Author Archives: David Worrell

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

Vaporized cannabis versus placebo for acute migraine: A randomized, double-blind, placebo-controlled crossover trial

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“Objective: To assess the efficacy of cannabis for the treatment of acute migraine.

Background: Preclinical and retrospective studies suggest cannabinoids may be effective in migraine treatment. However, there have been no randomized clinical trials examining the efficacy of cannabinoids for acute migraine.

Methods: In this randomized, double-blind, placebo-controlled, crossover trial, adults with migraine treated up to four separate migraine attacks, one each with vaporized (1) 6% Δ9-tetrahydrocannabinol (THC) (THC-dominant), (2) 11% cannabidiol (CBD) (CBD-dominant), (3) 6% THC + 11% CBD, and (4) placebo cannabis flower in a randomized order. Washout period between treated migraine attacks was ≥1 week. The primary endpoint was pain relief, and secondary endpoints were pain freedom and most bothersome symptom freedom, all assessed at 2-h post-vaporization.

Results: Ninety-two participants were enrolled and randomized, and 247 migraine attacks were treated. THC + CBD was superior to placebo at achieving pain relief (67.2% vs. 46.6%, odds ratio [95% confidence interval] 2.85 [1.22, 6.65], p = 0.016), pain freedom (34.5% vs. 15.5%, 3.30 [1.24, 8.80], p = 0.017), and most bothersome symptom freedom (60.3% vs. 34.5%, 3.32 [1.45, 7.64], p = 0.005) at 2 h, as well as sustained pain freedom at 24 h and sustained most bothersome symptom freedom at 24 and 48 h. THC-dominant was superior to placebo for pain relief (68.9% vs. 46.6%, 3.14 [1.35, 7.30], p = 0.008) but not pain freedom or most bothersome symptom freedom at 2 h. CBD-dominant was not superior to placebo for pain relief, pain freedom, or most bothersome symptom freedom at 2 h. There were no serious adverse events.

Conclusion: Acute migraine treatment with 6% THC + 11% CBD was superior to placebo at 2-h post-treatment with sustained benefits at 24 and 48 h.”

https://pubmed.ncbi.nlm.nih.gov/41469488

“Many people with migraine self-treat with cannabinoids or are interested in using cannabinoids to treat migraine. In this double-blind study, people with migraine treated up to 4 migraine attacks, 1 attack was treated with each of 3 vaporized cannabis flower treatments (THC 6%, CBD 11%, and THC 6% + CBD 11%) or placebo cannabis flower without THC or CBD, within the first 4 h of migraine attack onset. Four puffs of cannabis flower containing THC 6% + CBD 11% was superior to placebo at treating migraine attacks, though the study did not examine the long-term effects of frequent use.”

https://headachejournal.onlinelibrary.wiley.com/doi/10.1111/head.70025

Unveiling Neurological Benefits: A Review of Hemp Leaf, Flower, Seed Oil Extract, and Their Phytochemical Properties in Neurological Disorders

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“Neurological disorders such as epilepsy, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis present significant global health care challenges, with complex pathophysiology and limited therapeutic options that often carry substantial side effects.

Hemp-derived compounds, particularly from Cannabis sativa seeds, leaves, and flowers, have gained attention for their potential neuroprotective properties.

This review aims to synthesize the current evidence surrounding the therapeutic benefits of hemp-derived compounds, focusing on their bioactive phytochemical profiles, mechanisms of action, and therapeutic efficacy in treating neurological disorders.

A comprehensive review of pre-clinical and clinical studies was conducted, analyzing the phytochemical composition of hemp extracts, including cannabinoids (such as cannabidiol, CBD), terpenes, flavonoids, and polyunsaturated fatty acids. We explored their mechanisms of action through interactions with the endocannabinoid system, neurotransmitter receptors, inflammatory pathways, and oxidative stress mechanisms.

The review highlights the therapeutic potential of hemp-derived extracts in mitigating various neurological conditions. Pre-clinical and clinical studies have demonstrated their efficacy in reducing seizure frequency in epilepsy, protecting dopaminergic neurons in Parkinson’s disease, alleviating neuroinflammation and oxidative stress in Alzheimer’s disease, and promoting remyelination in multiple sclerosis.

The entourage effect, where cannabinoids, terpenes, and flavonoids work synergistically, enhances these therapeutic effects. Innovations in extraction technologies have optimized yield and preserved bioactivity, further enhancing clinical relevance.

Hemp-derived compounds exhibit significant neuroprotective and therapeutic potential for managing neurological disorders. However, challenges such as product standardization, safety profiles, and regulatory frameworks must be addressed for clinical translation. Further research is essential to optimize dosing, establish safety parameters, and develop standardized formulations, which will be crucial for fully harnessing the therapeutic potential of hemp-derived products in treating neurological conditions.”

https://pubmed.ncbi.nlm.nih.gov/41468178

https://www.liebertpub.com/doi/10.1177/25785125251410822


Targeting bladder cancer: Potent anti-cancer effects of cannabichromene and delta-9-tetrahydrocannabinol-rich Cannabis sativa strains

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“Objective: This study aimed to explore the anticancer potential of Cannabis sativa (C. sativa) strains, specifically PARIS, Dairy Queen (DQ), and super cannabidiol (sCBD), on bladder cancer cells. Given the increasing interest in cannabinoids like cannabichromene (CBC) and delta-9-tetrahydrocannabinol (THC) for their therapeutic properties, we evaluated their cytotoxic effects on urothelial carcinoma (UC) cell lines and their ability to inhibit cell migration and induce apoptosis in both two-dimensional cell models and three-dimensional ex vivo organ cultures (EVOCs).

Methods: C. sativa strains were screened for their cytotoxicity against UC cell lines (HTB-4 and HTB-9) using XTT assays. Their phytocannabinoid content was analyzed using high-performance liquid chromatography. We employed fluorescence-activated cell-sorting to determine apoptosis and cell cycle, migration assays to determine cell migration, and EVOCs to evaluate the cytotoxic effect on UC. Gene expression was determined by quantitative polymerase chain reaction.

Results: Three commercial C. sativa strains, PARIS, DQ, and sCBD, were found to have the most potent anticancer effects on bladder cancer cells. All extracts contain CBC and THC at different concentrations. In XTT assays on UC cell lines, PARIS had a half-maximal inhibitory concentration (IC50) of 21.58 μg/mL, while DQ and sCBD had similar cytotoxic activity with IC50 values for 48-h treatment of 17.99 μg/mL and 17.88 μg/mL, respectively. DQ and sCBD extracts were found to significantly reduce cell migration and increase the percentage of cells in S phase and G2/M phase within the cell population. In EVOCs, the extracts initiated cell death with the expression of apoptosis-related genes increased following exposure to treatment.

Conclusion: The findings suggest that C. sativa strains PARIS, DQ, and sCBD, containing CBC and THC, exhibit significant anticancer activity against UC cell lines and ex vivo models. These results underscore the therapeutic potential of CBC- and THC-rich C. sativa extracts in bladder cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/41467200

“This study highlights the potential of commercially available cannabis extracts in inhibiting UC tumors through programmed cell death, the expression of apoptosis-related genes, and cell migration inhibition. The findings emphasize the significance of cannabinoid-specific content over total cannabinoid concentrations in determining their cytotoxic effects. While personalized medicine based on specific strain compositions remains a distant goal, certain cannabinoids like CBC, THC, and CBD show promise in exerting cytotoxic effects.”

“Overall, these findings underscore the potential of cannabis-derived compounds as therapeutic agents in cancer treatment and warrant further investigation.”

https://www.sciencedirect.com/science/article/pii/S2214388225000335?via%3Dihub

Targeting Human Cancer Cells with Cannabidiol (CBD): Apoptotic Cytotoxicity in HeLa, MDA-MB-231, and CaCo-2 Lines

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“Cannabidiol (CBD), a phytocannabinoid derived from Cannabis sativa, has demonstrated therapeutic potential across various diseases, including cancer.

This study evaluates the cytotoxic effects of CBD on three human cancer cell lines (HeLa, MDA-MB-231, and CaCo-2) and two non-cancerous cell lines (HaCaT and HUVEC) used as a control. Cells were treated with CBD at concentrations of 5, 10, and 20 µM for 24, 48, 72, and 96 h. Cytotoxicity was assessed using MTT assays, nuclear morphology was evaluated via DAPI staining, and cell death mechanisms were analyzed through flow cytometry with apoptosis/necrosis markers. The LC50 values at 24 h were determined as follows: HeLa (9.4 µM), MDA-MB-231 (10.3 µM), and CaCo-2 (4.3 µM).

CBD treatment induced morphological changes characteristic of cell stress and death in cancer cells, observed by optical microscopy after 24, 48, 72, and 96 h of exposure. These findings highlight the potential of CBD as an adjunctive therapeutic agent for cancer treatment versus non-malignant cells.”

https://pubmed.ncbi.nlm.nih.gov/41465562

“The findings of this study confirm the potential of CBD as a cytotoxic agent with pro-apoptotic activity in cancer cells.”

“CBD appears to exert a multifaceted mechanism of action on tumor cells, involving both the endocannabinoid system and receptor-independent pathways.”

“In the present study, we demonstrated that CBD induces apoptosis in human cancer cells (HeLa, MDA-MB-231, and CaCo-2) while delaying apoptotic processes in non-malignant control cells (HaCaT and HUVEC). These findings underscore the potential of CBD as an adjunctive therapeutic agent for cancer treatment, highlighting its selective cytotoxic effects on malignant cells with limited impact on non-malignant cells.”

“These results underscore the potential of CBD as an adjunctive therapy in cancer treatment, particularly for colorectal adenocarcinoma, where it exhibited greater efficacy.”

https://www.mdpi.com/1422-0067/26/24/12136


Clinical Endocannabinoid Deficiency and Cognitive Continuity: A Longitudinal Case Study Challenging the Neurodegeneration Paradigm

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“Despite expanding acceptance of cannabis for medicinal use, empirical literature remains sparse regarding the long-term mental and neurobiological outcomes of continuous cannabis exposure over several decades. This self-case study examines the psychobiological trajectory of a biomolecular psychologist who has used cannabis intermittently since the 1970s and therapeutically since 2010 to manage polypharmacy withdrawal, opioid dependence, and psychiatric symptoms. The analysis integrates self-observational data, neurocognitive assessments, pharmacological history, and psychosocial context to evaluate outcomes on affect regulation, cognitive performance, neuroplasticity, and motivation. The case challenges persistent assumptions of irreversible cannabis-induced cognitive decline and supports the hypothesis that sustained cannabinoid modulation may promote neural resilience when employed within a biomolecularly informed framework. Findings are illustrative and intended to generate testable hypotheses rather than establish causality.”

“For more than half a century, the United States has maintained one of the most comprehensive prohibitions on biological cannabinoid research in modern science. The enactment of the Controlled Substances Act in 1970 effectively silenced
the empirical study of the plant Cannabis sativa and its naturally occurring cannabinoids, leaving a void in scientific understanding that has persisted for decades. The policy was founded less on biomedical evidence than on sociopolitical ideology—a moral model of addiction that conflated psychoactivity with deviance. By classifying naturally occurring
cannabinoids as Schedule I substances, federal policy positioned them alongside heroin and LSD, asserting “no accepted medical use and a high potential for abuse”. Consequently, generations of scientists were restricted from exploring naturally occurring cannabinoids’ molecular, neurobiological, and psychopharmacological functions.”

“While modern prohibition sought to erase the plant’s legitimacy, cannabis itself represents a biological constant—molecules with 12,500 years of medicinal use, abruptly vilified in the modern era. Archaeological and historical records confirm its continuous application in treating pain, inflammation, convulsions, and psychological distress throughout diverse civilizations. Across that immense timeline, humans relied on the plant’s phytochemical complexity—its cannabinoids, terpenes, and flavonoids—to modulate physiological systems long before those systems were scientifically named.”

“The endocannabinoid system (ECS), now recognized as one of the body’s principal homeostatic regulators, mediates neural, immune, and endocrine balance. Yet its formal discovery in the 1990s came paradoxically after half a century of federally enforced ignorance.”


“From a biomolecular perspective, cannabinoids act not as foreign intruders but as complementary ligands within a preexisting molecular conversation between the human body and its endogenous signaling systems. Their therapeutic potential lies not in chemical novelty but in biological familiarity—a fact consistently reaffirmed by modern neurobiological research despite legal obstruction.”

“This five-decade longitudinal case study provides a rare and informative window into the long-term psychobiological effects of sustained botanic cannabinoid use within a cognitively demanding professional context. Contrary to prohibition-era narratives that associate chronic cannabis exposure with cognitive decline, emotional dysregulation and motivational impairment, the findings of this investigation demonstrate a trajectory of preserved neurocognitive integrity, stabilized affective functioning, and enhanced adaptive resilience. These outcomes are consistent with contemporary psychoneuroimmunological models in which the endocannabinoid system operates as a central regulator of homeostatic equilibrium across neural, immune, and endocrine domains.”

https://zealjournals.com/wjbpr/content/clinical-endocannabinoid-deficiency-and-cognitive-continuity-longitudinal-case-study

Antibacterial Effect of Cannabinoids on Bacteria Associated with Persistent Endodontic Infections

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“Cannabinoids have been shown to have effective antibacterial applications.

With the limitations of current intracanal endodontic medicaments and the rise of bacterial resistance, it is important to investigate novel treatment strategies for endodontic infections. The aim of this study was to test the antibacterial efficacy of cannabinoids on bacteria in persistent endodontic infections: Enterococcus faecalis, Streptococcus mutans, and Fusobacterium nucleatum.

Planktonic bacteria were exposed to a negative control (no exposure), a positive control (3% NaOCl), and the experimental groups Cannabidiol (CBD), Cannabinol (CBN), and Tetrahydrocannabinol (THC). The Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) were also investigated. Biofilms were cultured and treated with cannabinoids. A crystal violet assay (CVA) and live/dead analysis assessed the biofilm degradation and inhibition, respectively. A statistical analysis was performed using an ANOVA.

CBD, CBN, and THC reached a MIC for both E. faecalis and S. mutans in planktonic forms. The MBC was found for the tested cannabinoids on planktonic E. faecalis. No MBC was found for S. mutans. The live/dead analysis of E. faecalis and S. mutans biofilms showed a decrease in the viability of the biofilm with an increased cannabinoid concentration. The CVA revealed that cannabinoids only degrade the E. faecalis biofilm. Planktonic F. nucleatum had no MIC for tested cannabinoids.

Cannabinoids have inhibitory effects on E. faecalis and S. mutans in the planktonic and biofilm states. No inhibitory effects of F. nucleatum were found at tested concentrations of all three cannabinoids.

The findings suggest that cannabinoids have distinct antibacterial effects on certain pathogens associated with persistent endodontic infections.”

https://pubmed.ncbi.nlm.nih.gov/41465362

https://www.mdpi.com/1422-0067/26/24/11936

Neuropathic Pain and Related Depression in Mice: The Effect of a Terpene and a Minor Cannabinoid in Combination

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“Background/Objectives: Neuropathic pain is one of the most severe types of chronic pain. Although it is difficult to manage, it often co-occurs with depression. Yet, no medication addresses the neuropathic pain and depression comorbidity. Therefore, developing integrated treatment strategies that address both pain and depression is a major public health priority and an unmet need affecting millions. 

Methods: In this study, we investigated the effect of combining a terpene, Beta-Caryophyllene (BCP), and cannabidiol (CBD) on neuropathic pain and associated depression. We employed a chronic constriction injury (CCI) neuropathic pain model and a series of behavioral tests to evaluate how oral administration of this combination influences neuropathic pain and depression-like behaviors in mice. We employed immunohistochemistry and proteomics approaches to explore the mechanism. 

Results: The analgesic effect of combining CBD and BCP is synergistic in neuropathic pain and also shows an antidepressant effect. Additionally, we found that this combination decreases neuroinflammation associated with CCI and affects specific genes involved in the inflammation. 

Conclusions: This work provides preclinical scientific evidence supporting the potential usefulness of this combination for neuropathic pain and associated depression.”

https://pubmed.ncbi.nlm.nih.gov/41463111

“Cannabis plants contain various non-psychoactive compounds, including Caryophyllene (BCP). BCP is a natural bicyclic sesquiterpene that acts as a natural ligand for the cannabinoid type 2 receptor (CB2) and is an FDA-approved food additive. It has several benefits, such as pain relief, antidepressant effects, and anti-inflammatory properties.

Given this background, the main goal of this study is to test the hypothesis that combining CBD and BCP is effective for neuropathic pain while also demonstrating antidepressant effects.”

“In conclusion, the proposed project introduces the concept that the combination of CBD and BCP can effectively relieve neuropathic pain while also addressing depression. This knowledge will advance the field by providing preclinical scientific evidence supporting the potential usefulness of this combination for neuropathic pain and associated depression.”

https://www.mdpi.com/2227-9059/13/12/3103


Therapeutic Potential for Cannabidiol on Alzheimer’s Disease-Related Neuroinflammation: A Systematic Review and Meta-Analysis

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“Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder characterized by chronic neuroinflammation; current interventions primarily offer symptomatic relief. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits multi-target therapeutic potential due to its established anti-inflammatory and neuroprotective properties.

While growing interest exists, the evidence regarding CBD’s effects on AD-related neuroinflammation has not been robustly consolidated in a quantitative meta-analysis. Therefore, this article reviews the current literature around CBD related to its potential in alleviating neuroinflammation, followed by a meta-analysis of preclinical and clinical studies using random-effects modeling to assess CBD efficacy on neuroinflammation and clinical outcomes in AD.

In preclinical AD models, the meta-analysis demonstrated that CBD significantly and consistently reduced key markers of neuroinflammation and reactive gliosis, specifically glial fibrillary acidic protein (GFAP) (p < 0.0001), Interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). Effects on other markers, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), were non-significant and heterogeneous.

Clinical evidence, though limited by small sample size and heterogeneity, showed a borderline significant benefit favoring CBD for overall behavioral symptoms (p = 0.05), agitation, and caregiver distress. Adverse events were typically mild.

We conclude that CBD demonstrates biologically consistent anti-inflammatory efficacy in preclinical AD models.

While current clinical data remains insufficient to substantiate efficacy, they suggest promising signals for behavioral control. Determining CBD’s full therapeutic potential in AD necessitates future rigorous, mechanism-driven trials with standardized preparations and biomarker-anchored endpoints.”

https://pubmed.ncbi.nlm.nih.gov/41465389

“CBD remains a biologically plausible, multi-pathway candidate for modulating neuroinflammation and behaviorally relevant circuits in AD.”

https://www.mdpi.com/1422-0067/26/24/11963