Phytocannabinoids Beyond THC & CBD
Betty Wedman- St Louis, Ph.D.
With over 500 active components produced in cannabis plants (1), phytocannabinoids have attracted the most interest in research and medical practice. The body’s own endocannabinoids can benefit from phytocannabinoid enhancement whether in the carboxylic acid form- THCA, CBDA, CBGA or CBDVA- or decarboxylated forms- THC, CBD, CBG, CBC, or CBN. Beta-caryophyllene can not re overlooked because it functions as both a phytocannabinoid and terpenoid by interacting with CB2 receptors (2).
Some researchers have labeled this as “marijuana’s moment” because phytocannabinoids are being recognized as modulators NOT blockers in stimulating homeostasis in the body. No other single plant has ever been identified to offer improved neurotransmission, inflammation reduction and improved immune function like the phytocannabinoids in cannabis. Pfizer, Merck and Eli Lily offered cannabis tonics from 1900 to 1930 with both Pfizer and Eli Lilly growing cannabis on Indiana farms to produce American-made products (3).
Today’s medical professionals need to be concerned that cannabis does not end up like red yeast rice (RYR). Red yeast rice contains the sterols for lipid-lowering effects that spawned the Mevacor and statin drug era. Only through education can all the beneficial properties of full-spectrum cannabis be recognized while the pharmaceutical industry develops a “one cannabinoid for one disorder” so it can be patented.
A May 2019 molecular biology study assayed eleven cannabinoids in a pre-clinical Alzheimer’s disease platform for their ability to remove intra-neuronal amyloid and neuroprotection. Nine of the 11 were able to remove intra-neuronal Ab, reduce oxidative damage and protect neuronal function (4). The combination of 2 cannabinoids- THC and CBN- led to synergistic neuroprotection. Cannabinol (CBN) is not produced by the plant but as cannabis ages and is exposed to oxygen, CBN forms. Cannabinol has been used as an indicator of poor or long term storage since days when the most availble cannabis came from outside the U.S. Research has now shown CBN offers sedative and analgesic properties in addition to stimulating bone growth.
Cannabinol administered orally binds more effectively to CB1 receptors than through inhalation (5). Peripheral application of CBN and CBC (cannabichromene) provide analgesic relief from chronic muscle pain like temporomandibular disorders and fibromyalgia (6).
Cannabinoids hold the key to immune system and neurobiology enhancement. Over two decades of research has been dedicated to understanding neural stem function and their repair (7). No wonder the U.S. government holds the patent on cannabis as a neuroprotectant (8). Cannabichromene (CBC) has been found to have a positive effect on the viability of mouse neural stem progenitor cells (9). CBC raised the viability of neural stem progenitor cells according to the Shinjyo and Di Marzo’s study while inhibiting differentiation into astroglia to compromise neuron receptors.
Aside from neurogenesis, cannabichromene exerts anti-inflammatory actions by activating the transient receptor potential ankyrin-type 1 (TRPA1) and inhibiting endocannabinoid inactivation (10). CBC significantly reduced LPS and its effect on TRPA1 in a colonic inflammation study.
Cannabigerol (CBG) is another phytocannabinoid present in Cannabis sativa L. that is attracting lots of pharmacological interest as an effective regulator of endocannabinoid signaling (12). CBG interacts with specific targets involved in carcinogenesis by blocking transient receptor potential TRPM8 and activating TRPV1 and TRPV2 channels. A colon carcinogensis study (13) showed CBG hampered colon cancer progression in vivo and inhibited colorectal cancer cell growth. Cannabigerol also exhibited the highest growth-inhibitory activity against cancer cell lines reported in a human oral epitheloid cancer study (14).
CBG is also noted for stimulating appetite in chemotherapy-induced cachexia rat studies (15,16).CBG modestly increased food intake and robustly attenuated cisplatin-induced weight loss.
Neuroprotection and inflammatory properties have been reported in numerous cannabigerol studies. CBG derivative VCE-003.2 administered orally in huntingtin-induced neurodegeneration improved neurogenesis (17) and improved neuropathological signs in amyotropic lateral sclerosis (18) and neuroprotection in Parkinson’s disease (19).
Other research areas of cannabigerol therapeutic benefits include bladder dysfunction reducing acetylcholine- induced contractions (20) and intestinal inflammation/colitis (21).
Beta-caryophyllene (BCP) is the most common terpene in most cannabis species and since it interacts with CB2 receptors, it is consider a cannabinoid with anti-inflammatory, analgesic and immunomodulatory benefits (22). CB2 receptor activity indicates potential for treatment of inflammation and pain (23) along with neuroprotective disorders- convulsions, depression, anxiety, and dementia (24).
Beta-caryophyllene significantly increased the anti-cancer activity of alpha-humulene and isocaryophyllene, as well as potentiated the anti-tumor activity of paclitaxel in numerous cell lines (26). These results suggest that BCP facilitates the passage of paclitaxel through cell membranes and potentiates its anti-cancer activity.
Despite no testing to access naive endocannabinoid system functioning, the medical community needs to focus on the more than 40 years of safety data (1973-present) available on cannabinoids. Doses of 10-1500 mg cannabidiol (CBD) per day have shown no significant side-effects. The reduction of pain and anxiety associated with current cannabinoid use indicates that cannabis works. The January 2019 Radius Global Market Research of over 2000 U.S. adults 18+ years old indicates that Americans have increased their use of cannabis and hemp products predominately to replace prescription medications.
The current lack of knowledge about cannabis science among health care professionals needs to change. Medical education and continuing education must include the science and application of cannabinoids so patients can be advised intelligently and supported by their health care providers. The recent discoveries of the medical properties of cannabis and cannabinoids in glaucoma, depression, neuralgia, multiple sclerosis, Alzheimer’s and cancer have provided momentum for better understanding the medical properties of this plant.
For a more complete look at the endocannabinoid system and cannabis use consult Cannabis- A Clinician’s Guide published by CRC Press, May 2018. Cannabis As Medicine is scheduled for release September 2019.
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- Schubert D, Kepchia D, Liang Z, et al. Efficacy of cannabinoids in a pre-clinical drug-screening platform for Alzheimer’s disease. Molecular Neurobiology May 2019.
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- Wong H, Cairns BE. Cannabidiol, cannabinol and their combinations act as peripheral analgesics in a rat model of myofascial pain. Arch Oral Biol 2019;104:33-39.
- Walker T, Huang J, Yound K. Neural stem and progenitor cells in nervous system function and therapy. Stem Cells Int 2016.
- U.S. Patent 6630507B1 Cannabinoids as antioxidants and neuroprotectants. October 7, 2003.
- Shinjyo N, Di Marzo V. The effect of cannabichromene on adult neural stem/progenitor cells. Neurochem Int 2013;63(5):432-7.
- Romano B, Borrelli F, Fasolino I, et al. The cannabinoid TRPA1 agonist cannabichromene inhibits nitric oxide production in macrophages and amelorates murine colitis. Br J Pharmacol 2013; 169(1):213-29.
- Ligresti A, Moriello AS, Starowicz K, et al. Anti-tumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 2006;318(3):1375-87.
- Navarro G, Varani K, Reyes-Resina I, et al. Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1-CB2 heteroreceptor complexes. Front Pharmacol 2018;9:632.
- Borrelli F, Pagano E, Romano B, et al. Colon carcinogenesis is inhibited by the TRPM8 antagonist cannabigerol, a cannabis-derived non-psychotropic cannabinoid. Carcinogenesis 2014;35(12):2787-97.
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- Brierley DI, Samuels J, Duncan M, et al. A cannabigerol-rich Cannabis sativa extract, devoid of [increment] 9-tetrahydrocannabinol, elicits hyperphagia in rats. Behav Pharmacol 2017;28(4):280-4.
- Brierley DI, Harman JR, Giallourou N, et al. Chemotherapy-induced cachexia dysregulates hypothalamic and systemic lipoamines and is attenuated by cannabigerol. J Cachexia Sarcopenia Muscle 2019.
- Aguareles J, Paraiso-Luna J, Palomares B, et al. Oral administration of the cannabigerol derivative XCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration. Transl Neurodegener 2019;8:9.
- Rodriguez-Cueto C, Santos-Garcia I, Garcia-Toscano L, et al. Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD 1-G93A transgenic mice, an experimental model of amyotrophic lateral sclerosis. Biochem Pharmacol 2018;157:217-226.
- Garcia C, Gomez-Canas M, Burgaz S, et al. Benefits of VCE-003.2, a cannabigerol quinone derivative, against inflammation-driven neuronal deterioration in experiemental Parkinson’s disease:possible involvement of different binding sites at the PPARg receptor. J Neuroinflammation 2018;15(1):19.
- Pagano E, Montanaro V, Di Girolamo A, et al. Effect of non-psychotropic plant-derived cannabinoids on bladder contractility:focus on cannabigerol. Nat Prod Commun 2015;10(6):1009-12.
- Couch DG, Maudslay H, Doleman B, et al. The use of cannabinoids in colitis:a systematic review and meta-analysis. Inflamm Bowel Dis 2018;24(4):680-97.
- Klauke A-L, Raz I, Pradier B, et al. The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain. E Neuropyschopharm 2014;24(4):608-20.
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Betty Wedman-St. Louis, Ph.D. is a licensed nutritionist specializing in digestive diseases, diabetes, cancer and environmental health issues who has been a practicing nutrition counselor for over 40 years. Her BS in Foods & Business from the University of Minnesota introduced her to how the food industry influences eating habits. Dr. Wedman-St. Louis completed her MS in Nutrition at Northern Illinois University where she studied the relationship between prolonged bed rest and space flight weightlessness nutrient requirements. She had a private practice at the Hinsdale Medical Center before completing her Ph.D. in Nutrition & Environmental Health from The Union Institute in Cincinnati. Dr. Wedman-St. Louis completed her doctorate internship at WUSF-Tampa in Multi-Media Production for distance learning and online course development. Dr. Wedman-St. Louis is the author of numerous published articles on current nutrition topics including bariatric surgery, lectin toxicity, phosphates in food, folate, Vitamin B12, seafood nutrition, alpha lipoic acid and diabetes. She has authored columns for The Hinsdale Doings, Chicago Sun Times and Columbia Missourian and has taught undergraduate and graduate courses on nutrition. She has written a personal health column for the Tampa Bay Times and maintains a private practice in Pinellas Park, Florida. Her website is www.betty-wedman-stlouis.com.