Are lab-made marijuana-like compounds a safe medicine or a deadly drug of abuse? Between evening news stories about epileptic children who appear cured after consuming marijuana extracts, juxtaposed with stories of lab-made marijuana-like compounds causing mass psychosis, the picture is not clear. To get a professional opinion on how epilepsy medicine could turn into a public health problem, I met with Dr. Aron Lichtman, professor in the Department of Pharmacology & Toxicology and the Associate Dean for Research and Graduate Studies in the School of Pharmacy at Virginia Commonwealth University.
Marijuana has such a broad spectrum of effects due to cannabinoids, which are “drugs that are found within cannabis (marijuana)...Our body actually manufactures naturally occurring marijuana-like chemicals,” Dr. Lichtman said.
Wait, you mean our bodies make the same chemicals found in the plants? I asked.
“Well, they’re not exactly the same chemicals. The chemicals are actually very different in structure, but they activate the same type of receptors, called cannabinoid receptors,” Dr. Lichtman explained. Cannabinoid receptors are found throughout the body, and depending on the receptor subtype and location, activation can have a ride range of effects.
One of the active ingredients in cannabis is tetrahydrocannabidiol (THC), which activates the cannabinoid receptor subtype 1 (CB1). CB1 receptors can be found in high numbers in the central nervous system. THC-mediated activation of CB1 produces a plethora of effects, including psychoactivity (the “high”), increased appetite, and reduced nausea and pain. Cannabinoid receptor subtype 2 (CB2) is also activated by THC. CB2 receptors are abundant in the immune system. In preclinical trials, CB2 stimulation appears to treat chronic inflammation by dampening an over active immune system. Excessive immune system activity is involved in pain and inflammatory diseases like multiple sclerosis.
Another compound found in cannabis is cannabidiol (CBD), which lacks the intoxicating effects of THC. The Food and Drug Administration classifies cannabidiol as a drug for treatment-resistant pediatric epilepsy. Cannabidiol is currently in clinical trials for irritable bowel syndrome, post-traumatic stress disorder, heart failure, and everything in between.
“It’s clear that there is medicine in that plant,” Dr. Lichtman said. Both CBD and THC have therapeutic potential. In addition, there are over four-hundred other compounds in cannabis that may have potential health benefits. Optimistic, in-progress clinical trials, combined with anecdotal reports broadcasted on social media, have created a buzz that CBD is a safe, homeopathic cure-all. Snake oil salesmen have convinced tobacco shops to stock CBD products: $50 for gummies, lotions, vape juices, and oils that make vague promises of health benefits that are not (yet) supported by research.
I wondered how something that sounds healthy, or maybe even inert, could possibly cause harm. However, in August 2018, nearly one hundred people overdosed on a marijuana-like compound in New Haven, Connecticut, and additional cases of mass intoxication requiring hospitalization have been reported all over the country.
Dr. Lichtman had to give me some background in the history of cannabinoid research in order to explain what went wrong in New Haven: “When a lot of this research first began, and the structure of THC was first elucidated, chemists began working on it, you know, trying to tweak the structure a little bit, to try to either improve it, maybe to limit side effects, improve therapeutic effects, and also to just understand how marijuana affects the brain.” The scientists created a library of information about promising THC and CBD variants that could help treat diseases, reject variants that only get you high, and how the chemists made everything. Excited to share this information with the world, they published manuscripts describing the synthesis and effects of each new compounds.
But those good intentions to make new medicines were polluted by unscrupulous individuals with backgrounds in chemistry, strong marketing ability, and a desire to make money regardless of the deleterious consequences. In sort of a Breaking Bad scenario, clandestine laboratories used information about which analogues were the strongest and which ones could get you the highest – the compounds rejected for therapeutic use – and began manufacturing them. These “synthetic cannabinoids” started being sold for recreational use, under the name “Spice” or “K2”.
“Marijuana itself and THC do not cause mortality...Whereas [synthetic cannabinoids], are much, much stronger, and are acting differently at the receptor,” Dr. Lichtman explained. Further, synthetic cannabinoids may be reacting with non-cannabinoid targets, too. The effects of these compounds are unpredictable batch to batch, but we do know that synthetic cannabinoids can cause psychosis, hallucinations, anxiety, self-injury, aneurysm, kidney failure, liver damage, vomiting, coma, seizure, heart attack, and death.
“We never saw it coming. That we can manufacture a drug that is 100 times stronger than THC, and we told the public how to do it…Some of my colleagues who are very prominent in the field, that are chemists, have been blamed for this. And that was never their intention,” Dr. Lichtman said.
Unfortunately for straight-edge consumers who believe in the healing power of CBD, psychoactive drugs are now contaminating their purported health products. An analysis performed by the Department of Pharmacology & Toxicology and the Department of Forensic Science at Virginia Commonwealth University revealed that e-cigarette juices claiming to contain “100% natural CBD extract” also contained THC, 5F-ADB (a synthetic cannabinoid), and/or dextromethorphan, an ingredient in cough syrup that is sometimes abused for its dissociative properties.
In short: “CBD” health products purchased from your local convenience shop are probably fake and/or will make you have a bad trip.
We are now at a crossroads: How can we develop new cannabinoid-based medicines, without creating the next wave of synthetic cannabinoids? The answer might lie in upregulating the body’s own endogenous cannabinoid system, rather than direct cannabinoid receptor activation. Typically, endocannabinoids are made on demand in the body and are rapidly degraded by enzymes, limiting their analgesic and anti-inflammatory effects.
The Lichtman Lab’s preclinical research with enzyme blockers causes accumulation of endocannabinoids in the body, with higher amounts at the site of injury in rodent models of traumatic brain injury or peripheral nerve injury. Other experiments involve positive allosteric modulators – compounds that potentiate the effects of already-activated cannabinoid receptors. Increasing the intensity and duration of cannabinoid receptor activation by endocannabinoids appears to reduce inflammation and pain-related behaviors in mouse models. Mice on these drugs do not show impaired motor coordination, and preliminary testing suggests that this indirect activation of cannabinoid receptors does not have abuse potential. Therefore, indirect activation of the endocannabinoid system may be the way to go for the future of cannabinoid research.
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