The plant
Background
Cannabis has been grown for food (seeds), fibres (stems) and medicinal purposes (flowers) for thousands of years – see History for more details. For medical cannabis, the flowers are the most important parts of the plant, as they contain the highest concentration of cannabinoids. It is a fast-growing plant (up to 6 meters tall in the wild) and blossoms naturally once a year. However, the height can be limited and flowering induced when grown in greenhouses by decreasing daily periods of light to approximately 12-14 hours; this changes the plant’s development stage from vegetative growth to flowering. Periods of uninterrupted darkness induces the plant to flower. Cannabis plants are divided into male and female. The female flowers are used for medical cannabis, as their cannabinoid content is higher1.
The term ‘hemp’ usually refers to cannabis plants grown for their fibres or seeds. The fibres are used in a variety of products, such as textiles, rope, paper, insulation, masonry products, carpets and more2. In Germany, the THC content of cannabis plants categorised as hemp must be below 0.2%.
Taxonomy
The taxonomic naming of plants is a hierarchical way of grouping them into ranked categories such as families, genera, species, and subspecies.
The genus ‘Cannabis’ belongs to the ‘Cannabaceae’ family (which also includes the hops used in the brewing industry). There is no fully agreed, general taxonomic set of species names within Cannabis, but one option is to limit the classification to a single species named ‘Cannabis sativa L.’, with two subspecies: Sativa and Indica. This classification is based partly on structural characteristics, with Sativa varieties being taller with longer and relatively thin leaves compared to the shorter, more broad-leafed Indica. Chemical composition – mainly THC content – has also been invoked when trying to establish a grouping of cannabis, and this has influenced the usage of the names Sativa and Indica. Today, the terms are often used to describe the expected effect of a given cannabis variety, with Sativa expected to be more uplifting and energising and Indica relaxing or sleep-inducing. This can make references to these subspecies confusing when it comes to their structural and therapeutic characteristics. Most varieties of Cannabis Sativa L. grown today are often referred to as ‘hybrids’, as they are highly interbred between these historical subspecies, and the plant structure is not indicative of cannabinoid content or composition2,3.
Chemical content
545 chemical compounds in all have been identified in cannabis plants. The most abundant and thoroughly studied class of secondary metabolites is the cannabinoids (>104), followed by the terpenes (120), flavonoids (26) and steroids (11). The cannabinoids and terpenes are synthesised in glandular trichomes (specialised hairs) especially found on female flowers4. The compounds are referred to as ‘secondary metabolites’, as they are not critical to plant growth, development, and reproduction but are important for survival in the environment. The cannabinoids are thought to protect the plants from UV light and drying out, and to play a role in the plant’s defence against threats such as insects5. The terpenes give the plants fragrance and flavour. The flavonoids play various roles that range from development and UV protection to defence and signalling between plants and microorganisms. They also provide the plants with taste, smell, and colour6-9. The flowers used to manufacture medical cannabis commonly contain ~16-20% cannabinoids, 1-2% terpenes and <0.1% flavonoids4. Research has focussed mainly on the cannabinoids Δ9 – tetrahydrocannabinol (THC) and cannabidiol (CBD), but there is increasing interest in the remaining secondary metabolites and their potential therapeutic benefits when combined (this is called the ‘entourage effect’)10,11. Examples of lesser-known cannabinoids include tetrahydrocannabivarin (THCV), cannabinol (CBN), cannabigerol (CBG) and cannabichromene (CBC)12. The major terpenes are β-myrcene, Pinene, Limonene, Linalool, β-Caryophyllene and α-Humulene4.
Biosynthetic pathways of secondary metabolites in the cannabis plant4.
Manufacturing medical cannabis
Growing medicinal plants in a reproducible manner requires an adequate quality-assurance system and typically occurs indoor to control factors such as humidity, lighting, diseases, insects, temperature, CO2 and more1. To ensure a high and consistent quality of medical cannabis, the plants are grown and processed according to GACP (Good Agricultural and Collection Practice) and GMP (Good Manufacturing Practice) guidelines. These guidelines are in place to permit manufacturers to control and document all production steps that might influence product quality. This eliminates the risk of contamination, mix-up and errors and ensures patient safety.
Cannabinoids are fat-soluble molecules with low solubility in water and can be extracted from the plant using solvents such as liquid CO2 and ethanol6. Extracts from the entire plant also contain some of the terpenes and flavonoids. The cannabinoids synthesised in the plant primarily exist in carboxylic acid form (e.g. THCA and CBDA) and are heated to convert them into the neutral forms (THC and CBD) used in medical preparations13. Liquid extracts mainly contain the neutral forms of the cannabinoids because the extraction process includes a heating step, whereas the dried flowers need to be heated by the patients to aid this conversion.
Heat promotes the conversion of the acidic forms of THC and CBD into the neutral forms used for medical purposes.
References
1. Monthony, A. S., Page, S. R., Hesami, M. & Jones, A. M. P. The Past, Present and Future of Cannabis sativa Tissue Culture. Plants 2021, Vol. 10, Page 185 10, 185 (2021).
2. Small, E. Cannabis : a complete guide. (CRC Press, 2016).
3. McPartland, J. M. Cannabis Systematics at the Levels of Family, Genus, and Species. Cannabis and Cannabinoid Research 3, 203–212 (2018).
4. Jin, D., Dai, K., Xie, Z. & Chen, J. Secondary Metabolites Profiled in Cannabis Inflorescences, Leaves, Stem Barks, and Roots for Medicinal Purposes. Scientific Reports 10, 1–14 (2020).
5. Gülck, T. & Møller, B. L. Phytocannabinoids: Origins and Biosynthesis. Trends in Plant Science 25, 985–1004 (2020).
6. Grof, C. P. L. Cannabis, from plant to pill. British Journal of Clinical Pharmacology vol. 84 2463–2467 (2018).
7. Gonçalves, J. et al. Cannabis and Its Secondary Metabolites: Their Use as Therapeutic Drugs, Toxicological Aspects, and Analytical Determination. Medicines 6, 31 (2019).
8. Andre, C. M., Hausman, J. F. & Guerriero, G. Cannabis sativa: The plant of the thousand and one molecules. Frontiers in Plant Science 7, (2016).
9. Mathesius, U. Flavonoid Functions in Plants and Their Interactions with Other Organisms. Plants 7, 30 (2018).
10. LaVigne, J. E., Hecksel, R., Keresztes, A. & Streicher, J. M. Cannabis sativa terpenes are cannabimimetic and selectively enhance cannabinoid activity. Scientific Reports 11, 8232 (2021).
11. Russo, E. B. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of Pharmacology 163, 1344–1364 (2011).
12. Zagzoog, A. et al. In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa. Scientific Reports 10, 20405 (2020).
13. Ladha, K. S., Ajrawat, P., Yang, Y. & Clarke, H. Understanding the Medical Chemistry of the Cannabis Plant is Critical to Guiding Real World Clinical Evidence. Molecules 25, (2020).