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What is the Better Approach for Creating “Medicines”?

Plant or Lab?

plant vs labThe Cannabis plant has been used for its medicinal properties for millennia. It also has psychogenic effects and abuse potential that seem to derive primarily from one component—delta-(9)-tetrahydrocannabinol, or THC. But the Cannabis plant, chemically speaking, is so much more, and the discovery and further elucidation, starting in 1964, of the human endocannabinoid system—a complex, widely dispersed neuromodulatory system that some consider to have the ultimate responsibility for “homeostasis” (that is, the maintenance of “steady state,” or “normal”)—has raised many more questions than have so far been answered:

  • How many potential medicinal agents are there in the Cannabis plant?
  • Might some of them have benefit without abuse potential?
  • How can these chemicals in the plant be isolated and tested?
  • Is it economically feasible to “harvest” these chemicals from the Cannabis plant?
  • If such chemicals have the potential to be approved by the FDA as “medicine,” how can we ensure their sufficient availability and purity when taking them from a plant?
  • Can we just “make” some of these chemicals in a laboratory?

The Cannabis plant Cannabis contains at least 500 different chemicals, categorized as cannabinoids, terpenoids, flavonoids, and omega fatty acids. Terpenoids are responsible for the well-known aromatic scent of cannabis being smoked, but also occur in many other plants. In fact, terpenoids are at least in part responsible for the scent of eucalyptus, the flavors of cinnamon, cloves, and ginger, the yellow color in sunflowers, and the red color in tomatoes. Terpenoids appear in many herbal remedies and are known to have specific effects on the human body that are only now being elucidated . . . but they may contribute to some of the effects of cannabis.1

While terpenoids are found in many flowering plants, cannabinoids are found only in Cannnabis, and there have been over 100 different cannabinoids identified to date. Many of them do not have well-characterized physiologic effects on the human body. Flavonoids are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea, and wine, and are generally thought to have beneficial effects on human health. Flavonoids are now considered as an essential ingredient in a variety of nutraceutical, pharmaceutical, medicinal, and cosmetic applications. While their diverse mecahnisms of action have not been clearly defined, flavonoids have been associated with anti-oxidative, anti-inflammatory, anti-mutagenic, and anti-carcinogenic properties.2

Many people, of varying scientific expertise, feel that Cannabis is most likely to have a medicinal benefit when the entire plant—comprising these other compounds as well as all these cannabinoids—is used, rather than extracts of the plant. This belief if known as the “entourage effect” and will be discussed in another post. In this post, we are going to focus on isolates of cannabinoids and explore the idea of whether the best approach to evaluating their safety and efficacy as potential medicines is to isolate the desired cannabinoids from the plant (they are thus called “phytocannabinoids”) or to synthesize (in a chemistry lab) or biosynthesize (harnessing genetically modified yeast or algae to produce them) the desired cannabinoids.

The issue of relative efficacy of phytocannabinoids vs synthetic cannabinoids is broad, not fully elucidated, and complex. We’ll focus here on some “bread and butter” issues. First, making medicine is a business. Navigating the FDA drug approval process3—even for an agent that isn’t a cannabinoid—is very costly and typically requires years of development. That process is much more complicated and expensive—at least for now—if the compound being studied is derived from Cannabis.4 A major part of navigating the approval process is demonstrating to the FDA the purity and consistency of a medicinal product, as well as a reliable supply chain or manufacturing process. This is notoriously difficult to do with botanical products, which includes phytocannabinoids. There are issues of “genetic drift,” in which even stable cultivars can mutate and lead to different chemical compositions from parent plants.5 There are issues of potential contamination, with pesticides, fertilizers, and other chemical additives, and even natural selection from lighting and temperature. There are potential infections with various plant viruses or fungi. While a selected plant strain may remain stable for many generations, the FDA has little track record of approving botanicals because of concerns like these. The notable exception: the recent approval of GW Pharmaceuticals’ phytoCBD, marketed as Epidiolex® with an orphan drug indication for rare, specific, and severe pediatric seizure disorders.6 GW secured a patent and an FDA-approved label for its plant-derived CBD. Synthetic CBD has been around for years and is easily obtained by researchers, but has not been taken through the drug development process for any specific indication. To expect other pharmaceutical companies to successfully cross these treacherous waters seems a lot to ask.

Cannabis plants can be bred and crossbred and manipulated to contain higher concentrations of selected cannabinoids, including those “minor cannabinoids” discussed in other posts that in wild-type Cannabis plants may be quite rare. In addition, even low-concentration cannabinoids can be derived from extraction from a large crop of plants. Still, it is sometimes easier to “create” the chemical structure in the laboratory. Standards exist for comparing synthetic cannabinoids to their phytocannabinoid counterparts. Taking a carefully and consistently synthesized chemical to FDA is likely to encounter less regulatory resistance than proposing the study of a botanical entourage or isolate.

“Synthetic cannabinoids” earned a bad name when they first appeared in the literature—and on the streets. Acute and sometimes fatal intoxication can occur with exposure to “K2” or “Spice.” These chemicals are similar to phytocannabinoids, and are sometimes misleadingly called “synthetic marijuana” (or “fake weed”). They may exert very strong agonism at the CB1 receptor (where THC causes its psychogenic effects). K2 and Spice are very different from synthetic cannabinoids that have been developed as potential medicinal agents.

With the pursuit of synthetic or biosynthetic single cannabinoids, researchers leave behind not only the entourage effect but also the collective experience of millions of people currently using botanical cannabis products to help treat a variety of ailments. However, there are substantial challenges in determining the right balance of these constituent chemicals in order to establish a defined product with which to move forward in clinical drug development, and with each increase in the number of “active” substances in a medicine, the challenges with respect to clinical evaluation and manufacturing precision increase exponentially. The synthetic pathway is consistent with how most other medications are currently developed. There are clear guidelines for drug discovery, evaluation of pharmacology and toxicology, quality control, and both pre-clinical and clinical research methods. That is how the first synthetic cannabinoids (THC)—dronabinol and nabilone—were approved years ago.

This route is challenging, too, however. As my friend and colleague Dr Marcel Bonn-Miller has written, “One challenge for single molecule cannabinoid drug development is that there seems to be growing sentiment, though unfounded in published scientific studies, that ‘natural’ cannabis is safer and better than pharmaceuticals. Another, somewhat related complicating factor in cannabinoid drug development is the existence and structure of the legislatively approved medicinal, and more recently ‘recreational,’ cannabis industries. From an economic standpoint, there is little incentive for the businesses able to sell cannabis products through legislatively sanctioned mechanisms to invest tens of millions of dollars into clinical research, because they are not currently required to do so. At the same time, pharmaceutical companies face the financial uncertainty of whether any drug (botanical or single molecule) brought to market through traditional drug development methods would be able to compete with the existing cannabis industry. From a regulatory standpoint, traditional drug development also faces significant challenges. Given that cannabis and many single molecule cannabinoids are still tightly regulated in most countries, there are substantial challenges with importing/exporting products, arduous requirements for conducting research, and few sources of raw botanical or synthetic materials that meet the quality standards needed for medicinal drug development. In sum, while there appears to be tremendous therapeutic potential for cannabinoid medicines, there is a need for the development of defined, consistent, and targeted products. Independent of whether these are botanical or single molecule substances, these products must pass established standards for quality, safety, and efficacy before being approved for use.”7

There are also synthetic agents that impact the endocannabinoid system by interfering with the usually-rapid metabolism of endogenous cannabinoids. That approach—more in keeping with traditional research as the agents are not themselves cannabinoids—will be discussed in a future post. There is yet no clear answer to the title question, but it is clear that we are potentially entering the “golden age” of cannabinoid research and discovery.

Charles Pollack, M.D.

Resources

  1. Nuutinen T. Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus. Eur J Med Chem. 2018;157:198-228. doi:10.1016/j.ejmech.2018.07.076
  2. Flavonoids: an overview | Journal of Nutritional Science | Cambridge Core. https://www.cambridge.org/core/journals/journal-of-nutritional-science/article/flavonoids-an-overview/C0E91D3851345CEF4746B10406908F52. Accessed February 4, 2020.
  3. Development & Approval Process | Drugs. FDA. http://www.fda.gov/drugs/development-approval-process-drugs. Published October 27, 2019. Accessed February 4, 2020.
  4. FDA and Cannabis: Research and Drug Approval Process. FDA. January 2020. http://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process. Accessed February 4, 2020.
  5. Plant Life: Genetic Drift. Plant Life. http://lifeofplant.blogspot.com/2011/04/genetic-drift.html. Accessed February 4, 2020.
  6. GW Pharmaceuticals | Cannabinoid Research & Medicines. GWPharm.com. https://www.gwpharm.com/healthcare-professionals/epidiolex. Accessed February 4, 2020.
  7. Bonn-Miller MO, ElSohly M, Loflin MJE, Chandra S, Vandrey R. Cannabis and Cannabinoid Drug Development: Evaluating Botanical Versus Single Molecule Approaches. Int Rev Psychiatry Abingdon Engl. 2018;30(3):277-284. doi:10.1080/09540261.2018.1474730

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