Dr. Mark A. Scialdone, a recognized expert in the field of organic chemistry who specializes in natural product chemistry, is an inventor of 37 issued US patents and the author of 17 peer-reviewed articles in science publications. From 1994 to 2013, he was employed as a principal investigator at DuPont Central Research and Development. Dr. Scialdone is a founding member of the Cannabis Chemistry Subdivision of the American Chemical Society from which he received the 2018 CANN-CHAS Heidolph Award for Excellence in Cannabis Chemistry. Scialdone is currently founder and president of BetterChem Consulting, which provides consulting services worldwide in the chemical, food, plant essential oil, and cannabis industries. He has guided clients on license applications, facility design and build out, equipment installation and optimization, and plant oil extraction for cannabis and hemp processing facilities.
Project CBD: Your presentation with Allyn Howlett at the International Cannabinoid Research Society conference in Toronto (June 2023) discussed the chemical conversion of CBD into Δ8-THC (delta-8 THC) and “numerous additional THC isomers . . . with unknown pharmacological and safety profiles.” Explain what an isomer is and why the lack of information regarding novel THC isomers is problematic.
Dr. Mark A. Scialdone: Isomers are similar molecules having different discrete arrangements of the same atoms creating molecules with different chemical and physical properties. The Δ8-THC being produced from the acid-catalyzed conversion of CBD is an unpurified reaction mixture that contains multiple, non-natural THC isomers, including Δ8-iso-THC and Δ4(8)-iso-THC. These are not present in cannabis and are only formed in the chemical conversion, whose impact on human health is unknown. What’s more, these non-natural THC isomers are difficult to measure — and they are also difficult, if not impossible, to remove from the reaction mixture to purify the Δ8-THC that’s produced. You need access to sophisticated analytical methods to discern product purity from the isomeric byproducts formed, which is why production from hemp-derived cannabinoid products needs to be done under the appropriate FDA regulations for API [active pharmaceutical ingredient] synthesis and manufacturing.
Project CBD: Are there other byproducts from CBD conversion to Δ8-THC that we should be concerned about in addition to these THC isomers?
Scialdone: In addition to the iso-isomers of THC, there are also abnormal isomers called regioisomers that are formed in the conversion reaction. Recently, degradation products such as olivetol as well as chlorinated compounds, have been found in commercial Δ8-THC products tested. The conversion of hemp-derived CBD into Δ8-THC and other synthetic compounds such as HHC (hexahydrocannabinol) occurs without proper regulatory oversight to ensure process standardization, product specification, and accurate third-party testing, all of which are mandated in state-licensed cannabis programs.
Project CBD: What comes to mind when you see an ad for “Δ8-THC pre-rolls” given that the plant doesn’t actually produce the Δ8-THC in the joint?
Scialdone: Did they spray or dip the flower or whole joint with synthetic Δ8-THC? How much Δ8-THC was added to the pre-roll? Did the manufacturers use a solvent to treat the flower? If a solvent is used, does it dissolve the phytocannabinoids and terpenes? What’s the actual Δ8-THC purity of what’s being applied to the flower? How much cheaper is it to produce Δ8-THC-pre-rolls than real cannabis pre-rolls? How much money are Δ8-THC producers making?
These non-natural THC isomers are difficult to measure, and they are also difficult, if not impossible, to remove from the reaction mixture to purify the Δ8-THC that’s produced.
Project CBD: Δ8-THC has proven to be a gateway drug of sorts for a new generation of unregulated, synthetic designer compounds — Δ10-THC, Δ12-THC, THCP, THCO, THCX, etc. — that are widely available. At issue are potent, intoxicating cannabinoids other than cannabis-derived Δ9-THC. Are these compounds actually derived from hemp? Does their greater cannabinoid receptor binding affinity translate into increased risk?
Scialdone: Only Δ8, Δ9, and Δ10 THC can be synthesized from hemp-derived CBD. All the others are made by chemical conversion. Producing and selling psychoactive products outside the regulatory auspices of the FDA or a state-regulated cannabis program is not ethical. These hemp hustlers are in it for the money, making active pharmaceutical ingredients using process chemistry and producing formulated end-products like vape pens, gummies, and sodas in garages, airplane hangars, basements, and warehouses. These products are sold over the internet, at gas stations, and in smoke shops to anyone with a credit card. Of course, the market for Δ8-THC and other recreational synthetics is only made possible by the ridiculousness of cannabis prohibition. End cannabis prohibition, the market for these products will go away and these compounds will be relegated to research labs, where they belong, not the marketplace.
Project CBD: What do you anticipate regarding the next iteration of the Farm Bill in terms of the legality of Δ8-THC and other synthetic intoxicants?
Scialdone: Unfortunately, I believe that this is a red herring since the USDA’s regulatory authority over hemp ends at harvest. The FDA is supposed to regulate hemp-derived CBD products. The FDA recognizes the need for a different regulatory pathway to properly regulate cannabis/hemp. But the FDA has failed to adopt a regulatory strategy to address this issue. The next version of the Farm Bill should clearly and concisely differentiate high Δ9-THC cannabis from industrial hemp. In no uncertain terms, the Farm Bill must be amended to close the specious THCA-hemp flower loophole that’s enabling the unregulated sale of concentrated, intoxicating, and synthesized cannabinoids. If farmers and manufacturers want to sell psychoactive cannabinoids, they should get a state-issued license to grow and process cannabis.
HerbalGram, the acclaimed quarterly journal of the American Botanical Council, recently published its 2021 “Herb Market Report,” which included data on sales of CBD as an herbal ingredient in mainstream and natural retail channels in the United States. The combined total from both channels — $58,293,034 — does not include CBD sales in licensed cannabis dispensaries or CBD products, such as vapes, tinctures, gummies, and other edibles sold online. (E-commerce sales of CBD in the U.S. in 2021 reached $2 billion, according to Statistica.)
The following excerpt analyzes CBD marketing trends reported by the American Botanical Council, a membership organization that educates consumers, health care professionals, journalists, and others about the safe and effective use of medicinal plants. Visit this link if you are interested in becoming an ABC member, which includes a subscription to HerbalGram.
A Top Selling Herbal Supplement
In 2021, for the fourth year in a row, CBD was the top-selling herbal supplement ingredient in natural retail stores. CBD first appeared on the natural channel’s top 40 list in 2017, ranking 12th, after sales growth of more than 300% from the previous year. Despite its top rank in 2021, sales of this ingredient have slowed in recent years.
In 2021, CBD sales in the natural channel totaled $38,931,696, a 24% decline. This was somewhat less than the nearly 37% decline seen in 2020. Sales appear to have peaked in 2019, when natural channel consumers spent more than $90.7 million on these products. Still, even after two years of declining sales, natural channel sales of CBD in 2021 were still significantly higher than when the ingredient first appeared on the top 40 list. Consumers spent roughly $31.3 million more on CBD products in 2021 compared to 2017 — a 413.4% increase in annual sales.
The marketing data firm SPINS tracks sales of two separate cannabis-derived ingredients: CBD and “hemp seeds and derivatives.” According to the FDA, “hemp” is defined as Cannabis sativa with a tetrahydrocannabinol (THC) concentration of 0.3% or less. (THC is the primary psychoactive compound in cannabis.) Cannabis sativa with more than 0.3% THC is considered “marijuana” or “cannabis.”1 SPINS’ CBD category typically includes sales of products that contain hemp-based CBD extracts, including CBD oils, gummies, and capsules.
Products in SPINS’ hemp seeds and derivatives category, such as hemp seed oil (also written as “hempseed” oil), often are marketed for their nutritional content. Hemp seed oil is rich in omega-3 and omega-6 fatty acids and has high levels of provitamin A, vitamin E, and various minerals (e.g., phosphorus, potassium, and calcium).2 The seeds of C. sativa do not naturally contain cannabinoids, but they can become contaminated with CBD from other plant parts during processing.3 Sales of hemp seeds and derivatives, which ranked 39th in the natural channel in 2021, also decreased from the previous year. Consumers spent $2,782,105 on these products in 2021 — a 14.1% decline from 2020.
CBD sales declined in 2021 for several possible reasons, including legal confusion, a lack of a clear path for FDA regulation, market saturation, and published reports of inaccurate label claims for some CBD products.
FDA Intransigence
On a federal level, CBD is not considered a legal dietary supplement ingredient. Under section 201(ff)(3)(B) of the Federal Food, Drug, and Cosmetic Act — in what some refer to as the “drug preclusion clause”4 — any substance that is an active ingredient in an approved drug product, or that is being publicly investigated as such, is excluded from the definition of a legal dietary supplement ingredient.5 In June 2018, the FDA approved Epidiolex® (GW Pharmaceuticals; Cambridge, UK), the first FDA-approved pharmaceutical drug to contain a “purified drug substance [CBD] derived from marijuana,” for the treatment of seizures associated with two rare epilepsy disorders.6 Since then, the FDA has maintained that CBD is an unapproved drug when sold as a dietary supplement (or in products for external use).7
The sheer number of product options may be overwhelming, and the diversity of advertised claims can muddle one’s understanding of CBD’s potential benefits.
In 2021, the FDA reaffirmed its position on CBD in supplements. Early that year, two natural products companies, Charlotte’s Web (Boulder, Colorado) and Irwin Naturals (Los Angeles, California), submitted new dietary ingredient (NDI) notifications to the FDA in an effort to get CBD approved as a supplement ingredient, in accordance with Section 8 of the Dietary Supplement Health and Education Act of 1994. Despite the companies’ submitting the required data demonstrating the “reasonable expectation of safety under the recommended conditions of use,” the FDA rejected the applications, citing the drug preclusion clause.8
The sheer number of product options may be overwhelming, and the diversity of advertised claims can muddle one’s understanding of CBD’s potential benefits.
The number and variety of CBD products available on the market also may have impacted sales in 2021. According to Adweek, approximately 2,000 CBD brands were sold in the United States in 2021 — down from about 3,000 the year before.[8] For some consumers, the sheer number of product options may be overwhelming, and the diversity of advertised claims can muddle one’s understanding of CBD’s potential benefits.
“An Alarming Lack of Understanding about CBD”
Based on the results of its July 2021 survey, the Consumer Brands Association reported an “alarming lack of understanding about CBD.” On a scale from one to 10, respondents rated their knowledge of CBD an average of 3.3. Nearly three-quarters of those surveyed also were confused about, or had no knowledge of, federal CBD regulations.9
In a February 2021 article in Nutritional Outlook, Jesse Karagianes, vice president of sales of the CBD natural products company CV Sciences (San Diego, California), was quoted as saying: “[T]he single largest factor which contributed to slow category sales was the deluge of inferior products hitting the market. From unfounded and unlawful health claims to inconsistency in CBD content, many CBD products do not deliver on what customers expect from them.”10
The results of several CBD product analyses published in recent years suggest that labels may not always accurately reflect the contents. In December 2021, Leafreport, an online CBD resource owned by Empire Media Network, published the results of analyses of 221 CBD products it sent to third-party laboratories for testing. The labs analyzed 35 oils, 40 topical products, 40 edibles, 22 beverages, 55 pet products, and 29 coffee or tea products. Leafreport found that only 40% of the products matched the levels of CBD stated on labels, with 28% of the products having CBD levels that failed to match label claims by more than 30%. On average, they found that, “the CBD content of the products was off from the label by nearly 25%.”11 A separate paper, published in February 2022, analyzed the CBD content of 11 commercially available CBD oils and found that only four (36.4%) matched the amount stated on the label.12
Health Benefits
Although CBD sales have slowed, research into the cannabinoid’s potential health benefits continues. In 2021, researchers published more than a dozen systematic reviews of CBD’s effects, including for mood disorders, anxiety disorders, dementia, multiple sclerosis, appetite, pain, and more.13 Although many review authors reported inconclusive findings due to low-quality studies, they noted that evidence from human clinical trials seems to support CBD’s positive effects on nociceptive pain (i.e., pain in response to stimuli), neuropathic pain, appetite, and neuropsychiatric symptoms in people with moderate to advanced dementia.14-16 A separate 2021 open-label, randomized controlled study of 3,000 people found that consumers taking one of 13 specified CBD products for four weeks had self-reported improvements in areas such as wellbeing (71%), anxiety (63%), and sleep quality (61%).17
Excerpted from HerbalGram, the quarterly publication of the American Botanical Council. May not be reprinted without permission from the source.
References
FDA regulation of cannabis and cannabis-derived products, including cannabidiol (CBD). US Food & Drug Administration website. Available at: www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. Accessed July 25, 2021.
Xu Y, Li J, Zhao J, et al. Hempseed as a nutritious and healthy human food or animal feed source: A review. International Journal of Food Science and Technology. 2021;56:530-543. Available at: https://drive.google.com/file/d/12bS4AXxqi0eJTP6d68MBsD6WiNy2-vhl/view. Accessed October 17, 2022.
Farinon B, Molinari R, Costantini L, Merendino N. The seed of industrial hemp (Cannabis sativa L.): Nutritional quality and potential functionality for human health and nutrition. Nutrients. 2020;12(7):1935. doi: 10.3390/nu12071935. Available at: www.ncbi.nlm.nih.gov/pmc/articles/PMC7400098/. Accessed October 17, 2022.
Krawiec S. CBD proving grounds: 2022 ingredient trends for food, drinks, dietary supplements, and natural products. Nutritional Outlook. February 2, 2022. Available at: www.nutritionaloutlook.com/view/cbd-proving-grounds-2022-ingredient-trends-for-food-drinks-dietary-supplements-and-natural-products. Accessed October 17, 2022.
FDA regulation of dietary supplement and conventional food products containing cannabis and cannabis-derived compounds. US Food and Drug Administration website. Available at: www.fda.gov/media/131878/download. Accessed October 17, 2022.
FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy [press release]. Silver Spring, MD: US Food and Drug Administration; June 25, 2018. Available at: www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms. Accessed October 17, 2022.
FDA warns four companies for illegally selling CBD products intended for use in food-producing animals. US Food and Drug Administration website. May 26, 2022. Available at: www.fda.gov/animal-veterinary/cvm-updates/fda-warns-four-companies-illegally-selling-cbd-products-intended-use-food-producing-animals. Accessed October 17, 2022.
Stanley TL. The CBD industry just shed 1,000 brands. Here’s why analysts still see strong growth ahead. Adweek. July 23, 2021. Available at: www.adweek.com/brand-marketing/the-cbd-industry-just-shed-1000-brands-heres-why-analysts-still-see-strong-growth-ahead/. Accessed October 17, 2022.
Unregulated and exploding: How the CBD market is growing amid a labyrinth of state approaches and rampant consumer confusion. Consumer Brand Association website. July 2021. Available at: https://consumerbrandsassociation.org/regulation/cbd/unregulated-and-exploding-how-the-cbd-market-is-growing-amid-a-labyrinth-of-state-approaches-and-rampant-consumer-confusion/. Accessed October 17, 2022.
Grebow J. COVID-19 plus legal uncertainty slowed CBD sales in 2020. What’s CBD in for in 2021? 2021 Ingredient trends to watch for food, drinks, and dietary supplements. Nutritional Outlook. February 11, 2021. Available at: www.nutritionaloutlook.com/view/covid-19-plus-legal-uncertainty-slowed-cbd-sales-in-2020-what-s-cbd-in-for-in-2021-2021-ingredient-trends-to-watch-for-food-drinks-and-dietary-supplements. Accessed October 17, 2022.
Olenik G. CBD market report: Over half of CBD products are mislabeled. Leafreport website. October 16, 2022. Available at: www.leafreport.com/education/cbd-market-report-over-half-of-cbd-products-are-mislabeled-15084. Accessed October 17, 2022.
Miller OS, Elder EJ, Jones KJ, Gidal BE. Analysis of cannabidiol (CBD) and THC in nonprescription consumer products: Implications for patients and practitioners. Epilepsy Behav. 2022;127:108514. doi: 10.1016/j.yebeh.2021.108514. Available at: https://pubmed.ncbi.nlm.nih.gov/34998268/. Accessed October 17, 2022.
PubMed search: “CBD review.” National Library of Medicine website. Available at: https://pubmed.ncbi.nlm.nih.gov/?term=cbd%20review&filter=pubt.systematicreview&filter=hum_ani.humans&filter=years.2021-2021. Accessed October 17, 2022.
Spanagel R, Bilbao A. Approved cannabinoids for medical purposes: Comparative systematic review and meta-analysis for sleep and appetite. Neuropharmacology. 2021;196:108680. doi: 10.1016/j.neuropharm.2021.108680. Available at: https://pubmed.ncbi.nlm.nih.gov/34181977/. Accessed October 17, 2022.
Grossman S, Tan H, Gadiwalla Y. Cannabis and orofacial pain: A systematic review. Br J Oral Maxillofac Surg. 2022 Jun;60(5):e677-e690. doi: 10.1016/j.bjoms.2021.06.005. Available at: https://pubmed.ncbi.nlm.nih.gov/35305839/. Accessed October 17, 2022.
Stella F, Valiengo LC, de Paula VJR, Lima CAD, Forlenza OV. Medical cannabinoids for treatment of neuropsychiatric symptoms in dementia: A systematic review. Trends Psychiatry Psychother. 2021;43(4):243-255. doi: 10.47626/2237-6089-2021-0288. Available at: https://pubmed.ncbi.nlm.nih.gov/34374269/. Accessed October 17, 2022.
Masterson D. Radicle Science highlights findings from large CBD study. NutraIngredients-USA website. May 9, 2022. Available at: www.nutraingredients-usa.com/Article/2022/05/09/radicle-science-highlights-findings-from-large-cbd-study. Accessed October 17, 2022.
