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Toxicity, addiction, withdrawal, overdose and death are not terms that are generally associated with use of the Cannabis Sativa plant. Yet, due to the federally restrictive scheduling of cannabis as a schedule 1 drug, clandestine labs consistently manufacture and distribute synthetic cannabinoids that have similar chemical structures, yet, present very different pharmacological, and thus, physiological effects for the user (Cooper, 2016).
What are Synthetic Cannabinoids
Synthetic cannabinoid drugs are a part of a much larger cat-and-mouse game compromising of “research chemicals”; chemical analogues of popular drugs (e.g. opioids, cannabinoids, amphetamines/stimulants, etc…) designed to mimic effects of the parent compound and squeak past federal regulations and DEA control (Hohmann et al., 2014). Often synthesized in China and/or India, such drugs are often (intentionally) mislabeled as “not for human consumption” to evade FDA scrutiny and regulation.
Notorious examples include “bath salts”, which are cathinone compounds (e.g. a-php, mephedrone, methylone and others) and “spice”, which mimic cannabinoid compounds (e.g. JWH-018,-007,-005,etc… ) and implicitly marketed as “legal highs” (Hohmann et al., 2014). While such drugs are being marketed to the user as “legal” alternatives to their long withstanding parent compounds, they are often untested and seriously lack in clinical data (or really any sort of data at all regarding safety, mechanism of action, LD50, etc…). Unlike cannabis itself, synthetic cannabinoids such as “spice” or “K2” have even been linked to a handful of fatalities!
Thus, the piggybacking of these compounds and their supposed effects onto that of cannabis itself is not only endangering the individuals that use them, but is antithetical and damaging to the patient-driven medical cannabis movement and community as a whole. This review aims to clearly delineate synthetic cannabinoid products, such as “spice” and “K2”, from naturally grown and cultivated cannabis, as well as unveil the insidious nature of the industry that produces them (“Made in China” has a whole new meaning now).
Safety of Cannabis vs Other Drugs
One of the pillars in the argument for medical cannabis is its extremely high safety profile, especially when compared to that of alcohol and tobacco (Lachenmeier & Rehm, 2015). Indeed, a popular argument for the use of cannabis in a therapeutic setting is the virtually nonexistent potential for lethal overdose. This is thought to be due to the “sparse” distribution of endocannabinoid receptors in the brainstem, where autonomic functions such as breathing are controlled (Harkenham, 1990). The same cannot be said of such synthetic cannabinoids on the market that are implicitly marketed for recreational, human use.
While some of these synthetic compounds do indeed act on the same receptors as cannabis does in our brains, this does not mean they act in the same manner. In fact, their mechanism of action and pharmacology can differ quite widely from the traditional cannabis plant and the phytocannabinoids it contains. THC, the main psychoactive component of cannabis that is responsible for the “high” it induces in the individual using it, is caused by only partial agonism of the CB1 receptors in the brain, whereas some of these synthetic cannabinoids act as full agonists, which are likely overstimulating these receptors and the signaling cascades that follow their activation (Shanks et al., 2016). JWH-018, one of the first synthetic cannabinoids discovered, has much higher CB1 receptor binding affinity than THC.
It also has a “faster onset and shorter duration of action relative to THC”, thus making it more likely to be abused like other short and fast acting drugs such as cocaine and heroin (Cooper, 2016). There are also long-acting synthetic cannabinoids such as HU-210 which, although present a lower abuse liability, do carry the very real risk of prolonged withdrawal syndrome due to the long half-life of the drug, which in this case is still five times as potent than THC (Cooper, 2016). The medical and recreational cannabis community already suffers from a lack of adequate clinical research and data regarding its full safety profile and long-term effects. Throwing synthetic cannabinoids with almost no clinical research behind them into this mix only hinders the progress made by cannabis patients, healthcare personnel and medical cannabis advocates.
Medical Efficacy of Synthetic Cannabinoids
It is important to note here that not all synthetic cannabinoids are as dangerous and potentially harmful as some of the aforementioned ones (the JWH family of compounds for instance). Pharmaceutical drugs such as Marinol and Sativex have shown great clinical efficacy in the treatment of various, FDA approved conditions and have thus undergone a rigorous level of testing and scrutiny before finding their way into the hands of patients. In fact, a recent 2017 study by Valdeolivas and colleagues demonstrated the marked efficacy of “Sativex-like phytocannabinoids” in the treatment of Huntington’s due to cannabis’ neuroprotective properties (2017).
This is not the case for the multitude of synthetic cannabinoids produced in clandestine labs scattered across countries such as China, India and Russia. To make matters worse, the USCC (United States China Commission), has concluded that the weakly regulated and poorly monitored pharmaceutical industry in China is responsible for a large quantity of “research chemicals” getting to the United States, with Fentanyl (an opioid painkiller much more powerful than morphine) and it’s derivatives being a major issue fueling the opioid epidemic in the United States. Indeed, this certainly gives the colloquially true statement “Made in China” a whole new meaning.
Part of the appeal of such synthetic compounds is due to the fact that many of these compounds can be legally obtained online and are often undetectable in most toxicology screens. Thus, many consumers believe they are simply using a substance that is a “cannabis alternative” assumed to be equally as safe and provide similar effects. However, this is almost never the case. Synthetic cannabis products such as “spice” are often a mixture of random dried herbs and plant matter that have been sprayed with the synthetic cannabinoid mixture. Indeed, the data shows how dangerous such substances really are. The “number of synthetic cannabis intoxication calls to poison control centers increased by 240 % between 2010 and 2011 (Wehrman, 2010).
A Physician’s Perspective on Synthetic Cannabis
While writing this piece, we to reached out to a prominent physician here in Chicago, who would have some unique insight into such cases of synthetic cannabis related consequences such as injuries and even fatalities:
“As an ER doctor, we have gotten significant warnings about the blood thinner found in the synthetic cannabis. Although I have not seen any cases personally, the fact there have been 4 deaths so far is very alarming.” –Rahul Khare, MD Emergency Physician and CEO of Innovative Express Care
As it stands, there is still much research to be done and knowledge to be gained about our own endocannabinoid system in humans and the role C. Sativa in modulating those systems. Recent studies have started to unearth various medical benefits attributed to the plant. However, the journey into the rabbit hole that is synthetic, untested cannabinoids created at clandestine laboratories around the world is one fraught with danger, misinformation and unwarranted risk to the consumer.
Synthetic Cannabis and Natural Cannabis are NOT the Same Thing
The attempt to align such dangerous and clearly understudied compounds with the natural cannabis plant itself is, at best, blatantly ignorant and misleading. However, the more likely explanation for that is simply that it is a marketing ploy to dupe consumers into believing they are consuming a substance with a similar effect and safety profile of cannabis itself. This is simply and demonstrably (as per the case studies and noted fatalities) not true.
The distribution of such substances under the guise of being related to cannabis is impeding societal and legislative progress in the world of cannabis. This is truly a disservice to mankind, especially when more and more patients are finding their way out of their dependencies and addiction to opioids through the use of real cannabis (Choo et al., 2016). While legislators are struggling to keep up with the production of new synthetic compounds designed to avert the law, it is necessary for the public to be aware and skeptical of such drugs, as they are often not what they claim to be.
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