoid Receptor Agonist (SCRA) was born. I think of this term as a great example of medicine and medical toxicology mansplaining something that already had an appropriate name for 30 years. So I beg of you – please just stick to cannabinoids and then we can specify by type or origin.

Cannabinoid receptors

Two main cannabinoid receptors exist in the human body – CB1 and CB2. For the purpose of this discussion, we will mainly focus on CB1. CB1 is a G protein found in the brain. This fact requires some emphasis. G proteins receptors engage cellular machinery and secondary messengers, as contrasted to an ion channel like the GABA-A receptor. CB1 is the most plentiful G protein in our cerebral cortex.2

The function of a cannabinoid receptor is to fine-tune the release of neurotransmitters via allosteric binding. Take the example of GABA release: Nerve impulses lead to the presynaptic release of a GABA which binds to a postsynaptic GABA-A receptor. Think of this system like a light switch with an on and off. Flip the switch and GABA is released and binds at the postsynaptic receptor leading to the downstream effects (e.g. lights on / hyperpolarization of the neuron). Cannabinoids turn this system into a light with an adjustable dimmer. Endogenous cannabinoids are synthesized on demand when the neurotransmitter binds across the synapse. They travel back to the cannabinoid receptor located presynaptically and decrease the amount of GABA being released. After these endogenous cannabinoids bind to their respective receptors they are quickly degraded and the process can start again. While we discussed only GABA, CB1 receptors also modulate the release of glutamate, dopamine, and norepinephrine.

Used with permission from the corresponding author.2

What are synthetic cannabinoids and where did they come from?

Despite centuries of human contact with plant-based cannabinoids (weed ☺), technical limitations of the late 1800’s and early 1900’s prevented the exact structure of THC to be known. By the 1960’s, technology improved sufficiently to allow the identification of the structure of medicinal alkaloids such as cocaine and morphine, as well as terpenes like THC. Once the structure of THC was known (1964) it was only a matter of time before first structurally similar synthetics were produced.

In the 1970’s, new synthetics were created in the search for the next great analgesic. Pfizer created dozens of cannabinoids and some even made it to human testing. Unfortunately, the psychoactive effects could not be separated from any potential anti-inflammatory effects and when all the test subjects got baked, development ceased on these compounds.

The first cannabinoid receptor was discovered in the 1980’s. It was previously believed that there was no receptor for cannabinoids as their lipophilicity allowed them to freely wash across cell membranes to exert their effects. The discovery of receptors let to the creation of hundreds of synthetic cannabinoids of many structure subtypes – designed to study the binding properties of the receptor. Some of these new compounds had binding affinities many times that of THC. They often had names based on who created them. Examples such as the JWH compounds were named for Clemson University’s Dr. John W. Huffman and AM compounds for Alexandros Makriyannis of Northeastern University. These compounds were never intended for human use and the potential of future therapeutics would be decades away. These new cannabinoids were designed only to learn about receptor binding and activity.

How did synthetic cannabinoids become novel drugs of abuse?

The early 2000’s provided fertile ground for the emergence of new drugs of abuse. Existing drugs laws in the US centered around the Controlled Substances Act (CSA) from the 1970’s and an addendum to the CSA from the 1980’s called the Analogue Act. In order to be included in the CSA, a drug had to be specifically named and approved by Congress. The Analogue Act made compounds that were similar in structure to already controlled substances, produced a similar effect in the body AND were for human consumption scheduled the same as the original compound. So if amphetamine was designated Schedule II by the CSA and I made some methamphetamine, in the hopes to skirt drug laws, the Analogue Act would prevent me from selling my Heisenberg Blue on the streets of San Diego free and clear from police intervention. Existing drug laws left synthetic cannabinoids completely unregulated. They were structurally different from THC, no one really knew the effects, and if placed in packages stating ‘not for human consumption’ (wink wink) there were no laws that applied.

Aside from legal loopholes, the early 2000’s provided another essential factor in the emergence of SCs as drugs of abuse – the internet. The compounds themselves were readily available as research tools and as calibration materials for mass spectrometers. The directions on how to make them were laid bare in scientific publications3 and patent filings. Even worse, these SC’s were relatively easy and inexpensive to produce.

Toxicity of Synthetic Cannabinoids

There is no consistent synthetic cannabinoid toxidrome and every single case has the potential to be completely different from prior reported exposures. We are dealing with an unknown dose of an unknown and possibly adulterated substance that works on a complex and poorly understood biochemical pathway . . . so yeah there’s that. Patterns of toxicity have emerged with various outbreaks and it is important to be aware of reported cases and alert Poison Control of cases that present to your hospital. Consult your local medical toxicology service if you have one.

The earliest cases presented with sympathomimetic features as well as seizures and generalized convulsions.4 Both ischemic and hemorrhagic strokes have been reported.5 Psychosis, especially in patients with underlying psychiatric disorders, is well documented in case reports.

The second notable outbreak involved a cluster of cases that presented with acute kidney injury after using a synthetic cannabinoid product containing the SC XLR-11. Some of the patients required hemodialysis but most recovered with supportive care.6

In 2016 patients presented in Los Angeles and New York with a catatonic-like state and bradycardia.7

2018 has seen cases of SCs contaminated with the superwarfarin brodifacoum. Hundreds of cases and multiple fatalities were reported.8 Most recently, SCs adulterated with fentanyl were reported.

Don’t drop your guard on these cases regardless of how many you have seen before (myself included). Plan for the unexpected and thoroughly assess for end-organ toxicity. The urine drug screen is useless here (almost always actually) and do not expect laboratory confirmation in a clinically meaningful timeframe. Consider sending an INR. Have a low threshold for imaging if clinically indicated. Provide aggressive supportive care. If you can, save samples of the patient’s blood and keep the drug if the patient has it on them. Notify public health authorities and see if they can use the samples. You very well may be on the leading edge of the next synthetic cannabinoid outbreak.

Summary

The endocannabinoid system works in part to modulate the release of neurotransmitters. It was relatively recently discovered and is at best incompletely understood. Synthetic cannabinoids are potent cannabinoid agonists with unpredictable clinical effects. There are not fake weed or synthetic marijuana but rather dangerous research chemicals. New SC’s are constantly being introduced in an effort to thwart drug laws. Thorough assessment for CNS, cardiac, renal, hepatic, and metabolic toxicity, as well as the presence of coagulopathy, is indicated. Consult the Poison Control Center (1-800-222-1222) and your local medical toxicology consult service and obtain samples if possible. Maybe it’s time to call old Lou at home and tell him about this. It’s about 3:15 am NYC time. Perfect . . .

hooded figure by sebastiaan stam

1. Pharmacol Rev. 2010;62(4):588-631. PubMed] Pertwee R, Howlett A, Abood M, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB₁ and CB₂.. 2010;62(4):588-631. 2. Mol Interv. 2011;11(1):36-51. PubMed] Seely K, Prather P, James L, Moran J. Marijuana-based drugs: innovative therapeutics or designer drugs of abuse?. 2011;11(1):36-51. 3. Bioorg Med Chem. 2008;16(1):322-335. PubMed] Huffman J, Thompson A, Wiley J, Martin B. Synthesis and pharmacology of 1-deoxy analogs of CP-47,497 and CP-55,940.. 2008;16(1):322-335. 4. Clin Toxicol (Phila). 2011;49(8):760-764. PubMed] Lapoint J, James L, Moran C, Nelson L, Hoffman R, Moran J. Severe toxicity following synthetic cannabinoid ingestion.. 2011;49(8):760-764. 5. Clin Toxicol (Phila). 2014;52(9):973-975. PubMed] Takematsu M, Hoffman R, Nelson L, Schechter J, Moran J, Wiener S. A case of acute cerebral ischemia following inhalation of a synthetic cannabinoid.. 2014;52(9):973-975. 6. Clin Toxicol (Phila). 2014;52(7):664-673. PubMed] Buser G, Gerona R, Horowitz B, et al. Acute kidney injury associated with smoking synthetic cannabinoid.. 2014;52(7):664-673. 7. N Engl J Med. 2017;376(3):235-242. PubMed] Adams A, Banister S, Irizarry L, Trecki J, Schwartz M, Gerona R. “Zombie” Outbreak Caused by the Synthetic Cannabinoid AMB-FUBINACA in New York.. 2017;376(3):235-242. 8. MMWR Morb Mortal Wkly Rep. 2018;67(21):607-608. PubMed] Moritz E, Austin C, Wahl M, et al. Notes from the Field: Outbreak of Severe Illness Linked to the Vitamin K Antagonist Brodifacoum and Use of Synthetic Cannabinoids – Illinois, March-April 2018.. 2018;67(21):607-608.