Dangerous Chemistry: The Threat of Unregulated Cannabinoids Poses a Grave Risk to Public Health
The combination of federal prohibition of cannabis, hemp legalization with no FDA guidance, and over-regulation and heavy taxation of legal cannabis markets have created a danger to public health that may be unparalleled in its reach and detriment.
Without going into the incredibly dysfunctional dynamics of legal cannabis, the current market creates a perfect storm for many unsafe and untested cannabis products to be sold directly to the public. Prohibition has also been a catalyst in creating a huge market for synthetic cannabinoids aimed to mimic the effects of THC, often with extraordinarily higher potency, which are known to cause great harm to humans (more below).
The 2018 Farm Bill has only exacerbated this public health disaster by legalizing hemp and hemp derivatives without specifying standard testing requirements on the purity and potency of hemp products. It also didn’t take long for the industry to outsmart the legislators by producing psychoactive, lab synthesized hemp derivatives that are sold as “legal hemp.” The FDA has compounded this issue by failing to regulate hemp CBD and its derivative products in any way. If there were legalization of cannabis products with appropriate regulation and less taxation, it’s doubtful that any of this would be happening.
Synthetic cannabinoids
Synthetic cannabinoids are chemical compounds created in a laboratory designed to mimic the psychoactive effects of delta-9-THC. They are either sprayed on dried plant material to be smoked or sold as liquids to be vaporized and inhaled in e-cigarettes or other devices. They are marketed as herbal incense or herbal smoking blends under trade names such as “Spice,” “K2, "Bliss," "Black Mamba," "Bombay Blue," "Fake Weed," "Genie" and "Yucatan Fire," to name a few. These products are now becoming more difficult to identify, masquerading as plain old THC on the market.
Although both THC derived from cannabis and synthetic cannabinoids stimulate the same CB1 and CB2 receptors, some synthetic cannabinoids are over 100-fold more potent than THC because they are direct agonists of the cannabinoid receptors, whereas THC is a partial agonist. Synthetic cannabinoids and their metabolites also have potentially longer half-lives, leading to prolonged psychoactivity along with unpredictable and sometimes potentially dangerous side effects. According to data from the US Toxicology Consortium Registry and studies using data from the Texas Poison Control records (PMID:22859662, 27413997), acute synthetic cannabinoid use can cause tachycardia, agitation and irritability, drowsiness, hypertension, nausea, confusion, dizziness, and chest pain. Serious physical and mental health harms associated with synthetic cannabinoid use have also been reported (reviewed in PMID 33414905) including renal injury, convulsions and seizures, rhabdomyolysis and hyperemesis syndrome, supraventricular and ventricular arrhythmias, pulmonary embolism, intracranial hemorrhage, delirium, multiple organ failure, psychosis, aggression and violence towards others, self-harm and suicide. A self-reported survey of 80,000 illicit substance users revealed that those who used synthetic cannabinoids were 30 times more likely to end up in an emergency department than users of traditional cannabis (PMID: 25759401).
Synthetic cannabinoids may also contain toxic contaminants, thus increasing the odds for adverse effects. Due to these potentially dangerous health outcomes, many synthetic cannabinoids are classified as controlled substances. However, because of the lack of regulation or enforcement and the ease of access, there is a growing epidemic in their use in the US and abroad, particularly among young men in their 20s. Moreover, novel synthetic cannabinoids continue to find their way onto the marketplace, making the pharmacological profiles of these new compounds difficult to predict and monitor.
Psychoactive hemp derivatives
The over-the-counter sale of psychoactive hemp derivatives was ambiguously legalized by the language of the 2018 Farm Bill, which amended the federal Controlled Substances Act to exclude hemp and hemp derivatives from the Schedule I definition of cannabis. Like many cannabis regulations, this language was a massive oversight by unsavvy regulators who lack the scientific knowledge to understand how easily cannabinoid conversion can be facilitated in a lab setting.
This has led to the widespread production of edibles, vapes and other products containing high concentrations of hemp-derived, psychoactive cannabinoids such as delta-8-THC, delta-8-THC acetate and THC-O-acetate and others. These products are being sold online, at smoke shops, gas stations and other outlets in the US and abroad. Similar to legal hemp CBD products, because of the lack of regulation, there are no protections to ensure the purity of the products, what actually may be contained in the formulation and the accurate concentrations of cannabinoids.
Delta-8-THC
Delta-8-THC is a psychoactive isomer of delta-9-THC. It is naturally present at very low levels in cannabis and hemp. While delta-8-THC has effects similar yet milder than THC, high intakes in its concentrated form can present some of the same adverse effects seen with high dose THC. In fact, there have been hundreds of adverse events such as vomiting, hallucinations, trouble standing, and loss of consciousness reported to national poison control centers regarding its consumption (PMID 36033151).
Delta-8-THC can be readily synthesized from hemp CBD (or THC) using organic solvents, strong acids and bases and metal catalysts, depending on the methods used. Some manufacturers may even use potentially unsafe household chemicals to make delta-8 THC. Improper removal of harmful by-products and impurities poses a significant risk to human health. It remains questionable whether companies producing these products would follow good manufacturing practices to ensure safe, clean products, particularly with companies cutting costs to remain competitive. In fact, of the existing toxicity reports, it is impossible to know if the delta-8 itself is to blame or the residual solvents that may be poisoning the humans who consume these products.
Delta-8-THC acetate, CBN acetate, CBD acetate, THC-O acetate
Hemp-derived delta-8-THC acetate, CBN acetate, CBD acetate and THC-O acetate are the newest craze in unregulated semi-synthetic cannabinoids being added to vapes and edibles and sold to the public. What’s different about these cannabinoids is that they are chemically altered to contain a phenyl acetate group formed through a reaction called acetylation. This enhances their lipophilicity (fat solubility) and ability to cross the blood-brain barrier, thereby enhancing their potency. Interestingly, cannabinoid acetylation isn’t novel. From 1955 to 1975, among other drugs, delta-9-THC acetate was investigated by the US military to determine how it might affect humans in a program designed to develop psychochemical warfare agents (PMID: 25057731). In those studies, delta-9-THC acetate was found to produce an approximate 200% greater degree of ataxia (poor coordination and muscle control) compared to delta-9-THC.
One of the problems with phenyl acetate is that when heated, it forms a highly toxic gas called ketene. Ketene is a toxicant that has been linked to the e-cigarette or vaping use-associated lung injury (EVALI) outbreak first identified in 2019 (PMID: 32320569). As of January 7, 2020, a total of 2558 hospitalized patients with nonfatal cases and 60 patients with fatal cases of EVALI have been reported to the Centers for Disease Control and Prevention. Studies provided evidence that during vaping, vitamin E acetate, which was added to illegally manufactured e-cigarettes and vape cartridges, formed ketene. Because of the similar substructure between vitamin E acetate and cannabinoid acetates, it was no surprise that researchers from Portland State University found that ketene is also formed when cannabinoid acetates are heated under vaping and dabbing conditions (PMID: 35801872). Their findings were consistent in detecting ketene in vaped condensates from delta-8-THC acetate, CBN acetate, CBD acetate, as well as from a commercial delta-8-THC acetate product purchased online.
Warnings related to ketene intoxication and lung damage from vaping THC-O acetate have also come out in a recent report in the Journal of Medical Toxicology (PMID 36508081). Not only is ketene of concern with smoking acetylated cannabinoids, but other unknown toxicants in these products (see below) are likely to pose a host of other pulmonary or organ toxicities. Are we prepared for a further epidemic of vape-related lung injuries? If nothing is done to regulate this new wild west, it may be coming.
Another problem with these cannabinoid acetates is how they are produced. For example, THC-O can be chemically synthesized from hemp CBD by first converting CBD to delta-8-THC and then combining it with acetic anhydride. Acetic anhydride is used to make other cannabinoid acetates, as well. It is an extremely toxic, caustic, flammable and explosive chemical that can be fatal if inhaled or swallowed and should only be handled using protective gear under a well-ventilated hood. It’s difficult to believe that completely unregulated companies are providing proper protections for their workers and implementing proper disposal procedures of these chemicals to protect the natural environment.
Conclusion
The bottom line is that patients and consumers are being treated as guinea pigs, with their health and possibly their lives on the line at the hands of greedy companies reaping a massive windfall from the unregulated cannabinoid market. Regulatory systems at the state and federal levels have failed to act and innocent consumers may be paying the price. Who knows how many deaths or life-threatening injuries it will take before governments act to regulate the hemp-derived and synthetic cannabinoid industries. We need federal legalization now, if for no other reason than to protect the public. Enough is enough. We have a major public health crisis on our hands.