Gut Microbiota & the Endocannabinoid System

Living inside and on each of us is a vast population of bacteria, fungi, protozoa, and viruses. Cumulatively, the microbiome includes as many cells as the human body and encodes 100 times more genetic material than the human genome. Up to 1,000 different species of bacteria live in the gut alone.

With this knowledge has come the realization that the microbiome is a key player in human health, affecting everything from mood to metabolism. Microbiota inside the gut – a hollow tube extending from the esophagus through the intestines to the anus – play a huge role in human disease. Disturbances to this system, also known as the gastrointestinal or digestive tract, have been associated with obesity, cancer, and neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease.

How it all works is a subject of ongoing scientific inquiry, one whose central discoveries have been widely publicized in popular and mass media in recent years. Yet there’s an important aspect of the link between human health and the microbiome that has received almost no attention outside the often obscure world of scientific journals: the role of the endocannabinoid system (ECS).

Current thinking suggests that the ECS serves as a sort of bridge between bacteria and the body itself, including the brain, relaying signals back and forth in a symbiotic, mutually beneficial relationship. At least that’s how it should be – but chronic imbalance or impairment of the gut microbiome, also called dysbiosis, can harm physical and mental health.

In the most basic sense, humans and other animals influence the “bugs” in their gut primarily through their diet, including the intake of so-called probiotic foods that promote a healthy microbiome. These bugs in turn help break down food and make nutrients more available to the body. We provide them sustenance and an amenable place to live, and they help us extract as much nutrition as we can from food in the digestive tract.

This in itself is awe-inspiring. But it also turns out to be incomplete. Groundbreaking research has shown that we also impact our gut microbiome through not only exercise and certain pharmaceuticals but also the consumption of cannabis, all via the common path of the ECS.

Cannabis for Gut Health

Interactions between gut microbiota and the endocannabinoid system were first explored in 2010. A Belgian research team showed that altering the gut microbiome of obese mice through prebiotics, foods that promote the growth of beneficial bacteria, altered ECS expression in fat tissue with implications for lipid metabolism and fat cell formation.1

More evidence came in 2015, when researchers in Canada administered a daily regimen of THC to mice sustained on a high-fat diet. Gut microbiome health in these animals improved after 3 to 4 weeks to more closely resemble that of animals fed a healthy, balanced diet.2

Few studies have investigated the effects of cannabis use on the human gut microbiome, but in 2017, researchers found key differences among 19 lifetime users and 20 non-users. Cannabis users possessed bacteria populations associated with higher caloric intake but lower BMI, though diet was thought to also play a role.

In 2018, researchers used archived anal swabs to assess the microbiomes of HIV-positive individuals. They found that cannabis use was associated with decreased abundance of two strains of bacteria linked to obesity.

Scientists are still trying to understand the details. But evidence is accumulating that the endocannabinoid system interacts directly and bidirectionally with bacteria in the gut, influencing the activity and makeup of the microbiome while simultaneously helping to transmit its messages to the body and brain. What’s more, microbiome health may be modified and even improved through plant cannabinoids, including both THC and CBD, as well as through the body’s own endocannabinoids, anandamide and 2-AG, whose production is stimulated through exercise and the consumption of certain foods.34567.8

A Pioneering Study

Just as the makeup of our microbiome depends on more than diet, the bacteria living in our gut do more than simply break down food. They also help regulate the epithelial barrier, a critical protective layer lining the interior of the long, narrow “tube” we call the gut or gastrointestinal tract. How do they do it? At least in part through interactions with the ECS, especially CB1 receptors, according to a pioneering 2012 study whose implications are still being sorted out.9

The epithelial barrier plays a hugely important role in maintaining overall health and warding off disease, says University of Calgary professor and researcher Keith Sharkey, who has studied the gut for decades and, more recently, both the microbiome and the ECS. He also served as senior author of the aforementioned 2015 study in which THC was administered to mice.

“The epithelial barrier is very crucial to maintaining what we call homeostasis, or the normal body’s functions,” Sharkey says. “The control of that fine lining is extremely carefully managed by the body. We have developed as mammals this very intricate control system, which prevents damage or quickly repairs damage, to prevent further erosion of our bodies. The bacteria we have in our gut contributes to that system. And it seems that the ECS is a very important control element.”

Sharkey is currently leading research to confirm whether CB1 receptors play a role in the acute regulation of epithelial barrier function. Preliminary evidence supports this hypothesis, he says.

Though he isn’t investigating concurrent changes to the microbiome, a link would make sense given that gut bacteria interact extensively with the epithelial barrier. “We live in a mutualistic symbiotic relationship,” Sharkey says.

Targeting the Microbiome

This all points in a predictable direction. If the ECS communicates with both the gut barrier and the microbiome, whose health is essential to human well-being, and we know we can manipulate the ECS through diet, exercise, and cannabis-derived compounds, might there be other ways to target the microbiome through the ECS in order to achieve specific health outcomes?

It’s a question the pharmaceutical industry has been actively investigating, says Cris Silvestri, a professor at Laval University in Quebec and Canadian Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health. Though no drugs have yet been developed for this purpose, Silvestri says the fast-growing field could start producing answers within the next five years that will point directly to pro- or post-biotics that can be used to tweak the gut microbiome via the ECS.

In fact, Silvestri and colleague Vincenzo DiMarzo say they’re already working with a pharmaceutical company on related research – though they can’t provide any details. Silvestri was, however, able to discuss another research project under development with the Quebec government, which is hoping to learn more about interactions between cannabis and the gut microbiome following Canada’s legalization of cannabis edibles earlier this year, Silvestri says.

“We’re in discussions for a project with the government to understand how edibles are going to affect your gut microbiome, and how is that potentially going to affect your response to edibles,” he says. “Is the gut microbiome going to change those cannabinoids, make them more or less active?”

Silvestri is also involved in two additional studies that will shed more light on this complex relationship. One is investigating effects on the gut microbiome of genetic modulation of the ECS, which increases 2-AG levels and suppresses CB1 activity in treated mice. This builds on research published in January 2020 by the same team showing that experimentally controlled alteration of the gut microbiome resulted in significant changes to gene expression and signaling within the endocannabinoidome, a broader system of receptors, enzymes, and lipid mediators related to the ECS.10

The other current study looks at ECS levels in the brains of so-called germ-free mice, which have no microbiome, and associated impacts on behavior and anxiety. It also evaluates effects on both after the introduction of a microbiome through a fecal microbiota transplant.

“The hope is that there will be therapeutic applications in the end,” Silvestri says. “The drive comes from being able in the future to harvest the functionality of these bugs to improve human health.”

THC & COVID-19

A cannabinoid science lab led by Prakash Nagarkatti at the University of South Carolina is also pioneering investigations into the ECS, the gut microbiome, and disease. It may even have found a clue for treating one of the most harmful complications of COVID-19 in some patients.

In a June 2020 study published in Frontiers in Pharmacology, Nagarkatti and colleagues demonstrated that administering THC to mice affected with a form of acute respiratory distress syndrome (ARDS) could stop the condition in its tracks.11 A severe consequence of the runaway immune response known as a cytokine storm, ARDS occurs in a small percentage of COVID-19 patients but is often fatal.

“We have a mouse model of ARDS, where we inject Staphylococcal enterotoxin B [a bacterial toxin], and the mice die within four or five days because of cytokine storm and ARDS in the lungs,” Nagarkatti says. “And we found that if you give THC, it cures the mice. They are just running around healthy. That was amazing.”

Nagarkatti doesn’t know exactly how it happens, but he does know it involves the microbiome. “What we found was that THC was changing the gut microbiome, as well as the microbiome in the lungs, and there were similar changes in the gut as well as in the lungs, and then on top of that, when we transplanted the fecal material from the cannabinoid-injected mice into the normal mice, even they became resistant to the ARDS or cytokine storm.”

Though this was demonstrated in mice and is therefore not directly transferable to humans – or COVID-19, for that matter – this is perhaps the first evidence that cannabinoids’ alteration of the gut microbiome can play a role in suppressing the systemic inflammation seen in a cytokine storm, Nagarkatti says.

Interestingly, in one of its first papers on the ECS and the microbiome back in 2017, Nagarkatti’s lab also demonstrated that treatment with a combination of THC and CBD altered the gut microbiome in mice in a way that reduced inflammation, in this case with beneficial implications for autoimmune disease.12

“Suppressing inflammation in the colon as well as systemically is very critical for preventing any type of disease, because right now inflammation is considered to be the underlying cause of everything, not only autoimmune disease but cardiovascular and neurodegenerative diseases, PTSD, Alzheimer’s, obesity, cancers, COVID-19,” Nagarkatti says. “You name it and there is inflammation.”

While the molecular mechanisms still need to be worked out, the ECS plays an important role in modulating inflammation through gut microbiota.13 Nagarkatti reports: “THC alters the microbiome in the gut in a way that seems to be beneficial in suppressing inflammation because bacteria that are favored by THC or cannabinoids seem to produce short-chain fatty acids that suppress inflammation.”

Unanswered Questions

Nagarkatti’s lab has also shown that THC treatment in mice leads to increased levels of bacteria in the beneficial genus Lactobacillus, often found in fermented foods and dietary supplements.14

Otherwise researchers know little about which specific “bugs” from among the roughly 1,000 species of bacteria in the gut are modulated by the ECS, or which species are themselves able to modulate the ECS, says Silvestri.

Indeed, there remains much more to learn about interactions between the ECS and the microbiome. Sharkey has his own list of unanswered questions that could become research priorities as the field progresses.

“We don’t quite know if it’s happening throughout the gut or if it’s restricted to certain regions of the gut,” he says. “We don’t know the interactions between various dietary constituents and the way that they change the microbial components of the gut as well as the ECS. We don’t know how many constituents of the cannabis plant are able to regulate the gut microbiome. We’ve yet to understand how the body’s own endocannabinoids really regulate epithelial barrier function.

“There are very, very many unanswered questions, but they are exciting because the consequences have the potential to be important for health,” he continues. “Almost daily when I look in the literature now, a new thing pops up that links the gut to bodily health: gut-heart connections, gut-lung connections, gut-kidney connections. So it would not surprise me to see a role for the ECS in many of those links. And we’re just scratching the surface of that right now.”


Nate Seltenrich, an independent science journalist based in the San Francisco Bay Area, covers a wide range of subjects including environmental health, neuroscience, and pharmacology.

Copyright, Project CBD. May not be reprinted without permission.


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9 Black athletes trailblazing the cannabis industry

For decades, the relationship between cannabis and sports was non-existent. Every major league except Major League Baseball has a ban on cannabis use. And the “character” issues associated with Black athletes and drug use has always been volatile.

Luckily, the ‘20s are shaping up to be a new era for cannabis and the Black athlete. From investments to deals with TV networks, Black athletes are quickly becoming champions of both sports and cannabis. Check out these athletes making history in the cannabis industry.

Being a gold medal Olympian makes you one of the best athletes in the world. And putting your face behind CBD might take you back to the #1 spot. 

GABBY DOUGLAS

Gabby Douglas swinging from gymnastic bar.
(AP Photo/Bullit Marquez)

When she’s not winning gold medals at the Summer Olympics, Gabby Douglas is making golden investments. Teaming up with other professional athletes, Gabby invested in Motive CBD. Motive’s product line is geared towards athletes, but with CBD popping up in every gentrified neighborhood, Gabby’s investment might win her a medal.

As one of the most respected and decorated athletes in America, Gabby could be a catalyst for future endorsements for the woman athlete. With topical creams and capsules focused on muscle and joint support, it wouldn’t be surprising if other individual women athletes like Serena Williams, Allyson Felix, or fellow gymnasts Simone Biles follow in her footsteps. Keep raising the bar higher and higher, Gabby.

Basketball players are some of the most influential athletes in the world. It’s no surprise that current and former NBA players are finding more than one way to get into cannabis.

KEVIN DURANT

Kevin Durant dunks during the World Basketball Championship.
(AP Photo/Mark J. Terrill)

After joining his former rival, winning back-to-back championships and heckling fans on Twitter with his burner account, Kevin Durant could definitely use a smoke. The NBA still has an active ban on cannabis use, thought they won’t test during the COVID bubble tournament. But KD hasn’t let the ban stop him from making investments. His venture capitalist firm, Thirty Five Ventures, has invested in both cannabis ordering technology and cannabis venture capital.

Durant has spoken out about marijuana, saying “there shouldn’t even be a huge topic around it.” And as one of the best and most visible players in the game, Durant’s views on cannabis are pivotal if the NBA is going to stop testing players for weed.

If the best player can get high and put up high scores, shouldn’t we all be able to?

MATT BARNES & STEPHEN JACKSON

Matt Barnes reacts after being fouled.
(AP Photo/David Zalubowski)

Former NBA champions Matt Barnes and Stephen Jackson were some of the most competitive and intimidating players in the league. Unless you knew them personally, you would’ve never known that for a lot of their games…they were high.

Since retirement, the two ballers have been very vocal about recreational and therapeutic cannabis use in sports. Apparently, some of our favorite hoopers are firing up more than jump shots before the game.

Stephen Jackson warms up.
(AP Photo/Bahram Mark Sobhani)

Barnes and Jackson have turned their advocacy into a multimedia endeavor with a video podcast called “All the Smoke.” Partnering with Showtime, the stoned duo talks to current and former NBA players, entertainers, and celebrities. And since the NBA season has been on a COVID-19 pause, “All the Smoke” has become a top basketball podcast.

NBA fans have never complained about players appearing to be high on the court, so maybe Barnes and Jackson are the ambassadors the league needs to reverse the ban on cannabis.

AL HARRINGTON

Al Harrington drives to the basket.
(AP Photo/Nam Y. Huh)

In the early 2000s, a NBA player being suspended for smoking weed was basically a PR death sentence. The perception of the ‘hip-hop’ generation and marijuana was not a healthy one. Hell, players couldn’t even wear basketball jerseys to the game because it lacked ‘professionalism.’ Well, that stigma has changed, at least off the court, and former NBA player Al Harrington is a big part of the movement.

A non-smoker until 2008, Harrington immediately realized the positive effects of cannabis. The mental health improvements and CBD creams post-surgery helped Harrington transition from being known as an ex-player to a true stoner. His cannabis company, Viola, produces in California, Oregon, Michigan, and Colorado.

Along with selling products, Viola is focused on increasing minority ownership, reinvesting in the community and creating opportunities for equity in the industry. Harrington never won the MVP award, but the advocacy work he’s done definitely deserves recognition.

GARY PAYTON

Gary Payton catches a high pass.
(AP Photo/John Raoux)

Gary Payton was never the tallest player while he played in the NBA, but he was known for being the biggest mouth in the league. The hall of famer, Olympian, and NBA champion is a cultural icon because of his game and his trash talk, but recently he’s done something no other NBA player has ever done. The Oakland native inked a licensing deal with cannabis lifestyle brand, Cookies.

The Gary Payton strain is a cross between The Y and Snowman, two of Cookies’ most sought after strains. Known for its “loud” smell, Gary Payton could run you about $70 for 3.5 grams.  But the dope packaging designs and the connection to this sports star probably make that price point manageable for superfans. Will Gary open the door for more athletes to use their likeness for cannabis? The pothead sports fan inside of me is excited to see.

Week after week, the gladiators of the NFL put their bodies and their futures on the line for the love of the game. But what people don’t see are the measures that players go through in order to perform.

EUGENE MONROE

Eugene Monroe runs a drill.
(AP Photo/Darron Cummings)

Eugene Monroe was one of the best football players in the world. The high school All-American became one of the best offensive tackles in college football. And as a top 10 pick in the NFL draft, Eugene made his presence felt on the professional level too.

The other thing that Eugene felt was the physical effects of the game. Chronic Trauma Encephalopathy, better known as CTE, is a brain injury detected in 90% of former NFL players examined.

The use of opioids to help with the physicality of the game has been commonplace in the league for years. But In 2016, Monroe became the first active player to advocate for cannabis use in the NFL – disregarding the opioid trend.

Now, as a member of the NFLPA Pain Management Committee and the Athletic Ambassador for Doctors for Cannabis Regulation, Monroe is taking a stand against the mistreatment of all players. Hopefully, Monroe can help push the NFL to a place of progress and equity for all players in the league.

CALVIN JOHNSON & ROB SIMS

Calvin Johnson warms up before an NFL football game.
(AP Photo/Rick Osentoski)

Yet again, two former Black players are stepping up to the plate, doing things with their earnings from the billion-dollar behemoth football industry. Calvin Johnson Jr. and Rob Sims aren’t the first NFL players to advocate for cannabis use, but they are the first to work with Harvard University. The two former players created Primitiv Group, a cannabis research company fighting the opioid crisis and finding the benefits of the flower.

Rob Sims enters an NFL football game.
(AP Photo/Rick Osentoski)

Based in Michigan, Primitiv is going to work with Harvard on how medical marijuna effects CTE. Since can’t be confirmed until death, science needs to get ahead of it by learning more. The behavior of players can be seen and felt in their everyday life, and it’s easy for serious symptoms to become commonplace. Disturbing behaviors like memory loss are normal for players who have been banging their brains inside of a helmet for 10+ years and are beginning to develop CTE.

With the trend towards federal legalization, there’s only a matter of time before the NFL finally realizes what must be done. Cannabis isn’t worse than the pills. If we can’t see eye to eye about that, then there will be unnecessary pain for future players.


The future is bright for Black athletes in cannabis. With more endorsements, investments and licensing deals bound to happen, when will all the pro leagues in America stop banning cannabis? Will we line up for new strains like we do new sneakers? Only time will tell, but I hope so.

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