The 2018 Farm Bill, New Regulations, and the FDA
The 2018 Farm Bill created an exciting new opportunity for U.S. farmers, the cultivation of hemp. Since then, it seems like hemp has been on every agriculture agenda. Seed World PRO has pulled together two experts to talk about the biology of the hemp plant as well as everything cannabinoids.
The 2018 Farm Bill removed hemp, defined as cannabis (Cannabis sativa L) with less than 0.3 percent delta-9-tetrahydrocannabinol (THC), from the definition of marijuana in the Controlled Substances Act (CSA). The 2018 Farm Bill preserved the authority of the Food and Drug Administration (FDA or Agency) to regulate hemp products. In testimony on July 25, 2019 before the Senate Committee on Agriculture, Nutrition and Forestry, Amy Abernethy, M.D., Ph.D. stated that:
Hemp products must meet any applicable FDA requirements and standards, just like any other FDA-regulated product.
For example, FDA’s existing authorities over foods, dietary supplements, human and veterinary drugs and cosmetics apply to hemp products to the extent such hemp products fall within those categories.¹
Consistent with the FDA’s view on its regulatory authority over hemp derived products, in 2018 the Agency determined that three food products made from hemp seed were Generally Recognized as Safe (GRAS).² Hemp seeds contain little or no THC. The FDA determined that the hemp seed derived products hulled seed, protein power and seed oil can be legally used in the U.S. food supply. The regulatory status in the U.S. of hemp derived cannabinoids remains uncertain. Currently, there is a growing market for the non-psychoactive cannabinoid cannabidiol (CBD) derived from hemp. CBD is being incorporated into a wide range of products including cosmetics, foods and beverages and is being promoted for treatment of a wide range of ailments including anxiety, pain and more.
FRANK CURTIS, COO NEW WEST GENETICS
In this PRO Power Talk, Frank Curtis dives into the biology of the hemp plant and gives an overview of where hemp genetics are today. Hemp is an extremely versitle plant. It's stalks, seeds, and leaves are used for everything from building materials, paper, foods, and cosmetic products. Cannabinoids might get the most attention, but there are many other uses.
Some hemp seeds are legal because the THC levels are below the threshold set in the 2018 Farm Bill. "Hot" seeds have THC levels that are too high. Curtis believes that the genetics already exist to produce legal hemp. To increase the THC level requires an act of Congress and will be difficult to do. However, the seed industry can comply with the current requirements and supply the industry research shows that 90% of THC levels are controled by genetics and only 10% is controled by the environment. Therefore, if growers purchase seeds with the right genetics they should not face legal challenges.
CANNABINOIDS
It is likely the cannabis plant evolved the ability to produce cannabinoids for protection against insects, fungi and other pests. Many cannabinoids have insecticidal and antimicrobial activity. The cannabis plant produces more than 100 different cannabinoids. Unlike THC, most of these cannabinoids are non-psychoactive.
Importantly, some cannabinoids interact with receptors in the human endocannabinoid system. The receptors in the human endocannabinoid system are found in the nervous and immune systems. The human endocannabinoid system is involved in regulating a large number of important functions including pain, appetite and inflammation. Consequently, cannabinoids have great potential as therapeutic agents. For example, THC prescribed as the pharmaceutical Marinol® is used as an appetite stimulant and as a therapy for pain management in cancer patients undergoing chemotherapy. More recently, in June 2018 the FDA approved the drug Epidiolex® for treatment of seizures associated with two very rare and severe pediatric forms of epilepsy. The active ingredient in Epidiolex® is the cannabinoid CBD.
Hemp and Cannabinoids
Hemp can be a cost-effective source of some cannabinoids. There are hemp varieties that produce relatively large amounts of CBD. The CBD is extracted from plant material by several different methods, including solvent or supercritical carbon dioxide extraction. Because the cannabis plant produces such a large array of different cannabinoids, investment in sophisticated purification steps is necessary to produce a relatively pure product. Extraction and purification of cannabinoids from hemp is particularly challenging when the cannabinoid is produced in small quantities in the plant.
Companies are investing in the breeding and genetic engineering of new varieties of hemp that produce larger quantities of the desired cannabinoids, while at the same time maintaining the level of THC at less than 0.3% on a dry weight basis. The breeding of these new hemp varieties will take a significant amount of time and investment. Furthermore, if the cannabinoid is intended for use as a pharmaceutical, producing a pharmaceutical grade cannabinoid suitable for clinical trials and FDA approval from the plant will be challenging.
Other Methods of Producing Cannabinoids
Cannabinoids, particularly minor cannabinoids can be produced by methods other than plant extraction. Methods have been developed for the chemical synthesis of some cannabinoids. For example, the THC found in Marinol® is produced by chemical synthesis. The advantage of chemical synthesis is that it frequently can be done in a FDA compliant manner. The disadvantage of chemical synthesis is that it may be expensive. Cannabinoids have complex chemical structures that may require many synthetic steps and purifications to produce in pure form.
The THC found in Marinol® is produced by chemical synthesis.
In principal, cannabinoids can also be produced by synthetic biology. The synthetic biology approach involves transforming a microorganism with genes isolated from the cannabis plant that code for cannabinoid biosynthetic enzymes. The goal is to transform the genetically engineered microorganism into a cannabinoid producing biosynthetic factory. The genetically engineered microorganism is grown in a fermentor and the cannabinoids are produced and purified. Although several companies are working to genetically engineer microorganisms to produce cannabinoids, the yields to date are extremely low, in the microgram per liter range, and therefore not suitable for commercial production of these compounds.³
A third approach that has achieved high levels of cannabinoid production is biocatalysis. In biocatalysis, cannabinoid biosynthetic enzymes are produced in a genetically engineered organism. One or more cannabinoid biosyntetic enzymes are placed in a solvent system containing a starting material that is converted by the cannabinoid biosynthetic enzyme into the desired cannabinoid product. Biocatalysis has achieved the production of many grams of cannabinoids, including cannabinoids only produced in very small amounts in the plant, in efficient time frames.⁴
The Future
Hemp is a fantastic source of fiber, protein and oil.
Pure CBD is also being produced in a cost-effective manner from hemp. Whether hemp will be a commercially viable source of low abundance cannabinoids is questionable. Hemp produces small quantities of many cannabinoids of commercial interest. Significant time and money will be required to breed or genetically engineer new hemp varieties containing increased amounts of cannabinoids of interest. Production of FDA compliant compounds in plants is also a significant challenge. The commercial production of cannabinoids through chemical synthesis, synthetic biology, biocatalaysis, or some combination of these approaches, offer greater promise for the commercial production of pure cannabinoids for use as nutraceuticals and pharmaceuticals.
¹ https://www.agriculture.senate.gov/imo/media/doc/Testimony_Abernethy%2007.25.19.pdf .
² http://www.fda.gov/food/cfsan-constituent-updates/fda-responds-three-gras-notices-hem-seed-dervied-ingredients-use-human-food .
³ Luo et al., Nature 567: 123-126 (2019)
⁴ Peet et al., U.S. Patent No. 10,336,978