Gastrointestinal (GI) illnesses are a frequent reason for using medical cannabis. These conditions include gastroesophageal reflux disease (GERD), two inflammatory bowel diseases — Crohn’s disease and ulcerative colitis — and irritable bowel syndrome (IBS).

The gut has two main functions, namely digestion of food and host defense, protecting us from foreign invaders like bacteria and viruses. The endocannabinoid system, which is widely distributed throughout the gastrointestinal system, is a key player in keeping these two important functions regulated. It is found in the gut’s nerves and in the cells of the immune system, working to maintain homeostasis of gastric motility (the muscular contractions that work to move food through the bowel), intestinal pain signaling, intestinal inflammation, and maintenance of the barrier of the gut lining.

The nerves in the gut are called the enteric nervous system, sometimes called the “second brain.” Cannabinoid receptors (CB1 and CB2) are found throughout these nerves. All disorders of the gut are thought to involve the enteric nervous system, making these receptors an attractive target for treatment when illness is present. Scientists have found that the number of cannabinoid receptors can increase (upregulate) in certain intestinal illnesses, indicating that the endocannabinoid system is mounting a response to try to restore balance.

In addition to cannabinoid receptors, other receptors, such as PPARs, GPR55, and TRPV1, are found throughout the gut and are involved in intestinal inflammation and pain. Since cannabinoids, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with these receptors, CB1 and CB2 are also therapeutic targets for treatment by anyone using cannabis medicine for gastrointestinal disorders.

Almost 80 percent of your immune system resides in the gut. The endocannabinoid system, including the CB2 receptors, is also present in these immune cells, ready to go into action to decrease inflammation when needed. However, if your endocannabinoid system is not working properly, it may not be able to mount the appropriate response to these triggers, leading to chronic intestinal symptoms.

Interestingly, people who have a mutation in the gene coding for one of the endocannabinoid system components are more likely to have IBS and chronic abdominal pain – evidence that endocannabinoid dysfunction may be one of the root causes of gut disorders.

Gastroesophageal Reflux

GERD is very common, affecting 20 percent of all adults. GERD occurs when the stomach contents flow backward into the esophagus, causing symptoms of heartburn, chest pain, difficulty swallowing, and/or a sensation of a lump in the throat. GERD is often treated with medications; however, there are reports of possible increased risk of dementia and cancer from these drugs. Other interventions include altering the diet, remaining upright after meals, losing weight, and stopping tobacco use.

Animal studies have shown that cannabinoid stimulation of the CB1 receptor inhibited acid secretion and decreased damage and inflammation in the lining of the stomach. Preclinical research also showed that cannabinoid activation of the CB1 receptor kept the lower esophageal sphincter (the “gate” between the esophagus and stomach that works to keep stomach contents from flowing back into the esophagus) from relaxing, thereby decreasing reflux. In one human study, synthetic THC given to healthy volunteers was shown to decrease the reflux rate (although there were issues in the study since the dose was very high and caused side effects). It is clear that more research is needed to understand the role of cannabis in the treatment of GERD.

Clinically, some medical cannabis patients with GERD report benefits, although some do not. (As with all conditions, it is unclear as to exactly why some patients respond to cannabis and others do not.) Anecdotal reports from positive responders state they have fewer episodes of heartburn, and if they have an episode, taking cannabis decreases their discomfort.

Most patients finding benefits are including some THC in their cannabis regimen, as this seems to be the cannabinoid most helpful for GERD, at least anecdotally. Some patients report a low-ratio CBD:THC product (such as 1:1, 2:1, or 4:1) helps decrease GERD symptoms with less intoxicating effects compared to THC-dominant products. Two aromatic cannabis terpenes, limonene and terpinolene, may also be beneficial for GERD symptoms.

Inflammatory Bowel Disease

IBD is a general term that refers to chronic inflammation of the bowel. The two main IBD conditions are Crohn’s disease and ulcerative colitis. The Centers for Disease Control reports approximately three million adults were diagnosed with IBD in 2015, up from two million diagnosed in 1999. The exact cause of IBD is unknown, but recent scientific investigation reports the changes in the gut are due to “uncontrolled activation of intestinal immune cells in a genetically susceptible host.” Remember that immune cells are regulated by the endocannabinoid system, suggesting that endocannabinoid dysfunction may be a root cause of IBD and may serve as a therapeutic target.

Crohn’s disease can affect any part of the gut but most commonly the small intestine, causing inflammation, ulcers, pain, bleeding, diarrhea, and weight loss. Ulcerative colitis is a chronic inflammatory condition affecting the large intestine, causing symptoms similar to Crohn’s. Both conditions are associated with an increased risk of colorectal cancer. According to a recent article, “current therapeutic options are insufficient for a successful treatment leading to a high rate of disability and intestinal surgery in IBD patients.”

Activation of the CB1 and CB2 receptors in animal models of colitis reduces inflammation. In a review of 51 scientific studies on cannabinoid treatment of colitis (only two were in humans), twenty-four different compounds, including synthetic cannabinoids as well as THC, CBD, and CBG, were found to be effective in reducing the severity of colitis.

Studies done in a number of different countries show about 10 to 12 percent of people with IBD are using cannabis to treat their symptoms. Studies in humans are limited but promising:

• A 2012 study investigating 11 patients with long-standing Crohn’s disease and 2 patients with ulcerative colitis reported that after 3 months of treatment, patients reported improvement in general health perception, social functioning, ability to work, physical pain, and depression. There was a statistically significant weight gain and increase in body mass index.
• A 2011 survey of 30 Crohn’s patients in Israel revealed 21 improved significantly with cannabis, finding less need for other medication and reduced need for surgery.
• A 2013 survey of 292 patients receiving care for IBD revealed approximately half reported either past or current use of cannabis. Of those, 32 percent reported medical use for abdominal pain, poor appetite, nausea, and diarrhea. Most reported that cannabis either completely relieved or was very helpful for symptoms. In this study, current users noted significant improvement in abdominal pain, poor appetite, nausea, and diarrhea.
• In a 2013 study of 21 patients with Crohn’s disease who did not respond to conventional treatments, inhaled THC or inhaled placebo was given over 8 weeks. Complete remission was achieved in 45 percent of the cannabis group and 10 percent of the placebo group; 90 percent of the cannabis group had lower severity scores versus 40 percent of the placebo group. Three patients using cannabis were able to wean off steroids. The cannabis patients reported better sleep and appetite with no significant side effects. Interestingly, all patients who achieved remission relapsed within two weeks of discontinuing the cannabis treatment.
• In 2019, two reports were published that reviewed hospital records through the National Inpatient Sample database, allowing researchers access to thousands of medical records. The first report looked at 615 hospitalized Crohn’s disease patients who used cannabis (legally or not) and compared them to Crohn’s patients who did not use cannabis. Cannabis users were found to have:

– Less stricturing disease (scarring built up secondary to chronic intestinal inflammation)
– Fewer bowel obstructions
– Fewer fistulas and abscesses
– Shorter hospital stays
– Fewer blood transfusions
– Less colectomy surgery (removal of the colon)
– Reduced IV nutrition requirements

• The second report, using the same database of medical records, included 6,002 patients with Crohn’s disease (2,999 cannabis users and 3,003 nonusers) and 1,481 patients with ulcerative colitis (742 cannabis users and 739 nonusers). This review found:

– Crohn’s patients using cannabis had statistically significant lower incidence of cancer, less need for IV nutrition, less anemia, and shorter hospital stays with lower hospitalization costs; however, this report found an increase in fistula/abscess, GI bleeding, and hypovolemia (a decrease in circulating blood in the vessels).
– Ulcerative colitis patients using cannabis have statistically significant lower frequency of postoperative infections and shorter hospital stays with lower hospitalization costs; however, fluid/electrolyte imbalance and hypovolemia were increased.

These reports stated that “recreational” cannabis was used. There was no mention of the type of cannabinoids used (THC, CBD, or other), nor was delivery method (smoking, edibles, etc.) or duration of use reported. Both significant benefits and risks were found, warranting further human clinical trials.

I have evaluated many patients with gastrointestinal disorders who have had successful results with cannabis treatment. Almost all patients with Crohn’s disease or ulcerative colitis who have been seen in my office have exhausted conventional options prior to seeking cannabis treatment, finding that they either were nonresponders or experienced intolerable side effects. Similar to the findings already mentioned, my patients report that their symptoms, including nausea, poor appetite, abdominal pain, diarrhea, and bloating, respond to cannabis treatment.

Many patients prefer to inhale THC since the onset of relief is immediate. Patients who are reluctant to use THC-rich cannabis can use lower CBD:THC ratios, such as 1:1 or 4:1, with similar benefits but less chance of intoxication. THCA (the unheated, nonintoxicating version of THC ) was found to be the main phytocannabinoid helping to regulate intestinal inflammation. With the increased availability of tinctures containing THCA, and CBDA as well, patients are finding that daily use of these raw cannabinoids, sometimes combined with CBD, is effective for anti-inflammatory effects, helping to prevent flare-ups.

Irritable Bowel Syndrome

As the most common diagnosis made by gastroenterologists, IBS affects thirty-five million people in the US alone. IBS is characterized by episodes of abdominal pain, bloating, excessive gas, and altered bowel habits (constipation, diarrhea, or mixed type). No clear cause of IBS has been identified, although endocannabinoid deficiency is suspected. There usually are no abnormalities on blood tests or an endoscopy, making IBS a diagnosis based solely on the patient’s history and symptoms, after ruling out other causes. IBS sufferers often struggle with other conditions, such as fibromyalgia, migraine headaches, temporomandibular joint disorders, chronic fatigue, gastroesophageal reflux, anxiety/depression, or chronic pelvic pain. Chronic stress has been linked to both the development and/or the exacerbation of IBS and should also be a focus of treatment.

There are three published human studies of cannabis use for IBS, all employing synthetic THC as the study drug. Not surprisingly, one study reported all participants to have had side effects and no benefits; the study dose of 10 milligrams THC was clearly too much for the non-cannabis users who participated. The second study used lower doses, 2.5 milligrams or 5 milligrams of synthetic THC compared to placebo, and found participants with IBS diarrhea or IBS mixed type had a reduction in colonic motility, meaning THC slowed down how fast food moved through the gut. And the third study involved giving low-dose dronabinol (pharmaceutical THC) for two days and had no effect on IBS diarrhea. As mentioned before, findings from studies using single synthetic cannabinoid compounds are difficult to translate to outcomes in patients using whole-plant preparations.

Clinically, many medical cannabis patients with IBS report benefits, most stating simply that “it helps calm the gut.” Some patients report substantial efficacy from low doses of THC taken in the evenings or just as needed when their gut is acting up. Others report using CBD preparations on a daily basis to control their symptoms. Additionally, some patients have reported that either THCA or CBDA, or both in combination, has helped with IBS, often with the patient achieving improvements in symptoms with low doses. Proper diet, regular exercise, and stress management support the endocannabinoid system, and in cases of IBS, patients find these additional interventions to be quite effective when combined with cannabinoid therapy.

It is important for patients with gut disorders to understand that long-standing inflammation will take time to respond to cannabinoid treatment. It may take eight to twelve weeks to experience significant benefits, although many report symptom reduction in the first few weeks. Edibles may cause further GI upset, so you should always read product labels to be sure you are not eating an ingredient that is a trigger for your symptoms. Terpenoids that have been found to specifically help the gut include terpinolene, beta-caryophyllene, limonene, and pinene.

This excerpt continues with a personal story of a young Crohn’s patient who benefited from a doctor-supervised medical cannabis regimen. Read more.

NOTE: All source references are included in Dr. Bonni Goldstein’s book, Cannabis is Medicine: How Medical Cannabis and CBD are Healing Everything from Anxiety to Chronic Pain. Copyright (C) 2020. Available from Little, Brown Spark, an imprint of Hachette Book Group, Inc.

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By Bonni Goldstein, MD on September 28, 2020

A tall, thin teenager with a crewcut, Robert came to my office with his parents seeking help in treating ulcerative colitis. Diagnosed two years prior, he was struggling with chronic abdominal; pain, bloody diarrhea, poor appetite, and weight loss. It was no surprise he expressed feeling depressed and hopeless. He had been on numerous treatments that did not help, and according to his parents, the pharmaceuticals he tried seemed to be making him sicker, not better. He had received multiple blood transfusions due to the anemia caused by loss of blood through his gut. At the most recent visit with his GI specialist, surgery to remove part of his colon was discussed, causing Robert much distress.

Prior to meeting with me, Robert’s parents caught him smoking cannabis. They were not surprised, as lately they had noticed something was different about him — maybe a lighter attitude and fewer complaints of discomfort. As a family, they googled “cannabis for ulcerative colitis” and decided to pursue this treatment with medical supervision, as they all agreed surgery would be a last resort. When I asked Robert how cannabis helped him, he reported that all of his physical symptoms were reduced, and that he felt “normal” for a few hours. He and his parents had concerns that he was buying cannabis from unknown sources and that he was at risk for getting into legal trouble. He stated maturely, “I feel like this could be my medicine, but I don’t want to be a criminal for using it.

I educated Robert and his parents about the endocannabinoid system, about the different phytocannabinoids, and about the promising, yet limited, research on cannabis use for Inflammatory Bowel Disease. I started Robert on low doses of a CBD:THC tincture (25:1) twice daily with the plan to increase every one to two weeks, aiming for a dose of 300 milligrams twice daily. We discussed using vaporized THC as needed for acute symptoms. After four weeks, he reported less diarrhea, less abdominal pain, and better appetite. He was sleeping better too and said his mood was improving. He continued to have blood in his stools, so THCA twice daily was added to the regimen.

Robert’s red blood cell count stabilized over the next six weeks. He gained weight and happily reported he had started playing basketball again, something he had not been able to do since his initial diagnosis. His lab tests revealed a decrease in the inflammatory markers, and although they were still elevated, the decrease was evidence that the inflammation in his body was starting to respond to treatment. Robert’s GI specialist is cautiously supportive of this treatment, as he too has seen Robert’s condition stabilize. Most importantly, Robert has reported a significant improvement in his quality of life, and for the first time in years, he feels optimistic about his future.

Excerpted from Cannabis is Medicine: How Medical Cannabis and CBD are Healing Everything from Anxiety to Chronic Pain by Dr. Bonni Goldstein. Copyright (C) 2020. Available from Little, Brown Spark, an imprint of Hachette Book Group, Inc.

Cannabis May Effectively Treat Crohn’s

Ohio researchers found Crohn’s Disease symptoms were 40-70% lower in patients using cannabis than non-users.

Gut Microbiota & the Endocannabinoid System

The endocannabinoid system regulates communication between gut microbiota and the brain, and THC and CBD promote a healthy microbiome.

Cannabis Therapeutics: Dr. Bonni Goldstein

Using cannabis medicine for intractable epilepsy, cancer, autism, and mental health conditions.

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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.”

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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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Sources

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In the last five years, the world has fallen in love with cannabidiol (CBD). Perhaps the biggest uptake has been in countries like the UK and United States where almost 10% of the population admit to having tried CBD oil. Most people probably assume that the cannabis or hemp plants used to make their CBD products can be found dripping in the magic molecule. But, actually, that’s not the case.

Cannabidiolic acid (CBDA) – the botanical precursor of CBD – is what’s found in fresh raw cannabis and hemp. CBD only comes into being when its acidic counterpart is exposed to heat.

Outside the inner sanctum of cannabinoid science, CBDA hasn’t gotten the column inches enjoyed by its botanical sibling. Indeed, for many years CBDA was mistakenly assumed to be an inactive compound. This notion – combined with CBDA’s instability whereby over time it begins to degrade – meant that scientific research into CBD’s acidic form has been fairly limited.

But CBDA is now undergoing a renaissance of sorts with increased media interest thanks to the launch of a patented CBDA “ester” (an intriguing molecular variant of CBD) and a host of positive anecdotal accounts of CBDA’s efficacy from medical cannabis patients and doctors.

What is CBDA?

Cannabidiolic acid was first isolated by Israeli scientist Raphael Mechoulam in 1965.¹ Through exposure to sufficient heat or sunlight, CBDA changes into CBD by going through a chemical process called decarboxylation in which the carboxyl group is lost.

While many of us associate decarboxylation with cannabis, the same chemical reaction occurs in cellular respiration. It’s the reason we all exhale CO2 as a byproduct of metabolism.

For many years, decarboxylated cannabinoids were considered the ‘activated’ compounds, producing more potent therapeutic effects in our bodies. However, this assumption has recently been turned upside down with studies showing CBDA’s activation of 5-HT1A serotonin receptors to be significantly more potent than CBD. And CBDA was also shown to have a stronger binding affinity than CBD as an antagonist at another important receptor known as GPR55.

These discoveries suggested that CBDA could indeed have an important place at the therapeutic table for conditions as varied as cancer, anxiety, epilepsy, and treatment-resistant nausea and vomiting.

CBDA for Nausea & Vomiting

Serotonin is perhaps the most widely known class of neurotransmitter due to its role in mood regulation. However, serotonin’s biological reach extends far beyond just keeping us happy. It is involved in such diverse physiological functions as nausea, vomiting, and intestinal movements.

Much of what we know about CBDA’s activation of 5-HT1A serotonin receptors is thanks to research by Erin Rock and her team at Guelph University in Ontario, led by neuroscientist Linda Parker. Rock examined the therapeutic application of both CBD and CBDA for different types of nausea and vomiting.² She showed that by binding with 5-HT1A receptors in a more potent fashion than CBD, CBDA suppressed nausea and vomiting caused by toxins and motion sickness.

Perhaps the most exciting breakthrough relates to CBDA’s remarkable success in reducing anticipatory nausea – the type of intense nausea one experiences prior to chemotherapy when patients feel horrible before treatment has even begun. Anticipatory nausea, it should be noted, has no effective pharmaceutical treatment.

In a different study examining the efficacy of combining CBDA with ondansetron, a standard antiemetic drug, Rock’s team found that even at very low doses CBDA enhanced the pharmaceutical drug’s anti-nausea effect.³ In fact, Rock goes on to assert that the amount of CBDA needed to reduce nausea was a staggering 1000 times less than required by CBD to have the same effect.

Furthermore, the Canadian scientists confirmed that CBDA is not intoxicating or impairing as it does not interact with CB1 cannabinoid receptors. This makes CBDA potentially a better option for patients who struggle with the mood-altering effects of THC-rich cannabis or dronabinol (FDA-approved synthetic THC).

CBDA & Epilepsy

CBD burst into the mainstream largely because of its celebrated anti-seizure effects. To date, the only approved CBD pharmaceutical in the United States is the purified CBD tincture, Epidiolex, for three types of drug-resistant epilepsy.

It’s not surprising that GW Pharma, the company behind Epidiolex, is looking closely at CBDA’s therapeutic potential. In pharmacokinetic studies comparing CBDA with CBD, GW scientists found CBDA to have superior bioavailability and faster onset than CBD – properties that make CBDA a very attractive option for drug development.

Not only did it require lower doses (thus reducing the chance of side effects), but CBDA was more effective in seizure reduction in certain parameters. Some of this data appears in GW’s patent application⁴ for the ‘Use of cannabinoids in the treatment of epilepsy,’ rather than in a peer reviewed study. But it certainly backs up Rock’s findings, as well as anecdotal reports coming from U.S. cannabis clinicians such as Bonni Goldstein and Dustin Sulak, who’ve had great success when treating patients with CBDA.

A Case History

Peruvian physician Max Almazora shared a compelling case study involving CBDA in a recent Society of Cannabis Clinicians webinar.

14-year-old Glendy came into his office having 10 seizures a day due to autoimmune encephalitis. Prior to seeing Dr. Almazora, she had at one point been in a medical coma for 45 days. She also contracted drug-induced hepatitis, which was caused by medication she’d been prescribed.

Glendy’s parents acquired CBD oil from the United States, which brought about some seizure reduction. However, buying imported CBD oil wasn’t financially viable for the family, so Dr. Almazora found a local source of CBD oil. Or so he thought.

It turns out, the CBD oil hadn’t been decarboxylated, and Glendy was in fact taking CBDA. This was later confirmed when the oil was sent off for analysis in a Californian lab. And guess what – her seizures reduced even further. In fact, at latest count, Glendy, now 16, only has ten seizures a year and no longer takes any pharmaceutical anti-epileptic drugs. Her cognitive development, anxiety, autistic-like behaviour, and overall quality of life have all markedly improved since switching to the CBDA oil.

“While I was already getting good results in my patients with cannabinoid treatments containing THC and CBD,” says Dr. Almazora, “CBDA has been especially effective in treating epilepsy, Parkinson’s, and inflammatory conditions. For me, the acidic cannabinoids open a whole spectrum of therapeutic possibilities.”

But medical scientists still have much to learn about CBDA’s multiple mechanisms of action with respect to epilepsy and other conditions. “I personally will be gathering more evidence that I hope will benefit patients,” Almazora asserts.

Anti-Inflammatory CBDA

With Glendy’s epilepsy caused by an autoimmune condition, it’s possible her positive response to CBDA in part could be attributable to the acid cannabinoid’s anti-inflammatory action, which may occur because of its role as a selective Cox-2 inhibitor.⁵

There are two types of Cyclooxygenase (Cox) enzymes: Cox-1 maintains the normal lining of the stomach and intestines, and Cox-2 has a pro-inflammatory effect. Non-steroidal anti-inflammatory drugs, such as aspirin and ibuprofen, inhibit both Cox-1 and Cox-2 enzymes. By inhibiting Cox-1, long-term use of these over-the-counter drugs can cause major gastrointestinal complications.

It’s therefore of therapeutic interest to develop selective Cox-2 inhibitors that bypass Cox-1 and relieve patients’ inflammation-related symptoms, while sparing them of any dangerous long term consequences. As a Cox-2 inhibitor, CBDA shows potential as a safer non-steroidal anti-inflammatory drug, although studies have yet to be carried out on humans.

One preclinical study⁶ also found that CBDA’s downregulation of Cox-2 enzymes may help prevent the spread of a certain type of invasive breast cancer typified by higher than normal levels of Cox-2. When the breast cancer cells were treated with CBDA over 48 hours, both Cox-2 and Id-1, a protein associated with the aggressive spread of breast cancer cells, were down-regulated, while Sharp-1 expression, a suppressor of breast cancer metastasis, increased. Although this is very much preliminary data, it suggests that for certain types of breast cancer, CBDA may halt the spread of malignant cells to other parts of the body.

A Synthetic CBDA Compound

In the last few months, Professor Mechoulam has generated headlines once again with the launch of a patented synthetic CBDA methyl ester. With its chemical structure subtly altered to make the methyl ester compound more stable than CBDA, Mechoulam and his team have begun to investigate the compound’s therapeutic use in conditions such as anxiety, depression,⁷ inflammatory bowel disease, nausea and vomiting, and as an alternative to steroids.

While this stabilised version of CBDA may be easier to work with in the lab, particularly for the development of pharmaceutical drugs, it’s not at all clear that it represents a significant improvement as a therapeutic modality compared to artisanal cannabis or hemp products containing CBDA.

When stored appropriately in a cool, dark cupboard away from sunlight (or even the refrigerator in hot climates), CBDA does not tend to degrade if it is consumed within a few months. However, if you’ve got an opened CBDA bottle that’s been hanging around for a couple of years in direct sunlight, it probably won’t have the same cannabinoid profile it once had – and your carrier oil may have gone rancid.

Get Some CBDA in Your Life

For the conscious consumer trying to navigate today’s largely unregulated market, the presence of CBDA in a cannabis oil extract suggests that it’s likely a true full-spectrum product, rather than a formulation made from CBD isolate or distillate, both of which require heat to decarboxylate.

If you happen to have access to a few fresh cannabis leaves or flower tops, you may want to add some to a salad or smoothie. It’s an easy way to get acidic cannabinoids into your system. Or as Dr. Dustin Sulak recommended at the 2019 CannMed conference in Pasadena, try putting a small amount of raw CBDA-rich bud into a cup of steeping tea – the heat won’t be sufficient for decarbing and you’ll get the benefits of this hitherto neglected cannabis compound.

Indeed, it seems that after all these years of living in CBD’s shadow, CBDA is finally gaining recognition as a safe, and in some ways more potent, alternative to its famous cannabinoid relative. For those who are already taking CBD oil, or for those who are thinking about it, small doses of a CBDA-rich product may be worth considering. And let Project CBD know if and how CBDA works for you.

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Mary Biles, a Project CBD contributing writer, is a journalist, blogger and educator with a background in holistic health and TV production. She is author of The CBD Book: The Essential Guide to CBD Oil and hosts the podcast Cannabis Voices. Her website is here.

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

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Footnotes

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Adapted from Healing with Cannabis: The Evolution of the Endocannabinoid System and How Cannabinoids Help Relieve PTSD, Pain, MS, Anxiety, and More by Cheryl Pellerin (Skyhorse Publishing, 2020).

Dr. Donald I. Abrams is an oncologist at San Francisco General Hospital, an integrative oncologist at the University of California-San Francisco (UCSF) Osher Center for Integrative Medicine, and a professor of clinical medicine at UCSF. He was also a member of the sixteen-person professionally diverse committee that produced the 486-page volume The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence, a 2017 update on the topic from the National Academies of Sciences, Engineering and Medicine.

“I’ve been an oncologist in San Francisco for thirty-six years now, and I venture to say that most of the cancer patients I’ve taken care of have used cannabis,” Abrams said in a May 3, 2019, interview. “But there isn’t a day that goes by where I don’t see a cancer patient with loss of appetite, nausea, vomiting, insomnia, pain, depression, or anxiety, and if I have one medicine that can decrease nausea and vomiting, enhance appetite, decrease pain, and improve sleep and mood, I consider that to be a valuable intervention. Instead of writing prescriptions for five or six pharmaceuticals that all could interact with each other or the chemotherapy I prescribe, I can recommend one very safe botanical.”

When Abrams was a medical intern and resident in 1970s San Francisco, many people used cannabis, including young people with cancer. He started an oncology fellowship at UCSF in 1980, a time when cannabis was popular and there weren’t many effective anti-emetics (drugs that help nausea and vomiting).

“We had prochlorperazine, or Compazine, and Tigan [trimethobenzamine hydrochloride] … but they weren’t very good,” Abrams said, “and young people getting young-people cancers, such as Hodgkin’s disease or testicular cancer, told us, ‘You know what? Cannabis is an effective anti-nausea therapy, better than your prescription meds.'” Abrams thinks that’s what led the National Institutes of Health National Cancer Institute and several pharmaceutical companies to investigate synthetic delta-9 THC as a potential anti-nausea medication.

“A number of studies were conducted in the ’70s and ’80s that allowed both dronabinol [synthetic THC in a capsule] and nabilone [oral THC analogue] to be approved in 1985 for treatment of chemotherapy-induced nausea and vomiting. I’m not sure how much of that I used for patients in those days,” he added, “but in 1992 the FDA expanded the indication for use of dronabinol to treat anorexia associated with weight loss in patients with HIV.”

That’s when he first really started with dronabinol, Abrams explained, “because I became an AIDS doctor after my training to be a cancer specialist, and that’s when I started to really prescribe a lot of dronabinol. And patients said, ‘You can keep it. I prefer to smoke cannabis because [dronabinol] takes too long to kick in and when it does I get too zonked.'” Delta-9 THC in sesame oil [dronabinol marketed as Marinol] is a very different medicine from whole-plant cannabis, Abrams said. “That’s what I learned in my first clinical trial.”

Whole Plant Cannabis Versus THC

In the mid-1990s and still today, the National Institute on Drug Abuse is the only official source of cannabis for clinical trials. And NIDA has a congressional mandate to fund only studies investigating substances of abuse as substances of abuse and not as therapeutic agents, Abrams said.

“So they could never fund a study that I was trying to do — to show that cannabis benefitted patients with AIDS wasting — but they could fund a study to see if it was safe for HIV patients on protease inhibitors to inhale cannabis. So that study ultimately got funded.” It was his first NIH-funded cannabis study. A third of the patients took dronabinol, 2.5 mg three times a day, a third smoked a whole-plant NIDA cigarette, and a third took a dronabinol placebo.

“The patients were each in our General Clinical Research Center for twenty-five days, during twenty-one of which they took the dronabinol or smoked the cannabis. And it was very clear to me which patients were on dronabinol because they were in bed pretty much all day long, totally wiped out. Whereas the cannabis patients were up and dancing, cleaning their rooms, and very much more activated. So yeah,” Abrams said, “I think it’s definitely a different medicine.”

One thing that’s fairly dramatic in his experience with cancer patients, Abrams added, is that “a lot of cancer patients at the end of their lives are put on opiates by well-meaning oncologists who are trying to ease their pain and suffering, both physical and emotional. And the patients say, ‘This doesn’t allow me to communicate with my family because I’m way too stoned.’ So they wean off of opiates and just use cannabis, and they like that a lot better.”

Abrams said medical cannabis has been legal in California for twenty-three years and recreational for two years, but in the days when a medical recommendation was needed, Abrams would write a letter that patients would take to the dispensary, and that would allow them to obtain cannabis for a year.

“But I didn’t say take this strain, this much, this many times a day,” he said. “I don’t think cannabis is a medication that needs a package insert. Most people can probably figure out how to use it. Every patient is different, every strain is different — I think the best recommendation is ‘start low, go slow.’ That’s become quite a mantra.” And Abrams thinks the pharmaceuticalization of cannabis is wrong.

“I think we should regard it as a botanical therapy that’s been around for 5,000 years and has significant benefits,” the oncologist said. “But to try to say that it’s a medicine using a pharmaceutically dominated paradigm might not be correct. I think it should be treated like saw palmetto and echinacea but regulated like tobacco and alcohol, and let responsible adults use it as they see fit.”

Cannabis for Cancer Symptoms & Chemotherapy Side Effects

Dr. Dustin Sulak is an integrative osteopathic physician and medical cannabis expert whose clinical practice has focused on treating refractory conditions in adults and children since 2009. He is the founder of Integr8 Health, with offices in Maine and Massachusetts, that follows more than 8,000 patients using medical cannabis and other integrative healing modalities. Sulak has published in the peer-reviewed literature, and lectures to health-care providers internationally on the clinical applications of cannabis. The following information is adapted, with permission, from Sulak’s educational website, Healer.com, which offers a range of programs about medical cannabis, as well as medical cannabis training and a certification program for physicians, other health professionals, and consumers.

When working with cancer patients, cannabis treatment efforts often take two distinct paths — using cannabis to reduce symptoms and improve treatment tolerability, or using cannabis, typically in high doses, to help kill the cancer. The goals aren’t mutually exclusive, according to Sulak, but each requires a different approach to dosing.

When used properly, cannabis can be a safe, effective treatment for cancer patients with chronic pain, insomnia, and chemotherapy-induced nausea and vomiting. Animal studies have shown that cannabinoids can prevent the development of neuropathic pain, a common chemotherapy side effect that can limit a patient’s chemo dose or course. Even after achieving cancer remission, many patients are left with debilitating neuropathic pain that can be permanent.

“Patients can often achieve significant improvements in quality of life with minimal side effects, using very low doses of cannabinoids in the range of 10 mg to 60 mg per day,” Sulak writes in his course materials: “A combination of THC, CBD, and other cannabinoids in various ratios can be used to fine-tune the benefits and minimize the side effects of cannabinoid treatment.”

Medical cannabis can help patients tolerate conventional cancer treatments like chemo and radiation, and can be used along with these treatments with a low likelihood of drug interaction. This means there is seldom a reason to avoid combining cannabis with conventional cancer treatments (with a few exceptions noted in the educational materials).

For patients with terminal cancer, cannabis offers many benefits in palliative care at the end of life. “It’s an incredibly useful addition to conventional treatments in hospice medicine,” says Sulak.

Cannabis to Fight Cancer and Promote Healing

Along with symptom relief and improved quality of life in cancer patients, cannabinoids also have shown anticancer effects in many cell and animal experimental models. And a large body of anecdotal evidence suggests that human cancers also respond to cannabinoid treatment, Sulak observes. Several patients have reported slowing or arresting tumor growth, and others have experienced full remission of aggressive cancers while using cannabis extracts.

To achieve these powerful anticancer effects, most patients need a higher dose than is needed for symptom relief — often 200 mg to 2,000 mg of cannabinoids a day, or the equivalent of one to two ounces of herbal cannabis a week. This treatment level may be cost effective if the cannabis is grown by a patient or caregiver outdoors, but purchasing this amount of medicine from a medical cannabis retailer could be expensive.

At these high doses, Sulak says, “a knowledgeable medical provider must monitor the treatment to prevent side effects and interactions with conventional cancer treatment. Patients must carefully titrate up to reach these high doses without significant adverse effects. Surprisingly, doses in the range of 2,000 mg/day can be well tolerated.”

Any medical treatment carries certain risks, he adds, but high-dose cannabis is nonlethal and much safer than conventional chemotherapy, though the effectiveness of high-dose cannabis for cancer hasn’t been studied in people. Some patients reaching very high doses report global improvement in symptoms and better quality of life. Others find that at ultrahigh doses the cannabis stops helping with symptoms like pain, anxiety, and sleep disturbance — benefits they easily achieved at lower doses. Still others fail to build tolerance to the adverse effects of high cannabis doses and find themselves stoned, groggy, and uncomfortable.

No Cookie-Cutter Solutions

Sulak says patients and students should beware of anyone who claims to have a cookie-cutter solution to cannabis dosing for cancer. The internet is full of ratios, doses, and other treatment plans for specific cancer types, but many of these claims are based on the success of a single patient or on partially relevant findings from the preclinical literature (cell and animal studies).

Cancer is incredibly complex, and “even the same type of cancer in two different individuals can respond very differently to standard or alternative treatments,” Sulak writes. “Because they’re abnormal cells, cancers do unusual things — like overexpress or fail to express cannabinoid receptors,” he adds. “Each individual’s inner physiologic environment, genetics, diet, and other factors produce a unique case. Good results from one case or one study can’t be broadly applied — at best they can be used as guides. A cancer treatment plan also must take into account an individual’s goals and personal preferences.”

Cannabinoids fight cancer through different mechanisms of action, including triggering cell death, preventing cell growth and division, preventing the growth of blood vessels that feed tumors, and preventing cancer cells from migrating to other areas of the body. Sulak notes that most individual accounts of success using cannabis to kill cancer involve high doses, but several patient accounts describe profound reductions in cancer burden while taking low-to-moderate doses.

“Unlike conventional chemotherapy treatments,” he writes, “we know that cannabinoids are nontoxic to normal cells. In conventional chemotherapy, the strategy is usually to use a drug that’s more toxic to cancer cells than it is to healthy cells, and to give the patient as much as he or she can tolerate. Intolerable side effects, like peripheral neuropathy or malnutrition from nausea and vomiting, often are the limiting factors in treatment.

“Cannabis dosing may be limited by side effects,” Sulak asserts, “but not by toxicity that will lead to long-term limitations.”

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Cheryl Pellerin, a writer who specializes in science journalism, is the author of Healing With Cannabis: The Evolution of the Endocannabinoid System and How Cannabinoids Help Relieve PTSD, Pain, MS, Anxiety, and More (Skyhorse Publishing), with a foreword by Jeffrey Y. Hergenrather, MD. Her first book, Trips: How Hallucinogens Work in Your Brain, with art by Robert Crumb, was translated into French and German.

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

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