Editing Cannabinol (section)

===Pharmacodynamics===
Both THC and CBN activate the [[CB1 receptor|CB1]] (K<sub>i</sub> = 211.2&nbsp;nM) and [[CB2 receptor|CB2]] (K<sub>i</sub> = 126.4&nbsp;nM) receptors.<ref name="Rhee_19972">{{cite journal | vauthors = Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R | title = Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase | journal = Journal of Medicinal Chemistry | volume = 40 | issue = 20 | pages = 3228–3233 | date = September 1997 | pmid = 9379442 | doi = 10.1021/jm970126f }}</ref> Each compound acts as a low affinity partial [[agonist]] at [[CB1 receptor]]s with THC demonstrating 5x–10× greater affinity to the CB1 receptor.<ref name="Rhee_19972" /><ref name="Springer-2005">{{Cite book |url=https://www.worldcat.org/oclc/65169431 |title=Cannabinoids |date=2005 |publisher=Springer | vauthors = Abood ME, Pertwee RG |isbn=3-540-22565-X |location=Berlin |oclc=65169431}}</ref><ref name="Corroon-2021">{{cite journal | vauthors = Corroon J | title = Cannabinol and Sleep: Separating Fact from Fiction | journal = Cannabis and Cannabinoid Research | volume = 6 | issue = 5 | pages = 366–371 | date = October 2021 | pmid = 34468204 | pmc = 8612407 | doi = 10.1089/can.2021.0006 }}</ref><ref name="Pertwee-2006" /><ref name="Andre-2016">{{cite journal | vauthors = Andre CM, Hausman JF, Guerriero G | title = Cannabis sativa: The Plant of the Thousand and One Molecules | journal = Frontiers in Plant Science | volume = 7 | pages = 19 | date = 2016-02-04 | pmid = 26870049 | pmc = 4740396 | doi = 10.3389/fpls.2016.00019 | doi-access = free }}</ref><ref name="Aizpurua-Olaizola-2017">{{cite journal | vauthors = Aizpurua-Olaizola O, Elezgarai I, Rico-Barrio I, Zarandona I, Etxebarria N, Usobiaga A | title = Targeting the endocannabinoid system: future therapeutic strategies | journal = Drug Discovery Today | volume = 22 | issue = 1 | pages = 105–110 | date = January 2017 | pmid = 27554802 | doi = 10.1016/j.drudis.2016.08.005 | s2cid = 3460960 | url = https://figshare.com/articles/journal_contribution/5028362 }}</ref> Like THC, CBN has a higher selectivity for [[CB2 receptor|CB2]] [[Receptor (biochemistry)|receptors]]<ref name="Rhee_19972" /><ref name="Pertwee-2006" /> which are located throughout the central and [[peripheral nervous system]], but are primarily associated with [[Immune system|immune function]]. CB2 receptors are known to be located on immune cells throughout the body, including [[macrophage]]s, [[T cell]]s, and [[B cell]]s. These immune cells have been shown to decrease production of immune-related chemical signals (e.g., [[cytokine]]s) or undergo [[apoptosis]] as a consequence of CB2 agonism by CBN.<ref name="NCI_C845102">{{Cite web |title=Cannabinol (Code C84510) |url=https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C84510 |work=NCI Thesaurus |publisher=National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services}}</ref> In cell culture, CBN demonstrates antimicrobial effects, particularly in instances of antibiotic-resistant bacteria.<ref>{{cite journal | vauthors = Pattnaik F, Nanda S, Mohanty S, Dalai AK, Kumar V, Ponnusamy SK, Naik S | title = Cannabis: Chemistry, extraction and therapeutic applications | journal = Chemosphere | volume = 289 | pages = 133012 | date = February 2022 | pmid = 34838836 | doi = 10.1016/j.chemosphere.2021.133012 | bibcode = 2022Chmsp.28933012P | s2cid = 244679123 }}</ref> CBN has also been reported to act as an [[TRPA1|ANKTM1]] channel agonist at high concentrations (>20nM).<ref name="Springer-2005" /> While some [[Cannabinoid|phytocannabinoids]] have been shown to interact with [[Nociception|nociceptive]] and immune-related signaling via [[transient receptor potential channel]]s (e.g., TRPV1 and TRPM8), there is currently limited evidence to suggest that CBN acts in this way.<ref name="Springer-2005" /><ref name="Muller-2019">{{cite journal | vauthors = Muller C, Morales P, Reggio PH | title = Cannabinoid Ligands Targeting TRP Channels | journal = Frontiers in Molecular Neuroscience | volume = 11 | pages = 487 | date = 2019-01-15 | pmid = 30697147 | pmc = 6340993 | doi = 10.3389/fnmol.2018.00487 | doi-access = free }}</ref> In preclinical rodent studies, CBN, [[anandamide]] and other CB1 agonists have demonstrated inhibitory effects on GI motility, reversible via CB1R blockade (i.e., antagonism).<ref name="Springer-2005" />

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., [[flavonoid]]s, [[terpenoid]]s, [[alkaloid]]s). 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.<ref name="Legare-2022">{{cite journal | vauthors = Legare CA, Raup-Konsavage WM, Vrana KE | title = Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals | journal = Pharmacology | volume = 107 | issue = 3–4 | pages = 131–149 | date = 2022 | pmid = 35093949 | doi = 10.1159/000521683 | doi-access = free }}</ref>

====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 [[Endocannabinoid system|endocannabinoids]] (i.e., endogenously produced cannabinoid receptor [[Ligand (biochemistry)|ligands]]).

{| class="wikitable"
! Full Name
! Known Receptor Targets
! Putative Therapeutic Properties
|- style="vertical-align: top;"
| Cannabichromene (CBC)
|
* Agonist at CB2,<ref name="Sampson-2021">{{cite journal | vauthors = Sampson PB | title = Phytocannabinoid Pharmacology: Medicinal Properties of ''Cannabis sativa'' Constituents Aside from the "Big Two" | journal = Journal of Natural Products | volume = 84 | issue = 1 | pages = 142–160 | date = January 2021 | pmid = 33356248 | doi = 10.1021/acs.jnatprod.0c00965 | s2cid = 229694293 }}</ref> TRPV3, and most potent phytocannabinoid at TRPA1<ref name="Sampson-2021" /><ref name="Muller-2019" />
* Very low efficacy at TRPV1 and TRPV4, but may reduce expression of TRPV4 in the presence of inflammation<ref name="Muller-2019" />
* High affinity for CB1 but no observed functional activity<ref name="Sampson-2021" />
* Antagonist at TRPM8<ref name="Muller-2019" />
|
* Antimicrobial and anti-inflammatory<ref name="Sampson-2021" />
* Potential neuroprotective effects<ref name="Sampson-2021" />
* Potential efficacy in treatment of inflammatory pain<ref name="Sampson-2021" />
|- style="vertical-align: top;"
| Cannabidiol (CBD)
|
* Very weak affinity for CB1 and CB2<ref name="Cherkasova-2022">{{cite journal | vauthors = Cherkasova V, Wang B, Gerasymchuk M, Fiselier A, Kovalchuk O, Kovalchuk I | title = Use of Cannabis and Cannabinoids for Treatment of Cancer | journal = Cancers | volume = 14 | issue = 20 | pages = 5142 | date = October 2022 | pmid = 36291926 | pmc = 9600568 | doi = 10.3390/cancers14205142 | doi-access = free }}</ref>
* Conflicting reports but generally described as negative allosteric modulator at CB1 & CB2, altering THC activity when THC & CBD are coadministered<ref name="Cherkasova-2022" />
* Agonist at TRPA1,<ref name="Muller-2019" /> TRPV1 (high potency at this “capsaicin receptor” without ablative effects<ref name="Muller-2019" />), TRPV2, TRPV3, PPARγ, 5-HT1A, A2 and A1 adenosine receptors<ref name="Cherkasova-2022" />
* Highest potency at TRPV1<ref name="Muller-2019" />
* Antagonist at GPR55, GPR18, 5-HT3A,<ref name="Cherkasova-2022" /> with highest potency as antagonist at TRPM8<ref name="Muller-2019" />
* Inverse agonist at GPR3, GPR6, and GPR12<ref name="Cherkasova-2022" />
|
* Anti-inflammatory<ref name="Mead-2019">{{cite journal | vauthors = Mead A | title = Legal and Regulatory Issues Governing Cannabis and Cannabis-Derived Products in the United States | journal = Frontiers in Plant Science | volume = 10 | pages = 697 | date = 2019-06-14 | pmid = 31263468 | pmc = 6590107 | doi = 10.3389/fpls.2019.00697 | doi-access = free }}</ref><ref name="Muller-2019" />
* Anti-convulsant<ref name="Mead-2019" />
* Potential efficacy in treatment of inflammatory and chronic pain<ref name="Muller-2019" />
|- style="vertical-align: top;"
| Cannabigerol (CBG)
|
* Low affinity agonist and partial agonist at CB1 and CB2, respectively<ref name="Sampson-2021" />
* Agonist at α2adrenoceptor<ref name="Sampson-2021" /> and TRP channels such as TRPA1, TRPV2, and TRPV3, with highest potency as agonist at TRPV1<ref name="Muller-2019" />
* Readily desensitizes but low affinity for TRPV4<ref name="Muller-2019" />

* Antagonist at 5-HT1A<ref name="Sampson-2021" /> and TRPM8<ref name="Muller-2019" />
|
* Anti-microbial, anti-inflammatory, and anti-nociceptive effects<ref name="Sampson-2021" />
* Neuroprotective properties via mitigation of oxidative stress<ref name="Sampson-2021" />
* Potential anti-tumor agent<ref name="Sampson-2021" />
* Potential efficacy in treatment of chemotherapy-induced muscle atrophy and weight loss<ref name="Sampson-2021" />
|- style="vertical-align: top;"
| Cannabinol (CBN)
|
* Agonist at CB1 and CB2, with some evidence of slightly higher affinity at CB2<ref name="Sampson-2021" />
* Low affinity agonist at TRPV1, TRPV2, TRPV3, TRPV4, and TRPA1,<ref name="Muller-2019" /> but readily desensitizes TRPV4<ref name="Muller-2019" />
* Antagonist at TRPM8<ref name="Muller-2019" />
|
* Antimicrobial and anti-inflammatory / immunosuppressive effects<ref name="Sampson-2021" />
* Potential efficacy in treatment of ocular disease and epidermolysis bullosa<ref name="Sampson-2021" />
* Reported neuroprotective effects (synergistic if coadministered with other cannabinoids)<ref name="Sampson-2021" />
* Relevance to pain, itch, and inflammation via TRP channel activity<ref name="Sampson-2021" />
|- style="vertical-align: top;"
| Tetrahydrocannabinol (THC) / Delta-9-Tetrahydrocannabinol (Δ<sup>9</sup>-THC)
|
* Agonist at CB1 and CB2, as well as GPR55, GPR18, PPARγ, and TRPA1<ref name="Muller-2019" /><ref name="Cherkasova-2022" />
* Antagonist at TRPM8<ref name="Muller-2019" /><ref name="Cherkasova-2022" /> and 5-HT3A<ref name="Cherkasova-2022" />
* Differing activity across TRP channels: highest potency phytocannabinoid at TRPV2; modest activity at TRPV3, TRPV4, TRPA1, and TRPM8; no activity observed at TRPV1<ref name="Muller-2019" />
* Importantly, 11-OH-THC, the active metabolite generated via first-pass-metabolism of THC, demonstrates different binding profile at TRP channels<ref name="Muller-2019" />
|
* Potential relevance to sleep induction (e.g., increased adenosine levels<ref name="Cherkasova-2022" />) and increased quality of sleep<ref name="Muller-2019" />
* Dose-dependent anxiolytic effects,<ref name="Muller-2019" /> with anxiogenic effects at high doses
* Appetite stimulation<ref name="Muller-2019" /><ref name="Legare-2022" />
* Anti-nausea<ref name="Muller-2019" /><ref name="Legare-2022" />
* 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)
|- style="vertical-align: top;"
| 2-Arachidonoylglycerol (2-AG)
|
* Partial agonist at CB1 (e.g., on lysosomal surface, increasing lysosomal integrity) and CB2<ref name="Cherkasova-2022" />
* Agonist at GPR55, GPR18, GPR119, PPAR, and robust activation at TRPV4<ref name="Muller-2019" /><ref name="Cherkasova-2022" />
|
* Anti-oxidative properties<ref name="Cherkasova-2022" />
* Increased lysosomal stability & integrity<ref name="Cherkasova-2022" />
* Attenuation of mitochondrial damage during cell stress<ref name="Cherkasova-2022" />
|- style="vertical-align: top;"
| Anandamide (AEA)
|
* Agonist at GPR18, GPR119, and PPAR, with robust activation at TRPV4, and very high efficacy at TRPA1<ref name="Muller-2019" /><ref name="Cherkasova-2022" />
* Potent partial agonist at GPR55<ref name="Cherkasova-2022" /><ref name="Legare-2022" />
* Low-affinity full agonist at TRPV1,<ref name="Muller-2019" /><ref name="Legare-2022" /> with similar but less potent affinity as compared to capsaicin<ref name="Muller-2019" />
* Antagonist at TRPM8<ref name="Muller-2019" />
| Anti-oxidative properties<ref name="Cherkasova-2022" />
|}

====Neurotransmitter interactions====
[[File:DSI_DSE_Diagram_-_Mechanism_of_Action_of_eCB_ligands_at_CB1R_in_the_brain.jpg|thumb|400x400px|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 [[2-Arachidonoylglycerol|2AG]] or [[Anandamide|AEA]] (two primary endocannabinoids).|left]]

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 [[2-Arachidonoylglycerol|2AG]] or [[Anandamide|AEA]] (two primary endocannabinoids). This mechanism of action is called depolarization-induced suppression of inhibition (DSI) or depolarization-induced suppression of excitation (DSE),<ref name="Diana-2004">{{cite journal | vauthors = Diana MA, Marty A | title = Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE) | journal = British Journal of Pharmacology | volume = 142 | issue = 1 | pages = 9–19 | date = May 2004 | pmid = 15100161 | pmc = 1574919 | doi = 10.1038/sj.bjp.0705726 }}</ref> depending on the classification of the [[Chemical synapse|presynaptic neuron]] acted upon by the retrograde messenger (''see diagram at left''). In the case of CB1R agonism on the presynaptic membrane of a [[Γ-Aminobutyric acid|GABAergic interneuron]], activation leads to a net effect of increased activity, while the same activity on a [[Glutamate (neurotransmitter)|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]].<ref name="Diana-2004" />