Researched wellness areas for phytocannabinoids like CBD

One of the speediest-growing subcategories of consumer natural health products is, without a doubt, the CBD sector. In a report, Grand View Research estimated the 2020 global consumer health CBD market to be worth $9.42 billion, with an anticipated compound annual growth rate (CAGR) of 24.6% from 2020 to 2027.

Research linking CBD to health and wellness is also a spirited activity worldwide, the results of which will continue to inform product development opportunities. According to Grand View Research’s report, CBD products are proliferating as oils; tinctures; concentrates; capsules; topical solutions such as lotions, salves and lip balms; as well as edibles encompassing coffees, gum/candies, chocolate and bakery products. The firm noted, “Various industries such as pharmaceuticals, personal care and cosmetics, nutraceuticals, and food and beverages are developing CBD-derived products for health and wellness purposes.”

Researchers have identified more than 110 cannabinoids and 120 terpenes, but authors of one paper asserted that the enzymatic reaction between a resorcinol and an isoprenoid group in the plant can result in nearly 150 phytocannabinoids.¹

Carl Germano, CDN, a board-certified clinical nutritionist and vice president for Verdant Oasis, said the emerging science illuminating the importance of the endocannabinoid system (ECS) and the role of hemp phytocannabinoids (including CBD) in supporting the ECS “will certainly dominate nutrition and medicine for decades to come.” However, he stated, focusing only on cannabidiol as one of more than 100 phytocannabinoids “negates the synergism of all family members that contribute to meaningful clinical benefit.”

Work, most of it in vitro and animal, continues to investigate how CBD and its phytocannabinoid siblings affect specific areas of human (and pet) health.

Bone health

CBD is generally thought to be associated with aiding relaxation, calming tension, hastening sleep onset, and easing aches and physical discomfort.

According to Germano, evidence is accumulating on the positive impact of phytocannabinoids, including CBD, on the musculoskeletal system. In the ECS, cannabinoid receptors CB1 and CB2 are somewhat commonly present in bone and have been found to help to regulate bone maintenance.² One group of researchers explained, “The CB1 receptor is present mainly in skeletal sympathetic nerve terminals, thus regulating the adrenergic tonic restrain of bone formation. CB2 is expressed in osteoblasts and osteoclasts, stimulates bone formation, and inhibits bone resorption.”

CB1 activity serves a protective role in regulating bone mass and may have positive impact on osteoporosis treatment.³ CB2 activity plays a vital role in bone mass maintenance by stimulating the cells that build up bone (osteoblasts) while inhibiting the cells that break down bone (osteoclasts). In animal studies, CBD has been shown to enhance healing of bone tissue and protect against bone loss.⁴ Preclinical trials demonstrated certain phytocannabinoids increase bone maintenance and healing.⁵ For example, one study showed a significant increase in collagen crosslink ratio by CBD, which is likely to contribute to the improved biomechanical properties of the fracture callus. Taken together, these data show that CBD may lead to improvement in fracture healing and demonstrate the critical mechanical role of collagen crosslinking enzymes.

Therefore, Germano emphasized—in addition to calcium, magnesium, vitamin D and boron—phytocannabinoids should be “at the core of any nutritional protocol addressing healthy bones and bone mass loss.”

Sports/fitness nutrition

In 2018, the World Anti-Doping Agency (WADA) removed CBD from its list of prohibited substances by use in athletes both in and out of competition; the U.S. Anti-Doping Agency (USADA) followed. In 2020, WADA updated its list with the following language: “All natural and synthetic cannabinoids are prohibited, e.g.: In cannabis (hashish, marijuana) and cannabis products. Natural and synthetic tetrahydrocannabinols (THCs). Synthetic cannabinoids that mimic the effects of THC. Except: Cannabidiol.”

A 2020 review concluded this “leaves the door open for CBD use by athletes.”⁶ The abstract pointed to preclinical studies indicating CBD may be useful to athletes because of “its anti-inflammatory, analgesic, anxiolytic, neuroprotective properties and its influence on the sleep-wake cycle. Unfortunately, almost no clinical data are available on CBD in the context of exercise, which makes its use in this context still premature.”

While protein and caffeine have dominated the exercise category, the role of the ECS in sports performance and recovery is beginning to become “one of the most important stories in sports nutrition,” Germano asserted.

One recent review explored various physiological and psychological effects of CBD that may be relevant to competitive sports and exercise, despite a lack of direct human studies.⁷ The authors analyzed preclinical animal studies indicating powerful anti-inflammatory, neuroprotective and analgesic CBD effects. The authors concluded the cumulative research merited moving forward with human studies. They wrote, “CBD may exert a number of physiological, biochemical and psychological effects with the potential to benefit athletes. However, well-controlled studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.”

Respiratory/immune health

CBD’s role in upper respiratory health is currently being investigated, and several in vitro studies have uncovered strong evidence to develop human clinical trials. A new study sought to quantify antiviral activity of 32 cannabinoids against Covid. The authors found two of the molecules—delta-9 THC and CBD—were more potent antivirals against the coronavirus than the reference drugs used in the study.⁸

In a murine model study that mimicked symptoms of acute respiratory distress syndrome, CBD treatment was shown to reverse symptoms through up-regulation of apelin, a peptide that plays a strong role in the central and peripheral regulation of immunity.⁹ The authors noted that CBD administration significantly increased the apelin expression, “suggesting a potential crosstalk between the apelinergic system and CBD.”

In another study, the authors suggested that cannabidiol launches numerous immunomodulatory and anti-inflammatory effects and also can mitigate uncontrolled cytokine production responsible for damage to lung tissue.¹⁰ CBD, as a peroxisome proliferation-activated receptor (PPAR) gamma agonist, regulates “fibroblast/myofibroblast activation and can inhibit the development of pulmonary fibrosis, thus ameliorating lung function.”

Inflammation levels are implicated in compromised immune function; one in vitro study suggested CBD acted as an anti-inflammatory agent in pro-inflammatory conditions.¹¹ In the experiment, epithelial cells, macrophages and lung fibroblast cells were treated with CBD, and it exerted differential effects on pro-inflammatory molecules interleukin (IL)-8 and monocyte chemotactic protein (MCP)-1, and reactive oxygen species (ROS) levels.

Anxiety

Anxiety and overall nervousness have catapulted to the top of many people’s wellness challenges list, and the ECS—as a recognized stress/mood and anxiety modulator—is a definitive target for CBD product development. Germano explained, “Both cannabinoid and other receptors including TRPV1, 5-HT1a, and GABA [gamma-aminobutyric acid] found in various regions of the brain are all targets for the ECS’s anti-anxiety effects.”

A review analyzing case reports, case series and randomized controlled trials (RCTs) utilizing CBD capsules or sublingual sprays either alone or in conjunction with other therapies in humans concluded that CBD (in dose ranges from 6 mg to 400 mg) has a “promising role” in the management of anxiety.¹²

In another review of CBD and anxiety disorders, the researchers concluded, “Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders, with need for further study of chronic and therapeutic effects in relevant clinical populations.”¹³

Additionally, CBD was shown effective in reducing anxiety in social anxiety disorder (SAD).¹⁴ In a double-blind study, 10 individuals with SAD received either 400 mg CBD or placebo. CBD was associated with significantly decreased subjective anxiety as shown by effects in participants’ limbic and paralimbic brain areas.

A similar study investigated the efficacy of CBD in treatment-naive SAD participants who underwent a simulated public speaking test. The randomized, placebo-controlled, double-blind study of 24 participants showed that those who consumed 600 mg CBD 90 minutes prior to the test had significantly reduced anxiety, cognitive impairment and discomfort during their speech performance. In contrast, the placebo group had markedly higher anxiety, cognitive impairment and discomfort.¹⁵

“Overall, there is tremendous potential and value for CBD and other phytocannabinoids in treatment of anxiety disorders,” Germano emphasized.

Skin

Research indicates that both CB1 and CB2 receptors are found in epidermal keratinocytes, cutaneous nerve fibers, dermal cells, melanocytes, eccrine sweat glands and hair follicles.¹⁶

Jeanette Jacknin, M.D., CEO of Dr. Jacknin’s Skincare LLC and author of “Smart Medicine for Your Skin,” asserted, “The research is very compelling that topical CBD and other cannabinoids can help in acne,^17,18 eczema¹⁹ and wounds.²⁰

According to in vitro research, CBD acts as a “highly effective sebostatic agent.”¹⁷ In one study, CBD administered to cultured human sebocytes inhibited lipogenesis of arachidonic acid and linoleic acid, among others, as well as suppressed sebocyte proliferation. The authors noted, “Our findings suggest that, due to the combined lipostatic, antiproliferative and anti-inflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.”

Jacknin suggested cannabinoids may also be useful for pruritis (itching). In a study of individuals with diagnosed pruritis, eight of 21 (38%) who applied a topical cannabinoid cream twice daily for three weeks reported complete elimination of their itching. “The three-week treatment period resulted in complete elimination of dry skin in 17 patients, or 81%, and complete elimination of itching in 38% of the patients,” she said.²¹

Improved bioavailability

As research ramps up—notably design and implementation of human clinical studies in the above-mentioned areas—bioavailability will become a more serious issue, especially for human trials. “It is well-recognized in the scientific literature that CBD and other cannabinoids, in general, show limited oral bioavailability due to their lipophilicity, poor aqueous solubility and extensive first-pass metabolism, commented Jesse Lopez, CEO of Geocann. “The issue of poor CBD bioavailability is not a new concept and, needless to say, there are various formulation methods that attempt to provide a much-needed solution.”

A review of the existing scientific literature shows that the number of studies is small with limited success improving absorption and bioavailability. “Simply put,” he emphasized, “the promise of the many health benefits of CBD and other cannabinoids cannot be realized without reaching therapeutic blood levels.”

A double-blind, crossover study compared the pharmacokinetic (PK) parameters of Geocann’s HempChoice Broad Spectrum Hemp Oil Extract formulated with VESIsorb to that of the same extract combined with the industry standard medium-chain triglyceride (MCT) oil.²² According to Lopez, the VESIsorb formulation showed statistically significant improvements for Cmax (maximum concentration observed), AUC (area under the curve, re: substance concentration in blood plasma as a function of time) and Tmax (time of maximum concentration observed).

Conclusion

Euromonitor International’s new white paper, “Breaking Stereotypes: Getting to Know the Cannabis Consumer,” describes six adult cannabis/CBD archetypes that serve as profiles of CBD target consumers. Shane MacGuill, the firm’s senior industry manager of nicotine and cannabis, commented, “Cannabis user profiling is relevant for cannabis-adjacent FMCG [fast-moving consumer goods] industries as more global consumers have access to cannabinoid-infused products. Cannabinoid consumers report drinking less alcohol, smoking less and taking fewer consumer health products across markets.”

In brief, the six archetypes are:

1. Seasoned (long-time) consumers (24% suffer from extreme stress).

2. Casual social (younger, newer consumers who use CBD as part of their lifestyle and 75% of whom take supplements).

3. Dabbler (occasional cannabis users).

4. Cannacurious (a broad group linked by an interest in adult-use cannabis but not much knowledge about CBD and CBD products).

5. Unsparked (only 8% see cannabis/CBD as a lifestyle enhancement).

6. Naysayer (not a direct target for CBD brands).

Naysayers and the unsparked aside, the field of CBD is fertile for both the imminent and distant future. Jacknin observed, “Every year there is more and more money and interest devoted to cannabis and cannabinoid research for almost all medical diseases and healthy aging.”

Lisa Schofield is a veteran writer and editor who got her start interviewing rock stars for national music magazines. She now writes and edits content for B2B media and suppliers in the natural health product industry. She has served as editor for Vitamin Retailer and Nutrition Industry Executive, and prior to that as associate editor for Whole Foods.

References

1 Hanuš LO et al. “Phytocannabinoids: a unified critical inventory.” Nat Prod Rep. 2016;33:1357-1392.

2 Bab I, Zimmer A, Melamed E. “Cannabinoids and the skeleton: from marijuana to reversal of bone loss.” Ann Med. 2009;41(8):560-567.

3 Idris AI et al. “Regulation of bone mass, bone loss and osteoclast activity by cannabinoid receptors.” Endocrinology. 2005;11:774-779.

4 Idris AI et al. “Regulation of bone mass, osteoclast function, and ovariectomy-induced bone loss by the type 2 cannabinoid receptor.” Endocrinology. 2008;149:5619-5626.

5 Kogan NM, Melamed E, Wasserman E. “Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts.” J Bone Miner Res. 2015;30(10):1905-1913.

6 Gamelin FX et al. “Cannabidiol in sport: Ergogenic or else?” Pharmacol Res. 2020;156:104764.

7 McCartney D et al. “Cannabidiol and Sports Performance: a Narrative Review of Relevant Evidence and Recommendations for Future Research.” Sports Med Open. 2020;6(1):27.

8 Raj V et al. “Assessment of antiviral potencies of cannabinoids against SARS-CoV-2 using computational and in vitro approaches.” Int J Biol Macromol. 2021;168:474-448.

9 Salles EL et al. “Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.” Cell Mol Med. 2020;24:12869-12872.

10 Esposito M et al. “The potential of cannabidiol in the COVID-19 pandemic.” Br J Pharmacol. 2020;177:4967-4970.

11 Muthumalage T et al. “Cannabidiol differentially regulates basal and LPS-induced inflammatory responses in macrophages, lung epithelial cells, and fibroblasts.” Toxicol Appl Pharmacol. 2019;382:114713.

12 Skelley JW. “Use of cannabidiol in anxiety and anxiety-related disorders.” J Am Pharm Assoc. 2020;60(1):253-261.

13 Blessing EM et al. “Cannavidiol as a Potential Treatment for Anxiety Disorders.” Neurotherapeutics. 2015;12(4):825-836.

14 Crippa JA et al. “Neural basis of anxioloytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report.” Psychopharmacol. 2011;25(1):121-130.

15 Bergamaschi MM et al. “Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients.” Neuropsychopharmacology. 2011;36:1219-1226.

16 Baswan SM, Klosner E, Glynn K. “Therapeutic Potential of Cannabidiol (CBD) for Skin Health and Disorders.” Clin Cosmet Investig Dermatol. 2020;13:927-942.

17 Olah A et al. “Cannabidiol exerts sebostatic and anti-inflammatory effects on human sebocytes.” J Clin Invest. 2014;124(9):3713-3724.

18 Spleman L et al. “The safety of topical cannabidiol (CBD) for the treatment of acne.” J Invest Dermatol. 2018;138(5):S180.

19 Petrosino S et al. “Anti-inflammatory properties of cannabidiol, a nonpsychotropic cannabinoid, in experimental allergic contact dermatitis.” J Pharmacol Exp Ther. 2018;365(3):652-663.

20 Sangiovanni E et al. “Cannabis sativa L. Extract and Cannabidiol Inhibit in vitro Mediators of Skin Inflammation and Wound Injury.” Phytotherapy Res. 2019;33(8):2083-2093.

21 Szepietowski JC, Reich A, Szepietowski T. “Emollients with endocannabinoids in the treatment of uremic pruritus: discussion of the therapeutic options.” Ther Apher Dial. 2005;9(3):277-279.

22 Knaub K et al. “A Novel Self-Emulsifying Drug Delivery System (SEDDS) Based on VESIsorb Formulation Technology Improving the Oral Bioavailability of Cannabidiol in Healthy Subjects.” Molecules. 2019;24:2967.