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
Special glands protruding from cannabis flowers express a series of unique molecules. Cannabinoids, as they are known, exist in cannabis. But it turns out that identical molecules are present in non-cannabis plants, as well. Researchers from Israel’s Weizmann Institute recently reported that they found cannabigerolic acid (CBGA) and other rare cannabinoids in Helichrysum umbraculigerum, a perennial shrub informally known as the woolly umbrella.1
A South African Botanical
Ferdinand Bohlmann and Evelyn Hoffman first discussed the chemical irregularity of Helichrysum. In a 1979 paper published in Phytochemistry2, they analyzed the South African species H. umbraculigerum, native to the eastern part of the country, where it was used in traditional medicine and fumigation rituals.
Bohlmann and Hoffman asserted that the plant’s tops — both leaves and flowers — produce cannabis-specific compounds. But a follow-up study conducted by Italian researchers in 2017 failed to find CBG or its acidic precursor in H. umbraculigerum flowers. They did, however, identify an analog of CBG known as Heli-CBG (also present in some fiber hemp varietals), which binds to the CB2 cannabinoid receptor.3,4
In a May 2023 article in Nature Plants, Weissman Institute scientists confirmed that woolly umbrella produces CBGA in trichomes on its leaves, but hardly any CBGA was present on its flowers. That’s different from cannabis, where CBGA and other cannabinoids are concentrated in trichomes on flower tops.1
Trichomes found on cannabis inflorescence (flowers) have a special cellular build, according to a 2022 study by University of British Columbia researchers in Current Biology. The gland’s bulbous head holds large porous cells that let acidic cannabinoids (CBGA, CBDA, THCA, etc.) move through the trichome.5 The Weizmann Institute team reported that H. umbraculigerum produces a similar cannabinoid transport network on its leaves.1
Sourcing Rare Cannabinoids in Non-Cannabis Shrubs
How did the Israeli scientists figure this out? They fed woolly umbrella precursor compounds responsible for making cannabinoids in cannabis. When given two precursors (hexanoic acid and phenylalanine), the shrub produced more cannabinoids compared to plants fed regular nutrients. This means that the same biosynthetic pathway exists in both cannabis flowers and woolly umbrella leaves.
The woolly umbrella shrub naturally produces on its leaves over 4% cannabigerolic acid alongside other rare cannabinoids. The shrub also contains water-soluble cannabinoids, which are not found in cannabis.
The woolly umbrella shrub produces CBGA in trichomes on its leaves, but not on its flowers.
Essentially, two different plant species have developed the same machinery to produce CBGA. Yet, woolly umbrella is evolutionarily distinct from cannabis. And unlike the shrub, cannabis makes two unique enzymes that flip CBGA into either THCA and/or CBDA.
Exploring a New Phytocannabinoid Toolkit
Thus, there are two toolboxes for cannabinoid phyto-synthesis in the phylogenetic tree. Terpenes and a few flavonoids accompany lipophilic cannabis flowers, whereas a complex array of flavones and water-soluble cannabinoids develop in H. umbraculigerum. By understanding their similarities and differences, we can better assess the therapeutic potential of each plant.
Cannabinoid compounds found in woolly umbrella dissolve more easily in water and can target specific areas of the body, such as the deeper bowel. But greater bioavailability, an argument for water-soluble cannabinoids, is not necessarily equivalent to greater potency. That which is absorbed quickly and easily also leaves the body and loses efficacy faster. And cannabinoid receptors have more affinity for fat-loving compounds compared to water-soluble agonists.6,7
Berman, P., de Haro, L.A., Jozwiak, A. et al. Parallel evolution of cannabinoid biosynthesis. Nat. Plants (2023).
Cannabigerol-ähnliche verbindungen aus Helichrysum umbraculigerum. Phytochemistry. 1979;18(8):1371-1374.
Pollastro, F., De Petrocellis, L., Schiano-Moriello, A., Chianese, G., Heyman, H., Appendino, G., & Taglialatela-Scafati, O. (2017). Amorfrutin-type phytocannabinoids from Helichrysum umbraculigerum. Fitoterapia, 123, 13–17.
Pollastro F, Taglialatela-Scafati O, Allarà M, Muñoz E, Di Marzo V, De Petrocellis L, Appendino G. Bioactive prenylogous cannabinoid from fiber hemp (Cannabis sativa). J Nat Prod. 2011 Sep 23;74(9):2019-22. doi: 10.1021/np200500p. Epub 2011 Sep 8. PMID: 21902175.
Livingston, S. J., Rensing, K. H., Page, J. E., & Samuels, A. L. (2022). A polarized supercell produces specialized metabolites in cannabis trichomes. Current biology : CB, 32(18), 4040–4047.e4. https://doi.org/10.1016/j.cub.2022.07.014
Li, X., Chang, H., Bouma, J. et al. Structural basis of selective cannabinoid CB2 receptor activation. Nat Commun 14, 1447 (2023).
Stadel, R., Ahn, K. H., & Kendall, D. A. (2011). The cannabinoid type-1 receptor carboxyl-terminus, more than just a tail. Journal of neurochemistry, 117(1), 1–18. https://doi.org/10.1111/j.1471-4159.2011.07186.x
Recently I was chatting with a friend who is casually interested in psychedelic science. He told me he hadn’t read as much coverage of psychedelics in popular magazines and other mainstream outlets lately, and asked whether research has slowed. My response? Not at all.
According to Pubmed, the online repository of the National Library of Medicine, last year saw far more papers published on psychedelics than ever before — about 33% more than in 2021, which itself was a 19% increase over 2020. And this year is well on pace to surpass 2022.
Every day another email arrives in my inbox with word about the latest papers, many of which address the promise of psychedelic-assisted therapy for depression, addiction, PTSD, and other mental health disorders.
But dig deep into the scientific literature and you’ll find plenty of outliers and oddities that have nothing to do with therapy per se, covering fascinating subjects like psychedelics for headaches or color-blindness; “entity” encounters; and the still-mysterious question of what, exactly, these compounds do to the brain.
Mood-Elevating Microdosing
Whether microdosing psychedelics can help people in meaningful ways independent of the placebo effect continues to be a subject of debate. A March 2023 paper in the journal Biological Psychiatry1 adds to the discourse by reporting that in a placebo-controlled study of 40 healthy male volunteers, microdosing LSD improved self-reported ratings of creativity, connectedness, energy, happiness, irritability, and wellness on dose days relative to non-dose days. However, microdosing was not sufficient to promote enduring changes to overall mood or cognition. Nor was it entirely harmless. Seven of the 40 participants reported treatment-related anxiety, and four dropped out as a result.
Psychedelics for Vegetative Patients
On the other end of the psychedelic spectrum are high doses that completely alter one’s perception of self and reality. If the psychedelic state represents a truly different, “higher” level of consciousness — as implied by the entropic brain theory first posited by Robin Carhart-Harris, David Nutt, and others in an influential 2014 paper2 — could psychedelics then be used to treat disorders of consciousness? More specifically, could they be administered as medicine to a minimally conscious or vegetative patient? And if so, what ethical challenges would be involved in such a treatment? These are some of the thought-provoking questions raised in an April 2023 article in Neuroscience of Consciousness.3
Methods of Action
Two other recent papers further investigate the neurobiology (the biological mechanisms through which nervous systems mediate behavior) and pharmacokinetics (the movement of drugs within the body) of various psychedelics.
On the former front, an article in the journal NeuroImage4 explores how three very different compounds eliciting psychedelic and psychedelic-like effects — nitrous oxide, ketamine, and LSD — induce common brain network changes. Although they act on different receptors (nitrous oxide and ketamine on the NMDA glutamate receptor; LSD on the 5-HT2A serotonin receptor), all three compounds produce consistent changes in specific brain regions involved in sensory integration and consciousness. They also similarly reduce within-network connectivity and increase between-network connectivity in the brain, the authors report.
DMT user survey: “Profound and highly intense experiences occurred.”
Another new paper, published in the European Journal of Drug Metabolism and Pharmacokinetics,5 refines our understanding of the body’s metabolism of N,N-dimethyltryptamine (DMT), a powerful psychedelic being explored as a potential treatment for depression. When DMT is taken alone, its effects are extremely short-lived, typically lasting no longer than about 15 minutes. When ingested as part of the psychedelic brew ayahuasca, which also includes compounds that impede the breakdown of DMT, its effects persist for many hours.
The new study relies on a series of experiments in healthy adults receiving intravenous DMT. According to the authors it is the first to determine, in detail, the full pharmacokinetic profile of DMT following a slow IV infusion in humans. “These findings provide evidence which supports the development of novel DMT infusion regimens for the treatment of major depressive disorder,” they conclude.
Real-World Trip Reports
Two additional studies published in March 2023 survey psychedelic drug users about their experiences with DMT, LSD, and psilocybin.
In Frontiers in Psychology6 comes a thematic and content analysis of the DMT experience developed from in-depth, semi-structured interviews with 36 “screened, healthy, and experienced” DMT users immediately following the trip. The study authors’ insights into how the compound alters “one’s personal and self-referential experiences of the body, senses, psychology, and emotions” are too complex to summarize here. Put it this way: “invariably, profound and highly intense experiences occurred.” The paper also covers convergences with alien-abduction, shamanic, and near-death experiences.
Finally, in the Journal of Psychopharmacology,7 we find survey results from thousands of users of LSD (n=1,996) and psilocybin mushrooms (n=1,368) compiled through the UK-based Global Drug Survey between November 2019 and February 2020. Positive changes were reported across all 17 outcomes evaluated (especially relative to insight and mood), the authors report. Variables most strongly associated with positive outcomes include psilocybin use (versus LSD), seeking advice before use, and seeking to treat post-traumatic stress disorder.
Negative effects were reported by nearly a quarter of respondents. They were most closely associated with LSD use (versus psilocybin) and younger age. Meanwhile, more intense psychedelic experiences were associated with both more positive and more negative outcomes, suggesting that higher doses can be riskier as well as more rewarding.
Murphy, Robin J et al. “Acute mood-elevating properties of microdosed LSD in healthy volunteers: a home-administered randomised controlled trial.” Biological psychiatry, S0006-3223(23)01164-2. 28 Mar. 2023, doi:10.1016/j.biopsych.2023.03.013
Carhart-Harris, Robin L et al. “The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs.” Frontiers in human neuroscience vol. 8 20. 3 Feb. 2014, doi:10.3389/fnhum.2014.00020
Rankaduwa, Sidath, and Adrian M Owen. “Psychedelics, entropic brain theory, and the taxonomy of conscious states: a summary of debates and perspectives.” Neuroscience of consciousness vol. 2023,1 niad001. 4 Apr. 2023, doi:10.1093/nc/niad001
Dai, Rui et al. “Classical and non-classical psychedelic drugs induce common network changes in human cortex.” NeuroImage vol. 273 (2023): 120097. doi:10.1016/j.neuroimage.2023.120097
Good, Meghan et al. “Pharmacokinetics of N,N-dimethyltryptamine in Humans.” European journal of drug metabolism and pharmacokinetics, 1–17. 22 Apr. 2023, doi:10.1007/s13318-023-00822-y
Michael, Pascal et al. “An encounter with the self: A thematic and content analysis of the DMT experience from a naturalistic field study.” Frontiers in psychology vol. 14 1083356. 27 Mar. 2023, doi:10.3389/fpsyg.2023.1083356
Kopra, Emma I et al. “Investigation of self-treatment with lysergic acid diethylamide and psilocybin mushrooms: Findings from the Global Drug Survey 2020.” Journal of psychopharmacology (Oxford, England), 2698811231158245. 6 Mar. 2023, doi:10.1177/02698811231158245
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.
In 2013, Noriko Shinjyo, Ph.D., a Research Associate at Chiba University in Japan, coauthored a study with Italian scientist Vincenzo Di Marzo on cannabichromene (CBC), a phytocannabinoid that exerts profound effects on the nervous system.1
Published in Neurochemistry International, their paper probed how CBC influences the fate of adult neural stem progenitor cells, which are described as “an essential component of brain function in health as well as in pathology.” As stem cells mature, they change and differentiate into new neurons and other cells. CBC was shown to have a positive effect on neural stem progenitor cells during their maturation phase, according to in vitro research.
Recently a different group of scientists has followed up on this decade-old discovery by delineating seven mechanisms through which CBC is able to protect and regenerate the nervous system. They reported their findings in Life, a Swiss scientific journal, noting that CBC, a “neurogenesis enhancer,” enables stem cells “to sustain their viability and differentiation.”2
What Are Neural Stem Cells?
Scientists have identified specific areas of the brain — the hippocampus and the lateral ventricles — where neural stem cells are created. These cells undergo a maturation process, known as differentiation, which is an important stage for young cells located in the spinal cord, brainstem, and brain regions programmed for muscle control. Young stem cells evolve into new neurons, but they can also form cells that comprise the protective sheath surrounding nerves.
Some neural stem cells differentiate into astroglial cells, also known as astrocytes. These abundant star-shaped cells populate the grey and white matter of the brain, where they regulate cerebral blood flow and the transmission of electrical impulses. They also play a crucial role in maintaining the blood-brain barrier and repairing the brain and spinal cord following an infection or a traumatic injury.
CBC is a “neurogenesis enhancer” that enables stem cells “to sustain their viability and differentiation.”
But a subpopulation of these mature cells remains dormant. That’s fortunate, given that active astrocytes can stunt the brain’s natural ability to regenerate after an injury. This means that a regulated maturation of neural stem cells, located in the brain and spinal cord, helps to protect and regenerate the nervous system. And this process is augmented by CBC, a cannabis compound, which regulates the production of new neurons, while also reducing the formation of active mature cells that may impede regeneration after a brain injury.
Can CBC Regenerate Embryonic Cells?
In 2023, a team of six Italian scientists published new details that explain how CBC protects and regenerates damaged neurons and nervous system components. They used a special type of spinal cord cell derived from an embryonic mouse, combined with neuroblastoma cells, to make their discovery. The team assessed changes in the genetic landscape of the cells after exposing them to CBC and a control media.
By further refining their analysis, the team elucidated newly discovered mechanisms behind cannabichromene. The plant cannabinoid helps to facilitate proper dopamine neuron and glutamate receptor maturation. And while various cannabinoids regulate the formation of the nerve’s protective sheath, their neuronal regeneration depends on other functions of CBC.
A Balancing Act with Choline
It seems that one newly found mechanism of CBC might work synergistically with tetrahydrocannabinol (THC), while also counteracting the effects of alpha-pinene, a terpene found in various cannabis chemovars and other botanicals.3
Alpha-pinene appears to act directly against CBC at a specific neurotransmitter that sends signals from muscle to neuron. That transmitter is in the choline family, which is protected by pinene but is broken down more rapidly under CBC exposure. Choline is important for cognition, brain development, neural stem cell maturation, muscle movement, and other basic functions.
THC downregulates the choline transmitter, while CBC boosts a gene that codes for a special choline-destroying enzyme; thus, both CBC and THC are implicated in the reduction of choline, and this can protect the nervous system and regenerate neurons. Alpha-pinene, on the other hand, keeps cognition taut by protecting choline. It’s a balancing act. The use of CBC, the scientists conclude, “could represent an important addition to the regeneration of the nervous system, but further experiments need to clarify and optimize how CBC could be effectively used for this purpose.”
Shinjyo, N., & Di Marzo, V. (2013). The effect of cannabichromene on adult neural stem/progenitor cells. Neurochemistry international, 63(5), 432–437. https://doi.org/10.1016/j.neuint.2013.08.002
Valeri A, Chiricosta L, D’Angiolini S, Pollastro F, Salamone S, Mazzon E. Cannabichromene Induces Neuronal Differentiation in NSC-34 Cells: Insights from Transcriptomic Analysis. Life (Basel). 2023 Mar 9;13(3):742. doi: 10.3390/life13030742. PMID: 36983897; PMCID: PMC10051538.
Russo, E. B., & Marcu, J. (2017). Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads. Advances in pharmacology (San Diego, Calif.), 80, 67–134. https://doi.org/10.1016/bs.apha.2017.03.004
If you’ve been to our website before, you’ll see it’s much easier to navigate now, thanks to the talented folks at Blue Dream, Ganjapreneur’s in-house creative agency.
You’ll also see that we have significantly increased our medical conditions-related content.
“The new Project CBD website is designed to make their educational content more accessible and discoverable,” explained Noel Abbott, CEO of Ganjapreneur and strategic advisor for Blue Dream. “It also includes an updated marketplace for ethical CBD brands to showcase their products.”
Migrating from another content management system and rebuilding our entire website was a huge job, encompassing our Japanese and Spanish language platforms, as well as more than 750 original articles in English.
The Project CBD team knows a lot about the cannabis plant but very little about website design and search engine optimization. The Blue Dream team has been a fantastic partner with much-needed expertise in those areas.
We look forward to an ongoing partnership with Blue Dream, as we expand our reporting on cannabis science, plant medicine, psychedelics, regenerative farming, and the social dimensions of health and drug policy.
If you’ve been to our website before, you’ll see it’s much easier to navigate now, thanks to the talented folks at Blue Dream, Ganjapreneur’s in-house creative agency.
You’ll also see that we have significantly increased our medical conditions-related content.
“The new Project CBD website is designed to make their educational content more accessible and discoverable,” explained Noel Abbott, CEO of Ganjapreneur and strategic advisor for Blue Dream. “It also includes an updated marketplace for ethical CBD brands to showcase their products.”
Migrating from another content management system and rebuilding our entire website was a huge job, encompassing our Japanese and Spanish language platforms, as well as more than 750 original articles in English.
The Project CBD team knows a lot about the cannabis plant but very little about website design and search engine optimization. The Blue Dream team has been a fantastic partner with much-needed expertise in those areas.
We look forward to an ongoing partnership with Blue Dream, as we expand our reporting on cannabis science, plant medicine, psychedelics, regenerative farming, and the social dimensions of health and drug policy.
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
For all modern medicine can do, many mysteries remain unsolved. What is long COVID? Is there really such thing as a “cure” for cancer? And how to explain the surprisingly high prevalence of fibromyalgia, a debilitating, lifelong disorder of the central nervous system without a known cause that affects between 2 and 4 percent of adults worldwide?
In the absence of an answer — or a cure — treatment is the name of the game for fibromyalgia. No single drug yet exists to address all of the disease’s effects on the body, which can include widespread aches and pains, sleeplessness, fatigue, anxiety, and depression. Instead, patients turn to a mix of whatever individual medications, therapies, and lifestyle changes (especially exercise) help ease symptoms and improve quality of life.
On the drug front, anti-depressants, analgesics, and muscle relaxants might be prescribed. But there’s another option that can address mood, pain, and more at once, all with fewer side effects: cannabis.
It’s not a new idea. Researchers have been investigating the use of cannabis to treat fibromyalgia’s constellation of symptoms for decades, with early clinical trials in the 2000s1-4 suggesting a possible benefit of both pure THC and flower in managing the disease. Nor is it necessarily surprising, given the ability of cannabis to target the ubiquitous, homeostasis-seeking endocannabinoid system.
Recently published papers — a series of reviews, two human studies, and an animal study — only bolster the case that cannabis can help those suffering from this confounding condition. Still more may be forthcoming, including through a newly announced randomized controlled trial in the Netherlands that will compare cannabis, oxycodone, and a combination of the two for pain relief in 60 fibromyalgia patients.5
Solid Evidence Base
Over the last few months a number of reviews have helped refine our understanding of the relationship between cannabis, the endocannabinoid system (ECS), and fibromyalgia symptoms. In November 2022, a paper in the journal Pain Reports6 provided the first systematic review and meta-analysis of previous studies measuring levels of circulating endocannabinoids and other fatty acid derivatives in patients with both fibromyalgia and chronic widespread pain.
Across the eight studies they analyzed, the Australia-based authors identified increased levels of oleoylethanolamide and stearoylethanolamide (endocannabinoid-like molecules called N-Acylethanolamines that don’t bind with the cannabinoid receptors) in patients with these conditions compared to controls. There were no differences observed in levels of the endocannabinoids anandamide and 2-AG.
“Available data strongly support the use of cannabinoids in treating fibromyalgia pain” due to “overwhelmingly positive treatment results.”
Still, the authors caution that “most studies did not account for variables that may influence ECS function, including cannabis use, concomitant medication, comorbidities, physical activity, stress levels, circadian rhythm, sleep quality, and dietary factors.” They call for additional study in this area and, more broadly, seek to “highlight the importance of investigating endocannabinoid activity in chronic widespread pain and fibromyalgia because it will underpin future translational research in the area.”
Other recent papers summarize the state of the science:
A review of clinical and preclinical research into cannabinoids, the ECS, and fibromyalgia in Pharmacology & Therapeutics7 (December 2022) agreed that “there is evidence for alterations in the endocannabinoid system in patients with fibromyalgia.”
A systematic review and meta-analysis of eight studies investigating the benefits of cannabinoids for chronic pain in Pain and Therapy8 (December 2022) reported that “cannabinoids might improve pain and quality of life in patients with fibromyalgia.”
And a narrative review also in Pain and Therapy9 (January 2023) on the efficacy, risks, and benefits of cannabinoids in the treatment of various pain subtypes concluded that “available data strongly support the use of cannabinoids in treating fibromyalgia pain” due to “overwhelmingly positive treatment results.”
Mice Respond to Cannabis Oil
Unlike some other areas of cannabinoid science, fibromyalgia research is not dominated by preclinical laboratory studies. But an October 2022 paper in Biomedicine and Pharmacotherapy10 offers an interesting parallel to previous human studies through the use of a well-established mouse model of fibromyalgia induced by reserpine, a drug that acts on the central nervous system (and is sometimes used to treat high blood pressure in humans).
The Italy- and Brazil-based authors sought to evaluate the effect of a “broad-spectrum” 11:1 CBD:THC cannabis oil in mice with reserpine-induced fibromylagia. They report that oral feeding of a single dose of cannabis oil was enough to mitigate some hallmarks of the condition in mice. Better yet, repeated administration over the course of two weeks reversed reserpine-induced mechanical and thermal sensitivity, and also reduced depressive-like behavior.
While the implications of these findings for human physiology and disease are perhaps unclear — given that we still don’t fully understand the etiology of fibromyalgia — they appear to lend yet more credibility to cannabis.
Cannabis Helps “Treatment-Resistant” Patients
Two new prospective cohort studies build upon this work with additional real-world data that may well wind up in future reviews. A November 2022 article in the journal Pain Practice11 covers a clinical trial in which 30 women suffering from fibromyalgia symptoms resistant to traditional pharmacological treatments were provided medicinal cannabis. That seemed to make all the difference. Comparing the women’s scores on the World Health Organization Quality of Life questionnaire before and after a month of cannabis use revealed “a marked improvement in general quality of life, general health, physical health, and psychological domain.”
And a similar, earlier study by researchers in Canada — with 323 fibromyalgia patients followed for 12 months — also found through quarterly physician assessments that initiating cannabis use was associated with improvements on a variety of fronts. As the authors report in the journal Arthritis Care & Research,12 observed reductions in pain intensity appeared to be partly explained by concurrent benefits to both sleep and mood.
“With suboptimal response to current medications, many patients with fibromyalgia seek … cannabis,” the authors conclude. “Medical cannabis may present a useful treatment strategy for patients with fibromyalgia in light of an effect on the triad of symptoms of pain, negative affect, and sleep disturbances.”
Schley, Marcus et al. “Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief.” Current medical research and opinion vol. 22,7 (2006): 1269-76. doi:10.1185/030079906×112651
Skrabek, Ryan Quinlan et al. “Nabilone for the treatment of pain in fibromyalgia.” The journal of pain vol. 9,2 (2008): 164-73. doi:10.1016/j.jpain.2007.09.002
Ware, Mark A et al. “The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial.” Anesthesia and analgesia vol. 110,2 (2010): 604-10. doi:10.1213/ANE.0b013e3181c76f70
Fiz, Jimena et al. “Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life.” PloS one vol. 6,4 e18440. 21 Apr. 2011, doi:10.1371/journal.pone.0018440
van Dam, Cornelis Jan et al. “Cannabis-opioid interaction in the treatment of fibromyalgia pain: an open-label, proof of concept study with randomization between treatment groups: cannabis, oxycodone or cannabis/oxycodone combination-the SPIRAL study.” Trials vol. 24,1 64. 27 Jan. 2023, doi:10.1186/s13063-023-07078-6
Kurlyandchik, Inna et al. “Plasma and interstitial levels of endocannabinoids and N-acylethanolamines in patients with chronic widespread pain and fibromyalgia: a systematic review and meta-analysis.” Pain reports vol. 7,6 e1045. 7 Nov. 2022, doi:10.1097/PR9.0000000000001045
Bourke, Stephanie L et al. “Cannabinoids and the endocannabinoid system in fibromyalgia: A review of preclinical and clinical research.” Pharmacology & therapeutics vol. 240 (2022): 108216. doi:10.1016/j.pharmthera.2022.108216
Giossi, Riccardo et al. “Systematic Review and Meta-analysis Seem to Indicate that Cannabinoids for Chronic Primary Pain Treatment Have Limited Benefit.” Pain and therapy vol. 11,4 (2022): 1341-1358. doi:10.1007/s40122-022-00434-5
Ang, Samuel P et al. “Cannabinoids as a Potential Alternative to Opioids in the Management of Various Pain Subtypes: Benefits, Limitations, and Risks.” Pain and therapy, 10.1007/s40122-022-00465-y. 13 Jan. 2023, doi:10.1007/s40122-022-00465-y
Ferrarini, Eduarda Gomes et al. “Broad-spectrum cannabis oil ameliorates reserpine-induced fibromyalgia model in mice.” Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie vol. 154 (2022): 113552. doi:10.1016/j.biopha.2022.113552
Hershkovich, Oded et al. “The role of cannabis in treatment-resistant fibromyalgia women.” Pain practice : the official journal of World Institute of Pain vol. 23,2 (2023): 180-184. doi:10.1111/papr.13179
Sotoodeh, Romina et al. “Predictors of Pain Reduction Among Fibromyalgia Patients Using Medical Cannabis: A Long-Term Prospective Cohort Study.” Arthritis care & research, 10.1002/acr.24985. 25 Jul. 2022, doi:10.1002/acr.24985
HerbalGram, the acclaimed quarterly journal of the American Botanical Council, recently published its 2021 “Herb Market Report,” which included data on sales of CBD as an herbal ingredient in mainstream and natural retail channels in the United States. The combined total from both channels — $58,293,034 — does not include CBD sales in licensed cannabis dispensaries or CBD products, such as vapes, tinctures, gummies, and other edibles sold online. (E-commerce sales of CBD in the U.S. in 2021 reached $2 billion, according to Statistica.)
The following excerpt analyzes CBD marketing trends reported by the American Botanical Council, a membership organization that educates consumers, health care professionals, journalists, and others about the safe and effective use of medicinal plants. Visit this link if you are interested in becoming an ABC member, which includes a subscription to HerbalGram.
A Top Selling Herbal Supplement
In 2021, for the fourth year in a row, CBD was the top-selling herbal supplement ingredient in natural retail stores. CBD first appeared on the natural channel’s top 40 list in 2017, ranking 12th, after sales growth of more than 300% from the previous year. Despite its top rank in 2021, sales of this ingredient have slowed in recent years.
In 2021, CBD sales in the natural channel totaled $38,931,696, a 24% decline. This was somewhat less than the nearly 37% decline seen in 2020. Sales appear to have peaked in 2019, when natural channel consumers spent more than $90.7 million on these products. Still, even after two years of declining sales, natural channel sales of CBD in 2021 were still significantly higher than when the ingredient first appeared on the top 40 list. Consumers spent roughly $31.3 million more on CBD products in 2021 compared to 2017 — a 413.4% increase in annual sales.
The marketing data firm SPINS tracks sales of two separate cannabis-derived ingredients: CBD and “hemp seeds and derivatives.” According to the FDA, “hemp” is defined as Cannabis sativa with a tetrahydrocannabinol (THC) concentration of 0.3% or less. (THC is the primary psychoactive compound in cannabis.) Cannabis sativa with more than 0.3% THC is considered “marijuana” or “cannabis.”1 SPINS’ CBD category typically includes sales of products that contain hemp-based CBD extracts, including CBD oils, gummies, and capsules.
Products in SPINS’ hemp seeds and derivatives category, such as hemp seed oil (also written as “hempseed” oil), often are marketed for their nutritional content. Hemp seed oil is rich in omega-3 and omega-6 fatty acids and has high levels of provitamin A, vitamin E, and various minerals (e.g., phosphorus, potassium, and calcium).2 The seeds of C. sativa do not naturally contain cannabinoids, but they can become contaminated with CBD from other plant parts during processing.3 Sales of hemp seeds and derivatives, which ranked 39th in the natural channel in 2021, also decreased from the previous year. Consumers spent $2,782,105 on these products in 2021 — a 14.1% decline from 2020.
CBD sales declined in 2021 for several possible reasons, including legal confusion, a lack of a clear path for FDA regulation, market saturation, and published reports of inaccurate label claims for some CBD products.
FDA Intransigence
On a federal level, CBD is not considered a legal dietary supplement ingredient. Under section 201(ff)(3)(B) of the Federal Food, Drug, and Cosmetic Act — in what some refer to as the “drug preclusion clause”4 — any substance that is an active ingredient in an approved drug product, or that is being publicly investigated as such, is excluded from the definition of a legal dietary supplement ingredient.5 In June 2018, the FDA approved Epidiolex® (GW Pharmaceuticals; Cambridge, UK), the first FDA-approved pharmaceutical drug to contain a “purified drug substance [CBD] derived from marijuana,” for the treatment of seizures associated with two rare epilepsy disorders.6 Since then, the FDA has maintained that CBD is an unapproved drug when sold as a dietary supplement (or in products for external use).7
The sheer number of product options may be overwhelming, and the diversity of advertised claims can muddle one’s understanding of CBD’s potential benefits.
In 2021, the FDA reaffirmed its position on CBD in supplements. Early that year, two natural products companies, Charlotte’s Web (Boulder, Colorado) and Irwin Naturals (Los Angeles, California), submitted new dietary ingredient (NDI) notifications to the FDA in an effort to get CBD approved as a supplement ingredient, in accordance with Section 8 of the Dietary Supplement Health and Education Act of 1994. Despite the companies’ submitting the required data demonstrating the “reasonable expectation of safety under the recommended conditions of use,” the FDA rejected the applications, citing the drug preclusion clause.8
The sheer number of product options may be overwhelming, and the diversity of advertised claims can muddle one’s understanding of CBD’s potential benefits.
The number and variety of CBD products available on the market also may have impacted sales in 2021. According to Adweek, approximately 2,000 CBD brands were sold in the United States in 2021 — down from about 3,000 the year before.[8] For some consumers, the sheer number of product options may be overwhelming, and the diversity of advertised claims can muddle one’s understanding of CBD’s potential benefits.
“An Alarming Lack of Understanding about CBD”
Based on the results of its July 2021 survey, the Consumer Brands Association reported an “alarming lack of understanding about CBD.” On a scale from one to 10, respondents rated their knowledge of CBD an average of 3.3. Nearly three-quarters of those surveyed also were confused about, or had no knowledge of, federal CBD regulations.9
In a February 2021 article in Nutritional Outlook, Jesse Karagianes, vice president of sales of the CBD natural products company CV Sciences (San Diego, California), was quoted as saying: “[T]he single largest factor which contributed to slow category sales was the deluge of inferior products hitting the market. From unfounded and unlawful health claims to inconsistency in CBD content, many CBD products do not deliver on what customers expect from them.”10
The results of several CBD product analyses published in recent years suggest that labels may not always accurately reflect the contents. In December 2021, Leafreport, an online CBD resource owned by Empire Media Network, published the results of analyses of 221 CBD products it sent to third-party laboratories for testing. The labs analyzed 35 oils, 40 topical products, 40 edibles, 22 beverages, 55 pet products, and 29 coffee or tea products. Leafreport found that only 40% of the products matched the levels of CBD stated on labels, with 28% of the products having CBD levels that failed to match label claims by more than 30%. On average, they found that, “the CBD content of the products was off from the label by nearly 25%.”11 A separate paper, published in February 2022, analyzed the CBD content of 11 commercially available CBD oils and found that only four (36.4%) matched the amount stated on the label.12
Health Benefits
Although CBD sales have slowed, research into the cannabinoid’s potential health benefits continues. In 2021, researchers published more than a dozen systematic reviews of CBD’s effects, including for mood disorders, anxiety disorders, dementia, multiple sclerosis, appetite, pain, and more.13 Although many review authors reported inconclusive findings due to low-quality studies, they noted that evidence from human clinical trials seems to support CBD’s positive effects on nociceptive pain (i.e., pain in response to stimuli), neuropathic pain, appetite, and neuropsychiatric symptoms in people with moderate to advanced dementia.14-16 A separate 2021 open-label, randomized controlled study of 3,000 people found that consumers taking one of 13 specified CBD products for four weeks had self-reported improvements in areas such as wellbeing (71%), anxiety (63%), and sleep quality (61%).17
Excerpted from HerbalGram, the quarterly publication of the American Botanical Council. May not be reprinted without permission from the source.
References
FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). US Food & Drug Administration website. Available at: www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. Accessed July 25, 2021.
Xu Y, Li J, Zhao J, et al. Hempseed as a nutritious and healthy human food or animal feed source: A review. International Journal of Food Science and Technology. 2021;56:530-543. Available at: https://drive.google.com/file/d/12bS4AXxqi0eJTP6d68MBsD6WiNy2-vhl/view. Accessed October 17, 2022.
Farinon B, Molinari R, Costantini L, Merendino N. The seed of industrial hemp (Cannabis sativa L.): Nutritional quality and potential functionality for human health and nutrition. Nutrients. 2020;12(7):1935. doi: 10.3390/nu12071935. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC7400098/. Accessed October 17, 2022.
Krawiec S. CBD proving grounds: 2022 ingredient trends for food, drinks, dietary supplements, and natural products. Nutritional Outlook. February 2, 2022. Available at: www.nutritionaloutlook.com/view/cbd-proving-grounds-2022-ingredient-trends-for-food-drinks-dietary-supplements-and-natural-products. Accessed October 17, 2022.
FDA regulation of dietary supplement and conventional food products containing cannabis and cannabis-derived compounds. US Food and Drug Administration website. Available at: www.fda.gov/media/131878/download. Accessed October 17, 2022.
FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy [press release]. Silver Spring, MD: US Food and Drug Administration; June 25, 2018. Available at: www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms. Accessed October 17, 2022.
FDA warns four companies for illegally selling CBD products intended for use in food-producing animals. US Food and Drug Administration website. May 26, 2022. Available at: www.fda.gov/animal-veterinary/cvm-updates/fda-warns-four-companies-illegally-selling-cbd-products-intended-use-food-producing-animals. Accessed October 17, 2022.
Stanley TL. The CBD industry just shed 1,000 brands. Here’s why analysts still see strong growth ahead. Adweek. July 23, 2021. Available at: www.adweek.com/brand-marketing/the-cbd-industry-just-shed-1000-brands-heres-why-analysts-still-see-strong-growth-ahead/. Accessed October 17, 2022.
Unregulated and exploding: How the CBD market is growing amid a labyrinth of state approaches and rampant consumer confusion. Consumer Brand Association website. July 2021. Available at: https://consumerbrandsassociation.org/regulation/cbd/unregulated-and-exploding-how-the-cbd-market-is-growing-amid-a-labyrinth-of-state-approaches-and-rampant-consumer-confusion/. Accessed October 17, 2022.
Grebow J. COVID-19 plus legal uncertainty slowed CBD sales in 2020. What’s CBD in for in 2021? 2021 Ingredient trends to watch for food, drinks, and dietary supplements. Nutritional Outlook. February 11, 2021. Available at: www.nutritionaloutlook.com/view/covid-19-plus-legal-uncertainty-slowed-cbd-sales-in-2020-what-s-cbd-in-for-in-2021-2021-ingredient-trends-to-watch-for-food-drinks-and-dietary-supplements. Accessed October 17, 2022.
Olenik G. CBD market report: Over half of CBD products are mislabeled. Leafreport website. October 16, 2022. Available at: www.leafreport.com/education/cbd-market-report-over-half-of-cbd-products-are-mislabeled-15084. Accessed October 17, 2022.
Miller OS, Elder EJ, Jones KJ, Gidal BE. Analysis of cannabidiol (CBD) and THC in nonprescription consumer products: Implications for patients and practitioners. Epilepsy Behav. 2022;127:108514. doi: 10.1016/j.yebeh.2021.108514. Available at: https://pubmed.ncbi.nlm.nih.gov/34998268/. Accessed October 17, 2022.
PubMed search: “CBD review.” National Library of Medicine website. Available at: https://pubmed.ncbi.nlm.nih.gov/?term=cbd%20review&filter=pubt.systematicreview&filter=hum_ani.humans&filter=years.2021-2021. Accessed October 17, 2022.
Spanagel R, Bilbao A. Approved cannabinoids for medical purposes: Comparative systematic review and meta-analysis for sleep and appetite. Neuropharmacology. 2021;196:108680. doi: 10.1016/j.neuropharm.2021.108680. Available at: https://pubmed.ncbi.nlm.nih.gov/34181977/. Accessed October 17, 2022.
Grossman S, Tan H, Gadiwalla Y. Cannabis and orofacial pain: A systematic review. Br J Oral Maxillofac Surg. 2022 Jun;60(5):e677-e690. doi: 10.1016/j.bjoms.2021.06.005. Available at: https://pubmed.ncbi.nlm.nih.gov/35305839/. Accessed October 17, 2022.
Stella F, Valiengo LC, de Paula VJR, Lima CAD, Forlenza OV. Medical cannabinoids for treatment of neuropsychiatric symptoms in dementia: A systematic review. Trends Psychiatry Psychother. 2021;43(4):243-255. doi: 10.47626/2237-6089-2021-0288. Available at: https://pubmed.ncbi.nlm.nih.gov/34374269/. Accessed October 17, 2022.
Masterson D. Radicle Science highlights findings from large CBD study. NutraIngredients-USA website. May 9, 2022. Available at: www.nutraingredients-usa.com/Article/2022/05/09/radicle-science-highlights-findings-from-large-cbd-study. Accessed October 17, 2022.
