Monthly Archives: May 2025

Exploring the Phytochemical and Toxicological Profile of Moroccan Cannabis Sativa L. Leaves Extract: Behavioral, Histological, and Oxidative Stress Assessments

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“Ethnopharmacological relevance: Cannabis sativa has been traditionally used in Moroccan medicine for centuries, either for its psychoactive or therapeutic effects. However, the safety profile of extracts from macerated leaves remains poorly documented in the scientific literature.

Aim of the study: This study, for the first time, evaluates the phytochemical composition and the toxicological profile of an ethanolic extract of Cannabis sativa (CEE) leaves in mice, focusing on behavioral effects, oxidative stress markers, and histopathological examination.

Materials and methods: The CEE was evaluated using HPLC analysis, secondary metabolites quantification, and in vitro antioxidant assays. Acute oral toxicity was assessed in female mice at doses from 500 to 3000 mg/kg, while oral subacute toxicity was evaluated over 7 days in male mice receiving 10, 30, or 50 mg/kg of CEE. Behavioral assessments included the open field, rotarod, and elevated plus maze tests. Additionally, body weight gain, organ coefficients, organ edema, oxidative stress markers, and histopathology of the brain, liver, kidneys, spleen, and testes were examined.

Results: CEE exhibited substantial amounts of polyphenols, flavonoids, tannins, and saponins, with notable antioxidant activity (DPPH IC50: 289.01 ± 0.003 μg/mL; FRAP IC50: 57.29 ± 6.7 μg/mL). No mortality was observed in the acute toxicity study. The 7-day treatment caused no sedation or motor impairment, rather, it showed anxiolytic effects. A significant increase in body weight gain was noted, particularly at 10 mg/kg, while no changes in organ coefficients or signs of organ edema were detected. However, MDA and catalase activity increased in the liver and brain at 50 mg/kg. Histopathological examination revealed signs of cellular stress without severe tissue damage.

Conclusions: CEE appears to be safe at moderate doses, with an LD50 above 3000 mg/kg. Further studies are needed to assess long-term effects.”

https://pubmed.ncbi.nlm.nih.gov/40436124/

https://www.sciencedirect.com/science/article/abs/pii/S0378874125007457?via%3Dihub

Cannabidiolic Acid Rescues Deficits in Hippocampal Long-Term Potentiation in Models of Alzheimer’s Disease: An Electrophysiological and Proteomic Analysis

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“In this study, we have examined the neuroprotective effects of cannabidiolic acid (CBDA) in models of Alzheimer’s disease (AD).

We used in vitro electrophysiological recording in hippocampal slices and performed proteomic analysis of cortical tissue from APPswe/PS1dE9 (APP/PS1) mice. In wild-type (WT) slices from C57BL6 mice, acute treatment with CBDA (10 μM) did not alter levels of hippocampal long-term potentiation (LTP); however, it did reverse the attenuation of LTP produced by acute beta amyloid peptide (Aβ42). We also examined the effects of CBDA or vehicle in APP/PS1 mice and WT littermates over a 5-week period at 8 months.

LTP levels recorded in slices from WT mice treated with CBDA at 1, 10, or 30 mg/kg (IP) or vehicle were similar. LTP was attenuated in slices from vehicle-treated APP/PS1 compared to vehicle-treated WT mice, while treatment of APP/PS1 mice with all doses of CBDA reversed the deficits in LTP. There was also a deficit in paired-pulse facilitation (PPF) in vehicle-treated APP/PS1 compared to WT, indicating altered synaptic function and transmitter release; this was reversed in slices from CBDA-treated APP/PS1 mice. Levels of cortical soluble Aβ42 were similar across CBDA- and vehicle-treated groups; however, the level of aggregated Aβ42 was decreased in the CBDA-treated group.

Proteomic analysis of cortical tissue from APP/PS1 cortex compared to WT revealed alterations in protein expression, with pathway enrichment analyses suggesting implicated canonical pathways, including mitochondrial dysfunction, protein sorting, and synaptogenesis; all were significantly improved by CBDA treatment. These changes likely facilitate the improvement in synaptic transmission and LTP we observed following CBDA treatment in APP/PS1 mice.

This research suggests that CBDA should be considered a novel therapy for AD.”

https://pubmed.ncbi.nlm.nih.gov/40430085/

https://www.mdpi.com/1422-0067/26/10/4944

Chemical Profiling of Polyphenolic Fraction of Cannabis sativa L. vr. Kompolti Industrial Inflorescences: Insights into Cannabidiol Neuroprotective Effects in a Cellular Model of Parkinson’s Disease

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“The ultra-high-performance liquid chromatography high-resolution mass spectrometry (LC-ESI-HR-MS/MS) technique was used to characterize the polyphenolic fraction of the hot water infusion (WI) of inflorescences of Cannabis sativa L. Kompolti variety, commercially used for food preparations or cosmetic purposes.

On water infusion extract, we applied a multidisciplinary approach, where NMR, MS, in vitro cell-free and cell-based assays coupled with in silico studies, were used to rationalize at the molecular level the effects of the major component Cannabidiol (CBD), in a model of Parkinson’s disease (PD). The phytochemical analysis by LC-MS/MS led to the tentative identification of many components belonging to different classes of polyphenols, such as phenolic acids, flavonoids, and their glycosides. CBD and cannabidiolic acid (CBDA) were also detected in good amounts in the infusion, together with several minor cannabinoids. In addition, the water infusion WI was evaluated for mineral content, total phenolic content, flavonoid content, and antioxidant capacity by DPPH and FRAP methods.

Notably, our results in a cellular model of PD highlight that CBD protects against rotenone-induced cell death without recovering neuronal morphology. These biological outcomes were rationalized by an in silico approach, where we hypothesize that CBD could influence the cellular response to oxidative stress via its interaction with the Keap1/Nrf2 pathway.

In summary, these results enriched the nutraceutical profile of the water infusion of the inflorescences of the Kompolti cultivar, which demonstrated a high CBD content.

This study could lead to the development of dietary supplements that could help in the management of clinical symptoms related to the antioxidant activity of CBD in the pathophysiology of PD, which remains poorly characterized.”

https://pubmed.ncbi.nlm.nih.gov/40431038/

“In summary, this multidisciplinary approach has provided further insight into the human health properties of C. sativa L. Kompolti infusions. When consumed as a beverage as part of a normal diet, the phytoconstituents could provide health benefits through their antioxidant activity in various diseases and would be promising for protection against environmental stresses that contribute to inflammatory processes, cancer, and other degenerative diseases.”

https://www.mdpi.com/2223-7747/14/10/1473

Beyond Cannabidiol: The Contribution of Cannabis sativa Phytocomplex to Skin Anti-Inflammatory Activity in Human Skin Keratinocytes

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“Background:Cannabis sativa L. (C. sativa) has a long history of medicinal use. Its inflorescences contain bioactive compounds like non-psychotropic cannabidiol (CBD), which is well known for its anti-inflammatory potential in skin conditions such as psoriasis, and psychotropic Δ-9-tetrahydrocannabinol (THC). Keratinocytes, the main cells in the epidermis, are crucial for regulating skin inflammation by producing mediators like IL-8 when stimulated by agents like TNFα. 

Methods: This study explores the anti-inflammatory effects of a standardized C. sativa extract (CSE) with 5% CBD and less than 0.2% THC in human keratinocytes challenged by TNFα. The aim of this study is to analyze the specific contributions of the main constituents of CSE to inflammatory responses in human keratinocytes by fractionating the extract and examining the effects of its individual components. 

Results: MTT assays showed that CSE was non-toxic to HaCaT cells up to 50 μg/mL. CSE inhibited NF-κB activity and reduced IL-8 secretion in a concentration-dependent manner, with mean IC50 values of 28.94 ± 10.40 μg/mL and 20.06 ± 2.78 μg/mL (mean ± SEM), respectively. Fractionation of CSE into four subfractions revealed that the more lipophilic fractions (A and B) were the most effective in inhibiting NF-κB, indicating that cannabinoids and cannflavins are key contributors. Pure CBD is one of the most active cannabinoids in reducing NF-κB-driven transcription (together with THC and cannabigerol), and due to its abundance in CSE, it is primarily responsible for the anti-inflammatory activity. 

Conclusions: This study highlights CBD’s significant role in reducing inflammation in human keratinocytes and underscores the need to consider the synergistic interactions of several molecules within C. sativa extracts for maximum efficacy. Standardized extracts are essential for reproducible results due to the variability in responses.”

https://pubmed.ncbi.nlm.nih.gov/40430467/

“In conclusion, the results of this study on CSE underscore the significant role of CBD in exerting anti-inflammatory effects in human keratinocytes.”

https://www.mdpi.com/1424-8247/18/5/647

Cannabidiol dose dependently reduces alcohol intake in mice via a non-5-HT1A receptor mechanism: Exploration of other potential receptor targets

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“Background and purpose: Binge drinking is a risky pattern of alcohol intake and a major predictor of alcohol use disorder (AUD). Current AUD medications have limited efficacy and poor patient compliance, calling for more effective therapeutics. Cannabidiol (CBD), a non-intoxicating component of cannabis, has emerged as a potential novel therapeutic. However, receptor mechanisms in CBD’s alcohol-related effects have not been investigated comprehensively.

Experimental approach: Using the murine drinking-in-the-dark model of binge drinking, our research aimed to confirm a reduction of alcohol consumption with CBD (7.5, 15, 30, 60, 120 mg kg-1) in male and female mice. Behavioural pharmacological approaches were used to explore CBD interactions with identified target mechanisms: serotonin-1A receptor (5-HT1AR) and peroxisome proliferator-activated receptor-gamma (PPARɣ), and the novel targets, chemokine receptor type-4 (CXCR4) and neuropeptide S receptor (NPSR).

Key results: Acute CBD dose dependently suppressed binge-like drinking and blood ethanol concentration. The effect was not driven by locomotor impairments and was maintained across sub-chronic treatment. Blockade of 5-HT1AR and PPARɣ had no impact on CBD’s reduction of alcohol consumption. Co-administration of subthreshold CBD doses and a NPSR antagonist implicated NPSR blockade as a potential mechanism contributing to CBD’s effect, whereas co-administration of CBD and a CXCR4 antagonist suggested CXCR4 was not involved. However, the potent and selective CXCR4 antagonist AMD3100 reduced ethanol consumption.

Conclusions and implications: CBD represents a promising candidate to reduce voluntary alcohol consumption. Mechanisms driving CBD’s alcohol-related effects remain unclear and may involve polypharmacology, including actions at the NPSR identified in the present study.”

https://pubmed.ncbi.nlm.nih.gov/40432283/

“These experiments consistently showed a dose-dependent suppression of alcohol consumption by CBD.”

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70070

Proteomic Analysis of Invasive Breast Cancer Cells Treated with CBD Reveals Proteins Associated with the Reversal of Their Epithelial-Mesenchymal Transition Induced by IL-1β

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“Cannabidiol (CBD) has shown promise in treating cancers with an inflammatory microenvironment.

Although it has been demonstrated that IL-1β induces epithelial-mesenchymal transition (EMT) of MCF-7 cells and CBD reverts this process, in restoring the epithelial non-invasive phenotype, there is limited understanding of how this cannabinoid regulates these processes.

In this work, MCF-7 cells were induced to adopt an aggressive phenotype (6D cells), which was reversed by CBD.

Then, protein expression was analyzed by mass spectrometry to compare 6D vs. MCF-7 cells and 6D+CBD vs. 6D cells proteomes. Novel proteins associated with EMT and CBD signaling were identified. Twenty-four of them were oppositely regulated by IL-1β and CBD, suggesting new points of crosstalk between the IL-1β and CBD signaling pathways.

From the data, two protein networks were constructed: one related to EMT with 58 up-regulated proteins and another with 21 related to CBD signaling. The first one showed the proteins BRCA1, MSN, and CORO1A as the key axis that contributes to the establishment of a mesenchymal phenotype. In the CBD signaling, the key axis was formed by SUPT16H, SETD2, and H2BC12, which suggests epigenetic regulation by CBD in the restoration of an epithelial phenotype of breast cancer cells, providing new targets for anticancer therapy.”

https://pubmed.ncbi.nlm.nih.gov/40429863/

“All these results provide new important insights that could help to understand how CBD counteracts the effects of IL-1β and the restoration of the epithelial phenotype as a possible control of cancer progression.”

https://www.mdpi.com/1422-0067/26/10/4721

The Anticonvulsant Effects of Different Cannabis Extracts in a Zebrafish Model of Epilepsy

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“Epilepsy is a widespread neurological disorder that remains a critical global public health challenge. While numerous antiepileptic drugs (AEDs) are available, many patients either fail to achieve adequate seizure control or experience significant side effects.

One promising alternative is pure cannabidiol (CBD), but using a whole cannabis extract may be equally effective and preferred for some patients.

In the current study, we employed the pentylenetetrazole (PTZ)-induced hyperactivity model in zebrafish to compare the effects of CBD with various cannabis extracts. We evaluated three cannabis strains, each subjected to three different extraction methods, and benchmarked the results against the commercially available AED valproic acid (VPA).

Our findings revealed that 5.7 µg/mL of CBD and 10 µg/mL of different extracts significantly reduced movement compared to PTZ and VPA. In addition, effective extracts produced effects similar to pure CBD despite containing much lower molecule levels.

These results reinforced and expanded previous evidence supporting the clinical potential of both CBD and whole cannabis extracts for seizure control while suggesting a possible entourage effect. Further research is necessary to determine which patients may benefit more from pure CBD versus those who might prefer whole cannabis extracts.”

https://pubmed.ncbi.nlm.nih.gov/40427547/

“In conclusion, our results validate and extend previous ones concerning the potential clinical effects of both CBD and whole cannabis extracts used for seizure control.”

https://www.mdpi.com/2218-273X/15/5/654

Medicinal cannabis in the management of anxiety disorders: A systematic review

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“Background: With rising anxiety disorder diagnoses, many individuals are seeking alternatives to standard pharmacotherapies, like medicinal cannabis. This systematic review focuses exclusively on anxiety-related disorders and examines a wide range of cannabis-based preparations and interventions.

Method: We searched MEDLINE, EMBASE, CINAHL, and PsycInfo (October-December 2023) for peer-reviewed empirical studies, excluding case series, case studies, and review papers. Inclusion criteria were studies on adults (18+ years) diagnosed with anxiety-related disorders, examining the efficacy or effectiveness of medicinal cannabis. Studies on recreational cannabis or cannabis-use-disorder were excluded. The MASTER and QualSyst tools were used to assess bias.

Results: Fifty-seven studies met the inclusion criteria: 40 % cohort (n = 23), 30 % randomised controlled trials (n = 17), 18 % cross-sectional (n = 10), 12 % qualitative or other designs (n = 7). The MASTER scale revealed a high risk of bias, with a mean score of 62.9 (out of 100) due to inadequate reporting. Among the 13 highest-quality studies, 70 % (n = 9) reported a positive improvement for disorders including generalised anxiety disorder (GAD), social anxiety disorder (SAD), and post-traumatic stress disorder (PTSD). 30 % (n = 4) reported a negative result for conditions like obsessive-compulsive disorder, trichotillomania, test anxiety and SAD. Over 90 % of all studies, including lower quality studies, reported positive outcomes for CBD and THC-based cannabis. However, 53 % (n = 30) either omitted, or included self-reported data on either form and/or dosage.

Conclusion: Medicinal cannabis demonstrates potential in reducing anxiety symptoms, but the long-term benefits and overall impact on quality of life remain unclear. Further high-quality, longitudinal research with standardised dosing is needed.”

https://pubmed.ncbi.nlm.nih.gov/40413923/

“Across a range of anxiety-related disorders, most high-quality studies found that medicinal cannabis reduced anxiety symptoms in individuals with GAD, PTSD and SAD.”

https://www.sciencedirect.com/science/article/pii/S0165178125002008?via%3Dihub

Role of Endocannabinoids in Glaucoma: A Review

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“Aims: A review of the published literature was done to understand the role of endocannabinoids in glaucoma.

Background: As evidence mounts that intraocular pressure (IOP) is not the only factor in the pathogenesis and progression of glaucoma, a look into other aspects is the need of the hour. From the first instance of a drop in IOP linked to marijuana in the 1970s to the present, research has been ongoing, mostly in animals and in vitro models, with a scarcity of human studies, to delve into the world of the endocannabinoid system (ECS).

Methods: PubMed, ScienceDirect, and Google Scholar were searched for studies relating to endocannabinoids and their role in glaucoma.

Results: The ECS comprises ligands, receptors, and the synthesizing and degrading enzymes and is ubiquitous throughout the human body, including the visual system, from the eye to the occipital lobe. Apart from the IOP-lowering effect of the system, another property being investigated and implicated as an attribute of its receptors is neuroprotection. This neuroprotection seems to be mediated by excitotoxicity reduction and changes in vascular tone by acting on cannabinoid receptors.

Conclusion: The possibilities are indeed immense, and further research into the complex relationship between ECS and glaucoma is imperative to enable us to develop therapies for this otherwise chronic, progressive neuropathy, where the only armament in our hands is early diagnosis and maintenance therapy.

Clinical significance: We still do not have drugs for the prevention of retinal ganglion cell loss and for neuroprotection in glaucoma. Drugs that target cannabinoid receptors can revolutionize glaucoma management owing to their IOP-lowering action and neuroprotective effects. Based on the findings, we argue that further studies on the ECS and its implications in glaucoma are warranted to develop newer, effective, and better-targeted treatment strategies.”

https://pubmed.ncbi.nlm.nih.gov/40417140/

“Currently, no drugs can target the loss of RGCs in glaucoma.
Therefore, drugs that can target CB1 receptors can change the
course of glaucoma treatment, as they can exert hypotensive
and neuroprotective effects in conjunction.”

https://www.jocgp.com/doi/pdf/10.5005/jp-journals-10078-1467

Cannabis- and HIV-related perturbations to the cortical gamma dynamics supporting inhibitory processing

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“The main psychoactive component in cannabis-Δ9-tetrahydrocannabinol-is known to have anti-inflammatory properties and to alter gamma oscillations, pointing to its potential as a therapeutic agent for people with HIV (PWH). However, it remains unknown how cannabis use among PWH interacts with the neural circuitry underlying inhibitory processing.

Herein, using a cross-sectional study design, we collected data from 108 cannabis users and non-users with and without HIV. Participants were interviewed regarding their substance use history and completed a paired-pulse somatosensory stimulation paradigm during magnetoencephalography (MEG). MEG data were imaged using a beamformer and peak voxel time series data were extracted to examine neural oscillations in response to the stimulation and the strength of spontaneous activity in the same tissue during the baseline period. Across all participants, we observed robust gamma oscillations following stimulation in the left primary somatosensory cortices, with responses to the second stimulation being strongly attenuated relative to the first, thus demonstrating somatosensory gating.

PWH who used cannabis exhibited stronger oscillatory gamma activity compared with non-users with HIV, while the latter group also exhibited elevated spontaneous gamma activity relative to all other groups. Finally, we found that a longer duration of time since HIV diagnosis was associated with less efficient inhibitory processing among PWH who did not use cannabis, but not among PWH who regularly use cannabis.

These findings provide new evidence that cannabis use may mitigate the harmful effects of HIV on oscillatory and spontaneous gamma activity serving inhibitory processing.”

https://pubmed.ncbi.nlm.nih.gov/40421314/

“Taken together, these findings suggest that regular cannabis use may have a neuroprotective effect on inhibitory processing in PWH by normalising spontaneous gamma activity and enhancing gamma oscillatory responses during sensory gating. This pattern indicates that cannabis use could potentially mitigate some of the neural disruptions associated with HIV, highlighting a promising target for future interventions aimed at preserving cognitive function in this population. Importantly, the capacity of cannabis to influence gamma dynamics underscores the broader role of the endocannabinoid system in shaping neural function in the context of HIV-related neuropathology.”

https://academic.oup.com/braincomms/article/7/3/fcaf190/8132827?login=false