Synthetic Cannabinoids Highlight the Need to Abandon the War on Drugs

As an emergency medicine resident in New York City, I am regularly confronted with a chief complaint that I had not seen during medical school on the West Coast — K2 intoxication.

While prevalence numbers are hard to come by, poison control calls in 2021 due to K2, otherwise known as synthetic marijuana, were significantly higher in New York state compared to Washington state even after accounting for difference in size of population. While the population of New York is roughly three times that of Washington, the number of K2-related calls to poison control that originated from New York was approximately 12 times the number of calls from Washington.¹

At the risk of simplifying a complex issue, the divergence in the two states’ political approaches to marijuana policy can explain much of this disparity in prevalence. That is to say, it is my view that our country’s ongoing embrace of prohibition is directly responsible for the scourge of K2.

Marijuana is classified as a Schedule I drug — the government considers it to have a high potential for abuse and no medical value. Other drugs listed in Schedule I include heroin, psychedelic mushrooms, LSD, and mescaline. Interestingly, fentanyl, methamphetamine, and cocaine are all Schedule II — the government has decided that they have a high potential for abuse and a medical value. What this means practically is that these drugs are available for medical use in a very limited number of settings. However, despite the reference to medical value and potential for abuse, it is clear to many that our drug policies are based upon anything but science and empiricism. While certainly not the panacea many of its most ardent supporters claim it to be, it is farcical to claim that there are no medical benefits to marijuana, whose many nuances we are only now beginning to elucidate. And this is to say nothing about the dubious validity of using medicinal value as a basis for determining what recreational substances are legally available. As alcohol makes abundantly clear, a substance need not have a medicinal benefit to have a valuable role to play in society. And as alcohol also demonstrates, the potential to cause harm does not necessitate prohibition.

Being Schedule I means it is exceedingly difficult to obtain permission to perform any research on marijuana. Until recently, the only federally available source of marijuana for research was a single strain produced in an outdoor farm at the University of Mississippi.² Not only was this supply of marijuana deemed inadequate by many scientists and other experts, but up until recently, the vast majority of marijuana research proposals that were granted federal funding were those whose aims were to investigate the potential harms of the plant. In fiscal year 2015, only 16.5% of cannabis-related grants funded by the National Institute on Drug Abuse (NIDA) investigated the therapeutic potential of marjiuana.³ Thus, due to regulatory and financial barriers, the government has created a Catch-22. The substance is Schedule I — deemed to have no established medical benefits — and yet research proposals investigating possible medical benefits were rarely federally approved and funded, thereby ensuring that marijuana would maintain its Schedule I status.

A Novel Workaround to Research Restrictions
In part as a response to these federal restrictions on research, organic chemist Dr. John Huffman circumvented this conundrum by creating a novel compound based closely upon delta-9 tetrahydrocannabinol (THC), the primary active ingredient in marijuana. By creating a substance with a distinct molecular structure, yet with effects that mimicked THC, he was able to sidestep this Catch-22. In doing so, he was able to research endocannabinoids — the body’s naturally produced neurotransmitters similar in structure to THC and the other psychoactive compounds found in marijuana — without going through the arduous, near-impossible federal approval structure for marijuana research.

This first compound was initially synthesized in 1995, and the first studies investigating binding affinities of endocannabinoid receptors in humans were published in 1998.⁴ However, as exemplified by the history of lysergic acid (LSD) and methylenedioxymethamphetamine (MDMA), when a novel compound with pleasant psychoactive effects is created in a lab for scientific evaluation, it tends to find its way out of the lab and into the bodies of eager consumers. And so it was with synthetic cannabinoids. In 2008, Dr. Huffman received an email alerting him that one of his novel synthetic cannabinoids, JWH-018, had been identified in herbal supplements being sold in Germany.⁵

Here was a substance whose effects were virtually indiscernible from whole marijuana yet not federally illegal. In the early 2010s, synthetic cannabinoids became ubiquitous. The chemical was sprayed on inert vegetative matter; sold in attractive, psychedelic-inspired packaging; and legally marketed as incense and “not for human consumption.” These products were easily obtained — online, in gas stations, and at smoke shops — with a number of companies attempting to carve out their corner of the market with intriguing product names, including Spice and K2.⁶

Inevitable harms from our prohibitionist drug policies
In response, the Drug Enforcement Agency (DEA) did what it often does and moved to outlaw this new substance with little input from the scientific and medical community and without comprehensive data about actual harms posed by these substances.⁷ But by this point, it was too late. An appetite had been built for synthetic cannabinoids, and entrepreneurial black-market chemists realized there was profit to be made. Instead of being deterred by the new illegality of their product, these chemists were instead inspired to outmaneuver the DEA. They made small changes to the molecule, hoping to preserve its familiar psychoactive effects while being dissimilar enough in structure to the original synthetic cannabinoids as to no longer be covered by the DEA’s emergency scheduling.

This set off a predictable game of whack-a-mole between the DEA and their chemist adversaries. Each time a new version of synthetic cannabinoids would be released to the market, the DEA would make it illegal, prompting yet another round of revisions to chemical structure to produce yet another novel and legal psychoactive substance.

The DEA emergently scheduled synthetic cannabinoids for the first time in 2011, and as of 2021, there were 40 synthetic cannabinoids listed under Schedule 1.⁶ The DEA identified 84 novel cannabinoids in 2016 alone.⁸ While the rate of synthesizing novel cannabinoids has likely slowed down since its peak in the 2010s, new molecules, with no history of human use, are regularly being synthesized and placed in the quasi-legal market and into bodies of willing consumers. The problem, however, is that you can only make so many changes to a chemical structure before it starts to have less predictable effects and really begins to belong to a class of drugs all its own.

Some may be surprised by the fact that intoxication with the first incarnation of K2 was virtually indiscernible from natural marijuana. Many of us, for one reason or another, are familiar with the effects of cannabis. We may even have cared for a patient or two who presented to the emergency department with a chief complaint of marijuana intoxication — like the mother-daughter pair I helped treat after they accidentally consumed marijuana edibles in their quest to find a natural sleep aid. These experiences of marijuana intoxication are an entirely distinct clinical phenomenon from our patients inebriated by K2. That’s because what started off as a predictable mimicker of THC now has a profound array of disturbing possible effects that include catatonic states, violent behavior, paranoia, kidney injury, stroke, seizures, and heart attacks.⁸

I believe that our federal drug policies are directly responsible for this Frankenstein-esque drug, K2. Seemingly unwilling to accept the reality that nearly every society has documented use of psychoactive substances, most of our elected leaders remain hell-bent on achieving Ronald Reagan’s quixotic drug-free world. While an impartial and evidence-based evaluator would almost certainly determine that the potential harms of marijuana use are far outweighed by the harms of an unregulated and illegal marijuana market, most of our laws are more inspired by the cult-classic “Reefer Madness” than by science.

This prohibitionist approach, only recently rejected in New York state with the cannabis legalization bill signed into law in March 2021, plays a large role in why I frequently see K2 intoxication as a chief complaint in my ED. In the absence of a regulated marijuana market, many people turn to the quasi-legal, bodega-available, cheap K2. Instead of a mild case of anxiety and tachycardia that can be seen with marijuana intoxication, those who consume K2 are often ending up chemically sedated while being monitored for the rare but concerning aforementioned side effects.

A Necessary Alternative
Nearly as striking as treating a K2 patient in my New York City ED is the relative absence of K2 in my hometown of Seattle. That is, in part, because marijuana enjoys widespread acceptance in Seattle. Washington state’s first step toward legal recognition was a medical marijuana law in 1998, followed by a Seattle law instructing cops to make marijuana enforcement their “lowest enforcement priority,” and then outright legalization of recreational marijuana in 2012.^9,10 What this means is that people who want marijuana as a way to recreate, connect, or even self-medicate have relatively easy access to a safe and regulated supply without risk of legal consequences. It makes sense, then, that there was not, and is not, much of a market for K2 among most Washingtonians. However, there are populations in the state within which K2 is more prevalent: the military, individuals who are incarcerated, and employees who are subjected to drug tests. Case in point: These are populations that are barred access to the state’s otherwise legal supply of cannabis.⁸

And lest one think this phenomenon is unique to marijuana, one only has to look at synthetic opioids to see that this troubling trend of increasingly dangerous novel drugs will continue. Heroin is expensive, bulky, and requires growing large fields of poppies — making it an unnecessarily risky enterprise in a world of prohibition. Synthetic opiates are the opposite — extremely potent, far less bulky, and cheaply made in a lab. As we have seen, this has led to fentanyl and its more dangerous derivatives flooding markets and all but replacing the heroin that consumers are often seeking, leading to the overdose crisis we are all too familiar with. But in an attempt to evade the illegality of heroin and fentanyl, other opioid derivatives — such as nitazenes — are making their way, legally, onto the market.¹¹ And as was the case with synthetic cannabinoids, I believe it’s only a matter of time before these derivatives have had one too many changes to the original opioid chemical structure and they stop acting like a predictable opiate. Or even more worrisome, they stop responding to naloxone.

We must use our experience on the frontline of the unintended, yet inevitable, consequences of the war on drugs to lobby our elected officials for policies that reduce, not perpetuate, harm — policies that acknowledge that people will always seek to alter their consciousness, that this doesn’t make them inherently criminal, and that doing so does not have to be dangerous to their health. By embracing harm reduction and evidence-based drug policies, we can reduce the prevalence of relatively dangerous synthetic cannabinoids while also decreasing the chances that our EDs will be flooded with other harmful derivatives of commonly used psychoactive substances. Indeed, this act of courage — of being willing to challenge our unjust but widely accepted prohibitionist drug policies — is not only the right thing to do, but required of us by our field’s own code of ethics.^12,13

References

1. National Poison Data System, American Association of Poison Control Centers. Synthetic Cannabinoids: 2021 Synthetic Cannabinoid calls to U.S. Poison Centers. You can reach your local poison control center by calling the Poison Help hotline: 1-800-222-1222. To save the number in your mobile phone, text POISON to 797979.
2. Erickson, BE. Cannabis Research Stalled by Federal Inaction. Chemical and Engineering News. 2020;98(25).
3. National Academies of Sciences, Engineering, and Medicine. Challenges and Barriers in Conducting Cannabis Research. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. National Academies Press. 2017.
4. Wiley JL, Compton DR, Dai D, et al. Structure-activity relationships of indole-and pyrrole-derived cannabinoids. Journal of Pharmacology and Experimental Therapeutics, 1998;285(3):995-1004.
5. Wang, L. John W Huffman — Organic chemist invented a compound in 1995 that is now at the center of a controversy brewing over synthetic marijuana. Chemical and Engineering News. 2010;88(26).
6. Howlett AC, Thomas BF, Huffman JW. The spicy story of cannabimimetic indoles. Molecules. 2021;26(20).
7. Drug Enforcement Administration Media Release. Chemicals used in “Spice” and “K2” type products now under federal control and regulation. March 1, 2011.
8. Centers of Disease Control and Prevention. Synthetic cannabinoids: An overview for healthcare providers. Centers for Disease Control and Prevention Health Studies. https://www.cdc.gov/nceh/hsb/chemicals/sc/healthcare.html
9. Washington State Department of Health. History in Washington. Washington State Department of Health You and Your Family. https://www.doh.wa.gov/YouandYourFamily/Marijuana/MedicalMarijuana/LawsandRules/HistoryinWashington
10. Office of the City Clerk. Initiative 75 measure. Seattle Office of the City Clerk. http://clerk.ci.seattle.wa.us/~public/initref/init75.htm
11. Vandeputte, M. M., Van Uytfanghe, K., Layle, N. K., St. Germaine, D. M., Iula, D. M., & Stove, C. P. (2021). Synthesis, Chemical Characterization, and μ-Opioid Receptor Activity Assessment of the Emerging Group of “Nitazene” 2-Benzylbenzimidazole Synthetic Opioids. ACS Chemical Neuroscience, 12(7), 1241-1251.
12.  American College of Emergency Physicians. (2017, January). Code of ethics for emergency physicians. American College of Emergency Physicians Policy Statements. https://www.acep.org/patient-care/policy-statements/code-of-ethics-for-emergency-physicians/
13. American Academy of Emergency Medicine. (2010, January 01). AAEM principles of ethics. American Academy of Emergency Medicine. https://www.aaem.org/about-us/our-values/code-of-ethics