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Note: Below text includes all content from the currently published (public) article. All text that I have rewritten and/or expanded on is identified using bold and strike-through font. I also created a diagram to highlight the unique nature of CBN metabolism, but somehow wikipedia is not allowing it to upload. I am working with WikiEdu staff to sort this out, but in the interim have sent an email to Prof. Wolozin with the image for his review.

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Cannabinol (CBN) is a mildly psychoactive cannabinoid that binds to cannabinoid receptors with more selectivity for CB2 over CB1[1][2][3] found in trace amounts from Cannabis.[4] CBN is mostly found in cannabis that is aged and stored, and is derived from the plant's main psychoactive chemical, tetrahydrocannabinol (THC).[5][6]

It was the first cannabis compound to be isolated from cannabis extract in the late 1800s. Its structure and chemical synthesis were achieved by 1940.[7]


Cannabinol (CBN) is a mildly psychoactive cannabinoid that acts as a low affinity partial agonist at both CB1 and CB2 receptors.[1][2][3] This activity at CB1 and CB2 receptors constitutes interaction of CBN with the endocannabinoid system (ECS), which is responsible for regulating many important functions in the body. Through its mechanism of partial agonism at the CB1R, CBN is thought to interact with other kinds of neurotransmission (e.g., dopaminergic, serotonergic, cholinergic, and noradrenergic).

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[7], followed by some of the first pre-clinical research studies to determine the effects of individual cannabis-derived compounds in vivo.[8] Although CBN shares the same mechanism of action as other more well-known phytocannabinoids (e.g., delta-9 tetrahydrocannabinol or D9THC), it has a lower affinity for CB1 receptors, meaning that much higher doses of CBN are required in order to experience physiologic effects (e.g., mild sedation) associated with CB1R agonism.[9][8] Although scientific reports are conflicting, the majority of findings suggest that CBN has a slightly higher affinity for CB2 as compared to CB1. Although CBN has been marketed as a sleep aid in recent years, there is a lack of scientific evidence to support these claims, warranting skepticism on the part of consumers.[9]

Formation

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Delta-9-THC can degrade into CBN from oxidation.[10][11]

Chemical Structure

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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 D9THC, well-known for underlying the subjective “high” experienced by cannabis users, as well as D8THC, and their synthetic analogs.[12][13] 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.[12]

Compared to D9THC, one additional aromatic ring confers CBN with a slower and more limited metabolic profile - see CBN Formation & Metabolism, below[12]. In contrast to THC, CBN has no double bond isomers nor stereoisomers. CBN can degrade into HU-345 from oxidation.[14] 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).[12]

CBN Formation & Metabolism

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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 D9THC, rather than from an acidic precursor form of CBN (e.g., D9THC arises through decarboxylation of THC-A).[12] CBN can be found in trace amounts in the Cannabis plant[4], 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).[5][6] This process of oxidation occurs via exposure to heat, oxygen, and/or light.[4][5][9] 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.[12]

When administered orally, CBN demonstrates a similar metabolism to D9THC, 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.[1] This metabolism starkly contrasts that of D9THC in terms of potency, given that 11-OH-THC has been reported to have 10x the potency of D9THC.[8]

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.[15] 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.[15] The bioavailability of CBN following administration via inhalation (e.g., smoking or vaporizing) is approximately 40% that of intravenous administration.[12]

Pharmacology

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CBN acts as a partial agonist at CB1 receptors with approximately 1/10th the affinity of THC. Compared to THC, CBN has a higher affinity to CB2 receptors, which are located throughout the central and peripheral nervous system, but are primarily thought to be located on immune cells and throughout the enteric nervous system relating to gastrointestinal function; however, it has lower affinities relative to THC.[16][17][3] Both THC and CBN activate the CB1 (Ki = 211.2 nM) and CB2 (Ki = 126.4 nM) receptors.[14] It is metabolised to 11-OH-CBN, which is a more potent CB1 agonist than CBN but acts as a weak antagonist at CB2.[1]

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 pre-clinical research studies to determine the effects of individual cannabis-derived compounds in vivo.[8]

Both THC and CBN activate the CB1 (Ki = 211.2 nM) and CB2 (Ki = 126.4 nM) receptors.[1] Each compound acts as a low affinity partial agonist at CB1 receptors with THC demonstrating 10-13x greater affinity to the CB1 receptor.[1][12][9][8][6][18] Compared to THC, CBN has an equivalent or higher affinity to CB2 receptors[1][8], which are located throughout the central and peripheral nervous system, but are primarily associated with immune function. CB2 receptors are known to be located on immune cells throughout the body, including macrophages, T cells, and B cells. These immune cells have been shown to decrease production of immune-related chemical signals (e.g., cytokines) or undergo apoptosis as a consequence of CB2 agonism by CBN.[3] In cell culture, CBN demonstrates antimicrobial effects, particularly in instances of antibiotic-resistant bacteria.[19] CBN has also been reported to act as an ANKTM1 channel agonist at high concentrations (>20nM).[12] While some phytocannabinoids have been shown to interact with nociceptive and immune-related signaling via transient receptor potential channels (TRPV1 and TRPM8), there is currently limited evidence to suggest that CBN acts in this way.[12][20] In preclinical rodent studies, CBN, anandamide and other CB1 agonists have demonstrated inhibitory effects on GI motility, reversible via CB1R blockade (i.e., antagonism).[12]

Neurotransmitter Interactions

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In the brain, the canonical mechanism of CB1 receptor activation is a form of short-term synaptic plasticity initiated via retrograde signaling of endogenous CB1 agonists such as 2AG or AEA (two primary endocannabinoids). This mechanism of action is called depolarization-induced suppression of inhibition (DSI) or depolarization-induced suppression of excitation (DSE)[21], depending on the classification of the presynaptic neuron acted upon by the retrograde messenger. In the case of CB1R agonism on the presynaptic membrane of a GABAergic interneuron, activation leads to a net effect of increased activity, while the same activity on a glutamatergic neuron leads to the opposite net effect. The release of other neurotransmitters is also modulated in this way, particularly dopamine, dynorphin, oxytocin, and vasopressin.[21]

Therapeutic Potential

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Although CBN is widely marketed as a sleep aid, there is currently no published scientific evidence to support this claim. While ongoing clinical trials seek to elucidate the role of CBN in sleep, the general public should exercise skepticism regarding these claims.[9]

As of November 2022, there are just three ongoing clinical trials to evaluate the medical use of CBN-containing products. These studies aim to evaluate the efficacy of CBN-containing products in the context of Epidermolysis Bullosa, insomnia disorder, and osteoarthritis of the knee.[22] Ongoing reports from these studies will yield much-needed scientific data in these areas.

Despite lacking clinical evidence, some research findings in molecular and cellular biology suggest that therapeutic mechanisms may arise through non-CB receptor activation. For example, studies in cell culture have shown that CBN interferes with neuroblastoma progression, an effect that persists even in the absence of CB1/2R expression.[23]

Scientists and clinicians remain determined to elucidate the therapeutic potential of cannabinoids, suggesting collaborative strategies such as the creation of a “cannabinoid receptor interaction matrix” (CRIM) to bolster ongoing efforts to disentangle the complex effects of ECS modulation throughout the body.[18] Future research seeking to evaluate CBN-containing therapeutics in sleep and other areas must utilize validated clinical metrics and reproducible methods of physiologic monitoring (e.g., polysomnography in the study of sleep) to determine whether CBN may truly offer efficacy in these domains.

 
Mary's Medicinals brand CBN (Cannabinol) 10 mg transdermal patches from a dispensary in Colorado, USA

Chemistry

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In contrast to THC, CBN has no double bond isomers nor stereoisomers.

CBN can degrade into HU-345 from oxidation.[24]

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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,[25] so the signatory countries to these international drug control treaties are not required by these treaties to control CBN.

United States

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According to the 2018 Farm Bill,[26] 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 percent or less. However, as of 2022 in the United States, CBN and other cannabis extracts remain illegal under federal law to prescribe for medical use or to use as an ingredient in dietary supplements or other foods,[27][28][29] and sales or possession of CBN could potentially be prosecuted under the Federal Analogue Act.[30] In December 2016, the Drug Enforcement Administration added marijuana extracts, which are defined as any "extract containing one or more cannabinoids that has been derived from any plant of the genus Cannabis, other than the separated resin", to Schedule I.[31]

Despite legislative obstacles presented by the federal government, cannabis laws at the state level have evolved substantially since the late 1990's. As of February 2022, more than 37 states, 3 territories, and the district of columbia have enacted states laws allowing the medical use of cannabis.[32] In 2013, the Department of Justice issued a memorandum advising attorneys to pursue federal prosecution of cannabis-related activity by individuals and/or entities only in instances where state legislation fails to protect any of eight specific federal safety interests listed therein (e.g., Preventing the distribution of marijuana to minors).[33] As a consequence, cannabis products in the United States are essentially regulated at the state level, while hemp products with <0.3% THC (i.e., those pertinent to the 2018 Farm Bill) are regulated by the FDA and FTC.[9] The vast majority of recreational cannabis products are not derived from hemp, and contain notably high percentages of THC. For example, more than 90% of THC-containing products in CO contain greater than 15% THC.[34]





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  1. ^ a b c d e f g Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, et al. (September 1997). "Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase". Journal of Medicinal Chemistry. 40 (20): 3228–3233. doi:10.1021/jm970126f. PMID 9379442.
  2. ^ a b Sampson PB (January 2021). "Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the "Big Two"". Journal of Natural Products. 84 (1): 142–160. doi:10.1021/acs.jnatprod.0c00965. PMID 33356248. S2CID 229694293.
  3. ^ a b c d "Cannabinol (Code C84510)". NCI Thesaurus. National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services.
  4. ^ a b c Morales P, Hurst DP, Reggio PH (2017). "Molecular Targets of the Phytocannabinoids: A Complex Picture". Progress in the Chemistry of Organic Natural Products. 103: 103–131. doi:10.1007/978-3-319-45541-9_4. ISBN 978-3-319-45539-6. PMC 5345356. PMID 28120232.
  5. ^ a b c Kroner GM, Johnson-Davis KL, Doyle K, McMillin GA (May 2020). "Cannabinol (CBN) Cross-Reacts with Two Urine Immunoassays Designed to Detect Tetrahydrocannabinol (THC) Metabolite". The Journal of Applied Laboratory Medicine. 5 (3): 569–574. doi:10.1093/jalm/jfaa020. PMID 32445358.
  6. ^ a b c Andre CM, Hausman JF, Guerriero G (2016-02-04). "Cannabis sativa: The Plant of the Thousand and One Molecules". Frontiers in Plant Science. 7: 19. doi:10.3389/fpls.2016.00019. PMC 4740396. PMID 26870049.
  7. ^ a b Pertwee RG (January 2006). "Cannabinoid pharmacology: the first 66 years". British Journal of Pharmacology. 147 (Suppl 1): S163–S171. doi:10.1038/sj.bjp.0706406. PMC 1760722. PMID 16402100. Cannabinol (CBN; Figure 1), much of which is thought to be formed from THC during the storage of harvested cannabis, was the first of the plant cannabinoids (phytocannabinoids) to be isolated, from a red oil extract of cannabis, at the end of the 19th century. Its structure was elucidated in the early 1930s by R.S. Cahn, and its chemical synthesis first achieved in 1940 in the laboratories of R. Adams in the U.S.A. and Lord Todd in the U.K.
  8. ^ a b c d e f Pertwee, Roger G (2006). "Cannabinoid pharmacology: the first 66 years: Cannabinoid pharmacology". British Journal of Pharmacology. 147 (S1): S163–S171. doi:10.1038/sj.bjp.0706406. PMC 1760722. PMID 16402100.{{cite journal}}: CS1 maint: PMC format (link)
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  12. ^ a b c d e f g h i j k Cannabinoids. Mary Ellen Abood, R. G. Pertwee. Berlin: Springer. 2005. ISBN 3-540-22565-X. OCLC 65169431.{{cite book}}: CS1 maint: others (link)
  13. ^ Katchan, Valeria; David, Paula; Shoenfeld, Yehuda (2016). "Cannabinoids and autoimmune diseases: A systematic review". Autoimmunity Reviews. 15 (6): 513–528. doi:10.1016/j.autrev.2016.02.008.
  14. ^ a b Russo EB, Marcu J (2017). "Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads". Cannabinoid Pharmacology. Advances in Pharmacology. Vol. 80. pp. 67–134. doi:10.1016/bs.apha.2017.03.004. ISBN 978-0-12-811232-8. PMID 28826544.
  15. ^ a b Stout, Stephen M.; Cimino, Nina M. (2014). "Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review". Drug Metabolism Reviews. 46 (1): 86–95. doi:10.3109/03602532.2013.849268. ISSN 0360-2532.
  16. ^ Mahadevan A, Siegel C, Martin BR, Abood ME, Beletskaya I, Razdan RK (October 2000). "Novel cannabinol probes for CB1 and CB2 cannabinoid receptors". Journal of Medicinal Chemistry. 43 (20): 3778–3785. doi:10.1021/jm0001572. PMID 11020293.
  17. ^ Petitet F, Jeantaud B, Reibaud M, Imperato A, Dubroeucq MC (1998). "Complex pharmacology of natural cannabinoids: evidence for partial agonist activity of delta9-tetrahydrocannabinol and antagonist activity of cannabidiol on rat brain cannabinoid receptors". Life Sciences. 63 (1): PL1–PL6. doi:10.1016/S0024-3205(98)00238-0. PMID 9667767.
  18. ^ a b Aizpurua-Olaizola, Oier; Elezgarai, Izaskun; Rico-Barrio, Irantzu; Zarandona, Iratxe; Etxebarria, Nestor; Usobiaga, Aresatz (2017). "Targeting the endocannabinoid system: future therapeutic strategies". Drug Discovery Today. 22 (1): 105–110. doi:10.1016/j.drudis.2016.08.005.
  19. ^ Pattnaik, Falguni; Nanda, Sonil; Mohanty, Shobhangam; Dalai, Ajay K.; Kumar, Vivek; Ponnusamy, Senthil Kumar; Naik, Satyanarayan (2022). "Cannabis: Chemistry, extraction and therapeutic applications". Chemosphere. 289: 133012. doi:10.1016/j.chemosphere.2021.133012.
  20. ^ Muller, Chanté; Morales, Paula; Reggio, Patricia H. (2019-01-15). "Cannabinoid Ligands Targeting TRP Channels". Frontiers in Molecular Neuroscience. 11: 487. doi:10.3389/fnmol.2018.00487. ISSN 1662-5099. PMC 6340993. PMID 30697147.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  21. ^ a b Diana, Marco A; Marty, Alain (2004). "Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE): DSI/DSE: two forms of CB1R-mediated plasticity". British Journal of Pharmacology. 142 (1): 9–19. doi:10.1038/sj.bjp.0705726. PMC 1574919. PMID 15100161.{{cite journal}}: CS1 maint: PMC format (link)
  22. ^ "Search of: cannabinol - List Results - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2022-11-18.
  23. ^ Cherkasova, Viktoriia; Wang, Bo; Gerasymchuk, Marta; Fiselier, Anna; Kovalchuk, Olga; Kovalchuk, Igor (2022-10-20). "Use of Cannabis and Cannabinoids for Treatment of Cancer". Cancers. 14 (20): 5142. doi:10.3390/cancers14205142. ISSN 2072-6694. PMC 9600568. PMID 36291926.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  24. ^ Kogan NM, Peters M, Mechoulam R (March 2021). "Cannabinoid Quinones-A Review and Novel Observations". Molecules. 26 (6): 1761. doi:10.3390/molecules26061761. PMC 8003933. PMID 33801057.
  25. ^ "UN International Drug Control Conventions". United Nations Office on Drugs and Crime. United Nations Commission on Narcotic Drugs.
  26. ^ Commissioner, Office of the (2021-10-18). "FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)". FDA.
  27. ^ Mead A (2019-06-14). "Legal and Regulatory Issues Governing Cannabis and Cannabis-Derived Products in the United States". Frontiers in Plant Science. 10: 697. doi:10.3389/fpls.2019.00697. PMC 6590107. PMID 31263468.
  28. ^ Mead A (May 2017). "The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law". Epilepsy & Behavior. 70 (Pt B): 288–291. doi:10.1016/j.yebeh.2016.11.021. PMID 28169144.
  29. ^ "Section 1308.11 Schedule I". Code of Federal Regulations. Office of Diversion Control, Drug Enforcement Administration, U.S. Department of Justice. Archived from the original on 9 February 2012.
  30. ^ "Federal Controlled Substance Analogue Act Summary". Erowid Analog Law Vault. January 2001.
  31. ^ "Establishment of a New Drug Code for Marihuana Extract" (PDF). Federal Register. 81 (240). 14 December 2016.
  32. ^ "State Medical Cannabis Laws". www.ncsl.org. Retrieved 2022-11-18.
  33. ^ US Attorney Marshall Letter to Rep. Blumenauer (2018). US Attorney Marshall Letter to Rep. Blumenauer. Available at: http://votehemp.com/PDF/Ltr_to_Earl_Blumenauer_110713.pdf (accessed November 18 2022).
  34. ^ Cash, Mary Catherine; Cunnane, Katharine; Fan, Chuyin; Romero-Sandoval, E. Alfonso (2020-03-26). Largent-Milnes, Tally (ed.). "Mapping cannabis potency in medical and recreational programs in the United States". PLOS ONE. 15 (3): e0230167. doi:10.1371/journal.pone.0230167. ISSN 1932-6203. PMC 7098613. PMID 32214334.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
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