Cannabis is one of the safest drugs a person can consume, compared to alcohol or cigarettes the health and social costs of the drug are relatively minimal. In the rare instances when users report negative side effects, they are usually benign and short-lived but may include symptoms such as anxiety, paranoia, confusion, dizziness, or loss of coordination.
Death, however, has never been included in any honest list of dangers regarding the use of cannabis, until now. Over the last decade thousands of deaths globally have been attributed to a new class of drugs that have hit the streets; Synthetic Cannabinoids and cannabinoid derivatives (SCs).
SCs were first invented in the 1970s with drugs such as Nabilone that were patented as anti-nausea medications for cancer patients and also used in clinical settings to study the body’s endocannabinoid system.
Fast-forward 30 years, and there are now hundreds of variations on those original molecules flooding the black market and causing a major rise in reports of hospital admissions and deaths.
In this article, we will look at the rise of synthetic cannabinoids, their effects, and what actions should be taken to reduce their dangers on public health.
The Rise of Synthetic Cannabinoids
Cannabis has been used for thousands of years for a variety of purposes, including for food, medicine, textiles, oil, and of course getting high. The active compound in the cannabis plant that recreational users (and some medicinal users) seek is a cannabinoid known as ∆-9 THC, which users report causes feelings of euphoria, relaxation, creativity, and increased appetite.
When THC enters the body, it acts like a key to trigger receptors in the body’s endocannabinoid system known as CB-1 receptors. These are found mostly in the brain, and thus give rise to the psychoactive effect of cannabis. In general, the effects are well tolerated by users, have a low occurrence of side effects, and are non-addictive.
THC is not the only trigger for these receptors, compounds produced by our own bodies and many compounds in plants known as terpenes, or phytocannabinoids, also act to trigger the same receptors, regulating many different processes in our bodies.
The first pharmaceutical cannabinoid was Nabilone, which was developed in 1975 and then given FDA approval for medical use and first hit the market in 1985. Over the next few years, many other THC derivatives were developed such as Marinol (Dronabinol) or Sativex (Nabiximol).
These were used primarily for administration in hospitals and in clinical studies, for the most part, because cannabis itself was highly illegal, and as a Schedule 1 substance, it was not approved for any medicinal uses. The synthetic forms or derivatives could, however, be given to patients or studied in that labs. However, from the start researchers noticed differences in their effects compared with those studies which used whole-plant cannabis.
In one such study using Dronabinol, patients experienced such severe anxiety and paranoia that the study had to be stopped. Even though cannabis is not considered a classic hallucinogen, throughout the 1990s and 2000’s several studies reported psychotic or hallucinogenic effects, which has been hypothesized to be caused by a lack of what has been termed the ‘Entourage Effect.’ This effect is a product of the other cannabinoids (CBD, CBN, etc.) or terpenes that are found in the cannabis plant which help to regulate the ‘high’ from cannabis; compounds which are not contained in pure THC derivatives, nor in synthetic THC.
Because of the legal implications of growing or possessing cannabis in most countries around the world, it did not take long for clandestine chemists to start producing synthetic cannabinoids. These are not exactly THC, but slightly different molecules, known as analogs, which trigger the CB-1 receptors in the brain. The chemical structure of these analogs can be readily altered, and because their chemistry is different from that of THC, they are not technically illegal and cannot be detected in drug tests.
As a hydrocarbon, the THC molecule is made up of a chain of carbons with hydrogen atoms attached. Simply replacing one of those hydrogens with another element, such as fluorine or other halogens, can alter it enough to escape the law, but it also greatly changes the way it interacts without bodies, often in detrimental and unpredictable ways.
The first SCs to hit the US and European markets was in 2008, and were marketing as herbal incense or ‘legal highs’ with names like “K2,” “Spice,” “Black Mamba,” and “Crazy Clown.” By 2014, more than 130 compounds had been identified. As fast as governments could identify and make these compounds illegal, chemists were changing their structure and developing new analogs. But they do not act like traditional THC, these compounds are untested, highly variable, and are leading to injuries and deaths.
The Dangers of Synthetic Cannabinoids
Because they are being developed so quickly, very little is known about the pharmacology or toxicology of SCs.
A 2015 report by the New England Journal of Medicine identified serval common side effects, including excited delirium, acute kidney injury, seizures, psychosis, hallucinations, cardiotoxic effects, coma, self-harm/suicide, and death. Unlike opioids, there is no antidote to SCs, and treatment is largely supportive, with many patients dying before they ever reach an emergency room.
By 2014, the number of injuries and deaths started to increase rapidly, and throughout the next few years, such reports were widespread, particularly in areas where the consequences of cannabis possession and use were relatively harsh or involving individuals who were subject to workplace drug screenings. A systematic review published in 2015 analyzed over 4,000 cases of emergency room admissions, 26 of which resulted in death. By 2016, reports were being published from all over the US and Europe, many of which were first-time users had no other substances in their bodies or had exhibited violent behaviors before collapsing over dead.
In one such report from the New England Journal of Medicine in 2015 between March and May of that year, an outbreak occurred in at least 12 US states, with Mississippi alone reporting more than 1,200 incidents and 17 deaths, and the Alabama department of health reporting over 1,000 emergency room visits and 5 deaths. The next July, a ‘Zombie Outbreak’ was reported in New York, in which 33 people from a single neighborhood were admitted due to consumption of a substance sold under the name “AK-47 24 Karat Gold.”
According to a report released by the CDC between 2010 and 2015, a total of 42,138 cases of toxic exposure to SCs had been reported by hospitals.
While THC is a partial agonist for CB-1 receptors, it is usually mediated by other cannabinoids and terpenes in the plant, and when those were taken away negative effects were realized. With the invention of novel compounds and THC analogs, they are a full agonist of CB-1 receptors, in some cases with up to 15 times the effective action.
As described above this can lead to death due to blood pressure increases or acute organ failure. Other reports, especially those on “Spice” from the UK, also describe the addictive nature of SCs. Studies on animals have shown acute cytotoxicity and cell death of large sections of the brain.
With all the dangers of SCs, why would users purchase them instead of safe and natural cannabis?
Reducing the Risk of Synthetic Cannabinoids
As mentioned above, the rise of THC derivatives in the 1980’s and later synthetic cannabinoids in the early 2000’s was mostly due to the classification of the plant as a Schedule 1 substance. SCs such as those patented by companies such as Pfizer eventually end up on the street as herbal incense products by black-market suppliers and clandestine chemists. As the US Drug Enforcement Agency moves to schedule the new analogs appearing on the streets, new ones are being developed in a sort of cat-and-mouse game, with no testing and often resulting in severe toxicity.
According to a 2016 report in Forensic Science International, “the emergence of new SCs are the result of subjecting them to control.” The more the government tries to stop people from selling or using these drugs, the more dangerous those drugs become.
In another study from the same journal in 2014, it was clearly stated that the illegal status of marijuana is the motivator for entrepreneurs to devise new classes of synthetic compounds, primarily among youth trying to find a ‘legal high’ or those subjected to employment or military drug screenings.
The answer to this issue is clear – repeating the same mistakes over and over again will never lead to a successful outcome. The war on drugs has made mostly benign and safe plants a criminal offense, and in response, criminals are working to get around those policies. The more the government tries to suppress these compounds rather than regulate them, the more dangerous they become and the more people are being negatively affected or killed by them.
If we are going to address this problem like a mature and rational society, we must first decriminalize cannabis to discourage the black market and then move to regulate the sale and distribution of novel chemicals and THC analogs.