Cannabinoids break down into 3 main classes:
endocannabinoids, phytocannabinoids, and synthetic cannabinoids.
Endocannabinoids are chemicals produced inside of your body that attach to the same receptors as some phytocannabinoids.3
The most well-known endocannabinoid receptors are the Cannabinoid Receptor 1 (CB1) and the Cannabinoid Receptor 2 (CB2).4
Endocannabinoid chemicals help maintain balance and harmony in a healthy body.5
Endocannabinoids were identified after discovering the mechanism of action of THC on CB1 and CB2 receptors.
Thus, cannabis exerts it effects, in part, by mimicking our endocannabinoid system.3
The 2 most extensively studied endocannabinoids, anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoylglycerol), and the enzymes responsible for endocannabinoid metabolism, make up the endocannabinoid system.
Anandamide and 2-AG, as well as other phytocannabinoids, have more molecular targets than just CB1 and CB2, such as Transient Receptor Potential (TRP) receptors and G-Protein receptor 55 (GPR55).5
One key feature of endocannabinoids is their precursors, present in lipid membranes, can be synthesized in one or two rapid enzymatic steps, and released into the extracellular space.
Thus, unlike exogenous cannabinoids, endocannabinoids can have an immediate effect.5
Initially, endocannabinoid receptors were thought to be present only in the nervous system.
We now know that these receptors are found throughout the body regulating major system processes.5
Research targeting the endocannabinoid system has uncovered the extreme complexity of this widespread and versatile system.
It is predicted that future therapeutic discoveries will take advantage of these novel pathways.5
Phyto-, meaning plant, cannabinoids are chemicals found in and extracted from the cannabis plant.
The cannabis plant contains over 100 known phytocannabinoids.
The highest percentage of phytocannabinoids are found in the unseeded flower buds of female plants.22
THC and CBD are the most widely studied phytocannabinoids.
EPIDIOLEX® is the only FDA-approved phytocannabinoid product, CBD oral Solution, which is approved for the treatment of seizures associated with rare epilepsies.6,7
Hemp and cannabis are both varietals of the Cannabis sativa L. genus.
Hemp was traditionally grown for fiber and seeds, whereas cannabis was grown for phytocannabinoids.
With the new Agricultural Act (2018; often referred to as the “Farm Bill”), hemp plants may be grown with larger flowers to increase their phytocannabinoid content, but products derived from hemp still must contain less than 0.3% THC on a dry-weight basis.8
It is unclear whether this means 0.3% THC in the dry plant or finished product.
Cannabis sativa L. plants are soil remediators that absorb toxic chemicals from the soil.
When phytocannabinoids are extracted from these plants, toxic chemicals from the soil can also be in the extraction.
Thus, rigorous growing, harvesting, extraction, manufacturing, and testing practices must be performed to ensure safe and consistent product.23
New scientific research is discovering that phytocannabinoids interact with many receptors beyond CB1 & CB2.9
Moreover, research from FDA-approved cannabinoids has shown an array of known side effects as well as drug-drug interactions.6
There isn’t a scientific definition of non–FDA approved “medical marijuana,” but it is generally considered to be a product containing phytocannabinoids from the cannabis plant intended to relieve symptoms of an ailment.
Numerous state programs allow patients to be dispensed medical marijuana with a doctor’s recommendation (not prescription).
Each state has different regulations to oversee the production of phytocannabinoid products for medical marijuana.
While most try to have a safe and consistent product, caution is warranted.10-12
Synthetic cannabinoids are chemicals made in a laboratory to mimic phytocannabinoids, which are chemicals found naturally in the cannabis plant.
These mimic the phytocannabinoid THC.
There are many illegal synthetic cannabinoid products that are sold online and in stores.
Some of these illegal products have caused illnesses and deaths.16
Synthetic cannabinoids can be THC analogues that act as full agonists at cannabinoid receptors and have biologically active metabolites.
Synthetic cannabinoids may be more potent than cannabis-derived THC.
The FDA-approved synthetic THC formulations nabilone (Cesamet®) and dronabinol (Syndros®; Marinol®) are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy treatment; dronabinol is also indicated for treatment of anorexia associated with weight loss in patients with AIDS.13-15
FDA-approved synthetic THC formulations have a product label that explains their side effects and safety, noting that they should be dosed at low concentrations to help reduce side effects.
Research is opening new possible uses for synthetic cannabinoids in the treatment of neurological conditions, including agitation in Alzheimer’s,16 non-motor symptoms of Parkinson’s,17 and the treatment of seizures.18
Most research is being performed ex-US, but some US sites are actively studying the medical benefits of synthetic THC or synthetic CBD in the treatment of neurological conditions.19-21
Safety concerns with non–FDA approved cannabinoid products cannot be emphasized enough.
With illegal formulations proliferating and touted as “safe,” consumers can easily fall into harm’s way.
The CDC has multiple reports of acute poisonings, severe bleeding, and deaths due to illegal synthetic cannabinoids.
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2. Pertwee RG. Cannabinoid pharmacology: the first 66 years. Brit J Pharmacol. 2006;147(Suppl 1):S163-S171.
3. Ramer R, Schwarz R, Hinz B. Modulation of the endocannabinoid system as a potential anticancer strategy. Front Pharmacol. 2019;10:1-17.
4. Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):1-23.
5. Maccarrone M, Bab I, Biro T, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36(5):277-296.
6. EPIDIOLEX [package insert]. Carlsbad, CA: Greenwich Biosciences, Inc.; 2018.
7. FDA News Release: FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms. Accessed August 20, 2019.
8. United States Department of Agriculture. Agricultural Marketing Service. https://www.ams.usda.gov/sites/default/files/media/2018FarmBill.pdf. Accessed August 20, 2019.
9. Ibeas Bih C, Chen T, Nunn AVW, Bazelot M, Dallas M, Whalley BJ. Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics. 2015;12(4):699-730.
10. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling accuracy of cannabidiol extracts sold online. JAMA. 2017;318(17):1708-1709.
11. Vandrey R, Raber JC, Raber ME, et al. Cannabinoid dose and label accuracy in edible medical cannabis products. JAMA. 2015;313(24):2491-2493.
12. FDA Warning Letters and Test Results for Cannabidiol-Related Products 2015 to 2019. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products. Accessed August 20, 2019.
13. Marinol [package insert]. North Chicago, IL: AbbVie Inc; 2017.
14. Cesamet [package insert]. Somerset, NJ: Meda Pharmaceuticals Inc; 2015.
15. Syndros [package insert]. Chandler, AZ: Insys Therapeutics, Inc; 2017.
16. Ruthirakuhan M, Herrmann N, Gallagher D, et al. Investigating the safety and efficacy of nabilone for the treatment of agitation in patients with moderate-to-severe Alzheimer's disease: study protocol for a cross-over randomized controlled trial. Contemp Clin Trials Commun. 2019;15:1-7.
17. Peball M, Werkmann M, Ellmerer P, et al. Nabilone for non‑motor symptoms of Parkinson’s disease: a randomized placebo‑controlled, double‑blind, parallel‑group, enriched enrolment randomized withdrawal study (The NMS‑Nab Study). J Neural Transm (Vienna). 2019;126(8):1061-1072.
18. Mascal M, Hafezi N, Wang D, et al. Synthetic, non-intoxicating 8,9-dihydrocannabidiol for the mitigation of seizures. Sci Rep. 2019;9(1):1-6.
19. National Institutes of Health. Search results: synthetic cannabinoids. https://clinicaltrials.gov/ct2/show/NCT04001010. Accessed August 20, 2019.
20. National Institutes of Health. Search results: dronabinol. https://clinicaltrials.gov/ct2/results. Accessed August 20, 2019.
21. National Institutes of Health. Search results: nabilone. https://clinicaltrials.gov/ct2/results. Accessed August 20, 2019.