Unraveling Cannabidiol’s Dual Modulatory Role in Schizophrenia: Network Pharmacology and In Vivo Validation of Neuroinflammatory and Behavioral Modulation

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“Schizophrenia (SCZ), a chronic psychiatric disorder, is characterized by cognitive impairment, hallucinations, and delusions, with current antipsychotic treatments offering limited efficacy and considerable side effects.

Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown promise in treating neurological and psychiatric conditions, though its precise mechanisms in schizophrenia remain unclear.

Using network pharmacology, this study predicts CBD’s targets and pathways in schizophrenia, highlighting LPS-induced neuroinflammation and implicating 5-HT1AR-MAPK signaling as one potential contributor.

In vitro, CBD (10 mg/kg, i.p.) treatment significantly reduced pro-inflammatory cytokines (e.g., NO, IL-1β, IL-6, TNF-α) and modulated the 5HT1AR-MAPK pathway, including increased 5HT1AR expression and decreased MAPK/ERK1/2 phosphorylation (p < 0.05).

In vivo, CBD alleviated SCZ-like symptoms in a ketamine-induced animal model, reducing anxiety in the open field (p < 0.01) and elevated plus maze tests (p < 0.01), improving spatial memory in the Y-maze (p < 0.01) and social behavior (p < 0.0001) after 5 consecutive days of treatment. Critically, we validated CBD’s central anti-inflammatory effects by demonstrating reduced pro-inflammatory cytokine levels in both plasma and brain tissues (p < 0.05). Further correlation analysis established a direct link between brain cytokine suppression and behavioral improvements, integrating in vitro findings from BV2 microglial cells with in vivo neuroinflammatory and behavioral outcomes.

These findings suggest the potential therapeutic benefits of CBD for SCZ, though further research, particularly clinical trials, is required to validate its efficacy and establish it as a novel therapeutic strategy.”

https://pubmed.ncbi.nlm.nih.gov/41369966

“Cannabidiol (CBD), a non-intoxicating compound found in Cannabis sativa, has emerged as a promising remedy in the therapeutic landscape for a wide array of neuropsychiatric conditions.”

https://link.springer.com/article/10.1007/s12035-025-05608-8

Development and Characterization of a High-CBD Cannabis Extract Nanoemulsion for Oral Mucosal Delivery

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“The cannabidiol (CBD)-rich cannabis extract CAN296 shows anti-inflammatory and anticancer activity relevant to oral lichen planus (OLP), oral graft-versus-host disease (oGVHD), and oral squamous cell carcinoma (OSCC), but its high lipophilicity limits aqueous dispersion.

This study developed a stable Tween-based nanoemulsion optimized for oral mucosal delivery.

Ethanol-dissolved CAN296 was nanoemulsified using a 1% Tween/Span system. Physical stability was visually assessed; droplet size and morphology were examined by dynamic light scattering (DLS) and transmission electron microscopy (TEM); and wettability was measured by static contact angle (SCA). Additional evaluations included temperature stability (25 °C vs. 4 °C), in vitro release using a dialysis membrane, and scanning electron microscopy (SEM) of membrane-associated droplets.

Nanoemulsions with ≥80% Tween 80 incorporated CAN296 up to 800 µg/mL, clear at 400 µg/mL, and uniformly turbid at 800 µg/mL. DLS and TEM confirmed spherical nanoscale droplets, and SCA indicated favorable cohesion and wettability. Stability was maintained for 30 days at 4 °C. Dialysis studies demonstrated strong membrane association with limited diffusion, supported by SEM visualization of membrane-bound droplets.

The Tween-dominant (≥80%) nanoemulsion stably incorporated CAN296 up to 800 µg/mL, demonstrated nanoscale uniformity, improved 4 °C stability, and strong membrane retention under static conditions, suggesting potential for localized oral delivery.”

https://pubmed.ncbi.nlm.nih.gov/41373676

“Cannabis-derived extracts rich in cannabidiol (CBD) have significant therapeutic potential in immune-mediated and oncologic oral diseases due to their anti-inflammatory, immunomodulatory, and pro-apoptotic effects.”

“This research established a Tween-dominant nanoemulsion capable of stabilizing a robust concentration of CBD-rich cannabis extract. This optimized system remains stable under refrigeration, exhibits favorable wettability and membrane retention, and provides a physically stable, ethanol-compatible platform for oral mucosal delivery of cannabis extract.”

https://www.mdpi.com/1422-0067/26/23/11525

Molecular Modeling and Analysis of Cannabinoid and Cannabinoid-like Molecules Combining K-Means Clustering with Pearson Correlation and PCA

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“More recently, cannabinoid molecules have been widely studied for their potential to treat various diseases.

We used a multidisciplinary approach, combining molecular docking and machine learning tools, to identify cannabinoid-based molecules as potential acetylcholinesterase inhibitors.

We brought together molecules from the classes of cannabinoids, stilbenoids, isoflavones, and other natural products, along with their electronic structure and absorption, distribution, metabolism, excretion and tolerable toxicity (ADMET) data. A novel machine learning framework (MolSimEx, Molecular Similarity Explorer) combining K-means clustering,

Pearson correlation, and principal component analysis was developed to address the similarities of these groups. From the dataset, 30 molecules were selected based on docking scores below -11 kcal/mol. The K-means clustering yielded high classification accuracy on the dataset, correctly grouping the cannabinoid analogues. Additionally, these analogues clustered with classical acetylcholinesterase inhibitors such as huprine-X, huprine-W, and donepezil when considering ADMET and electronic descriptor data.

Radulanin J showed the highest correlation (0.41) with donepezil’s profile, suggesting the potential of cannabinoid-derived compounds as acetylcholinesterase inhibitors.”

https://pubmed.ncbi.nlm.nih.gov/41373674

“We have identified a set of 30 molecules, out of 253 derived from phytocannabinoids, flavonoids, and terpenoids, as potential new inhibitors against the hAChE (6O4W) enzyme.”

https://www.mdpi.com/1422-0067/26/23/11520

“Acetylcholinesterase inhibitors (AChEIs) are drugs that block the enzyme acetylcholinesterase, preventing the breakdown of the neurotransmitter acetylcholine, thus increasing its levels in the brain to improve nerve cell communication. They are used primarily to treat symptoms of Alzheimer’s disease”

“Provides a blueprint for developing new treatments for Alzheimer’s by targeting AChE, a key enzyme in neurotransmission.”

The Endocannabinoid System: Scientific Insight and Biblical Reflection

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“The endocannabinoid system (ECS) is typically associated with using cannabis or cannabinoids. However, the ECS is a complex regulatory network within the human body that plays a vital role in maintaining physiological homeostasis. The ECS can become dysregulated through various mechanisms.

This article describes the physiology of the ECS using a biblical worldview. Nurses who understand the causes of ECS dysfunction can help lead patients toward lifestyle habits that reflect God’s design for balance, resilience, and wholeness.”

https://pubmed.ncbi.nlm.nih.gov/41359460

“The endocannabinoid system (ECS) is a crucial regulatory network in the human body, often linked to cannabis use but primarily responsible for maintaining physiological balance. This article explores the ECS from a biblical perspective, emphasizing its role in health and homeostasis.

Dysregulation of the ECS can occur through various mechanisms, and nurses who grasp these causes can guide patients towards lifestyle choices that align with a holistic approach to health, reflecting a divine design for balance and resilience.

Understanding the ECS can empower healthcare professionals to support patients in achieving overall well-being.”

https://journals.lww.com/journalofchristiannursing/abstract/2026/01000/the_endocannabinoid_system__scientific_insight_and.11.aspx

“Natural and synthetic cannabinoids finely regulate the endogenous cannabinoid system.”

https://www.sciencedirect.com/science/article/pii/S1043661825004475

The History and Use of Medical Cannabis

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“Archaeological and historical evidence indicate that cannabis has been used for medicinal purposes for almost 5,000 years. Although cannabis once was valued for its therapeutic properties, shifting social norms and political influences led to its criminalization and widespread stigma. This article explores the historical trajectory of medical cannabis from early therapeutic uses to integration into Western medicine, subsequent prohibition, and cautious resurgence. Implications for Christian healthcare providers are discussed. Key historical milestones are noted along with a comprehensive view of cannabis’ evolving role in health and healing across cultures and centuries.”

https://pubmed.ncbi.nlm.nih.gov/41359459

“Cannabis has been used medicinally for nearly 5,000 years, but its acceptance has fluctuated due to changing social norms and political pressures. Initially valued for its therapeutic benefits, cannabis faced criminalization and stigma, impacting its use in Western medicine. This article traces the history of medical cannabis, highlighting key milestones from its early use to its prohibition and recent cautious re-emergence. It also examines the implications for Christian healthcare providers, offering a broad perspective on cannabis’ role in health and healing across different cultures and eras.”

https://journals.lww.com/journalofchristiannursing/abstract/2026/01000/the_history_and_use_of_medical_cannabis.10.aspx

Bioreactor-Based Suspension Cultures of Cannabis sativa for Enhanced Production of Anti-Inflammatory Cannabinoid Derivatives

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“Cannabis sativa synthesizes diverse cannabinoids with significant pharmacological value, but existing suspension cultures show low metabolite yields and limited scalability.

This study establishes bioreactor-based cell suspension system to enhance cannabinoid biosynthesis in C. sativa. Petiole explants cultured on MS medium with 4 mg/L BAP and 0.01 mg/L NAA produced 95.83 ± 0.74% friable callus. Suspension cultures accumulated 352.29 ± 3.90 g/L fresh biomass in 28 days, showing 22.4-fold increase upon scale-up in stirred-tank bioreactor.

Methanolic extracts (60 °C) showed strong anti-inflammatory activity, reducing TNF-α and IL-6 by 88.40 ± 0.87 and 92.03 ± 1.55% at 30 μg mL-1 without cytotoxicity. Metabolomic profiling identified putative cannabinoid derivatives, with THCA-C1 (0.05%) exhibiting highest binding affinity (-8.4 kcal/mol) to inflammatory targets based on docking and dynamics analyses.

Overall, these results provide the first evidence for scalable cannabinoid biosynthesis in bioreactor-grown C. sativa cell suspensions, underscoring their potential for sustainable production of anti-inflammatory therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/41359809

https://pubs.acs.org/doi/10.1021/acs.jafc.5c10683


Medical Cannabis and Opioid Receipt Among Adults With Chronic Pain

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“Importance: Medical cannabis is increasingly considered a substitute for prescription opioid medications for chronic pain, driven by the urgent need for opioid alternatives to combat the ongoing epidemic.

Objective: To determine the association between participation in the New York State (NYS) medical cannabis program and prescription opioid receipt among adults with chronic pain.

Design, setting, and participants: This cohort study used data from the NYS Prescription Monitoring Program (PMP) from September 2018 through July 2023. Adults prescribed opioids for chronic pain who were newly certified for medical cannabis use in NYS were recruited from a large academic medical center and nearby medical cannabis dispensaries in the Bronx, New York. Monthly dispensation of medical cannabis to study participants was monitored for 18 months. Data analyses were performed from February 3, 2025, to July 15, 2025.

Exposure: Portion of days covered each month by pharmacist report of dispensed medical cannabis.

Main outcomes and measures: Prescription opioid receipt, defined as NYS PMP-reported prescription monthly opioid dispensation (mean daily dose in morphine milliequivalents [MME]), was assessed with marginal structural models adjusted for time-invariant and time-varying confounders, including self-reported unregulated cannabis use. Nonprescribed opioid use was also assessed during the study period.

Results: Among 204 participants, the mean (SD) age at baseline was 56.8 (12.8) years, and 113 (55.4%) were female. At baseline, participants’ mean (SD) pain severity score was 6.6 (1.8) out of 10, and mean (SD) pain interference score was 6.8 (1.9) out of 10. Baseline mean (SD) daily MME was 73.3 (133.0). During the 18-month follow-up period, participants’ mean (SD) daily MME decreased to 57.4 (127.8). This reduction in mean daily MME was associated with the monthly portion of days covered with medical cannabis; compared with no medical cannabis dispensed, participants dispensed a 30-day supply of medical cannabis were exposed to 3.53 fewer MME per day (β = -3.53; 95% CI, -6.68 to -0.04; P = .03).

Conclusions and relevance: In this cohort study, participation in NYS’s medical cannabis program was associated with reduced prescription opioid receipt during 18 months of prospective follow-up, accounting for unregulated cannabis use.”

https://pubmed.ncbi.nlm.nih.gov/41359313

“These findings suggest that participation in a pharmacist-directed medical cannabis program may help reduce prescription opioid receipt among adults with chronic pain.”

https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2842414

Evaluation of long-term safety profile of an EU-GMP certified Cannabis sativa L. strain in a naturally aging preclinical model

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“Aging is characterized in part by chronic, low-grade inflammation, a major driver of cognitive decline, metabolic imbalance and organ dysfunction. Despite its central role in age-related morbidity, pharmacological strategies with well-defined long-term safety profiles remain limited.

Phytocannabinoids have been proposed as modulators of neuroinflammatory and metabolic pathways, but their chronic safety during natural aging is poorly characterized.

Our team has previously reported the acute and 28-day repeated-dose toxicity profile of an EU-GMP certified Cannabis sativa L. strain (Cannabixir® Medium Flos). Here, we extend this work by assessing its long-term safety in a naturally aging preclinical model. Mature to older mice received chronic, intermittent administration of Cannabixir® Medium Flos (2.5, 5, and 10 mg/kg), defined as daily weekday dosing for 3 or 6 months. Clinical and histopathological evaluations were conducted with a focus on systemic and central nervous system safety.

Chronic administration was well tolerated across all doses and durations.

Body weight remained stable despite increased food intake. Respiratory quotient values were preserved and close to 1 across all groups. Histological analyses confirmed preserved neuronal and glial architecture with no evidence of central nervous system injury or other organ-level toxicity. Long-term, intermittent Cannabixir® Medium Flos administration was well tolerated in naturally aged mice, with no adverse effects on systemic physiology or central nervous system integrity.

Together with prior acute and sub-chronic toxicity data, these findings provide robust evidence supporting the long-term safety of EU-GMP certified Cannabis sativa L. strain in the context of aging.”

https://pubmed.ncbi.nlm.nih.gov/41357885

“Importantly, the endocannabinoid system itself undergoes profound remodeling with aging, including reduced endocannabinoid tone, altered receptor expression and impaired signaling efficiency, changes that correlate with increased vulnerability to inflammation, metabolic imbalance, and neurodegeneration. These age-related alterations highlight the importance of evaluating the long-term safety of cannabinoid-based interventions in naturally aging bodies.”

“These findings suggest the potential for phytocannabinoid-mediated neuroprotection via modulation of the endocannabinoid system, although the precise molecular pathways remain to be elucidated.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1716366/full

Multifaced roles of cannabinoid therapy in cancer: balancing analgesia, antitumor potential, and systemic toxicity

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“Introduction: Cannabinoids hold promise in oncology for symptom relief and antitumor effects, though concerns about safety and efficacy persist. This study assessed the impact of JWH-182 and phytocannabinoids NC1 – Cannabixir® Medium dried flowers and NC2 – Cannabixir® THC full extract, in a murine breast cancer model with paclitaxel-induced peripheral neuropathy (CIPN).

Methods: Female BALB/c mice with breast tumors received paclitaxel alone or combined with cannabinoids, and outcomes included pain sensitivity, tumor progression (imaging and histopathology), cachexia (body weight, food intake, imaging), as well as hematological and organ toxicity profiles.

Results: All cannabinoids alleviated neuropathic pain, with NC1 most effective for central and thermal protection (72% and 100%, p < 0.0001), NC2 showing strong central and mechanical benefit (>60% and >33%), and JWH-182 intermediate (∼50%). Tumor growth was not significantly altered, but metastasis incidence was 41.7% for NC1, 58.3% for NC2, compared with 70% for PTX, suggesting antitumoral activity. Effects on cachexia were modest, JWH-182 tended to improve food intake, whereas NC1 and NC2 reduced it, yet body weight remained stable and significant muscle loss was observed only with NC2 (p < 0.05). Hematology showed immunomodulatory effects, with cannabinoids reversing lymphopenia (p = 0.0005), raising monocytes and neutrophils, and partly restoring platelets. Toxicity was highest with NC2 (renal and hepatic injury), moderate with NC1, and lowest for kidney with JWH-182 but with greater hepatic inflammation.

Conclusion: Cannabinoids show potential in oncology by relieving CIPN and influencing tumor dynamics, with mostly neutral effects on cachexia. GMP-certified formulations enhance translational value, though safety concerns warrant further study.”

https://pubmed.ncbi.nlm.nih.gov/41357884

“Cannabinoids have emerged as promising agents in oncology for both symptom relief and potential antitumor effects. By acting on cannabinoid receptors 1 and 2 (CB1R, CB2R), Tetrahydrocannabinol (THC) and Cannabidiol (CBD) help regulate pain, appetite, and inflammation, making them effective in managing CIPN, cancer pain, and cachexia.

Preclinical studies also suggest that cannabinoids can inhibit tumor growth, metastasis, angiogenesis, and reverse chemoresistance, with potential to enhance chemotherapy efficacy and reduce its toxicity.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1691893/full

Full-spectrum cannabis extracts for women with chronic pain syndromes: a real-life retrospective report of multi-symptomatic benefits after treatment with individually tailored dosage schemes

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“Chronic pain syndromes (CPS) are debilitating conditions for which cannabis extracts and cannabinoids have shown promise as effective treatments. However, accessibility to these treatments is limited due to the absence of suitable formulations and standardized dosage guidelines. This is particularly critical for women, who present sex-specific differences in pain burden, pain perception, and pain-related cannabinoid pharmacology.

We conducted a retrospective open-label cross-sectional study on 29 female CPS patients who received full-spectrum cannabis extracts (FCEs) with standardized compositions produced by two patient-led civil societies. An individually tailored dosage protocol was used, with dosage schemes adjusted based on individualized clinical assessments of initial conditions and treatment responses. Patients received either CBD-dominant extracts, THC-dominant extracts, or a combination of both. To evaluate the results, we conducted a comprehensive online patient-reported outcome survey covering core CPS symptoms, comorbidities, personal burden, and quality of life-including open-ended questions to capture the practical and subjective impacts of CPS and FCEs treatment on patients’ lives.

Despite most patients already using medications for pain and mood disorders, all reported some level of pain relief, and most reported improvements in cognitive function, motor abilities, professional activities, irritability, anxiety, melancholy, fatigue, and sleep quality. Qualitative content analysis of open-ended responses revealed that FCEs had relevant positive effects on practical and subjective domains, as well as personal relationships. No patients had to discontinue extract use due to adverse effects, and most reduced or ceased their use of analgesic and psychiatric medications. The optimal dosage regime, including CBD-to-THC proportions, was established through a response-based protocol, varied considerably, and showed no clear link to specific pain types.

These real-life results strongly suggest that a broad scope of benefits can be achieved by using flexible dosing schemes of cannabis extracts in managing diverse CPS conditions in female patients. Therefore, this study highlights the significance of tailoring treatment plans to individual CPS cases. Moreover, it demonstrates the feasibility of utilizing quality-controlled cannabis extracts produced by civil societies as either adjuncts or primary pharmacotherapeutic options in CPS management.”

https://pubmed.ncbi.nlm.nih.gov/41357862

“Studies with isolated cannabinoids revealed relief of chronic pain, inflammation, depression, and other CPS-associated comorbidities in animal models.

Isolated cannabidiol (CBD) has shown analgesic and anti-inflammatory effects in humans, while tetrahydrocannabinol (THC) seems to produce pain relief by modulating neuronal activity in pain-associated areas of the central nervous system, such as the periaqueductal area, and the descending supraspinal inhibitory pathways, often involved in cases of CPS. Accordingly, THC isolated oil promoted significant relief of chronic neuropathic pain in comparison to placebo.”

“Our study provides compelling real-world evidence of the broad, integrative benefits of full-spectrum cannabis extracts (FCEs) for women with chronic pain syndromes (CPS).”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1538518/full