Cannabidiol reverses depression-like behaviors by enhancing hippocampal synaptic plasticity in rats with chronic restraint stress

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“Background and aim: Major depressive disorder is a prevalent psychiatric condition associated with impaired neuroplasticity, particularly in the hippocampus. Although selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed, their delayed onset and adverse effects highlight the need for alternative therapies. Cannabidiol (CBD), a non-psychotomimetic cannabinoid, has shown antidepressant-like properties, but its mechanistic link to hippocampal synaptic plasticity remains unclear. This study aimed to evaluate the effects of CBD on depression-like behaviors and hippocampal neuroplasticity in rats subjected to chronic restraint stress (CRS).

Materials and methods: Sixty male Wistar rats were randomly divided into six groups: Non-stressed vehicle (NV), CRS vehicle (SV), escitalopram-treated CRS (SE, 10 mg/kg), and CBD-treated CRS at 10, 30, or 100 mg/kg (SC10, SC30, and SC100). Rats were subjected to CRS for 28 days and treated daily through intraperitoneal injection. Depression-like behaviors were assessed using the forced swim test (FST) and sucrose preference test (SPT). Locomotor activity was evaluated through the open-field test (OFT). Hippocampal dendritic spine density (Golgi-Cox staining) and long-term potentiation (LTP, electrophysiology) were measured on day 28.

Results: CRS induced behavioral despair (↑ immobility in FST) and anhedonia (↓ sucrose preference in SPT), accompanied by reduced hippocampal spine density. At all doses, CBD significantly reduced immobility, comparable to escitalopram. Notably, only CBD at 100 mg/kg and escitalopram reversed anhedonia. All CBD-treated groups showed an increase in dendritic spine density, with SC10 producing the greatest enhancement. Moreover, CBD at 100 mg/kg markedly improved hippocampal LTP at 1 h and 2 h post-stimulation, an effect not observed with escitalopram. Locomotor activity remained unaffected.

Conclusion: CBD demonstrated potent antidepressant-like effects in a CRS rat model, alleviating behavioral despair and anhedonia while enhancing hippocampal dendritic spine density and synaptic strength. These findings suggest CBD as a promising candidate for stress-related mood disorders, with mechanistic actions distinct from conventional SSRIs and potential utility in patients unresponsive to current therapies.”

https://pubmed.ncbi.nlm.nih.gov/41113223/

https://veterinaryworld.org/Vol.18/September-2025/22.php

Cannabis Laws and Opioid Use Among Commercially Insured Patients With Cancer Diagnoses

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“Importance: Pain is a prevalent cancer-related symptom, but limited research investigates whether cannabis is an effective analgesic for cancer pain.

Objective: To examine the association of medical and recreational cannabis dispensary availability on prescription opioid dispensing among commercially insured patients with cancer.

Design, setting, and participants: This cross-sectional study used synthetic control to investigate the association of cannabis dispensary openings with pain medication dispensing among patients with cancer. Data were extracted from Optum’s deidentified Clinformatics Data Mart database from January 1, 2007, to December 31, 2020. The study population included patients aged 18 to 64 years with a cancer diagnosis and at least 6 months of continuous enrollment. Associations were estimated by age, race and ethnicity, and sex. Data were analyzed between December 2024 and February 2025.

Exposures: Exposures included indicators for whether a medical or recreational cannabis dispensary was open in each state-quarter.

Main outcomes and measures: The outcome measures for opioids prescriptions were (1) the rate of patients with a prescription per 10 000 patients, (2) the quarterly mean days’ supply per prescription, and (3) the quarterly mean number of prescriptions per patient.

Results: The study included a mean (SD) of 3.05 (0.86) million patients annually across the US (mean [SD] age, 43.7 [9.6] years; mean [SD] 59.0% [0.32%] female). Medical cannabis dispensary openings were associated with significant reductions in all opioid outcomes. The rate of patients with cancer with opioid prescriptions changed by -41.07 per 10 000 (95% CI, -54.78 to -27.36 per 10 000; P < .001), the quarterly mean days’ supply by -2.54 days (95% CI, -3.16 to -1.92 days; P < .001), and the mean number of prescriptions per patient by -0.099 (95% CI, -0.121 to -0.077; P < .001). Recreational dispensary openings were also associated with reductions in opioid outcomes, though estimated treatment effects were smaller. The rate of prescriptions changed by -20.63 per 10 000 (95% CI, -35.35 to -5.91 per 10 000; P = .049), the mean daily supply by -1.09 days supplied per prescription (95% CI, -1.72 to -0.46 days; P = .04), and the mean number of prescriptions per patient by -0.097 (95% CI, -0.134 to -0.060; P = .01).

Conclusions and relevance: This study’s findings indicate cannabis may be a substitute for opioids in the management of cancer-related pain. However, further research directly observing cannabis use is needed to evaluate the efficacy of cannabis as a treatment for cancer-related pain.”

https://pubmed.ncbi.nlm.nih.gov/41105418/

“These findings indicate that medical or recreational cannabis laws may be significantly associated with reduced opioid use among patients diagnosed with cancer.”

https://jamanetwork.com/journals/jama-health-forum/fullarticle/2840030

Exploring multitarget molecular mechanisms of cannabidiol in Alzheimer’s disease treatment using molecular simulations and modeling

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“Alzheimer’s disease is a progressive neurodegenerative disorder marked by amyloid-β (Aβ) plaque deposition and neurofibrillary tangles composed of hyperphosphorylated tau. Dysregulation of glycogen synthase kinase-3β (GSK3β) promotes tau hyperphosphorylation and amplifies Aβ-induced neurotoxicity, driving pathogenesis. Despite extensive research, current therapies targeting these core mechanisms remain largely ineffective at halting disease progression.

Based on prior clinical and preclinical evidence, we hypothesize that cannabidiol (CBD), a non-psychoactive phytocannabinoid, may exert multitarget therapeutic effects in AD by modulating Aβ aggregation, tau hyperphosphorylation, and GSK3β activity.

We investigated CBD’s interactions with Aβ-42/40, tau, and GSK3β using molecular docking, molecular dynamics simulations and ADMET predictions.

Our results show that CBD binds to Aβ with binding free energies of -7.81 kcal/mol, -7.46 kcal/mol, and -7.25 kcal/mol, disrupting aggregation by interacting with key residues (HIS6, HIS13, HIS14, GLU14, GLU22, ASP15, and ASP23). MD simulations confirm that CBD destabilizes Aβ’s β-sheet structure, preventing fibril formation. CBD binds tau with binding free energies of -9.91 kcal/mol, -9.70 kcal/mol, and -9.66 kcal/mol, disrupting tau aggregation and preventing neurofibrillary tangle formation. MD simulations show that CBD induces structural changes in tau, reducing β-sheet packing and inhibiting tau-tau interactions. CBD also binds to GSK3β with binding energies of -8.94 kcal/mol, -8.51 kcal/mol, and -8.41 kcal/mol, competing with ATP to inhibit its kinase activity and reduce tau phosphorylation. ADMET analysis indicates CBD’s favorable oral bioavailability and low toxicity.

These findings support CBD as a promising multitarget therapeutic for AD, warranting further preclinical and clinical investigations.”

https://pubmed.ncbi.nlm.nih.gov/41105605/

https://journals.sagepub.com/doi/10.1177/13872877251386440

Advancing cervical cancer treatment: integrating cannabinoids, combination therapies and nanotechnology

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“Background: Cervical cancer remains a major global health challenge, with the highest incidence and mortality rates observed in sub-Saharan Africa. Despite progress in prevention and treatment, the management of advanced and recurrent disease remains difficult.

Aim: This review explores the potential role of cannabinoids in cervical cancer therapy, with a focus on their integration into existing treatment strategies, combination therapies, and nanotechnology-based delivery systems.

Methods: A critical synthesis of preclinical studies and emerging therapeutic approaches was conducted, examining the anticancer properties of cannabinoids, their mechanisms of action, and their application within combination and nanotechnology-based treatment modalities.

Results: Cannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD) demonstrate anticancer effects by inducing apoptosis, inhibiting cell proliferation, and suppressing metastasis. Mechanistic studies highlight their ability to promote oxidative stress, modulate key signalling pathways, and influence immune responses in cervical cancer cells. Combination therapies involving cannabinoids with chemotherapy, radiotherapy, and immunotherapy show enhanced efficacy and reduced drug resistance. Furthermore, nanotechnology-based delivery systems offer advantages including targeted drug release, improved solubility, controlled dosing, and decreased systemic toxicity.

Conclusion: Cannabinoids represent a promising adjunct in cervical cancer management. However, successful clinical translation requires optimisation of formulations, establishment of dosing protocols, and comprehensive safety evaluation. Future research should also explore biomarker-driven personalised medicine approaches. Standardisation, along with addressing regulatory and ethical challenges, will be crucial for the integration of cannabinoid-based therapies into mainstream cervical cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/41102423/

“The convergence of cannabinoids, nanotechnology, and combination therapies presents a promising frontier in cervical cancer treatment. This approach leverages the synergistic potential of cannabinoids with conventional treatments such as chemotherapy, radiotherapy, and immunotherapy, while using nanotechnology for targeted delivery. The integration of these elements could enhance treatment efficacy and minimize side effects.”

https://link.springer.com/article/10.1007/s00432-025-06323-6

Molecular targets of cannabinoids and their derivatives in epilepsy – a review with focus on CBD

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“In recent years, cannabinoids and their derivatives have been tested for efficacy in epilepsy therapy and related disorders. Many of them may help alleviate ailments associated with seizures. An in-depth study of cannabinoid derivatives and the receptors on which they operate give us a chance for more effective use of these substances in epilepsy therapy.

Many studies point to the beneficial synergy of cannabinoids with chemotherapeutics and the increase in effectiveness of the latter. As a result, both alternatives to drug treatment and support for the pharmacotherapy are being developed.

In this review, we focused on compounds such as Δ9-THC, CBDV, Δ9-THCA, Δ9-THCV, H2CBD and their receptors as well as on CBD’s actions, and the enzymes, ion channels, and transporters engaged in the fundamental causes of epileptic seizures.

Treating epilepsy and drug-resistant epilepsy are the two common medical uses of cannabinoids. We looked at approximately 150 current scientific articles from peer-reviewed journals to explore the molecular effects of cannabinoids in these applications. Our goal was to improve physician awareness of factors influencing treatment decisions and potential adverse reactions to minimize medical errors and optimize patient care.”

https://pubmed.ncbi.nlm.nih.gov/41098593/

“In conclusion, while CBD now stands as a recognized and effective treatment for specific forms of epilepsy, a deeper, integrated understanding of its comprehensive mechanisms, validated efficacy across diverse populations, and long-term safety profile remains essential. Continued collaborative efforts among scientists, clinicians, and policymakers, coupled with stringent critical appraisal of evidence, will be key to unlocking the full and safe potential of cannabinoids in epilepsy therapy.”

https://www.frontierspartnerships.org/journals/acta-biochimica-polonica/articles/10.3389/abp.2025.15251/full

The Endocannabinoid System in the Development and Treatment of Obesity: Searching for New Ideas

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“Obesity is a complex, multifactorial disease and a growing global health challenge associated with type 2 diabetes, cardiovascular disorders, cancer, and reduced quality of life. The existing pharmacological therapies are characterized by their limited number and efficacy, and safety concerns further restrict their utilization.

This review synthesizes extensive knowledge regarding the role of the endocannabinoid system (ECS) in the pathogenesis of obesity, as well as its potential as a therapeutic target. A thorough evaluation of preclinical and clinical data concerning endocannabinoid ligands, cannabinoid receptors (CB1, CB2), their genetic variants, and pharmacological interventions targeting the ECS was conducted.

Literature data suggests that the overactivation of the ECS may play a role in the pathophysiology of excessive food intake, dysregulated energy balance, adiposity, and metabolic disturbances.

The pharmacological modulation of ECS components, by means of CB1 receptor antagonists/inverse agonists, CB2 receptor agonists, enzyme inhibitors, and hybrid or allosteric ligands, has demonstrated promising anti-obesity effects in animal models. However, the translation of these findings into clinical practice remains challenging due to safety concerns, particularly neuropsychiatric adverse events.

The development of novel strategies, including peripherally restricted compounds, hybrid dual-target agents, dietary modulation of endocannabinoid tone, and non-pharmacological interventions, promises to advance the field of obesity management.”

https://pubmed.ncbi.nlm.nih.gov/41096816/

“Taken together, the growing body of evidence suggests that targeting the ECS, either pharmacologically or through lifestyle interventions, may open a new chapter in the prevention and treatment of obesity.”

https://www.mdpi.com/1422-0067/26/19/9549

Cardiovascular Effects of Cannabidiol: From Molecular Mechanisms to Clinical Implementation

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“Cannabidiol (CBD) and other phytocannabinoids are gaining attention for their therapeutic potential in cardiovascular disease (CVD), the world’s leading cause of death.

This review highlights advances in understanding the endocannabinoid system, including CB1 and CB2 receptors, and the mechanisms by which CBD exerts anti-inflammatory, antioxidative, vasoprotective, and immunomodulatory effects.

Preclinical and translational studies indicate that selective activation of CB2 receptors may attenuate atherogenesis, limit infarct size in ischemia-reperfusion injury, decrease oxidative stress, and lessen chronic inflammation, while avoiding the psychotropic effects linked to CB1.

CBD also acts on multiple molecular targets beyond the CB receptors, affecting redox-sensitive transcription factors, vascular tone, immune function, and endothelial integrity.

Early clinical trials and observational studies suggest that CBD may lower blood pressure, improve endothelial function, and reduce sympatho-excitatory peptides such as catestatin, with a favorable safety profile. However, limited bioavailability, small sample sizes, short study durations, and uncertainty about long-term safety present challenges to its clinical use. Further research is needed to standardize dosing, refine receptor targeting, and clarify the role of the endocannabinoid system in cardiovascular health.

Overall, current evidence supports CBD’s promise as an adjunct in CVD treatment, but broader clinical use requires more rigorous, large-scale studies.”

https://pubmed.ncbi.nlm.nih.gov/41096874/

“In summary, although cannabinoids have not yet reached clinical maturity for broad implementation in cardiovascular therapeutics, the underlying scientific evidence is promising, and preliminary findings are encouraging. Bridging the translational gap prudently will demand methodologically rigorous, multidisciplinary research efforts, ensuring that any future clinical claims are grounded in robust human evidence.”

https://www.mdpi.com/1422-0067/26/19/9610

Cannabis-Derived Compounds Against Plasmodium sp.: A Systematic Review of Preclinical Studies

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“Objective: This study aims to evaluate preclinical studies on the effects and toxicity of cannabis-derived compounds against Plasmodium sp.

Methods: A literature search was conducted in Web of Science, PubMed, Scopus and LILACS databases until December 2024. Studies that assessed the activity or toxicity of cannabis against Plasmodium sp. in in vitro or in vivo studies were included. Two reviewers independently performed the study selection, data extraction and methodological assessment.

Results: Eight studies published between 2001 and 2022 were included, with the majority conducted in North America (n = 5). Most in vitro studies focused on assessing antimalarial activity through half-maximal inhibitory concentration (IC50), which ranged from 0.16 to 4.1 μg/mL, indicating mild to high activity.

For the in vivo studies, all reported positive effects, including moderate antimalarial activity and disease tolerance. The toxicity profile of these compounds has not been extensively studied, and most studies present an unknown or unclear risk of bias due to insufficient methodological information.

Conclusions: Future studies should provide more comprehensive details on study design and further validate these findings, especially concerning toxicity.”

https://pubmed.ncbi.nlm.nih.gov/41093288/

https://onlinelibrary.wiley.com/doi/10.1111/tmi.70044

Full Spectrum Cannabis Oil for the treatment of chronic pain and sleep dysfunction in myofascial temporomandibular disorder: a case report

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“Medicinal cannabis has been the subject of extensive research, with recent studies demonstrating its potential in managing chronic pain and enhancing quality of life.

This case report examines the use of medicinal cannabis in a patient treated at the School of Dentistry of Araçatuba (FOA-UNESP). The patient, a 28-year-old female with no comorbidities, presented with chronic muscular TMD and reported poor sleep quality. Full-spectrum cannabis oil (1:1 ratio of THC to CBD), was prescribed for a period of 60 days, with a maximum dosage of 10 drops per day. Pain intensity was measured using the Visual Analog Scale (VAS), while sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Evaluations were conducted at three intervals: baseline, day 30, and day 60. To ensure patient safety, pre- and post-treatment blood tests were performed, and dosage adjustments were made every three days under the supervision of the study’s medical team.

The results revealed significant improvements in pain management, with the patient’s orofacial pain score decreasing from 7 to 3 on the NRS. Additionally, sleep quality improved, as reflected by a lower PSQI score (global sleep quality at level 6 at the end), indicating more restorative sleep. Throughout the treatment period, the patient experienced mild side effects, including drowsiness and gastrointestinal discomfort, which were effectively managed through dosage modifications.

In conclusion, full-spectrum cannabis oil shows promise as a therapeutic strategy for managing orofacial pain and improving sleep quality, providing significant relief in conditions where other interventions are ineffective or poorly tolerated. Further research is warranted to better understand the therapeutic mechanisms and potential side effects of medicinal cannabis in the management of chronic pain and related conditions.”

https://pubmed.ncbi.nlm.nih.gov/41092177/

“In conclusion, the use of Full Spectrum Cannabis Oil in this case was associated with a clinically meaningful reduction in chronic orofacial pain and improvement in sleep quality, with no adverse effects or laboratory abnormalities observed during the treatment period. These outcomes suggest that individualized cannabinoid-based therapy may be a safe and effective approach for selected patients with temporomandibular disorders and comorbid sleep disturbances.”

https://www.scielo.br/j/bjb/a/bK69ZBYPSB4dJ9yqcFxSzcf/?lang=en

Antinociceptive, anti-inflammatory, and anti-dysmenorrheal activities of aerial parts of Cannabis sativa L. from the sub-middle region of the Vale do São Francisco

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“Introduction: Cannabis sativa L. has been used for thousands of years to treat intestinal and uterine diseases and as an anti-inflammatory, analgesic, and antiepileptic, among others. This study aimed to conduct preclinical studies based on the ethnopharmacological properties of C. sativa.

Methods: For this purpose, the police and health authorities provided the raw plant material, and a crude ethanolic extract of the aerial parts of C. sativa (APCs) was produced, which was subsequently chemically analyzed using combined chromatographic and spectrometric methods. Subsequently, APCs were administered to Swiss mice and Wistar rats for evaluation using the open field test, acetic acid-induced abdominal contraction model, hot plate test, formalin test, carrageenan-induced paw edema, Saccharomyces cerevisiae-induced fever, and primary dysmenorrhea models.

Results: Chemical analysis suggests the presence of classic cannabinoids, such as cannabidiol, tetrahydrocannabinol, and cannabigerol, as well as flavonoids and alkaloids. The doses used in the open field test were 1, 3, 10, 30, and 100 mg/kg (gavage, po), with the last two doses responsible for reducing mobility and inducing hypothermia in the animals. In subsequent pharmacological protocols, the doses used were 1, 3, and 10 mg/kg (gavage, po). In the abdominal contraction model, the number of writhing events was reduced by APCs at a dose of 10 mg/kg [median 0.5 (Q25 = 0; Q75 = 5.75, p < 0.05)]. In the hot plate test, the doses of 1, 3, and 10 mg/kg increased the latency time to 17.67 ± 1.33, 18.50 ± 1.31, and 17.33 ± 1.69 s (p < 0.05), respectively. In the formalin test, the effect was restricted to the first phase, with values of 42.33 ± 7.588, 45.50 ± 6.657, and 39.50 ± 7.869 s (p < 0.05) in paw-licking time. In paw edema, the doses of 1 and 3 mg/kg were more constant, restricting the volume to 0.168 ± 0.004 and 0.150 ± 0.004 mL (p < 0.05), respectively. In dysmenorrhea, the doses of 3 and 10 mg/kg reduced abdominal contractions [0 (Q25 = 0; Q75 = 3.0) and 1.0 (Q25 = 0; Q75 = 3.0)].

Conclusion: APCs at the tested doses did not promote an antipyretic effect. These data indicate that APCs have antinociceptive, anti-inflammatory, and anti-dysmenorrheal effects in animal models.”

https://pubmed.ncbi.nlm.nih.gov/41089847/

“Cannabis sativa L. is a plant from the family Cannabaceae and one of the oldest to be domesticated in the world, with its use dating back to approximately 12,000 years in the Central Asian region.”

“C. sativa has a variety of indications in traditional medicine, in the most diverse forms of use (tea, smoke, vapor, etc.), and is used as a wound healing agent, analgesic, anticonvulsant, hypnotic, tranquilizer, anesthetic, anti-inflammatory, antibiotic, antiparasitic, antispasmodic, digestive, appetite stimulant, diuretic, aphrodisiac, antitussive, and expectorant.”

“Our results suggest that APCs contain classic cannabinoids, flavonoids, and alkaloids, and that classic cannabinoids, THC, and CBD are present. The administration of APCs promoted behavioral changes in the animals consistent with the pharmacological effects of these substances, such as reduced ambulation and hypothermic effect at doses of 30 and 100 mg/kg. In pharmacological studies, antinociceptive, anti-inflammatory, and anti-dysmenorrheal effects were observed in different experimental models and in the 1–10 mg/kg dose range; however, the APCs failed to show an antipyretic effect at these doses.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1677987/full