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ICRS 2023: Report from Toronto

Toronto skyline

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

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

CBD & THC

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

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

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

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

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

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

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

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

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

Pain, Opioids & Addiction

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

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

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

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

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

On the Shoulders of Giants

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

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

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

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CBD Market Report

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

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.

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Mechoulam on the Future of Cannabinoid Research

I was fortunate to cross paths with Raphael Mechoulam, “the father of cannabis research,” at several science conferences over the years. The most memorable occasion was the 22nd annual meeting of the International Cannabinoid Research Society (ICRS) in Freiburg, Germany, in July 2012. Mechoulam delivered a plenary speech at the symposium, addressing the future of cannabinoid research and key areas of study that should be pursued.

It was exactly fifty years earlier, in 1962, when Mechoulam launched his scientific investigation into the chemistry of cannabis. In 1963, he and Yuval Shvo first reported the molecular structure of cannabidiol (CBD). And the following year Mechoulam coauthored a paper that elucidated the molecular structure of tetrahydrocannabinol (THC). Although he didn’t know it at the time, Mechoulam had lit a slow burning fuse that would detonate a revolution in medical science.

As a young scientist, Mechoulam set out to understand how cannabis works; he ended up unlocking a treasure trove of information about how we work. Known affectionately as “Raphi” to many of the scientists he mentored, Mechoulam tirelessly promoted cooperation between researchers around the world to advance the study of the body’s “endocannabinoid system,” which produces chemicals similar to THC, CBD, and other plant cannabinoids, and mediates their effects.

In 1992, Mechoulam’s research group at Hebrew University in Jerusalem discovered an endogenous THC-like compound that activates receptors in the mammalian brain. He named it “anandamide,” the bliss molecule. And in 1995, Mechoulam and his team identified a second endocannabinoid compound, 2-arachidonoyglycerol or 2-AG for short. Anandamide and 2-AG are part of an internal lipid neurotransmitter system that regulates a wide range of physiological processes, including appetite, mood, pain perception, and immune function.

“Planning Research for the Next Half Century”

“It’s time to plan ahead for the next half a century,” Mechoulam, age 81, told the Freiburg ICRS attendees, who had gathered to honor his 50 years as a pioneer cannabis scientist. Mechoulam cited three specific areas that should be research priorities: CBD, the CB2 cannabinoid receptor, and a cluster of endogenous fatty acid compounds in the brain that he referred to as FAAA’s.

Mechoulam set out to understand how cannabis works. He ended up unlocking a treasure trove of information about how we work.

Keep in mind that this was in 2012, when CBD was virtually unknown to the general public. But it was already a hot topic among ICRS scientists who were probing the compound’s anti-inflammatory, antioxidant, anticonvulsant, anti-tumoral, neuroprotective, and analgesic properties. The preclinical science was truly jaw-dropping, and Mechoulam envisioned a wide array of therapeutic applications for CBD and its derivatives. But clinical studies of plant cannabinoids were lagging because of strict drug laws in the United States and elsewhere.

THC directly activates both cannabinoid receptor subtypes — CB1 and CB2. However, when THC binds to CB2, it does not trigger the psychoactive high that cannabis is known for because CB2 receptors are not concentrated in the brain. THC binding to CB1, the abundant central nervous system receptor, causes the intoxicating effect. Consequently, researchers set their sights on healing without the high by experimenting with drugs that stimulate the CB2 receptor — while bypassing CB1 in the brain.

CB2 receptors are present throughout the immune system, the peripheral nervous system, metabolic tissue, skin cells, and in many internal organs. Aberrant CB2 signaling is implicated in a raft of autoimmune, neurodegenerative, metabolic, and psychiatric disorders. This makes modulating CB2 an attractive target for drug development and therapeutic intervention.

A Cluster of FAAA’s

Mechoulam was particularly excited about the third area of research — the FAAA’s — which comprise a cluster of fatty acid compounds in the brain. Little is known about “the chemistry of the human personality” or the innate biochemical variations that that may account for individual differences in temperament, he explained, adding: “Accumulation of such knowledge is essential for a future biochemical basis of psychology.”

If specific chemical differences “are the cause, or one of the causes, of the differences in personalities,” then it’s essential “to look for a large ‘catalog’ of compounds, which cause central nervous system effects,” Mechoulam asserted. “The variability of such a cluster of compounds – their levels, their ratios and presumably their effects, not only as individual compounds, but also as a group” (a type of entourage effect) could result in “an infinite number of individual differences.”

Little is known about the chemistry of the human personality or the innate biochemical variations that that may account for individual differences in temperament.

Mechoulam drew attention to the importance of several dozen endocannabinoid-like lipids and other FAAA’s, which include various fatty acid amides of amino acids (and their derivatives, such as ethanol amides) or fatty acid esters with glycerol and related compounds. A partial list of these compounds had been identified and analyzed by Heather Bradshaw’s group at the University of Indiana. Some of these compounds were “evaluated for their biological effects,” Mechoulam noted. “Amongst them are anandamide, 2-AG, NADA, palmitoyl ethanolamide (PEA), oleoyl ethanolamide (OEA), stearoyl ethanolamide, and a few others,” whose individual effects vary considerably, but “the joint effects of groups of these components . . . have not been evaluated.”

Mechoulam and his colleagues looked closely at “oleoyl serine,” which is anti-osteoporotic, but is also found in the brain. “Arachidonoyl serine,” another endogenous lipid compound of interest, “lowers damage caused by closed head injury.” And he observed that “oleoyl glycine” and PEA concentrations are enhanced after damage in a specific brain region. These studies gave rise to the concept of the “endocannabinoidome” — an expanded endocannabinoid system that encompasses a plethora of fatty acid neurotransmitters in addition to anandamide and 2-AG.

“It is tempting to assume,” Mechoulam concluded, “that the huge possible variability of the levels and ratios of substances in such a cluster of compounds may allow an infinite number of individual differences, the raw substance which of course is sculpted by experience. If this intellectual speculation is shown to have some factual basis it may lead to major advances in molecular psychology.”

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

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Mental Health & the CB2 Receptor

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

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

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

CB2 & Schizophrenia

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

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

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

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

CB2 & Depression

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

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

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

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

Targeting CB2 in CNS Disorders

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

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

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

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

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

Nate Seltenrich, an independent science journalist based in the San Francisco Bay Area, covers a wide range of subjects including environmental health, neuroscience, and pharmacology. Copyright, Project CBD. May not be reprinted without permission.

Footnotes

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

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