Каннабинол (CBN): происхождение, свойства и взаимодействие с эндоканнабиноидной системой.

Naturally occurring cannabinoid

Cannabinol (CBN) is a mildly psychoactive cannabinoid (e. g., CBD) that acts as a low affinity partial agonist at both CB1 and CB2 receptors. This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS). In 1896 Cannabinol was first discovered in Cannabis by Thomas Barlow Wood, W. T Newton Spivey, and Thomas Easterfield. In the early 1930s CBNs structure was identified by Robert Sidney Cahn, marking the first development of a cannabis extract. Its chemical synthesis were achieved by 1940, followed by some of the first basic research studies to determine the effects of individual cannabis derived compounds in vivo. Although CBN shares the same mechanism of action as other phytocannabinoids (e. g., Delta 9 tetrahydrocannabinol, Δ9 THC), it has a lower affinity for CB1 receptors, meaning that much higher doses of CBN are required in order to experience effects, such as mild sedation.

Cannabinoid receptor agonists are categorized into four groups based on chemical structure. CBN, as one of the many phytocannabinoids derived from Cannabis Sativa L, is considered a classical cannabinoid. Other examples of compounds in this group include dibenzopyran derivatives such as Δ9 THC, well known for underlying the subjective "high" experienced by cannabis users, as well as Δ8 THC, and their synthetic analogs. In contrast, endogenously produced cannabinoids (i. e., endocannabinoids), which also exert effects through CB agonism, are considered eicosanoids, distinguished by notable differences in chemical structure. Compared to Δ9 THC, one additional aromatic ring confers CBN with a slower and more limited metabolic profile (see ). In contrast to THC, CBN has no double bond isomers nor stereoisomers. CBN can degrade into HU 345 from oxidation. In the case of oral administration of CBN, first pass metabolism in the liver involves the addition of a hydroxyl group at C9 or C11, increasing the affinity and specificity of CBN for both CB1 and CB2 receptors (see 11 OH CBN).

This diagram represents the biosynthetic and metabolic pathways by which phytocannabinoids (e. g., CBD, THC, CBN) are created in the cannabis plant. Starting with CBG A, the acidic forms of certain phytocannabinoids are generated via enzymatic conversion. From there, decarboxylation (i. e., catalyzed by combustion or heat) yields the most well known metabolites present in the cannabis plant. CBN is unique in that it does not arise from a pre existing acidic form, but rather is generated through the oxidation of THC. CBN is unique among phytocannabinoids in that its biosynthetic pathway involves conversion directly from Δ9 THC, rather than from an acidic precursor form of CBN (e. g., Δ9 THC arises through decarboxylation of THC A). CBN can be found in trace amounts in the Cannabis plant, found mostly in cannabis that is aged and stored, allowing for CBN formation through the oxidation of the cannabis plant's main psychoactive and intoxicating chemical, tetrahydrocannabinol (THC). This process of oxidation occurs via exposure to heat, oxygen, and/or light. Although reports are limited, CBN A has also been measured at very low levels in the cannabis plant, thought to have formed via hydrolyzation of THC A (see Phytocannabinoid Biosynthesis diagram, below). When administered orally, CBN demonstrates a similar metabolism to Δ9 THC, with the primary active metabolite produced through the hydrolyzation of C9 as part of first pass metabolism in the liver. The active metabolite generated via this process is called 11 OH CBN, which is 2x as potent as CBN, and has demonstrated activity as a weak CB2 antagonist. This metabolism starkly contrasts that of Δ9 THC in terms of potency, given that 11 OH THC has been reported to have 10× the potency of Δ9 THC. Due to high lipophilicity and first pass metabolism, there is low bioavailability of CBN and other cannabinoids following oral administration. CBN metabolism is mediated in part by CYP450 isoforms 2C9 and 3A4. The metabolism of CBN may be catalyzed by UGTs (UDP glucuronosyltransferases), with a subset of UGT isoforms (1A7, 1A8, 1A9, 1A10, 2B7) identified as potential substrates associated with CBN glucuronidation. The bioavailability of CBN following administration via inhalation (e. g., smoking or vaporizing) is approximately 40% that of intravenous administration.

CBN was the first cannabis compound to be isolated from cannabis extract in the late 1800s. Its structure and chemical synthesis were achieved by 1940, followed by some of the first preclinical research studies to determine the effects of individual cannabis derived compounds in vivo. Both THC and CBN activate the CB1 (Ki = 211.2 nM) and CB2 (Ki = 126.4 nM) receptors. Each compound acts as a low affinity partial agonist at CB1 receptors with THC demonstrating 10–13× greater affinity to the CB1 receptor. Compared to THC, CBN has an equivalent or higher affinity to CB2 receptors, In cell culture, CBN demonstrates antimicrobial effects, particularly in instances of antibiotic resistant bacteria. CBN has also been reported to act as an ANKTM1 channel agonist at high concentrations (>20nM). In preclinical rodent studies, CBN, anandamide and other CB1 agonists have demonstrated inhibitory effects on GI motility, reversible via CB1R blockade (i. e., antagonism).

CBN is not listed in the schedules set out by the United Nations' Single Convention on Narcotic Drugs from 1961 nor their Convention on Psychotropic Substances from 1971, so the signatory countries to these international drug control treaties are not required by these treaties to control CBN.

According to the 2018 Farm Bill, extracts from the Cannabis sativa L. plant, including CBN, are legal under US federal law as long as they have a delta 9 Tetrahydrocannabinol (THC) concentration of 0.3% or less, though sales or possession of CBN could potentially be prosecuted under the Federal Analogue Act.