User:Mkf pm801/Cannabinol

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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[4], followed by some of the first pre-clinical research studies to determine the effects of individual cannabis-derived compounds in vivo.[5] 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.[6][5] 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.[6]

Chemical Structure[edit]

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.[7][8] 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.[7]

Compared to D9THC, one additional aromatic ring confers CBN with a slower and more limited metabolic profile - see CBN Formation & Metabolism, below[7]. In contrast to THC, CBN has no double bond isomers nor stereoisomers. CBN can degrade into HU-345 from oxidation.[9] 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).[7]

Formation & Metabolism[edit]

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).[7] CBN can be found in trace amounts in the Cannabis plant[10], 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).[11][12] This process of oxidation occurs via exposure to heat, oxygen, and/or light.[10][11][6] 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.[7]

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.[5]

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.[13] 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.[13] The bioavailability of CBN following administration via inhalation (e.g., smoking or vaporizing) is approximately 40% that of intravenous administration.[7]

Pharmacology[edit]

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.[5]

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][7][6][5][12][14] Compared to THC, CBN has an equivalent or higher affinity to CB2 receptors[1][5], 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.[15] CBN has also been reported to act as an ANKTM1 channel agonist at high concentrations (>20nM).[7] 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.[7][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).[7]

In considering the efficacy of cannabis-based products, there remains controversy surrounding a concept termed “the entourage effect”. This concept describes a widely-observed but poorly-understood synergistic effect of cannabinoid activity 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].

Common Cannabinoids - Putative Receptor Targets & Therapeutic Properties[edit]

The below 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[2], TRPV3, and most potent phytocannabinoid at TRPA1[2][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[2]

·       Antagonist at TRPM8[16]

·       Antimicrobial and anti-inflammatory[2]

·       Potential neuroprotective effects[2]

·       Potential efficacy in treatment of inflammatory pain[2]

*Cannabidiol (CBD) ·       Very weak affinity for CB1 and CB2[18]

·       Conflicting reports but generally described as negative allosteric modulator at CB1 & CB2, altering THC activity when THC & CBD are coadministered[18]

·       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[18]

·       Highest potency at TRPV1[16]

·       Antagonist at GPR55, GPR18, 5-HT3A[18], with highest potency as antagonist at TRPM8[16]

·       Inverse agonist at GPR3, GPR6, and GPR12[18]

·       Anti-inflammatory[19][16]

·       Anti-convulsant[19]

·       Potential efficacy in treatment of inflammatory and chronic pain[16]

*Cannabigerol (CBG) ·       Low affinity agonist and partial agonist at CB1 and CB2, respectively[2]

·       Agonist at α2adrenoceptor[2] 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]

·       Antagonist at 5-HT1A[2] and TRPM8[16]

·       Anti-microbial, anti-inflammatory, and anti-nociceptive effects[2]

·       Neuroprotective properties via mitigation of oxidative stress[2]

·       Potential anti-tumor agent[2]

·       Potential efficacy in treatment of chemotherapy-induced muscle atrophy and weight loss[2]

*Cannabinol (CBN) ·       Agonist at CB1 and CB2, with some evidence of slightly higher affinity at CB2[2]

·       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[2]

·       Potential efficacy in treatment of ocular disease and epidermolysis bullosa[2]

·       Reported neuroprotective effects (synergistic if coadministered with other cannabinoids)[2]

·       Relevance to pain, itch, and inflammation via TRP channel activity[2]

*Tetrahydrocannabinol (THC)

or

Delta-9-Tetrahydrocannabinol (D9THC)

·       Agonist at CB1 and CB2, as well as GPR55, GPR18, PPARγ, and TRPA1[16][18]

·       Antagonist at TRPM8[16][18] and 5-HT3A[18]

·       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[18]) 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[18]

·       Agonist at GPR55, GPR18, GPR119, PPAR, and robust activation at TRPV4[16][18]

·       Anti-oxidative properties[18]

·       Increased lysosomal stability & integrity[18]

·       Attenuation of mitochondrial damage during cell stress[18]

Anandamide (AEA) ·       Agonist at GPR18, GPR119, and PPAR, with robust activation at TRPV4, and very high efficacy at TRPA1[16][18]

·       Potent partial agonist at GPR55[18][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[18]

Neurotransmitter Interactions[edit]

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)[20], 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.[20]

Therapeutic Potential[edit]

Although CBN is widely marketed as a sleep aid, there is currently no published scientific evidence to support this claim. Most clinical studies date prior to 1980, with mixed results further clouded by a lack of validated sleep questionnaires, physiological data, and appropriate sample sizes.[6] While ongoing clinical trials seek to elucidate the role of CBN in sleep, the general public should exercise skepticism regarding these claims.[6]

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

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.[21] 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.[18]

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.[14] 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.

Although clinical research of CBN remains in its infancy, investigations of therapeutic profiles of other cannabinoids, such as D9THC and CBD, have led to three cannabis-based medications that are FDA-approved in the United States (see Table under 'Cannabinol and the Controlled Substances Act').

Legal status[edit]

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

United States[edit]

According to the 2018 Farm Bill,[23] 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,[19][24][25] and sales or possession of CBN could potentially be prosecuted under the Federal Analogue Act.[26] 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.[27]

In the United States, complex and conflicting legislation at the federal vs. state level has generated much confusion regarding the legality of cannabis extracts such as CBN. This leaves many individuals wondering - Is CBN legal in the US? What is the difference between cannabis and hemp, as defined by the US federal government?

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 state laws allowing the medical use of cannabis.[28] 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).[29] 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.[6] 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.[30]

Schedule Classifications Definition[31] Examples[31][19]
Schedule 1 ·       No currently accepted medical use

·       High abuse potential

Cannabis (“marihuana”), THC (and all isomers), Mescaline, Peyote, Psilocybin, MDMA, LSD, heroin, ecstasy, “marihuana extracts”
Schedule 2 ·       Currently accepted medical use

·       High abuse potential, “with use potentially leading to severe psychological or physical dependence”

Cocaine, coca leaves, Opioids/opiates (e.g., morphine, fentanyl, opium), methamphetamine

*Combination products with <15mg hydrocodone (Vicodin) per dosage unit

Schedule 3 ·       Accepted medical use

·       Moderate/low potential for abuse and dependence

Tylenol with codeine (products with <90mg codeine per dosage unit), ketamine, anabolic steroids, testosterone
Schedule 4 ·       Accepted medical use

·       Low risk of abuse and dependence

Tramadol, Ambien, Valium, Ativan, Xanax
Schedule 5 ·       Accepted medical use

·       Less abuse potential, includes preparations with limited quantities of specific narcotics

Robitussin, Lomotil, Lyrica (products with <200mg codeine / 100mL)

Cannabinol and the Controlled Substances Act[edit]

While only tetrahydrocannabinols are listed separately from marijuana in Schedule I, the language used to define “marihuana” includes all chemical constituents present in the Cannabis sativa L plant (i.e., “every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin”). For this reason, cannabinol and other cannabinoids derived from the cannabis plant, along with their analogs, all technically remain classified as schedule I substances under federal law.[31][19] Despite this, there are currently three cannabis-based medications that have obtained FDA-approval (see table below).

Generic/Brand Name

(DEA Schedule Classification)

Year of FDA-Approval: Medical Indications Chemical Structure
Dronabinol/Marinol

(Schedule III)

1985: chemotherapy-induced nausea and vomiting, anorexia and AIDS-related weight loss[17] synthetic D9THC analog, orally-administered[17]
Nabilone/Cesamet

(Schedule II)

1985 (re-approved in 2016): chemotherapy-induced nausea & vomiting[17] synthetic, structurally similar to THC, orally-administered[17]
Cannabidiol/Epidiolex

(Schedule IV)

2018: intractable seizure disorders (e.g., Dravet syndrome, Lennox-Gastaut syndrome) in patients 2+ years of age[19][17] 98% pure plant-derived CBD solution, orally-administered[17]

Cannabinol and the 2018 Farm Bill (Agriculture Improvement Act of 2018)?[edit]

While the Controlled Substances Act does not define hemp, this 2018 legislation defines it as cannabis (i.e., the plant itself along with its extracts such as terpenes and cannabinoids) that contains a THC concentration equal to or less than 0.3% by weight. This legislation also requires all cultivation of hemp to be tightly regulated at the state level with required THC testing. If hemp cultivation is taking place with no evidence of THC testing at the state level, the United States Department of Agriculture and/or the FDA have explicit authority to issue a plan for such testing.[19]

References[edit]

  1. ^ a b c d e 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 c d e f g h i j k l m n o p q r s Sampson, Peter B. (2021-01-22). "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. ISSN 1520-6025. PMID 33356248.
  3. ^ a b "Cannabinol (Code C84510)". NCI Thesaurus. National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services.
  4. ^ 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.
  5. ^ 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)
  6. ^ a b c d e f g Corroon, Jamie (2021-08-31). "Cannabinol and Sleep: Separating Fact from Fiction". Cannabis and Cannabinoid Research: can.2021.0006. doi:10.1089/can.2021.0006. ISSN 2578-5125. PMC 8612407. PMID 34468204.{{cite journal}}: CS1 maint: PMC format (link)
  7. ^ 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)
  8. ^ 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.
  9. ^ 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.
  10. ^ a b 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.
  11. ^ a b 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.
  12. ^ a b 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac 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)
  17. ^ a b c d e f g h i j k Legare, Christopher A.; Raup-Konsavage, Wesley M.; Vrana, Kent E. (2022). "Therapeutic Potential of Cannabis, Cannabidiol, and Cannabinoid-Based Pharmaceuticals". Pharmacology. 107 (3–4): 131–149. doi:10.1159/000521683. ISSN 0031-7012.
  18. ^ a b c d e f g h i j k l m n o p q r 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)
  19. ^ a b c d e f g 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.
  20. ^ 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)
  21. ^ "Search of: cannabinol - List Results - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2022-11-18.
  22. ^ "UN International Drug Control Conventions". United Nations Office on Drugs and Crime. United Nations Commission on Narcotic Drugs.
  23. ^ Commissioner, Office of the (2021-10-18). "FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD)". FDA.
  24. ^ 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.
  25. ^ "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.
  26. ^ "Federal Controlled Substance Analogue Act Summary". Erowid Analog Law Vault. January 2001.
  27. ^ "Establishment of a New Drug Code for Marihuana Extract" (PDF). Federal Register. 81 (240). 14 December 2016.
  28. ^ "State Medical Cannabis Laws". www.ncsl.org. Retrieved 2022-11-18.
  29. ^ 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).
  30. ^ 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)
  31. ^ a b c "Drug Scheduling". www.dea.gov. Retrieved 2022-12-05.
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