The Phytocannabinoids Story
Out of more than 100 compounds in the cannabis plant, phytocannabinoids, such as THC, CBD, and cannabinol (CBN), were the first ones to be identified and isolated.1,2
Then in 1988, while scientists were investigating how THC exerted its effects, the endocannabinoid system was discovered within the human body.2
This led to the exploration of how cannabinoids, including both the plant molecules and synthetic versions developed in laboratories that mimic their effects, might be used for therapeutic purposes.
Cannabidiol (CBD), the by-product of heating CBDA, is one of the major cannabinoids derived or synthesized from cannabis.2,3
CBD has very low affinity for cannabinoid receptor CB1 and so is lacking euphoric side effects.4
It is under investigation because of its anticonvulsant properties, as well as other conditions.5,6
EPIDIOLEX® is a specific formulation approved for specific epilepsies.7
Cannabidivarin (CBDV), a lesser-known cannabinoid, is produced from cannabidivaric acid (CBVA).
Studies have been done in rodent models of epilepsy and autism spectrum disorder.7,8
It is under investigation for potential anticonvulsant properties.
Cannabidiolic acid (CBDA) is how CBD naturally occurs in the plant.
Testing of CBDA in rodent and rodent-like models illustrates that CBDA works on the serotonin receptor (specifically 5-HT1A) to prevent vomiting and suppress nausea and anxiety.9
Tetrahydrocannabinol (THC), most commonly in its delta-9 form, is the by-product of heating THCA.1,2
It is a major cannabinoid that may be derived from cannabis or synthesized.2
It is primarily responsible for marijuana’s psychotropic properties.2
Recreational and therapeutic uses: FDA-approved synthetic and analogue products, such as Marinol® and Syndros®, are indicated for nausea and vomiting related to chemotherapy and anorexia associated with AIDS.6,7
Tetrahydrocannabinolic acid A (how THC naturally occurs in the cannabis plant).
Limited study in rodents in nausea.10
Tetrahydrocannabivarin, a lesser-known cannabinoid, is produced from tetrahydrocannabidivaric acid (THCVA).
Studies have been conducted in rodent models of both Parkinson’s disease and insulin sensitivity (a model of diabetes).11,12
It is under investigation for potential use in type 2 diabetes.13
Not All Cannabinoid Products Are Created Equal
Products that sound similar may not be equivalent for various reasons, including potential differences in development, manufacturing, testing, and approval.
The term “medical marijuana” refers to using the whole plant or its extracts to treat medical problems.
The FDA does not recognize the whole marijuana plant as medicine.
Research on extracts from the marijuana plant, called cannabinoids, has led to FDA-recognized medicines, proving this research is possible.
Continued research may lead to more FDA-approved medications.
The cannabis varieties used for medical or recreational marijuana are generally the same plants, grown in the same conditions, and subjected to the same cannabinoid extraction process. It is the intent of use that separates these 2 terms legally.
Medical marijuana laws are in constant flux, but as of August 2019, 34 states, the District of Columbia, Guam, Puerto Rico, and the US Virgin Islands have comprehensive programs for access to medical marijuana.8
Medical marijuana is dispensed for use without any substantial research proving safety or efficacy. In contrast, the FDA requires carefully conducted research (randomized, placebo-controlled clinical trials) in hundreds to thousands of human patients to determine the benefits and risks of a possible medication.
A systemic review by the National Academy of Sciences (2017) highlighted the lack of appropriate evidence for the use of medical marijuana to treat neurological conditions.9
The American Association of Neurology (AAN) position statement noted that “it is not appropriate to extrapolate the results of trials of standardized preparations to other non-standardized, non-regulated medical marijuana products which may be commercially available…”10
Caution and monitoring are warranted when patients use medical marijuana. Repeated independent research has shown that these products may have inaccurate labels, and unknown constituents can be present in non–FDA approved products (eg, pesticides, heavy metals, or THC).11,17,26,39 Learn more about the state of cannabinoid testing.
Hemp and marijuana are both types of cannabis.
Historically, hemp has been used to produce fibers and seeds for manufacturing, while marijuana has been used for recreational products.
Because marijuana is federally illegal, retailers became interested in growing hemp for CBD. The 2018 Farm Bill descheduled CBD derived from hemp but only if there is less than 0.3% THC on a dry-weight basis.12
The FDA notes that these products must not be used as supplements or foods, nor can they be used to treat a medical condition.
Changes in the 2014 Agriculture Act and the 2018 Agriculture Improvement Act, also known as the “Farm Bill,” expanded the federal definition of hemp, first specifying it for research (2014) and then for other non-consumed products (2018).13
The Food and Drug Administration (FDA) maintains oversight of hemp-derived consumer products, including those used as a food or food ingredient, or as an ingredient in body products, cosmetics, dietary supplements, and therapeutic products.
The USDA maintains oversight of program implementation. This includes developing regulations and guidance for the commercial production of industrial hemp in the United States, as well as, regulations for individual states or tribes. USDA will not begin reviewing plans until regulations go into effect at the end of 2019 for crop growth in 2020.14
While the 2018 Agriculture Improvement Act stipulates that hemp-derived products can have no more than 0.3% THC by dry weight, some purveyors are interpreting this to apply to finished product. This misinterpretation could lead to products being sold with high levels of THC – as much as 80 mg of THC in a single 30-mL bottle of hemp-derived CBD oil.15
Hemp-derived products may pose a risk to the public with unintended high dose exposure to THC. Moreover, hemp plants are soil remediators that absorb toxic chemicals from the soil they are grown in.16
When phytocannabinoids are extracted from these plants, toxic chemicals from the soil can also be in the extraction. Rigorous growing, harvesting, extraction, manufacturing, and testing practices must be performed to ensure safe products for consumption.16 Even products undergoing state testing may have inaccurate labels due either to lab quality issues or the post-testing degradation of cannabinoid content.11,17
FDA-Approved Cannabinoid Formulations
The U.S. Food and Drug Administration (FDA) is responsible for protecting public health by regulating products such as medical drugs, medical devices, tobacco products, food, and cosmetics.18
When a product is “FDA-approved,” that means it has gone through a series of rigorous tests to assess safety and efficacy.19
With growing interest in the development of medicines from cannabis, the FDA is concerned that non–FDA approved products can put the health and safety of consumers at risk.
The FDA requires carefully conducted research studies (randomized, placebo-controlled clinical trials) in hundreds to thousands of patients to determine the benefits and risks of a possible medication before it can be marketed to the public or physicians.19
The FDA has approved 4 cannabinoid products: a plant-derived cannabidiol, EPIDIOLEX®, a CBD oral solution for the treatment of seizures associated with 2 rare, severe forms of epilepsy; and 3 formulations of 2 synthetic THC cannabinoid products, dronabinol and nabilone (Marinol®, Syndros®, Cesamet®) for the treatment of nausea and vomiting associated with cancer chemotherapy or loss of appetite and weight loss in people with AIDS.7,20-22
The FDA has not approved any marijuana or hemp products purchased at dispensaries, retail shops, or online for treating any medical conditions or as dietary supplements. It is also not legal to sell foods containing THC or CBD in interstate commerce.23
As patient and consumer demand increases, so does the need for greater scientific understanding of cannabis and cannabinoids. Clinical trials to examine the medical validity and safety of these dispensary and retail products have not been conducted, thus they are not FDA approved.
Testing of Schedule I products can seem daunting, but there are paths through the FDA and DEA to perform research on these restricted products.24,25
Without FDA approval and oversight, products are susceptible to error or corruption in production and marketing. Patients are left on their own to guess at the content and quality of non–FDA approved cannabinoid products.11,17,26
FDA has approved 3 synthetic cannabinoids and 1 plant-derived cannabinoid.
• Anorexia associated with weight loss in adult patients with AIDS
• Nausea and vomiting associated with chemotherapy in adult patients who failed conventional antiemetics
EPIDIOLEX® is a plant-derived cannabidiol that is indicated for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome in patients 2 years of age and older.15
1. Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. N Engl J Med. 2015;373(11):1048-1058.
2. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Brit J Pharmacol. 2006;147(suppl 1):S163-S171.
3. Taura F, Sirikantaramas S, Shoyama Y, et al. Cannabidiolic-acid synthase, the chemotype-determining enzyme in the fiber-type Cannabis sativa. FEBS Lett. 2007;581(16):2929-2934.
4. Amada N, Yamasaki Y, Williams CM, Whalley BJ. Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. Peer J. 2013;1:e214.
5. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376(21):2011-2020.
6. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016;15(3):270-278.
7. EPIDIOLEX [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc.; 2018.
8. National Conference of State Legislatures. State medical marijuana laws. http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx. Published July 2, 2019. Accessed August 20, 2019.
9. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research (2017). http://nap.edu/24625. Accessed on August 20, 2019.
10. Patel A, Fee D, Brust JCM, et al. Position statement: use of medical marijuana for neurologic disorders. Am Acad Neurol. 2014:1-4.
11. Bonn-Miller MO, Loflin MJE, Thomas BF, et al. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318(17): 1708-1709.
12. H.R. 5485 – Hemp Farming Act of 2018. https://www.congress.gov/bill/115th-congress/house-bill/5485. Accessed August 20, 2019.
13. National Institute of Food and Agriculture. Industrial hemp. https://nifa.usda.gov/industrial-hemp. Accessed August 20, 2019.
14. United States Department of Agriculture. Agricultural Marketing Service. Hemp. https://www.ams.usda.gov/rules-regulations/farmbill-hemp. Accessed August 20, 2019.
15. United States Department of Agriculture. Agricultural Marketing Service. Subtitle G–hemp production. https://www.ams.usda.gov/sites/default/files/media/2018FarmBill.pdf. Accessed August 20, 2019.
16. Girdhar M, Sharma NR, Rehman H, et al. Comparative assessment for hyperaccumulatory and phytoremediation capability of three wild weeds. 3 Biotech. 2014;4(6):579-589.
17. Vandrey R, Raber JC, Raber ME, et al. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA. 2015;313(24):2491-2493.
18. U.S. Food and Drug Administration. Regulated products. https://www.fda.gov/industry/import-basics/regulated-products. Updated August 3, 2018. Accessed August 20, 2019.
19. U.S. Food and Drug Administration. The FDA’s drug review process: ensuring drugs are safe and effective. https://www.fda.gov/drugs/drug-information-consumers/fdas-drug-review-process-ensuring-drugs-are-safe-and-effective. Updated November 24,2017. Accessed August 20, 2019.
20. Marinol [package insert]. North Chicago, IL: AbbVie Inc; 2017.
21. Cesamet [package insert]. Somerset, NJ: Meda Pharmaceuticals Inc; 2015.
22. Syndros [package insert]. Chandler, AZ: Insys Therapeutics, Inc; 2016.
23. U.S. Food and Drug Administration. FDA regulation of cannabis and cannabis-derived products: questions and answers. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-questions-and-answers#farmbill. Updated April 2, 2019. Accessed August 20, 2019.
24. United States Drug Enforcement Administration. DEA speeds up application process for research on Schedule I drugs. https://www.dea.gov/press-releases/2018/01/18/dea-speeds-application-process-research-schedule-i-drugs. Published January 18, 2018. Accessed August 20, 2019.
25. U.S. Food and Drug Administration. Marijuana research with human subjects. https://www.fda.gov/news-events/public-health-focus/marijuana-research-human-subjects. Updated April 2, 2019. Accessed August 20, 2019.
26. U.S. Food and Drug Administration. Warning letters and test results for cannabidiol-related products. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products. Updated July 24, 2019. Accessed August 20, 2019.
27. SATIVEX [product monograph]. Mississauga, Ontario: Bayer Inc; 2015.
28. Iannotti FA, Hill CL, Leo A, et al. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci. 2014;5(11):1131-1141.
29. Zamberletti E, Gabaglio M, Woolley-Roberts M, et al. Cannabidivarin treatment ameliorates autism-like behaviors and restores hippocampal endocannabinoid system and glia alterations induced by prenatal valproic acid exposure in rats. Front Cell Neurosci. 2019;13(367):1-15.
30. Bolognini D, Rock EM, Cluny NL, et al. Cannabidiolic acid prevents vomiting in Suncus murinus and nausea-induced behaviour in rats by enhancing 5-HT1A receptor activation. Brit J Pharmacol. 2013;168:1456-1470.
31. Rock EM, Kopstick RL, Limebeer CL, Parker LA. Tetrahydrocannabinolic acid reduces nausea-induced conditioned gaping in rats and vomiting in Suncus murinus. Brit J Pharmacol. 2013;170:641-648.
32. García C, Palomo-Garo C, García-Arencibia M, Ramos JA, Pertwee RG, Fernández-Ruiz J. Symptom-relieving and neuroprotective effects of the phytocannabinoid ∆9-THCV in animal models of Parkinson’s disease. Brit J Pharmacol. 2011;163:1495-1506.
33. Wargent ET, Zaibi MS, Silvestri C, et al. The cannabinoid ∆9-tetrahydrocannabivarin (THCV) ameliorates insulin sensitivity in two mouse models of obesity. Nutr Diabetes. 2013;3:e68.
34. Jadoon KA, Ratcliffe SH, Barrett DA, et al. Efficacy and safety of cannabidiol and tetrahydrocannabivarin on glycemic and lipid parameters in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel group pilot study. Diabetes Care. 2016;39(10):1777-1786.
35. U.S. Food and Drug Administration. What We Do. https://www.fda.gov/about-fda/what-we-do. Accessed on August 20, 2019.
36. United States Drug Enforcement Administration. Drug Scheduling. https://www.dea.gov/drug-scheduling. March 2018. Accessed on August 20, 2019.
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38. European Monitoring Centre for Drugs and Drug Addiction. European Drug Report. Trends and Developments. May 2016. http://www.emcdda.europa.eu/publications/edr/trends-developments/2016_en. Accessed on August 20, 2019.
39. Jikomes N, Zoorob M. The cannabinoid content of legal cannabis in Washington State varies systematically across testing facilities and popular consumer products. Scientific Reports. 2018;8:4519.