Understanding the Science of Cannabis Product Development

The rapidly expanding global market for cannabis products should be based on the medical science of cannabis and how it interacts with the human endocannabinoid system. Companies that base their brands on the science of the entourage effect and develop products around plant genetics using cutting-edge extraction technology will rule global market share, reshape our medical system and recreate how we choose to find relaxation and stimulation. Current political and economic situations have created non-science-based markets and products that are not serving medical patients, and are not designed to fill the research gaps we desperately need to fill to legitimize the emerging anecdotal evidence. By understanding whole-plant extractions better, allowing for their medical use and removing restrictions on research and development, businesses will be able to better plan for long-term profitability and sustainability.

Recorded history has been written by the victors, and the propagandizing of Cannabis sativa L. in the U.S. is an obvious and tragic example. We quickly forget the history on which we should be making decisions and worse, we sometimes base our future on a revised version of it. Less than 100 years ago, a handful of men took thousands of years of knowledge and successfully distorted it for their own financial and political gain. We allowed the copacetic relationship between cannabis and humans to be severely maligned by propaganda, and hundreds of thousands of lives have been medically, socially and financially destroyed to serve a few (1). While underground medical practitioners, caregivers, and scientists have made some progress in unraveling the last century of lies, we are still on the path that a small group of men devised (2).  Current progress to legalize cannabis will further our understanding of this important plant as medicine, but education and de-stigmatization on a larger scale needs to occur. 

Traditionally, medicines have been created from plants and were often whole-plant preparations or basic tinctures or extractions until science advanced and we understood how to better isolate the most active agent in plants. There were many known preparations of Cannabis sativa and it was used widely for treating a number of ailments, primarily pain management. One of the first medical isolations was the alkaloid morphine from opium poppies by Friedrich Wilhelm Adam Serturner in 1805 (3). This was closely followed by other isolates as well as the invention of the hypodermic needle in the early 1850s. Since cannabis is not water soluble, it could not be directly injected into people, which contributed to its medical decline. Its use was completely decimated after its political damning in the early 1900s (4).  Morphine and other opiate-derived drugs quickly supplanted cannabis as the primary pain management tool. From there, chemists learned to synthesize morphine, and its derivatives have been developed into multiple products, many of which have now devastated millions of people’s lives. 

Aside from the water insolubility and political pressure, another issue facing cannabis was determining a “safe” dosage.  Once its use and research declined, however, it’s difficult to argue that the creation of the “one-pill-fits-all” system that developed in pharma has been safe or effective for everyone when one considers the addiction, side effects, and deaths associated with prescription drug use. We have also recently discovered that people have genetic predispositions, as well as metabolic differences, to drug toxicity and efficacy (5,6). This new area of research in individual reactions and efficacy is very complicated, and requires extensive testing, to pair an individual with a drug that will be effective and not have harmful side effects.  

Now, more than a century later, the pharmaceutical industry, based on isolation of single molecules, has created a clinical trial process that is not equipped to handle the multitude of compounds and natural variations of whole-plant preparations. This leaves us in a similar position as in years ago of having a lack of the “approved” type of data that other drugs were allowed to explore because of their federal scheduling. However, the rising tide of anecdotal evidence of overwhelmingly safe cannabis use as a medicine is piling up, and medical doctors and researchers are starting to piece together some of the important components for specific treatments and preparations.

The safety of using whole plant applications in anecdotal evidence, as well as its historical use, lends itself to researching chemovars to support more immediate access for medical treatments. Isolation is laborious and expensive in practicable terms for commercial production of products. The only way to procure a single pure molecule is by using preparatory chromatography after extraction. This process is not scalable for the production required to extract the low quantities of cannabinoids (CBD) found in hemp. One way to alleviate this issue is to grow cannabis for high levels of a specific cannabinoid and extract for its boiling point. If we do not find a way to approve whole plant research and use, this industry will be taken over by the usual synthesizing of the molecules to produce quantity.

Medical cannabis legalization in the U.S. began in 1996 when California legislatively passed Proposition 215 (7); from there Oregon, Washington and Alaska all became legal medical use states. They legalized on the medical use of Cannabis sativa L.-the whole plant and not a low tetrahydrocannabinol (THC) varietal recently defined as “hemp.” There were no restrictions on cannabis cultivars, and there were no recommended dosages.  A patient could simply grow and extract the medicine they needed from the plant and treat themselves like humans have done for thousands of years. To date, no death has occurred from cannabis consumption, no prevalent addiction exists and the plant has proven to help reduce the need to pile pharmaceutical drug on top of pharmaceutical drug to treat what are often debilitating side effects. We knew as early as the late 1880s that cannabis extracts could be successfully used to wean people off opiate addiction and yet we continue to ignore the science because of the politics.

In 1889, an article by Dr. E. A. Birch in The Lancet, still one of the world’s leading medical journals, outlined the application of cannabis for the treatment of opium and chloral hydrate withdrawal symptoms-the mixture reduced the opium craving and acted as an anti-emetic, which is a drug that is effective against vomiting and nausea.

(Click to enlarge) Figure 1: The human endocannabinoid system, an internal system of connected signaling mechanisms, regulates a huge variety of effects in our bodies: metabolism, homeostasis, restfulness and anxiety, pain, mood and more (12).

So how can we understand some of this history through the lens of extraction and formulation science? How do we avoid repeating history’s mistakes when we think about new product development? How can we incorporate modern scientific advancements with traditional knowledge? One of the most significant and recent scientific discoveries since that time is the endocannabinoid system (Figure 1) (12). This internal system of connected signaling mechanisms regulates a huge variety of effects in our bodies: metabolism, homeostasis, restfulness and anxiety, pain, sexual health, mood and more. Our bodies naturally have molecules that interact with our endocannabinoid system, and there are other molecules (such as THC and other cannabinoids) that also interact with the same receptors. Additionally, the evidence is accumulating that having more of the other naturally occurring biomolecules from the cannabis plant, such as terpenes and flavonoids, elicits very different effects that work far better than single molecule preparations alone. This theory has been named the entourage effect, and, given the complexity and number of different compounds in cannabis, it will take some time and careful research to fully understand the various important active compounds for treating specific ailments (13). There are clearly specific cultivars with specific chemical profiles that can be grown reproducibly that are useful for specific medical treatments, and not for others. But it’s only a matter of time before the analytical chemistry and big data analyses can begin to make the connections. This is where understanding the complexities of extractions, isolations and formulations will be useful to harness the full capability of the plant.

How we do plan science-based formulations in a constantly and rapidly changing regulatory environment? For a business plan to be of value in this growing industry, its 5- to 10-year plan must be considered in this mercurial and changing environment. As an example, many startups have moved from “cannabis” to “hemp” when creating CBD  product-based businesses (9). This migration hasn’t been based on science but simply because the regulations around cannabis-derived CBD are severely restrictive, legally punitive and financially unsupported by a federal banking system. In fact, the science shows over and over again that isolating and purifying the cannabinoids vastly reduces their medical efficacy. 

Cannabis is an extremely malleable plant that has the ability to be cultivated for high levels of certain cannabinoids. It seems strange that current regulations focus on one or maybe two specific molecules (THC and CBD) that don’t even naturally occur in a freshly harvested cannabis plant. Why is it that the legalization platform did not occur on cannabigerolic acid (CBGA) or cannabigerol (CBG)? As the mother of all cannabinoids (the molecular precursor for the enzymatic processes to synthesize the other naturally occurring cannabinoids), CBGA is not psychoactive and therefore could have been politically acceptable (8). With the growing ability to genetically modify plants, we have begun to breed for the end-product, which can improve processing and medical efficacy through more full spectrum profiles.

Because of political bias, we are growing an industry based on a single molecule-CBD-that has a medical Bell Curve. The Bell Curve refers to medical treatment and sustained efficacy. In a Bell Curve response, over time, an increase in the dosage does not correspond to an increase in efficacy. However, when a whole plant treatment is provided, efficacy increases-this is medicine (10). Unfortunately, legislators and regulators did not and largely still do not know this important fact when building a legal foundation for an industry based on medical use. Our challenge as scientists, and business professionals, is to inform legislators, regulators and the public that single-molecule products are being produced because of our political environment, not because it is rooted in medical science. Unless the medical science is based in research around the newly discovered endocannabinoid system, we have not progressed past the disinformation spread by prohibition and 19^th century medical practices.

I have had the privilege to read and watch a multitude of business pitches in the past few years. What is truly disturbing are two things. First, CBD-only products are being touted as a “cure all.” CBD is a powerful cannabinoid, but it is not a “cure all.” Second, the laser focus on only CBD and the continued demonizing of THC (the so-called “recreational cannabinoid”) is continuing to support and spread the propaganda around Cannabis sativa L. that began in the early 1930s. Not only has CBD been shown to work better when there is a small amount of THC present (and most often other terpenoids and biomolecules-the entourage effect), but THC itself is medically relevant for a wide range of ailments. 

The sheer number of companies adding CBD into everything is damaging the cannabis industry. Not only are companies acquiring CBD from questionable sources that contain impurities and pesticides, they are then adding this into products that are often the only legal form of medicine for patients to consume. They are marketing CBD products that contain minuscule or no actual CBD in them. This is snake oil and it won’t take long for people who try it to make the correct conclusion that these CBD products do not work. The danger is they will assume all CBD products are fake and will stop buying all medically active cannabis products.  Again, science is not prevailing here but instead political restrictions and opportunistic product developers.

(Click to enlarge) Figure 2: To produce a full spectrum extract for pharmaceutical-grade products, the most commonly used methods are supercritical CO2 and ethanol (14).

Along these lines, the descriptors around whole plant extracts need to be defined. I read one pitch deck that naively bragged their products would be “full-spectrum distillates.” The distillation process is designed to purify mixtures and separate molecules from those with different boiling points and molecular weights. The vast majority of all the other biomolecules such as terpenoids, fats, lipids, chlorophyll and waxes are removed. Therefore, by definition, a distillate cannot be “full spectrum” (11). To produce a full-spectrum extract for pharmaceutical grade products, the most commonly used methods are supercritical CO₂ and ethanol (14) (Figure 2). Supercritical and subcritical CO₂ (Figure 3) create a vast variety of end products that can contain precious terpenes, and be tuned to acquire targeted cannabinoids in the material (15). A warm ethanol extraction is by far the most efficient method, and will perform an exhaustive extraction, which means pulling all of the compounds out of the plant, including chlorophyll that can be quickly filtered from the crude oil. The down side is the loss of terpenes in the solvent recovery process. But a preprocessing of steam distilling will remove purified terpenes that are added into a final formulation can create a more truly full-spectrum extract. Cold ethanol extraction will also help retain terpenes. It is a much slower process and not as efficient, but it can eliminate the need for post processing the crude oil.

(Click to enlarge) Figure 3: Supercritical and subcritical CO2 create a vast variety of end products that can contain precious terpenes, and be tuned to acquire targeted cannabinoids in the material (15).

Understanding how different extraction protocols are performed and the various outcomes is crucial in the product development process. A combination of extraction methods is often successfully used to create greater processing efficiencies and a greater diversity of products on the shelf with a single batch of material. However, it’s not only a good extraction and formulation that will make a successful product or brand. Every product line is dependent on a message and the line should be created to solve a problem or fill a niche. In the educated connoisseur and medical markets, how and why it is made is the inherent value of the brand. Consumers will pay more for products and brands that bring value to their community. These are the consumers that are aware of the social destruction and medical ills created and propogated by prohibitionists, and will listen when you create a product that restores the value and honor of the relationship between humans and cannabis.

The scientific and business leaders of this growing industry cannot perpetuate the disinformation of the past. We cannot build an industry based in health and well-being and sustain it without bringing the public and politicians along with us into an era of new medical science based on the endocannabinoid system, the entourage effect, and how to create whole-plant formulations and their application to individuals. It is time we investigated the real science, and develop products for brands that take our culture to the next step, and not pander to old medical practice, the traditional pharmaceutical model and short-sighted investors.  It will take a concerted effort. Product development and placement are the platform on which to build and heal our bodies, minds, culture and environment.  

References

1. https://medicalmarijuana.procon.org/view.timeline.php?timelineID=000026text_4_reference_(2017).
2. https://www.seniorstoner.com/education/anslinger-hearst-rockefeller-cannabis-history/ (2015).
3. https://www.uchicagomedicine.org/forefront/news/2005/may/as-morphine-turns-200-drug-that-blocks-its-side-effects-reveals-new-secrets (2005).
4. https://www.pbs.org/wgbh/pages/frontline/shows/dope/etc/cron.html
5. https://www.washingtonpost.com/national/health-science/can-genetic-testing-help-doctors-better-prescribe-antidepressants-theres-quite-a-debate/2019/03/29/626e4fec-2bd7-11e9-984d-9b8fba003e81_story.html?utm_term=.652c9f2a42a8 (March 2019).
6. https://www.merckmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-metabolism (2019).
7. https://ballotpedia.org/California_Proposition_215,_the_Medical_Marijuana_Initiative_(1996)
8. https://www.alchimiaweb.com/blogen/cannabigerol-cbg/ (2018).
9. http://hemplogic.blogspot.com/2017/12/big-pharma-vs-hemp-based-cbds-and.html (2017).
10. https://accugentix.com/blog/cannabis-using-scientific-or-slang-names/ (Jan. 30, 2019).
11. https://rhizosciences.co/full-spectrum-cannabis-extracts-superior-cbd/ (2015).
12. https://www.sciencedirect.com/topics/neuroscience/endocannabinoid-system. Multiple abstracts (2009-2018).
13. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165946/ (2011).
14. https://blog.edenlabs.com/hemp-extraction-and-the-versatility-of-the-coldfinger-ethanol (2018).
15. https://blog.edenlabs.com/ethanol-vs-co2-which-method-is-best (2019).

About the Guest Columnists

Dr. Amber Wise is currently the Science Director at Medicine Creek Analytics, a certified cannabis testing laboratory in Washington state. She was previously the Science Director at Avitas, a licensed cannabis grower and processor in Washington and Oregon. Direct correspondence to: amber@medicinecreekanalytics.com

A.C. Braddock is CEO of Eden Labs, a 25-year-old extraction technology company and a career entrepreneur with extensive success in business development, product placement, brand development, business infrastructure and creating modern company cultures. Her mission is the furthering of whole plant medicines, healthy extraction methodologies and socially responsible business practices. She is Chair of BOD for NCIA, Vice Chair of Washington’s Cannabis Alliance and BOD of The Initiative. Direct correspondence to: ACBraddock@edenlabs.com

How to Cite This Article
A. Wise and A.C. Braddock, Cannabis Science and Technology 2(3), 16-20 (2019).