Minor Cannabinoids: Part 1 

Introduction 

The cannabis plant has been grown and cultivated for thousands of years for medical, industrial and recreational uses. Hemp was one of the first crops widely cultivated for industry, its high fibre content made it useful in fabrics, textiles and food. Humans realised the potential for cannabis as medicine as early as 2700BC in Ancient China (Pain, 2015) whereby medicinal remedies were originally passed down through word-of-mouth, and later through written recordings. However, it wasn’t until 1964 that the active compounds THC and CBD were first isolated and still not until 1988 that the endocannabinoid system – the largest receptor system in the body – was discovered! (Devane et al., 1988; Nazarenus & Cox, 2019) 

What are Minor Cannabinoids? 

Within the Cannabis sativa plant there are a whole range of compounds, called secondary metabolites, which possess bioactive properties, including over 120 phytocannabinoids (plant-derived cannabinoid compounds) along with a range of related phenolic compounds such as polyphenols, terpenoids, and flavonoids (Pertwee et al., 2014; Flores-Sanchez & Verpoorte, 2008).  

• Common minor cannabinoids are listed below: 

• Cannabigerol (CBG) 
• Cannabigerolic acid (CBGA) 
• Cannabigerovarin (CBGV) 
• Cannabidiolic acid (CBDA) 

• Delta-8-tetrahydrocannabinol (Δ8- THC) 
• Cannabinol (CBN) 
• Cannabinolic acid (CBNA) 
• Cannabichromene (CBC) 
• Tetrahydrocannabivarin (THCv) 
• Cannabidivarin (CBDv) 

Next week’s article will contain a more in-depth summary of these minor cannabinoids along with a review of some current research into their medicinal and commercial benefits. 

Minor cannabinoid is a term used to describe any cannabinoid that is not present in high quantities within the commonly available strains of cannabis. This essentially means any phytocannabinoid other than delta 9 -THC and cannabidiol is considered to be ‘minor’. These chemical compounds are not used by the plant for growth or reproduction, but rather secondary metabolites confer a selective advantage for survival, for example by attracting pollinators or protecting against environmental stressors, such as predators or fungal infections (Teoh, 2015). The cannabis plant creates these chemicals to act on other organisms than itself, and it is these biologically active properties which makes cannabinoids so useful.  

Where are they found? 

Phytocannabinoids and terpenoids are synthesised and stored in small glandular structures on the surface of the plant, called trichomes (Wang et al., 2021; Gülck & Møller, 2020). The cannabinoids found within trichomes vary in their chemical structure, bioavailability and mechanisms of action, yet they all affect specific receptors in brain and body cells (known as CB1 and CB2) to alter or regulate many biological functions (Walsh et al., 2021). 

Cannabinoids in the plant are found mainly in their “raw” or acidic forms (Flores-Sanchez & Verpoorte, 2008), meaning they have a carboxylic acid group attached to their main structure. Cannabigerolic acid (CBGA), known as the ‘mother cannabinoid’, is the first cannabinoid to appear during the plants growth and is the cannabinoid from which the subsequent acidic and neutral phytocannabinoids are derived. 

When heat is applied to these acidic cannabinoids, they lose their carboxylic acid group to become the neutral cannabinoids you may be more familiar with, cannabigerolic (CBG), cannabidiol (CBD) and tetrahydrocannabinol (THC). This process is called decarboxylation (Filer, 2022). Although the names may sound similar, the acid group makes a big change to the effects of the cannabinoids within the body. For example, THCA is a non-psychoactive substance whereas its decarboxylated counterpart, THC, has very strong psychoactive effects and is responsible for the ‘high’ associated with marijuana.  

Why are they useful? 

The medicinal benefits of minor cannabinoids are currently being studied due to their range of potential benefits, including neuroprotection (Stone et al., 2020), antinociception (Rodriguez et al., 2022), anti-inflammation and more (Walsh et al., 2021). 

McPartland and Russo summed up the entourage effect quite well when they said, “Primary active ingredients may be enhanced by secondary compounds, which act in beneficial synergy.” (McPartland & Russo, 2001). In simple terms, cannabinoids have been shown to work synergistically, along with terpenes, to produce a greater beneficial effect when administered together rather than in their isolated forms (Ryan et al., 2006). Although there were multiple cannabinoids discovered and isolated in the 1960s, most of the clinical research that followed focused solely on THC and it’s recreational and medicinal mechanisms (Russo & McPartland, 2003). It is only recently that the true potential of the minor cannabinoids has been uncovered (Russo, 2011; Mechoulam, 2005). 

The refinement of cannabis genetics has allowed for the selection of desirable plant characteristics over generations, including selection for high cannabinoid production (Russo, 2019). Strains are bred over time to display desirable cannabinoid and terpene profiles which can be sold as dried flower or extracted for industrial and medicinal use. There are over 600 modern cannabis strains which are commercially available (Bailey et al., 2016). 

References 

Bailey Rahn, Brian J. Pearson, Robert N. Trigiano & Dennis J. Gray (2016) The Derivation of Modern Cannabis Varieties, Critical Reviews in Plant Sciences, 35:5-6, 328-348, DOI: 10.1080/07352689.2016.1273626 

Devane, W. A., Dysarz, F. A., 3rd, Johnson, M. R., Melvin, L. S., & Howlett, A. C. (1988). Determination and characterization of a cannabinoid receptor in rat brain. Molecular pharmacology, 34(5), 605–613. 

Filer C. N. (2022). Acidic Cannabinoid Decarboxylation. Cannabis and cannabinoid research, 7(3), 262–273. https://doi.org/10.1089/can.2021.0072 

Flores-Sanchez, I.J. & Verpoorte, R. Secondary metabolism in cannabis. Phytochem Rev 7, 615–639 (2008). https://doi.org/10.1007/s11101-008-9094-4 

Gülck, T., & Møller, B. L. (2020). Phytocannabinoids: Origins and Biosynthesis. Trends in plant science, 25(10), 985–1004. https://doi.org/10.1016/j.tplants.2020.05.005 

McPartland, J. M. DO, MS & Russo, E. B. MD (2001) Cannabis and Cannabis Extracts, Journal of Cannabis Therapeutics, 1:3-4, 103-132, DOI: 10.1300/J175v01n03_08 

Mechoulam R. (2005). Plant cannabinoids: a neglected pharmacological treasure trove. British journal of pharmacology, 146(7), 913–915. https://doi.org/10.1038/sj.bjp.0706415 

Nazarenus, C. & Cox, J., (2019). The Discovery of the Endocannabinoid System. Medical Cannabis Handbook for Healthcare Professionals, 28-37. Springer Publishing Company. DOI:10.1891/9780826135735.0003 

Pain, S. A potted history. Nature 525, S10–S11 (2015). https://doi.org/10.1038/525S10a 

Pertwee, R. G. (Ed.). (2014). Handbook of cannabis. Oxford University Press, USA. 

Rodriguez, C., Ouyang, L., & Kandasamy, R. (2022). Antinociceptive effects of minor cannabinoids, terpenes and flavonoids in Cannabis. Behavioural pharmacology, 33(2&3), 130–157. https://doi.org/10.1097/FBP.0000000000000627 

Russo E. B. (2011). Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British journal of pharmacology, 163(7), 1344–1364. https://doi.org/10.1111/j.1476-5381.2011.01238.x 

Russo E. B. (2019) The case for the entourage effect and conventional breeding of clinical cannabis: No “strain”, no gain. Frontiers in Plant Science. DOI=10.3389/fpls.2018.01969 

Russo, E.B. & McPartland, J.M. (2003) Cannabis is more than simply Δ9-tetrahydrocannabinol. Psychopharmacology 165, 431–432. https://doi.org/10.1007/s00213-002-1348-z 

Ryan, D., Drysdale, A. J., Pertwee, R. G., & Platt, B. (2006). Differential effects of cannabis extracts and pure plant cannabinoids on hippocampal neurones and glia. Neuroscience letters, 408(3), 236–241. https://doi.org/10.1016/j.neulet.2006.09.008 

Stone, NL, Murphy, AJ, England, TJ, O’Sullivan, SE. A systematic review of minor phytocannabinoids with promising neuroprotective potential. Br J Pharmacol. 2020; 177: 4330– 4352. https://doi.org/10.1111/bph.15185 

Teoh E. S. (2015). Secondary Metabolites of Plants. Medicinal Orchids of Asia, 59–73. https://doi.org/10.1007/978-3-319-24274-3_5