By Nicole Foss, MBA, MSN, RN, NeXtraction04.01.21
Disclosure: Statements regarding phytocompounds, ingredients, indications and products have not been evaluated by the FDA and are not intended to diagnose, treat, cure, or prevent any disease or health condition. No content in this article, regardless of date, should be used as a substitute for direct medical advice from your doctor or other qualified clinician.
Cannabis* has a colorful history in the U.S. Once widely used as medicine in the 1800s, cannabis underwent a confusing (and racially fueled) re-branding to eventually become a primary target in the “War on Drugs.”
(*Cannabis: Referring to formal naming of flowering annual plant genus within the Cannabaceae family. Can be further defined into species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Cannabis includes both “hemp” and “high-THC” chemovars.)
Initially, sometime around 1911, state-level legislation began prohibiting the cultivation of cannabis which culminated in federal-level prohibition with the passage of the “Marihuana Tax Act” of 1937. Then, as part of the 1960’s cultural awakening, there was a resurgence in cannabis interest and consumption. The movement was quickly abolished and pushed “underground” by the Controlled Substances Act of 1970, which classified “marijuana” or “cannabis” as a schedule 1 drug, the label reserved for “addictive compounds with no medicinal benefits.”
Fast forward to 1996, to a starkly different opinion on cannabis with the establishment of the first “medical marijuana” measure (in California) allowing patients with “qualifying” (debilitating and chronic) medical conditions to access cannabis for medicinal relief. The relief is now largely understood to be effects from what is known technically as phytocompounds.
A pivotal point in phytocompound research, manufacturing, product development, and availability took place in 2009, when Oregon established and implemented a low-THC cannabis (hemp) research program that shaped the framework for the Agricultural Act of 2014 (United States Congress, 2014).
The 2014 Act allowed state-level hemp pilot programs to launch with institutions of higher education across the country. These programs emphasized cultivation techniques and field data gathering for a better understanding of hemp’s growing characteristics. It was not until 2018, when the most recent Agricultural Act passed, that low-THC cannabis, known as “hemp,” and its phytocannabinoid extract and phytocompounds would be considered legal for commerce and transport.
Simultaneous to the expansion of hemp research program development and federal-level Agricultural Acts, Washington and Oregon established the first “Adult-Use Markets” (sometimes referred to as Recreational Markets). These new markets allowed for the sale and oversight of high-THC cannabis flower (formerly called marijuana) and consumer goods products. Fast forward to November 2020, 36 states and four territories have medical cannabis programs and 15 states and three territories have adult-use markets. As of January 2021, all but three states have either submitted or already established regulations allowing for hemp-based consumer goods products (including “smokable flower” and phytocannabinoid extracts). While a few states do not currently provide their residents legal access to cannabis, this does not prohibit a resident from having hemp-based products sent to their home for private use as per the 2018 Agricultural Improvement Act.
In cosmetics, hemp seed oil** (or sometimes loosely called hemp oil) gained momentum as an early placeholder-ingredient and hero to the hemp industry at the close of the 20th century, (the hemp pioneer, Hempz, was founded in 1998), but phytocannabinoids, in the form of raw concentrate, were less widely adopted by the industry until approximately the arrival of the COVID-19 pandemic, which brought a sweeping change of heightened awareness to consumer health and wellness, spurring multiple market opportunities for hemp-derived products.
(**Hemp seed oil refers to an omega-rich oil that is formed when hemp seeds are pressed. Hemp seed oil does not usually contain any appreciable amount of phytocannabinoids, though it is rich in other phytocompounds. The potential for reform has not gone unnoticed by regulatory departments and legal counsels for top cosmetic, food, and beverage brands. The changing tone from legal departments and executives now grants a new “green light” to chemists and formulators, who were previously stonewalled by the historical misperception of cannabis.)
This has sparked the need for access to peer-reviewed literature (predominantly international), stability studies, and an upward battle for education by formulators eager to get up to speed on cannabinoids and cannabinoid ingredient uses in daily consumer products. The lack of cohesive education from the cannabis industry makes it all the more challenging to formulators who are faced with the importance of creating a balanced phytocompound profile within a formulation, as well as with the complex decision of delivery through “raw concentrate,” “nano-emulsion,” “oil-emulsion,” or the hundreds of other innovative technologies available for use in delivery of lipid-based molecules.
New Look, New Possible Applications
First discovered in 1992 by Lumír Hanuš and William Devane, the Endocannabinoid System (ECS) is thought to be comprised of two parts: receptors and compounds. At least two (if not 10 or more) receptors and numerous compounds, both endogenous and external, work together to form this complex hemostatic system.
These pathways span from head to toe and are present on many types of cells. The complex regulatory system is involved with monitoring and regulating hormones, motor coordination, pain modulation, and, likely, neuroprotection. This chemical receptor network responds to the body’s naturally produced endocannabinoids, 2-AG and Anandamide, and tens if not more than 100 phytocannabinoids. (For purposes of this discussion, cannabinoids generally fall into three categories: endocannabinoids, phytocannabinoids, and synthetic cannabinoids).
Plant-derived cannabinoids, phytocannabinoids, fall into three smaller sub-categories: acidic cannabinoids (plant-based); neutral cannabinoids (processed); and metabolic cannabinoids (created by chemical reactions rather than by the plant or excessive processing). Acidic cannabinoids are thought to be more bioavailable (as supported by recent animal studies—Hannon M, et al., 2020) due to their added chemical group (a carboxyl group). The acidic cannabinoids (e.g., CBDa, CBGa, THCa, CBCa) were previously thought to be inactive and possibly unstable and were thus abandoned for their neutral counterparts CBD, CBG, and Delta-9-THC. Neutral phytocannabinoids are thus widely researched and have an expanding list of clinical studies (both human and animal). New research is released nearly daily uncovering potential applications for the numerous chronic illnesses that lower the quality of life of billions of people in the world.
Then there is the concept of the synergistic effects of phytocompounds such as terpenoids (terpenes), flavonoids, and cannabinoids working harmoniously within the ECS. Though still open to debate, the synergistic effects are sometimes referred to as the “entourage effect.” While the science behind terpenes is expanding, it is often used within the adult-use, high-THC cannabis industry to define a completely different classification system, whereby terpenes are used to categorize common indica, sativa, and hybrid-like “strains” (chemovars) as a way to sell/categorize cannabis flower in adult use markets.
These categories reflect “induced effect” on the consumer. As such, terpenes are likely what cannabis connoisseurs claim are responsible for the sedating (anti-anxiolytic) or alerting effects of cannabis; aka indica and sativa, respectively. Ironically “indica” and “sativa” are also common terms when cannabis producers (cultivators) refer to plant growth structure, where indica-type (also called Afghani) plants are bushy, more squat, wide-growing patterned, and where sativa-like (tropical) plants grow tall and lengthy often with “skinnier” leaves. It is confusing—I know.
Anecdotally, there is little to no doubt that the phytocompounds perform synergistically to induce effects on the body. The most elemental realization of this is the fact that a pure D9THC market (unregulated or regulated) does not exist. This is because Delta9THC alone is quite intolerable. Unlike the unpleasant nature of D9THC, cannabidiol (CBD) is well tolerated and, according to the World Health Organization, non-addicting and non-toxic (World Health Organization, 2018). The pathways and implications of this new compound class would seem to be endless in its impacts on the human body in disease and aging.
The new overlap of wellness, beauty, self-care, and dawn of “inflamm-aging” has also fueled the expansion of cannabinoids being researched in R&D departments. Inflammation, according to cannabis research published worldwide, suggests several inflammatory pathways and receptors. The CB2 receptor, a main endocannabinoid receptor, is thought to play a key role in inflammation alongside phytocannabinoids. But the research does not stop there. The transient receptor potential channels (TRP), Adenosine receptors (A2A), and Cyclooxygenase (COX-2) pathways show great promise when it comes to a multitude of phytocannabinoid induced activation or inhibition as related to inflammation. These TRP channels are the same as those for capsaicin and turmeric.
Anti-inflammatory cytokines may also play a role in the harmonious function of cannabinoids and terpenes. One study suggests that deficits in working memory and an age-related increase in pro-inflammatory cytokines were both reversed by beta-caryophyllene (BCP), a popular cannabis terpenoid (Lindsey, et al., 2019). Another terpene, Terpinolene, alongside NSAID administration in animals, was suggested to exert a synergistic anti-inflammatory and analgesic effect (Macedo, E., et al., 2016).
Cannabinoids do not stop at reducing skin and muscle inflammation; they have also been shown to effect neuroinflammation. Cellular (in vitro) neuroinflammation models show promise for phytocompounds such as CBG in reduction of pro-inflammatory cytokines (i.e., IL-1β, TNF-α, IFN-γ) and potential effects against neuroinflammation and oxidative stress (Gugliandolo A., et al., 2018).
Cannabigerolic acid (CBGa), discovered in 1965, is naturally abundant within the hemp plant and is referred to as the “stem cell” of cannabinoids. Many cannabinoids are naturally formed from CBGa through normal chemical synthesis of this compound into more commonly known counterparts such as CBDa (hemp varieties) and THCa (adult use varieties). Not surprisingly, an expanding amount of CBGa-specific hemp genetics are now being produced, allowing for another expansion of the cannabinoid market to include CBGa and CBG-based extracts.
CBGa is thought to have a weak binding affinity to CB1 and CB2. Despite the possible inactivity at these traditional endocannabinoid receptors, the whole class of acidic cannabinoid [acids], including CBGa, have shown to be more potent PPARγ agonists than their decarboxylated analogues (Nadal X., et al., 2017). Many other chemical pathways such as the 5HT (serotonin) have shown promise when it comes to cannabinoids (Resstel, et al., 2009).
Which cannabinoid profile, which terpenoid profile, which extraction method, and which delivery method are the questions cosmetic chemists are now asking themselves. The information exists for cosmetic chemists to answer these important, questions, and a plethora of anecdotal evidence is mounting behind fast-growing consumer demand which is further driving capital market spending and deployment of resources to research and the science behind the “glow up” of cannabis.
About the Author: Nicole Foss MBA, MSN, RN is vice president, NeXtraction Inc. She may be reached at info@nextraction.com.
References
Cannabis* has a colorful history in the U.S. Once widely used as medicine in the 1800s, cannabis underwent a confusing (and racially fueled) re-branding to eventually become a primary target in the “War on Drugs.”
(*Cannabis: Referring to formal naming of flowering annual plant genus within the Cannabaceae family. Can be further defined into species: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Cannabis includes both “hemp” and “high-THC” chemovars.)
Initially, sometime around 1911, state-level legislation began prohibiting the cultivation of cannabis which culminated in federal-level prohibition with the passage of the “Marihuana Tax Act” of 1937. Then, as part of the 1960’s cultural awakening, there was a resurgence in cannabis interest and consumption. The movement was quickly abolished and pushed “underground” by the Controlled Substances Act of 1970, which classified “marijuana” or “cannabis” as a schedule 1 drug, the label reserved for “addictive compounds with no medicinal benefits.”
Fast forward to 1996, to a starkly different opinion on cannabis with the establishment of the first “medical marijuana” measure (in California) allowing patients with “qualifying” (debilitating and chronic) medical conditions to access cannabis for medicinal relief. The relief is now largely understood to be effects from what is known technically as phytocompounds.
A pivotal point in phytocompound research, manufacturing, product development, and availability took place in 2009, when Oregon established and implemented a low-THC cannabis (hemp) research program that shaped the framework for the Agricultural Act of 2014 (United States Congress, 2014).
The 2014 Act allowed state-level hemp pilot programs to launch with institutions of higher education across the country. These programs emphasized cultivation techniques and field data gathering for a better understanding of hemp’s growing characteristics. It was not until 2018, when the most recent Agricultural Act passed, that low-THC cannabis, known as “hemp,” and its phytocannabinoid extract and phytocompounds would be considered legal for commerce and transport.
Simultaneous to the expansion of hemp research program development and federal-level Agricultural Acts, Washington and Oregon established the first “Adult-Use Markets” (sometimes referred to as Recreational Markets). These new markets allowed for the sale and oversight of high-THC cannabis flower (formerly called marijuana) and consumer goods products. Fast forward to November 2020, 36 states and four territories have medical cannabis programs and 15 states and three territories have adult-use markets. As of January 2021, all but three states have either submitted or already established regulations allowing for hemp-based consumer goods products (including “smokable flower” and phytocannabinoid extracts). While a few states do not currently provide their residents legal access to cannabis, this does not prohibit a resident from having hemp-based products sent to their home for private use as per the 2018 Agricultural Improvement Act.
In cosmetics, hemp seed oil** (or sometimes loosely called hemp oil) gained momentum as an early placeholder-ingredient and hero to the hemp industry at the close of the 20th century, (the hemp pioneer, Hempz, was founded in 1998), but phytocannabinoids, in the form of raw concentrate, were less widely adopted by the industry until approximately the arrival of the COVID-19 pandemic, which brought a sweeping change of heightened awareness to consumer health and wellness, spurring multiple market opportunities for hemp-derived products.
(**Hemp seed oil refers to an omega-rich oil that is formed when hemp seeds are pressed. Hemp seed oil does not usually contain any appreciable amount of phytocannabinoids, though it is rich in other phytocompounds. The potential for reform has not gone unnoticed by regulatory departments and legal counsels for top cosmetic, food, and beverage brands. The changing tone from legal departments and executives now grants a new “green light” to chemists and formulators, who were previously stonewalled by the historical misperception of cannabis.)
This has sparked the need for access to peer-reviewed literature (predominantly international), stability studies, and an upward battle for education by formulators eager to get up to speed on cannabinoids and cannabinoid ingredient uses in daily consumer products. The lack of cohesive education from the cannabis industry makes it all the more challenging to formulators who are faced with the importance of creating a balanced phytocompound profile within a formulation, as well as with the complex decision of delivery through “raw concentrate,” “nano-emulsion,” “oil-emulsion,” or the hundreds of other innovative technologies available for use in delivery of lipid-based molecules.
New Look, New Possible Applications
First discovered in 1992 by Lumír Hanuš and William Devane, the Endocannabinoid System (ECS) is thought to be comprised of two parts: receptors and compounds. At least two (if not 10 or more) receptors and numerous compounds, both endogenous and external, work together to form this complex hemostatic system.
These pathways span from head to toe and are present on many types of cells. The complex regulatory system is involved with monitoring and regulating hormones, motor coordination, pain modulation, and, likely, neuroprotection. This chemical receptor network responds to the body’s naturally produced endocannabinoids, 2-AG and Anandamide, and tens if not more than 100 phytocannabinoids. (For purposes of this discussion, cannabinoids generally fall into three categories: endocannabinoids, phytocannabinoids, and synthetic cannabinoids).
Plant-derived cannabinoids, phytocannabinoids, fall into three smaller sub-categories: acidic cannabinoids (plant-based); neutral cannabinoids (processed); and metabolic cannabinoids (created by chemical reactions rather than by the plant or excessive processing). Acidic cannabinoids are thought to be more bioavailable (as supported by recent animal studies—Hannon M, et al., 2020) due to their added chemical group (a carboxyl group). The acidic cannabinoids (e.g., CBDa, CBGa, THCa, CBCa) were previously thought to be inactive and possibly unstable and were thus abandoned for their neutral counterparts CBD, CBG, and Delta-9-THC. Neutral phytocannabinoids are thus widely researched and have an expanding list of clinical studies (both human and animal). New research is released nearly daily uncovering potential applications for the numerous chronic illnesses that lower the quality of life of billions of people in the world.
Then there is the concept of the synergistic effects of phytocompounds such as terpenoids (terpenes), flavonoids, and cannabinoids working harmoniously within the ECS. Though still open to debate, the synergistic effects are sometimes referred to as the “entourage effect.” While the science behind terpenes is expanding, it is often used within the adult-use, high-THC cannabis industry to define a completely different classification system, whereby terpenes are used to categorize common indica, sativa, and hybrid-like “strains” (chemovars) as a way to sell/categorize cannabis flower in adult use markets.
These categories reflect “induced effect” on the consumer. As such, terpenes are likely what cannabis connoisseurs claim are responsible for the sedating (anti-anxiolytic) or alerting effects of cannabis; aka indica and sativa, respectively. Ironically “indica” and “sativa” are also common terms when cannabis producers (cultivators) refer to plant growth structure, where indica-type (also called Afghani) plants are bushy, more squat, wide-growing patterned, and where sativa-like (tropical) plants grow tall and lengthy often with “skinnier” leaves. It is confusing—I know.
Anecdotally, there is little to no doubt that the phytocompounds perform synergistically to induce effects on the body. The most elemental realization of this is the fact that a pure D9THC market (unregulated or regulated) does not exist. This is because Delta9THC alone is quite intolerable. Unlike the unpleasant nature of D9THC, cannabidiol (CBD) is well tolerated and, according to the World Health Organization, non-addicting and non-toxic (World Health Organization, 2018). The pathways and implications of this new compound class would seem to be endless in its impacts on the human body in disease and aging.
The new overlap of wellness, beauty, self-care, and dawn of “inflamm-aging” has also fueled the expansion of cannabinoids being researched in R&D departments. Inflammation, according to cannabis research published worldwide, suggests several inflammatory pathways and receptors. The CB2 receptor, a main endocannabinoid receptor, is thought to play a key role in inflammation alongside phytocannabinoids. But the research does not stop there. The transient receptor potential channels (TRP), Adenosine receptors (A2A), and Cyclooxygenase (COX-2) pathways show great promise when it comes to a multitude of phytocannabinoid induced activation or inhibition as related to inflammation. These TRP channels are the same as those for capsaicin and turmeric.
Anti-inflammatory cytokines may also play a role in the harmonious function of cannabinoids and terpenes. One study suggests that deficits in working memory and an age-related increase in pro-inflammatory cytokines were both reversed by beta-caryophyllene (BCP), a popular cannabis terpenoid (Lindsey, et al., 2019). Another terpene, Terpinolene, alongside NSAID administration in animals, was suggested to exert a synergistic anti-inflammatory and analgesic effect (Macedo, E., et al., 2016).
Cannabinoids do not stop at reducing skin and muscle inflammation; they have also been shown to effect neuroinflammation. Cellular (in vitro) neuroinflammation models show promise for phytocompounds such as CBG in reduction of pro-inflammatory cytokines (i.e., IL-1β, TNF-α, IFN-γ) and potential effects against neuroinflammation and oxidative stress (Gugliandolo A., et al., 2018).
Cannabigerolic acid (CBGa), discovered in 1965, is naturally abundant within the hemp plant and is referred to as the “stem cell” of cannabinoids. Many cannabinoids are naturally formed from CBGa through normal chemical synthesis of this compound into more commonly known counterparts such as CBDa (hemp varieties) and THCa (adult use varieties). Not surprisingly, an expanding amount of CBGa-specific hemp genetics are now being produced, allowing for another expansion of the cannabinoid market to include CBGa and CBG-based extracts.
CBGa is thought to have a weak binding affinity to CB1 and CB2. Despite the possible inactivity at these traditional endocannabinoid receptors, the whole class of acidic cannabinoid [acids], including CBGa, have shown to be more potent PPARγ agonists than their decarboxylated analogues (Nadal X., et al., 2017). Many other chemical pathways such as the 5HT (serotonin) have shown promise when it comes to cannabinoids (Resstel, et al., 2009).
Which cannabinoid profile, which terpenoid profile, which extraction method, and which delivery method are the questions cosmetic chemists are now asking themselves. The information exists for cosmetic chemists to answer these important, questions, and a plethora of anecdotal evidence is mounting behind fast-growing consumer demand which is further driving capital market spending and deployment of resources to research and the science behind the “glow up” of cannabis.
About the Author: Nicole Foss MBA, MSN, RN is vice president, NeXtraction Inc. She may be reached at info@nextraction.com.
References
- Gugliandolo A, Pollastro F, Grassi G, Bramanti P, Mazzon E. In Vitro Model of Neuroinflammation: Efficacy of Cannabigerol, a Non-Psychoactive Cannabinoid. Int J Mol Sci. 2018;19(7):1992. Published 2018 Jul 8. doi:10.3390/ijms19071992
- Hannon MB, Deabold KA, Talsma BN, Lyubimov A, Iqbal A, Zakharov A, Gamble LJ, Wakshlag JJ. Serum cannabidiol, tetrahydrocannabinol (THC), and their native acid derivatives after transdermal application of a low-THC Cannabis sativa extract in beagles. J Vet Pharmacol Ther. 2020 Sep;43(5):508-511. doi: 10.1111/jvp.12896. Epub 2020 Jul 31. PMID: 32735381.
- Lindsey, L., Daphney, C., Oppong-Damoah, A., Uchakin, P., Abney, S., Uchakina, O., ... Murnane, K. (2019, June 04). The cannabinoid receptor 2 Agonist, β-caryophyllene, improves working memory and REDUCES circulating levels of specific proinflammatory cytokines in aged male mice. Retrieved February 23, 2021, from https://www.sciencedirect.com/science/article/abs/pii/S0166432819304516?via%3Dihub
- Macedo, E. M., Santos, W. C., Sousa, B. P., Neto, Lopes, E. M., Piauilino, C. A., Cunha, F. V., Sousa, D. P., Oliveira, F. A., & Almeida, F. R. (2016). Association of terpinolene and diclofenac presents antinociceptive and anti-inflammatory synergistic effects in a model of chronic inflammation. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 49(7), e5103. https://doi.org/10.1590/1414-431X20165103
- Nadal X, Del Río C, Casano S, et al. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. Br J Pharmacol. 2017;174(23):4263-4276. doi:10.1111/bph.14019
- Resstel, L. B., Tavares, R. F., Lisboa, S. F., Joca, S. R., Corrêa, F. M., & Guimarães, F. S. (2009). 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioral and cardiovascular responses to acute restraint stress in rats. British journal of pharmacology, 156(1), 181–188. https://doi.org/10.1111/j.1476-5381.2008.00046.x
- World Health Organization- Expert Committee on Drug Dependence. (2018). CANNABIDIOL (CBD) Critical Review Report.
- United States Congress. https://www.congress.gov/bill/113th-congress/house-bill/2642
