Explore the vast range of titles available.

Cannabidiol (CBD) and cannabidivarin (CBDV) are natural cannabinoids which are consumed in increasing amounts worldwide in cannabis extracts, as they prevent epilepsy, anxiety, and seizures. It was claimed that they may be useful in cancer therapy and have anti-inflammatory properties. Adverse long-term effects of these drugs (induction of cancer and infertility) which are related to damage of the genetic material have not been investigated. Therefore, we studied their DNA-damaging properties in human-derived cell lines under conditions which reflect the exposure of consumers. Both compounds induced DNA damage in single cell gel electrophoresis (SCGE) experiments in a human liver cell line (HepG2) and in buccal-derived cells (TR146) at low levels (≥ 0.2 µM). Results of micronucleus (MN) cytome assays showed that the damage leads to formation of MNi which reflect chromosomal aberrations and leads to nuclear buds and bridges which are a consequence of gene amplifications and dicentric chromosomes. Additional experiments indicate that these effects are caused by oxidative base damage and that liver enzymes (S9) increase the genotoxic activity of both compounds. Our findings show that low concentrations of CBD and CBDV cause damage of the genetic material in human-derived cells. Furthermore, earlier studies showed that they cause chromosomal aberrations and MN in bone marrow of mice. Fixation of damage of the DNA in the form of chromosomal damage is generally considered to be essential in the multistep process of malignancy, therefore the currently available data are indicative for potential carcinogenic properties of the cannabinoids.

Dermatological diseases pose a significant burden on the quality of life of individuals and can be challenging to treat effectively. In this aspect, cannabinoids are gaining increasing importance due to their therapeutic potential in various disease entities including skin diseases. In this synthetic review, we comprehensively analyzed the existing literature in the field of potential dermatological applications of a lesser-known subgroup of cannabinoids, the so-called minor cannabinoids, such as cannabidivarin (CBDV), cannabidiforol (CBDP), cannabichromene (CBC), tetrahydrocannabivarin (THCV), cannabigerolic acid (CBGA), cannabigerol (CBG), cannabielsoin (CBE), cannabimovone (CBM) or cannabinol (CBN), while drawing attention to their unique pharmacological properties. We systematically searched the available databases for relevant studies and analyzed the data to provide an overview of current thematic knowledge. We looked through the full-text, bibliographic and factographic databases, especially Scopus, Web of Science, PubMed, Polish Scientific Journals Database, and selected the most relevant papers. Our review highlights that minor cannabinoids exhibit diverse pharmacological activities, including anti-inflammatory, analgesic, antimicrobial, and anti-itch properties. Several studies have reported their efficacy in mitigating symptoms associated with dermatological diseases such as psoriasis, eczema, acne, and pruritus. Furthermore, minor cannabinoids have shown potential in regulating sebum production, a crucial factor in acne pathogenesis. The findings of this review suggest that minor cannabinoids hold therapeutic promise in the management of dermatological diseases. Further preclinical and clinical investigations are warranted to elucidate their mechanisms of action, determine optimal dosage regimens, and assess long-term safety profiles. Incorporating minor cannabinoids into dermatological therapies could potentially offer novel treatment options of patients and improve their overall well-being.

Epilepsy is a neurological disorder mainly characterised by recurrent seizures that affect the entire population diagnosed with the condition. Currently, there is no cure for the disease and a significant proportion of patients have been deemed to have treatment-resistant epilepsy (TRE). A patient is deemed to have TRE if two or more antiepileptic drugs (AEDs) fail to bring about seizure remission. This inefficacy of traditional AEDs, coupled with their undesirable side effect profile, has led to researchers considering alternative forms of treatment. Phytocannabinoids have long served as therapeutics with delta-9-THC (Δ9-THC) receiving extensive focus to determine its therapeutic potential. This focus on Δ9-THC has been to the detriment of analysing the plethora of other phytocannabinoids found in the cannabis plant. The overall aim of this review is to explore other novel phytocannabinoids and their place in epilepsy treatment. The current review intends to achieve this aim via an exploration of the molecular targets underlying the anticonvulsant capabilities of cannabidiol (CBD), cannabidavarin (CBDV), delta-9-tetrahydrocannabivarin (Δ9-THCV) and cannabigerol (CBG). Further, this review will provide an exploration of current pre-clinical and clinical data as it relates to the aforementioned phytocannabinoids and the treatment of epilepsy symptoms. With specific reference to epilepsy in young adult and adolescent populations, the exploration of CBD, CBDV, Δ9-THCV and CBG in both preclinical and clinical environments can guide future research and aid in the further understanding of the role of phytocannabinoids in epilepsy treatment. Currently, much more research is warranted in this area to be conclusive.

Δ 9 -Tetrahydrocannabinol (Δ 9 -THC) inhibits tics in individuals with Tourette syndrome (TS). Δ 9 -THC has similar affinities for CB 1 /CB 2 cannabinoid receptors. However, the effect of HU-308, a selective CB 2 receptor agonist, on repetitive behaviors has not been investigated. The effects of 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced motor-like tics and Δ 9 -THC were studied with gene analysis. The effects of HU-308 on head twitch response (HTR), ear scratch response (ESR), and grooming behavior were compared between wildtype and CB 2 receptor knockout (CB 2 −/− ) mice, and in the presence/absence of DOI or SR141716A, a CB 1 receptor antagonist/inverse agonist. The frequency of DOI-induced repetitive behaviors was higher in CB 2 −/− than in wildtype mice. HU-308 increased DOI-induced ESR and grooming behavior in adult CB 2 −/− mice. In juveniles, HU-308 inhibited HTR and ESR in the presence of DOI and SR141716A. HU-308 and beta-caryophyllene significantly increased HTR. In the left prefrontal cortex, DOI increased transcript expression of the CB 2 receptor and GPR55, but reduced fatty acid amide hydrolase (FAAH) and α/β-hydrolase domain-containing 6 (ABHD6) expression levels. CB 2 receptors are required to reduce 5-HT 2A/2C -induced tics in adults. HU-308 has an off-target effect which increases 5-HT 2A/2C -induced motor-like tics in adult female mice. The increased HTR in juveniles induced by selective CB 2 receptor agonists suggests that stimulation of the CB 2 receptor may generate motor tics in children. Sex differences suggest that the CB 2 receptor may contribute to the prevalence of TS in boys. The 5-HT 2A/2C -induced reduction in endocannabinoid catabolic enzyme expression level may explain the increased endocannabinoids’ levels in patients with TS.

Background Autism spectrum disorder (ASD) has a high cost to affected individuals and society, but treatments for core symptoms are lacking. To expand intervention options, it is crucial to gain a better understanding of potential treatment targets, and their engagement, in the brain. For instance, the striatum (caudate, putamen, and nucleus accumbens) plays a central role during development and its (atypical) functional connectivity (FC) may contribute to multiple ASD symptoms. We have previously shown, in the adult autistic and neurotypical brain, the non-intoxicating cannabinoid cannabidivarin (CBDV) alters the balance of striatal ‘excitatory–inhibitory’ metabolites, which help regulate FC, but the effects of CBDV on (atypical) striatal FC are unknown. Methods To examine this in a small pilot study, we acquired resting state functional magnetic resonance imaging data from 28 men (15 neurotypicals, 13 ASD) on two occasions in a repeated-measures, double-blind, placebo-controlled study. We then used a seed-based approach to (1) compare striatal FC between groups and (2) examine the effect of pharmacological probing (600 mg CBDV/matched placebo) on atypical striatal FC in ASD. Visits were separated by at least 13 days to allow for drug washout. Results Compared to the neurotypicals, ASD individuals had lower FC between the ventral striatum and frontal and pericentral regions (which have been associated with emotion, motor, and vision processing). Further, they had higher intra-striatal FC and higher putamenal FC with temporal regions involved in speech and language. In ASD, CBDV reduced hyperconnectivity to the neurotypical level. Limitations Our findings should be considered in light of several methodological aspects, in particular our participant group (restricted to male adults), which limits the generalizability of our findings to the wider and heterogeneous ASD population. Conclusion In conclusion, here we show atypical striatal FC with regions commonly associated with ASD symptoms. We further provide preliminary proof of concept that, in the adult autistic brain, acute CBDV administration can modulate atypical striatal circuitry towards neurotypical function. Future studies are required to determine whether modulation of striatal FC is associated with a change in ASD symptoms. Trial registration clinicaltrials.gov, Identifier: NCT03537950. Registered May 25th, 2018—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03537950?term=NCT03537950&draw=2&rank=1 .

As a library of cannabinoid (CB) derivatives with (-)- -cannabidiol (CBD) or (-)- -cannabidivarin (CBDV) scaffold, we synthesized nine novel cannabinoids: 2-hydroxyethyl cannabidiolate (2-HEC), 2-hydroxypentyl cannabidiolate (2-HPC), 2,3-dihydroxypropyl cannabidiolate (GCBD), cyclohexyl cannabidiolate (CHC), -hexyl-cannabidiolate (HC), 2-(methylsulfonamido)ethyl cannabidiolate (NMSC), 2-hydroxyethyl cannabidivarinolate (2-HECBDV), cyclohexyl cannabidivarinolate (CHCBDV), and -hexyl cannabidivarinolate (HCBDV). Their binding and intrinsic effects at the CB1- and CB2-receptors and the effects on inflammatory signaling cascades were investigated in in vitro and ex vivo cell models. Binding affinity was studied in membranes isolated from CB-receptor-transfected HEK293EBNA cells, intrinsic functional activity in Chinese hamster ovary (CHO) cells, and activation of nuclear factor κB (NF-κB) and nuclear factor of activated T-cells (NFAT) in phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO)-treated Jurkat T-cells. Inhibition of interleukin (IL)-17-induced pro-inflammatory cytokines and chemokines [IL-6, IL-1β, CC-chemokine ligand 2 (CCL2), and tumor necrosis factor (TNF)-α] was studied in RAW264.7 macrophages at the RNA level. Pro-inflammatory cytokine (IL-1β, IL-6, IL-8, and TNF-α) expression and prostaglandin E2 (PGE ) expression were investigated at the protein level in lipopolysaccharide (LPS)-treated primary human monocytes. Derivatives with long aliphatic side chains at the ester position at R [HC ( )] as well as the ones with polar side chains [2-HECBDV ( ), NMSC ( ), and 2-HEC ( )] can be selective for CB2-receptors. The CBDV-derivatives HCBDV and CHCBDV demonstrated specific binding at CB1- and CB2-receptors at nanomolar concentrations. 2-HEC, 2-HPC, GCBD, and NMSC were agonists at CB2-receptor and antagonists at CB1-receptor. CHC bound both receptors at submicromolar ranges and was an agonist for these receptors. 2-HECBDV was an agonist at CB2-receptor and an antagonist at the CB1-receptor despite its modest affinity at this receptor (micromolar range). NMSC inhibited NF-κB and NFAT activity, and 2-HEC, 2-HPC, and GCBD dose-dependently inhibited PMA/IO-stimulated NFAT activation. CHC and HC dose-dependently reduced IL-1β and CCL2 messenger RNA (mRNA) expression. NMSC inhibited IL-1β, CCL2, and TNF-α at lower doses. At higher doses, it induced a pronounced increase in IL-6 mRNA. 2-HEC, 2-HPC, and GCBD dose-dependently inhibited LPS-induced IL-1β, TNF-α, and IL-6 synthesis. NMSC further increased LPS-stimulated IL-1β release but inhibited IL-8, TNF-α, and PGE . The CBD- and CBDV-derivatives studied are suitable for targeting CB-receptors. Some may be used as selective CB2 agonists. The length of the aliphatic rest at R of CBD (pentyl) and CBDV (propyl) did not correlate with the binding affinity. Higher polarity at R appeared to favor the agonistic activity at CB2-receptors.