Monthly Archives: July 2025

Uncovering the molecular targets of phytocannabinoids: mechanistic insights from inverse molecular docking fingerprint approaches

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“Introduction: Among diverse chemical profile of Cannabis sativa L., over 100 phytocannabinoids have been identified. The major cannabinoids ΔΔ -9-THC and CBD are well-studied, with approved palliative and therapeutic applications such as appetite stimulation, antiemetic therapy, pain management and epilepsy treatment. However, ΔΔ -9-THC’s psychotropic effects limit its broader use. Minor cannabinoids exhibit therapeutic promise for a variety of conditions, potentially offering therapeutic potential without the adverse effects of ΔΔ -9-THC.

Methods: We explored 14 cannabinoids with an inverse molecular docking approach, docking each cannabinoid into >50000>50000 human protein structures from the ProBiS-Dock database. We validated our inverse molecular docking protocol using retrospective metrics (ROC AUC, BEDROC, RIE, enrichment factors, total gain). We apply the novel inverse molecular docking fingerprint method to better analyze the binding patterns of different cannabinoids and extend the methodology to include hierarchical clustering of fingerprints.

Results: Our analysis of the inverse molecular docking results identified high scoring targets with potential as novel protein targets for minor cannabinoids, the majority associated with cancer, while others have connections with neurological disorders and inflammation. We highlighted GTPase KRas and hematopoietic cell kinase (HCK) as very promising potential targets due to favorable docking scores with almost all investigated cannabinoids. We also find multiple matrix metalloproteinases among the top targets, suggesting possible novel therapeutic opportunities in rheumatic diseases. An analysis of inverse molecular docking fingerprints shows similar binding patterns for cannabinoids with similar structures, minor structural differences still suffice to change the affinity to specific targets. Hierarchical clustering of inverse molecular docking fingerprints revealed two main clusters in protein binding pattern similarity, the first encompassing THC-class and similar cannabinoids, as well as CBL-class cannabinoids, while the second contained CBD, CBC, and CBG-class cannabinoids. Notably, CBL-class cannabinoids exhibited binding patterns more similar to THC-class cannabinoids than their CBC-class precursors, possibly offering potential therapeutic benefits akin to THC with fewer psychotropic effects.

Discussion: This study highlights the therapeutic potential of minor cannabinoids and identifies their potential novel protein targets. Moreover, we demonstrate the utility of inverse molecular docking fingerprinting with clustering to identify compounds with similar binding patterns as well as identify pharmacophore-related compounds in a structurally agnostic manner, paving the way for future drug discovery and development.”

https://pubmed.ncbi.nlm.nih.gov/40657640/

“We firmly believe that this study provides a springboard paving the way for experimental validations in vitro and in vivo, hopefully leading to novel therapies with cannabinoids.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1611461/full

In Silico Assessment of Cannabidiol From Cannabis sativa as an Antiviral Agent Against Key Shrimp Pathogens in Aquaculture

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“Shrimp aquaculture plays a crucial role in global food production but is increasingly threatened by viral and microsporidian pathogens such as White Spot Syndrome Virus (WSSV), Enterocytozoon hepatopenaei (EHP) and Infectious Hypodermal and Haematopoietic Necrosis Virus (IHHNV). Conventional reliance on antibiotics to combat these infections has raised serious concerns regarding antimicrobial resistance, environmental contamination and food safety. Additionally, environmental stressors such as salinity shifts and poor water quality exacerbate disease outbreaks, leading to severe production losses across Asia and Latin America.

To explore eco-friendly therapeutic alternatives, this study assessed the antiviral potential of cannabidiol (CBD), a bioactive compound extracted from Cannabis sativa seed oil, identified through GC-MS analysis.

Using molecular docking techniques, we evaluated CBD’s interactions with key viral proteins: VP28 of WSSV, the tubulin β-chain of EHP and the capsid protein of IHHNV. The docking results revealed strong binding affinities of -6.61 kcal/mol (EHP), -6.72 kcal/mol (IHHNV) and -5.38 kcal/mol (WSSV), indicating stable and potentially inhibitory interactions. Structural models were retrieved from RCSB PDB and SwissModel, while ligand preparation and docking were performed using AutoDock 4.2.

CBD also demonstrated favourable pharmacokinetic and safety profiles, with predictions indicating no mutagenicity, hepatotoxicity or cardiotoxicity, and acceptable drug-likeness characteristics.

Compared to other plant-derived compounds previously tested in shrimp disease models, CBD exhibited superior binding stability, more interaction residues and better bioavailability scores.

These findings highlight CBD as a promising dual-function agent, capable of both modulating shrimp immunity and directly inhibiting key viral pathogens.

These findings highlight cannabidiol (CBD) as a promising dual-action compound, with the potential to both enhance shrimp immune responses and exert direct antiviral effects against key pathogens. This study lays a robust groundwork for future in vivo validations, formulation strategies and regulatory frameworks, ultimately supporting the development of sustainable, precision-based aquaculture health management.”

https://pubmed.ncbi.nlm.nih.gov/40657679/

https://onlinelibrary.wiley.com/doi/10.1111/jfd.70015

Retrospective Multicenter Chart Review Study of Adjunctive Cannabidiol for Seizures Associated with Lennox-Gastaut Syndrome, Dravet Syndrome and Tuberous Sclerosis Complex

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“Introduction: Effectiveness and tolerability of plant-derived highly purified cannabidiol (CBD) in patients with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC)-associated epilepsy in clinical practice in Germany were evaluated.

Methods: This multicenter, retrospective, chart review study analyzed patients with LGS, DS, or TSC-associated epilepsy receiving ≥ 1 dose of adjunctive CBD (Epidyolex® 100 mg/mL oral solution). Treatment characteristics, seizure outcomes, physician-rated Clinical Global Impression of Change (CGI-C), treatment retention rates, and adverse events (AEs) were analyzed ≤ 12 months.

Results: Among 202 patients identified (159 LGS; 34 DS; 9 TSC), median (interquartile range; range) age was 18.0 (7.9-32.0; 0.3-72.0) years, and median (range) number of prior and concomitant antiseizure medications was 6 (1-24) and 3 (1-7), respectively. Median target CBD dose was 11.1 mg/kg/day (17.6, 15.2, and 9.9 mg/kg/day in the < 6, 6-17, and ≥ 18 years subgroups, respectively). Responder rates (≥ 50% seizure reduction) for total seizures at 3 (n = 194) and 12 (n = 168) months were 43.3% (37.0-50.0% across ages) and 44.0% (37.0-52.5% across ages), respectively, and for generalized tonic-clonic seizures 54.3% (n = 94) (50.0-66.7% across ages) and 47.7% (n = 88) (37.8-66.7% across ages), respectively. Median (range) number of seizure days per month significantly decreased from 30 (0.3-30) to 18 (0-30) in the 3 months before the last 3 months of CBD treatment (p < 0.001). Any improvement in CGI-C was observed in 62% of patients. Of those with available data at 3 and 12 months, 89.6% and 67.1% remained on CBD, respectively. Retention was similar across age groups. AEs reported in ≥ 5% of patients were sedation and diarrhea.

Conclusions: In patients with LGS, DS, or TSC-associated epilepsy, adjunctive CBD was associated with a reduction in seizure frequency across age groups. CBD demonstrated tolerability consistent with its known profile, and 67% of patients remained on treatment at 12 months.”

https://pubmed.ncbi.nlm.nih.gov/40650804/

https://link.springer.com/article/10.1007/s40120-025-00788-w

Public Attitudes Toward the Drug Enforcement Administration’s Proposal to Reschedule Marijuana: A Cross-Sectional Mixed-Methods Analysis

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“Introduction: On May 21, 2024, the Drug Enforcement Administration (DEA) published a proposed rule to reschedule marijuana from schedule I to III under the Controlled Substance Act (CSA), followed by a 60-day open comment period. The purpose of this study was to analyze the public attitudes regarding the proposed rule and identify trends based on time of comment submission and recurring arguments throughout the comments.

Methods: This was an observational, cross-sectional, mixed-methods study. Comments from the proposal were stratified according to the submission date as early (May 21 to June 11), mid- (June 12 to July 2), and late (July 3-22) respondents. Investigators were assigned an equal number of comments to code as in favor of, against, or no clear position on rescheduling. Comments were further coded based on type of comment (form letters, personal anecdotes), rationale for comment (racism, decriminalization, safety, and economic factors), and whether descheduling was favored. Chi-square tests were used to analyze categorical data. A random sample of comments was selected to assure a 5% margin of error.

Results: More than 42,000 comments were submitted. Of these, 380 comments were selected and coded, with 42% (n = 158) in support of rescheduling, 55% (n = 211) against rescheduling, and 2.9% (n = 11) with no clear position. Of all comments coded, 71% wanted to go further and were in support of descheduling. The early responses consisted of a majority in favor of rescheduling, while the mid- and late responses consisted of more comments against rescheduling (X 2 [2, N = 369] = 35.8, p < 0.00001). Of the comments against rescheduling, a large majority supported descheduling (X 2 [2, N = 265] = 32.0, p < 0.0001). As for comment structure, 69% (n = 263) of all comments coded were form letters, while 8.4% (n = 32) were personal anecdotes.

Conclusion: The number of comments in support of rescheduling decreased with time, only dominating the early respondent wave. Despite a larger number of negative attitudes toward the DEA’s proposed rule of rescheduling marijuana from schedule I to III, a majority of comments supported taking a step further to deschedule marijuana all together.”

https://pubmed.ncbi.nlm.nih.gov/40655530/

“The study’s findings suggest that future cannabis policy discussions may need to address not just rescheduling, but potentially more far-reaching reforms to align with evolving public sentiment. As the conversation around marijuana regulation continues, policymakers will need to carefully balance public health and safety concerns with growing calls for increased access and reduced criminalization.”

https://karger.com/mca/article/8/1/117/928534/Public-Attitudes-Toward-the-Drug-Enforcement

Exploring the Potential of Phytocannabinoids Against Multidrug-Resistant Bacteria

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“The rapid emergence of multidrug-resistant (MDR) bacterial pathogens poses a critical threat to global health, creating an urgent need for novel antimicrobial agents.

In this study, we evaluated a small library of natural and semisynthetic phytocannabinoids against a broad panel of MDR Gram-positive bacterial strains, evidencing very good activity in the low µM range.

We provide evidence of the antibacterial activity of the two separated enantiomers of cannabidiol, offering novel insights into the stereochemical aspects of their bioactivity.

To investigate the possible molecular targets and clarify the mechanism of action, we employed Inverse Virtual Screening (IVS), a computational approach optimized for predicting potential protein-ligand interactions, on three selected MDR bacterial species. Interestingly, key targets belonging to important bacterial metabolic pathways and defense mechanisms were retrieved, and the results were used to rationalize the observed biological activities.

To the best of our knowledge, this study marks the first application of IVS to microorganisms, offering a novel strategy for identifying bacterial protein targets. The results pave the way for future experimental validation, structure-based drug design, and the development of novel antibacterial agents.”

https://pubmed.ncbi.nlm.nih.gov/40647911/

“These findings suggest that these phytocannabinoids likely exert their antibacterial effects via multi-target inhibition, interfering with multiple essential bacterial pathways.”

https://www.mdpi.com/2223-7747/14/13/1901

Dysregulation of the Cannabinoid System in Childhood Epilepsy: From Mechanisms to Therapy

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“Epilepsy affects over 12 million children worldwide, with approximately 30% classified as having drug-resistant epilepsy (DRE), often accompanied by neuropsychiatric comorbidities that severely impact quality of life.

The endocannabinoid system (ECS) functions as a multifaceted neuromodulatory network regulating neuronal excitability, synaptic plasticity, and immune homeostasis from early life through adolescence and into aging. In pediatric epilepsies, alterations in ECS components, particularly CB1 receptor expression and endocannabinoid levels, reveal disorder-specific vulnerabilities and therapeutic opportunities.

Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown strong preclinical and clinical efficacy in treating DRE and is approved for Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. Other ECS-based strategies, such as the use of CB1 receptor-positive allosteric modulators, can selectively enhance endogenous cannabinoid signaling where and when it is active, potentially reducing seizures in conditions like Dravet and absence epilepsy. Similarly, FAAH and MAGL inhibitors may help restore ECS tone without directly activating CB1 receptors.

Precision targeting of ECS components based on regional expression and syndrome-specific pathophysiology may optimize seizure control and associated comorbidities. Nonetheless, long-term pediatric use must be approached with caution, given the critical role of the ECS in brain development.”

https://pubmed.ncbi.nlm.nih.gov/40650012/

“In conclusion, alterations in the ECS are likely involved in the pathophysiology of childhood epilepsy. Precision targeting of ECS components, considering regional CB1R density, fluctuating eCB levels, and syndrome-specific ECS pathophysiology, may offer a more rational and safer strategy for pediatric epilepsy cases with multifactorial etiologies. “

https://www.mdpi.com/1422-0067/26/13/6234

Multi-Target Protective Effects of β-Caryophyllene (BCP) at the Intersection of Neuroinflammation and Neurodegeneration

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“Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist β-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of β-amyloid induced neurotoxicity.

Our data showed that BCP significantly protected human microglial HMC3 cells from Aβ25-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action.

Notably, the use of CB2R- or PPARγ-selective antagonists revealed that the observed NF-κB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPARγ) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1α, and BDNF, indicating the involvement of neurotrophic pathways.

Clear neuroprotective properties for BCP have been highlighted in Aβ1-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment.

Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of Aβ-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application.”

https://pubmed.ncbi.nlm.nih.gov/40649806/

“In conclusion, the results of our study suggest a pleiotropic mechanism of action for the development of BCP neuroprotective effects in relation to amyloid-induced neuroinflammation and synaptic impairment, encouraging further investigations into an in vivo model of amyloid-dependent cognitive damage to clarify the exact mechanism of action of BCP and confirm whether this natural molecule may represent a novel option for the treatment of NDDs.

Furthermore, the potent anti-inflammatory effects exerted by BCP through the interaction of CB2 and PPARγ receptors support the therapeutic potential of BCP in a broad range of conditions, including neurodegenerative and metabolic diseases, neuropathic pain, and cancer. Taking into consideration the safety of BCP in humans, dietary use, and its efficacy in various experimental models of disease, BCP may be further explored as co-supplementary drug in experimental studies.”

https://www.mdpi.com/1422-0067/26/13/6027

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.” https://www.ncbi.nlm.nih.gov/pubmed/18574142

Unveiling the Antioxidant Role of Hemp Oils in Cancer Prevention and Treatment

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“The global incidence of cancer continues to rise at an alarming rate, with annual cases projected to increase by 47% from 19.3 million in 2020 to 28.4 million by 2025.

Cannabis sativa L. was among the earliest plants investigated for potential anticancer therapies, due to its more than 100 bioactive constituents that confer notable antioxidant properties.

Hemp-derived extracts, particularly those rich in cannabidiol (CBD), exhibit notable synergistic biological effects, including the inhibition of cancer cell proliferation, angiogenesis, and metastasis, alongside the promotion of apoptosis.

These pharmacological attributes suggest that hemp oils may serve as promising alternatives or adjuncts to conventional chemotherapy, offering potential therapeutic benefits with a reduced risk of severe adverse effects.

This review discusses the current literature on hemp oils, with emphasis on their roles in cancer prevention, therapeutic efficacy, and potential toxicity in humans. Furthermore, it explores the various extraction methods employed in hemp oil production and examines their chemical compositions, offering a comprehensive understanding of the principal antioxidant constituents responsible for their bioactivity to the readers.”

https://pubmed.ncbi.nlm.nih.gov/40647426/

“Cancer is strongly associated with oxidative stress induced by free radicals, which damage cellular components, leading to genetic mutations, the disruption of normal cellular functions, and the promotion of carcinogenesis.

Hemp oils, which are rich in natural antioxidants such as cannabinoids, flavonoids, and terpenes, have been proposed as potential mediators to lessen oxidative stress and inhibit cancer progression by neutralizing free radicals and modulating biological pathways involved in cancer development.

This review presents a comprehensive analysis of the antioxidant and anticancer properties of hemp oils, with a particular focus on their potential role in cancer prevention and treatment in humans. It also addresses extraction techniques, chemical composition, therapeutic applications, and the potential toxicological risks associated with their use.”

“Hemp oils contain a complex matrix of bioactive compounds including cannabinoids, terpenes, flavonoids, and fatty acids that act synergistically to exert antioxidant and anticancer effects. Mechanistic studies demonstrate their ability to reduce oxidative stress, induce apoptosis, inhibit angiogenesis, and target cancer stem-like cells.’

https://www.mdpi.com/2072-6694/17/13/2128

Short-Term Incubation of H9c2 Cardiomyocytes with Cannabigerol Attenuates Diacylglycerol Accumulation in Lipid Overload Conditions

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“Fatty acids (FAs) play a crucial role in human physiology, including energy production and serving as signaling molecules. However, a dysregulation in their balance can lead to multiple disorders, such as obesity and metabolic syndrome. These pathological conditions alter the balance between the heart’s energetic substrates, promoting an increased reliance on FAs and decreased cardiac efficiency.

A therapeutic application of a non-psychotropic phytocannabinoid, cannabigerol (CBG), seems to be a promising target since it interacts with different receptors and ion channels, including cannabinoid receptors-CB1 and CB2, α2 adrenoceptor, or 5-hydroxytryptamine receptor.

Therefore, in the current study, we evaluated a concentration-dependent effect of CBG (2.5 µM, 5 µM, and 10 µM) on H9c2 cardiomyocytes in lipid overload conditions. Gas-liquid chromatography and Western blotting techniques were used to determine the cellular lipid content and the level of selected proteins involved in FA metabolism, glucose transport, and the insulin signaling pathway. The glucose uptake assay was performed using a colorimetric method.

Eighteen-hour CBG treatment in the highest concentration (10 µM) significantly diminished the accumulation of diacylglycerols (DAGs) and the saturation status of this lipid fraction. Moreover, the same concentration of CBG markedly decreased the level of FA transporters, namely fatty acid translocase (CD36) and plasma membrane fatty acid-binding protein (FABPpm), in the presence of palmitate (PA) in the culture medium.

The results of our experiment suggest that CBG can significantly modulate lipid storage and composition in cardiomyocytes, thereby protecting against lipid-induced cellular dysfunction.”

https://pubmed.ncbi.nlm.nih.gov/40643519/

“In our research, we presented evidence suggesting that CBG treatment, especially in higher concentrations (10 µM), may offer substantial benefits in the states associated with excessive lipid availability, which was demonstrated in the H9c2 cell model. The results obtained in our experiment suggest that CBG possesses the ability to alter the metabolism of H9c2 cells by influencing FA storage and utilization while also attenuating the inflammatory pathways activated in a high-lipid environment. These findings indicate that CBG may represent a promising therapeutic candidate for further investigation concerning lipotoxicity and insulin resistance development. Moreover, CBG is predisposed to be a metabolic modulator by altering the levels and cellular location of CD36, a major regulator of myocardial lipid metabolism and a therapeutic target for metabolic disturbances.”

https://www.mdpi.com/2073-4409/14/13/998

The DEC2-SCN2A Axis is Essential for the Anticonvulsant Effects of Cannabidiol by Modulating Neuronal Plasticity

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“Impairment of neuronal plasticity is involved in a spectrum of neurological disorders such as epilepsy, yet its regulatory mechanisms remain incompletely understood.

Here, it is reported that the basic helix-loop-helix transcription factor DEC2 serves as a pivotal regulator of both neuronal plasticity and epileptogenesis through its repression of sodium voltage-gated channel alpha subunit 2 (SCN2A). Knockdown of DEC2 in hippocampal neurons elevates intrinsic excitability and synaptic transmission, exacerbating seizure susceptibility and severity. Conversely, overexpression of DEC2 in hippocampus reduces intrinsic excitability and synaptic transmission, ultimately decreasing seizure susceptibility. Mechanistically, DEC2 functions as a transcriptional repressor of Scn2a by directly binding class B E-boxes (CACGTG) in its promoter. Additionally, DEC2 forms complexes with myoblast determination protein 1 (MYOD1) and occupies the CAGCTG E-boxes within the Scn2a promoter; however, this interaction does not affect Scn2a transcription in vivo.

These findings also reveal that cannabidiol (CBD) can modulate the DEC2-SCN2A axis. Notably, CBD predominantly enhances DEC2’s direct transcriptional repression of SCN2A.

In summary, this study identifies DEC2 as a critical regulator of neuronal plasticity in epilepsy progression, suggesting a novel therapeutic pathway for epilepsy treatment.”

https://pubmed.ncbi.nlm.nih.gov/40641288/

https://advanced.onlinelibrary.wiley.com/action/oidcStart?redirectUri=%2Fdoi%2F10.1002%2Fadvs.202416315