Tag: Endocannabinoid System

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Dr. Andrew Weil on Cannabis and Integrative Medicine

Dr. Andrew Weil is the founder and director of the Arizona Center for Integrative Medicine at the University of Arizona College of Medicine. His early publications (The Natural Mind and From Chocolate to Morphine) focused on exploring altered states of consciousness. He is the author of several bestselling books, including Spontaneous Healing (1995), Eating Well for Optimum Health (2000), and Healthy Aging (2007).

NM: As someone who has been researching cannabis for decades, how do you feel about the current legalization situation worldwide and in Japan, in particular?

Dr. Andrew Weil: I think the trend very clearly is that in most developed countries, cannabis is being made legal first for medical uses and then also for recreational uses. And that’s true throughout North America, in many European countries, and I think in some South American countries, as well. So, my feeling is that Japan is very out of step with other developed countries.

However, it has taken a long time to get where we are today in the United States. And cannabis is still in Schedule One of the Controlled Substances Act, making it unavailable at the federal level for therapeutic use. It’s urgent that we get it out of Schedule One. I think that’s going to happen very soon. Most U.S. states have legalized cannabis for medical use and 24 states have legalized recreational use.

NM: Please tell us about the history of cannabis use in folk medicine.

Dr. Weil: Cannabis has a long history of use in folk medicine throughout the world. In North America when it was used widely as a medicine in the 1800s and early 1900s, people were unaware of its use as an intoxicant. They didn’t know you could get high on cannabis. It was mostly available as a tincture for medical use, and if people had alterations of consciousness they didn’t mention it to their doctors. It was used for things like menstrual cramps and headaches and a wide variety of complaints. It was very safe. But it fell into disfavor in Western countries probably starting in the 1920s and 1930s when recreational use of cannabis began and the plant was demonized and then eventually made illegal.

NM: What characterizes cannabis as a medicinal plant?

Dr. Weil: I’m trained as a botanist as well as a medical doctor and the use of medicinal plants is one of my career interests. I teach at the University of Arizona about the medical botany and I have used a lot of medicinal plants in my practice of medicine. In general, I think that botanical medicine is safer than pharmaceutical medicine, that the chances of causing harm are much less.

There is a close relationship between our biochemistry and cannabis biochemistry.

Cannabis is a really special case. It has very complex, very unusual chemistry, unlike any other plant. Some of the compounds in it are not found elsewhere in nature. And there’s a wide array of chemical compounds that probably all contribute to its effects. I would say that cannabis is also distinguished by how safe it is. You can’t really calculate a lethal dose of cannabis. For almost all drugs that we use in medicine, the dangerous dose is not very much higher than the therapeutic dose. You really can’t kill people with cannabis. You can’t say that about most other medicines. So just on safety alone, it’s worth using it. And then cannabis has unique effects for a wide range of conditions, everything from the treatment of pain, treatment of asthma, treatment of immune conditions.

But I think there are also some problems with using cannabis as medicine. One is that because the chemistry of it is so complex, we don’t really know what constituents are the ones we really want, what’s responsible. And there are so many different forms of cannabis, there are many varieties, there are many strains with varying chemistry. I have many patients that want to use cannabis, and they who ask me what product should they get? I really don’t know what to tell them because there’s so many products out there. And I think for doctors, this creates difficulty because doctors like medicines that are standardized and that produce standard effects.

The other problem with cannabis is that there’s a wide range of individual responses to it. For example, some people can use cannabis before bedtime, and they say it helps them fall asleep. Others say if they use before bedtime, they can’t sleep, they stay awake all night. So that kind of variation in individual response also creates difficulties in the practical use of this. I think for doctors, we really need to have some sort of standardized products, not single compounds like Marinol, but a whole complex extract of cannabis that’s characterized, that we know what’s in it, like Sativex [a tincture with a 1:1 THC:CBD ratio] which is available in the UK and in Canada. I think we need products like that for doctors to feel more comfortable about recommending it.

NM: When you started cannabis research in the 1960’s, the endocannabinoid system was not yet known to exist. When it was discovered in the 1990s, what was your reaction?

Dr. Weil: We’ve seen this kind of pattern before with opioids where the compounds in opium were found to interact with opioid receptors in the body. Why are these receptors there? They’re not there to interact with molecules from the poppy plant. They’re there to interact with compounds produced in our bodies that have the similar effects. The same thing with the endocannabinoids. I think for one thing this points out how connected we are to nature and that we’re not separate from plants and in some ways we’re meant to experiment with plants and see how they interact with us. It looks as if the endocannabinoid system regulates many very basic functions in the body. It regulates appetite, pleasure, pain, perception. Cannabinoid receptors are distributed throughout the body and brain, and I think that also accounts for some of the varied effects of cannabis and the possibility that it can treat many different conditions.

NM: Does the fact that we have an endocannabinoid system set cannabis apart from the rest of the medicinal plants?

Dr. Weil: Yes, it does. Clearly there is a close relationship between our biochemistry and cannabis biochemistry. So, I think in some ways it’s logical that we find ways to use it.

NM: How do you define integrative medicine?

Dr. Weil: Integrative medicine is not alternative medicine. It doesn’t reject Western conventional medicine but tries to build on it. And the Center that I have at the University of Arizona trains physicians, and we try to teach them all the things they should have learned in medical school but didn’t. You know, starting with nutrition, with information about botanical medicine, with information about the strengths and weaknesses of other systems of medicine like traditional Chinese medicine, for example, about mind-body interactions, about spirituality and medicine, and a whole range of other subjects. So, as I said, we don’t reject conventional medicine and we don’t reject conventional medications, but we pay a great deal of attention to lifestyle and to the use of natural remedies whenever possible.

Integrative medicine is becoming very popular and mainstream in the United States, probably more so than anywhere else. I think one reason for that is our healthcare system is in such disarray and the cost is unsupportable. Integrative medicine offers the promise of lowering healthcare costs and improving outcomes both by shifting the emphasis to prevention and health promotion rather than disease management and then also by bringing into the mainstream treatments that are not dependent on expensive technology. I include pharmaceutical drugs in that category.

In general, I think that botanical medicine is safer than pharmaceutical medicine. The chances of causing harm are much less.

Our Center has graduated almost 3,000 physicians from an intensive two-year training and integrative medicine. The majority of medical schools in the US have joined a consortium for integrative medicine. There are many textbooks on integrative medicine out there. This is the kind of medicine people want. And I think the economic advantages of it are becoming more and more apparent. I’ve always said that one day we’ll be able to drop the word integrative and it’ll just be good medicine.

NM: Who studies at the Integrative Medicine Center at the University of Arizona?

Dr. Weil: Physicians who’ve completed residency training, and they’re of all ages. We’ve had people just out of residency, we’ve had people in their 60s who are very senior in their career. We’ve had people from all specialties, but mostly MDs, doctors of osteopathy and nurse practitioners and physicians assistants, some dentists. That’s our main training and it’s a two-year 1,000-hour fellowship, which is taught both in person and by distance learning.

NM: What are their motivations?

Dr. Weil: Good question. I think one major motivation is that a lot of these people have become very disillusioned with the practice of medicine as it now is. And many of them were thinking of dropping out of medicine altogether because the practice of it has become so unsatisfactory until they discovered this program and it renewed their reasons for why they went into medicine in the first place. I think also that some people come to us because they realize that there’s a big demand for this kind of medicine. Some people are sent to us by their institutions, by medical centers, who sponsor a person to do this because they see having someone on their staff trained in this way is an advantage that increases their competitive edge in the marketplace. So, I think there are a lot of different reasons why people come to us.

NM: Do you teach nurses as well?

Dr. Weil: Yes, we train PhD nurses, but we have another program for other, what we call allied health professionals, which is everything from RNs, physical therapists, psychologists. So that’s a different training. And we also train residents. We have a program called Integrative Medicine and Residency that’s been adopted by, I think, over 100 residencies in North America, some in Europe as well. And that’s a condensed curriculum, I think, from about 150 hours. That’s a required, accredited part of residency training in a number of fields. And our goal is to have that be a part of all residency training so that one day, whether you go to a psychiatrist or a dermatologist, that person will have learned the basics of nutrition and health and mind-body interactions and botanical medicine and so forth.

NM: Is cannabis as medicine taught in the curriculum?

Dr. Weil: Yes, first of all, there’s been a big demand for information about cannabis from our Fellows, the people in our programs, they want to learn about it. So, we have developed a curriculum on the use of cannabis and this includes lectures on cannabis, particularly with the use of cannabis and cancer, but also generally in cannabis as medicine. That’s a course that we have available for people. And also, let me say, we’ve had quite a number of physicians from Japan who’ve come to us and have graduated from that program. I think we’ve got about 15 graduates in Japan.

NM: What is the major difference between conventional medicine and integrative medicine?

Dr. Weil: I think in conventional medicine in the U.S. — and this is probably true in Japan, as well — the time allowed for patient visits has gotten smaller and smaller. I remember at one point they talked about two-minute doctors in Japan. It’s not that much better in the U.S. With that little time, you can’t really take a full history. You can’t ask questions about a person’s lifestyle. I’ll just give you one example. There’s a condition that we call GERD, gastroesophageal reflux disease. I can’t tell you how many patients I’ve seen in the past, I’d say 10 years, who’ve gone to doctors and complained about indigestion or heartburn. And without any questions being asked about their diet, their use of coffee, their use of alcohol, whether they smoke, their stress, they’re put on a prescription for one of these acid-blocking drugs that are quite dangerous. You know, once you start them, it’s very hard to get off. They have many, many side effects that are not good. But nobody ever asked about what a person was doing that might contribute to their indigestion. And often these conditions can be cured just by making simple changes in what people are doing.

NM: Where do cannabis-derived pharmaceutical products stand in the larger framework of cannabis therapeutics?

Dr. Weil: I think most people would prefer to use cannabis in its natural state, whether they smoke it or take some oral preparation. They’re less interested in the pharmaceutical versions. And one of the best of those, the product Sativex that’s made in the UK, is not allowed in the U.S. Our FDA has banned its use and that’s really a shame because I think that’s one of the better products out there. Some years ago, our government allowed the use of Marinol, which is synthetic THC, especially for cancer patients. Most people did not like that. And people who were familiar with the effects of cannabis said that this was very different and they didn’t like the way it made them feel and they would prefer to use cannabis itself.

Integrative medicine is not alternative medicine. It doesn’t reject Western conventional medicine but tries to build on it.

So as I said earlier, I think it would be useful to have pharmaceutical products available for doctors to recommend. But I think many people will still prefer to use whole cannabis in one form or another.

NM: Those who criticize integrative or alternative medicine cite a lack of scientific evidence as their reason. What is your thoughts on that?

Dr. Weil: Well, first of all, our curriculum in at our center is very evidence based and everything is supported by research. You know that when you hear conventional doctors say there’s no evidence, there’s no research. Often they’re just not aware of the research that’s there, they haven’t read the papers. So, it’s a matter of making them aware of it. There’s been a tremendous amount of research on cannabis. There’s still a lot more we need to know, but there’s a great deal of research and good scientific evidence supporting its use. We rate levels of evidence, and a high level may be a controlled randomized clinical trial (RCT), but there are also observational studies. There are case reports, and there’s a great deal of other kinds of evidence. And it’s worth keeping in mind that a lot of the medications that are on the market – this is certainly true in North America – have been backed by RCTs and are terrible drugs. They are very bad, and after some years people admit it and they get pulled off the market. That’s in conventional medicine. So, there’s evidence and there’s evidence; what I teach at our center is that we should use a sliding scale of evidence.

NM: Would you elaborate on scientific evidence?

Dr. Weil: The greater the potential of a treatment to cause harm, the stricter the standards of evidence it should be held to for efficacy. I think if we followed that rule in conventional medicine, we would have saved ourselves a lot of trouble. For example, in the late 20th century in this country, most women were urged to take hormone replacement at menopause. And we knew the risks of that, an increased cancer risk. We assumed there was evidence for the benefits that were being promoted and we didn’t have that, we didn’t follow that rule. I teach many patients breathing exercises, simple breath control methods that I find to be very effective. There have been very few RCTs on breath because it’s not taken seriously, but I’m not bothered by that because I know from my own experience that these things work, and the potential for harm is negligible.

NM: Do you think non-approved (non-pharmaceutical) medical cannabis should be available?

Dr. Weil: Yes, I’d like to see both routes that doctors could prescribe it and also that patients could go to dispensaries and buy cannabis preparations to use themselves, which is now true in most states. But that requires getting it out of this drug Schedule One. And as I said, I think that’s gonna happen fairly soon.

NM: If the prescription of non-approved medical cannabis products is allowed in the US, would there be many doctors who want to prescribe it?

Dr. Weil: I think so, just because the demand from patients is so great. And probably there are now many doctors who grew up during the ‘60s and experimented themselves with cannabis and know its effects and probably would be very interested in using it if it were legally available.

NM: Dr. David Meiri in Israel has stated that medical cannabis could be largely divided into two categories; pharmaceuticals containing specific compounds to treat specific diseases, and whole plant products for general wellness. Would you agree?

Dr. Weil: Yeah, I think I agree with that. I think that both should be available.

NM: What do you think is the ideal framework that would allow the maximum number of people to benefit from medical cannabis?

Dr. Weil: In most U.S. states there are dispensaries where most people have access to cannabis drugs. The problem is that, as I have said, they vary so much in quality and potency. But they’re there and people can have access to them. What we don’t have are preparations that doctors would feel comfortable prescribing. So, I’d like to see more development of that, but I think there will be both of those worlds.

NM: Do you think the reason some doctors do not want to prescribe non-approved medical cannabis is because they do not know enough about it?

Dr. Weil: Yes, I think there needs to be more information. That’s what we’re trying to do in our trainings by including this information for doctors who come to us and we have some online courses on cannabis medicine. Some of them are available to the general public. Yeah, I think education information is key. Cannabis is such an interesting plant. Cannabis sativa literally means “useful hemp.” It is one of the most useful plants ever. You know, it provides us with an edible seed, an edible oil, a high-quality fiber, a medicine, and an intoxicant. That’s a great many ways for one plant to serve us. It seems to me that cannabis just wants to serve us. It has as far back as you go in history. You can’t find truly wild hemp that has not been associated with human beings. It has co-evolved with us. And I think our society in recent years has been very unwise in rejecting it. Even in Japan, as in the US, this plant has been very important. There are so many fiber products that have been made from hemp, many textiles. The seeds are very nutritious. The oil from them is a very high-quality edible oil. You can make wonderful foods from them. And the medicinal uses are also part of that. So, I think we have not made good use of that plant and it’s time for that to change.

I don’t think CBD does much by itself. I think it’s more useful when THC is also present.

NM: I’d like to ask about THC. The euphoric effect THC has often been called an “adverse side effect.” But doesn’t THC also have significant medicinal properties? And how does this relate to CBD?

Dr. Weil: In the U.S., there’s been a great deal of promotion of CBD for a wide variety of conditions. Personally, I don’t think CBD does much by itself. I think it’s more useful when THC is also present. That doesn’t mean it has to be present in such amounts that it makes people crazy. But I think that the consciousness altering effect of THC is one important component of cannabis, although some people will not be comfortable with that. There are some forms of cannabis that are available here in dispensaries that are very mild in their psychoactive effect. And there’s some that are to me very, very strong, and I would warn people to be cautious about using. A lot of the pharmaceutical companies are trying to come up with compounds that have useful effects with no psychoactive effect. So, okay, if they want to do that, fine. But I think the psychoactivity is one important component of cannabis. And it may be that when people get high on it, the change in consciousness may be responsible for some of the benefit with, say, their perception of pain. That may be a useful effect.

NM: Of course, alcohol also produces euphoria.

Dr. Weil: But alcohol is a much more toxic drug, a much more dangerous drug. And we’ve made that legal and make money from it. I think that, by comparison, cannabis is much safer, a much more benign agent.

NM: If cannabis is rescheduled to a Schedule Two category, would that mean that all products currently sold in dispensaries will be available for doctors to prescribe?

Dr. Weil: I don’t know. That would be up to the FDA what products it authorizes. And I think that doctors would like to see some sort of standardized products with known effects. That’s why I think something like Sativex would be much more acceptable than the array of things available in dispensaries. But again, one of the problems with cannabis compared to other natural products is the chemistry is so complex and so diverse. Which cannabinoids do you standardize for? And then it’s not just the cannabinoids, there are terpenes and essential oils and other things, all of which may contribute to the effects. How do you standardize for that? I don’t know the answer.

NM: As we speak, the 75-year-old Cannabis Control Act in Japan is about to be reformed.

Dr. Weil: I’m delighted to hear that there’s some movement in Japan, because as I said, I think Japan is really out of step with other developed nations now. It’s important to see attitudes there toward cannabis change. That’s great. I applaud your work in Japan and wish you all success.

Naoko Miki is a book translator and a co-founder of Green Zone Japan, a non-profit organization which brings up-to-date, evidence-based information on cannabis to Japanese medical professionals and the general public. She also translates Project CBD articles for its Japanese language site. Copyright, Project CBD. May not be reprinted without permission.

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ICRS 2023: Report from Toronto

Toronto skyline

I counted over 175 talks and posters at the 33rd annual gathering of the International Cannabinoid Research Society (ICRS), which convened in Toronto at the end of June. In accordance with longstanding ICRS policy, all speakers presented new findings and data that had not yet been published in a peer-reviewed journal. But this year’s 4-day ICRS conference was notable not only for its cutting-edge science. It was also the first ICRS meeting since the passing of its cofounder and guiding light Raphael Mechoulam.

Several colleagues paid homage to Mechoulam in a moving memorial session that honored his many contributions to the burgeoning field of cannabinoid science, which has grown to encompass numerous academic and clinical disciplines. The wide range of topics addressed at the conference is both a reflection of the endocannabinoid system’s ubiquitous role in health and disease and a testament to the enduring mysteries of plant medicine.

CBD & THC

Cannabidiol (CBD) figured prominently in several noteworthy oral presentations and posters that explored the therapeutic potential of plant cannabinoids from various angles. A few highlights:

CBD for breast cancer recovery. Researchers from McGill University in Montreal reported a case study of a 52-yr-old breast cancer survivor who experienced significant improvement in neuropathy symptoms and quality of life following self-administration of 300 mg/day of CBD isolate for six weeks.

CBD for post-concussion syndrome. John Patrick Neary and a team of scientists in Western Canada examined CBD’s impact on 3 female patients who suffered from post-concussion syndrome. They found that cannabidiol helped restore blood pressure dynamics and improve cardiac function in patients who consumed doses as low as 50 mg/day or as high as 400 mg/day.

CBD for psychosis.Dutch scientists from Utrecht University reported that impaired functioning of the brain’s default mode network “likely contributes to psychosis vulnerability.” They found that a CBD treatment regimen of 600 mg daily for four weeks attenuated dysfunctional default mode connectivity in a study of 31 recent-onset psychosis patients.

THC better than CBD for obesity. Israeli scientists assessed the impact of chronically administered CBD and THC on obesity and related metabolic disorders. Given the appetite-arousing qualities of cannabis (“the munchies”), it seems paradoxical that the “prevalence of obesity and metabolic diseases are lower in cannabis users compared to non-users,” the Israelis noted. Experiments on mice yielded biphasic results: 10 mg/kg of purified THC stimulated weight gain and impaired glucose-tolerance in mice, but 30 mg/kg of THC had the opposite effect, leading to a reduction in weight gain and improved glucose-tolerance. While CBD treatment enhanced glucose-tolerance regardless of weight gain, THC showed greater promise as an anti-obesity compound, according to this study. The researchers concluded that “chronic oral consumption of sufficient concentrations of THC, but not CBD, ameliorates diet-induced obesity and . . . metabolic disorders.”

Sufficient concentrations of THC, but not CBD, reduces diet-induced obesity and metabolic disorders.

CBD-rich cultivars for anxiety. University of Colorado researcher L. Cinnamon Bidwell examined the effects of three cannabis chemovars with different THC:CBD ratios. Not surprisingly, the CBD-dominant chemovar with little THC was associated with significant reductions in anxiety and tension among cannabis users as compared to the THC-dominant and the mixed THC:CBD chemovars.

Cannabis and cortisol. Washington State University researchers probed the chronic and acute effects of cannabis use on human cortisol rhythms. “Stress relief is the most cited reason for habitual cannabis use,” they noted in their assessment of how cannabis consumption impacts levels of cortisol, a stress-related hormone. “We found a significant decrease in cortisol concentrations following acute cannabis use,” they concluded. “These findings corroborate cannabis users’ self-reported experience of decreased stress following cannabis use.”

CBG and CBC. Preliminary results from a “double-blind, placebo-controlled, crossover, field trial” underscored the anxiolytic, stress-relieving, and memory-enhancing potential of cannabigerol (CBG), which produced greater reductions in anxiety than placebo. Cannabicromene (CBC), another minor phytocannabinoid, was reported to exert effects through various pathways, including the CB2 cannabinoid receptor, ion channels TRPA1 and TRPA4, and the nuclear receptor PPAR-gamma.

Pain, Opioids & Addiction

Pain, opioids, and addiction comprised a major area of focus at ICRS 2023. Much of this research involved animal models and other preclinical experiments that shed light on the subtleties and inner workings of the endocannabinoid system. Medical scientists, for example, at Mount Sinai’s Department of Psychiatry and Neuroscience probed the neurobiological underpinnings of CBD’s ability to attenuate opioid relapse. Building on their previous work, which showed that CBD lessens cue-induced heroin-seeking in an animal model of relapse, the Mount Sinai lab identified “discrete biological pathways impacted by heroin” in the nucleus accumbens (NAc), the brain region that regulates motivation and reward: “Bioinformatic analysis revealed that CBD reversed a number of metabolic and cell signaling pathway alterations induced by heroin particularly in the NAc shell.”

Neuroscientists at Indiana University explored how allosteric modulation of the CB1 cannabinoid receptor affected opioid self-administration and relapse. Allosteric modulators can either enhance or weaken how a receptor signals. A negative allosteric modulator (NAM) — a synthetic research compound identified as GAT358 — reduced the reinforcing properties of morphine by altering the shape of the CB1 receptor and weakening its signal. This approach might “represent a viable therapeutic route to decrease opioid addictive behaviors and relapse,” the scientists surmised. The same lab reported that GAT358 suppressed “opioid-mediated unwanted side effects including tolerance and withdrawal” but did not block opioid analgesia.

The wide range of topics at ICRS is both a reflection of the endocannabinoid system’s ubiquitous role in health and disease and a testament to the enduring mysteries of plant medicine.

CBD, it should be noted, also acts as a negative allosteric modulator at the CB1 receptor, meaning that CBD doesn’t cause the CB1 receptor to signal (like THC does) but CBD influences how it signals. If the CB1 receptor is like a dimmer switch, then CBD turns it down a notch. It’s also possible for a positive allosteric modulator (PAM) to turn the dimmer switch up a notch and amplify CB1 signaling.

The Indiana University group led by Andrea G. Hohmann studied PAMs as well as NAMs, fine-tuning CB1 receptor signaling in both directions. They found that strengthening CB1 signaling via positive allosteric modulation “could suppress neuropathic pain without producing unwanted CNS side effects or tolerance.” Tweaking the CB1 receptor in such a manner avoided potential problems (intoxication, impairment) associated with direct activation of CB1 by THC or various synthetic cannabinoids. Mohammed Mustafa of Virginia Commonwealth University reported that positive allosteric modulation of the CB1 receptor also reduced somatic withdrawal signs of nicotine-dependent mice.

On the Shoulders of Giants

2023 saw the passing of two research pioneers who were giants in the field of cannabinoid science. Mary E. Abood, PhD, conducted groundbreaking studies on the structure and function of cannabinoid receptors. She also identified other receptor subtypes that bind to cannabinoids. A leading figure in the ICRS since its founding in the early 1990s, Abood was known for mentoring young women scientists. After her death on Feb. 19, 2023, the ICRS announced the creation of the “Mary E. Abood ICRS Women in Cannabinoid Research Fund” to support women trainees and investigators.

Mechoulam, 92, passed away three weeks after Abood died. For all his stunning achievements as a chemist, perhaps his greatest contribution was how he nurtured a robust noncompetitive spirit, an ethos of cooperation and collegiality that persists among scientists involved in cannabinoid research. This was evident at the dinner and awards ceremony at the end of conference — an ICRS tradition — as young scientists were acknowledged for their research accomplishments and recently elected ICRS officers were introduced. When ICRS president-elect Ziva Cooper, the director of UCLA’s Center for Cannabis and Cannabinoids, greeted the group, it felt like a generational hand-off had occurred, a passing-of-the-baton from the old guard to younger scientists who stand on the shoulders of giants.

Martin A. Lee is the director of Project CBD. He’s authored and edited several books, including Smoke Signals, Acid Dreams, and The Essential Guide to CBD. © Copyright, Project CBD. May not be reprinted without permission.

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Gut Feeling

Gut microorganism

Pain, anxiety, and sleep are major drivers of medical cannabis use. But gastrointestinal symptoms, such as nausea and upset stomach, aren’t far behind.1 Even small doses of cannabis can soothe the stomach and stimulate the appetite. In fact, of the four cannabis-derived drugs approved so far by the U.S. Food and Drug Administration, three are prescribed for the treatment of chemotherapy-induced nausea and vomiting.

One gastrointestinal condition long associated with self-medication through cannabis is inflammatory bowel disease (IBD). A flurry of recent research bears this out. In a newly published survey of 162 IBD patients in Puerto Rico, where medical cannabis is legal but recreational use is punishable with prison time, about 25% anonymously reported using cannabis to treat their symptoms. Among these, nearly all said it offered relief.

Findings from another recent survey of New York and Minnesota medical cannabis dispensary patients were similar. And two new reviews aimed at physicians and researchers concur that while further study is needed, the evidence to date leaves little doubt that IBD patients are helped by cannabis.

ECS & the Gut

On a molecular level, this all makes sense. The endocannabinoid system is widely distributed throughout the gastrointestinal system, including not only CB1 and CB2 cannabinoid receptors but also other cannabinoid targets like PPARs, GPR55, and TRPV1. The job of the endocannabinoid system here, as everywhere, is to maintain order and balance, and the endogenous compounds (ligands) that interact with these receptors can be supported in this task by cannabis-derived and synthetic cannabinoids.

(The concentration of cannabinoid receptors in the gut also helps to explain cannabis hyperemesis syndrome, in which an overabundance of exogenous cannabinoids, particularly THC, triggers debilitating nausea, vomiting, and pain that typically resolves when cannabis use stops.)

Even small doses of cannabis can soothe the stomach and stimulate the appetite.

Inflammatory bowel disease is an umbrella term for two chronic disorders of the gut: Crohn’s disease, characterized by inflammation of the lining of the digestive tract; and ulcerative colitis, which involves inflammation and sores along the lining of the large intestine (colon) and rectum. Symptoms of both include diarrhea, fatigue, abdominal pain, reduced appetite, and weight loss.

IBD in Puerto Rico

In 2016, the government of Puerto Rico legalized medicinal cannabis for a relatively short list of specific conditions, including Crohn’s disease. Only non-smokable preparations are permitted, and all unauthorized cannabis use and possession remains illegal. As of March 2022, approximately 120,000 patients were registered in the program.

The recent survey was conducted through a clinic at the University of Puerto Rico Center for Inflammatory Bowel Diseases with around 900 patients. Ultimately 162 adults (85 males) completed the 27-item questionnaire. Among these, 60 (37%) reported current or past cannabis use, of which 39 used it to treat abdominal pain, 25 to treat weight loss, and 10 to treat diarrhea, among other symptoms.

But the most telling findings involve these patients’ perceptions of cannabis use as a treatment for IBD. The vast majority of current and past users noted that cannabis was beneficial for their health (94%), that it offered an improvement in their quality of life (84%), and that they would recommend it to other patients (86%). The study was published in March 2023 in the International Journal of Environmental Research and Public Health.2

Fewer ER Visits in New York & Minnesota

When researchers with Stony Brook University Hospital, Northwestern University, and Albert Einstein College of Medicine surveyed IBD patients in New York and Minnesota about their cannabis use, both states only allowed medical use. This study was conducted at medical cannabis dispensaries and relied on self-reported IBD diagnoses. Generally speaking, the 236 eligible respondents reported mild-to-moderate IBD disease activity. Most used cannabis at least once a week, primarily through high-THC vape pens and cartridges.

Euphoria was by far the most common side effect reported.

Again, the most notable findings reveal just how helpful these patients found cannabis in managing inflammatory bowel disease. Respondents reported fewer IBD-related emergency-room visits (a common concern across the patient population) in the year after they began using cannabis. They also saw a reduced impact of symptoms on their daily life. Euphoria was by far the most common side effect (75.4%), with drowsiness, memory lapses, dry mouth, anxiety, and paranoia all reported in low-single-digit percentages. The results appeared in the Journal of Clinical Gastroenterology in October 2022.3

Rave Reviews

Scientific review papers are typically circumspect in tone, more inclined to highlight evidence gaps than to draw grand conclusions. But two recently published reviews are clear when it comes to the benefits of cannabis for inflammatory bowel disease patients.

“Cannabinoid usage in IBD treatment comes with promising results as reported in the majority of the selected studies,” reads a systemic review of the literature from 2012 to 2022 published in the journal Cureus. “The selected studies’ point of convergence is that they confirmed the promising role of cannabinoids in steering improvements in IBD treatment through some objective clinical rating scales such as weight gain, Harvey-Bradshaw Index, Mayo score, CDAI score, and general well-being.” The main caveats? Heterogeneous study designs and a dearth of high-quality evidence for ideal dosage and mode of administration.

The second new review, set to be published in July in Current Opinion in Gastroenterology,4 similarly concludes that “there is a considerable amount of patient-reported outcome data that is significant in supporting the use of cannabis to provide symptom relief and overall increase in quality of life in patients with IBD.”

The authors do make an important distinction between symptoms and underlying conditions, however, by noting that existing evidence addresses the former, not the latter: “There are no data that cannabis has any benefit in decreasing the inflammation/fibrosis that continues to affect patients with IBD.”

This doesn’t mean that cannabinoids have been proven ineffective in addressing the root cause of IBD, just that there’s no evidence yet establishing that they do. “The most important point is that gastroenterologists need to ask their patients about their [cannabinoid] use, including discussion of the benefits and risks of using them,” the authors conclude.

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Leung, Janni et al. “Prevalence and self-reported reasons of cannabis use for medical purposes in USA and Canada.” Psychopharmacology vol. 239,5 (2022): 1509-1519. doi:10.1007/s00213-021-06047-8
  2. Velez-Santiago, Alondra et al. “A Survey of Cannabis Use among Patients with Inflammatory Bowel Disease (IBD).” International journal of environmental research and public health vol. 20,6 5129. 15 Mar. 2023, doi:10.3390/ijerph20065129
  3. Greywoode, Ruby et al. “Medical Cannabis Use Patterns and Adverse Effects in Inflammatory Bowel Disease.” Journal of clinical gastroenterology, 10.1097/MCG.0000000000001782. 14 Oct. 2022, doi:10.1097/MCG.0000000000001782
  4. Saidman, Jakob et al. “Inflammatory bowel disease and cannabis: key counseling strategies.” Current opinion in gastroenterology vol. 39,4 (2023): 301-307. doi:10.1097/MOG.0000000000000946

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Beta-Caryophyllene: Terpene Powerhouse

Project CBD recently reported on studies indicating that cannabis terpenes — the compounds that give the plant its robust and distinctive smell — activate the CB1 cannabinoid receptor. What’s more, in the presence of THC (also a CB1 agonist), terpenes appear to modulate cannabinoid activity in varied and interesting ways.1,2 Today we focus on spicy-peppery beta-caryophyllene (BCP), one of the most common cannabis terpenes, which acts on several targets that impact the endocannabinoid system, not just CB1.

BCP is also a component of black pepper, basil, oregano, cinnamon, hops, rosemary, cloves, and citrus, as well as many leafy greens. Approved by the United States Food and Drug Administration for use as a flavoring and fragrance agent in food, this powerhouse sesquiterpene has been the subject of considerable medical-science research. Recent papers explore the potential role of BCP in treating a wide range of conditions including non-alcoholic fatty liver disease, chronic pain, and substance abuse.

A “Dietary Cannabinoid”

Beta-caryophyllene, a weak CB1 agonist, is what scientists refer to as a “full agonist” at the CB2 cannabinoid receptor, which plays an important role in regulation of immune function and inflammation. Its presence in many foods and spices and its strong affinity for CB2 has earned BCP recognition as the first known “dietary cannabinoid.”

Multiple studies have shown that beta-caryophyllene also interacts with peroxisome proliferator-activated receptors (PPARs, pronounced pee-parrs) located on the surface of the cell’s nucleus. CBD also activates these receptors, which regulate metabolism and energy homeostasis.

Given the role of PPARs and the endocannabinoid system in modulating metabolic processes, a group of researchers based in Turin, Italy, wanted to see if BCP was effective in a cellular model of non-alcoholic fatty liver disease, the most common chronic liver disorder worldwide with a global prevalence of more than 30%.3

Because of its presence in many foods and spices and its strong affinity for the CB2 receptor, beta-caryophyllene is known as a “dietary cannabinoid.”

Writing in the International Journal of Molecular Sciences in March 2023,4 the researchers note that not only did they observe improvements in diseased liver cells, but they also confirmed through the use of specific receptor antagonists that these changes were indeed mediated by CB2 and two PPAR receptor types: PPAR-alpha and PPAR-gamma.

(Interestingly, multiple large epidemiological studies5 — including one published in May 2023 in the journal PLoS One6 — have linked cannabis use with reduced risk of fatty liver disease. This new evidence out of Italy suggests that activation of CB2 and PPAR receptors may be at least partly responsible.)

Alzheimer’s & Substance Abuse

Other studies in recent years have added to our understanding of beta-caryophyllene’s myriad potential health benefits and multiple methods of action. In 2014, for example, Chinese researchers at Chongqing Medical University reported that BCP prevented cognitive impairment in a mouse model of Alzheimer’s. This positive cognitive outcome “was associated with reduced beta-amyloid burden in both the hippocampus and the cerebral cortex,” according to their paper in the journal Pharmacology,7 which identified CB2 receptor activation and the PPAR-gamma pathway as mediators of BCP’s neuroprotective effects.

More recently, a July 2022 paper in BioFactors8 by Iranian scientists reviewed the antioxidant and immunomodulatory effects of beta-caryophyllene, which was shown to reduce relevant proinflammatory cytokines while increasing anti-inflammatory cytokines. CB2 and PPAR-gamma, among other cellular pathways, were cited as key mechanisms of action.

And a December 2022 article in Current Neuropharmacology,9by researchers in Brazil, investigated BCP’s potential “as a new drug for the treatment of substance use disorders.” The authors reviewed previous preclinical studies using animal models of addiction to cocaine, nicotine, alcohol, and methamphetamine. “Remarkably,” they concluded, the terpene “prevented or reversed behavioral changes resulting from drug exposure,” with evidence again pointing to the involvement of both CB2 and PPAR-gamma.

Painkiller

Finally, a paper by scientists with an Indian company called Vidya Herbs, which produces a black-pepper-seed extract called Viphyllin, suggests that beta-caryophyllene can reduce pain in mice primarily via activation of CB2, PPAR-alpha, and a third pathway also shared with cannabidiol: the TRPV1 (pronounced trip-vee-one) ion channel.

Published in the Journal of Pain Research10 in February 2022, the study involved administration of both 90% pure beta-caryophyllene and the black-pepper extract Viphyllin, which contains at least 30% beta-caryophyllene alongside lesser quantities of limonene, beta-pinene, and sabinene (three terpenes that can also be found in various cannabis strains).

Medical scientists are studying beta-caryophyllene as a treatment for non-alcoholic fatty liver disease, chronic pain, and substance abuse.

When Viphyllin was given at about three times the dose of pure BCP, the two treatments proved to be similarly effective at reducing pain in all four behavioral models employed.

In three of these tests, the researchers also used blockers of CB1, CB2, TRPV1, and PPAR-alphato evaluate how Viphyllin worked on the molecular level. They found that CB2, PPAR-alpha, and TRPV1 were most responsible for conveying the black pepper extract’s analgesic effect, but that the common terpene target CB1 may have played a role, as well.

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Raz, Noa et al. “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.” Biochemical pharmacology vol. 212 (2023): 115548. doi:10.1016/j.bcp.2023.115548
  2. LaVigne, Justin E et al. “Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity.” Scientific reports vol. 11,1 8232. 15 Apr. 2021, doi:10.1038/s41598-021-87740-8
  3. Younossi, Zobair M et al. “The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.” Hepatology (Baltimore, Md.) vol. 77,4 (2023): 1335-1347. doi:10.1097/HEP.0000000000000004
  4. Scandiffio, Rosaria et al. “Beta-Caryophyllene Modifies Intracellular Lipid Composition in a Cell Model of Hepatic Steatosis by Acting through CB2 and PPAR Receptors.” International journal of molecular sciences vol. 24,7 6060. 23 Mar. 2023, doi:10.3390/ijms24076060
  5. Kim, Donghee et al. “Inverse association of marijuana use with nonalcoholic fatty liver disease among adults in the United States.” PloS one vol. 12,10 e0186702. 19 Oct. 2017, doi:10.1371/journal.pone.0186702
  6. Du, Rui et al. “Marijuana use is inversely associated with liver steatosis detected by transient elastography in the general United States population in NHANES 2017-2018: A cross-sectional study.” PloS one vol. 18,5 e0284859. 18 May. 2023, doi:10.1371/journal.pone.0284859
  7. Cheng, Yujie et al. “β-Caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway.” Pharmacology vol. 94,1-2 (2014): 1-12. doi:10.1159/000362689
  8. Baradaran Rahimi, Vafa, and Vahid Reza Askari. “A mechanistic review on immunomodulatory effects of selective type two cannabinoid receptor β-caryophyllene.” BioFactors (Oxford, England) vol. 48,4 (2022): 857-882. doi:10.1002/biof.1869
  9. Asth, Laila et al. “Effects of β -caryophyllene, A Dietary Cannabinoid, in Animal Models of Drug Addiction.” Current neuropharmacology vol. 21,2 (2023): 213-218. doi:10.2174/1570159X20666220927115811
  10. Venkatakrishna, Karempudi et al. “ViphyllinTM, a Standardized Black Pepper Seed Extract Exerts Antinociceptive Effects in Murine Pain Models via Activation of Cannabinoid Receptor CB2, Peroxisome Proliferator-Activated Receptor-Alpha and TRPV1 Ion Channels.” Journal of pain research vol. 15 355-366. 5 Feb. 2022, doi:10.2147/JPR.S351513

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Which Terpenes Enhance the Cannabis High?

Ten years ago, most cannabis consumers couldn’t tell a terpene from a cannabinoid. But today things are different. Cannabis flower is categorized according to terpene profile. Product manufacturers add terp blends back into edibles and concentrates. Limonene is practically a household name.

And for good reason. Sure, terpenes impart desirable flavors and aromas. They appear to be good for the body, as well.1 Now it turns out that some terpenes also may contribute to the cannabis high.

A 2021 study2 by University of Arizona scientists concluded that certain terpenes are “cannabimimetic” (in a mouse model of cannabis intoxication) and can selectively enhance cannabinoid activity.

And this month comes a brand-new paper in the journal Biochemical Pharmacology3 by Israeli researchers who report that three cannabis terpenes — at concentrations similar to those found in actual cannabis plants — significantly boost THC signaling at the CB1 receptor.

CB1 Activation

Using an in vitro cellular model, the Israeli team compared CB1 receptor activation by 16 different cannabis terpenes to that of THC alone and to THC-terpene blends with a botanically relevant ratio of 10:1.

When tested individually, all 16 terpenes activated CB1, at about 10% to 50% of activation of THC alone. This is notable in and of itself, though not a huge surprise. While their chemical structures differ quite a bit, terpenes and cannabinoids share key features; both belong to a larger group of plant compounds called terpenoids. In fact, cannabinoids are technically classified as “terpeno-phenolic” substances.

Varying Responses

Next, the researchers tested terpenes and THC together. What they found runs the gamut. In the cases of beta-pinene and geraniol, the mixtures actually produced a smaller effect than the sum of the individual parts, as if these terpenes negated some of THC’s activity.

For eight of the THC-terpene blends, including some of the most common cannabis terpenes — alpha-pinene, beta-caryophyllene, bisabolol, eucalyptol, humulene, myrcene, nerolidol, and terpinolene — CB1 activation equaled that of THC alone. The presence of the terpene seemed to make no difference.

A 2021 study reports that some terpenes are “cannabimimetic” and can enhance cannabinoid activity.

But with three other terpene-THC blends — linalool, ocimene, and terpineol — the researchers observed an additive effect, meaning that CB1 activity equaled the sum observed with THC and the terpene separately. In other words, if the terpene was a 3 and THC was a 7, the blend was a 10.

Finally, three of the terpenes — limonene, borneol, and sabinene — produced a synergistic effect in combination with THC. In these cases, the whole was greater than the sum of its parts: an 11 or 12 rather than the expected 10.

THC-Terpene Synergies

The researchers consider this latter point their most significant finding. It represents the first demonstration of THC-terpene synergism in an in vitro controlled setting, and lends the paper its title: “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.”

Is this evidence of the fabled cannabis entourage effect? Strictly speaking, no, according to the paper’s authors. They note that the term “entourage effect,” as originally coined in a 1998 article in the European Journal of Pharmacology,4 refers to cases where compounds that don’t directly bind to CB1 or CB2 nonetheless boost the activity of the endocannabinoid system.

Since terpenes do activate CB1, this doesn’t fit with the original concept of the entourage effect. “Given that cannabis terpenes demonstrate direct agonism at CB1 receptor,” the authors contend, “THC-terpene effects are beyond the classical definition of entourage.”

Therapeutic Applications?

Semantics aside, the paper’s fundamental findings around THC-terpene interactions, at ratios similar to those in the cannabis plant and at very low terpene concentrations, could have significant implications for both future research and real-world cannabis use.

The simple fact that different terpenes can modify THC activity in different ways seems worthy of attention on its own, but the authors put particular emphasis on their discovery of a synergistic effect for limonene, borneol, and sabinene. While limonene is among the most common cannabis terpenes, borneol is less so, and sabinene is rarer still. As a result, they suggest that these terpenes could be intentionally added to cannabis extracts to maximize effectiveness of their THC content.

Terpenes could be added to cannabis extracts to maximize the effectiveness of their THC content.

“The use of selected terpenes may enable reducing the THC dose in some treatments, and as a result, potentially minimizing the THC-related adverse effects,” they conclude. “This would also help in adjusting the treatment to more sensitive populations such as children and elderly.”

The authors continue, “Enrichment with selected terpenes may allow for composition adjustment to personal needs and to changes during chronic use, such as for daytime versus for sleep.”

Of course, these statements are speculative and not necessarily supported by clinical research. They also smack a bit of marketing-speak, which is not surprising given that four of the authors are employees of the Bazelet Group, a medical cannabis manufacturer in Israel that boasts of using a “breakthrough technology” to “formulate specific desired [cannabinoid-terpene formulations] to supply enhanced therapeutic effect in various medical conditions.”

As always in cannabis science and medicine, the real world is far more complex than the lab, and preclinical findings don’t always translate into lived experience. But at the very least, the study provides further evidence of interactions between terpenes, cannabinoids, and the endocannabinoid system — something Project CBD will explore further in a subsequent article on beta-caryophyllene, the “super terpene.”

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. An independent science journalist based in the San Francisco Bay Area, he covers a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. Cox-Georgian, Destinney et al. “Therapeutic and Medicinal Uses of Terpenes.” Medicinal Plants: From Farm to Pharmacy 333–359. 12 Nov. 2019, doi:10.1007/978-3-030-31269-5_15
  2. LaVigne, Justin E et al. “Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity.” Scientific reports vol. 11,1 8232. 15 Apr. 2021, doi:10.1038/s41598-021-87740-8
  3. Raz, Noa et al. “Selected cannabis terpenes synergize with THC to produce increased CB1 receptor activation.” Biochemical pharmacology vol. 212 (2023): 115548. doi:10.1016/j.bcp.2023.115548
  4. Ben-Shabat, S et al. “An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2-arachidonoyl-glycerol cannabinoid activity.” European journal of pharmacology vol. 353,1 (1998): 23-31. doi:10.1016/s0014-2999(98)00392-6

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Getting to Know Cannabigerol with Bonni Goldstein, MD

This transcript is adapted from CannMed’s weekly podcast, hosted by Ben Amirault, who recently interviewed Bonni Goldstein, MD, one of the country’s most respected and experienced medical cannabis physicians. Dr. Goldstein has treated thousands of patients with medical cannabis. She is the medical director of Canna-Centers Wellness & Education and the clinical advisor to Cannformatics. She is also the author of Cannabis is Medicine: How Medical Cannabis and CBD are Healing Everything from Anxiety to Chronic Pain. Dr. Goldstein will be leading the Medical Practicum at CannMed 2023 (May 15-17), where she will also be speaking about CBG and other minor cannabinoids during the main session.

Ben Amirault, CannMed: I wanted to discuss one of the so-called minor compounds that you’ll be covering during your talk at CannMed this month. You have said that cannabigerol, or CBG, is one of your favorite cannabinoids. Why?

Dr. Goldstein: It appears that CBG does a lot of things that THC does and a lot of things that CBD does — but maybe even a little bit better. It’s kind of a bridge between THC and CBD. CBG is not intoxicating or impairing. It seems to be effective at lower doses compared to CBD. And it does appear to address some of the main issues that people turn to cannabis for — inflammation, pain, anxiety, sleep problems, depression, and cancer. So, like it checks all the boxes, especially for people who don’t want to get high and who don’t have the ability to pay for very high doses of CBD.

CannMed: It’s interesting that you say CBG is a bridge between THC and CBD. Is that because CBG is a precursor for the other plant cannabinoids?

Dr. Goldstein: CBG’s parent compound, cannabigerolic acid (CBGA), is kind of known as the mother of all the cannabinoids in that it’s the compound that’s found in immature cannabis flower. And then, based on the genetics of the plant and the enzymes that it’s exposed to, CBGA changes into CBDA and/or THCA, which turn into CBD and THCA when heated. CBGA hasn’t really been studied very much. I would say it is highly understudied. But I suspect that we will eventually find out that CBGA has some very interesting anti-inflammatory and anti-cancer properties. We don’t know really know yet. But at least CBG is being studied. I constantly look at the scientific literature, and just this year there’s a study published from Israel on how CBG may be helpful for multiple sclerosis. And there’s another study that looked at CBG’s mechanism of action in terms of how it works for pain and inflammation. So, there’s a lot of interest in CBG, which is really exciting.

CannMed: For what conditions do you think CBG has the most promise? What are you most interested in?

Dr. Goldstein: I think CBG holds a lot of promise for people who struggle with inflammation, pain, and mood disorders, like anxiety or depression. Ethan Russo, along with other researchers, recently did a survey of CBG users. About 70 percent of people said CBG was superior to their conventional medication. It was highly rated for anxiety, pain, depression, and sleep problems. I don’t know that it’s a direct sleep agent, but when you are having less anxiety and less pain you likely will fall asleep a little bit easier and maybe sleep better. It’s noteworthy that much of this anecdotal data is supported by findings from preclinical research.

CBG holds a lot of promise for people who struggle with inflammation, pain, and mood disorders, like anxiety or depression.

CannMed: In the survey you mentioned, was that CBG being taken by itself or in combination with other cannabinoids?

Dr. Goldstein: In the survey, I think they tried to sort that out, and it was people taking plant CBG that they buy in the hemp market because most CBG products that are on the market do not contain a significant amount of THC. They are coming from hemp plants, so they are readily available on the hemp market. I’ve seen it as flower, I’ve seen it as topical, which has anti-bacterial and anti-psoriatic effects. Psoriasis is a well-known condition where people get not only joint pain but they also get these thick red patches and scales on their skin. It can be a very difficult condition. And CBG has been found to have anti-psoriatic properties. It acts on the skin cells themselves and inhibits the build-up of those scaly patches. I think this just goes to show that the applications of cannabinoids are truly wide-ranging. People often ask: How is it possible that these compounds can do so many things? Well, they have multiple targets in the brain and body and that’s what makes them so amazing. Remember, the pharmaceutical model is “this medicine addresses this specific target.” Whereas cannabinoids are what we call promiscuous – they go to a lot of targets.

CannMed: How does CBG differ in its targets from other plant cannabinoids? Does it work on the same receptors with similar mechanisms of action?

Dr. Goldstein: There’s overlap with some of the actions of THC and CBD, for example. But then there are also some opposite reactions. CBD and CBG have opposite reactions at a specific serotonin receptor — 5HT1A — where CBD binds to it and CBG blocks it. They both act at that receptor, but in different ways. CBG also overlaps with CBD by binding to what we call PPAR receptors [on the surface of the cell’s nucleus]. And both of these plant cannabinoids interact with TRP [ion] channels to help with inflammation and pain.

CBG is the only cannabinoid that has been found to work at the alpha-adrenergic receptor, which mediates pain perception and inflammation. There are pharmaceuticals for ADHD or behavioral issues, for example, which target this receptor. CBG is always a compound I consider when treating children who have either behavior or other types of difficulties. I have used it in some of my patients with autism. Some families report their child is calmer, has better focus, even speech is improving in some of the children with autism who are non-verbal. But other parents report that CBG makes their child way too hyper. That may be a dosing issue. Why not try it? We know that it’s safe. And it’s under medical supervision. We start with very low doses so that we can control what’s going on and of course there’s a lot of oversight. The parents are watching, I’m watching. We’re just trying to make sure that we do no harm. Thus far, I’d say about 60 percent of kids that try CBG seem to get some benefit from it.

CannMed: I’m glad you brought up ADHD. Full disclosure: my son has been diagnosed with ADHD. I was surprised to learn that CBG might be helpful for that.

Dr. Goldstein: We don’t have clinical trials to say, yes this is definitively beneficial or detrimental for children. But we may be on the cusp of having those trials, which would be very exciting. In my practice, which is in California, I am allowed to work with parents to try different cannabinoids to see what might help. We do it very methodically. As I discuss in my book, we have a saying, ‘Rule it in or rule it out’. We start low dose, and we titrate up. We focus on one compound to see if there are benefits. And remember, too, that sometimes when we’re seeing a benefit it may be because the child is also on CBD — and maybe that combination is working well. If you add a compound and see enhanced benefits, you don’t know if it’s working because of that particular compound or the combination of the two if they’re already on something else. There’s a lot of trial and error involved, and it takes time to sort it out. I always tell families when I first meet them that we’re going to be working together for quite some time. It’s not like we just pick something and it immediately works great. We might get lucky. That happens, but that’s not the usual case.

CannMed: Another thing that stood out to me was this idea of CBG enhancing the body’s function. I was wondering if you could speak a bit to that.

Dr. Goldstein: A number of endocannabinoids, including CBD and CBG, delay the breakdown of our endocannabinoids. Remember, our endocannabinoids are our inner cannabis-like compounds, which our body releases on demand in response to a trigger, usually something that is stressing us, whether it be an illness or a traumatic insult or an infection of some sort. Your body cranks out these endocannabinoids to help maintain balance among all the various messages that our cells are constantly sending and receiving. The endocannabinoid system is a physiological regulator, and it’s helping you stay in balance. We can enhance our own natural endocannabinoid system with plant cannabinoids, which delay the breakdown of endogenous cannabinoids so that they last longer. It’s kind of like the way some anti-depressants work by increasing how long serotonin is hanging around.

We can enhance our own natural endocannabinoid system with plant cannabinoids.

CannMed: Now correct me if I’m wrong, but physical exercise is another way to spur your body into creating endocannabinoids?

Dr. Goldstein: Yes.

CannMed: Would supplementing with CBD or CBG be an effective way to keep anandamide in the system and get more benefits from our natural cannabinoids?

Dr. Goldstein: Theoretically you could look at it that way. I don’t know that there’s a direct correlation, as in take a dose and now you have extra anandamide. But I do think the literature supports this whole idea of cannabinoids being anti-inflammatory, antioxidant, neuroprotective — and one dose is not going to do the trick. It’s helpful to think in terms of a wellness regimen that includes cannabinoids, of course, in addition to other healthy things that you should be doing to enhance your endocannabinoid system – healthy diet, exercise, good sleep, really trying to control your stress.

CannMed: Could you speak to how CBG might enhance the effects of other cannabinoids or situations where you think the combination is useful?

Dr. Goldstein: There’s a 2019 animal study that showed the combination of CBD and CBG decreased neuroinflammation. They were looking specifically at neurodegenerative disorders with dementia, what we call Lou Gehrig’s Disease or ALS. And it showed in this preclinical study that CBD and CBG worked together and gave better results for protecting against neuroinflammation. This ties into the concept of the entourage effect, whereby combinations of cannabinoids and terpenes appear to enhance the benefits, the positive results. Another recent study showed that CBG in addition to THC and/or CBD has anti-cancer effects in test tube experiment looking at certain brain tumor cells. When some of my cancer patients come to me with advanced cancer, very poor prognosis — and I’ve been doing this now for a number of years — I add CBG into the mix. To me there is no harm in doing so. It doesn’t cause the impairment that anti-cancer doses of THC can sometimes cause.

CannMed: What other scenarios or situations do you encounter where you think CBG is either the right tool or might be a good companion if you have already started a cannabis regimen and you’re not getting the right results?

Dr. Goldstein: I think that if you’re trying to treat anxiety, pain, inflammation, and you are not getting great results with either THC and/or CBD, which, of course, are the two most common cannabinoids being used right now, then certainly the addition of CBG is worth a try. Remember too, that when you combine cannabinoids sometimes you can get away with a lower dose of either or both, while getting an enhanced effect from that entourage. Because there are studies that show sub-therapeutic doses of cannabinoids — meaning doses not expected to do anything clinically — when combined will work better. For a lot of people high, high doses are just not financially feasible. And sometimes that combination of small amounts of two compounds actually is more effective. As for what I would recommend CBG for — anxiety, pain, psoriasis, I use it in my patients with autism, I use it in my patients with cancer. Because it’s safe, and if somebody’s struggling and conventional medicine is not helping them or it is only helping to a point, I don’t see any reason, especially under medical supervision, not to try CBG and other cannabinoids when there’s compelling preclinical research that begs for clinical trials.

CBG is always a compound I consider when treating children who have behavior or other types of difficulties.

CannMed: It seems like CBG is very well tolerated by patients, but are there adverse reactions that you’ve run into?

Dr. Goldstein: I haven’t really seen a lot of adverse reactions, except for a few specific ones related to the population of children that I take care of. In some kids with autism, it’s just too overstimulating. It makes behavior go off the charts. So, I warn the families about this before we get started. It may be a dosage thing. Dosing is very, very important. Lower doses may be overstimulating. If that’s the case, we might try higher doses. But that’s specifically related to a certain population. I have not observed or heard of too many side effects from adults taking CBG. Some patients say that CBG is somewhat alerting, meaning it feels a little up. So, you would not want to take CBG right before bedtime. You figure out how you respond to it, and then don’t use it at night if that’s the effect you get. On the other hand, some people say it helps with sleep. Maybe it’s helping with sleep because it’s calming and decreases anxiety. When a doctor hands you an antidepressant or an opioid, nobody knows how you’re going to respond if you’ve not taken that before. It’s the same thing with CBG. There is always a chance when you take a new medication that you may be the person who doesn’t respond very well. Or you might be the person who gets a great result.

CannMed: CBG is still one of the lesser-known cannabinoids. How easy is it to access CBG products?

Dr. Goldstein: In the video that I put up on YouTube, there’s a slide that shows some of the CBG products. You can get it as flower if you want to vaporize it. You can get it as a topical, as I’ve mentioned. Mostly I’ve seen it in tincture form, which means an extract in a bottle where you have a little eyedropper or syringe and you measure out your dose and squirt it under the tongue. I don’t endorse any company, but certainly a quick Google search will lead you to where you can find CBG. And of course, always, always before you purchase anything, you want to make sure you get a Certificate of Analysis (CoA) so you see what is supposed to be in that bottle before you buy it. And if a CoA isn’t available or not readily transparent, move on to the next product.

CannMed: We actually did a podcast with a laboratory professional who was talking about how some manufacturers will even falsify their CoA’s. She had some good tips for being able to spot the real ones and the less scrupulous ones. So, Bonni, before I let you go, I want to thank you so much for talking about CBG with us. I look forward to hearing your talk on some of the other cannabinoids at CannMed 2023, where you’re also going to be leading our Medical Practicum, along with Dustin Sulak, Kevin Spelman, and Eloise Thiessen. Could you give us a sneak quick preview of what people can expect at the Practicum and why you believe it’s important to have events like this to educate clinicians and laypersons about cannabis medicine.

Dr. Goldstein: It’s important because for health care professionals there is no full board training program, no residency or internship that focuses on cannabis therapeutics. The feedback we’ve gotten is it’s very helpful to hear directly from clinicians who are actually practicing this type of specialty and who are exploring the nuances of cannabis medicine. The practicum is a full day of education. We start off with endocannabinoid system physiology, the physiology of the cannabinoids and other constituents of the plant. Dr Kevin Spelman, who’s a brilliant botanist and herbalist with many years of experience, is one of the teachers. His lectures are amazing. Especially coming from my world as an MD, an allopathic world, it was a big change for me to understand botanical medicine. Having him on board really helps bridge that gap for those of us who are coming from the allopathic field. During the practicum, we also go through clinical applications for cannabis, special considerations for geriatric patients, chronic pain treatment. I’ll be talking about pediatrics, my area of specialty. And then there will be practical panels where we’ll be giving case reports and advice on how to help your patients pick the right medicine. It’s really a full day with lots of information for anyone who wants to advance their knowledge. I really enjoy it. It’s great to be around like-minded people, and it’s great to hear about other people’s experiences. I always learn something from my colleagues at CannMed, from people in the audience, and from the other speakers.

For more information on Dr. Goldstein, visit her YouTube channel Bonni Goldstein MD. She occasionally posts on Instagram, and she is also on LinkedIn. To hear the full CannMed podcast with Dr. Bonni Goldstein, go here.

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CBD Enhances Glucose Metabolism via Nuclear Receptors

Cannabinoid receptors CB1 and CB2 are the definitive and best-known targets of endogenous and plant-derived cannabinoids, but they’re far from the only ones.

Several phytocannabinoids, including cannabidiol (CBD), for example, and the two primary endocannabinoids — anandamide and 2-AG — have been shown to interact with peroxisome proliferator-activated receptors, or PPARs1 (pronounced pee-parrs), which are found on the surface of the cell’s nucleus. This may help to explain how CBD, which has little affinity for either CB1 or CB2, can do so much.

Get to Know the PPARs

PPARs are a group of nuclear receptors that play important roles in regulating metabolism, inflammation, and gene expression. Triggered by hormones, endocannabinoids, and other fatty acid derivatives, and various nutritional compounds,2 PPARs are expressed in different parts of the body:

  • PPAR-a(PPAR-alpha) is found in the liver, kidney, heart, and skeletal muscle, as well as adipose (fat) tissue and the intestinal tract;
  • PPAR-b(PPAR-delta) is expressed in adipose tissue, skeletal muscle, heart, and liver; and
  • PPAR-y (PPAR-gamma), which comes in two forms, is expressed in almost all tissues of the body including the colon, the cardiovascular system, and immune cells.

The first evidence of an endocannabinoid interacting with PPARs came in 2002, when a research team in Tennessee showed that a metabolite of 2-AG activated PPAR-a.3 Since then many more breakthroughs have been made, and peroxisome proliferator-activated receptors are now viewed as an extension of the classic endocannabinoid system (ECS).

PPARs are now viewed as an extension of the classic endocannabinoid system.

Two recent papers reiterate the point that to really understand cannabinoids (especially CBD) and the ECS, it’s essential to get to know the PPARs.

CBD, Psychosis & Glucose Metabolism

A March 2023 study in the journal Frontiers in Psychiatry4 suggests that CBD may act through a PPAR receptor to enhance cerebral glucose metabolism, alterations of which are associated with a host of metabolic and cognitive disorders.5

The paper describes the case of a 19-year-old man in Germany who presented at the Cologne Early Recognition and Intervention Center with “a marked cognitive decline within [six] months, anhedonia, ambivalence, social withdrawal, poverty of speech, and brief, limited intermittent psychotic symptoms, particularly delusions and hallucinations.”

Prior to this, the man had no psychiatric history, the authors note. He had never taken anti-psychotic drugs nor received psychological treatment. And besides an uncle with bipolar disorder, he had no family history of other psychiatric or neurological diseases.

The man’s doctors — two of the paper’s four authors — knew that over the last decade-plus, CBD has begun to be recognized through animal and human studies as a novel therapeutic compound for psychosis that acts via indirect effects on the ECS.6,7 They wanted to try it.

“Due to its excellent tolerability and promising efficacy … and its innovative new mechanisms of action, we decided to offer a respective treatment with cannabidiol to [the] patient,” they write.

The prescription was 600 mg of pure CBD orally per day for 30 days. And it worked. The authors report a substantial clinical improvement in attention, visual processing, visuomotor speed, working memory, and other parameters beginning by day seven, with no adverse events or side effects. That’s quite notable in and of itself — but it’s their investigation of potential mechanisms of action that really contributes to the conversation.

Mechanisms of Action

Using brain scans and blood draws, the researchers observed that this reduction in clinical symptoms was accompanied by enhancement of cerebral glucose utilization — a critical metabolic process whose impairment is implicated in Alzheimer’s Disease, schizophrenia, diabetes, obesity, and more.8

They suggest that the underlying mechanism linking CBD intake, cerebral glucose utilization, and improved psychiatric symptoms may be none other than PPAR-y, one of the three known PPAR receptors. PPAR-y plays an essential role in regulating glucose homeostasis and neuroinflammation, and is directly activated by both CBD and the endocannabinoid anandamide (AEA). (AEA’s molecular fatty-acid cousins, PEA and OEA, activate PPAR-a.)

The activation of PPAR-γ by CBD may be one of the mechanisms relevant to the promising antipsychotic effects of cannabidiol.

The proposed link between CBD, cerebral glucose metabolism, psychiatric symptoms, and PPAR-y makes sense, even if it has yet to be proven definitively. Previous research has linked CBD’s efficacy in treating psychosis to its ability to boost AEA,9 which binds with PPAR-y. PPARs in general are recognized as a potential target for treating psychiatric disorders.10 And a 2022 study showed that CBD treatment improved both glucose metabolism and memory in a rat model of Alzheimer’s Disease.11

“The direct or indirect activation of PPAR-γ by cannabidiol may represent one of the various possible mechanisms relevant to the promising antipsychotic effects of cannabidiol,” the authors conclude. Yes, more research is needed — but what matters most to the patient is that it helps.

Cannabidiol Goes Nuclear

A review article in the journal Phytomedicine12 also published in March 2023 provides a broader look at the clinical implications of CBD’s affinity for PPAR-y. Appearing under the catchy title “Cannabidiol goes nuclear: The role of PPARy,” the paper summarizes existing research into the many ways in which interactions between the two influence human health.

Based on an examination of 78 previous articles, the Iran-based authors determined that CBD’s effects on a long list of conditions (Alzheimer’s disease and memory loss, Parkinson’s disease and movement disorders, multiple sclerosis, anxiety and depression, cardiovascular disease, immune conditions, cancer, and obesity) are mediated at least in part by PPAR-y.

The ubiquitous receptor manages this not only through glucose homeostasis, the authors write, but also by changing the expression of various genes implicated in insulin release, lipid metabolism, inflammation, and immunity. And they note that many effects of CBD can be prevented by synthetic PPAR-y antagonists, which are utilized as research tools.

Ultimately, the review underscores that PPAR-y is a key target for CBD — and argues quite convincingly that “[the receptor’s] activation by CBD should be considered in all future studies.”

Nate Seltenrich, Project CBD contributing writer, is the author of the column Bridging the Gap. He is an independent science journalist based in the San Francisco Bay Area, covering a wide range of subjects, including environmental health, neuroscience, and pharmacology. © Copyright, Project CBD. May not be reprinted without permission.

Footnotes

  1. O’Sullivan, Saoirse Elizabeth. “An update on PPAR activation by cannabinoids.” British journal of pharmacology vol. 173,12 (2016): 1899-910. doi:10.1111/bph.13497
  2. Scandiffio, Rosaria et al. “Beta-Caryophyllene Modifies Intracellular Lipid Composition in a Cell Model of Hepatic Steatosis by Acting through CB2 and PPAR Receptors.” International journal of molecular sciences vol. 24,7 6060. 23 Mar. 2023, doi:10.3390/ijms24076060
  3. Karkhanis, Anil et al. “15-Lipoxygenase Metabolism of 2-Arachidonylglycerol: Generation of a Peroxisome Proliferator-Activated Receptor α Agonist.” Journal of medicinal chemistry vol. 57,11 (2014): 4830-4840.
  4. Koethe, Dagmar et al. “Cannabidiol enhances cerebral glucose utilization and ameliorates psychopathology and cognition: A case report in a clinically high-risk mental state.” Frontiers in psychiatry vol. 14 1088459. 3 Mar. 2023, doi:10.3389/fpsyt.2023.1088459
  5. Rebelos, Eleni et al. “Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review.” Journal of clinical medicine vol. 10,7 1532. 6 Apr. 2021, doi:10.3390/jcm10071532
  6. Rohleder, Cathrin et al. “Cannabidiol as a Potential New Type of an Antipsychotic. A Critical Review of the Evidence.” Frontiers in pharmacology vol. 7 422. 8 Nov. 2016, doi:10.3389/fphar.2016.00422
  7. Davies, Cathy, and Sagnik Bhattacharyya. “Cannabidiol as a potential treatment for psychosis.” Therapeutic advances in psychopharmacology vol. 9 2045125319881916. 8 Nov. 2019, doi:10.1177/2045125319881916
  8. Rebelos, Eleni et al. “Brain Glucose Metabolism in Health, Obesity, and Cognitive Decline-Does Insulin Have Anything to Do with It? A Narrative Review.” Journal of clinical medicine vol. 10,7 1532. 6 Apr. 2021, doi:10.3390/jcm10071532
  9. Davies, Cathy, and Sagnik Bhattacharyya. “Cannabidiol as a potential treatment for psychosis.” Therapeutic advances in psychopharmacology vol. 9 2045125319881916. 8 Nov. 2019, doi:10.1177/2045125319881916
  10. Matrisciano, Francesco, and Graziano Pinna. “The Strategy of Targeting Peroxisome Proliferator-Activated Receptor (PPAR) in the Treatment of Neuropsychiatric Disorders.” Advances in experimental medicine and biology vol. 1411 (2023): 513-535. doi:10.1007/978-981-19-7376-5_22
  11. de Paula Faria, Daniele et al. “Cannabidiol Treatment Improves Glucose Metabolism and Memory in Streptozotocin-Induced Alzheimer’s Disease Rat Model: A Proof-of-Concept Study.” International journal of molecular sciences vol. 23,3 1076. 19 Jan. 2022, doi:10.3390/ijms23031076
  12. Khosropoor, Sara et al. “Cannabidiol goes nuclear: The role of PPARγ.” Phytomedicine: international journal of phytotherapy and phytopharmacology vol. 114 (2023): 154771. doi:10.1016/j.phymed.2023.154771

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Cancer & the CB2 Receptor

The cannabinoid receptor CB1, primary target of THC in the brain, is known for mediating the cannabis high. And its counterpart CB2, mainly expressed in immune cells throughout the body, is understood to play an important role in inflammatory processes. These abstractions are accurate as far as they go, but as with anything related to the endocannabinoid system, reality is far more complex.

Project CBD’s recent article on the passing of Raphael Mechoulam noted that the esteemed scientist believed CB2 should be a focus of future cannabinoid science. The CB2 receptor interacts with THC, CBD, endocannabinoids, and other compounds in a multitude of organs including skin and bone.

Recent research — including papers co-authored by Mechoulam well into his 80s — has confirmed that aberrant CB2 signaling is implicated in a raft of autoimmune, neurodegenerative, metabolic, and psychiatric disorders. CB2 is also an increasingly hot topic in cancer research.

In this two-part series, Project CBD will explore some of the latest studies and what they reveal about what we know — and still don’t know — about this ubiquitous, somewhat mysterious cell receptor.

This week: cancer. Next week: cognitive and mood disorders, including some of Mechoulam’s final work before his death in March at the age of 92.

Prostate Cancer & a New CB2 Ligand

Three studies from the first few months of 2023 probe the function of CB2 in three different cancer models. While their findings are complex and not necessarily conclusive, they contribute to a growing body of knowledge about the potential efficacy of cannabinoids in cancer treatment.

A paper published in February in International Journal of Molecular Sciences1 offers two insights for the price of one: first, another look at how the CB2 receptor functions in a cellular model of cancer; and second, new evidence that a compound called 3-3′-Diindolylmethane (DIM) — present in cruciferous vegetables such as cauliflower, cabbage, broccoli, Brussels sprouts, and a number of leafy greens — exerts anti-cancer effects through the CB2 receptor.

By testing DIM on two different human prostate cancer cell lines, the Italy- and UK-based researchers observed that the compound activated naturally expressed CB2 receptors in both lines — and that in one, known as “PC3,” CB2 activation led to cell death, an effect that was reversed when the researchers blocked the CB2 receptor with an antagonist.

DIM was already known to have an anti-cancer effect more broadly. What had not been previously observed, the authors note, is CB2’s role in mediating this effect in a human cancer cell line. “We can conclude that DIM is a CB2 receptor ligand with a potential anti-prostate cancer effect,” they write.

If true, cruciferous vegetables join saffron, black pepper, cloves, oregano, and some other spices as foods containing compounds that interact with the CB2 receptor in beneficial ways.

But don’t head to the market for a cartload of cauliflower and cabbage just yet. The concentrations of DIM used in the study are too high to be obtained through diet alone, the authors note, and administration by supplements may be required.

Colon Cancer: Case Closed?

A second February 2023 study in the International Journal of Molecular Sciences2 comes to a similar conclusion regarding CB2’s role in colon cancer. Researchers in Israel investigated how the CB2 receptor functioned in a mouse model of colon cancer (utilizing “knockout” mice missing the receptor altogether), and they analyzed genomic data in a large human population to determine the relationship between CB2 variants and colon cancer incidence.

In both cases, the authors write, their findings indicate that “endogenous CB2 activation can modulate the immune response and consequently reduce tumorigenesis” and that “CB2 protects against the development of colon cancer.”

Yet despite their seemingly unambiguous findings, the authors also acknowledge that previous studies have come to very different conclusions about the role of CB2 in cancer.

“CB2 has been investigated in multiple cancer types and models of inflammation,” they write, “and there are controversial results regarding the effect on tumor progression.” For example, past studies have found that CB2 expression is associated with a poor prognosis in humans; that CB2 antagonists, or blockers, suppress tumor growth; that CB2 activation promotes tumor growth in models of colon cancer; and that CB2 agonists inhibit tumor growth. The researchers attribute this ambiguity to variations in animal cancer models and cancer cell lines.

Lung Cancer: A Different Answer

Sure enough, a different study published a month earlier in Frontiers in Immunology3 using a different mouse model of non-small cell lung cancer seems to show something else altogether.

Within knockout mice deficient of CB2 in the “tumor microenvironment” — the normal cells, molecules, and blood vessels that surround a tumor cell, including immune cells expressing high levels of CB2 — a team of Austria-based researchers observed a reduction in tumor burden relative to “wild-type” mice. They also found that CB2-deficient mice responded significantly better to a form of immunotherapy known as anti-PD1.

Together, these findings indicate that CB2 receptors in the tumor microenvironment of non-small cell lung cancer “may act as an immunosuppressor … thereby promoting tumor growth.”

You read that right: the opposite of what the other two papers found. Be that as it may, it still seems clear enough that CB2 modulates cellular immune response in ways directly relevant to cancer progression — and that the clinical implications of this link still need to be worked out.

Read part 2 of this 2-part series: Mental Health & the CB2 Receptor

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.

Footnotes

  1. Tucci, Paolo et al. “The Plant Derived 3-3′-Diindolylmethane (DIM) Behaves as CB2 Receptor Agonist in Prostate Cancer Cellular Models.” International journal of molecular sciences vol. 24,4 3620. 11 Feb. 2023, doi:10.3390/ijms24043620
  2. Iden, Jennifer Ana et al. “The Anti-Tumorigenic Role of Cannabinoid Receptor 2 in Colon Cancer: A Study in Mice and Humans.” International journal of molecular sciences vol. 24,4 4060. 17 Feb. 2023, doi:10.3390/ijms24044060
  3. Sarsembayeva, Arailym et al. “Cannabinoid receptor 2 plays a pro-tumorigenic role in non-small cell lung cancer by limiting anti-tumor activity of CD8+ T and NK cells.” Frontiers in immunology vol. 13 997115. 9 Jan. 2023, doi:10.3389/fimmu.2022.997115

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Mental Health & the CB2 Receptor

In the first part of this series, we reviewed recent research into the role of the CB2 cannabinoid receptor in cancer proliferation. This week we turn our attention to another fascinating aspect of CB2 function: its impact on psychiatric and mood disorders despite not being concentrated in the central nervous system (CNS).

After all, the CNS is the domain of its sibling, the CB1 cannabinoid receptor — the primary target of THC and the mediator of cannabis’ intoxicating effects. CB2, by contrast, is more prominently expressed in the peripheral nervous system, where it regulates inflammation, pain, and neuroprotection. CB2 is found to a much lesser extent in the brain, where it modulates dopamine signaling, neuroinflammation, and neurogenesis.

The CB2 receptor was of particular interest to visionary cannabinoid scientist Raphael Mechoulam. In the year prior to his recent passing at age 92, Mechoulam was still actively involved in research investigating CB2 in a variety of disease models. Here we look at a couple of his final papers on CB2 and mental health, as well as two related reviews published in the same timeframe.

CB2 & Schizophrenia

First comes a paper on CB2’s role in schizophrenia, a condition related to psychosis whose symptoms include hallucinations, delusions, disorganized thinking, social withdrawal, decreased emotional expression, and apathy. Coauthored by Brazilian scientists affiliated with the University of São Paulo, it appeared in the journal Progress in Neuro-Psychopharmacology & Biological Psychiatry1 in July 2022.

“The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients,” the authors explain. That much is clear. Given this, they wanted to know, how might “HU-910,” a synthetic research compound that selectively activates the CB2 receptor, affect behavior in a rodent model of the disease?

Through a series of tests, they found that HU-910 administration did indeed produce an anti-psychotic-like effect through the CB2 receptor. The authors suggest that these results “support further research on the potential therapeutic properties of this compound to treat schizophrenia.”

But their conclusion that HU-910 could serve as a drug warrants some caution. Cannabinoid receptors don’t function simply as on/off switches. As Project CBD has addressed in the past relative to proposed therapies for bone disease, Alzheimer’s Disease, and autoimmune dysfunction, selective CB2 agonists thus far have been disappointing in the clinical context due to unintended consequences and other unwelcome outcomes resulting from the receptor’s wide reach in the body.

CB2 & Depression

The very last paper bearing Mechoulam’s name before his death — among a body of work encompassing 379 total articles listed at Pubmed — concerns the role of the CB2 receptor in mediating the antidepressive effect of cannabidiolic acid-methyl ester (CBDA-ME). Titled “Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats,” it appeared in the February 2023 special issue of the International Journal of Molecular Sciences,2 which explored the biological mechanisms of cannabinoids in mental health.

CBDA-ME is a stable synthetic analogue of cannabidiolic acid (CBDA), the raw, unheated version of CBD present in cannabis flower. (The fact that CBDA becomes CBD in the presence of sunlight or heat makes it difficult to study, hence the need for a more stable CBDA-related compound.) First described in 19693 by Mechoulam and a coauthor, CBDA-ME has in recent years been shown to exert anxiolytic,4 anti-hyperalgesic,5 and anti-depressive6 effects in male rodents at low doses.

The Israel-based authors assessed the antidepressant effect of CBDA-ME in mice through a common laboratory model known as the “forced swim test.” Among the authors’ findings, one stands out (and makes its way into the paper’s title): a synthetic CB2 antagonist called “AM-630” blocked CBDA-ME’s anti-depressive effect in female rats, but not in males, indicating that the CB2 receptor is involved in mediating the compound’s effect.

Does this suggest that CB2 activation — perhaps indirectly triggered by CBD or CBDA as well as CBDA-ME — could help fight depression, at least in women? Possibly, the authors conclude, but “the cumulative data indicate that these pathways are still ambiguous and require future research in order to fully understand the mechanisms of action of acute CBDA-ME in relieving the symptoms of depression.”

Targeting CB2 in CNS Disorders

Two other reviews from 2022 provide a broader perspective on CB2’s role in several emotional, cognitive, and psychiatric disorders — from addiction and anxiety to Huntington’s and Parkinson’s diseases.

A report published in the International Journal of Molecular Sciences, coauthored by Emmanuel Onaivi at William Patterson University in New Jersey and a team of Japanese scientists, concludes that CB2 receptors “are highly expressed in neuropsychiatric and neurodegenerative disorders, and that selective CB2 ligands have promising effects on the symptomatic management of these disorders.”

However, given the potential for such drugs to have significant side effects, the authors also recommend further study of cannabis-derived compounds to target CB2 in tandem with CB1, as well as less directly through the broader endocannabinoid system.

Next, an April 2022 review in Frontiers in Psychiatry7 notes that recent findings of CB2’s presence in several brain areas and different brain cell types, including neurons and glia, indicate that “CB2 may closely relate the immune system and the brain circuits regulating inflammation, mood, and cognitive functions.” This receptor is particularly implicated in neuropsychiatric diseases associated with neuroinflammation, according to the European scientists, who conclude that future research should continue to zero in on the critical link between CB2, inflammation, and psychiatric disorders.

Read part 1 of this 2-part series: Cancer & the CB2 Receptor

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.

Footnotes

  1. Cortez, Isadora Lopes et al. “HU-910, a CB2 receptor agonist, reverses behavioral changes in pharmacological rodent models for schizophrenia.” Progress in neuro-psychopharmacology & biological psychiatry vol. 117 (2022): 110553. doi:10.1016/j.pnpbp.2022.110553
  2. Hen-Shoval, Danielle et al. “Cannabinoid Receptor 2 Blockade Prevents Anti-Depressive-like Effect of Cannabidiol Acid Methyl Ester in Female WKY Rats.” International journal of molecular sciences vol. 24,4 3828. 14 Feb. 2023, doi:10.3390/ijms24043828
  3. Mechoulam, R et al. “Carboxylation of resorcinols with methylmagnesium carbonate. Synthesis of cannabinoid acids.” Journal of the chemical society D: chemical communications vol. 1,7 (1969): 343-344. doi:10.1039/C29690000343
  4. Pertwee, Roger G et al. “Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT1A receptor-mediated suppression of nausea and anxiety in rats.” British journal of pharmacology vol. 175,1 (2018): 100-112. doi:10.1111/bph.14073
  5. Zhu, Yong Fang et al. “An evaluation of the anti-hyperalgesic effects of cannabidiolic acid-methyl ester in a preclinical model of peripheral neuropathic pain.” British journal of pharmacology vol. 177,12 (2020): 2712-2725. doi:10.1111/bph.14997
  6. Hen-Shoval, D et al. “Acute oral cannabidiolic acid methyl ester reduces depression-like behavior in two genetic animal models of depression.” Behavioural brain research vol. 351 (2018): 1-3. doi:10.1016/j.bbr.2018.05.027
  7. Kibret, Berhanu Geresu et al. “New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders.” International journal of molecular sciences vol. 23,2 975. 17 Jan. 2022, doi:10.3390/ijms23020975
  8. Morcuende, Alvaro et al. “Immunomodulatory Role of CB2 Receptors in Emotional and Cognitive Disorders.” Frontiers in psychiatry vol. 13 866052. 15 Apr. 2022, doi:10.3389/fpsyt.2022.866052

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The Plant, the Whole Plant & Nothing But the Plant

It has long been known that resinous cannabis flower tops are infused with robust therapeutic properties. But there are also pharmacologically active components in other parts of the plant that shouldn’t be ignored when assessing the health benefits of cannabis.

The earliest reference to the therapeutic use of cannabis dates back to 2700 BC in ancient China, “the land of hemp and mulberry.” Cannabis (“Ma”) was subsequently included in the Shennong Ben Cao Jing, humankind’s first pharmacopeia, which had been assembled by Emperor Shen Nung, the legendary father of traditional Chinese medicine, who is credited with introducing the custom of drinking tea. Ma was recommended for more than a hundred ailments, including gout, rheumatism, malaria, constipation, beri-beri, and absent-mindedness.

The Shennong Ben Cao Jing called Ma one of the “Supreme Elixirs of Immortality.” It was said to confer longevity and good health. If consumed over a long period of time, Ma could “enable one to communicate with the spirit light and make the body light. It mainly supplements the center and boosts the qi [chi]. Protracted taking may make one fat, strong, and never senile.”1

When consumed in excess, however, “it may make one behold ghosts and frenetically run about.”

Seeds of Health

In traditional Chinese medicine, protein-rich cannabis seeds figured prominently both as a food source and a remedy — apparently more so than resinous cannabis flower tops. The seeds don’t contain CBD, THC, or any other cannabinoids. But modern science confirms that cannabis seeds are an excellent source of omega 3 fatty acids, which are indispensable biochemical building blocks for a healthy endocannabinoid system.

A 2011 study published in Nature Neuroscience states: “Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.”2 Low levels of omega-3 fatty acids have been linked to neuropsychiatric diseases and impaired emotional behavior.

“Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions.”

Our endocannabinoids — the “marijuana-like” compounds that bind to the cannabinoid receptors CB1 and CB2, as well as other receptors in the brain and body — are actually derivatives or byproducts of omega 3 and omega 6 omega fatty acids. These are referred to as “essential” fatty acids because they can’t be produced by the body in adequate amounts and therefore must be ingested.

But the typical Western diet skews heavily toward corn, wheat, and other cereal grains, which are high in omega 6, whereas today we eat much less food — fish, nuts, leafy greens — that is rich in omega 3. This dietary imbalance is a major factor that contributes to many chronic diseases. It turns out that cannabis seeds (commercially available as hempseed oil, hemp hearts or hempseed protein powder) are gifted with an excellent balance of omega 3 and omega 6 fatty acids.

The Root of the Matter

Practitioners of traditional Chinese medicine also used an extract from raw cannabis roots to treat infections and to help women during childbirth. A decoction made by boiling the roots could be consumed orally as a tincture or juice or applied topically as a poultice.

Herbalists and healers have employed cannabis root preparations to treat a wide range of maladies not only in China but in other parts of the world. The first reference to the therapeutic properties of cannabis roots in Western medicine is found in the Natural Histories (77 AD) by Pliny the Elder. The Latin naturalist wrote that “the roots [of the cannabis plant] boiled in water ease cramped joints, gout too, and similar violent pain.”

Cannabis roots are endowed with medicinal compounds that have anti-inflammatory and analgesic properties.

As is the case with cannabis seeds, the roots don’t contain THC or CBD or any of the so-called minor cannabinoids. Nor are aromatic essential oils (which give cannabis flower its lively fragrance) present in the roots. Instead, the roots are endowed with other medicinal components that have analgesic and anti-inflammatory properties. Various alkaloids and sterols unique to cannabis roots are noteworthy antioxidants. Friedelin, a triterpenoid compound found in algae and lichen, as well as in cannabis roots, is known to reduce fevers.

A 12th century Persian medical text cited the antipyretic (fever-reducing) action of cannabis roots. And in 1542 the German physician Leonard Fuchs noted that a compress made with hemp root extract can soothe inflamed skin: “The raw root, pounded and wrapped, is good for the burn.” A hundred years later, English botanist John Parkinson recommended a decoction of hemp root “to cool inflammation of the head or any other part.” And Nicholas Culpepper’s Compleat Herbal, published in 1653, also mentions hemp roots as a remedy for inflammation.3

But keep in mind that cannabis is a bioaccumulator, meaning that its roots can draw heavy medals and other toxins from the soil. While that’s a great asset for cleaning up a contaminated ecosystem, it’s not what you want when growing an herb for human consumption. Where and how cannabis is cultivated are crucial factors that must be considered to avoid exposure to harmful material and to maximize the health benefits of the plant.

Flower Power

Cultivating high-quality cannabis isn’t rocket science, but it involves significant attention to detail. A hearty, adaptable plant that almost anyone can grow, cannabis lends itself to high-tech horticulture and sophisticated breeding methods designed to coax desired traits into prominence and fine-tune the quality of the high. The complexity of gourmet ganja — an adaptogen and euphoriant with an extraordinary range of smells and flavors and psychoactive subtleties — has reached a level of artistry comparable to today’s wine industry.

Growing the kindest bud ultimately depends on an ancient gardening ritual known as “sexing the plants,” a practice that entails separating male and female plants in their early stages to avoid pollination. Known as sinsemilla (Spanish for “without seeds”), the unfertilized female flower tops, oozing THC and CBD and a kaleidoscope of essential oils, are what cannabis is most famous for. The sexually frustrated females produce bigger buds with more sticky, aromatic resin in an unrequited attempt to catch pollen that never arrives.

Carl Linnaeus, the father of modern botany, wrote about this in his 1753 treatise Dissertation on the Sexes of Plants. The eminent Swedish scientist describes growing Cannabis sativa on his windowsill, an experience he greatly enjoyed:

“In the month of April, I sowed the seeds of hemp (Cannabis) in two different pots. The young plants came up plentifully . . . I placed each by the window, but in different and remote compartments. In one of them I permitted the male and female plants to remain together, to flower and bear fruit, which ripened in July . . . From the other, however, I removed all the male plants, as soon as they were old enough for me to distinguish them from the females. The remaining females grew very well, and presented their long pistilla in great abundance, these flowers continuing a very long time, as if in expectation of their mates . . . It was certainly a beautiful and truly admirable spectacle, to see the unimpregnated females preserve their pistilla so long green and flourishing, not permitting them to fade, till they had been for a very considerable time exploded, in vain, to access the male pollen . . .”4

Cannabis has been likened to a “pharmacological treasure trove.” CBD and THC are the crown jewels of this treasure trove. They are the power couple of cannabis therapeutics. But there are also dozens of secondary cannabinoids, terpenes, and flavonoids in the shimmering female inflorescence, each with specific healing attributes, which interact synergistically so that the therapeutic impact of whole plant cannabis is greater than the sum of its parts. From tap root to bud, whether seeded or seedless, the plant is the alpha and omega of cannabis medicine.

References

  1. Shou-zhong, Y. The Divine Farmer’s Materia Medica: A Translation of the Shen Nong Ben Cao Jing. Boulder, CO: Blue Poppy Press, 1997.
  2. Lafourcade M, Larrieu T, Mato S, Duffaud A, Sepers M, Matias I, De Smedt-Peyrusse V, Labrousse VF, Bretillon L, Matute C, Rodríguez-Puertas R, Layé S, Manzoni OJ. Nutritional omega-3 deficiency abolishes endocannabinoid-mediated neuronal functions. Nat Neurosci. 2011 Mar;14(3):345-50. doi: 10.1038/nn.2736. Epub 2011 Jan 30. PMID: 21278728.
  3. Ryz NR, Remillard DJ, Russo EB. Cannabis Roots: A Traditional Therapy with Future Potential for Treating Inflammation and Pain. Cannabis Cannabinoid Res. 2017 Aug 1;2(1):210-216. doi: 10.1089/can.2017.0028. PMID: 29082318; PMCID: PMC5628559.
  4. A Dissertation on the Sexes of Plants. Translated from the Latin of Linnaeus by James Edward Smith, F.R.S., into English and published 1786. Cited in Lee, Martin A. Smoke Signals. New York: Scribners: 2012, p. 22.

Martin A. Lee is the director of Project CBD. He’s authored and edited several books, including Smoke Signals, Acid Dreams, and The Essential Guide to CBD. © Copyright, Project CBD. May not be reprinted without permission.

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