-
Cannabis and Cannabinoid Research Oct 2021In recent years, marketers of cannabis (i.e., marijuana) products have claimed that cannabinol (CBN) has unique sleep-promoting effects. Despite a plausible mechanism,... (Review)
Review
In recent years, marketers of cannabis (i.e., marijuana) products have claimed that cannabinol (CBN) has unique sleep-promoting effects. Despite a plausible mechanism, it is possible that such claims are merely rooted in cannabis lore. The aim of this narrative review was to answer the question: "Is there sufficient clinical evidence to support claims that CBN has sleep-promoting effects?" A systematic search of PubMed/MEDLINE was performed to evaluate the published evidence. The abstracts of 99 human studies were screened for relevance by the author and reviewed for compliance with the inclusion criteria. The characteristics and principal findings were extracted from eight full-text articles that met inclusion criteria for detailed review. Pre-clinical and clinical research investigating the effects of CBN is dated and limited, with the preponderance of human studies occurring in the 1970-1980s with small sample sizes lacking diversity in sociodemographic characteristics. Studies specifically assessing subjective effects associated with sleep, such as sedation or fatigue, are rare. Most importantly, published clinical trials investigating associations between CBN and validated sleep questionnaires and/or formal polysomnography were not identified in this review. In addition, evidence demonstrating that CBN itself elicits cannabis-like effects in humans is mixed, with the majority of available evidence demonstrating a lack of such an effect. Consequently, there is insufficient published evidence to support sleep-related claims. Randomized controlled trials are needed to substantiate claims made by manufacturers of cannabis products containing CBN. These studies should specifically evaluate its effects on sleep through polysomnography, or at minimum, through validated sleep questionnaires, and use dosages significantly higher than those found in currently available cannabis products marketed for sleep (typically ≤5 mg). Individuals seeking cannabis-derived sleep aids should be skeptical of manufacturers' claims of sleep-promoting effects.
Topics: Cannabinoids; Cannabinol; Cannabis; Dronabinol; Humans; Sleep
PubMed: 34468204
DOI: 10.1089/can.2021.0006 -
Drug Metabolism and Disposition: the... Dec 2021The legalization of cannabis in many parts of the United States and other countries has led to a need for a more comprehensive understanding of cannabis constituents and...
The legalization of cannabis in many parts of the United States and other countries has led to a need for a more comprehensive understanding of cannabis constituents and their potential for drug-drug interactions. Although (-)--Δ-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are the most abundant cannabinoids present in cannabis, THC metabolites are found in plasma at higher concentrations and for a longer duration than that of the parent cannabinoids. To understand the potential for drug-drug interactions, the inhibition potential of major cannabinoids and their metabolites on major hepatic cytochrome P450 (P450) enzymes was examined. In vitro assays with P450-overexpressing cell microsomes demonstrated that the major THC metabolites 11-hydroxy-Δ-tetra-hydrocannabinol and 11-nor-9-carboxy-Δ-THC-glucuronide competitively inhibited several major P450 enzymes, including CYP2B6, CYP2C9, and CYP2D6 (apparent values = 0.086 ± 0.066 µM and 0.90 ± 0.54 µM, 0.057 ± 0.044 µM and 2.1 ± 0.81 µM, 0.15 ± 0.067 µM and 2.3 ± 0.54 µM, respectively). 11-Nor-9-carboxy-Δ- tetrahydrocannabinol exhibited no inhibitory activity against any CYP450 tested. THC competitively inhibited CYP1A2, CYP2B6, CYP2C9, and CYP2D6; CBD competitively inhibited CYP3A4, CYP2B6, CYP2C9, CYP2D6, and CYP2E1; and CBN competitively inhibited CYP2B6, CYP2C9, and CYP2E1. THC and CBD showed mixed-type inhibition for CYP2C19 and CYP1A2, respectively. These data suggest that cannabinoids and major THC metabolites are able to inhibit the activities of multiple P450 enzymes, and basic static modeling of these data suggest the possibility of pharmacokinetic interactions between these cannabinoids and xenobiotics extensively metabolized by CYP2B6, CYP2C9, and CYP2D6. SIGNIFICANCE STATEMENT: Major cannabinoids and their metabolites found in the plasma of cannabis users inhibit several P450 enzymes, including CYP2B6, CYP2C9, and CYP2D6. This study is the first to show the inhibition potential of the most abundant plasma cannabinoid metabolite, THC-COO-Gluc, and suggests that circulating metabolites of cannabinoids play an essential role in CYP450 enzyme inhibition as well as drug-drug interactions.
Topics: Biotransformation; Cannabidiol; Cannabinoids; Cannabinol; Cannabis; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dronabinol; Drug Interactions; Glucuronosyltransferase; HEK293 Cells; Hepatobiliary Elimination; Humans
PubMed: 34493602
DOI: 10.1124/dmd.121.000442 -
Cannabis and Cannabinoid Research Aug 2022The objective of this study was to evaluate the safety and efficacy of medications commonly used in autism spectrum disorder (ASD) and compare this to what current... (Observational Study)
Observational Study
The objective of this study was to evaluate the safety and efficacy of medications commonly used in autism spectrum disorder (ASD) and compare this to what current research has shown regarding medical cannabis use in this population. Searches were performed to collect information surrounding currently used medications and their safety and efficacy profiles, biologic plausibility of cannabis use for symptoms of ASD, and studies detailing cannabis' safety and efficacy profile for use in the ASD population. Results were used to compare medications to cannabis as a proposed treatment. The heterogeneity of ASD produces great difficulties in finding appropriate treatment, leading to many medication changes or treatment trials throughout a patient's life. Commonly prescribed medications display varying levels of efficacy, safety, and tolerability between patients and symptoms targeted. Some of the most common side effects cited are also considered the most troubling symptoms associated with ASD; aggression, anxiety, irritability, and a negative effect on cognition, leading many patients to discontinue use as the side effects outweigh benefits. Recent case reports and retrospective studies have displayed the potential efficacy, safety, and tolerability of cannabidiol (CBD)-rich medical cannabis use for treating both core symptoms of ASD and many comorbid symptoms such as irritability and sleep problems. Studies have also identified circulating endocannabinoids as a possible biomarker for ASD, providing another possible method of diagnosis. Currently, there are no approved medications for the core symptoms of ASD and only two medications Food and Drug Administration approved for associated irritability. Prescribed medications for symptoms associated with ASD display varying levels of efficacy, safety, and tolerability among the heterogeneous ASD population. At the time of this study there are no published placebo-controlled trials of medical cannabis for ASD and the observational studies have limitations. CBD-rich medical cannabis seems to be an effective, tolerable, and relatively safe option for many symptoms associated with ASD, however, the long-term safety is unknown at this time.
Topics: Autism Spectrum Disorder; Cannabidiol; Cannabis; Hallucinogens; Humans; Medical Marijuana; Retrospective Studies; United States
PubMed: 34432543
DOI: 10.1089/can.2020.0154 -
British Journal of Pharmacology Aug 2011Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system.
BACKGROUND AND PURPOSE
Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system.
EXPERIMENTAL APPROACH
The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested.
KEY RESULTS
CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors.
CONCLUSIONS AND IMPLICATIONS
These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.
Topics: Amides; Amidohydrolases; Animals; Arachidonic Acids; COS Cells; Cannabinoid Receptor Modulators; Cannabinoids; Cannabis; Chlorocebus aethiops; Endocannabinoids; Ethanolamines; Glycerides; HEK293 Cells; Humans; Lipoprotein Lipase; Monoacylglycerol Lipases; Palmitic Acids; Plant Extracts; Polyunsaturated Alkamides; Rats; Transient Receptor Potential Channels
PubMed: 21175579
DOI: 10.1111/j.1476-5381.2010.01166.x -
BMJ Open Aug 2023Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a...
Cannabinol (CBN; 30 and 300 mg) effects on sleep and next-day function in insomnia disorder ('CUPID' study): protocol for a randomised, double-blind, placebo-controlled, cross-over, three-arm, proof-of-concept trial.
OBJECTIVE
Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a constituent of derived from delta-9-tetrahydrocannabinol, could be an effective treatment. Despite this, the isolated effects of CBN on sleep have yet to be systematically studied in humans.
METHODS
The present protocol paper describes a randomised, double-blind, placebo-controlled, single-dose, three-arm, cross-over, proof-of-concept study which investigates the effects of CBN on sleep and next-day function in 20 participants with clinician-diagnosed insomnia disorder and an Insomnia Severity Index Score ≥15. Participants receive a single fixed oral liquid dose of 30 mg CBN, 300 mg CBN and matched placebo, in random order on three treatment nights; each separated by a 2-week wash-out period. Participants undergo overnight sleep assessment using in-laboratory polysomnography and next-day neurobehavioural function tests. The primary outcome is wake after sleep onset minutes. Secondary outcomes include changes to traditional sleep staging, sleep-onset latency and absolute spectral power during non-rapid eye movement (NREM) sleep. Tertiary outcomes include changes to sleep spindles during NREM sleep, arousal indices, absolute spectral power during REM sleep and subjective sleep quality. Safety-related and exploratory outcomes include changes to next-day simulated driving performance, subjective mood and drug effects, postural sway, alertness and reaction time, overnight memory consolidation, pre and post-sleep subjective and objective sleepiness; and plasma, urinary, and salivary cannabinoid concentrations. The study will provide novel preliminary data on CBN efficacy and safety in insomnia disorder, which will inform larger clinical trials.
ETHICS AND DISSEMINATION
Human Research Ethics Committee approval has been granted by Bellberry (2021-08-907). Study findings will be disseminated in a peer-reviewed journal and at academic conferences.
TRIAL REGISTRATION NUMBER
NCT05344170.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Cannabinol; Sleep; Polysomnography; Sleep Latency; Randomized Controlled Trials as Topic
PubMed: 37612115
DOI: 10.1136/bmjopen-2022-071148 -
Plants (Basel, Switzerland) Oct 2022Cannabis ( L.) is an outstanding source of bioactive natural products, with more than 150 different phytocannabinoids isolated throughout the decades; however, studies... (Review)
Review
Cannabis ( L.) is an outstanding source of bioactive natural products, with more than 150 different phytocannabinoids isolated throughout the decades; however, studies of their bioactivity have historically concentrated on the so-called "big four" [∆-THC (), CBD (), CBG () and CBC ()]. Among the remaining products, which have traditionally been referred to as "minor cannabinoids", cannabinol (CBN, ) stands out for its important repercussions and implications on the global scientific landscape. Throughout this review, we will describe why CBN () deserves a prominent place within the so-called "cannabinome", providing an overview on its history, the syntheses developed, and its bioactivity, highlighting its promising pharmacological potential and the significant impact that the study of its chemistry had on the development of new synthetic methodologies.
PubMed: 36365350
DOI: 10.3390/plants11212896 -
Evidence-based Complementary and... 2022Cholangiocarcinoma (CCA) is a very aggressive tumor. The development of a new therapeutic drug for CCA is required. This study aims to evaluate the antitumor effect of...
Cholangiocarcinoma (CCA) is a very aggressive tumor. The development of a new therapeutic drug for CCA is required. This study aims to evaluate the antitumor effect of ∆-tetrahydrocannabinol (THC), the major psychoactive component of marijuana (), and cannabinol (CBN), a minor, low-psychoactive cannabinoid, on CCA cells and xenograft mice. THC and CBN were isolated, and their identities were confirmed by comparing H- and C-NMR spectra and mass spectra with a database. Cell proliferation, cell migration, and cell apoptosis assays were performed in HuCCT1 human CCA cells treated with THC or CBN. The phosphorylation of signaling molecules in HuCCT1 cells was detected. To determine the effects of THC and CBN in an animal model, HuCCT1 cells were inoculated subcutaneously into nude mice. After the tumors reached an appropriate size, the mice were treated with THC or CBN for 21 days. Tumor volumes were monitored and calculated. The H- and C-NMR data of THC and CBN were almost identical to those reported in the literature. THC and CBN significantly inhibited cell proliferation and migration and induced apoptosis in HuCCT1 cells. The phosphorylation of AKT, GSK-3/, and ERK1/2 decreased in HuCCT1 cells treated with THC or CBN. CCA xenograft mice treated with THC showed significantly slower tumor progression and smaller tumor volumes than control mice. THC and CBN induced apoptosis in CCA by inhibiting the AKT and MAPK pathways. These findings provide a strong rationale for THC and CBN as therapeutic options for CCA.
PubMed: 36452140
DOI: 10.1155/2022/6477132 -
Journal of Natural Products May 2020Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, ) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, ), we performed a...
Spurred by a growing interest in cannabidiolquinone (CBDQ, HU-313, ) as a degradation marker and alledged hepatotoxic metabolite of cannabidiol (CBD, ), we performed a systematic study on the oxidation of CBD () to CBDQ () under a variety of experimental conditions (base-catalyzed aerobic oxidation, oxidation with metals, oxidation with hypervalent iodine reagents). The best results in terms of reproducibility and scalability were obtained with λ-periodinanes (Dess-Martin periodinane, 1-hydroxy-1λ,2-benziodoxole-1,3-dione (IBX), and SIBX, a stabilized, nonexplosive version of IBX). With these reagents, the oxidative dimerization that plagues the reaction under basic aerobic conditions was completely suppressed. A different reaction course was observed with the copper(II) chloride-hydroxylamine complex (Takehira reagent), which afforded a mixture of the hydroxyiminodienone and the halogenated resorcinol . The λ-periodinane oxidation was general for phytocannabinoids, turning cannabigerol (CBG, ), cannabichromene (CBC, ), and cannabinol (CBN, ) into their corresponding hydroxyquinones (, , and , respectively). All cannabinoquinoids modulated to a various extent peroxisome proliferator-activated receptor gamma (PPAR-γ) activity, outperforming their parent resorcinols in terms of potency, but the iminoquinone , the quinone dimers and , and the haloresorcinol were inactive, suggesting a specific role for the monomeric hydroxyquinone moiety in the interaction with PPAR-γ.
Topics: Cannabidiol; Cannabinoids; Oxidation-Reduction; PPAR gamma; Quinones; Reproducibility of Results; Resorcinols
PubMed: 32315173
DOI: 10.1021/acs.jnatprod.9b01284