Month: April 2023

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CBD Enhances Glucose Metabolism via Nuclear Receptors

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

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

Get to Know the PPARs

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

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

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

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

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

CBD, Psychosis & Glucose Metabolism

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

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

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

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

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

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

Mechanisms of Action

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

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

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

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

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

Cannabidiol Goes Nuclear

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

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

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

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

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

Footnotes

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

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THC & CBD-Rich Cannabis for Fibromyalgia

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.”

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. 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
  2. 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
  3. 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
  4. 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
  5. 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
  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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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

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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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Celtic Hemp

Have you heard of Celtic Hemp? In a recently published paper in Cannabis and Cannabinoid Research, Dr. John M. McPartland and Saoirse E. O’Sullivan trace hemp’s prehistoric journey from Asia to Hibernia — now modern-day Ireland. Like much of Europe, cannabis arrived in Ireland when written records were scarce.

The authors rely on archeological, linguistic, and pollen analyses as they document the migration of cannabis across Europe. Ancient pollen, extracted from mud, contains signals from cannabis’s past. Seeds from crops and rare archeological artifacts provide additional clues attesting to hemp’s intimate relationship with humankind.

Thousands of years ago, the medicinal properties of cannabis were remarked in ancient texts. At this time, humans living closer to the plant’s area of origin on the Tibetan plateau relied on fibers from cannabis stalks for textiles. By 400 BCE, humans left evidence of cannabis where Celtic culture is thought to have originated.

The Birthplace of Celtic Culture

People of the Yamnaya culture, encompassing modern Ukraine, utilized cannabis crops earlier than the Celtic culture that emerged in Europe during the Iron Age (1200-550 BC). Cannabis fibers and water-logged seeds first appeared in Hallstatt, a region near modern Austria, which is considered the birthplace of the Celtic peoples.

But the words used for cannabis and hemp were all borrowed from another culture. The lack of an ancestorial word for hemp or cannabis in Proto-Celtic implies that the inhabitants of Halsttatt spoke a language unrelated to early precursors of the Celtic lexicon.

The Celtic people did not record their earliest history. Druids, religious figures in the Celtic political system, instead memorized large volumes of oral history.

The Roman Conquest

By the first century BC, when Romans had conquered much of Europe, Celtic peoples settled in parts of France, Spain, and Ireland. Peoples of Brittany in France spoke Old Breton, which included the word coarch to describe hemp fiber. Iunobrus, a Breton Monk, used the word canap to describe cannabis in 848 AD, borrowing the word from Roman Latin. (The Romans, in turn, had borrowed the Latin phrase from the Greek kannabis, which the Greeks got from the Scythians.) Words describing “hemp” or “cannabis” eventually became part of the Middle Irish tongue.

McPartland and O’Sullivan note that Roman-British missionaries brought cannabis to the Galleic Celts in Hibernia. The onset of hemp cultivation in Hibernia correlated chronologically (and proximally) with the founding of Romano-British monasteries.

The people of Hibernia wrote with the Celtic Tree Alphabet, known formally as Ogham. They carved symbols in a vertical line, indicating letters in a word. Around 400 Ogham examples remain throughout Ireland, which are mostly carved into stone monuments.

The full scholarly report on the origins of cannabis in Ireland by John M. McPartland and Saoirse E O’Sullivan can be accessed here.

Travis Cesarone is a freelance writer and communicator focusing on medical cannabis sciences. © Copyright, Project CBD. May not be reprinted without permission.

Reference

McPartland, J. M., & O’Sullivan, S. E. (2023). Origins of Cannabis sativa in Ireland and the Concept of Celtic Hemp: An Interdisciplinary Review. Cannabis and cannabinoid research, 0.1089/can.2022.0263.

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Ode to a Vanishing Handcraft

At first glance, Cannabis Textiles is a quiet, unassuming book, without slick, staged photos or superlative descriptions of indigenous cultures. Such simplicity reflects the book’s inner beauty, which documents the history of a disappearing handcraft, that of traditional hemp cultivation and fabric production.

hempcraft

Skoglund’s book focuses primarily on indigenous hemp cultures in Europe and Asia. Her passion for hemp was lit while pursuing her Master’s thesis studies at the Swedish School of Textiles, University of Borås and in Uppsala, Sweden in the 1970s, when she discovered a significant absence of recorded information on traditional hemp craft.

“It was almost taboo to talk about hemp, because it was intimately connected to drugs and was banned in Sweden [until 2003],” she told Project CBD.

Skoglund began to weave with hemp yarn herself, while scouring the historical record for mentions of the craft. She used DNA and microscopic testing methods to determine the fiber content of a number of antique textiles kept in museums and archives, and found many that were made completely or partially from hemp fibers.

A Bast Fiber Plant

Long before 1842, when William O’Shaughnessy brought psychoactive cannabis indica from India to the West, a type of cannabis commonly known as hemp was grown in kitchen gardens across Europe and East Asia, “near castles and monasteries, mansions and simple farms,” writes Skoglund. Hemp, a bast fiber plant, was cultivated for its seeds and medicinal properties, but mainly for its fiber. Fiber from other bast plants, such as flax and hops, was often blended with hemp fiber.

Skoglund details how hemp fabrics have been made as far back as neolithic China, and for centuries were used in Europe and Asia to make everyday clothing, as well as for ritual purposes such as religious ceremonies, weddings, funerals, etc. Hemp cottage industries were popular in medieval Europe, and were often overseen by professional craft guilds.

“Textile production is about botany,” says Skoglund, “and is based on interdisciplinary research between horticultural and textile history.” The history of hemp textile craft, she says, is one of many examples of how domestic work, especially that done by women, was considered trivial and was not well-documented. Priests or other prominent men, she writes, “recorded our history, but they had no insight into the household production of textiles at all. Instead, they focused on economics and the goods they wanted to produce.” Skoglund is dedicated to changing that oversight, at least as it concerns hemp fiber.

“A Hundred Operations”

In medieval Italy, hemp fabric was known as quello dello cento operioni, or “that of a hundred operations,” an apt name given the many steps it took to make it. Skoglund’s straightforward descriptions of growing, harvesting, drying, soaking, retting, pounding, scutching, hackling, spinning, weaving, bleaching, mangling, and dyeing have a strangely calming effect. Each step is visceral and earthy, part of a complex, intimate human relationship with plants rarely seen in the post-industrial 21st century.

Contrary to prevailing assumptions that hemp-fiber fabric is universally heavy and coarse, homespun hemp linen can be quite fine, with a high thread count and a soft hand. The key to quality is the knowledge and skill of the producer. Skoglund describes how in Europe, only young male hemp plants were chosen for producing high-quality fabric. They were grown in sunny, sheltered locations, often in kitchen gardens, under conditions that kept the plants thin and spindly, with flexible stalks that yielded the finest fibers. Taller, denser female hemp plants were grown for seeds, their coarser fiber made into rope, sacks, sailcloth, rugs, tarps, saddlebags, etc. The word canvas comes from the French canvasse, meaning “cannabis cloth.”

Skoglund explains how after harvest, hemp stalks are retted, typically by leaving them lying in the field or soaking for a couple of weeks in the clear water of a lake, pond, or stream, where naturally-occurring anaerobic bacteria loosens and separates the fibers from the woody core. The hemp fibers are then dried and bleached in the sun, broken by beating them with a mallet or scutching knife, hackled to comb and align them, and given a last brushing to remove any rogue stems or other debris before twisting them into roving to be spun by hand, often with a drop spindle. The finished hemp yarn is traditionally woven into fabric on treadle, frame or backstrap looms.

Cotton & Synthetic Fiber

Hemp grows in most climates but thrives in the fertile soil found in river valleys, especially near limestone outcroppings. This fast-growing botanical needs only moderate water and nitrogen, helps remediate contaminated soils, and absorbs CO2. Hemp fabric is resistant to stain and rot, naturally antibacterial, UV protective, and biodegradable.

Hemp is also stronger and more durable than cotton, now the most widely-produced non-food crop in the world. Cotton, historically a slave-labor crop, has had a devastating social and environmental impact, requiring vast amounts of water, chemical fertilizers, and pesticides. In contrast, hemp’s many sustainable, eco-friendly attributes make it a valuable ally in the climate crisis era.
Prior to the invention of the cotton gin in New England in 1793, American wives and mothers organized spinning bees with hempen thread to clothe the revolutionary army. Despite its impeccable patriotic pedigree, industrial hemp became collateral damage in the US government’s war on drugs. Since the passage of the 2018 Farm Bill, which re-legalized US hemp cultivation, there has been renewed interest in hemp textiles and other hemp fiber products. But compared to growing hemp for CBD extraction, hemp textiles have gotten short shrift in the US and Europe. And much of the hemp clothing that’s currently mass manufactured in Asia is artificially retted and drenched in noxious chemicals.
For thousands of years, humans covered their bodies with plant and animal fibers. Yet now, many of us walk around literally clothed in petrochemicals. According to a 2022 report by Changing Markets Foundation, 69% of the fiber in today’s fabrics (polyester, acrylic, nylon, spandex, etc.) are synthetically produced from fossil fuels.

Much of this fabric is made by exploited labor into “fast fashion” garments that shed synthetic microfibers, wreaking havoc as they sneak into our bloodstream and lodge in our bodies while making their way to the furthest reaches of the planet. Fiber-shedding from fossil fabrics is responsible for a significant percentage of the microplastics that have been polluting our environment, causing particle toxicity, oxidative stress, and inflammation.

Cannabis Textiles in Hemp Garden Cultures reads like a dreamy, slow-fashion antidote to the “fossil-fabric” pandemic.

A Living Tradition

With the advent of cheap industrial cotton and synthetic fibers, the craft of domestic hemp fabric nearly disappeared during the 20th century. Today, traditional hemp fabric is only produced by women in isolated pockets of Thailand, Vietnam, China, Turkey, and Romania — all places where Skoglund has traveled and researched.

Skoglund’s study of hemp fabric history continues. Currently, she is analyzing the hemp fibers of religious textiles found in an old Icelandic church and plans to use Strontium Isotope testing to determine their origin. But aside from the curious hobbyist trying her hand at making homegrown hemp clothing, why should we care about an ancient craft that requires so much labor?

Without banging us over the head with a drop spindle, Skoglund’s book gives us clues. By bringing to life the slow, tangible, mindful construction of garden hemp fabric, she suggests the intangible — the straw-into-gold enchantment of handcrafts and the value of everyday things measured by an algorithm that honors nature, creativity, and longevity. Skoglund’s book is a bittersweet elegy to traditional hemp cultures, yet it also challenges us to ask whether a world poisoned by plastic can make space once again for the manifold magic of this amazing plant.

Buy book

Melinda Misuraca is a Project CBD contributing writer with a past life as an old-school cannabis farmer specializing in CBD-rich cultivars. © Copyright, Project CBD. May not be reprinted without permission.

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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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Cannabinoids for Tinnitus?

Recently my wife returned from a night out with a ringing in one ear and significantly diminished hearing. It was a sure sign of injury caused by standing too close to a speaker. She was upset with herself for being so careless and concerned that the condition would persist. For the next couple days, she got extra sleep to aid recovery, and for good measure took an extra dose or two of CBD.

For many other people of all ages, tinnitus is indeed a chronic condition that has nothing to do with loud ‘80s cover bands in small clubs. Risk factors span a wide range of physical and psychological conditions including concussion, smoking, certain medications, ear infection, high blood pressure, anxiety, depression, and, most commonly, age-related hearing loss.

And it’s not just ringing. Technically, tinnitus (pronounced tih-NITE-us or TIN-ih-tus) is the perception of sound originating from within the nervous system that’s unrelated to external stimulation. Tinnitus can also be experienced as buzzing, whirring, humming, whooshing, clicking, and hissing. Whatever the precise nature of the phantom sound, it often comes with a constellation of symptoms related to the disruption such a condition can bring: sleep problems, difficulty concentrating, low mood, etc. Estimates vary, but tens of millions of people in the United States alone likely suffer from chronic tinnitus.

My wife’s ringing tinnitus did fade, and her hearing gradually improved over the course of a few days. The CBD she took may or may not have helped, but according to a recent survey of tinnitus patients, she wasn’t alone in trying — or at least in being interested in cannabis as a potential remedy.

Auditory & Other Symptoms

The survey, whose findings were published in February 2023 in the Journal of Otolaryngology – Head & Neck Surgery1evaluated cannabis perceptions and consumption among 45 adult tinnitus patients randomly selected and recruited from an outpatient ear, nose, and throat clinic in Ontario, Canada.

Among the 45 respondents, median age 55, only 10 said they were current cannabis users (19 had never used, and 16 had used in the past). But of the 10 current users, eight reported that cannabis did help with some of their tinnitus-related symptoms — if not necessarily the sound itself. Seven of the eight found it helpful for sleep disturbances, seven for pain, six for emotional complaints, four for functional difficulties, and three for dizziness symptoms. Only three of the ten found cannabis helpful for the actual auditory symptoms characterizing tinnitus.

But many more patients were willing to try, perhaps as an indication of the intractability of chronic tinnitus. All but two of the 45 respondents said they’d consider cannabis as a treatment, with 29 seeking help for sleep disturbances, 27 for emotional complaints, 25 for functional disturbances, and nine for pain. Of note, however, 41 of the 45 said they’d turn to cannabis for auditory symptoms — the primary concern for most tinnitus patients yet the least improved by cannabis according to the survey’s 10 current users.

Interestingly, and perhaps unfortunately for patients, previous reviews in 2020 and 20192 also concluded there was insufficient evidence that cannabis can diminish chronic tinnitus.

Mixed Findings

A December 2020 review in the journal Laryngoscope Investigative Otolaryngology3 by researchers at Yale University and nearby University of Connecticut tackles the question head-on. Its title: “Does cannabis alleviate tinnitus? A review of the current literature.”

And its conclusion? “While animal studies have revealed that cannabinoid receptors likely have a role in modulating auditory signaling, there is no compelling data either from animal or human studies for the use of cannabinoids to alleviate tinnitus.”

There could be a role for cannabinoids in the management of tinnitus through their anticonvulsant effects.

In fact, there’s some evidence from animal research that cannabinoid administration may actually induce or exacerbate tinnitus. That’s what appeared to happen in rats injected with the synthetic CB1 agonists WIN55,212‐2 and CP55,940 in a 2010 study4 and THC and CBD in a 1:1 ratio in a 2011 follow-up study.5

As far as human studies, the review authors also summarize two previous surveys in 2010 and 2019, a 1975 clinical trial and a 2006 case study — whose cumulative findings are, at best, entirely unclear.

Despite all this, there is a potential biological rationale for the treatment of tinnitus with cannabinoids, the authors explain. Other animal studies have suggested that cannabinoid receptor expression in the cochlear nucleus may vary with tinnitus symptomatology. And since the most widely accepted hypothesis for the pathophysiology of tinnitus relates to something called “neuronal hyperexcitability” — a mechanism that has also been observed in epilepsy, they note — “there is a potential role of cannabinoids in the management of tinnitus through its anticonvulsant effects.”

Cannabinoid Receptors Influence Hearing

Finally, a November 2020 review in Frontiers in Neurology6 adds more complexity and subtlety to the issue. The article wisely notes that animal studies showing cannabinoids to potentially worsen tinnitus have focused on CB1 agonists. This excludes compounds that target, among others:

  • CB2 receptors, which influence immune function and are “increasingly recognized as essential in understanding nervous system pathological responses”
  • and “non-classical” cannabinoid targets like TRP (“trip”) channels, which mediate processes including vision, taste, olfaction, touch and hearing.

While the collective evidence to date is mixed and inconclusive, it’s also incomplete. The potential is huge for new animal studies using cannabinoids other than CB1 agonists, and for more robust human studies (indeed any clinical trial at all) to contribute fresh insights to this burning, buzzing question.

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. Mavedatnia, Dorsa et al. “Cannabis use amongst tinnitus patients: consumption patterns and attitudes.” Journal of otolaryngology – head & neck surgery vol. 52,1 19. 24 Feb. 2023, doi:10.1186/s40463-022-00603-8
  2. Zheng, Yiwen, and Paul F Smith. “Cannabinoid drugs: will they relieve or exacerbate tinnitus?.” Current opinion in neurology vol. 32,1 (2019): 131-136. doi:10.1097/WCO.0000000000000631
  3. Narwani, Vishal et al. “Does cannabis alleviate tinnitus? A review of the current literature.” Laryngoscope investigative otolaryngology vol. 5,6 1147-1155. 30 Oct. 2020, doi:10.1002/lio2.479
  4. Zheng, Yiwen et al. “The effects of the synthetic cannabinoid receptor agonists, WIN55,212-2 and CP55,940, on salicylate-induced tinnitus in rats.” Hearing research vol. 268,1-2 (2010): 145-50. doi:10.1016/j.heares.2010.05.015
  5. Zheng, Y et al. “Acoustic trauma that can cause tinnitus impairs impulsive control but not performance accuracy in the 5-choice serial reaction time task in rats.” Neuroscience vol. 180 (2011): 75-84. doi:10.1016/j.neuroscience.2011.02.040
  6. Perin, Paola et al. “Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective.” Frontiers in neurology vol. 11 505995. 23 Nov. 2020, doi:10.3389/fneur.2020.505995

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Cancer & the CB2 Receptor

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

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

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

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

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

Prostate Cancer & a New CB2 Ligand

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

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

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

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

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

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

Colon Cancer: Case Closed?

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

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

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

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

Lung Cancer: A Different Answer

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

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

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

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

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

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

Footnotes

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

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Mental Health & the CB2 Receptor

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

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

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

CB2 & Schizophrenia

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

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

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

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

CB2 & Depression

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

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

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

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

Targeting CB2 in CNS Disorders

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

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

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

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

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

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

Footnotes

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

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Downstream Effects: April 2023

This is first of an occasional column that updates developments pertaining to articles previously published by Project CBD. We start with some positive news from the Golden State. Then a follow-up on our investigative report about Curaleaf, the world’s biggest cannabis company. And freedom of expression takes a hit when it comes to cannabis advocacy in the Czech Republic.

Plastic Pollution in California

Inspired by Project CBD’s exposé, “Bag the Tags” (June 29, 2022), California state senator Ben Allen has introduced a bill to end the onerous requirement to apply a plastic tag to every cannabis plant grown by licensed cultivators, as is currently mandated under the state’s track-and-trace program. Sponsored by CannaCraft, Inc., a major cannabis producer (and longtime friend of Project CBD), and supported by several organizations including the National Product Stewardship Council and the California Cannabis Industry Association, Senate Bill 622 seeks to mitigate unnecessary labor and operational costs for cannabis cultivators, while eliminating the creation of millions of pounds of plastic waste that can’t be recycled.

As Project CBD reported last year: “With over 2,000 acres licensed to grow cannabis, California cannabis farmers put between 30 and 55 million plants in the ground every year. The tags are the definition of ‘single use’ – they can only be used on one plant and never re-used during subsequent growing seasons. That’s a lot of plastic tags for an industry with green pretensions.”

The ostensible purpose of imposing the tag rule was to monitor cannabis grown in California to make sure that it would not end up in the illicit market within or outside the state. But the factsheet summarizing SB 622 emphasizes that “individual plant tags are completely ineffective in preventing diversion.” Why? Because cannabis can’t be diverted until the plants are harvested! And the tags are removed and discarded after they are pulled from the ground.

The SB 622 factsheet asserts: “In a state that prides itself on championing environmentally sensitive initiatives designed to stop climate change and improve the environment, it is antithetical and irresponsible to continue to mandate plastic plant tagging, which does nothing to prevent diversion.”

The solution: “SB 622 replaces the individual plastic plant tagging with a digital plant tag, which provides the same level of transparency into the number of plants in the ground at any given time. Digital plant tagging is currently used by traditional farmers and has been recognized as an effective alternative by the California Farm Bureau as well as the U.S. Department of Agriculture.”

Curaleaf’s Complaint: Too Much Social justice!

In February 2023, Project CBD published a story about Curaleaf, the scandal-ridden, multistate and multinational company, which has achieved a leading position in the U.S. cannabis industry with nine-figure backing from unsavory Russian billionaires. “Small producers have long been wary of the cannabis industry coming under domination by multistate operators (MSOs) with the worst practices of corporate America,” we reported. “But the revelations of Russian oligarch money in the coffers of leading MSO Curaleaf appear to vindicate even the most cynical observers.”

Several states have launched investigations into Curaleaf’s business practices that were highlighted in our article, including product safety and labor violations. In April, New Jersey regulators declined to renew Curaleaf’s lucrative adult-use cannabis license, citing the layoffs following the closure of one of its cultivation facilities, as well as the company’s clash with unions and lack of transparency.

Things aren’t going well for Curaleaf in New York, either. According to a report in Green Market Report, Curaleaf CEO Boris Jordan feels social justice efforts have been “taken too far” in some states where cannabis is legal. In particular, Jordan was critical of the rollout of the adult-use market in New York, which has prioritized retail licenses for equity applicants, while delaying participation by well-heeled MSOs that already hold medical cannabis licenses.

“They went off on these programs, and we’re going to give these assets to felons and people that have two heads and this kind of stuff,” Jordan fumed while threatening to retaliate: “We’re talking to New York . . . If they don’t play ball and they violate the rules, we’re going to sue.”

“The industry has to consolidate,” Jordan asserted. “There’s no way there’s going to be 100 cannabis companies ten years from now. It’s probably going to be three or four large operators.”

Sure enough, in March a lawsuit was filed by a group called the Coalition for Access to Regulated & Safe Cannabis,” which includes Curaleaf and several other MSOs (Acreage Holdings, Green Thumb Industries, PharmaCann). The complaint argues that there is no provision in NY’s legalization law that stipulates equity applicants should be prioritized in the initial phase of the adult-use retail dispensary license rollout.

A few months earlier, Jordan spoke at MJBizCon in Las Vegas and predicted that the marijuana industry would inevitably undergo massive consolidation with a few companies controlling the global supply chain — a development he apparently favors. “The industry has to consolidate,” he warned. “There’s no way there’s going to be 35 or 40 or 50 or 100 cannabis companies ten years from now. It’s probably going to be three or four large operators.” Jordan obviously assumes that Curaleaf will be one them.

The future cannabis cartel will bring operating down costs by emulating the tobacco industry in order “to earn a very healthy margin,” he explained. Big tobacco companies “all use the same packaging. They all use the same paper. They all use the same machines. They all use basically everything the same, and they have different brands.”

But unlike Big Tobacco, there are hundreds of cannabis varietals with unique terpene and cannabinoid profiles, and cannabis products can be consumed in different ways — via inhalation, ingestion, or topical application. Cartels that operate to the detriment of small businesses are not conducive to a diverse, inclusive industry or a wide array of product choices.

Reefer Madness in Prague

As Project CBD reported a year-and-a-half ago: “Of all the post-Communist countries in Eastern Europe, the Czech Republic is seen as the one that has best finessed the transition to an open society.” A thriving alternative culture with a vibrant cannabis and psychedelic scene exists in Prague and other parts of Bohemia and Moravia, the two regions that comprise the Czech Republic.

But in November 2021 Robert Veverka, editor-in-chief and publisher of the Czech cannabis magazine Legalizace, was convicted by a district court for promoting “toxicomania,” i.e., positive depictions of cannabis. He was fined, and given a two-and-a-half year suspended sentence.

“The biggest danger of cannabis is its illegality,” Veverka told Project CBD shortly after the verdict. “We want to have cannabis social clubs. we want to stop the war on drugs. Every adult should have a right to grow in their own garden.”

Undaunted, he vowed to fight the decision.

But last month, the Czech Court of Appeal ruled against Veverka. He was ordered him to pay a fine of 250,000 Czech crowns (more than $10,000) and he was banned from publishing his magazine. In effect, the judge opined that it is legal to write about cannabis only if one criticizes it. Veverka called the recent ruling “a relic of totalitarianism.”

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