cannamimetics unlocks ’s cannabinoid family tree · 2019. 8. 30. · copyright © 2019 precision...

Precision Plant Molecules, LLC

Copyright © 2019 Precision Plant Molecules www.precisionplantmolecules.com [email protected]

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CANNAMIMETICS UNLOCKS HEMP’S CANNABINOID FAMILY

TREE

Following Mother Nature’s Lead to Access Rare, Naturally Occurring Minor Cannabinoids with

Therapeutic Qualities

Hemp-derived Products Can Now Be Made with Consistent Phytochemical Profiles

Disclaimer: The information provided by PPM herein includes statements and assumptions that are subject to change and should be verified independently. These statements have not been evaluated by the Food and Drug Association. Hemp-derived products, mentioned herein, are not intended to diagnose, treat,

cure, or prevent any disease.

http://www.precisionplantmolecules.com/

Copyright © 2019 Precision Plant Molecules

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TABLE OF CONTENTS

Understanding Phytosynthesis ..................................................................................... 3

Cannamimetics, Minor Cannabinoids and Bespoke Plant Medicine Profiles .............. 7

Phytocannabinoid Series: Olivetol, Orcinol and Varinol ................................................. 8

Cannabis sativa and Hemp ........................................................................................ 12

Members of the CBD Family ...................................................................................... 13

Genetic Engineering and Pharma Approaches ........................................................... 16

PPM’s Scientific Advancements and Application of Cannamimetics ............................ 21

Conclusion ................................................................................................................. 22

Appendix: Why Plant Medicine and CBD Doesn’t Quite Fit the FDA’s SOP ................. 24

Meet the Authors ....................................................................................................... 26

For More Information ................................................................................................. 30

Bibliography .............................................................................................................. 31


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UNDERSTANDING PHYTOSYNTHESIS

The Hemp Plant as a Medicine Factory

At harvest there are well over 500 phytochemicals present in the hemp plant. No wonder the trichome is called a pharma factory. There are even more identified natural compounds when you count those that appear and then phytosynthesize into other compounds during the plant’s life cycle. You have probably heard that CBGA is the mother cannabinoid, the precursor to both the CBD and THC sides of the family tree of cannabinoids. For this reason, harvesting hemp very early yields higher levels of CBGA and CBG compared to later in the plant’s life when there are miniscule amounts. Studying the biological and chemical processes in the hemp plant reveal that CBG begets CBC and in turn begets CBL and then CBT. And don’t forget the lineage of CBGA, CBD, CBE, and CBF. These cannabinoids, all trace back to CBGA, which is technically called the olivetol series. Different enzymatic reactions in the plant create the varinol branch of the family and orcinol branch. Of note, the highly sought after cannabinoid, THC-V, doesn’t even come from the THC side of the family but from the varinol branch. On the marijuana (high THC) side of the cannabis sativa plant family, you’ve probably heard that old weed is sleepy time weed, often referred to as couch weed. A more scientific description is that THC degrades with time, temperature, and UV-light, oxidizing to become CBN. Of critical importance to hemp growers is closely tracking the increase in THC levels during the last few weeks before harvest. In just a few days during late stage maturation, hemp can go “hot” with the THC level shooting up from low concentrations in high CBD potency hemp varieties to THC levels that exceed the Federal limit of no more than 0.3% to qualify as legal hemp. A crop can become illegal after a particularly hot day if not immediately harvested and lawfully must be destroyed. Growing conditions are constantly changing. Daily and nightly temperatures differ each growth season. The character and amount of light, humidity, timing of water input, soil and nutrients factors, stresses like pests and biologic contaminants, and other conditions are never exactly the same, harvest to harvest, even with indoor grown hemp. Variation is inherent in Mother Nature.


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How Inconsistent Hemp Biomass Can be Processed into Products with Consistent Profiles of Cannabinoids to Improve their Medicinal Efficacy Because botanical medicine is inconsistent by Nature, Cannamimetics allows a smoothing and enhancement of the variability in extracts and concentrates made from plants, harvest to harvest, to ensure consumers are afforded the ideal amount and combination of the healing attributes of bioactive cannabinoids, including terpenes, flavonoids, polyphenols and other nutrients from hemp in each and every serving. Consistency results in superior plant remedies. Similar to the potency differences of cannabinoids in hemp plants, important and rare terpenes vary plant to plant and year to year, based on genetic, environmental and developmental factors. Cannamimetics can also be applied to follow the terpene synthases pathways involving encoded enzymes and complex interactions that result in pharmacologically active classes of metabolites that improve human health.


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Mother Nature’s Dynamic Process – Growth Phases From Seed (or Clone from a Mother Plant) to Vegetative to Flowering to Maturity

In 1964, it was first understood that CBG was the precursor of all other cannabinoids.1 During the hemp plant’s life, CBGA can be formed by the C-isoprenylation of olivetolic acid along with geranyl diphosphate to become either CBDA or THCA, the acidic versions of the two most known and studied phytocannabinoids, and eventually, via decarboxylation, CBD and THC.

In 1966, the biogenesis of cannabinoids from geranyl diphosphate and olivetolic acid was first reported. The genetic inheritance of the enzymes that are responsible for the creation of the major cannabinoids is complex and has been studied diligently in regards to CBDA and THCA, albeit hindered by the global “prohibition,” since the 1940s. Although a single enzymatic reaction may seem simple, it becomes complex by the presence of a host of THCA- and CBDA-synthase-related-pseudogenes, deviating greatly from a simple Mendelian model, and a multitude of plant specific environmental and development factors.2

As mentioned earlier in PPM’s description of Cannamimetics, nature guides science. There is so much more to Mother Nature’s phytosynthesis than simply stating there is a framework of compounds that are derived from an aromatic starter.

1 Hanuš, L.O., Meyer, S.M., Muñoz, E., Taglialatela-Scafati, O., & Appendino, G. (2016). Phytocannabinoids: a unified critical inventory. Nat. Prod. Rep, 12. 2 Ibid.


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Terpene Synthases in Cannabis Sativa Plants

A variety of different monoterpenes and sesquiterpenes are important parts of cannabis, as they define some of the original organoleptic properties and could also influence medicinal effects of different cannabis strains and varieties. There are postulated to be nine cannabis terpene synthases that have been identified in two subfamilies: TPS-a and at least TPS-b.3 According to research, there are two pathways to form the general 5-carbon isoprenoid diphosphate precursors of all terpenes during terpene biosynthesis in plants. The formulation of cannabis resin differs based on genetic, environmental, and developmental factors and although concentrations and ratios of cannabinoids are relatively predictable, terpene profiles are often unknown and generally less predictable.4

3 Booth, J. K., Page, J. E., & Bohlmann, J. (2017). Terpene synthases from Cannabis sativa. PloS one, 12(3). 4 Ibid.


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CANNAMIMETICS, MINOR CANNABINOIDS AND BESPOKE PLANT

MEDICINE PROFILES Cannamimetics simply means following Mother Nature’s lead. It is well known and extensively researched that during a hemp plant’s growth, various enzymatic, oxidation, photochemical and other bioprocesses produce cannabinoids and other bioactive compounds, transforming them during the course of the plant’s growth cycle. PPM coined the term Cannamimetic to describe naturally inspired ways to access the important bioactive, “minor” cannabinoids that currently manifest in existing hemp cultivars in de minimis concentrations. More consistent and effective plant-based extracts and concentrates can be formulated with these cannabinoids. Basically, PPM customized an existing scientific term, biomimetic, which means copying biochemical processes in Nature. A paper by Hanus, Meyer, et al succinctly captures the essence of Cannamimetics: “Nature is a biogenetically (sic) tinkerer, and prefers to re-use, recycle and re-assemble rather than creating ex novo something new.” The plant’s family tree of cannabinoid offspring and the plant’s inner workings during its life cycle reveal all we need to know to improve human health with plants. With the great advantage of being a hemp-derived botanical product and being able to dial in a consistent profile of naturally-occurring plant compounds with therapeutic properties, Cannamimetics is essentially the science and application of the phytosynthesis pathways that have evolved in Mother Nature.


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PHYTOCANNABINOID SERIES OLIVETOL, ORCINOL AND VARINOL

Olivetol Series The olivetolic phytocannabinoids are the most widely studied in literature and include both CBD and THC. It is considered the ‘classic’ because they are the compounds present in all varieties of cannabis sativa.5

Orcinol Series The orcinolic phytocannabinoids have been found in Nepalese and Brazilian samples of the cannabis plant but have also been identified as major compounds in non-Cannabis species.6

Varinol Series The varinolic phytocannabinoids have been found in higher quantities in C. indica and C. sativa. They were once rare, but are now targets of selective breeding.7

5 Phytocannabinoids Guide: Cayman Chemical. (2018, June). Retrieved from https://www.caymanchem.com/Literature/phytocannabinoid-guide 6 Ibid. 7 Ibid


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Cannabinol Cannabinol (CBN) was the first phytocannabinoid isolated from cannabis in 1896 and is the only phytocannabinoid that exists in all the alkyl versions from methyl to pentyl. CBN is an isolation artifact derived from the oxidative aromatization of corresponding THC-type derivatives. The aromatization of THC to CBN is due to the sulfur dehydrogenation at 250 degrees celsius.8 Cannabinol’s molecular formula is C21H26O2. Its molecular weight is310.437 g/mol and it has a boiling point of 185°C.

Cannabigerol Cannabigerol (CBG) is exclusively produced by the cannabis plant and was first discovered in 1964 by Gaoni and Mechoulam.9 The concentration of CBG at harvest in most plants is very low. However, its presence is crucial for cannabinoid synthesis. It is structurally considered the cyclohexenyl-opened analog of CBD. CBG is derived from CBGA present in the trichome heads which originally was biosynthesized by the combination of olivetolic acid and geranyl pyrophosphate. Then, through a series of synthases, CBGA transforms into the acid form of the three main cannabinoids: THCA, CBDA, and CBCA. The chemical formula of CBG is C21H32O2. It has a molecular weight of 316.48 g/mol and has a wide range of boiling points.10

8 Phytocannabinoids Guide: Cayman Chemical. (2018, June). Retrieved from https: //www.caymanchem.com/Literature/phytocannabinoid-guide 9 Cannabigerol CBG: The main precursor to all cannabinoids. (2018, May 15). Retrieved from https://www.alchimiaweb.com/blogen/cannabigerol-cbg/ 10 Ibid.


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Complexity of Enzymatic Biosynthesis - CBGA The research performed by Yang, Matsui et al and published in 2016 demonstrates how complex Mother Nature is and provides us with a sense for the enzymatic and biochemical activity early in the plant’s life cycle for the production of CBGA.11 As you will note in the abstract below, the simple explanation of “CBGA is formed via a geranyl-transferase from Olivetolic Acid and Hexanoyl-coenzyme A and after the earlier polyketide synthase” doesn’t quite give Mother Nature enough credit for her genius.

Abstract Structural Basis for Olivetolic Acid Formation by a Polyketide Cyclase from Cannabis sativa. Yang X, Matsui T, Kodama T, Mori T, Zhou X, Taura F, Noguchi H, Abe I, Morita H.

In polyketide biosynthesis, ring formation is one of the key diversification steps. Olivetolic acid cyclase (OAC) from Cannabis sativa, involved in cannabinoid biosynthesis, is the only known plant polyketide cyclase. In addition, it is the only functionally characterized plant α+β barrel (DABB) protein that catalyzes the C2-C7 aldol cyclization of the linear pentyl tetra-β-ketide CoA as the substrate, to generate olivetolic acid (OA). Herein, we solved the OAC apo and OAC-OA complex binary crystal structures at 1.32 and 1.70 Å resolutions, respectively. The crystal structures revealed that the enzyme indeed belongs to the DABB superfamily, as previously proposed, and possesses a unique active-site cavity containing the pentyl-binding hydrophobic pocket and the polyketide binding site, which have never been observed among the functionally and structurally characterized bacterial polyketide cyclases. Furthermore, site-directed mutagenesis studies indicated that Tyr72 and His78 function as acid/base catalysts at the catalytic center. Structural and/or functional studies of OAC suggested that the enzyme lacks thioesterase and aromatase activities. These observations demonstrated that OAC employs unique catalytic machinery utilizing acid/base catalytic chemistry for the formation of the precursor of OA. The structural and functional insights obtained in this work thus provide the foundation for analyses of the plant polyketide cyclases that will be discovered in the future.12

11 Yang, X., & Matsui, T., et al. (2016, March). Structural basis for olivetolic acid formation by a polyketide cyclase from Cannabis sativa. 12Ibid.

https://www.ncbi.nlm.nih.gov/pubmed/?term=Yang%20X%5BAuthor%5D&cauthor=true&cauthor_uid=26783002

https://www.ncbi.nlm.nih.gov/pubmed/?term=Matsui%20T%5BAuthor%5D&cauthor=true&cauthor_uid=26783002

https://www.ncbi.nlm.nih.gov/pubmed/?term=Kodama%20T%5BAuthor%5D&cauthor=true&cauthor_uid=26783002

https://www.ncbi.nlm.nih.gov/pubmed/?term=Mori%20T%5BAuthor%5D&cauthor=true&cauthor_uid=26783002

https://www.ncbi.nlm.nih.gov/pubmed/?term=Zhou%20X%5BAuthor%5D&cauthor=true&cauthor_uid=26783002

https://www.ncbi.nlm.nih.gov/pubmed/?term=Taura%20F%5BAuthor%5D&cauthor=true&cauthor_uid=26783002

https://www.ncbi.nlm.nih.gov/pubmed/?term=Noguchi%20H%5BAuthor%5D&cauthor=true&cauthor_uid=26783002

https://www.ncbi.nlm.nih.gov/pubmed/?term=Abe%20I%5BAuthor%5D&cauthor=true&cauthor_uid=26783002

https://www.ncbi.nlm.nih.gov/pubmed/?term=Morita%20H%5BAuthor%5D&cauthor=true&cauthor_uid=26783002


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Simplified Examples of Phytosynthesis Processes

Cannabinoid Synthesis from CBGA

f (Heat, Light, Time, etc.)

THC → CBN

CBC → CBL

f (Synthase, Time, Decarboxylation, and other factors)

CBGVA → THCVA → THCV

CBGA → THCA, CBDA, CBCA, CBGA

→ THC, CBD, CBC, CBG


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CANNABIS SATIVA AND HEMP Phytocannabinoid and Terpene Biochemistry

13 CBGA –– The Mother Cannabinoid

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13 Hartsel, J.A., Hickory, B., Eades, J., & Makriyannis, A. (2016). Cannabis sativa and hemp. Nutraceuticals. 53: 735-754. 14 Ibid.


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MEMBERS OF THE CBD FAMILY Naturally Occurring CBD Derivatives There are over 100 natural cannabinoids identified in the cannabis sativa plant and a number have been classified as CBD-type compounds.

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15 Morales, P., Reggio, P. H., & Jagerovic, N. (2017). An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol. Frontiers in pharmacology, 8, 422.


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Synthetic CBD Analogs (also Metabolites)

16 Some of these analogs are naturally occurring and some are not. The goal of drug discovery by pharmaceutical companies is to improve the potency, efficacy, safety or pharmacokinetic properties of a compound. In the majority of cases, plant pharmacopeia is the inspiration for the research.17 Since pharmaceutical companies can’t patent a natural compound, inventing an analog that isn’t naturally occurring but has some or all or improved therapeutic properties, allows the pharmaceutical company to recoup their R&D and clinical trials investment with intellectual property protection.

16 Morales, P., Reggio, P. H., & Jagerovic, N. (2017). An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol. Frontiers in pharmacology, 8, 422. 17 Jagerovic, N., Morales, P., & Reggio, P.H. (2017). An overview on medicinal chemistry of synthetic and natural derivatives of cannbidiol. Front. Pharmacol. 8:422.


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Various Other CBD Derivatives

Derivatives of CBD manifest during the development of the hemp plant. Just as CBGA becomes CBG and veers off on either the THCA or CBDA branches of the cannabinoid family tree, the acidic cannabinoid CBDA and then its non-acidic form, CBD, continue to branch based on enzymatic, developmental and environmental factors, and interactions among all of other concurrent phytosynthesis processes taking place in the plant, day to day, week by week.

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18 Morales, P., Reggio, P. H., & Jagerovic, N. (2017). An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol. Frontiers in pharmacology, 8, 422.


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GENETIC ENGINEERING AND PHARMA APPROACHES

Selective Breeding and Genome Editing to Increase Potency of Rare Minor Cannabinoids in Hemp Varieties

At some point, generational breeding and/or systems utilizing CRISPR genome editing techniques will yield “minor” cannabinoids and important terpenes in greater abundance but it is taking time. The estimated biological maximum of oil is approximately 30-40% by weight in the plant – remember the plant does many things during its life other than make oil and push it into the trichomes. Companies like New West Genetics, Front Range Biosciences, and Oregon CBD Seeds are leading companies pursuing methods and techniques to increase the phytosynthesis of minor cannabinoids that are not expressed in large concentrations in the current varieties available to growers. The difficulty of breeding for stable ratios of multiple cannabinoids, e.g., a ratio of CBD:CBG, 5:1 ratio, or CBD:CBN, 1:1 ratio, is why Cannamimetics will always have a role in improving the health of many people with highly effective and consistent entourages of phytocompounds.


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Bio-Engineering to Manufacture Cannabinoids in a Laboratory

Genetically engineering organisms to grow in yeast, e. Coli, algae or other host “biofactories” to manufacture cannabinoids in pure forms has been a popular topic in the news lately. This scientific methodology of making changes in the DNA of the organism, is a pathway that some believe is attractive for the pharma industry and will be a reality at some point in the future. For example, yeast fermentation is used to biosynthesize insulin for humans and was pioneered by Genentech. Previously, it was obtained from livestock pancreases. Companies like Ginkgo BioWorks, Hyasynth Biologicals, Willow BioSciences, InMed Pharmaceuticals, Amyris, Demetrix and others are in a race to figure out and then overcome the scaling obstacles to making highly pure cannabinoids in this bioengineered manner. Even a cell free pathway using sugar as the starting material to make CBD has now been discovered.19

19 Valliere, M. A., Korman, T. P., Woodall, N. B., Khitrov, G. A., Taylor, R. E., Baker, D., & Bowie, J. U. (2019, February 04). A cell-free platform for the prenylation of natural products and application to cannabinoid production. Retrieved from https://www.nature.com/articles/s41467-019-08448-y


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Chemical Synthesis of Non-Plant Derived Cannabinoids by Pharmaceutical Companies Traditional pharma methods to synthesize both cannabinoids and new synthetic analogs or prodrugs will no doubt earn a place in the traditional drug marketplace based on future clinical trials. These compounds will typically be highly pure, single molecule drugs. The two advantages that are typically cited as advantages to chemical synthesis: 1. cannabinoid molecules can be made in a laboratory without the impurities or inconsistencies compared to a botanically derived medicine and 2. the large scale and agricultural intensity of hemp cultivation is avoided. Not surprisingly, the pharma market is advocating that consumers should favor highly purified cannabinoids, made in a beaker in a lab, as opposed to whole plant extracts or even isolation and purification of cannabinoids from hemp.

In a laboratory not using botanical ingredients, Noramco chemically synthesizes THC which is known by its international generic name, Dronabinol. This synthetic form of THC was approved by the FDA in 1986. It is sold under trade names Marinol and Syndros and the drug is an appetite stimulant, antiemetic, and sleep apnea reliever. It is only approved by the FDA as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting. The pharmaceutical formulation, an oily resin in capsules, is available by prescription in the US, Canada, Germany, Australia, and New Zealand. The synthetic THC is not available in inhalable or other forms of delivery, e.g., ingestibles, topicals, etc.

Noramco, one of the largest manufacturers of controlled substances in the world, is planning on introducing to the Canadian medical marijuana market a synthetic CBD. Other companies working on chemically synthesizing cannabinoids include Zynerba Pharmaceuticals, Insys Therapeutics and Axim Biotechnologies. GW Pharmaceuticals appears to be pursuing both chemical synthesis methodologies as well as isolating and purifying cannabis sativa-derived cannabinoids via extraction techniques. 60% of the new drugs on the market in the last few decades were inspired by natural pharmacophore. According to a study by Newman and Cragg, 35% of drugs have a direct natural origin. Plant medicine is obviously not new. Animals and humans are quick to figure out what will help them or what will kill them. Plants have been eaten raw, cooked, boiled, distilled, extracted, roasted, rubbed, mixed, and fermented by mankind. Notable 20th century approved drugs include Taxol from the yew tree for cancer treatment and penicillin first made from mold!


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In general, it is the goal of pharmaceutical companies to take inspiration from Mother Nature for new drugs and using iterative experimentation, big data, and other tools, develop chemically synthesized drugs they can submit to the multi-year clinical trial process and then sell under patent to recoup their development cost investment.

Innovations Take Time: Cannabis Sativa is a Complex Organism that has been Cultivated and Used for 10,000 Years. It is Finally Being Taken Seriously for its Therapeutic Properties by Traditional Pharma Companies and Governments.

Since there are so many hundreds of known phytochemicals in hemp, there is the exciting potential of discovering new bioactive metabolites beyond CBD. Currently, there is significant research underway to increase understanding of nearly 20 minor cannabinoids in the hemp plant. Science is also gaining a deeper appreciation for an even greater number of terpenes and their therapeutic, wellness and medicinal benefits. But some folks wonder what is so special about cannabinoids and terpenes that are just now being investigated considering pharma companies synthesize thousands of compounds each year to find the next “big” drug? The most important answer is that a number of cannabinoids and terpenes actually work. And they often work best together. Current studies are fast building on the sparse scientific research of the past hundred years when Western clinical research was severely restricted because of hemp’s botanical cousin, high-THC strains of the cannabis sativa plant, that put the kibosh on extensive academic and private industry research for even non-psychotropic hemp varieties of the cannabis sativa plant. Hippocrates prescribed willow bark for fevers, pain, and inflammation in the 4th century B.C. but it took science quite a long time to synthesize the active ingredient, Acetylsalicylic acid (Bayer filed their US patent #644 077 in 1900).


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Now sold for pennies a dose, OTC, aspirin may be natural pharmacopeia’s best selling drug of literally all-time. In the near future, a number of hemp’s phytocompounds will have the scientific research to substantiate their effectiveness and hemp plant-based medicines will catch up after 100 years of “Prohibition” to improve the well being and health of many, many people globally


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PPM’S SCIENTIFIC ADVANCEMENTS AND APPLICATION OF CANNAMIMETICS PPM applies Cannamimetics science and proprietary processing methodologies to bring its CPG and contract manufacturing company customers plant-derived bulk ingredients, including whole plant, concentrates, distillates, isolates and tailored profiles of cannabinoids, terpenes and other phytochemicals with therapeutic attributes. Consistently.

CBN PPM’s R&D team has successfully developed proprietary processes to provide the marketplace with hemp-derived CBN distillate at levels of purity levels greater than 70% and with 0.0% THC.

CBG Similarly, PPM has developed proprietary processes to produce CBG in a whole plant, full spectrum CBD oil at either a 10:1 or 5:1 ratio, CBD:CBG. Based on a customer’s formulation and requirements, a bespoke CBD:CBG ratio in distillate form can be produced, as well as high purity CBG-dominant distillate or isolate.

Future Products– Varins, Acidics and Others PPM scientists are currently working on proprietary techniques to process, isolate and purify the acidic and varin versions of cannabinoids recognized to have therapeutic properties. For example, CBDA and THC-V, and other cannabinoid-based products are PPM R&D priorities. CBC is also of great interest to the marketplace and being investigated by PPM’s R&D team. The scientific backgrounds and research CVs of PPM’s R&D team which includes three PhDs in organic chemistry and plant medicine are evidence of PPM’s commitment to advancing the science and providing innovative CBD and minor cannabinoid-based ingredients to leading consumer product supply chains worldwide.


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CONCLUSION

The biosynthetic plasticity of cannabis sativa creates a very rich research and development arena where more naturally occurring phytocannabinoids will be proven to have significant health and well-being attributes. And the existing phytocannabinoids and other plant nutrients and compounds will be better understood and their therapeutic properties proven by clinical testing. Coaxing the plant via breeding, genetically engineering, pharmaceutically synthesizing, or following the trail of phytosynthesis in the plant (aka Cannamimetics) will allow the development of products and drugs with either an entourage of bioactive phytochemicals or the single molecule that will change lives. Some will be plant derived. Others will be novel molecules that don’t occur in nature.

The 2018 Farm Bill, increasing consumer acceptance of cannabis sativa, global demand, societal changes, and a wide-open research field are all contributing to the substantial resources, expertise and capital, being invested in understanding and ultimately providing consumers with rare naturally occurring and in the case of some companies, synthetic non-psychotropic cannabinoids (not “spice” or other illicit and dangerous forms of synthetic THC).

There is no doubt there will be a spectrum of cannabinoid-based products, ranging from medicinal to recreational, from successful clinical trial proven single molecules for a single approved indication, from organic, artisanal plant extracts to chemically synthesized molecules, from yeast-grown to isolated and purified plant-derived cannabinoids, from whole plant, earthy, skunky tinctures to liposomal-enhanced ingestibles to high tech vape pens.

Whether made by the plant or plant-derived phytocannabinoids, or made in a beaker or petri dish, a future class of non-phytocannabinoids will again be an important addition to the pharmacopeia, just as they were for thousands of years before the global prohibition that started in the 1930s and is now accelerating in its reversal. PPM scientists will be the first to admit how humbling it is to study, research and experiment in the pursuit of Cannamimetics pathways. Mother nature is amazing. She reminds the PPM R&D team every day of her genius. We know some of her mysteries will never reveal themselves and we can only marvel at some of her wonders. As scientists at PPM and globally on the plant side of the fence (as compared to bioengineering and pharma approaches) attempt to unravel and then mimic natural plant processes with plant-based materials for medicine and therapies, they are supremely motivated to develop processing methodologies and


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techniques to offer people phytocannabinoids that are naturally occurring, non-toxic, non-addictive, non-intoxicating and an alternative to existing drugs and medicines to improve their wellness and quality of life. The sheer number of phytochemicals that Mother Nature has provided us with and our rapidly advancing understanding of the mammalian endocannabinoid system will contribute to many treatments and even cures for many diseases and ailments. These are exciting times of discovery and at long last, a realization of the pioneering efforts of researchers and plant devotees that advocated for decades against strong forces to untether these bioactive cannabinoids, terpenes and other phytocompounds with powerful medicinal attributes.


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APPENDIX

Why Plant Medicine and CBD Doesn’t Quite Fit the FDA’s Standard Operating Procedure The randomized, double-blind controlled studies that became standard in the 1950s for drug clinical trials are not well suited for multi-compound natural products because having more than one bioactive phytocompound exponentially increases the variables that need to be controlled. In fact, the FDA has only approved several herbal prescription drugs and none involve hemp or cannabis. The sole FDA approved cannabis plant-derived drug is a single, isolated and purified cannabinoid, CBD, in the drug called Epidiolex made by GW Pharmaceuticals that was approved in June 2018. The other FDA approved cannabinoid type drug is also a single molecule, a synthesized form of THC, marketed under the international generic name, Dronabinol. The consistency of botanicals and plant extracts pose a challenge for the standard clinical trial protocol as potencies as well as the ratios of the bioactive compounds can vary. The simple question that is difficult to answer is knowing which compound or combination of compounds in what proportions in a plant extract is effective as medicine. Therapeutic effects become even more complex to understand because everybody is different. “One size fits all” does not apply in herbal medicine. Even with common drugs, some people find relief with ibuprofen while other folks use acetaminophen. Some people use one for headaches and the other for muscle aches. Is the natural sleep aid, melatonin, effective for you? It is an OTC drug in the US but a prescription drug in other countries – go figure! Does Benadryl knock you out or perk you up? Each person reacts differently to treatment, whether it is with a FDA approved drug or a plant-based remedy. Cannabinoids and the other compounds in hemp act uniquely on a person’s endocannabinoid system, no different than pharmaceutical drugs and their pharmacokinetic effect. The pharmacodynamics are also somewhat different in different people. Accordingly, the well recognized entourage effect of the various phytochemicals in the hemp plant is obviously a challenge for the FDA. Another complexity the FDA has to address with all medicines is that clinical trials are not real world conditions. And most health problems don’t tend to be a single malady that can be alleviated by a single molecule. The clinical trial process does work but has limitations. Even when a single molecule is approved for a single indication like pain, the FDA process is not failsafe as with the case of opioids that were approved to be safe and effective based on parameters thought to be prudent but have led to widespread addiction.


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The good news is that the FDA is committed to sorting out how to allow consumers access to hemp-derived and other plant based medicines. Dietary supplements are regulated under the FDA’s DSHEA regulations established about 25 years ago. Food and cosmetics have their own regulatory framework. Both are different than the clinical trial framework for what the FDA defines as drugs. Another FDA pathway for approval of ingredients is named GRAS (Generally Regarded As Safe). Coming back to hemp-derived bioactive phytochemicals like CBD, CBN, CBG, CBC, terpenes, terpenoids, and polyphenols that are non-addictive, non-toxic and non-psychotropic (i.e., non-intoxicating), in theory, GRAS surely would be the simplest pathway out of the maze we are in. At some point, all of the regulatory confusion (or at least most) will be sorted out and even more people will be able to benefit from the hemp plant after almost 100 years of marginalization and illegal status. PPM is committed to participating in the dialogue that the FDA has encouraged to resolve the situation in a way that allows consumers choices and access to safe, properly labeled, and efficacious naturally derived health and wellness products.


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MEET THE AUTHORS

Malik Nishonov, Ph.D –– Senior Research & Development Chemist Malik Nishonov received his Ph.D. in organic chemistry and chemistry of natural products from the Institute of the Chemistry of Plant Substances at the Sciences Academy of Uzbekistan. At PPM, Malik works on isolating and purifying cannabinoids as a highly experienced researcher in medicinal plant chemistry. He is advancing canna science by inventing techniques to isolate minor cannabinoids, including CBN, as well as formulating whole plant-based products with specific profiles. He contributes to the R&D team’s continuous improvement of PPM’s proprietary, scalable methods to remediate THC from hemp-derived full spectrum oils and distillates for those customers who require a THC-free, whole plant product. At the Science Academy, Malik Nishonov isolated and elucidated the chemical structures of twenty novel alkaloids, flavonoids, proanthocyanidins, and phenol compounds. He held a post-doctoral fellowship at the Center for Drug Discovery of the University of Georgia and conducted research on projects targeted DNA and RNA viruses. This work led to important discoveries of highly specific HIV Integrase inhibitors that are granted by US and World patent offices. Malik received the Outstanding Research Award from the Academic Council of the Institute of Chemistry of Plant Substances. He has published over thirty scientific peer-reviewed journal articles, holds two patents, and has established himself as a renowned speaker in the international scientific landscape. Contact: [email protected]

Luping Yan, Ph.D –– Senior Research Chemist Dr. Luping Yan trained extensively in pharmacognosy and natural products then gained experience in food, supplements, and agricultural industries focused on plant-based medicinal and nutraceutical research and product innovation. He is a critical contributor to the PPM R&D efforts. Luping’s specific qualifications in purification techniques and molecular structure characterization allow him to lead several of PPM’s minor cannabinoid isolation and purification projects. Dr. Yan earned a PhD in Organic Chemistry from the University of British Columbia, a Master’s in Medicinal Chemistry (Natural Products) from West China

mailto:[email protected]


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College of Pharmaceutical Sciences, Sichuan University, China, and conducted post-doctoral research at Essa Pharma in Vancouver and Houston, where he synthesized natural products with high bioactivity. At Kemin Industries in Iowa, Luping’s work led to a series of novel marigold extractions, saponifications, and filtrations that positioned the company as a global leader in that segment. At Vega, the Danone sports nutrition subsidiary, he worked with product and method development, as well as labeling and regulatory affairs teams. Luping has a track record of creatively overcoming challenges associated with the complexity of purifying therapeutic compounds and medicinal drugs obtained from plants and other natural sources. With over ten years of experience in academia and industry, Dr. Yan is a passionate scientist who inspires PPM’s R&D team on a daily basis with his insights, optimism and leadership. Contact: [email protected]

Andrea Holmes, Ph.D –– Chief Growth Officer

Serving as CGO, Andrea drives the commercial development process with customers focused on the introduction of novel formulations and ingredients involving both major and emerging cannabinoids, as well as product lines containing a full spectrum or specific phytocannabinoid ratios that are 100% THC free. She is the key liaison between customers, industry and academic research collaborators, and PPM’s R&D and product development teams. She also leads PPM’s marketing initiatives and relationship building with hemp industry companies and regulatory agencies. She is motivated to change each person’s world for the better and do so in each interaction, as well as with products created with scientific innovation. Pushing all team members at PPM to higher levels is one of Andrea’s superpowers which in turn helps PPM bring its customers and end-use consumers the benefits of new and efficacious cannabinoid-based products. Dr. Andrea Holmes received her Ph.D. in organic chemistry at New York University and was a National Institutes of Health post-doctoral Fellow at Columbia University in the Department of Chemistry and Columbia Medical College, College of Physicians and Surgeons in New York City. She is a Professor of Chemistry at Doane University in Nebraska and holds appointments at the University of Nebraska in Lincoln and the University of Nebraska Medical Center. She was the recipient of the Presidential Early Career Award that was funded by the National Science Foundation and a national recipient of Henry Dreyfus Teacher Scholar award. Andrea published over 60 articles on nano-structured materials, miniaturized sensors, surface modifications for antimicrobial resistance, and has developed colorimetric sensors to detect warfare agents, abused narcotics, and cannabinoids.



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Contact: [email protected]

David Symonsbergen –– Chief Science Officer Serving as CSO, David leads PPM’s science “factory” that is inspired by the philosophy of Edison’s original industrial research lab. Dave executes PPM’s research and development equivalent to other world-renowned, science advancing chemistry, and pharmaceutical research institutions. Taking innovation to commercialization through process and scale development is also Dave’s forte and responsibility. He leads inquiry into PPM’s scientific and customer-specific research work to increase bioavailability and enhancing terpenes, terpenoid and flavonoid profiles. His background in synthetic organic and organometallic chemistry provides the foundation for advancing both isolation and purification of unique cannabinoid ratios that become ingredients in novel hemp-derived phytocannabinoid products. A former medicinal chemist and top producer at one of the largest pharmaceutical companies in the world, Dave’s understanding of both pharmacokinetics and bioavailability contribute to PPM’s ever-expanding product line. The PPM company principles of safety, efficacy, quality and consistency are foremost priorities in Dave’s scientific approach. Dave earned a Masters in Synthetic Organic Chemistry at the University of Nebraska and has worked for several companies including Novartis and Rieke Metals. David most recently founded and served as the CEO at Novel Chemical Solutions. He is tireless, creative, a first principal thinker,continuously experimenting, and discovering innovative techniques and methodologies to enhance PPM’s proprietary processes so they meet the exacting standards of both PPM customers and the people whose quality of life is improved by non-psychotropic phytocannabinoids. Contact: [email protected]

Steve Kazemi –– Chief Operating Officer Serving as COO, Steve executes PPM’s strategy of becoming the leading non-psychotropic cannabinoid-based ingredient supplier globally. He delivers results through his engaged leadership style and creative insight. His depth of experience, keen operational oversight, and dedication to advancing PPM’s science-based approach to extraction, refinement and purification provides him with great fulfillment knowing he is contributing to humankind by getting the most out of the complex cannabis plant to help people improve the quality of their lives. Steve, a decisive and resolute leader, has over 20+ years of executive operational experience and demonstrated expertise in the development, management and positioning of complex manufacturing and production facilities




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in the dietary supplement industry. Steve earned a bachelor’s degree in Chemistry from the University of New Mexico and served as the principal partner for Pure Cultures, strategically developing its business model to provide distributors with high-quality probiotic options, and silage inoculants from concept to shelf. Previously, he worked at other microbiome and plant-based science-based companies in the Colorado biotechnology community including Hauser Chemical Research manufacturing the Taxol chemotherapy drug and Nutraceutix. Contact: [email protected]

Jazmin Oliver –– Research & Development Chemist Jazmin Oliver is a key member of PPM's research and development team. Jazmin has a diverse scientific background and brings to PPM hemp industry insight from her career experiences. Jazmin helped design PPM’s proprietary refinement and purification process to ensure our customers can depend on PPM products to be 'to spec' each and every time. In addition to making superior quality and purity products, Jazmin’s priorities include safety, compliance, process efficiency and data analytics as she continues to contribute to fractional distillation, isolation and unique cannabinoid formulation advancements. Jazmin holds a dual Bachelor’s degree in Medicine and Public Health from the University of North Florida in Jacksonville, Florida. She studied in various capacities for the World Health Organization and the United Nations before entering medical school at St. James School of Medicine in Anguilla. Her medical school experience led her to PPM because she is passionate about education on cannabinoids and their medicinal properties. Contact: [email protected]

Jonathan Waldorf–– Analytical Lab Manager Jonathan is an analytical chemist with 20 years of experience. At PPM, he is responsible for all analytical laboratory operations and hires, trains and manages all lab technicians. He ensures that the HPLC and GC/FID/MS instruments are properly maintained, performs quality control procedures, and conducts both internal and external validations. Jonathan's analytical lab operates 24x7 to support all PPM R&D and production activity. Most importantly, he makes sure that the PPM analytics are world-class and that PPM technicians conduct each and every analysis with accuracy, reproducibility, and consistency. Jonathan's expertise has significantly contributed to PPM's intensive process controls,




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research and development successes, and optimization of production processes. Jonathan received his BS degree in Biology at Georgia Southern University. Since 1999, he has held high-level positions in industry where he supervised over 75 employees conducting testing for highly sophisticated and exacting customers, including the DOE, DOD, and EPA. Jonathan and the technician teams he managed used a plethora of analytical instruments and techniques, including LCMS, HPLC, GCMS, ICPMS, Hg analyzers, and other analysis equipment. His competence in volatile and semi-volatile analysis is extremely important for chemical profiling of PPM's hemp biomass and extracts. Contact: [email protected]

FOR MORE INFORMATION

Learn more about PPM on our website at www.precisionplantmolecules.com or contact us at

[email protected]

Disclaimer: The information provided by PPM herein includes statements and assumptions that are subject to change and should be verified independently. These statements have not been evaluated by the Food and Drug Association. Hemp-derived products, mentioned herein, are not intended to diagnose, treat,

cure, or prevent any disease.

http://www.precisionplantmolecules.com/



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