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.”
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
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
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
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
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.
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.”
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
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
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.
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
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
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
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
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
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
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
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
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
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.
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
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
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
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
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.
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
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
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
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
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
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
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
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
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
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.
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
Shou-zhong, Y. The Divine Farmer’s Materia Medica: A Translation of the Shen Nong Ben Cao Jing. Boulder, CO: Blue Poppy Press, 1997.
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.
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.
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.
