Terpenes and terpenoids are important components of medicinal aromatic plants, including cannabis, with their pharmacological effects, along with resins and essential oils. Terpenes, unlike terpenoids, are basic hydrocarbons. It contains functional groups of a wide variety of chemical elements. However, terpenes and terpenoids are often used interchangeably. Terpenes make up the largest group of phytochemicals. It has been reported that terpenes have been isolated from essential oil obtained from flowers, roots, and leaves. Terpenes are widely used in industry, perfumery, food additives, and traditional medicines. So what are cannabis terpenes?
Cannabis plants typically consist of terpenes up to 3-5% of the dry mass of the female sputum. Cannabis terpenes are typically simple mono and sesquiterpenes derived from two and three isoprene units, respectively. Terpenoids or isoprenoids are another important major plant metabolite group. Isoprenoids act like plant hormones (gibberellic acid, abscisic acid, and cytokinins) in primary metabolism, they are an important component of the cell membrane (sterols), they carry oxygen to cells (ubiquinones) and they play an effective role in photosynthesis (chlorophylls and plastoquinones). In secondary metabolism, they take part in communication and plant defense mechanisms.
120 terpene groups have been identified in cannabis. Of the terpene groups, 61 are monoterpenes, 52 are sesquiterpenoids, 2 are triterpene, 1 are diterpene and 4 are terpenoid derivatives. Terpenes are named according to the number of repeated 5-carbon isoprene units, such as 10-carbon monoterpenes, 15-carbon sesquiterpenes, and 30-carbon triterpenes. Terpenes vary depending on different conditions such as environmental conditions, age of the plant, basic lipid production requirement. Terpenes present in marijuana have a wide range of known biological effects, and some may play a role in regulating and/or altering the effects of THC and other cannabinoids.
Structure and Types of Cannabis Terpenes
The terpenes that contribute to the flavor and aroma of cannabis are mostly monoterpenes and sesquiterpenes. Sesquiterpene caryophyllene oxide is the main volatile substance detected by narcotic dogs. Monoterpenes and sesquiterpenes are found in many plants. There are more than 30000 known terpenes in nature.
Considerable attention is paid to the “entourage effect” theory, based on the known pharmacological effects of cannabinoids and/or terpenes. This theory is an emphasized mechanism where cannabis compounds act synergistically to regulate the overall psychoactive effects of the plant, primarily through the action of THC. In other words, the Entourage Effect is the synergy that occurs when multiple cannabis compounds work together to produce a potent effect.
Major monoterpenes such as α-pinene, β-Myren, and limonene have been reported to have anti-inflammatory, analgesic, and sedative properties, respectively, which have been evaluated in animal models. The amount of terpene determined by gas chromatography is high in leaves and buds of diploid and tetraploid cannabis species. It has been reported that the amount of terpene and the variety of aroma in the flower vary according to the degree of maturity of the female flowers. It has been reported that the leaf terpene content of tetraploid species is high.
While the total leaf terpene content of the tetraploids was determined as 8.80 mg g-1, the bud terpene content was determined as 11.58 mg g-1. In diploid species, the total terpene content was determined as 5.13 mg g-1 in leaves, while it was determined as 8.94 mg g1 in buds. In general, since sesquiterpene formation is high in tetraploid leaves and buds, terpene amounts were found at high levels.
Experts have found that drying the female flowers results in the loss of monoterpenoids rather than sesquiterpenoids, but none of the essential components of the oil are completely eliminated. Researchers have reported that terpene yield and flower aroma vary depending on the maturity degree of the inflorescences and whether the inflorescences are collected or not. It has not been determined whether there is a relationship between the terpene composition of the essential oil and the “fragrance quality”. Some terpenes found in cannabis essential oil are pharmacologically active and may synergize the effects of cannabinoids.
In their study on whether the terpene content of hemp can be used in the chemical taxonomic field, the researchers determined the terpene content using gas chromatography by growing 162 genotypes of different origins in a glass greenhouse. 48 terpenoid compounds were determined and the closeness of genotypes was discussed by subjecting to principal component analysis.
In the study, it was determined that the diversity determined in terms of the chemical content of the genotypes was morphologically similar to the previous species definition at the level of 91%. In the study, it was determined that a broad-leaved genotype belonging to the C. Indica species originating from Afghanistan gave higher content than the other genotypes. This genotype has been reported to have high concentrations of guaiol and other unidentified compounds.
Pharmacological effects have been identified for some cannabis terpenes and have been reported to trigger the effects of cannabinoids. Terpenes have been used in traditional medicine for centuries due to their potential in biomedicine, and some of them have not yet been discussed in detail. The medicinal properties of terpenes have been reported in numerous in vitro, animal, and clinical studies to be anti-inflammatory, antioxidant, analgesic, anticonvulsive, antidepressant, anxiolytic, anticancer, antitumor, neuroprotective, anti-mutagenic, anti-allergic, antibiotic. They show low toxicity and high bioavailability and reach the brain barrier through the skin and blood. Due to their very low toxicity, these terpenes are already widely used in food additives and cosmetics. Thus, they have been proven to be safe and well-tolerated.
Terpenes are produced by biosynthetic pathways predicted for cannabis secondary metabolites controlled by genetically determined enzyme systems. This provides plant breeders with alternatives to develop medicinal cannabis varieties with diverse terpene profiles and particularly targeted medicinal uses. Recently, the essential oils of hemp have gained economic importance in terms of flavor and fragrance.
Some of the monoterpenes and sesquiterpenes found in cannabis and obtained from other herbal and synthetic sources are used in commercial drugs. There may also be many terpenes in cannabis that have not yet been identified. The highly variable array of terpene side-chain substitutions results in different physiological responses in humans. Some terpenes stimulate the membranes of the pulmonary system, calm the pulmonary passages and facilitate the absorption of other compounds.
Other Phytochemicals in Cannabis
Cannabis has become one of the most researched plants in recent years, drawing the attention of the scientific community around the world. It has been cultivated for thousands of years due to its use as a source of textiles as well as medicinal, food, and recreational use. The phytochemicals in the cannabis strain are quite complex, with more than 700 compounds from different chemical classes identified. Amino acids, fatty acids, and steroids represent primary metabolism, while cannabinoids, flavonoids, stilbenoids, terpenoids, lignans, and alkaloids represent secondary metabolites.
The concentrations of the compounds present depend on the plant tissue, age, genotype, growing conditions (nutrition, humidity, and light level), harvest time, and storage conditions. Production of cannabinoids increases when plants are under stress; It has also been reported that ecological differences are also effective. Hemp seeds generally contain about 25-35% lipid and 20-25% crude protein by weight. In addition to fiber and oil, it is a source of ∆-9-tetrahydrocannabinol (THC), the main active chemical compound in its structure.
Hemp oil contains polyunsaturated fatty acids (PUFA), these fatty acids include various essential fatty acids such as linoleic and α-linolenic acid. Essential fatty acids serve as raw materials for structural lipids and precursors of biochemicals that regulate many bodily functions. Regarding the chemical composition of cannabis, in addition to the cannabinoid fraction, more than 20 flavonoids have been identified, belonging to the chemical classes of flavones or flavonols. The hemp seed oil has shown antioxidant activity, possibly due to its high content of flavonoids.
The cannabis plant and its products consist of a wide variety of chemicals. This number is expected to increase with the identification of 750 identified compounds and many new compounds with and without cannabinoid structure. Some of these compounds are unique to cannabis, for example, there are more than 60 cannabinoids, while terpenes with about 140 members are also quite common in other plants. The term “cannabinoids” represents a group of C21 terpene phenolic compounds that have hitherto been uniquely found in cannabis.
As a result of the development of synthetic cannabinoids (e.g. nabilone; HU-211, or CT-3) and the discovery of chemically distinct cannabinoid receptor endogenous ligands (“endocannabinoids”; e.g. anandamide, 2-arachidonic glycerol), the term “phytocannabinoids” has been proposed for certain cannabis components. In the article, due to its rich chemical content and various pharmaceutical effects, the classification of phytochemicals in the cannabis plant and the commercial values of the major chemicals have been brought together in the light of recent scientific studies.
Flavonoids belong to one of the largest groups of natural compounds containing more than 10,000 different structures. Although these secondary metabolites are distributed in different extracellular and subcellular parts of the plant (membranes, chloroplasts, vacuoles, and nuclei), their biochemical and physiological structures are not yet clear. According to the latest literature, the effectiveness of cannabinoids, terpenes, and flavonoids in the treatment of headaches, migraines, and other pains is possible with optimal standardized synergistic natural compounds. However, the main terpenes identified have been noted to have anti-inflammatory, anti-allergic, and cytoprotective pharmacological properties.
With respect to other compounds found in cannabis, terpenes are responsible for the plant’s characteristic odor. While both mono and sesquiterpenes are detected in cannabis roots and tops, they are mostly produced in glandular hairs. The discovery in the study of plant steroid hormones, commonly referred to as brassinosteroids, was the detection of growth-promoting activity in a rapeseed pollen extract. Early experiments using brassinosteroids focused on the responses of exogenously applied growth regulators, including root elongation, leaf opening, microtubule reorientation, and ATPase activity. Therefore, steroids are among the most important chemical compounds for plant growth.
In addition to the medicinal potential of beneficial cannabinoids in the cannabis plant’s own leaves and flowers, both ripe cannabis seeds and seed meal are excellent sources of dietary fat, fiber, and protein. Hemp is an invaluable source for animal feed, especially due to its high oil (35.5% seed and 11.1% seed meal), protein (24.8% seed and 33.5% seed meal), and carbohydrate (27.6% seed and 42.6% seed meal) content.
As an industrial plant food source, both hemp and hemp products are rich sources of protein and polyunsaturated fat, as well as significant amounts of vitamins and beneficial minerals. Alpha-tocopherol is the only form of vitamin E that meets human requirements. Unlike tocopherol, which tends to be found in the gut, it is preferentially secreted into the plasma. β-tocopherol can interfere between fatty acid chains in the membrane bilayer, resulting in increased membrane fluidity. Individual tocopherols in the Finola variety are 5 mg/100 g alpha-tocopherol and 85 mg/100 g gamma-tocopherol, for a total of 90 mg/100 g. Hemp is also a very important source of Phosphorus (1160 mg P/100g), Potassium (859 mg K/100g), Magnesium (483 mg P/100g), and Calcium (145 mg Ca/100g).
Phenolic Compounds in Cannabis
- Flavonoids
Flavonoids are products found throughout the plant body and have many functions in plant biochemistry, physiology, and ecology. It plays a very important role in both human and animal nutrition and health. Hemp contains phenolic compounds called flavonoids. These compounds normally act as antioxidants in plants and protect against oxidative stress. More than 20 flavonoids have been reported in cannabis strains.
These include apigenin, luteolin, quercetin, kaempferol, cannflavin A, cannflavin B (cannabis specific), sitosterol, vitexin, isovitexin, kaempferol, and orientin. Cannaflavin A and Cannaflavin B are methylated isoprenoid flavones. In some pharmacological studies, hemp flavonoids have been found to inhibit prostaglandin E2 production by Cannaflavin A and B, while other studies have shown only a modulation with cannabinoids. It has been observed that the incidence of chronic diseases such as neurodegenerative diseases, cancers, and cardiovascular diseases decreased with the intake of phenolic compounds.
Similar to terpenes, many of these compounds have also been shown to have anti-inflammatory, neuroprotective, and anti-cancer effects. Cannaflavin A and B have a strong anti-inflammatory effect. Cannflavin A has been shown to inhibit PGE-2 30 times more potently than aspirin. In skin studies, β-sitosterol has been shown to reduce local topical inflammation by 65% and chronic edema by 41%. Among other phenolic compounds found in cannabis, research is ongoing on stilbenoids, phenolic amides, and lignans, and their effects have not yet been demonstrated.
- Stilbenoids
Stilbenoids are phenolic compounds widely distributed in plants. 19 stilbenoids have been identified in cannabis. In addition to taking part in the defense mechanisms of plants, they control resting factors (plant chilling need) through growth inhibitors. Stilbenoids, found in wood tissues and roots, has antifungal and antibacterial activity. They are also repellent to insects.
Although some cannabis stilbenoids have been reported to be antibacterial, some others, such as bibenzyl 3,4-dihydroxy-5-methoxy bibenzyl, 3,3-dihydroxy-5,4-dimethoxy bibenzyl, 3,4-dihydroxy-5,3-dimethoxy-5-isoprenyl bibenzyl, have been reported. It was determined that it did not show antibacterial, estrogenic, germination, and growth-inhibiting properties. Stilbenoids have been reported to have a relaxing effect, and have been reported to have antineoplastic, neuroprotective, cardiovascular disease protective, antioxidant, antimicrobial, and antiaging effects.
- Alkaloids
Alkaloids are another important secondary metabolite in plants. However, alkaloids are a very large and heterogeneous group of compounds that can be obtained not only from plants but also from microorganisms, insects, and animals. Although alkaloids are basic in character, they are nitrogen compounds with biological activity at low doses and are obtained from amino acids. Ten alkaloids have been identified in cannabis. Choline, neurine, L-(+)-isoleucine-betaine, and muscarine are proto-alkaloids, while hordenine is phenethylamine and trigonelline is a pyridine.
Cannabisativin and anhydrous-Cannabisativin are polyamines derived from spermidine in the subclass of dihydro peri phylline. These are 13-membered cyclic compounds in which the polyamine spermidine is attached to the b-position via its N-atoms terminal and to the carboxyl carbon of a C14-fatty acid. Piperidine and pyrrolidines have also been identified in cannabis. These alkaloids have been isolated and identified from roots, leaves, stems, pollen, and seeds.
In plants, alkaloids often act as a defense against predators due to their toxicity, bitter taste, and effects on the central nervous system, resulting in increased survival rates of the species. Although the effects of alkaloids on human physiology are very diverse, some alkaloids act on the nervous system and sometimes cause hallucinations, while others act on the muscles. Because of these negative properties, alkaloids can even cause death. However, they form one of the raw materials of important drugs.
- Lignanamides and Phenolic Amides
Researchers have reported that 11 compounds identified as phenolic amides and lignan amides are present in cannabis fruits and roots. N-trans-Coumaroyltyr amine, N-trans-Feruloyltyr amine, and N-trans-Caffeoyltyr amine are phenolic amides. However, hemp is in the group of lignan amides-A, -B, -C, -D, -E, -F, -G, and gross amide. Lignanamides are bound to the lignan group, and cannabis lignan amides are classified as lignans of the Arytnaphthalene derivative type. Phenolic amides have cytotoxic, anti-inflammatory, antineoplastic, cardiovascular, and moderate pain relief effects.
It has been reported that Grossamide, Cannabisin-D, and -G from Lignanamides have cytotoxic effects. The presence and accumulation of phenolic amides against physiological damage and UV light in plants provide chemical protection against pests. It has also been reported that they play a role in the flowering process, sexual organogenesis, and virus resistance. In addition, it has been reported that they have a role in the process of healing and suberization (such as shrinkage, mushrooming, rubbing). For Lignanamides cannabis-B and -D, a strong nutritional inhibition has been reported. It is also reported that lignans have an insecticidal effect.
Cannabinoids and Their Relationship to Cannabis Terpenes
Today, the term cannabinoids include not only plant cannabinoids, which are also known as phytocannabinoids, but also endocannabinoids and synthetic analogs of both groups. Endocannabinoids include 2-Arachidonyl glycerol and other endogenous ligands, following the discovery of the first endogenous ligand, N-Arachidonyl ethanolamine. Both are synthesized on demand. Enzymes responsible for the biosynthesis and degradation of endocannabinoids, which are cannabinoid receptors, form the endocannabinoid system.
In recent years, the endocannabinoid system has received great attention as a potential therapeutic target in many pathological conditions. It is known that it participates in physiological processes such as appetite, blood pressure, modulation of pain, embryogenesis, control of nausea and vomiting, memory, learning, and immune response, as well as positive results in pathological conditions. It is emphasized that changes in endocannabinoid levels may be associated with Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and multiple sclerosis, as well as diseases such as anorexia and irritable bowel syndrome.
Changes in endocannabinoid level have also been associated with cancer affecting the growth, transport, and invasion of certain tumors. The effects of cannabinoids on diseases in which they are effective in terms of health are examined. The main cannabinoids of the cannabis strain are THC, CBD, CBDA, CBG, CBGA, CBGV, and CBGVA. Receptors that do not activate most cannabis compounds are also often referred to as cannabinoids. Hemp contains many compounds. But delta9-tetrahydrocannabinol is the main compound that is a psychoactive substance.
The term “cannabinoids” is used for most of the chemicals identified in cannabis extracts. This group represents the most studied compounds of the cannabis strain. Cannabinoids are 22 carbon terpene phenolic compounds, of which 70 have been identified so far and can be divided into 10 main structures. All other compounds not included in the main groups are considered subgroups. Neutral compounds are formed by the decarboxylation of irregularly reciprocating acids. Although decarboxylation occurs in the living plant, it increases during storage at elevated temperatures after harvest.
Both forms turn into secondary products under the influence of temperature, light, and auto-oxidation. Cannabis produces its own secondary metabolites containing alkyl Resorquinol and monoterpene groups. The most researched phytocannabinoid is THC, which binds the G-protein pair called the cannabinoid receptor. The main activity of this compound is to cause an acute transient psychotic reaction in healthy individuals when applied as a pure compound.
The psychoactive activities of cannabinoids are well known. In in vivo and in vitro clinical studies, it has been observed that antinociceptive, antiepileptic, cardiovascular, immunosuppressive, antiemetic, appetite stimulation, antineoplastic, anti-inflammatory, neuroprotective antioxidants have positive effects on psychiatric syndromes such as depression, anxiety, and sleep disorders, and some other pharmacological effects.
Cannabinoid acids are present in the fresh herb as the primary metabolite leading to cannabinoids and are not psychotropic. These acidic phytocannabinoids decarboxylases with heat, UV exposure, and long-term storage to form active cannabinoids. The predominant cannabinoid acids are Tetrahydrocannabinolic acid converted to THC, Cannabidiolic acid converted to cannabidiol, Cannabigerolic acid converted to cannabigerol, Cannabicromenic acid converted to cannabichromene, Cannabichromenic acid converted to Tetrahydrocannabivar, cannabidiol acid converted to tetrahydrocannabivarin Hydrocanna.
- 9-tetrahydrocannabinol
9-Tetrahydrocannabinolic acid is a form of cannabinoid and is the primary psychoactive active ingredient. This compound is the acid formed as a result of the removal of carbon dioxide from the amino acid by heating or aging THC. There are also other compounds in this chemical mix, such as CBD and CBG, that play a role in regulating the action of THC. Especially THC is concentrated in the flowers of female plants. For this reason, varieties containing high THC have been developed in the last 10-15 years. While the THC content is 1-3%, the strongest content can be up to 6-13% during the full flower period.
As a result of HPLC analyzes using two diploids and one tetraploid species, the researchers reported that the THC content at the level of ploidy levels was similar to the CBD content, but the CBD content was approximately 35% higher than the THC content. Cannabidiolic acid was determined as 64.16 mg g-1 in diploid buds and 69.89 mg g-1 in tetraploid buds. A 34.3% decrease in Cannabigerolic acid and a 15.2% increase in CBDVA content were determined in tetraploid buds.
While components such as cannabinol, cannabicyclol, and 8tetrahydrocannabinol could not be detected in leaves and buds, cannabidivarin was not detected at all from leaves. As a result, it was reported that the cannabinoid content of leaves was 35% lower than the content of flower buds.
- Cannabidiol
Cannabidiol was isolated in 1940. They are decomposition products of THC and are formed after long-term storage. They are formed in the biosynthesis of CBD, CBGA-containing cannabinoid class. Cannabidiols are the second most studied cannabinoids in cannabis due to their interaction with the endocannabinoid system and being high in certain varieties. Although this class of drug type is not found in high concentrations in cannabis, it has been noted that it may be a cannabinoid found at significant levels in fiber type cannabinoids that do not have Tetrahydrocannabinolic acid or Cannabidiolic acid synthesis.
Cannabidiol has been reported to potentiate the benefits of THC, such as pain reduction while reducing its negative side effects such as irritability and anxiety. CBD is also known for its anxiety-reducing and anti-inflammatory effects. The presence of CBD-type cannabinoids, which can be found in cannabis at levels up to 10%, has been mentioned.
- Nabilone
It is a synthetic cannabinoid and has the effect of tetrahydrocannabinol, the primary psychoactive compound naturally found in the cannabis plant. Studies have shown that Nabilone is significantly superior to prochlorperazine, domperidone, and alizapride in the treatment of chemotherapy-associated nausea and vomiting in cancer patients. On the other hand, patients preferred nabilone for continuous use. These results led the Department of Health Canada to approve the marketing of this product.
Marketed under the name Cesamet®, nabilone has been available in 1 mg powder form in Canada since 1982. The recommended dose is 2-6 mg day-1. Nabilone is commercially available in capsule form in the USA, UK, and Germany. In addition to these positive features, it is reported to have side effects such as drowsiness, dizziness, dry mouth, headache, etc.
Primary Metabolites in Cannabis
Primary metabolites are substances essential for living things and essential for the formation and maintenance of life. For all living things, including viruses, enzymes are primary metabolites that allow them to break down with all substances involved in nucleic acid and protein synthesis. Photosynthetic pigments and enzymes are also primary metabolites for photosynthetic plants. The most important primary metabolites are fatty acids and amino acids.
- Fatty acids
Fatty acids differ from each other in the number of carbon atoms between 12-C and 24-C, and the degree of unsaturation. In particular, 3 unsaturated fatty acids; oleic acid, linoleic acid, and linolenic acid forms are dominant in plants. About 8% of the hemp seed oil is saturated fatty acids. The researchers determined that 7.5% of the oil is SFA in the form of about 5% palmitic acid, 1.5% stearic acid, and 0.2% behenic acid. The main saturated fatty acids in hemp seed oil are palmitic and stearic acid.
Experts emphasized that the fatty acid composition was similar in all three samples they analyzed. Accordingly, it was determined that linoleic acid was the most dominant group, representing more than 56% of the fatty acid content in all samples. Among the other unsaturated fatty acids, the change in linolenic acid ranges between 14.55-15.02%, oleic acid 12.74-12.79%, and γ-linolenic acid 2.94% 3.03%, palmitic acid, which is one of the main saturated acids, between 7.03-7.35% and stearic acid between 2.62-2.78%.
Unsaturated fatty acids are known to have beneficial effects, especially in the treatment of cardiovascular diseases. Based on the report published by Momchilova and Nikolova-Damyanova, the dissociation of fatty acids with more than one double bond in the short carbon chain is faster than fatty acids with a shorter chain. Therefore, γ-linolenic acid with a double bond with a shorter carbon chain dissolved faster than α-linolenic acid with a longer carbon chain.
The efficacy of 2,2′-diphenyl-2-Picrylhydrazil radical scavenging activity of extracts from cannabis sources expressed as % inhibition is examined. It highlights the possibility of using the waste material after oil extraction as a natural source of antioxidants. While the total amount of polyphenols in the seeds was 51.5%, the inhibition rate was 46.8% in flour and 8.2% in oil extracts.
- Amino acids
Essential amino acids from amino acid groups are mainly responsible for the postprandial stimulation of muscle protein synthesis. Infants have very critical nutritional requirements due to rapid growth and immaturity of gastrointestinal tract function, and nine amino acids have been identified as essential for infants. These are Threonine, Methionine, Phenylalanine, Histidine, Lysine, Valine, Leucine, Cysteine, Arginine. It is emphasized that it is very important to be taken for low birth weight babies. According to the amino acid content of different hemp varieties, the varieties differ in terms of amino acid content.
Total sulfur amino acids were determined as 4.04 g per 100 g of hemp protein. Arginine is found in high amounts in hemp seeds. When the average values are examined; It is found that the amounts of amino acids are as follows: Threonine 3.48 g, Methionine 2.26 g, Phenylalanine 4.31 g, Histidine 2.90 g, Lysine 4.08 g, Valine 5.14 g, Isoleucine 6.19 g, Leucine 4.61 g, Serine 5.21 g, Glycine 4.74 g, Glutamic acid 17.83 g, Proline 4.61 g, Alanine 4.98 g, Tyrosine 3.49 g, Arginine 11.99 g, and protein 100 g-1. Especially, essential amino acids were more stable than non-essential amino acids and differences between varieties were less.
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