By: Jake Freudenburger (medical student) and Dr. Jokūbas Žiburkus, PhD for Canntelligence
Misconceptions remain widespread as it pertains to cannabis. A situation is initially described incorrectly by an individual; the idea spreads to others; the story changes and grows from person to person, and thus a misconception is born. One of the most dangerous misconceptions facing the public today involves synthetic cannabinoids, often referred to as “synthetic marijuana.” The issue lies in the name itself. Initially, the term “marijuana” carried a racist, derogatory association. In the last three decades, marijuana has become widely associated with positive medicinal benefits, ranging from reducing epilepsy (1,2) and helping with Crohn’s disease (3). Although the term marijuana is improper, it is not nearly as taboo as it once was. With eight states and Washington D.C. legalizing marijuana and 28 states legalizing medical marijuana (3), the term is increasingly perceived in a positive light. The problem is that, when it pertains to synthetic cannabinoids, the layperson tends to skip over the term “synthetic” and just read “marijuana.” As a result, they see this drug as producing “marijuana-like” effects, a belief that is echoed by the FBI (4). Therefore, it’s no surprise that a 2012 government survey found that 1 in 9 high school seniors in the U.S. had used synthetic cannabinoids, often called synthetic marijuana (the second-most commonly used illegal drug for that age group) (5). Thus, instead of using the term marijuana for the plant, cannabis is the appropriate name and should be used by everyone, including state and federal regulators. Using the correct terminology consistently and publicly will further differentiate these two words and clarify the vast difference between natural, medicinal cannabis preparations versus synthetic marijuana derivatives.
Factually, synthetic analogs or ‘synthetic marijuana’ effects are completely divergent from the effects of real cannabis, as seen in the table below. Why is this the case?
|Natural Cannabis (6)||Synthetic Cannabis (7,12)|
|Mild Increase in heart rate||Significant increase in heart rate (tachycardia)|
|Mild Lowering of blood pressure||Significant increase in blood pressure (hypertension)|
|Red eyes and dilated pupils||Agitation|
|Altered perception (of time, self, etc.)||Hallucinations|
|Intensified sensations (touch, taste, sound, etc.)||Seizures/Convulsions|
|Irritation of lungs (causing coughing, phlegm, etc.)||Heart attack|
We must first understand the origin of the molecule itself to answer this question. In 1995, a professor at Clemson University, named John W. Huffman, produced synthetic cannabinoids in the lab to study the effects of cannabinoids on the brain. When his research was published, manufacturers in Germany began synthesizing the drug, marketing it as having “marijuana-like effects”, and calling it K2, Spice, fake weed, Kush, among many other names. One of the most common components in these compounds is JWH-018 (named after the aforementioned professor who initially synthesized the drug). Since its creation, there have been over 700 different cannabinoids synthesized, and that is just the amount that is known.
Manufacturers of this drug (primarily in China and Russia) continuously change the molecular composition of these drugs to circumvent laws in countries. So when JWH-018, for example, gets outlawed, they simply change the composition and call it JWH-019, which has not specifically or officially been addressed by local and federal governments. As a result, the legal system remains one step behind and obscure chemicals with unknown effects in these packages continue to be sold in the marketplace.
The name synthetic cannabinoids largely came about because, according to Yasmin Hurd, PhD, Professor of Psychiatry, Pharmacology and Systems Therapeutics, and Neuroscience at Mount Sinai Medical Center, these compounds attach to the same receptor as organic cannabinoids, CB1. The problem is that designer drugs have a much stronger affinity or are full agonists* for these receptors, that make some of them over hundreds of times more potent than THC, the psychoactive component of cannabis (6). To drug users, this greater potency might be attractive, with them believing it will give them a greater high. The effect is actually quite the contrary. Because these synthetic cannabinoids are full agonists, rather than partial agonists like natural THC is, they maximally activate the CB1 receptors, leading to dangerous physiologically and psychological limits (6).
Research shows that it is virtually impossible to fatally overdose on natural cannabis. The reason it is virtually impossible to fatally overdose on natural cannabis is because its lethal dose is thousands of times higher than its effective dose. As a result, one would have to consume thousands of grams of cannabis in a short period of time, which is physically impossible. On the other hand, 50-100 cups of coffee can be lethal. The reason in part is the self-regulating properties of the CB1 receptor system function. CB1 activation is linked to the neuroendocrine response that produces a hormone called pregnenolone. This hormone has been shown to be released when THC levels in the body start rising. It is believed that pregnenolone acts in a negative feedback mechanism. Increased activation of CB1 receptors causes the release of this hormone, which acts as a signal-specific inhibitor to prevent over activation of the CB1 receptors (7). Although the exact mechanisms are unknown, it is probable that this negative feedback mechanism is rendered weedier and the hormone does not have the effectiveness in controlling CB1 function with synthetic cannabinoids as it does with THC. This is likely because of the aforementioned pharmacological makeup of the two chemicals. Because THC is a partial agonist with a manageable binding affinity, it would not be too difficult for pregnenolone to interfere with THC binding to CB1 receptors. However, SCs have been documented as having a binding affinity orders of a magnitude greater than THC, so this natural hormone is likely either less effective, or completely ineffective, at interrupting the binding, and as such, it fails to prevent over activation of the CB1 receptors. It is believed that over activation of these receptors is what causes a good amount of the aforementioned negative health effects, most notably seizures and psychosis. Additionally, because of the uncertain chemical makeup of SCs, it is entirely possible that these chemicals bind to non-CB1 receptors throughout the body, likely contributing to the seemingly random and diverse nature of the negative health effects of smoking synthetic cannabis.
The combination of the full agonist and high potency is dangerous enough, but what is even more problematic is that these CB1 receptors are extremely prominent in the brain (10). The over activation of these receptors in places like the prefrontal cortex and the temporal cortex cause psychosis and seizures, respectively says Hurd (8). This makes for a dangerous combination of issues that led to a 221% increase in calls to the Center for Disease Control regarding synthetic marijuana in 2015 (11). Additionally, the CDC reported 3x as many deaths in the first part of 2015 due to synthetic marijuana in comparison to the same time range in 2014 (11). That number may not be completely indicative of the actual number of deaths as it is very difficult for labs to detect synthetic cannabinoids in the blood or urine. As such, the correlation is taken from anecdotal evidence. There are likely many more cases that are not known because of the lack of ability to detect these drugs.
The composition of synthetic marijuana is constantly changing. While we don’t know exactly what chemicals are in each package of these drugs, we do know that the effects are NOTHING like that of marijuana. Synthetic marijuana is NOT “marijuana-like”, and should not be perceived as such.
*Partial and Full Agonist Analogy
Chemical agonist molecules that bind to receptors located on cell membranes can be compared to a key fitting into a lock. Now imagine that these receptor locks can be opened only partially with partial agonists that only partially open the doors. A full agonist will instead open the lock completely and keep that door wide open, losing control of its normal functions. Such over activation of the receptors and wide open doors can lead to many adverse effects, as reported with synthetic cannabinoids, which are full CB1 receptor agonists.
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