Pharmacological characterization of cannabidiol as a negative allosteric modulator of the 5-HT2A receptor

Posted on January 7, 2025 by David

“Promising clinical evidence suggests that psychedelic compounds, like lysergic acid diethylamide (LSD), have therapeutic value for treatment of psychiatric disorders. However, they often produce hallucinations and dissociative states, likely mediated by the serotonin (5-HT) receptor 5-HT_2A, raising challenges regarding therapeutic scalability.

Given the reported antipsychotic effects of cannabidiol (CBD) and its promiscuous binding at many receptors, we assessed whether CBD could modulate 5-HT_2A signaling.

Activation of the 5-HT_2A intracellular signaling events were assessed using resonance energy transfer- or fluorescence-based biosensors in HEK 293 cells and in rat primary cortical neurons. In 5-HT_2A-transfected HEK 293 T cells, CBD antagonized LSD-mediated Gq activation in a saturable way, while leaving β-arrestin2 recruitment unaffected. CBD decreased Gq activation mediated by the 5-HT_2A-specific agonist DOI as well as LSD-mediated activity in primary rat neonatal cortical neurons. Using Site Identification by Ligand Competitive Saturation (SILCS) simulations, we also predicted that the putative binding site of CBD overlapped with that of oleamide, a positive allosteric modulator of 5-HT_2A, and could displace the binding of orthosteric ligands toward the external binding pocket.

Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT_2A.”

https://pubmed.ncbi.nlm.nih.gov/39761844/

“Based on these findings, we propose that CBD acts as a negative allosteric modulator of 5-HT_2A.”

https://www.sciencedirect.com/science/article/abs/pii/S0898656825000014?via%3Dihub

“Efficacy and safety of negative allosteric modulators of 5-hydroxytryptamine 2A receptors in the treatment of Alzheimer’s disease psychosis: A systematic review and meta-analysis. Our results suggest that negative modulators of 5-HT2A receptors are beneficial and well-tolerated in the treatment of ADP.”

https://pubmed.ncbi.nlm.nih.gov/37166012/

Cannabinoid receptor ligands modulate fibrosis and inflammation in idiopathic pulmonary fibrosis: a preliminary study

Posted on January 6, 2025 by David

“Background/aim: No specific pharmacological treatment regimen for idiopathic pulmonary fibrosis (IPF) exists. Therefore, new antiinflammatory therapeutic strategies are needed. Cannabinoids (CBs), known for their inflammation-modulating and antifibrotic effects, may be potential medication candidates for treating IPF. We aim to evaluate the inflammation-modulating and antifibrotic effects of CB receptor (CBR) agonists and antagonists in lipopolysaccharide-stimulated normal human lung fibroblast, epithelial cells, IPF fibroblast cells, and monocytes.

Materials and methods: We detected CBRs in normal human lung fibroblasts (LL24) and IPF fibroblast cells (LL29), epithelial cells (A549) and monocytes (THP-1) by flow cytometry. We determined TGF-β1, IL-8, and TNF-α inflammatory cytokines in the LL24, LL29, A549, and THP-1 cell culture supernatants on days 1 and 5 by ELISA. We evaluated the cell viability in LL24, LL29, and A549 cells on days 1, 3, and 5 spectrophotometrically and detected collagen Type I (ColI) production in the LL24 and LL29 cell culture supernatants on days 1, 3, and 5 by ELISA.

Results: LL24, LL29, A549, and THP-1 cells exhibited CB1 (CB1R) and CB2 (CB2R) receptors. CB1R and CB2R agonists WIN55,212-2 and JWH015 inhibited fibroblastic and epithelial cell proliferation on day 5. TGF-β1 and TNF-α release increased, while IL-8 release decreased in LL24, LL29, A549, and THP-1 cells in response to the administration of WIN55,212-2 and JWH015 at a 10^-2 mM concentration. CB1R and CB2R antagonists AM251 and AM630 did not block agonistic responses, suggesting a nonclassical CBR-mediated pathway. CB2R agonist JWH015 decreased ColI expression in IPF lung fibroblasts LL29 on day 3.

Conclusion: These results suggest that CB signaling regulates the progression of pulmonary inflammation and fibrosis via CBR activation. This may offer a potential pharmacological tool for developing antifibrosis therapies.”

https://pubmed.ncbi.nlm.nih.gov/39758842/

https://journals.tubitak.gov.tr/biology/vol48/iss6/4/

Three new α-glucosidase inhibitors from aqueous extract of Cannabis sativa leaves: isolation, characterisation, and kinetic study

Posted on January 6, 2025 by David

“α-Glucosidase inhibitory assay-guided isolation of the aqueous extract from Cannabis sativa leaves afforded three new compounds named cannabisaldehyde (8), cannacone A (9), and canniprene C (10), along with eight previously known compounds (1–7, 11). The structures of new compounds were determined through extensive analysis of various spectroscopic data. Of isolated compounds, cannacone A (9) demonstrated most potent inhibition against maltase and sucrase with IC₅₀ values of 80.0 and 82.9 μM, respectively. Cannacone A (9) inhibited both maltase and sucrase by competitive mechanism.”

https://pubmed.ncbi.nlm.nih.gov/39756038/

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2448841

“Alpha-glucosidase inhibitors (AGIs) are used to treat type 2 diabetes and to prevent or delay the development of type 2 diabetes in people at risk.”

“Alpha-glucosidase inhibitors are antihyperglycemic agents that lower blood glucose by delaying the digestion and absorption of complex carbohydrates.”

The antibacterial and antibiofilm role of cannabidiol against periodontopathogenic bacteria

Posted on January 1, 2025 by David

“Aims: Bacterial resistance and systemic risks associated with periodontitis underscore the need for novel antimicrobial agents. Cannabis sativa is a promising source of antimicrobial molecules, and cannabidiol (CBD) attracts significant interest. This study evaluated the antibacterial and antibiofilm activity of CBD against periodontopathogens, and assessed its toxicity in vivo model.

Methods and results: Antibacterial activity was determined by the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC). Biofilm inhibition was determined the Minimum Inhibitory Concentration of Biofilm (MICB50). Toxicity was assessed using Caeonorhabditis elegans. The periodontopathogens tested were Actinomyces naeslundii (ATCC 19039), Peptostreptococcus anaerobius (ATCC 27337), Veillonella parvula (ATCC 17745), Fusobacterium nucleatum (ATCC 10953) and Aggregatibacter actinomycetemcomitans (ATCC 43717). CBD exhibited antibacterial effects with MICs of 0.39 to 3.12 μg ml-1 and MICB50 of 0.39 μg ml-1 to 1.56 μg ml-1 against biofilms, without toxicity below 375 μg ml1.

Conclusion: The results suggest that CBD is a non-toxic product with antibacterial and antibiofilm potential, exhibiting promise as a therapeutic alternative for oral diseases.”

https://pubmed.ncbi.nlm.nih.gov/39737707/

https://academic.oup.com/jambio/advance-article-abstract/doi/10.1093/jambio/lxae316/7934962?redirectedFrom=fulltext&login=false

Genotoxicity study of Cannabis sativa L. extract

Posted on January 1, 2025 by David

“Cannabis sativa L., a member of the Cannabaceae family, has been thoroughly investigated for its diverse therapeutic properties, primarily attributed to cannabinoids such as delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Secondary, metabolites like terpenes also exhibit pharmacological effects.

This study examined the genotoxicity of a whole Cannabis sativa flower extract 160.32 mg/mL using three OECD-recommended protocols: the Ames test, micronucleus test, and comet assay. Five groups of six Wistar rats were used. Three doses of the extract (500, 1000, and 2000 mg/kgbw) or negative control (placebo) were administered orally, while cyclophosphamide monohydrate (20 mg/kgbw) was used as a positive control via intraperitoneal injection. Blood was collected for the comet test, and the animals were euthanized for bone marrow collection for the micronucleus test.

The Cannabis extract did not increase the number of revertant bacterial colonies at (375, 250, 125, and 62.5 μg/plate) in TA100 or TA98, nor did it affect the number of micronucleated polychromatic erythrocytes (MNPCEs) or the ratio of polychromatic to normochromatic erythrocytes (PCEs/NCEs). It also did not alter the index or frequency of DNA damage in hematopoietic cells.

These results suggest no genotoxic effects, supporting its potential therapeutic use.”

“Cannabis sativa extract shows no significant genotoxic effects in tested models.”

“Study supports therapeutic use of whole Cannabis sativa extract.”

https://www.sciencedirect.com/science/article/pii/S2214750024002476

https://pubmed.ncbi.nlm.nih.gov/39816045/

https://www.forbes.com/sites/emilyearlenbaugh/2024/12/30/cannabis-study-finds-no-genotoxic-effects/

Cannabichromene from full-spectrum hemp extract exerts acute anti-seizure effects through allosteric activation of GABAA receptors

Posted on December 30, 2024 by David

“The approval of Epidiolex, an anti-epileptic drug containing cannabidiol (CBD) as its active component, has brought hope to patients with refractory epilepsy. However, the anti-seizure effect of full-spectrum hemp extract (HE), a CBD-enriched hemp oil, remains unclear.

In this study, we investigated the anti-seizure effect of HE using drug-induced seizure models.

Our findings revealed that HE significantly reduced seizure susceptibility comparable to CBD at the same doses. Moreover, we explored the pharmacokinetic properties of CBD in HE and observed improved characteristics such as faster oral absorption, enhanced brain distribution, and slower elimination.

We further assessed the anti-seizure effects of the other five main non-addictive components in HE.

Among these components, cannabichromene (CBC) and cannabinol (CBN) showed significant anti-seizure effects. To gain insights into the mechanisms of CBC and CBN, we investigated their allosteric modulation on the GABA_A receptor.

Our results revealed that CBC enhanced GABA-induced currents in both Xenopus laevis oocytes and mouse primary cortical neurons. Additionally, we identified V436 in the β2 subunit of the GABA_A receptor as a critical binding site for CBC.

These findings provide compelling evidence for the anti-seizure activities of HE and shed light on its underlying mechanisms.

Our study provides insights into the broader therapeutic potential of hemp extracts and suggests their possible development as anti-seizure treatments.”

https://pubmed.ncbi.nlm.nih.gov/39734535/

https://www.sciencedirect.com/science/article/pii/S2667325824001572?via%3Dihub

Safety and effectiveness of cannabinoids to Danish patients with treatment refractory chronic pain-A retrospective observational real-world study

Posted on December 29, 2024 by David

“Background: Cannabinoids are considered a therapeutic option to patients suffering from treatment refractory chronic pain (TRCP) insufficiently relieved by conventional analgesics or experiencing intolerable adverse events (AEs) from those. This study aimed to explore safety and effectiveness of oral cannabinoids among patients with TRCP.

Methods: A retrospective study was conducted among Danish patients with TRCP being prescribed oral cannabinoids. Data on AEs and changes in pain intensity by numeric rating scale (NRS) before and after initiation of oral cannabinoid therapy were analysed.

Results: Among 826 eligible patients ≥18 years old, 529 (64%) were included for data analysis at first follow-up (F/U1) (median 56 days from baseline) and 214 (26%) for second follow-up (F/U2) (median 126 days from F/U1). Mean age was 60 ± 15.9 years and 70% were females. AEs were in general reported mild to moderate by 42% of patients at F/U1 and 34% at F/U2. AEs were mainly related to gastrointestinal (F/U1: 17% and F/U2: 13%) and nervous system disorders (F/U1: 14% and F/U2: 11%). Reduction in NRS was significantly different at both follow-up consultations compared with baseline (<0.0001). Clinically relevant pain reduction (NRS ≥30%) was reported by 17% at F/U1 and 10% of patients at F/U2 in intention-to-treat analysis whereas the figures were 32% and 45% respectively, in per-protocol analysis.

Conclusion: Oral cannabinoid therapy seems to be safe and mildly effective in patients with TRCP. Randomized controlled trials with focus on comparable pain characteristics in diagnostical homogenous patient subgroups are needed for further improvement of evidence level for relief of chronic pain using oral cannabinoids.

Significance: The findings in this retrospective study conducted in a real-world clinical setting suggest a favourable safety profile of cannabinoids. Moreover, one-sixth (intention-to-treat) and one-third (per-protocol) of patients with chronic pain refractory to conventional analgesics, or experiencing intolerable adverse effects, benefited significantly from therapy with oral cannabinoid regimens. Combination of THC and CBD seems overall more effective than cannabinoid monotherapy. Conduction of randomized controlled trials investigating safety and efficacy of cannabinoid therapy to diagnosis specific patient subgroups with comparable clinical and pathophysiological chronic pain characteristics is warranted, hence contributing further to the process of clinical evidence clarification currently in progress.”

https://pubmed.ncbi.nlm.nih.gov/36394124/

“In conclusion, oral cannabinoid therapy in general appears to be safe and effective for relief of chronic pain in some patients, including a subset of patients with cancer-related pain (9%), not responding adequately to conventional treatment regimens or experiencing intolerable AEs. Moreover, beneficial effects on sleep and QoL were reported by the patients receiving oral cannabinoid therapy, although the assessment was not performed in a validated manner. Hence, our study confirms previously reported findings related to patients with chronic pain receiving oral cannabinoid therapy and in that way the study contributes further to the evidence pyramid at the level of observational studies. “

https://onlinelibrary.wiley.com/doi/10.1002/ejp.2054

Chronic cannabidiol administration modulates depressive and cognitive alterations induced by social isolation in male mice

Posted on December 29, 2024 by David

“Cannabidiol (CBD), a non-psychotropic compound derived from Cannabis sativa, is known for its potential therapeutic effects on central nervous system (CNS) disorders.

This study investigates the effects of chronic CBD administration on depressive and cognitive alterations induced by social isolation in male C57BL/6 mice. The experimental design involved adult mice subjected to either group housing or 12 weeks of social isolation. Behavioral assessments, including the sucrose preference test, open field test, light/dark box, novel object recognition, and tail suspension test, were performed to evaluate the impact of CBD on emotional and cognitive alterations. Additionally, hippocampal gene expression for cannabinoid type 1 receptors (CB1R), serotonin type 1A receptors (5HT1AR), and brain-derived neurotrophic factor (BDNF) were analyzed.

Results indicate that CBD mitigated anhedonia in isolated mice and reduced immobility episodes in the TST. However, CBD did not exert significant anxiolytic effects and unexpectedly induced anxiety-like behavior in group-housed mice. The study also revealed that social isolation impaired recognition memory and reduced BDNF expression, while CBD treatment protected memory in isolated mice.

These findings suggest that CBD has potential antidepressant and neuroprotective effects in social isolation-induced depressive models, although its anxiogenic effects in non-stressed mice warrant further investigation.”

https://pubmed.ncbi.nlm.nih.gov/39725273/

“Cannabidiol (CBD) is a non-psychotropic, lipophilic phytocannabinoid of Cannabis sativa plants. CBD has been reported as a potential therapeutic agent for central nervous system (CNS) disorders due to its high permeability across the blood-brain barrier and its pleiotropic neuropharmacological effects “

“The results of this study demonstrate that chronic CBD administration attenuates depressive-like behaviors and protects cognitive function in SI male mice. Specifically, CBD mitigated anhedonia, a hallmark of depression, and reduced immobility in the TST, indicating an antidepressant-like effect.”

https://www.sciencedirect.com/science/article/abs/pii/S0166432824005643?via%3Dihub

Cannabinoids as cytotoxic agents and potential modulators of the human parasite Trichomonas vaginalis

Posted on December 27, 2024 by David

“Trichomoniasis, a globally prevalent sexually transmitted infection caused by Trichomonas vaginalis, affects approximately 278 million people each year. It presents a challenge due to resistance to the current treatment, Metronidazole (MTZ), which is also associated with side effects.

Cannabis sativa, with more than 100 phytocannabinoids and numerous studies for therapeutic applications, including parasitic infections, has undergone a significant shift in acceptance worldwide, highlighted by legalizations and substantial revenue projections.

In this context, the present study delves into the effects of cannabinoids, specifically WIN 55,212-2 (WIN), Cannabivarin (CBV) showcasing their anti-parasitic actions that influence the growth and morphology of T. vaginalis. The analysis extends to encompass the pharmacokinetic properties of these cannabinoids.

Among the analyzed cannabinoids, CBV stands out for adhering to Lipinski’s rules, indicating its potential suitability for oral drug delivery. They also demonstrated inhibitory effects on the growth of T. vaginalis trophozoites and a reduction in the parasite’s adhesion to host cells. Several morphological alterations were observed, such as membrane projections, blebbing, autophagosomes and damaged hydrogenosomes.

These results highlight the need for further research to explore the therapeutic potential of cannabinoids and understand their mechanisms of action in T. vaginalis.”

https://pubmed.ncbi.nlm.nih.gov/39724679/

“The treatment of trichomoniasis faces significant challenges, primarily due to the limited options and drug resistance issues associated with nitroimidazole derivatives like Metronidazole. However, exploring alternative therapeutic approaches is crucial. One promising avenue is the use of C. sativa and its compounds which have demonstrated anti-parasitic properties. In conclusion, cannabinoids inhibit T. vaginalis proliferation and alter its morphology, warranting further research into their therapeutic potential and mechanisms of action. Such exploration could revolutionize the current understanding and treatment of parasitic infections, offering new hope for combating these persistent pathogens.”

https://www.sciencedirect.com/science/article/pii/S0753332224016809?via%3Dihub

Cannabis sativa alleviates experimentally acetic acid- induced ulcerative colitis in rats: targeting CB1/SIRT/MAPK signaling pathways

Posted on December 26, 2024 by David

“Background: Ulcerative colitis (UC) is a frequent inflammatory bowel disease (IBD) that causes long-lasting inflammation in the innermost lining of the rectum and colon.

Objective: The aim of this study was to evaluate the therapeutic effect of Cannabis sativa (C. sativa) on the amelioration of acetic acid-induced colitis in rats.

Materials and methods: Group 1: normal control group was intrarectally administered saline solution (0.9%); group 2: acetic acid (AA) group was given AA intra-rectally (2 mL of 4% (v/v) in 0.9% NaCl) once.; group 3&4: This group represented the ulcerative colitis-induced rats that were injected with acetic acid intra-rectally, then s.c. injection with C. sativa (20 and 40 mg/kg daily for 8 days).

Results: Colonic architectural abnormality significantly improved after pretreatment with C. sativa. Additionally, it significantly reduced the MDA level and prevented the depletion of GSH content. Moreover, C. sativa administration showed suppressive activities on pro-inflammatory cytokines, including NF-κB, MAPK, ERK, PI3K, AKT, HIF-1α, and TLR4. Moreover, it significantly upregulated the level of SIRT and CB1 in the colon tissue.

Conclusion: This study provided a novel impact for CB1 receptor activation produced by C. sativa against AA-induced UC in rats through inhibiting the TLR-4 MAPK/ERK, PI3K, and NFκB signaling pathways.”

https://pubmed.ncbi.nlm.nih.gov/39721800/

https://www.tandfonline.com/doi/full/10.1080/08923973.2024.2445733