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Kitdumrongthum, S.; Trachootham, D. Active Substances in Cannabis, Endocannabinoid System, and Metabolism. Encyclopedia. Available online: https://encyclopedia.pub/entry/42780 (accessed on 30 June 2024).
Kitdumrongthum S, Trachootham D. Active Substances in Cannabis, Endocannabinoid System, and Metabolism. Encyclopedia. Available at: https://encyclopedia.pub/entry/42780. Accessed June 30, 2024.
Kitdumrongthum, Sarunya, Dunyaporn Trachootham. "Active Substances in Cannabis, Endocannabinoid System, and Metabolism" Encyclopedia, https://encyclopedia.pub/entry/42780 (accessed June 30, 2024).
Kitdumrongthum, S., & Trachootham, D. (2023, April 04). Active Substances in Cannabis, Endocannabinoid System, and Metabolism. In Encyclopedia. https://encyclopedia.pub/entry/42780
Kitdumrongthum, Sarunya and Dunyaporn Trachootham. "Active Substances in Cannabis, Endocannabinoid System, and Metabolism." Encyclopedia. Web. 04 April, 2023.
Active Substances in Cannabis, Endocannabinoid System, and Metabolism
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This entry is adapted from the peer-reviewed paper 10.3390/molecules28062791

Since legalization, cannabis/marijuana has been gaining considerable attention as a functional ingredient in food. ∆-9 tetrahydrocannabinol (THC), cannabidiol (CBD), and other cannabinoids are key bioactive compounds with health benefits. Endocannabinoids have been shown to regulate a variety of different receptors and channels, including TRP channels and the G-protein-coupled receptors GPR55, GPR18, GPR119, γ-aminobutyric acid (GABA), and glycine receptors.

cannabis toxicity individual variation

1. The Active Substances in Cannabis

Cannabis sativa L. (C. sativa), generally known as cannabis, hemp, or marijuana, is a member of the Cannabaceae family. The genus Cannabis is subdivided into three species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis [1][2][3][4]. Cannabis plants are thought to have originated in Central and South Asia, including India, Pakistan, Afghanistan, China, Kazakhstan, and Uzbekistan. Their leaves and female flowers contain various secondary metabolites, whereas the seeds are a source of omega-3 fatty acids [5].
The cannabis plant is abundant in phytochemicals, with over 545 recognized substances and over 140 types of cannabinoids. The major cannabinoids found in cannabis are C21 terpene phenolic compounds and C22 in the carboxylate form. In addition, the plant also includes a variety of noncannabinoid terpenes and phenols, alkanes, sugars, nitrogenous compounds (e.g., spermidine alkaloids or muscarine), flavonoids, noncannabinoid phenols, phenylpropanoids, steroids, and fatty acids [2][3][6][7]. The structures of the leading bioactive compounds in C. sativa were revealed in a study by Liu and colleagues [8].
Among the phytocannabinoids, the compounds with the most potent physiological and psychotogenic effects include trans- delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), alongside others such as cannabinol (CBN), cannabigerol, and cannabichromene [9][10]. THC takes the form of four stereoisomers, while only the (–)-trans-isomer occurs in nature. Two structurally similar compounds, ∆9-tetrahydrocannabinol-2-oic acid and ∆9-tetrahydrocannabinol-4-oic acid (THCA), are also detected. THCA can be partially converted to THC by heat. The other active isomer of THC is delta-8-Tetrahydrocannabinol (∆8-THC), which is present at lower amounts [3][11].
THC is the key and most potent psychoactive ingredient in cannabis, and that which causes highness upon intake. In addition, THC provides antiemetic, anti-inflammatory, and pain-relieving effects for neuropathy and chronic pain. Therefore, the level of THC in cannabis products can determine their potencies [2]. Depending on the species, the amount of the psychoactive component THC can vary. Due to its higher content of THC content than other species, C. sativa is the most commonly explored.
The categorization of cannabis as either drug-type or nondrug-type is based on THC concentration [12]. Drug-type cannabis with a psychotropic effect (marijuana) contains 1.0–20% THC; the intermediate type contains 0.3–1.0% THC; and the fiber type (hemp), which is found in textiles and food, contains 0.3% THC [13]. Cannabis sativa L. comprises all forms of hemp and marijuana, with high genomic and phenotypic variation across multiple lineages [14]. Marijuana lineages are utilized for medical and recreational consumption, while hemp lineages are exploited in the industry for fiber or oil extraction.
The genetic background and environmental conditions of cultivation influence the variations in the chemical components and properties of cannabis [14][15]. A recent study in the US reported the chemotaxonomic analysis of various cannabis samples grown in six states of the US [16]. The results show that there is variation in the bioactive compounds, as the majority of samples were THC-dominant, while the minority showed a balance of THC: CBD and CBD dominance. Though the total amount of terpenes positively correlated with the total amount of cannabinoids, there is variation in the diversity of type. THC-dominant (“Type I”) cultivars display a more diverse array of terpene profiles than those of the balanced THC: CBD (“Type II”) and CBD-dominant (“Type III”) cultivars [16].

2. The Endocannabinoid System (ECS)

The biological effects of phytocannabinoids from the cannabis plant are mediated by cannabinoid receptors (CNR), members of the G-protein-coupled receptor family. Two types of CNR have been identified, including cannabinoid receptor 1 (CB1), which is found mainly in the central nervous system, and cannabinoid receptor 2 (CB2), which is found in peripheral tissues such as immune cells. Both receptors bind to endocannabinoids, leading to signal transduction and downstream effects [17]. The classical endocannabinoids include N-arachidonoylethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) [18].
AEA is biosynthesized from membrane-phospholipid precursors via the action of N-acyltransferase (NAT) and N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) enzymes. The generation of 2-AG is catalyzed by the diacylglycerol lipases (DAGLα/β) enzyme. The endocannabinoid system’s activity can be terminated by hydrolysis and/or oxidation. AEA is hydrolyzed to arachidonic acid and ethanolamine by fatty acid amide hydrolase (FAAH), while 2-AG is hydrolyzed to arachidonic acid and glycerol by monoacyl-glycerol lipase (MAGL) [17][18][19]. AEA and 2-AG can be oxidized by cyclooxygenase-2 and numerous lipoxygenases [20].
More molecules have recently been identified as endogenous cannabinoids, such as 2-arachidonoyl glyceryl ether (noladin ether, 2-AGE), O-arachidonoylethanolamine (virodhamine), N-arachidonoyldopamine (NADA), and oleic acid amide (oleamide, OA) [21]. AEA has a high affinity to the CB1 receptor as a partial agonist, and a low affinity to the CB2 receptor. In contrast, 2-AG shows a moderate affinity for both receptors and acts as a complete agonist [22]. The exogenous THC is a partial CB1 and CB2 agonist, whereas the affinity of phytocannabinoid CBD to both CB1 and CB2 receptors is low [23][24].
Recently, new types of phytocannabinoids have been identified and extracted from C. Sativa, including ∆9-tetrahydrocannabiphorol (∆9-THCP) and cannabidiphorol (CBDP), which are the homologs of ∆9-THC and CBD, respectively. ∆9-THCP has a high affinity to both CB receptors, while the pharmacological effects of CBDP are unknown [2][25]. Binding between endocannabinoids and CB receptors results in the modulation of synaptic transmission in multiple pathways, regardless of synaptic nature and transmission duration [26].
Endocannabinoids have been shown to regulate a variety of different receptors and channels, including TRP channels and the G-protein-coupled receptors GPR55, GPR18, GPR119, γ-aminobutyric acid (GABA), and glycine receptors. THC and several phytocannabinoids mediate their bioactivities through the cannabinoid receptors, and further act as agonists to GPR55, GPR18, PPAR, transient TRPA1, TRPV2, TRPV3, and TRPV4. In contrast, endocannabinoids act as antagonists to TRPM8 and 5-HT3A [18][22][27].

3. Cannabinoid Receptors and Cannabinoids Effects

CB1 and CB2 are members of the G-protein-coupled receptor family, and are distributed throughout our bodies. In humans, CB1 is encoded by the CNR1 gene and consists of 472 amino acids. CB1 receptors are mainly located on central and peripheral neurons [17]. Full-length CB1 is found in the brain and skeletal muscle. In contrast, the CB1b isoform is more abundant in liver and pancreatic islet cells [28]. CB1 expression is highest in the olfactory bulb, hippocampus, basal ganglia, and cerebellum. It expresses at a moderate level in the cerebral cortex, septum, amygdala, hypothalamus, parts of the brainstem, and the dorsal horn of the spinal cord [29]. In the peripheral nervous system (PNS), CB1 is highly expressed in sympathetic nerve terminals [30]. CB1 is also expressed in some non-neuronal cells, such as immune cells [24]. Interestingly, variants in the CNR1 gene were found in heavy cannabis users [17][31].
CB2 is derived from the CNR2 gene and composed of 360 amino acids. At the protein level, CB2 shares 44% sequence homology with CB1 [17]. CB2 receptors are found primarily in immune cells and some neurons both inside and outside the brain. Moreover, one CB2 isoform is mainly expressed in the testes, but present at lower levels in brain reward regions. Another CB2 isoform is highly expressed in the spleen, but has also been found at lower levels in the brain [24][32].
Owing to its more robust expression in multiple types of cells, CB2 has a significant advantage over CB1 as a therapeutic target. On the other hand, CB1 is predominantly expressed in the central nervous system (CNS), which is the primary receptor responsive to ∆9-THC and contributes to the psychoactive effects of cannabis [25].

4. THC Metabolism

The metabolism of THC occurs mainly in the liver and other organs, including the brain, small intestine, heart, and lungs [30][31]. Cytochrome P450s (CYPs), including CYP2C9, CYP2C19, and CYP3A4, are the key phase I enzymes responsible for the liver metabolism of THC [33][34].
There are over 100 THC metabolites, and most of them are monohydroxylated compounds [35]. The C-11 position in THC’s structure is the most attacked site of CYPs in humans, and the major metabolites of THC are the active metabolite 11-hydroxy-THC (11–OH–THC) and the inactive metabolite 11-carboxy-THC (THC–COOH) [35]. Subsequently, these metabolites undergo glucuronidation as a phase II reaction, or, less commonly, conjugation with amino acids, fatty acids, sulfate, and glutathione [35].

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Sarunya Kitdumrongthum
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Dunyaporn Trachootham
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