Beyond CBD: More Natural Cannabinoids by the Cannabis and Hemp plants

There are many more cannabinoids beside CBD that are made uniquely by the cannabis plant along with its cousin, hemp. To date, more than 100 different cannabinoids have been identified. These cannabinoids can be divided into 6 main classes. The quantity of each class varies depending on a variety of factors such as plant strain, growing conditions, soil conditions and extraction process used. Many of the CBD products sold, particularly full spectrum products, likely contain significant levels of these cannabinoids and most of the time, the buyer has no information regarding the levels of these different classes of cannabinoids. These classes are:

• Cannabigerols (CBGs)
• Cannabichromenes (CBCs)
• Cannabidiols (CBDs)
• Tetrahydrocannabinols (THCs)
• Cannabinol (CBN) and cannabinodiol (CBDLs)
• Other cannabinoids such as cannabicyclol (CBL), cannabielsoin (CBE), cannabitriol (CBT) and other miscellaneous types.

Most of the non-CBD and non-THC cannabinoids appear to have similar “action profiles”, but research is in the very early stages. To date, however, there is no indication that any of the non-CBD and non-THC cannabinoids are unsafe. We just don’t know exactly how they work as separate chemical entities OR how they work within the well known yet poorly described entourage effect. (1)

Cannabinoid Receptors

There are two receptors described so far that cannabinoids and endocannabinoids can bind to. These are known as CB1 and CB2. These receptors are acted upon by three different groups of substances:

• The endocannabinoids: these are substances produced in mammals like humans which are the natural binding substances or signaling molecules for the endocannabinoid system. The major endocannabinoids are arachidonoylethanolamine (anandamide or AEA) and 2-arachidonoylglycerol (2-AG). Less well known endocannabinoids include lysophosphatidylinositol (LPI), 2-arachidonyl glyceryl ether (noladin ether) and virodhamine (OAE).
• Plant cannabinoids like THC, CBD and others
• Synthetic cannabinoids like dronabinol (Marinol), nabilone (Cesamet, Canemes), Rimonabant and JWH-018 (“spice”).

There are also other receptors that the cannabinoids bind to. These receptors are located throughout the body and are being actively studied to see how they may affect human response to all of the cannabinoid groups. (2), (3)

CB1 Receptors

These receptors are found throughout the brain and spinal cord, though they are also found in the lungs, blood vessels, muscles, the digestive tract, the immune system and in other body systems. Binding of a suitable material to CB1 receptors can change or affect memory, the appetite, the immune response, the perception of pain, movement and cognitive processes.

CB2 Receptors

CB2 receptors are more prominent in areas outside the brain and spinal cord. These receptors are found on cells of the immune system, on peripheral nerves, muscle cells and others. This receptor constitutes another active area of study.

“Other” Cannabinoids

Cannabigerols (CBGs)

The cannabigerols (CBGs) are a major constituent of cannabis plants, including hemp. CBG’s are garnering quite a bit of interest because they are non-intoxicating. The CBGs bind, although a bit more weakly than CBD, to the CB2 receptor, acting to activate them. CBGs also appear to weakly inhibit the action of CB1 receptors.(4)

Cannabigerols are the “parent compounds” for other cannabinoids. So far, CBG appears to act as an anti-inflammatory agent, an analgesic, and may kill or inhibit the growth of cancer cells. These studies are in early stages, but the anti-inflammatory effects may be the most prominent.

The cannabigerols include:

• Cannabigerol (CBG)
• Cannabigerol monomethylether (CBGM)
• Cannabigerolic acid (CBGA)
• Cannabigerolic acid monomethylether (CBGAM)
• Cannabigerovarin (CBGV)
• Cannabigerovarinic acid (CBGVA)

Cannabichromenes (CBCs)

Even for chemical names, this one is a serious tongue twister! Not much is currently known about the CBCs, These materials appear to act via receptors other than CB1 or CB2 and function as potent anti-inflammatory agents. (5) The CBCs appear to bind to another group of receptors, the transient receptor potential ankyrin 1 or TRPA1. These TRPA1 receptors are involved in pain and temperature perception. The CBCs also have antibacterial activity. (6)

The cannabichromenes include:

• Cannabichromene (CBC)
• Cannabichromenic acid (CBCA)
• Cannabichromevarin (CBCV)
• Cannabichromevarinic acid (CBCVA)

Cannabidiols (CBDs)

The cannabidiols (CBDs) as a group are non-intoxicating and non-psychoactive. They exert anti-anxiety, anti-depressant, antipsychotic and anti-cancer effects in addition to acting as antioxidants, anti-inflammatory agents and anti-nausea agents. If you are looking to buy CBD oil, check out our top list of the  best CBD oil tinctures

Members of the CBD class of cannabinoids bind weakly to CB1 receptors and act as an “inverse agonist” at the CB2 receptors. (7) An inverse agonist is an agent that binds to a receptor in a way similar to the natural binding substance (ligand) but evokes an opposite response than what would naturally occur. This type of binding is believed to explain some of the effects of CBD, such as moderating the effect of THC.

Another member of the CBD family is cannabidivarin or CBDV. CBDV is a precursor for THCV (see below) and tends to be more prominent in C. indica strains. CBDV appears to be a sedative, an analgesic, and an anti-inflammatory agent with additional appetite stimulating and anti-tumor actions. Some of the most intense interest in cannabidivarin, however, is due to its potential to serve as a treatment of autism spectrum disorder.(8)

The cannabidiols include:

• Cannabidiol (CBD)
• Cannabidiol monomethylether (CBDM)
• Cannabidiolic acid (CBDA)
• Cannabidiorcol (CBD-C1)
• Cannabidivarin (CBDV)
• Cannabidivarinic acid (CBDVA)

Tetrahydrocannabinols (THCs)

The THCs are some of the best known cannabinoids and this class of materials bind to the CB1 receptor. It is psychoactive and is useful in treating pain, muscle spasm, glaucoma, nausea, insomnia, anxiety, some seizure disorders and some digestive disorders. (9)

The THCs (both the delta-8 and the delta-9 THCs) include:

• Delta-8-tetrahydrocannabinols

o Delta-8-tetrahydrocannabinol (Δ8-THC)

o Delta-8-tetrahydrocannabinolic acid (Δ8-THCA)

• Delta-9-tetrahydrocannabinols

o Delta-9-tetrahydrocannabinol (THC)

o Delta-9-tetrahydrocannabinol-C4 (THC-C4)

o Delta-9-tetrahydrocannabinolic acid A (THCA-A)

o Delta-9-tetrahydrocannabinolic acid B (THCA-B)

o Delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4)

o Delta-9-tetrahydrocannabiorcol (THC-C1)

o Delta-9-tetrahydrocannabiorcolic acid (THCA-C1)

o Delta-9-tetrahydrocannabivarin (THCV)

o Delta-9-tetrahydrocannabivarinic acid (THCVA)

Cannabinols (CBNs) and Cannabinodiols (CBDLs)

Cannabinols have some mild psychoactive (intoxicating) action, though some believe CBNs to be non-psychoactive. These compounds are found at higher levels in aged cannabis. The CBNDs appear to have some anti-bacterial and neuroprotective effects. No human studies have been done, but CBNs may be useful as tools to treat Alzheimer’s disease and other neurodegenerative disorders. It also has anti-inflammatory and anti-glaucoma properties. (10)

Cannabinodiols are psychoactive and are derived from the CBNs.

The cannabinols and the cannabinodiols include:

• Cannabinodiol (CBND)
• Cannabinodivarin (CBVD)
• Cannabinol (CBN)
• Cannabinol methylether (CBNM)
• Cannabinol-C2 (CBN-C2)
• Cannabinol-C4 (CBN-C4)
• Cannabinolic acid (CBNA)
• Cannabiorcool (CBN-C1)
• Cannabivarin (CBV)

Other Cannabinoids

The cannabinoids will be keeping chemists, pharmacologists and other researchers busy for many years. There are, in addition to the cannabinoids described, other cannabinoid classes including cannabitriols, cannabielsoins, cannabicyclols and “miscellaneous” cannabinoids yet to be fully described and tested. Cannabis is an ancient plant and it seems to have spent many millennia developing new cannabinoids to keep scientists really, really busy!

References Cited

1. Chen, A., Some of the Parts: Is Marijuana’s “Entourage Effect” Scientifically Valid? https://www.scientificamerican.com/article/some-of-the-parts-is-marijuana-rsquo-s-ldquo-entourage-effect-rdquo-scientifically-valid/ (Accessed 4/2020)
2. Svíženská I, Dubový P, Šulcová A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures—a short review. Pharmacology Biochemistry and Behavior. 2008 Oct 1;90(4):501-11.
3. Ligresti A, De Petrocellis L, Di Marzo V. From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiological reviews. 2016 Oct;96(4):1593-659.
4. Navarro Brugal G, Varani K, Reyes-Resina I, Sánchez de Medina V, Rivas-Santisteban R, Sánchez-Carnerero Callado C, Vincenzi F, Casano S, Ferreiro-Vera C, Canela Campos EI, Borea PA. Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1-CB2 heteroreceptor complexes. Frontiers in Pharmacology, 2018, vol. 9, p. 632. 2018 Jun 21.
5. Pollastro F, Caprioglio D, Del Prete D, Rogati F, Minassi A, Taglialatela-Scafati O, Munoz E, Appendino G. Cannabichromene. Natural Product Communications. 2018 Sep;13(9):1934578X1801300922.
6. Turner CE, Elsohly MA. Biological activity of cannabichromene, its homologs and isomers.J Clin Pharmacol. 1981 Aug-Sep;21(S1):283S-291S.
7. Ligresti A, De Petrocellis L, Di Marzo V. From phytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex pharmacology. Physiological reviews. 2016 Oct;96(4):1593-659.
8. Guy G, Wright S, Brodie J, Woolley-roberts M, Maldonado R, Parolaro D, Luongo L, Neill J, inventors; Gw Research Ltd, assignee. Use of cannabidivarin in the treatment of autism spectrum disorder, associated disorders and schizophrenia. United States patent application US 16/124,549. 2019 Mar 7.
9. Pacher P, Kogan NM, Mechoulam R. Beyond THC and Endocannabinoids. Annual Review of Pharmacology and Toxicology. 2019 Oct 3;60.
10. Citti C, Braghiroli D, Vandelli MA, Cannazza G. Pharmaceutical and biomedical analysis of cannabinoids: A critical review. Journal of pharmaceutical and biomedical analysis. 2018 Jan 5;147:565-79.