Cannabis Science and Technology July/August 2021

In this interview, Dr. Marion McNabb discusses her latest study as well as her background and key insights into the medical cannabis industry.

How Dr. Marion McNabb is Looking to Take the Medical Cannabis Industry to the Next Level

Sheila Gibson, the founder of Aura IP Law, shares her insights, knowledge, and advice on cannabis IP, including emerging topics.

Intellectual Property and Cannabis: A Look at the Current Landscape and Emerging Topics

Isolated CBD, full-spectrum oil, and even smokable hemp are all being diluted down by a draconian regulatory framework that needs to be changed to facilitate growth, innovation, and prosperity throughout the industry.

Hemp Regulations and the Restrictions on Innovation

This article outlines types of cooling equipment that contribute to sustainability and energy-efficiency; how to develop a customized cooling strategy that meets growers’ sustainability goals; and steps growers can take to improve operating costs and more.

Is Carbon-Neutral Cannabis Possible?

Zacariah Hildenbrand, PhD, of Inform Environmental, LLC and one of 

’s Editorial Advisory Board (EAB) members, is hosting a new seminar series called “The Science of Cannabis and Hemp.” The first installment of this series will air on Thursday, September 16th at 2 pm EST from this link: 

Hildenbrand will be joined by several friends and colleagues throughout the series where they plan to have enlightening conversations on several technical topics in this new frontier of medicine. Topics of coverage include the various chemical classes found in cannabis and hemp, commercial cannabis/hemp analysis, genetics, and the effects of various environmental factors on phytochemical content. Each installment will also feature a live q&a session with the audience. The series is being presented by Curtis Mathes Grow Lights, Orxata Media Group, Medusa Analytical, and Shimadzu.

Articles

Zacariah Hildenbrand, PhD, of Inform Environmental, LLC and one of Cannabis Science and Technology’s Editorial Advisory Board (EAB) members, is hosting a new seminar series called “The Science of Cannabis and Hemp.”

Educational Science Seminar Series Launching Today

Agtech innovator, Dewey Scientific, announced the online publication of new data expressing the first experimentally validated disease resistance gene in cannabis (1). The research article is titled, “

Discovery and Genetic Mapping of PM1, a Powdery Mildew Resistance Gene in Cannabis sativa L

,” (2) and able to be found under the special topic “Cannabis IPM – Insect Pests and Diseases” by 

Dewey Scientific’s main objective from this study was to provide the groundwork for the discovery of additional sources of genetic resistance to the various pathogens that can infect 

“This discovery and characterization of naturally occurring powdery mildew resistance breaks important new ground, helping to elevate our understanding of the cannabis crop to that of other economically vital agricultural commodities such as hops, berries, or grapevines,” said Dr. Jordan Zager, Dewey Scientific cofounder and CEO (1). “The identification and characterization of PM1 is the first step in establishing the next generation of cannabis cultivars that are suited both for large scale production and optimal efficiency. At Dewey, we’ve already integrated this key resistance gene into over a dozen commercial-ready varieties through classic breeding techniques.”

Authors included on this peer-reviewed research are Dewey Scientific cofounder Paul D. Mihalyov, PhD and Oregon CBD Director of Research & Development Andrea R. Garfinkel, PhD. Genotyping technologies were provided by Lighthouse Genomics and Génome Québec. Dewey Scientific’s founding team also includes Chief Science Officer Dr. Mark Lange, who is one of the world’s foremost experts on terpene biochemistry and natural product biosynthesis. Lange and Dr. Zager have published additional research in peer-reviewed scientific journals, such as 

“Pest control strategies that require active management can be difficult to communicate and synchronize across vulnerable farms. Instead, using plant varieties with a naturally robust immune system can make a grower’s life much easier,” said Mihalyov (1). “Taking advantage of natural genetic resistance is also a more sustainable approach than the ‘spray and pray’ method.”

For several plant pathogenic fungi, powdery mildew has become a commonly used term. This includes fungi from the genus 

, affecting both commercially cultivated hemp and cannabis. In other studies, resistant plants may have been occasionally recognized. This scientific investigation is the first to track and verify its genetic heritability. Located in the open-access manuscript (2), the authors were also able to develop a genetic marker to detect 

 with a simple assay, allowing the trait to be introduced into any cultivar using classical breeding methods instead of transgenics or gene editing.

https://www.businesswire.com/news/home/20210830005595/en/Dewey-Scientific-Announces-Peer-Reviewed-Research-Identifying-the-First-Powdery-Mildew-Resistance-Gene-in-Cannabis

https://www.frontiersin.org/articles/10.3389/fagro.2021.720215/full?utm_source=F-NTF&utm_medium=EMLX&utm_campaign=PRD_FEOPS_20170000_ARTICLE

https://academic.oup.com/plphys/article/180/4/1877/6117720

Dewey Scientific discovers the first powdery mildew resistant gene found in cannabis.

Peer-Reviewed Research Identifies the First Powdery Mildew Resistance Gene in Cannabis 

Suppose some medical problem arises and you go to a doctor to have your problem treated. To be able to perfectly treat any problem you might have, your doctor would have to have a complete understanding of:

. Your doctor would have to have a perfect understanding of the science behind human health, including, for example, human anatomy, physiology, cell biology, neurology, and psychology. He would have to have perfect understandings both of the body functioning that’s common across people in society (population health), as well as that which is idiosyncratic to you (genomics).

. Your doctor would have to have a perfect understanding of the science behind the symptoms, causes, and nature of progression of all human disease, including, for example epidemiology and pathology.

How medications and treatments address disease

. Your doctor would have to have a perfect understanding of disease treatment, including, for example, pharmacology, physical therapy, and surgery.


Of course, no doctor out there has such a complete understanding of human health and disease. In fact, all doctors on the planet taken as a whole do not have such a complete understanding of health and disease.

Society’s ability to treat medical conditions is intimately tied to the extent of its knowledge and use of science and technology. No doubt, we’ve come a long way over the millennia. On the other hand, we still have so far to go.

Focus, now, specifically on medications used to treat dysfunction and disease (as opposed to devices, surgery, diet, etc.).

Before the 19th century, medicines generally consisted of plants and plant-based extracts, which contain a large variety of bioactive compounds. Advances in natural product chemistry and extraction technologies during the 19th century stimulated a “seminal” transition in Western medicine, shifting the focus away from multi-component extracts (whole plant), toward purified isolates, either natural, or later, synthetic (see Figure 1).

The isolation of morphine from opium by Friedrich Sertürner in 1805 was “the first isolation of a natural product from a plant,” which “kick-started natural product chemistry.” As researcher Eyan Huxtable notes (1):

"The isolation of morphine from opium —the first isolation of a natural product—was a seminal event in the development of pharmacology as an independent discipline. The purification kick-started natural product chemistry and quickly led to the isolation of a host of other alkaloids [including strychnine, caffeine, quinine, nicotine, and codeine].…

As a consequence of his studies, Sertürner established the principle that plants contain active substances that, on isolation, carry the therapeutic properties of the plant."

Over subsequent decades, analytical chemists and apothecaries (medicinal chemists) continued to isolate and characterize “the active principles in medicinal plants.” By the latter half of the 19th century, pharmacology had been established as a scientific discipline (2). Furthermore, the isolation and purification of plants’ active compounds became increasingly essential for medications for several reasons, including the newfound ability to administer accurate doses, the ability to prevent toxic effects due to impurities in the plant, and, by the end of the century, the ability to synthesize structurally similar substances based on better understandings of chemical structures (3).

During this period, the latter half of the 19th century, the top ten causes of death were all due to bacterial infections. Bacteria, such as those causing tuberculosis, diphtheria, scarlet fever, and whooping cough, spread through the air from person-to-person. Bacteria, such as that causing malaria, spread from insects or animals to people. Bacteria, such as that causing dysentery, cholera, or typhoid fever, spread due to lack of proper sanitation. Finally, bacteria causing post-injury infections spread due to lack of proper medical sanitation practices (see Figure 2 below).

Paul Ehrlich, a late-19th century German researcher, significantly shaped the course of drug discovery in Western medicine. Ehrlich studied how our immune systems respond to bacterial infections, that is, how our bodies generate antitoxins, or antibodies, to fight the toxins released by bacteria that have invaded our systems. Ehrlich’s research led to the 

concept: the idea that an isolated compound (the treatment) could be used to hit a single disease target in the body (bacterial infection), thereby curing the disease, while leaving the rest of the body intact. Magic bullets are 

: they have single actions with few side effects (4). Ehrlich’s 1909 discovery of Salvarsan, “the first effective – but rather toxic – remedy for syphilis,” was the first magic bullet discovered (penicillin was another) (5). In 1908, Ehrlich received the Nobel Prize in Physiology or Medicine for his research on our immune response to toxins (6). He also pioneered the concept of cell receptors, ligands, and the lock-and-key concept of drug target mechanisms (7). That is, he provided the notion of a clear entity (a receptor) for medications to target.

Ehrlich’s work has had a profound effect on drug discovery since then, for establishing the 

"Currently, the main paradigm in drug discovery is the development of target-specific inhibitors... This mainstream view has its origins in the so-called “magic bullet” as enunciated by Paul Ehrlich over 150 years ago. Indeed, such concept was engraved in the mind of many health professionals and researchers as the top achievement in drug discovery."

In short, subsequent drug discovery efforts focused on matching isolated substances (one drug) to isolated targets. Researchers searched for isolated compounds (as opposed to whole plant extracts) from natural products — or better yet, they artificially synthesized compounds to serve as treatments. And they used those isolated compounds to act as activators (ligands) of isolated targets, such as specific enzymes or cloned receptors (as opposed to more holistic tissue cultures). This new paradigm was strictly adhered to by Western medicine. The Western medicine perspective starkly contrasted with the approach taken by Eastern medicine, namely, using whole plant medicines to address holistic health problems (see Figure 2).

Continued research efforts led to advances in pharmacological science and technology. Efforts to focus on single or isolated 

were aided by advances in (i) extraction technologies (mass spectrometry) enabling researchers to better isolate compounds from natural ingredients; (ii) chemical science enabling researchers to understand and recreate the structures of extracts; and (iii) synthesis technologies that enabled researchers to artificially recreate and potentially enhance natural products (9)

tissue cell culturing (10). Efforts to match isolated treatments to isolated targets were aided by advances in bioinformatics (such as genomics, metabolomics, proteomics) and screening (for example, HTS, microarrays, assays, chemical libraries) technologies (11).

Bifurcation of Holistic and Western Medicine

The development of the science and technology needed for researchers to be able to identify and isolate single compounds from plant extracts changed the course of Western medicine. This ability led scientists to the principle that a single active component in a plant acting on a single target in the human body was wholly responsible for the plant’s therapeutic effects. And it was this principle that caused the practice of medicine to bifurcate into two forms: conventional and alternative.

Centering around the use of purified isolates in treating disease, 

, is reductionistic in nature. Its paradigm is “one drug, one target and one disease" (12). In contrast, traditional 

forms of medicine, which include, among others, herbal or whole plant medicine, traditional Chinese medicine, and Ayurvedic (Indian) medicine, are more holistic in nature. Alternative forms of medicine view plants and people each as embodying intertwined systems of activity. This alternative paradigm views diseases as being due to systemic problems in the body and draws upon synergistic relationships in whole plant extracts to treat multifaceted dysfunction in the body (13).

The newfound ability to isolate individual compounds, together with the one-compound-one-target presumption, radically changed how plants were used in Western medicine. Henceforth the 

healthcare industry insisted on the exclusive use of isolated compounds in healthcare – rather than whole plant extracts – for three reasons (14). The use of isolates enabled:

2. Elimination of toxic effects due to impurities in plant product, and

3. Synthesis of related compounds for use in other valuable drugs.

(15). This demand for purity comes from the assumption that the compound forming the basis of the drug is the sole factor causing the desired outcome. In this case, the presence of any impurities – intentional (dilutors or toxins) or unintentional (residual plant compounds) in nature – might influence the efficacy (potency) and/or safety of the pharmaceutical products (16). This assumption, which forms the basis of Western medicine, stands in stark contrast to the fundamental assumption held by practitioners of whole plant medicine that multiple compounds within plants work together in our bodies to create synergistic therapeutic outcomes (17).

The Current State of Pharmacological Science and Technology

Sertürner’s isolation of morphine kicked off 19th century through early-20th century advances in microbial and pharmacological science and technology. Numerous other discoveries occurred in compound extraction, purification, and synthesis, not to mention Ehrlich’s work in establishing the one drug-one target paradigm. Taken collectively, these myriad advances paved the way for the introduction of a series of vaccines, together with improvements in sanitation, that largely eradicated death due to acute disease (see Figure 3).

Now that acute infections were treatable, mid- and late-20th century people were able to live longer lives. The bad news is that since treatments have since been available for acute infections, people have been living long enough to suffer and die from chronic health conditions (see Figure 3).

The ability to treat acute infections was, indeed, a tremendous achievement of the 19th and 20th century pharmaceutical industry. At the same time, however, during this period, Western society became locked into a specific drug discovery paradigm: one drug, one target. This paradigm was designed to address a specific disease environment (single-faceted bacterial infections), which has since been replaced by a completely different environment (multi-faceted chronic conditions). Yes, acute infections still occur, but we now have the treatments to address them (18).

Yet, since we’ve conquered acute diseases, what we’ve needed – and still lack – are treatments that effectively address the new, multi-faceted diseases that have come to replace acute diseases as the main causes of death.

Over recent decades, pharmaceutical companies have been increasing their resource expenditures on new drug discovery. While science and technology have progressed enormously, the discovery of new drugs that have been effective in treating our current health problems has been dwindling. As Rutgers researchers report in, “Plants and human health in the twenty-first century” (19):

"… [D]espite the remarkable progress made by chemistry, pharmacology, molecular biology, genome research and high-throughput screening, the NCE [new chemical entity] pipelines of pharmaceutical companies are at historically low levels."

At the same time, historical methods used to treat disease are becoming less effective, for two primary reasons. First, new bacteria and other pathogens have been emerging that are resistant to traditional treatments. Second, existing medications designed under the one drug, one target paradigm are not effective at addressing chronic conditions with multifaceted targets. More from the Rutgers researchers (20):

"The NCE paradigm of the twentieth century attempts to treat complex diseases with a ‘single golden molecular bullet’. The first flaw in this paradigm appeared relatively recently when problems of resistance to antimicrobial and anticancer drugs became apparent. The multifactorial nature of many complex diseases, such as diabetes, heart disease, cancer and psychiatric disorders, is also an important consideration. Most of these diseases cannot be ascribed to a single genetic or environmental change but arise from a combination of genetic, environmental or behavioral factors."

The healthcare industry has been using an old paradigm to address healthcare for a new world. What the industry needs is a new paradigm that will address conditions present in the new environment.

Parts of society have already been moving in a new direction. Patients, for their part, have been transitioning away from the take-a-pill-to-treat-a-symptom approach to a new holistic, live-a-healthier-lifestyle approach. What used to be considered alternative lifestyles – traditional Eastern practices, including functional foods, whole plant medicine, and meditation – are becoming more mainstream. As a case in point, a 2018 press release by Hexa Research reveals large expected growth in the global herbal medicine market, “driven by rising popularity of herbal therapeutics compared to conventional drugs” (21):

"The global herbal medicine market is expected to reach USD 117.02 billion by 2024, driven by rising popularity of herbal therapeutics compared to conventional drugs. The market for herbal medicines and remedies is anticipated to record profitable growth due to their cost-effectiveness as compared to allopathic ones."

The Federal government is also dipping its toe into the herbal water. In 1994, Congressed passed the Dietary Supplement and Health Education Act (DSHEA). Under this new act, dietary supplements, which include herbs and botanicals, can be more freely marketed, as long as no claims are made as to disease prevention, curing or detection. Instead, manufactures can make structure–function claims about products related to improving or maintaining normal physiological functions of the body (22). According to the FDA, “In the 25 years since the Dietary Supplement Health and Education Act of 1994 (DSHEA) was enacted, the dietary supplement market in the U.S. has grown from approximately 4,000 products to somewhere between 50,000 and 80,000 products” (23).

At the same time, healthcare providers, while not exactly embracing whole plant extracts, have at least realized the benefits of more holistic treatments. Providers are increasingly prescribing 

, that is, combinations of single isolate pharmaceutical compounds, to treat diseases that have become resistant to single-therapy treatments or that have never been effectively addressed by single-therapy treatments. Combination therapy has been used to treat, for example, tuberculosis, HIV/AIDs, cancer, cardiovascular disease, metabolic disease, and autoimmune disease (24–27).

Advocates of more holistic approaches to medicine generally tout the 

associated with whole plant extracts. Essentially, whole plant synergies result from having a multiplicity of compounds that are simultaneously absorbed by the body and work on different targets to create complementary effects. As Brazilian researchers Fabio Carmona and Ana Maria Soares Pereira so pithily express (28):

"The mechanisms of synergism among the compounds present in a single herbal extract are mainly related to two factors: the simultaneous solubility of a group of substances with different polarities, and the multiplicity of targets that these substances can act on, including enzymes, receptors, ion channels, transport proteins, antibodies, and many others."

As compared with using purified isolates, the use of whole plant extracts may provide better outcomes at lower doses with fewer side effects (29).

More holistic approaches to medicine, including whole plant medicine, have tremendous potential to help our healthcare system better address the 21st century environment for a variety of reasons.

Newer technologies being developed to enhance drug discovery efforts increasingly draw upon synthetic compounds as potential treatments for disease. Synthetic compounds are structurally simpler than natural molecules, which makes them easier to characterize and analyze. This brings to mind the idea of looking for your lost car keys underneath the street lamp, because that’s where the light is. It is thus not terribly surprising that recent drug discovery efforts using synthetic compounds as potential treatments have not been fruitful. On the other hand, nature offers a virtually untapped resource for researchers, which contains vast numbers of structurally complex compounds that have been naturally designed — “co-evolved” — to work together. More from Rutgers researchers (30):

"Nevertheless, comparative analysis of structural diversity in natural-product mixtures and combinatorial libraries suggests that nature still has an edge over synthetic chemistry, despite the fact that combinatorial libraries display more elemental diversity. Indeed, superior elemental diversity does not compensate for the overall molecular complexity, scaffold variety, stereochemical richness, ring-system diversity and carbohydrate constituents of natural-product libraries. It is generally believed that the complexity, diversity and vast number of plant-produced secondary metabolites will continue to constitute a resource beyond the capacity of current synthetic chemistry."

The completion of the Human Genome Project in 2003 (31) opened the research floodgates, leading to a better understanding of how our bodies work, specifically, the nature of similarities and differences across individuals and populations. The Project led to vast new areas of study, including (32):

: the study of the structure, function, evolution, and mapping of the genome.

: the study of how genes express themselves.

the study of proteins, that is, molecules that perform a host of functions in living organisms, including catalyzing metabolic reactions and responding to stimuli.

(plant and human): the study if metabolites, that is, the substances involved in cell metabolism.

Research into all the different omics has created a huge glut of information, which, in turn, has led to the development of a whole new set of tools to analyze these data, bioinformatics.


: “an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex.”

Notably, the omics technologies, together with bioinformatics platforms, are much better suited to the study of whole plant diversity and synergy than any other technologies to date. In other words, these new technologies open the door to the study of whole plant medicine (33).

Integration of the new life sciences with technologies are shifting the way researchers approach living organisms, from a reductionist view to a systems view. With a deeper understanding of how our bodies work, together with the tools needed to continue exploring new-found complex interrelationships, researchers are gaining new integrated understandings of living cells and organisms. Researchers are now redirecting their energy away from focusing on treating symptoms to focusing more on treating underlying disease.

Unsurprisingly, within this new systems paradigm there’s been an increasing acceptance of whole plant medicine, which "has been described as the ‘‘herbal shotgun’’ approach, as opposed to the ‘‘silver bullet’’ method of conventional medicine to distinguish the multitargeted approach of herbals from the monotarget approach of synthetic drugs addressing specific enzymes or receptors.…In recent years this ‘‘shotgun approach’’, understood as a therapeutic strategy which aims at multiple targets in an organism, has gained an increasing acceptance" (34).

Transitioning to 21st Century Drug Discovery

One of the primary reasons researchers have historically focused their studies on using isolated compounds to act on isolated targets is that doing so makes an intractable problem as easy as possible to manage. Unfortunately, simplifying the problem to make it easier to find solutions has led to solutions that don’t solve the problem. So then the task with which researchers are now faced is one of trying to address the more difficult problem of finding complex substances (e.g., combination therapies such as whole plant extracts) that address dysfunction in complex systems (people with chronic health conditions).

The good news is twofold. First, more systemic approaches to medicine – whole plant medicine in particular – have existed for thousands of years. A rich store of knowledge gathered over the millennia, for example embodied in traditional Chinese and Ayurvedic medicine, exists to guide practitioners in developing and applying combination therapy and whole plant medicine (

Second, the science and technology of drug discovery has come a long way since Sertürner successfully isolated morphine from poppies. More than two centuries of improvements in chemistry and extraction technologies and almost three decades of improvements in omics sciences and bioinformatics technologies has better prepared researchers to shift to a new paradigm.

What’s needed is to combine the best of Eastern and Western science and technology to discover the complex substances needed to treat our modern complex conditions.

Working with complex systems is difficult because they have funky characteristics, such as 

, that is, synergies, where 1 + 1 = 3, and 

, where small changes in initial conditions can cause large differences in outcomes. Perhaps an example will help clarify the challenge.

Researchers at St. Jude Children’s Research Hospital in Memphis, TN, conducted a study using two different treatments for leukemia, mercaptopurine (MP) and methotrexate (MTX).35 The researchers tested four different treatment scenarios:

: MP in combination with a low dose of MTX (L-MTX)

: MP in combination with a high dose of MTX (H-MTX)

The researchers reported, “Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments.” What the study showed is that the isolated treatments, MP alone and H-MTX alone, generated much more activity than the combination treatments, MP + MTX, did. Specifically, the researchers reported that “Only 14% of genes that changed when these medications were given as single agents also changed when they were given together.” If I’m understanding this correctly, when MP and MTX were administered separately, a total of 124 different genes reacted. However, when the two treatments were combined and administered together, only 17 of the original 124 genes still reacted under the new scenario. In this case, then, a lot of activity was prevented (perhaps unwanted side effects) by combining the treatments, rather than by administering either of them separately.

What we have, then, is an inability for researchers to predict what will happen when separate treatments are combined, simply by knowing what will happen when the treatments are undertaken in isolation. In this case, 

 investigate not just single components in isolation, but all different combinations of the individual components. The number of tests researchers must conduct under this new paradigm is thus exponentially greater than the number needed under the old, one drug, one target paradigm. That’s the challenge.

The current environment in Western medicine is not amenable to implementing a new system that combines traditional Eastern and Western approaches, that is, the paradigm needed to address 21st healthcare problems. Many of the forces in the current Western system – much science and technology, the FDA approval process, provider methods of practice, payment systems, etc. – are geared toward supporting a one drug, one target paradigm. As such, several aspects of the current system must change to make the environment more receptive to the new paradigm. Specifically, Western society needs: a new mindset for participants in the healthcare system; new technologies compatible with combination therapies; standardization of supply of whole plant products; and new regulations supporting development, safety, and efficacy of combination therapies.

As mentioned earlier, the new omics and bioinformatics sciences and technologies have led to whole new understandings of systems biology. Unfortunately, the majority of the Western medicine community has long-since been entrenched in the old, one drug, one target environment. Consequently, the industry must change its training and practice perspectives, from those centered around isolated bioactive agents and generic targets, to those that are more consistent with holistic conceptions of living organisms, one which recognizes both the homogeneous, as well as the heterogeneous, nature of patients (36).

The completion of the Human Genome Project marked a transition point in time regarding the process used to discover new drug candidates (37). Before the genome was sequenced, the new drug discovered efforts involved the 

. Researchers would start by finding new drug candidates. These were discovered by identifying active ingredients identified either from traditional use of medicinal products, from libraries of molecules whose pharmacology had been determined, or simply by chance. Once a drug candidate was found, researchers tried to find a target in the body that the drug could be used to affect.

The Human Genome Project provided a much better understanding of how substances act on various targets in the body to create outcomes. This new understanding changed the nature of drug discovery to the 

. Researchers now start by finding a target in the body to hit so as to change an outcome, from an “unhealthy” one, to a “healthier” one. After finding the target, new technologies are used, 

(HTS) technologies, which enable researchers to screen very large volumes of different substances.

Whole plant extracts contain hundreds of different compounds, many in trace amounts, which makes them exceedingly difficult to work with. Consequently, HST technologies have evolved to employ synthetic compounds, which are easier to characterize and analyze. Suppliers have been focusing on creating libraries of that contain vast arrays of isolated and well-characterized synthetic compounds. Unfortunately, whole plant extracts are now incompatible with many current HST technologies. What’s needed, then, is more advanced science and technology enabling researchers to more quickly and easily extract, characterize, and analyze compounds from natural sources (38).

The good news is that science and technology are both moving in this direction. For example, researchers are developing a new branch of pharmacology, 

, which combines systems biology with polypharmacology in the development of combination therapies (39). Furthermore, new characterization and screening technologies, combined with “spectral databases” are emerging as tools for discovering potential natural product therapies (40). Finally, research in the cannabis industry in particular is generating new extraction (41) and characterization technologies (42) specific to cannabis, but which methods can surely be adapted to use for other whole plant substances.

Transitioning to 21st Century Medicine: The Promise of Whole Plant Medicine

 O2VAPE is a vape equipment manufacturer that primarily supplies the legal cannabis and cannabidiol (CBD) markets in all 50 states and Puerto Rico. We provide high-quality, portable cannabis vaping products for recreational and medicinal consumers. We provide a lifetime guarantee on all of our vape batteries and are best known for our patented Flip Ultra and Flip Platinum products, as well as our award winning heavy metal tested cartridges and our new all glass cartridges containing no metals. We have always been focused on safety, quality, and innovation for the cannabis market. O2VAPE has never developed or sold nicotine or tobacco products.

As a veteran-owned company, do you do any educational outreach for veterans researching medical cannabis as a treatment option?

 As a veteran of the U.S. Navy, it has always been important to me to keep the veteran community top of mind since so many veterans rely upon cannabis medicine. I founded O2VAPE out of my garage in 2013 and we now serve veterans across the country. Currently, we have been conducting outreach in order to educate veterans and all consumers about the threat posed by the ban on shipping vaping equipment. The thing I’m most concerned about is how this law will choke the supply chain for the equipment that many of my fellow veterans and other medicinal cannabis patients around the country use to take their medication. We have worked hard to get to where we are by always putting the safety of our customers first.

In the December COVID-19 stimulus bill, there was a provision classifying all vape products as cigarettes, subjecting them to the same regulations as cigarettes. What kind of impact do you believe this will have on the cannabis vaping industry?

 We’re still analyzing all of the short-term and long-term ramifications, but it will be millions of dollars in extra costs and lost revenue. In legal cannabis markets across the country, the vaping component of our industry drives billions of dollars in revenue and creates thousands of jobs. By sliding this into the back of the stimulus package the law change misrepresents our vape customers as nicotine addicts and our technology as tobacco driven; it effectively aims to destroy our ability to serve consumers with the equipment we develop. The “stimulus” in this act actually puts people’s livelihoods at risk and businesses like mine in an even greater struggle than the pandemic created. Additionally, it will force consumers into a dangerous black market that should not exist.

The cannabis industry is federally unregulated; do you see cannabis vaping products going down a path toward Food and Drug Administration (FDA) approval? If so, what do you expect that will do the industry (will people be prepared for that level of testing and quality control)? Has your company taken any measures to prepare for that?

 We manage regulations from multiple entities, but just not directly from the federal government at this time. Currently, the Food and Drug Administration (FDA) does regulate Electronic Nicotine Delivery Systems (ENDS), which includes e-cigarettes, and the law snuck into the December stimulus package attempts to link these nicotine devices with those manufactured exclusively for use with cannabis. We think this is a gross overreach, particularly because O2VAPE and most responsible cannabis vape manufacturers have always followed strict quality and testing standards. We thoroughly test all of our products for durability and safety. We also age gate our purchases so there are safeguards to ensure that underage consumers are not purchasing our products. Safety has always been our highest priority and compliance with all the regulations around the country within the markets where we have customers is paramount.

Opioids have become a worldwide issue because of their addictive properties. As a U.S. Navy veteran, do you use medical cannabis as a treatment option? Or do you see medical cannabis as an alternative to using prescribed medication?

 I absolutely support the use of cannabis as a treatment option for veterans and anyone else who would like to replace or supplement their more traditional drug treatment regimen. Thousands of U.S. veterans are still forced to navigate uncharted waters when wanting to supplement or replace their prescription treatment regimen with cannabis. As a result, veterans are forced to fend for themselves to find information on the benefits and uses of medical cannabis.

Do you have any further you would like to add?

 More than anything, I am concerned that the impact of the legislation in the December stimulus bill will reduce access to critical cannabis vaping supplies for those who depend upon them for medicine and will drive consumers to the black market. We know now that the black market was responsible for the terrible vaping-related illnesses of 2019, and to purposely push people in that direction is the height of irresponsibility. Whether through our O2VAPE brand or our sister company O2Holistic, we are all about providing people safe and trustworthy products. Consumers—and especially veterans—deserve simple and safe access without being driven to black market providers..

The COVID-19 pandemic affected all types of businesses, such as those found in the cannabis industry. Though it was hit hard from the virus, the cannabis industry suffered another blow in the form of the December 2020 COVID-19 stimulus package, which included a provision classifying all vape products as cigarettes, subjecting them to the same regulations as cigarettes. Here, U.S. Navy veteran Dana E. Shoched, president and chief executive officer of O2VAPE, discusses the impacts this legislation may have on the cannabis vaping industry.

The Cannabis Vaping Industry Faces New Struggles

Can you tell us a little bit about your background? How did you become interested in medical cannabis?

 I have a PhD in economics, and I am a researcher and consultant in the area of systems dynamics, with experience in healthcare and technology. I use modeling and data analysis to look at how the healthcare system or technology systems create value for different participants or stakeholders, how systems evolve over time, and how to generate better outcomes at the system level.

I had tried cannabis recreationally, but it wasn’t my thing. And, truth be told, my attitudes toward cannabis had been negatively shaped by the stigma. I had become aware of medical cannabis during the early 1990s, when it was receiving attention for its use by AIDS patients. However, at the time, I quickly dismissed the idea that cannabis could provide actual health benefits, though I condoned its use by patients as a means of escaping from their disease.

I came to cannabis in 2015 when my brother asked me to help him figure out how to improve the benefits he was getting from cannabis to treat his multiple sclerosis (MS) pain. His neurologists told him that he might benefit from using medical cannabis, but the doctor could provide no guidance himself, so my brother was left to figure it out on his own. I was shocked to hear that cannabis was actually providing positive effects, but all that really mattered to me at that point was helping him figure out how to use it more effectively. I started reading about cannabis, and I haven’t stopped reading. The more I know about cannabis, the less I feel I know, but the more intrigued I become. Cannabis challenges me in all my areas of interest: healthcare, science and technology, industry evolution, market competition, and general system dynamics.

Please tell us about your article “Transitioning to 21st Century Medicine: The Promise of Whole Plant Medicine.” What inspired you to write this piece and what do you hope people will take away from it?

 My article, “Transitioning to 21st Century Medicine: The Promise of Whole Plant Medicine,” describes how advancements in science and technology have led the pharmaceutical industry to evolve to where it is today, why the industry has not been more effective in discovering effective treatments for patients, and how to change the system so as to generate more effective treatments.

My brother’s experience with MS in general, and cannabis in particular, has made me a strong and passionate advocate for alternative healthcare treatments. At the same time, the part of my brother’s journey with his health problems that has had an impact on me, perhaps more than anything else, is how poorly the traditional healthcare system has been able to meet his needs. Since I’ve been learning about and advocating for medical cannabis, I’ve seen just how many other people have had that same experience.

Let me say that I have tremendous respect for doctors and all the other people in the healthcare system who do their best to help others. In fact, my father was a private practice physician, and he was my hero and role model. But I think the current healthcare system is failing a lot of patients. As a game theorist and researcher, I’ve seen how the system has evolved, and I understand why it generates the outcomes it does. A good friend once told me that it’s useless for a consultant to tell someone they have a problem unless she can also tell that person how to fix the problem. My purpose for writing this article is to tell people what the problem is, why it exists, and how to fix it. 

What do you hope will change in the cannabis industry? Where do you find the most difficulties and how do you deal with them?

 Cannabis is a very new industry that has sprung up from scratch and whose operations are being figured out by industry participants as they go. The industry’s product (a drug), its scientific and technological potential, its medical potential, and its commercialization potential have all attracted a huge variety of participants. The sheer absence of information, amount of misinformation, and the disinformation out there, combined with the massive complexity of the plant, the supply chain, and the medical use has created unparalleled amounts of chaos. The uniqueness of the cannabis industry, particularly its botanical and medical complexities, means there will always be chaos. However, I think two areas need particular attention.

One big problem that I believe must be addressed is the wholesale lack of accuracy and transparency of information about the contents of cannabis products. Testing standards must be established and enforced so that cannabis product contents can be accurately assessed. All users must be ensured that the cannabis products they buy are free from toxins that could be harmful to their health. All users, and medical users in particular, must have access to product contents—profiles of cannabis compounds and any other additives—so they know what they’re getting and can figure out which products work for them and which do not.

The other big problem is regulation. The Schedule I classification of cannabis is clearly impeding development of the industry. Aside from that, I think the power of the regulators must be tempered. As it stands, regulators can—and do—change regulations on a dime. This has been devastating for anyone currently conducting any type of activity in the cannabis industry, and it has severely dampened much more entry into the industry. So much beneficial activity—science, technology, and medical advancements—are being terribly delayed by the Schedule I classification and harsh regulatory regime in cannabis.

How do you deal with the stigma surrounding cannabis?

 I, myself, had bought into the cannabis stigma. I had tried it; there were plenty of people I knew and respected who used it, and I still condemned its use. However, as soon as I learned about the endocannabinoid system (ECS) in our bodies and how wondrously cannabis acts on our ECS, I was absolutely convinced of the tremendous potential of cannabis for helping with our health and well-being. Education is what convinced me, and I believe education is what will convince others. I will educate anyone who will listen about cannabis.

Do you think there should be more research into the medicinal properties of the cannabis plant and its interactions with the endocannabinoid system?

 Absolutely! We have just begun to understand the plant and how it works in our bodies. And it was scientists trying to figure out how cannabis works in the body that led to the discovery of the ECS in the first place. In other words, studying cannabis and the ECS helps us understand more about how our bodies work in all areas, not just in cannabis or the ECS. At the same time, the more we understand about how the plant interacts with our ECS, the better able we will be to use cannabis extracts and isolates, not to mention design derivatives and synthetics to improve our health and well-being.

I believe the applications researchers discover for using cannabis, cannabinoids, and endocannabinoids to improve health and well-being are going to mushroom. And it doesn’t stop there. The science and technology—plant genetics, cultivation techniques, extraction techniques, molecular chemistry, mass spectrometry, emulsion technologies, medical delivery mechanisms, and pharmacokinetics, just to name a few—are all being pushed to their limits and advancing quickly, thanks to research and development in cannabis. These advances in the science and technology of cannabis will have massive follow-on effects in many other industries.

Do you think whole plant medicine has the potential to overcome pharmaceutical medications?

 I believe plant medicine has the potential to fantastically supplement current and future non-plant medicines developed by the pharmaceutical industry. But for the historical achievements by pharmaceutical companies, we would still be dying young from bacterial infections. Traditional pharmaceutical techniques have had a huge amount to offer and will continue to do so. At the same time, traditional medical treatments would be massively enhanced by the addition of whole plant medicine.

What topics to you plan to tackle next in your cannabis writing?

 I’m currently looking at how licensed cannabis suppliers—growers, processors, distributors, and retailers—for both medical and recreational uses and in different states are configured in the industry. Are most activities conducted by independent companies? Are companies aggregating horizontally, that is, forming chain locations? Are they aggregating vertically, that is, performing more than one activity in the supply chain? Both regulatory pressures and competitive pressures affect how companies choose to configure themselves across the various activities in the supply chain. The configurations that result from these pressures will have important implications for the accessibility of cannabis for consumers, such as: Will there be much variety in forms and formulations of use? Will prices be high or low? Will quality be high or low? Will recreational use squeeze out medical use?

Do you have any additional comments you would like to add?

 Most traditional scientists and healthcare industry participants recoil at the suggestion that cannabis be legal and widely available for medical use. Their immediate reaction tends to be, “we don’t know enough about how it works in the body!” In other words, using cannabis is risky.

Whether or not cannabis is risky is not the appropriate question. Every substance on the planet is potentially risky, if used inappropriately. All it takes is a quick glance at the labels or inserts for any package of medication to see that any medication involves risk.

The appropriate question to ask is: Do the benefits of cannabis exceed the risks? For most people, the answer is yes.

It will probably take decades for researchers to really figure out how cannabis works in the body. However, in the meantime, millions of people either do not have access to, or have been utterly failed by, other forms of medication. What do all these researchers propose all these people do until researchers are satisfied that they finally know enough about how cannabis works to recommend its use?

“Transitioning to 21st Century Medicine: The Promise of Whole Plant Medicine,”, please visit: 

https://www.cannabissciencetech.com/view/transitioning-to-21st-century-medicine-the-promise-of-whole-plant-medicine.

Cannabis’s biggest antagonist is the stigma that surrounds it. Whole plant medicine has the potential to significantly benefit the pharmaceutical industry by complementing their efforts to bring patients relief from their ailments. Systems dynamics consultant/researcher, Ruth Fisher, PhD, explains how cannabis has the option to flourish but needs to stop having its efforts for growth and research hampered by opinions.

Whole Plant Medicine Is the Future

Eberhardt Kuhn, PhD, is the marketing manager for food, cannabis, and hemp at Shimadzu Scientific Instruments and an acclaimed chromatographer with more than 30 years of experience in this field. He has also worked for companies like Restek, Agilent, and Bio-Rad.

Dr. Kuhn has had the opportunity to speak at various conferences and events in over 30 countries. He holds expertise in chromatographic separations, column chemistry, and scientific instrumental analysis of food, including determination and identification of contaminants (pesticides, heavy metals, and food contact materials such as per- and polyfluoroalkyl substances [PFAS]), food quality, food adulteration and confirmation of food authenticity, and general analytical method development. Dr. Kuhn is currently interested in cannabis and hemp analytics—potency, terpenes, contamination—and educating the public on the numerous benefits of cannabis and hemp.

® Editorial Advisory Board members please visist: 

www.cannabissciencetech.com/cannabis-science-and-technology-editorial-advisory-board

Cannabis Science and Technology® is pleased to announce the addition of Eberhardt Kuhn, PhD, to its editorial advisory board (EAB).

Eberhardt Kuhn, PhD, Joins Cannabis Science and Technology® Editorial Advisory Board

As the cannabis industry continues to grow across the US and globally, so too are multistate operators (MSOs). MSO’s are a sign that the cannabis industry is here to stay as investments and infrastructure for big players continue to come online. However, these larger companies face many challenges in setting up shop, often dealing with banking issues and the various state-by-state legal frameworks. Frank Knuettel, CEO of Terra Tech Corp. (now Unrivaled Brands Inc.), recently spoke with us about the various challenges his company faces, their plans to expand into the largest West Coast MSO, and more.

Can you tell us about your company, Terra Tech Corp. and the recent merger with Unrivaled?

: Terra Tech is an 11-year-old company that we believe was the first US plant-touching company that was listed on the US Stock Exchange. We have been publicly listed on the over-the-counter (OTC) Markets Group since 2012. We recently merged with Unrivaled, and pursuant to that, we rebranded the company as Unrivaled Brands Inc., with the intent of building the largest West Coast-based multistate operator (MSO). Currently, we have operations in California, Oregon, and Nevada, across all types of cannabis assets, whether it be cultivation, distribution, brands, delivery, or dispensaries. So, we are a vertically integrated West Coast-based cannabis MSO.

What is your vision for the future as the rebranded company Unrivaled Brands Inc.?

: I think we have a lot of great opportunities. The California, Oregon, and Nevada markets are in and of themselves approximately 30% of the national market, so we have an opportunity now to build a large, deep West Coast-based cannabis MSO. And I say opportunity now, but there are protective moats against the industry who are protecting the industry with the federal illegality. And to the same extent, there are protective moats around, especially California and Oregon, in that a lot of the large MSOs have tended to focus more on the limited licensed Midwest and East Coast states and have a small or nonexistent footprint in the California and Oregon markets at this time. So, we can use our platform and our asset base to really create a large enterprise and some of the largest cannabis markets in the country.

What challenges to do you face as a multi-state operator? How do the different state regulations impact your business?

: Well, that is a pretty significant question, in that, at the moment, we have federal illegality and fairly different regulatory regimes, depending on the states in which we or any cannabis company operate. So, we're basically creating individual subsidiaries in various states because the state regulatory environments each have fairly different operating processes. On top of that, because of the federal illegality, we also have significant headwinds with respect to commercial banking, insurance, and other things.

I would say commercial banking is probably the most complicating factor of our business and the lack of access to mainstream banks, cash management, credit cards, and that sort of thing. So, there's quite a few headwinds. But, frankly, it’s the headwinds that everyone in the industry experiences and it’s part of what gives us the opportunity and runway to create a larger competitive operating enterprise right now.

In your various cultivation sites, do you follow individual state guidelines, or do you implement the most stringent rules from one given state to all your locations? For example, California might require more testing for pesticides than say Nevada does.

: Yes, we strictly comply with all the regulatory requirements in a state in which we operate in. We do our best where possible to facilitate a standard process across all our operations—and that facilitates just a greater level of efficiency with respect to our operating team and our cultivation team. It allows them to move, from state to state, a little more easily and that we have a common process. So, we try to sort of raise, across the company, our processes and procedures to the stricter markets in which we operate, so we have that common platform.

Can you tell us a little bit about the manufacturing and processing operations? What is a typical turn-around to create products? How does automation fit in?

: The turnaround time varies depending upon the type of product. For example, flower, packaged flower, or pre-rolls are manufactured in-house because of the importance of freshness. Our turnaround time post-harvest and drying period is short, in a matter of days or weeks at most, whereas for edibles and vapes, there's a longer turnaround time because we use an outside processor for the distillate.

On the automation side, depending on the brand and price point in which we sell pre-rolls—and by that, I mean, we have several different brands leading from Korova, which is our high-end brand, down to Sticks, which is a little bit more of our budget brand or a price point brand and Cabana, which is more of a lifestyle brand—so it varies also a little bit depending on that. In that, for our Sticks brand, we have pre-roll machines and both the jarring and the pre-rolls are all automated, whereas with Korova, we do some mixture of either to a pre-roll machine or hand packing, just to ensure quality. I would say the automation in the industry has made considerable strides in the last few years and the quality of the systems has risen quite dramatically. And that's across the board, whether it's with respect to jarring and pre-rolling or edibles production. A lot of edibles production is still done at the kitchen level by hand, although that also, as I mentioned, is seeing great and significant strides forward on the automation side.

Do you use any software or technology to monitor your products from start to finish?

: We do. It varies depending on the system. We have an enterprise resource planning

(ERP) system, that is what we call seed-to-sale, and it manages the process in the grow environment through production and in the inventory into the dispensaries, the point-of-sale system and through the sale, down to the individual end user or customer. Our ERP system is end-to-end, through the entire manufacturing and growing, cultivation processing, and sale process.

Further to that, in cultivation facilities, for example, there's some pretty advanced fertigation systems, as they're called, which is a system that provides both water and nutrients. We have our own formula for the nutrient system or the fertigation system. That's all automated, depending on tests we receive back with respect to plant cycle and its development cycle.

So, the fertigation system changes the formula over the development cycle, and that's all automated out of central complex in our cultivation facilities. So, obviously, with those items, plus the automation of the backend processing, there's a fair number of systems that are either in place or going into place that are increasingly rapid clip in our industry.

Do you have any advice for newcomers to the field?

: I have spent much of my career is early stage, high growth, somewhat chaotic industries. And because of the incredibly high growth in our space, overlaid with the regulatory environment and the relatively early stage, it's an exciting industry right now to be part of and fits well with my experience in other industries or companies. I think, frankly, that the evolution in our society, with respect to cannabis, has been dramatic. We have further to go, but the number of states that have legalized, in one way or another, has been really impressive and supportive of the overall growth.

With that said, it's exciting. It's swiftly growing. There's a cool vibe and culture to it. But it is challenging. And unlike mainstream industries, because of the regulatory environment, there are more hurdles and barriers that need to be overcome to be able to put out a successful product or a good quality product. I guess the biggest thing I could say is not to underestimate the complexity of the industry, despite what is a relatively simple and straightforward concept.

Do you have any plans to expand your reach further, perhaps into the East coast eventually?

: I think it's certainly something we actively consider when the timing is appropriate. But I'll say it's not now. We have, as I mentioned earlier in our discussion, a very large market in which we operate that is still in its early stages. The number of dispensaries in California, for example, is approximately the same number that exist in Colorado, which is a state maybe approximately one fifth the size. So, the California market, despite having a long cultural history in cannabis, is still in fairly early stages in legal cannabis.

Since there's a highly fragmented market with relatively few or any national players, there's a long runway for us to build our operation out on the West Coast. So, our focus for the near, or medium term, is to really make, produce, and build a company that's the largest West Coast MSO out there. And then, from there, we'll see where we go, whether that's organic expansion by way of licensing, for example, in the tri-state area, which, all within the last year, all three states last year legalized for adult-use. So, it remains to be seen how we’ll tackle that, whether it be organic growth or merge with some other party. But really the focus right now for the near and medium term is out West because the opportunity is so significant.

If there is a change to the federal status, how would that impact you guys as an MSO?

: A lot of it depends on what that change looks like. There are discussions and bills currently in Congress or recently in Congress that provide anything from safe banking, called the Safe Act, which provides access to commercial banks, which, as I mentioned earlier, would be a significant value to the industry, all the way to full legalization. And along the way, there are all kinds of aspects and considerations with respect to whether it's managed at the state or federal level, what expungement or social equity issues are included, what tax items are addressed, whether interstate commerce is allowed. Frankly, I think right now, as it tends to be the case with legislation at the federal level and, especially in cannabis, it's very murky in my mind which way legislation is going to go and at what time.

There's an omnibus bill now that was introduced by Senator Schumer last week that would fully legalize cannabis. But by all accounts, there are not enough votes in the Senate to pass it. Some of the co-sponsors are refusing to do anything less and that calls into question the previously held belief that while the full legalization wouldn't have the votes that the Senate would tip it over to the Safe Act or some sort of banking act, that's in question now with some of the senators’ comments.

I wish I had a crystal ball to be able to figure out what the legislative environment looked like around the bend, because that would have a significant impact on our strategy and our processes and operations. But, at this point, I just don't have any clear insight into it, and trying to plan for it is therefore very difficult.

Do you guys do any in-house testing for your products or is it all third party?

: We have, before any of our products are shipped or hit the shelves, we are required to have third-party testing on various matters, whether pesticides or chemicals or anything else like that. We also do in-house testing with respect to developing new genotypes or strains in our laboratories. So, we have, I would say, two layers. We have a layer of R&D testing in-house, and then, a regulatory layer to ensure health and safety for the consumers.

Since you are multistate operators, but you obviously can't ship between states, how do you manage the product formulation? Does one group come up with product formulation and then you send a recipe out?

: Yes, with respect to edibles, that's correct. It's formula-based, or recipe-based, and we can obviously share the recipe across states. With respect to flower and similar products, we cannot ship across state lines. So, we have essentially separate genetics testing and development in any state in which we operate.

In this interview, Frank Knuettel, CEO of Terra Tech Corp. (now Unrivaled Brands Inc.), discusses the various challenges his company faces, their plans to expand into the largest West Coast multistate operator (MSO), and more.

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