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The Curious Case of Cannabis

Cannabis has the potential to both harm and help the human body. Here’s what physiologists are learning about this controversial substance.
By Dara Chadwick

Feature_Cannabis_Jan22_illustrationEver pulled at a loose thread in a piece of cloth and been fascinated by its unwinding path? That’s how the science feels for researchers studying the physiology of cannabis.

“Like any area of science, the more you find out, the more you find out how little you know,” says Norbert Kaminski, PhD, professor of pharmacology and toxicology and director of the Center for Research on Ingredient Safety and Institute for Integrative Toxicology at Michigan State University in Lansing. 

Scientists have identified more than 100 naturally occurring compounds in the plant known as cannabis sativa. The two most studied of these compounds, known as cannabinoids, are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the main psychoactive component in cannabis, responsible for making users feel “high,” while CBD does not appear to have psychoactive effects. 

Humans have an extensive history of using cannabis for both recreational and medicinal purposes. Identified as a potential drug of abuse, research efforts have long focused on why—and how—cannabis is harmful. But in 1990, a National Institute of Mental Health researcher named Lisa Matsuda, PhD, published a seminal paper identifying mechanisms responsible for how cannabinoids affect the central nervous system. This work opened the door to a new line of research into the potential benefits of cannabis, according to Kaminski.

“Cannabinoids have always been controversial. People have had a hard time accepting the fact that the molecules present in cannabis may have therapeutic activity.”

Norbert Kaminski, PhD

Today, physiologists are studying everything from how cannabis can help athletes recover after tough workouts to its potential to reduce inflammation associated with neurodegenerative diseases and with aging. Yet this research can be fraught not only with regulatory hurdles, but with stigma and misperceptions—from fellow scientists and the public. 

“Cannabinoids have always been controversial,” Kaminski says. “People have had a hard time accepting the fact that the molecules present in cannabis may have therapeutic activity.”

According to Kaminski, the targets through which these molecules mediate their activity—known as cannabinoid receptors—are “bona fide therapeutic targets that could be exploited again and again.”

Researchers currently know of two cannabinoid receptors, CB1 and CB2, that can preferentially be targeted with different cannabinoids, Kaminski says. His laboratory has been studying cannabinoid receptors in the immune system since the early 1990s. 

CB1 is highly expressed in the brain, while both CB1 and CB2 are expressed in cells and tissues within the immune system, he says. “CB1 is responsible for the euphoric feeling people get when they smoke cannabis,” he says. “When CB1 was first discovered, I was curious about whether that receptor was expressed within the immune system, and we worked quickly to publish an accelerated communication describing the expression of CB1 in immunocompetent cells. Shortly afterward, CB2 was identified, which is even more highly expressed in the immune system than CB1.”

Today, Kaminski’s work focuses on the anti-inflammatory properties of cannabinoids. “Inflammation is really an underlying component of virtually all diseases,” he says. “The disease that we’re interested in is what used to be called neuroAIDS and is now called HIV-associated neurocognitive disorder.”

Kaminski is studying whether cannabinoids can slow this disorder. People with HIV often have high levels of circulating activated monocytes, which fuel inflammation, he says. In some people with HIV, nearly 60% of circulating monocytes are activated, he adds. 

“When we looked at HIV patients who used medical marijuana, their levels of circulating activated monocytes were similar to those of healthy individuals,” typically somewhere between 5% and15%, he says. “It was quite striking. We published that work, and since then, two other laboratories have confirmed that observation.”

Kaminski is also looking at inflammatory monocytes that cross the blood-brain barrier, creating responses in the brain that accelerate neurocognitive disorder. 

“We are finding that cannabinoids are able to inhibit the production and secretion of certain proteins that drive inflammation,” he says, particularly a pro-inflammatory cytokine called interleukin-1 beta. “If you can block production of that cytokine, that is part of the mechanism of anti-inflammatory activity.”

Kaminski’s lab is culturing monocytes isolated from human blood with astrocytes to learn more about how they interact. “We can do those experiments in vitro and then add different cannabinoids to those cultures to see how we can impair the production of inflammatory mediators,” he says.

An ‘uncontrolled’ experiment

Kaminski’s focus on studying HIV developed somewhat by accident, he says. His National Institutes of Health funding came from the National Institute on Drug Abuse, which he says was funding only cannabinoid work focused on combatting drug addiction. “It was recognized early on that drugs of abuse were a cofactor for AIDS,” he says. “But many of the mechanisms we’re studying could be applicable to other neurodegenerative diseases like Alzheimer’s and multiple sclerosis. These are all diseases where the immune system plays an important role, especially by inflammatory cells.”

Jennifer Bizon, PhD, professor and chair of the Department of Neuroscience and co-director of the Cognitive Aging and Memory Center at the University of Florida in Gainesville, recently received funding to conduct preclinical studies focused on cannabis’ impact on age-related cognitive function. She and her husband and research partner, Barry Setlow, PhD, professor in the Department of Psychiatry at the University of Florida College of Medicine, are collaborating on this work.

“Overactive inflammatory processes have been linked to Alzheimer’s disease and memory dysfunction,” Bizon says. “There is reason to think that cannabis may actually have some neuroprotective effects or the ability to stave off cognitive decline.”

“Legalization and medicalization have opened up this whole new population that is availing themselves of cannabis. But the research has not caught up.”

Barry Setlow, PhD

But both Bizon and Setlow express concern about the pace of medicalization (and legalization) of marijuana and about the targeted marketing of products containing THC and CBD to people over age 65.

“It’s an uncontrolled experiment because the vast majority of research concerning cannabis has been on teenagers and young adults,” Setlow says. “Legalization and medicalization have opened up this whole new population that is availing themselves of cannabis. But the research has not caught up.”

The couple hopes to change that. One area of their research focuses on the influence of cannabis on GABAergic signaling systems. “We know that certain GABAergic signaling systems in the aged brain are altered,” Bizon says. “An acute mechanism of action of cannabis could be influencing those GABAergic signaling systems that are altered and pushing them in a direction that is beneficial.”

They are using rat models to gather full-dose response curves of a range of cannabis doses, noting that dosing of animals in research tends to be higher than the dose a person might consume. “Some of the doses in which we’re seeing pretty robust effects on cognitive tests are actually of a dose that is very low relative to what has been published in young rat populations or other preclinical studies,” Bizon says.

They are using both smoke and edibles to deliver THC to the rats. Bizon says they hope to determine the potential impacts of both routes of administration and of using cannabis over time. “Our current hypothesis is that there are acute mechanisms whereby cannabis may be acting that may be beneficial in the aged brain,” she says. “But also, there is a lot of potential for the chronic use of cannabis to reduce inflammation.”

One notable observation from their initial results is the difference in how cannabis affects the young and old. “In our older rats, we see an enhancement of performance,” Bizon says. “But the same dose of drug in young animals impairs performance. So, it’s having very different effects in the context of aging.”

Bizon also notes that another important exploration is how a person’s sex influences the effects of cannabis. “We do see fairly robust sex differences in terms of how the drug acts,” she says, adding that female rats show stronger effects than male rats. “I don’t know that we have the data yet to say for sure that it’s cognitively enhancing in one sex and not the other. But I think that is worth mentioning, particularly in the context of aging, where there’s also hormonal changes in midlife in women and certainly changes in men.”

Evolving research

Researchers are also studying the effects of cannabis on cardiovascular function. Christian Cheung, a graduate student who works in the laboratory of Jamie Burr, PhD, associate professor in human health and nutritional sciences at the University of Guelph in Ontario, Canada, published a study on whether cannabis use precedes greater cardiovascular disease risk in healthy people. As exercise physiologists, Cheung and Burr are curious about the impact of cannabis on the physiological effects of exercise. “But there was also a large gap on the fundamental cardiovascular function side of things,” Cheung says. “That’s how we ended up applying cannabis in that context.”

The team looked at cannabis users and non-users cross-sectionally, matching individuals in each group outside of their cannabis use. The cannabis user group included people who self-identified as smoking cannabis at least once a week for at least three years. Those in the control group never smoked.

The paper, “Habitual Cannabis Use Is Associated with Altered Cardiac Mechanics and Arterial Stiffness, but not Endothelial Function in Young Healthy Smokers,” was published in the January 2021 issue of the Journal of Applied Physiology. It found that while young healthy cannabis smokers demonstrated lower apical rotation and greater aortic stiffness than the control group, endothelial function and cardiac responses to certain exercises didn’t differ between cannabis users and nonusers.

“A lot of our hypotheses were built on the fact that cigarette smoking would negatively impact our outcomes, so we hypothesized that cannabis smoking might as well,” Cheung says. “We measured vascular function in this study. We know that this function is well-established to be reduced in cigarette smokers, but not in cannabis users. That’s one finding that certainly surprised us, and we’re hoping to follow up to get an idea of why there might be a discrepancy there.”

The study itself faced some challenges, Cheung says. “As a university lab, we’re recruiting from a young population,” he says. “They may not have had enough exposure to cannabis. A regular cannabis user who’s young is still going to have used much less cannabis than one who’s maybe used a bit less but is much older.”

Another challenge was finding people who openly use cannabis recreationally, even though cannabis is now legal for recreational use in Canada. “I think there’s still a lot of stigma associated with recreational cannabis use,” Cheung says.

Burr says the two hope to study more about cannabis’ role and effect in exercise. “What we’ve concluded is that we know a lot less than people probably assume we do, based on the fact that this has been a banned substance for a long time,” he says. “There’s actually very little evidence for or against cannabis use. A lot of the research that’s been done comes from the 1970s, and techniques and understanding have evolved since then.”

Challenges abound

The evolution of cannabis research—and how it’s done—is a topic of great interest to physiologists. Kirsten Thornhill, a researcher pursuing a doctorate in health sciences from Rocky Mountain University of Health Professions in Provo, Utah, is the first in her program to propose cannabis research. She’s just beginning to design her study, which hypothesizes that CBD will have a positive effect on the duration of delayed onset muscle soreness and athlete recovery. “From what I’ve seen in the literature, clinically, CBD has been shown to have anti-inflammatory effects,” she says. “We hypothesize that CBD will have anti-inflammatory effects at the skeletal muscle level. Hopefully, we’ll be able to do muscle biopsies to analyze the different anti-inflammatory markers within individual skeletal muscle fibers to physiologically determine if it does have an effect.”

“Designing a study and bringing it to fruition is hard enough. But when you layer in all these regulatory factors … it feels like an extra layer of avenues you need to navigate.”

Kirsten Thornhill

Thornhill, who has a background in exercise physiology and metabolism, welcomes the opportunity to pioneer this research, noting the many moving parts of designing a cannabis study. “We’re looking at what dosage we should give these athletes,” she says. “Do we go with traditional oil or an edible? There’s so much variability.”

With a part-time role as a CBD educator, Thornhill is well-versed in some of the misconceptions and challenges that exist around cannabis, including cultural differences. “Being a born-and-raised Cali girl, I didn’t realize how normalized and part of the culture it really is,” she says. “Here in Utah, cannabis is only legal with a medical marijuana card, unless it has a THC content of less than 0.3%.”

These differences create challenges for researchers. While the U.S. Food and Drug Administration has softened its stance on cannabis research somewhat, the field remains tightly regulated. “Designing a study and bringing it to fruition is hard enough,” Thornhill says. “But when you layer in all these regulatory factors … it feels like an extra layer of avenues you need to navigate.”

Yet, research can help shift the narrative around cannabis’ potential benefits and overcome misconceptions about what cannabis can and can’t do. Opinions are quite split between overly favorable and overly harsh, Cheung says. “What I hope to get out of our research is to actually develop a body of literature that people can properly evaluate and get a better idea about where cannabis lies in between those opinions,” he says. “Because as the saying goes, there’s two opinions and the truth probably lies somewhere in the middle.”  

 

This article was originally published in the January 2022 issue of The Physiologist Magazine.

 
The Burdens of Studying Cannabis

Conducting research on cannabis in the U.S. can be challenging because of barriers put up by its drug classification. The U.S. Drug Enforcement Administration (DEA) classifies cannabis as a Schedule I drug, the most restrictive regulatory category, as defined by the Controlled Substances Act of 1970. This designation indicates that regulators view a substance as having both a high potential for abuse and no medical value. 

In addition to undergoing the standard funding application processes, scientists who want to study cannabis in the U.S. are required to register with the DEA, and for human studies, the U.S. Food and Drug Administration. DEA registration can include a requirement to meet facility inspection and security standards. Researchers may also have state regulations to navigate. After these approvals, researchers must apply to the National Institute on Drug Abuse (NIDA) for access to research-grade cannabis.

Historically, a single DEA-licensed producer, the University of Mississippi, Oxford, has supplied all cannabis for research use in the U.S.—and then only for academic research, not for prescription drug development. Critics say this research-standardized cannabis is not representative of the variety of cultivars and products available to users via dispensaries. On May 14, 2021, however, the DEA announced it was expanding the number of licensed cannabis producers. Accepted applicants are undergoing the approval process and, once approved, will be able to begin production. Learn more at https://bit.ly/DEACannabisExpansion