Author Archives: David Worrell

Pharmacological, Molecular Mechanisms, and Therapeutic Potential of β-Caryophyllene and β-Caryophyllene-Rich Plants in Liver Diseases

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“β-caryophyllene, a bicyclic sesquiterpene widely abundant in various plant essential oils, has garnered growing attention for its potential biological effects and therapeutic benefits in liver diseases. This review systematically evaluates preclinical evidence on the pharmacological properties of BCP with emphasis on its hepatoprotective effects primarily through its anti-inflammatory, antioxidant, antifibrotic, and immunomodulatory actions.

BCP is classified as a dietary cannabinoid due to its ability to activate cannabinoid type 2 receptors in the endocannabinoid system and thereby influence key cellular signaling pathways involved in lipid metabolism and tissue remodeling. Emerging studies also highlight BCP interaction with PPAR nuclear receptor and AMPK signaling, further corroborating its role in regulating lipid homeostasis.

In the present review, we compile, summarize, and critically analyze findings from in vitro and in vivo studies on nonalcoholic fatty liver disease, recently termed as metabolic dysfunction-associated fatty liver disease (MAFLD), alcoholic liver disease, and liver fibrosis, highlighting the pharmacological and molecular mechanisms underlying therapeutic effects. These studies consistently demonstrate a reduction in hepatic steatosis, collagen deposition, and hepatocellular markers reflecting a broad spectrum of hepatoprotective effects.

Taken together, the pharmacological properties and mechanistic insights place BCP as a promising natural compound with nutraceutical, phytopharmaceutical, or dietary supplement applications for liver diseases. Despite the robust preclinical evidence, clinical validation remains scarce. Therefore, regulatory toxicology and efficacy studies are needed to establish the therapeutic potential of BCP in liver diseases and its integration as a nutraceutical or phytopharmaceutical in the clinical usage.”

https://pubmed.ncbi.nlm.nih.gov/41489519

“BCP is one of the important constituents in Cannabis with an abundance of 35%. In addition to its presence in Cannabis, BCP is largely present in numerous edible plants.”

“In conclusion, BCP represents a promising therapeutic avenue for managing liver diseases due to its ability to modulate multiple interrelated molecular and cellular pathways.”

“With continued research, BCP has the potential to evolve from a natural product with hepatoprotective properties to an effective adjunct or alternative in liver disease therapy, offering new hope for patients and advancing the field of liver health management.”

https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202502436R


Effect of patient marijuana use on perioperative opioid requirements

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“The effect of chronic marijuana use on patients is unknown, including in the surgical setting. Marijuana produces many effects on the body, which should be considered when providing medical care.

Chronic marijuana use may affect surgical opioid requirements. To explore this possibility, an observational study was completed by conducting a retrospective chart review of patients who underwent surgery with general anesthesia.

Patients were identified in the electronic medical record via self-reporting as marijuana users (users) or nonmarijuana users (nonusers). Users and nonusers were case-matched based on age, gender, weight, and procedure. After case matching, 570 patients’ charts were analyzed, and intraoperative opioid, intraoperative propofol, and post-anesthesia care unit opioid requirements were compared.

Marijuana users required less intraoperative opioids (mean [standard deviation (SD)] 27.2 [20.5] morphine milligram equivalents [MMEs]) compared to those who were marijuana nonusers (31.3 [22.1] MME).

These results show a statistically significant difference in the intraoperative opioid requirement between case-matched users and nonusers (p = 0.02), with p = 0.013 after statistical adjustment for racial differences between the marijuana user and nonuser cohorts. Users and nonusers required similar amounts of intraoperative propofol (242.2 [220.2] and 257.8 [250.9], respectively) and post-operative opioids (7.3 [6.0] and 8.0 [9.0], respectively). The differences in intraoperative propofol and post-operative opioid requirements were not different statistically with p-values of 0.43 and 0.31, respectively.

Based on this study population, marijuana users required less intraoperative opioids when compared to case-matched marijuana nonusers, with no difference in intraoperative propofol or post-operative opioid requirements.

Perspective: Typical preoperative screening includes queries about patient substance use including marijuana, but details such as frequency and length of use are infrequently asked. The addition of these details to the assessment may provide improved understanding of a patient’s surgical opioid requirements.”

https://pubmed.ncbi.nlm.nih.gov/41123263

https://wmpllc.org/ojs/index.php/jom/article/view/3918

Cannabidiol suppresses emergency MDSCs generation by disturbing EEF1B2-mediated C/EBP β protein synthesis in colorectal adenomas

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“Background: Colorectal cancer often develops from adenomas over years, necessitating early intervention. Myeloid-derived suppressor cells (MDSCs) are major immune suppressive cell types in colon cancer development from adenomas through early inflammation-induced emergency myelopoiesis. Cannabidiol (CBD) is reported to function in psychosis, coronavirus infection and some cancers through immune regulation. However, its target and underlying mechanisms in colorectal adenomas are unknown.

Methods: The antitumor effect of CBD was validated in two classical colorectal adenomas models including azoxymethane (AOM)/dextran sulfate sodium salt (DSS) induced mice model and high-fat fed Apcmin/+ mice model. Single-cell RNA sequencing was used to identified the immune environment change after CBD treatment in mice colorectal adenomas. Target responsive accessibility profiling was used to find the target of CBD in MDSCs. Subsequently, multiple immunology assays and molecular biology experiment were employed to explore the adenomas prevention mechanisms of CBD.

Results: Here, we found that CBD prevented the incidence of colorectal adenomas in AOM/DSS model and high-fat diet fed Apcmin/+ mice model. Our single-cell RNA sequencing data and the results of immunofluorescence revealed that CBD treatment significantly decreased the number of MDSCs in both two colon adenomas models. Mechanistically, CBD bound to the guanine nucleotide exchange factor domain of EEF1B2, inhibiting its function in translational elongation and subsequent C/EBPβ synthesis. This disruption suppressed the differentiation and generation of MDSCs, leading to enhanced T-cell activation and prevention of colorectal adenoma progression.

Conclusion: Our findings reveal EEF1B2-mediated C/EBPβ protein synthesis as a crucial pathway in MDSC generation and highlight the potential of CBD as an early intervention strategy for colorectal adenomas.”

https://pubmed.ncbi.nlm.nih.gov/41485775

“In this study, we found that CBD prevented the progression of colorectal adenomas via targeting inhibition the function of EEF1B2 to suppress the generation of MDSC from bone marrow in the condition of adenomas induced systemic inflammation. The underlying mechanism was that EEF1B2 inhibition prevented MDSC differentiation and generation through disturbing the protein synthesis of the key transcription factor C/EBPβ.”

“This study implies that CBD may be a potential compound for clinical translation for colorectal adenomas in clinical use, which makes significant therapeutic implications in the early medical intervention for colorectal adenomas and is an effective strategy to inhibit MDSCs generation and relieve immune suppressive environment in MDSCs involved diseases.”

https://jitc.bmj.com/content/14/1/e013081

Cannabidiol Alleviates LPS-Induced Depressive-Like Behaviors Via Improving Mitochondria Function

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“Mitochondrial autophagy has been regarded as a new signaling pathway for the action of antidepressant drugs.

The neuroprotective properties of the non-psychoactive cannabinoid cannabidiol (CBD) have been demonstrated in different animal models of neurological disorders. However, the therapeutic effect of cannabidiol on neuroinflammation-induced depression and its underlying molecular mechanisms involved has not been comprehensively studied.

In this study, depressive-like behaviors were induced in male C57BL/6 mice by LPS injection, with intragastric administration of CBD (70 or 140 mg/kg/day) for 6 days.

Our results demonstrated that CBD treatment significantly attenuated lipopolysaccharide (LPS)-induced depressive-like behaviors, accompanied by a marked amelioration of synaptic healthiness in the hippocampal region.

CBD effectively inhibited reactive oxygen species production, normalized the levels of oxidative stress markers, and restored superoxide dismutase activity, involving a mechanism that promotes mitochondrial biogenesis and mitophagy. In addition, LPS-induced neuroinflammation was reduced by CBD, as evidenced by a marked decrease in neuroinflammatory activation markers. CBD also inhibited LPS-activated inflammasome activation by targeting NLRP3/IL-1β/Caspase-1 signaling pathway.

These findings suggest that CBD may be a potential therapeutic drug for managing major depressive disorder.”

https://pubmed.ncbi.nlm.nih.gov/41484536

https://link.springer.com/article/10.1007/s12035-025-05614-w

Medical Cannabis for Best Supportive Care of Patients Affected by Cancers of the Head and Neck: A Narrative Review

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“Cancers of the head and neck, including malignancies of the oral cavity, pharynx, larynx, and salivary glands, are often associated with severe symptoms that negatively impact quality of life. Patients commonly experience pain, nausea, cachexia (severe weight loss), dysphagia (difficulty swallowing), and xerostomia (dry mouth), all of which can be exacerbated by both the disease and its treatments, such as surgery, radiation, and chemotherapy.

Research has demonstrated that medical cannabis can be effective in managing symptoms such as chronic pain, nausea, vomiting, and anxiety, making it a valuable option in cancer care. Its ability to interact with the endocannabinoid system to reduce nociception (pain perception) and inflammation makes it particularly suitable for the complex symptom burden of patients with head and neck cancer.

This review explores the role of the endocannabinoid system and medical cannabis in mitigating symptoms and improving patient outcomes, as well as its place within the comprehensive care of patients with cancers of the head and neck.”

https://pubmed.ncbi.nlm.nih.gov/41482365

“Medical cannabis is a very interesting and emerging tool in the supportive care of patients with head and neck cancers, offering relief from pain, nausea, loss of appetite, and psychological distress. It complements existing therapies and provides an alternative or adjunct to conventional symptom management strategies, particularly for patients who do not tolerate traditional medications well.”

https://iv.iiarjournals.org/content/40/1/50

Medical Cannabis and Opioid Receipt Among Adults With Chronic Pain

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“Question  Is participation in the New York State (NYS) medical cannabis program associated with reduced prescription opioid receipt among adults with chronic pain?

Findings  In this cohort study of 204 adults with chronic pain, participation in the NYS medical cannabis program, defined as monthly dispensation of medical cannabis reported by the dispensary pharmacist, was associated with significantly reduced prescription opioid receipt.

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

Abstract

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

Medical Cannabis Program Lowers Chronic Pain Opioid Prescriptions

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“Access to medical cannabis through a state-regulated program was associated with significantly lower rates of opioid prescriptions among adults with chronic pain, according to findings recently published in JAMA Internal Medicine.

The study included 204 adults enrolled in the New York State medical cannabis program, which provided monthly access to medical cannabis through a dispensary pharmacist, and 142 ultimately obtained the treatment. The data spanned from September 2018 through July 2023. Researchers measured prescription opioid receipt via mean daily dose in morphine milliequivalents (MME) and compared it with how many days’ worth of cannabis individuals were dispensed each month based on pharmacists’ reports.

After 18 months, the mean daily MME decreased by 22%, from 73 to 57.

The authors noted that instead of measuring medical cannabis exposure via its legalization status, they directly analyzed pharmacy dispensation amounts, a more accurate indicator of uptake. Randomized clinical trials are needed to see whether medical cannabis reduces opioid use, they added.”

https://pubmed.ncbi.nlm.nih.gov/41481315

https://jamanetwork.com/journals/jama/fullarticle/2843608

Cannabidiol Enhances SIRT1 and Autophagy for the Maintenance of Human Mesenchymal Stem Cells

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“Background/aim: Mesenchymal stem cells (MSCs) are used to treat various degenerative diseases. However, their therapeutic potential is limited by cellular aging during in vitro cultivation. This study aimed to explore whether cannabidiol (CBD) can delay MSC aging by enhancing the expression of Sirtuin 1 (SIRT1) and autophagy, two key anti-aging regulators.

Materials and methods: CBD, the most important non-psychotomimetic phytocannabinoid derived from the Cannabis sativa plant, was used to up-regulate SIRT1 and autophagy in order to maintain MSC stemness. MSCs were treated with CBD and assessed for cell viability, doubling time, key gene/protein expression, relative senescence-associated β-galactosidase (SA-β-gal) assay, relative telomere length, and telomerase expression.

Results: CBD significantly increased the expression of SIRT1 and autophagy-related markers in MSCs. Furthermore, CBD preserved MSC stemness by promoting the deacetylation of SRY-box transcription factor 2 (SOX2) through SIRT1, and delayed cellular senescence by enhancing autophagy, reducing SA-β-gal activity, maintaining proliferation capacity, and supporting telomere function.

Conclusion: CBD promotes MSC stemness and delays cellular senescence, potentially through the activation of SIRT1 and autophagy. These findings suggest that CBD may serve as a promising agent for preserving MSC function in regenerative medicine.”

https://pubmed.ncbi.nlm.nih.gov/41482390

“Cannabidiol (CBD) is the major non-psychotomimetic phytocannabinoid derived from the Cannabis sativa plant. Numerous studies have demonstrated its broad pharmacological effects, including antidepressant, anti-inflammatory, antiemetic, neuroprotective, analgesic, antibacterial, anticonvulsant, anxiolytic, antipsychotic, antitumor, and immunomodulatory activities. Recently, CBD has been shown to extend lifespan and improve health span in various models”

“This study demonstrates that an optimal concentration of CBD enhances MSC proliferation and promotes SIRT1 activation, thereby inducing autophagy and maintaining stemness through the regulation of SOX2. Moreover, CBD was found to delay cellular senescence and preserve replicative potential in MSCs. Collectively, these findings highlight CBD as a promising modulatory agent for improving MSC longevity and therapeutic quality, with potential implications for regenerative and anti-aging applications.”

https://iv.iiarjournals.org/content/40/1/222

Phytocannabinoids as anti-inflammatory agents: Synergistic effects when combined with Cannabis sativa matrices

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“Ethnopharmacological relevance: Cannabis sativa L. has a long history of traditional use for the treatment of pain and inflammatory disorders in both Asian and European medical systems, which supports its investigation as a source of bioactive compounds with potential relevance for chronic immune-mediated diseases.

Aim of the study: This study evaluated the ten major non-psychotropic phytocannabinoids for their anti-inflammatory and antioxidant activities, and for synergistic interactions with non-cannabinoid matrices derived from the same plant (polar, non-polar and terpenoid).

Material and methods: Anti-inflammatory effects were assessed in macrophage-differentiated THP-1 cells by measuring pro-inflammatory cytokine production (ELISA) and nuclear factor kappa B (NF-κB) pathway activation (luciferase reporter assay).

Results: All tested phytocannabinoids demonstrated anti-inflammatory effects, in particular, cannabidivarin (CBDV) reduced IL-6, TNF-α production and also inhibited NF-κB activation. Several phytocannabinoids, especially their acidic forms, exhibited high oxygen radical absorption capacity (ORAC), but none showed significant cellular antioxidant activity (CAA), possibly due to limited bioavailability. Importantly, several phytocannabinoid-matrix mixtures displayed synergistic anti-inflammatory effects, with combinations containing cannabigerol (CBG) or cannabinol (CBN) being particularly potent.

Conclusion: These findings highlight the potential of lesser-known phytocannabinoids, especially in combination with specific C. sativa L. matrix components, to modulate inflammatory pathway supporting their development as functional ingredients for managing chronic gut-associated inflammation.”

https://pubmed.ncbi.nlm.nih.gov/41478536

“Full plant chemical complexity outperforms single phytocannabinoid alone.”

“Non-psychotropic phytocannabinoids present promising functional food ingredients.”

https://www.sciencedirect.com/science/article/abs/pii/S0378874125018276?via%3Dihub

Extract engineering of Cannabis sativa yields novel antibacterial cannabinoids targeting Staphylococcus aureus and methicillin-resistant Staphylococcus aureus

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“Cannabis sativa is a phytochemically rich plant producing over 500 compounds, with cannabinoids recognized as its most bioactive constituents.

However, the natural exploration and exploitation of novel, pharmacologically active cannabinoids remain limited due to their trace abundance in the plant. To address this challenge, we employed an extract engineering strategy in which enriched fractions of major cannabinoids were chemically transformed through oxone/acetone oxidation under mild conditions.

This approach enabled the purification of seven cannabinoid analogs, including rare and previously undescribed compounds, in appreciable quantities. The structures of these analogs were elucidated using high-resolution mass spectrometry combined with comprehensive 1D and 2D NMR spectroscopy.

Antibacterial susceptibility assay revealed that out of seven compounds, Compound 1, 5, and 7 exerted significant inhibitory activity against both Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) pathogens.

A Checkerboard study revealed the synergistic interaction between active hits and Rifampin in both S. aureus and MRSA. The biofilm-based assay demonstrated the antibiofilm potential of the identified hits. The mechanistic exploration elucidated the cell membrane-based targeting of the potent hits, validated through scanning electron microscopy. Moreover, the Propidium iodide assay performed using flow cytometry and fluorescence microscopy revealed the membrane disruption effect of the identified hits. In addition, the ATP quantification study demonstrated a major decline in ATP levels along with an augmentation in ROS production in the MRSA pathogen.

Thus, this work establishes extract engineering as a powerful strategy to unlock rare cannabinoid scaffolds and highlights their potential as leads for combating multidrug-resistant Staphylococcus infections.”

https://pubmed.ncbi.nlm.nih.gov/41478197


“Cannabis sativa has diverse phytochemical composition and therapeutic potential.”

“In summary, comprehensive antistaphylococcal evaluation of the cannabinoid-based molecules demonstrated strong antibacterial activity against both S. aureus and MRSA pathogens, along with synergistic interaction when combined with standard drugs. Notably, the potent molecules expressed low propensity for the development of resistance in the MRSA strain. Moreover, the antibiofilm action of the potent hits highlighted their curative role…”

https://www.sciencedirect.com/science/article/abs/pii/S0045206825013288?via%3Dihub