Chemistry:Cannabinol

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Short description: Naturally-occurring cannabinoid
Cannabinol
Cannabinol.svg
Cannabinol 3D.png
Legal status
Legal status
  • CA: Unscheduled
  • UK: Class B
  • US: Unscheduled
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC21H26O2
Molar mass310.437 g·mol−1
3D model (JSmol)
Melting point76–77 °C (169–171 °F) [1]
Solubility in waterInsoluble in water,[2] soluble in methanol[3] and ethanol[4] mg/mL (20 °C)
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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.[5] In the early 1930s CBNs structure was identified by Robert Sidney Cahn.[6][7], marking the first development of a cannabis extract.

Its structure and 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.

Chemical structure

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 § CBN Formation & Metabolism). 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).

Synthesis and metabolism

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).

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.

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.

Pharmacology

This timeline represents a simplified history of CBN with an emphasis on the complexity surrounding cannabis legislation in the US.

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.[8]

Both THC and CBN activate the CB1 (Ki = 211.2 nM) and CB2 (Ki = 126.4 nM) receptors.[9] Each compound acts as a low affinity partial agonist at CB1 receptors with THC demonstrating 10–13× greater affinity to the CB1 receptor.[9][10][11][8][12][13] Compared to THC, CBN has an equivalent or higher affinity to CB2 receptors,[9][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.[14] In cell culture, CBN demonstrates antimicrobial effects, particularly in instances of antibiotic-resistant bacteria.[15] CBN has also been reported to act as an ANKTM1 channel agonist at high concentrations (>20nM).[10] While some phytocannabinoids have been shown to interact with nociceptive and immune-related signaling via transient receptor potential channels (e.g., TRPV1 and TRPM8), there is currently limited evidence to suggest that CBN acts in this way.[10][16] In preclinical rodent studies, CBN, anandamide and other CB1 agonists have demonstrated inhibitory effects on GI motility, reversible via CB1R blockade (i.e., antagonism).[10]

In considering the efficacy of cannabis-based products, there remains controversy surrounding a concept termed “the entourage effect”. This concept describes a widely reported but poorly-understood synergistic effect of certain cannabinoids when phytocannabinoids are coadministered with other naturally-occurring chemical compounds in the cannabis plant (e.g., flavonoids, terpenoids, alkaloids). This entourage effect is often cited to explain the superior efficacy observed in some studies of whole-plant-derived cannabis therapeutics as compared to isolated or synthesized individual cannabis constituents.[17]

Putative receptor targets

The table highlights several common cannabinoids along with putative receptor targets and therapeutic properties. Exogenous (plant-derived) phytocannabinoids are identified with an asterisk while remaining chemicals represent well-known endocannabinoids (i.e., endogenously produced cannabinoid receptor ligands).

Full Name Known Receptor Targets Putative Therapeutic Properties
*Cannabichromene (CBC)
  • Agonist at CB2,[18] TRPV3, and most potent phytocannabinoid at TRPA1[18][16]
  • Very low efficacy at TRPV1 and TRPV4, but may reduce expression of TRPV4 in the presence of inflammation[16]
  • High affinity for CB1 but no observed functional activity[18]
  • Antagonist at TRPM8[16]
  • Antimicrobial and anti-inflammatory[18]
  • Potential neuroprotective effects[18]
  • Potential efficacy in treatment of inflammatory pain[18]
*Cannabidiol (CBD)
  • Very weak affinity for CB1 and CB2[19]
  • Conflicting reports but generally described as negative allosteric modulator at CB1 & CB2, altering THC activity when THC & CBD are coadministered[19]
  • Agonist at TRPA1,[16] TRPV1 (high potency at this “capsaicin receptor” without ablative effects[16]), TRPV2, TRPV3, PPARγ, 5-HT1A, A2 and A1 adenosine receptors[19]
  • Highest potency at TRPV1[16]
  • Antagonist at GPR55, GPR18, 5-HT3A,[19] with highest potency as antagonist at TRPM8[16]
  • Inverse agonist at GPR3, GPR6, and GPR12[19]
  • Anti-inflammatory[20][16]
  • Anti-convulsant[20]
  • Potential efficacy in treatment of inflammatory and chronic pain[16]
*Cannabigerol (CBG)
  • Low affinity agonist and partial agonist at CB1 and CB2, respectively[18]
  • Agonist at α2adrenoceptor[18] and TRP channels such as TRPA1, TRPV2, and TRPV3, with highest potency as agonist at TRPV1[16]
  • Readily desensitizes but low affinity for TRPV4[16]
  • Anti-microbial, anti-inflammatory, and anti-nociceptive effects[18]
  • Neuroprotective properties via mitigation of oxidative stress[18]
  • Potential anti-tumor agent[18]
  • Potential efficacy in treatment of chemotherapy-induced muscle atrophy and weight loss[18]
*Cannabinol (CBN)
  • Agonist at CB1 and CB2, with some evidence of slightly higher affinity at CB2[18]
  • Low affinity agonist at TRPV1, TRPV2, TRPV3, TRPV4, and TRPA1,[16] but readily desensitizes TRPV4[16]
  • Antagonist at TRPM8[16]
  • Antimicrobial and anti-inflammatory / immunosuppressive effects[18]
  • Potential efficacy in treatment of ocular disease and epidermolysis bullosa[18]
  • Reported neuroprotective effects (synergistic if coadministered with other cannabinoids)[18]
  • Relevance to pain, itch, and inflammation via TRP channel activity[18]
*Tetrahydrocannabinol (THC) / Delta-9-Tetrahydrocannabinol (Δ9-THC)
  • Agonist at CB1 and CB2, as well as GPR55, GPR18, PPARγ, and TRPA1[16][19]
  • Antagonist at TRPM8[16][19] and 5-HT3A[19]
  • Differing activity across TRP channels: highest potency phytocannabinoid at TRPV2; modest activity at TRPV3, TRPV4, TRPA1, and TRPM8; no activity observed at TRPV1[16]
  • Importantly, 11-OH-THC, the active metabolite generated via first-pass-metabolism of THC, demonstrates different binding profile at TRP channels[16]
  • Potential relevance to sleep induction (e.g., increased adenosine levels[19]) and increased quality of sleep[16]
  • Dose-dependent anxiolytic effects,[16] with anxiogenic effects at high doses
  • Appetite stimulation[16][17]
  • Anti-nausea[16][17]
  • In combination with CBD, potential efficacy in treatment of spasticity, neuropathic pain and muscle spasticity (see Sativex: THC-containing therapeutic approved in Europe as treatment for Multiple Sclerosis)
*2-Arachidonoylglycerol (2-AG)
  • Partial agonist at CB1 (e.g., on lysosomal surface, increasing lysosomal integrity) and CB2[19]
  • Agonist at GPR55, GPR18, GPR119, PPAR, and robust activation at TRPV4[16][19]
  • Anti-oxidative properties[19]
  • Increased lysosomal stability & integrity[19]
  • Attenuation of mitochondrial damage during cell stress[19]
Anandamide (AEA)
  • Agonist at GPR18, GPR119, and PPAR, with robust activation at TRPV4, and very high efficacy at TRPA1[16][19]
  • Potent partial agonist at GPR55[19][17]
  • Low-affinity full agonist at TRPV1,[16][17] with similar but less potent affinity as compared to capsaicin[16]
  • Antagonist at TRPM8[16]
 Anti-oxidative properties[19]

Neurotransmitter interactions

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).

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 (see diagram at left). 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]

Pharmacokinetics

A small study of six cannabis users found a highly variable half life of 32 ±  17 hours upon intravenous administration.[22] Similar to CBD, CBN is metabolized by the CYP2C9 and CYP3A4 liver enzymes and thus the half-life is sensitive to genetic factors that effect the levels of these enzymes.[23]

Legal status

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

United States

According to the 2018 Farm Bill,[25] 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,[26][27] though sales or possession of CBN could potentially be prosecuted under the Federal Analogue Act.[28]

References

  1. ↑ Cannabinol from PubChem
  2. ↑ CRC Handbook of Chemistry and Physics. CRC Press. 2012. pp. 3–90. ISBN 978-1-43988049-4. https://books.google.com/books?id=-BzP7Rkl7WkC&pg=PA3-90. 
  3. ↑ "Cannabinol solution, analytical standard, for drug analysis". Sigma-Aldrich. https://www.sigmaaldrich.com/SE/en/product/cerillian/c046. 
  4. ↑ "Cannabinol". Biotrend. http://www.biotrend.com/spec/BN0125.pdf. 
  5. ↑ https://pubs.rsc.org/en/content/articlelanding/1899/ct/ct8997500020
  6. ↑ https://pubs.rsc.org/en/content/articlelanding/1932/jr/jr9320001342
  7. ↑ https://bpspubs.onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0706406
  8. ↑ 8.0 8.1 8.2 "Cannabinoid pharmacology: the first 66 years". British Journal of Pharmacology 147 (Suppl 1): S163–S171. January 2006. doi:10.1038/sj.bjp.0706406. PMID 16402100. 
  9. ↑ 9.0 9.1 9.2 "Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase". Journal of Medicinal Chemistry 40 (20): 3228–3233. September 1997. doi:10.1021/jm970126f. PMID 9379442. 
  10. ↑ 10.0 10.1 10.2 10.3 Cannabinoids. Berlin: Springer. 2005. ISBN 3-540-22565-X. OCLC 65169431. https://www.worldcat.org/oclc/65169431. 
  11. ↑ "Cannabinol and Sleep: Separating Fact from Fiction". Cannabis and Cannabinoid Research 6 (5): 366–371. October 2021. doi:10.1089/can.2021.0006. PMID 34468204. 
  12. ↑ "Cannabis sativa: The Plant of the Thousand and One Molecules". Frontiers in Plant Science 7: 19. 2016-02-04. doi:10.3389/fpls.2016.00019. PMID 26870049. 
  13. ↑ "Targeting the endocannabinoid system: future therapeutic strategies". Drug Discovery Today 22 (1): 105–110. January 2017. doi:10.1016/j.drudis.2016.08.005. PMID 27554802. https://figshare.com/articles/journal_contribution/5028362. 
  14. ↑ "Cannabinol (Code C84510)". NCI Thesaurus. National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C84510. 
  15. ↑ "Cannabis: Chemistry, extraction and therapeutic applications". Chemosphere 289: 133012. February 2022. doi:10.1016/j.chemosphere.2021.133012. PMID 34838836. Bibcode: 2022Chmsp.289m3012P. 
  16. ↑ 16.00 16.01 16.02 16.03 16.04 16.05 16.06 16.07 16.08 16.09 16.10 16.11 16.12 16.13 16.14 16.15 16.16 16.17 16.18 16.19 16.20 16.21 16.22 16.23 16.24 16.25 16.26 16.27 16.28 "Cannabinoid Ligands Targeting TRP Channels". Frontiers in Molecular Neuroscience 11: 487. 2019-01-15. doi:10.3389/fnmol.2018.00487. PMID 30697147. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 "Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals". Pharmacology 107 (3–4): 131–149. 2022. doi:10.1159/000521683. PMID 35093949. 
  18. ↑ 18.00 18.01 18.02 18.03 18.04 18.05 18.06 18.07 18.08 18.09 18.10 18.11 18.12 18.13 18.14 18.15 18.16 18.17 "Phytocannabinoid Pharmacology: Medicinal Properties of Cannabis sativa Constituents Aside from the "Big Two"". Journal of Natural Products 84 (1): 142–160. January 2021. doi:10.1021/acs.jnatprod.0c00965. PMID 33356248. 
  19. ↑ 19.00 19.01 19.02 19.03 19.04 19.05 19.06 19.07 19.08 19.09 19.10 19.11 19.12 19.13 19.14 19.15 19.16 "Use of Cannabis and Cannabinoids for Treatment of Cancer". Cancers 14 (20): 5142. October 2022. doi:10.3390/cancers14205142. PMID 36291926. 
  20. ↑ 20.0 20.1 "Legal and Regulatory Issues Governing Cannabis and Cannabis-Derived Products in the United States". Frontiers in Plant Science 10: 697. 2019-06-14. doi:10.3389/fpls.2019.00697. PMID 31263468. 
  21. ↑ 21.0 21.1 "Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE)". British Journal of Pharmacology 142 (1): 9–19. May 2004. doi:10.1038/sj.bjp.0705726. PMID 15100161. 
  22. ↑ "Single-dose kinetics of deuterium-labelled cannabinol in man after intravenous administration and smoking". Biomedical & Environmental Mass Spectrometry 14 (9): 495–499. September 1987. doi:10.1002/bms.1200140904. PMID 2960395. 
  23. ↑ "Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review". Drug Metabolism Reviews 46 (1): 86–95. February 2014. doi:10.3109/03602532.2013.849268. PMID 24160757. https://zenodo.org/record/1093138. 
  24. ↑ "UN International Drug Control Conventions". United Nations Office on Drugs and Crime. United Nations Commission on Narcotic Drugs. https://www.unodc.org/unodc/en/commissions/CND/conventions.html. 
  25. ↑ Office of the Commissioner (2021-10-18). "FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)" (in en). FDA. https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd. 
  26. ↑ "The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law". Epilepsy & Behavior 70 (Pt B): 288–291. May 2017. doi:10.1016/j.yebeh.2016.11.021. PMID 28169144. 
  27. ↑ "Section 1308.11 Schedule I". Code of Federal Regulations. Office of Diversion Control, Drug Enforcement Administration, U.S. Department of Justice. http://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_11.htm. 
  28. ↑ "Federal Controlled Substance Analogue Act Summary". Erowid Analog Law Vault. January 2001. https://www.erowid.org/psychoactives/law/analog/analog_info1.shtml. 

External links

  • Erowid Compounds found in Cannabis sativa



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