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

“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

“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 faecalisStreptococcus 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

Resurrected Ancestral Cannabis Enzymes Unveil the Origin and Functional Evolution of Cannabinoid Synthases

“Cannabinoids, such as tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) and cannabichromenic acid (CBCA), are bioactive and medicinally relevant compounds found in the cannabis plant (Cannabis sativa L.). These three compounds are synthesised from a single precursor, cannabigerolic acid (CBGA), through regioselective reactions catalysed by different cannabinoid oxidocyclase enzymes.

Despite the importance of cannabinoid oxidocyclases for determining cannabis chemotype and properties, the functional evolution and molecular mechanism of this enzyme family remain poorly understood. To address this gap, we combined ancestral sequence reconstruction and heterologous expression to resurrect and functionally characterise three ancestral cannabinoid oxidocyclases.

Results showed that the ability to metabolise CBGA originated in a recent ancestor of cannabis and that early cannabinoid oxidocyclases were promiscuous enzymes producing all three THCA, CBDA and CBCA. Gene duplication and diversification later facilitated enzyme subfunctionalisation, leading to extant, highly-specialised THCA and CBDA synthases. Through rational engineering of these ancestors, we designed hybrid enzymes which allowed identifying key amino acid mutations underlying the functional evolution of cannabinoid oxidocyclases. Ancestral and hybrid enzymes also displayed unique activities and proved to be easier to produce heterologously than their extant counterparts.

Overall, this study contributes to understanding the origin, evolution and molecular mechanism of cannabinoid oxidocyclases, which opens new perspectives for breeding, biotechnological and medicinal applications.”

https://pubmed.ncbi.nlm.nih.gov/41454532

“Cannabinoids are specialised metabolites produced by the plant Cannabis sativa L. (cannabis).”

https://onlinelibrary.wiley.com/doi/10.1111/pbi.70475

Cannabigerol Exerts In Vivo and In Vitro Anti-Inflammatory Effects via Inhibition of the MAPK and NF-κB Pathways

Cannabis sativa L. has a long history of use and contains more than 80 cannabinoids. However, although cannabigerol (CBG), which acts as a biosynthetic precursor of its most abundant phytocannabinoids, has anti-inflammatory effects, the exact mechanism of action remains underexplored.

In this study, we explored the anti-inflammatory potential of CBG to assess its potential for therapeutic and industrial applications.

CBG was extracted from the cannabis cultivar ‘Pink Pepper’ In vitro assays were performed via RAW 264.7 mouse macrophages stimulated with lipopolysaccharide, and in vivo efficacy was evaluated through a carrageenan-induced paw edema mouse model to confirm the activity of CBG in acute inflammation.

Nitric oxide production, mRNA, and protein expression of inflammatory mediators were suppressed by CBG treatment in a process downregulated through the MAPK and NF-κB pathways. Although paw edema was not statistically significantly reduced, oral administration of CBG suppressed the expression of COX-2, iNOS, TNF-α, IL-1β, and IL-6 in the carrageenan-induced mouse model.

CBG has been demonstrated to exert significant anti-inflammatory effects via modulation of key inflammatory mediators and signaling pathways in both in vivo and in vitro models.

Our findings further support the potential of CBG as a bioactive compound for further anti-inflammatory research.”

https://pubmed.ncbi.nlm.nih.gov/41423277

https://www.jmb.or.kr/journal/view.html?doi=10.4014/jmb.2509.09034

Cannabidiol attenuates the LPS/D-Galactosamine-induced acute liver injury by inhibiting parkin-mediated ubiquitination of MFN2

Ethnopharmacological relevance: Acute liver injury (A-LI) is a clinical syndrome that can rapidly progress to acute liver failure, resulting in high mortality and poor prognosis. Cannabis sativa L. is an important herbaceous plant that has been widely used in folk medicine since ancient times. Cannabidiol (CBD) is its most abundant non-psychoactive compound, exhibiting hepatoprotective, anti-inflammatory, and antioxidant properties. However, the protective effect of CBD against A-LI and its mechanism remain unclear.

Objective: This study aimed to investigate the protective effects of CBD on A-LI and elucidate the underlying molecular mechanisms.

Methods: In vivo, an A-LI mouse model was induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or CBD. H&E staining, alanine aminotransferase (ALT), aspartate aminotransferase (AST) level assay, TUNEL staining, TEM, IF, RT-qPCR, Western blot, Co-IP and adeno-associated virus (AAV) infection were performed. In vitro, RAW264.7 cells were stimulated with LPS. CCK-8, ELISA, MMP, mitochondrial ROS assay, siRNA knockdown and plasmid overexpression were performed.

Results: CBD (2.5 or 5 mg kg-1) mitigated LPS/D-GalN-induced liver damage, suppressed inflammatory cytokine expression, reduced hepatocellular apoptosis, and inhibited oxidative stress. CBD treatment increased hepatic mitofusin-2 (MFN2) protein while decreasing Parkin-MFN2 binding and MFN2 ubiquitination. In RAW264.7 cells, CBD pretreatment (2.5 or 5 μM) dose-dependently attenuated LPS-induced inflammation, apoptosis, and mitochondrial dysfunction and likewise elevated MFN2 levels while limiting its ubiquitination. MFN2 knockdown abolished CBD’s protective effects, whereas MFN2 overexpression restored them. Consistently, AAV-mediated delivery of MFN2-targeting short hairpin RNA reversed the hepatoprotective action of CBD in vivo.

Conclusion: CBD mediates anti-inflammatory and hepatoprotective effects by inhibiting MFN2 degradation through disrupting the interaction between Parkin and MFN2. These results provide molecular evidence for application of CBD in treatment of A-LI and provide references to the drug development for A-LI.”

https://pubmed.ncbi.nlm.nih.gov/41419044

“The natural plant extract cannabidiol (CBD) attenuates acute liver injury.”

Cannabis sativa L. (family Cannabaceae) is a valuable natural plant resource that has been used as a folk medicine since ancient times.”

https://www.sciencedirect.com/science/article/abs/pii/S037887412501760X?via%3Dihub

Changes in sleep quality during the 12 months following medical cannabis initiation

Background: Poor sleep quality is a commonly reported reason for medical cannabis (MC) use, yet evidence regarding its long-term impact on sleep remains limited. This study evaluated changes in subjective sleep quality over a 12-month period among adults initiating MC treatment in Pennsylvania and explored whether preferred route of administration and referring condition were associated with observed changes.

Methods: A total of 137 adults newly referred for MC in PA completed the Pittsburgh Sleep Quality Index (PSQI) at baseline and at 3, 6, 9, and 12 months. Linear mixed effects models assessed changes in PSQI global and subscale scores over time. Additional models evaluated whether preferred administration route (oral vs. other) and referring condition (chronic pain, anxiety, PTSD) were associated with differences in observed outcomes.

Results: Global sleep quality scores, where higher values indicate poorer sleep quality, were significantly higher at baseline than at each follow-up point (p < .0001), with no significant differences among follow-up assessments, suggesting early and sustained improvements in self-reported sleep quality. Improvements were observed across all PSQI subscales. No significant relationships were found between sleep quality scores and either administration route or referring condition.

Conclusions: These findings suggest that MC may be associated with improvements in subjective sleep quality, though its impact did not vary as a function of administration route or primary referring condition. Additional research using objective sleep measures and controlled designs is needed to clarify MC’s role in sleep quality.”

https://pubmed.ncbi.nlm.nih.gov/41422305

https://link.springer.com/article/10.1186/s42238-025-00376-7

Letters From the Field: Challenges and Opportunities in the Development of Botanical Drugs From Cannabis

“Cannabis and cannabis-derived products (CCDPs) have gained recognition for their therapeutic potential, driving legal and social shifts worldwide. In the United States, state-level medical cannabis programs exist alongside the federal drug development framework, which remains the gold standard for ensuring safety and efficacy.

The Food and Drug Administration (FDA) botanical drug development guidance provides a structured approval pathway for plant-derived products, including CCDPs, accounting for their unique chemical complexity. Despite this guidance, significant gaps persist in preclinical and clinical data, particularly for minor cannabinoids.

Development of botanical drugs from cannabis is further complicated by regulatory oversight from the Drug Enforcement Administration, which constrains the cultivation, handling, and distribution of cannabis and imposes logistical and security requirements during drug development.

This article discusses the unique experience of drug developers navigating the scientific and regulatory challenges inherent in advancing CCDPs toward FDA drug approval. Collaborative efforts among federally compliant drug developers, regulatory bodies, healthcare providers, academic institutions, investors, and patients/patient advocacy groups are critical to generate rigorous, reproducible evidence to support the safe and effective use of CCDPs in medical conditions where they hold the greatest therapeutic potential. Such partnerships can advance studies that elucidate cannabinoid pharmacology, optimize dosing with rigorously characterized materials via clinically relevant routes, and identify clinical outcomes that are meaningful to patients.

Advancing CCDPs through federally compliant drug development pathways will enable the translation of promising botanical therapies into safe, effective, and evidence-based treatments, ultimately informing clinical practice and benefiting patients.”

https://pubmed.ncbi.nlm.nih.gov/41421888

https://www.clinicaltherapeutics.com/article/S0149-2918(25)00407-2/abstract

Cannabinoid and cannabinoid related receptors in fibroblasts, inflammatory and endothelial cells of the equine hoof with and without laminitis: novel pharmacological target

Background: Evidence suggests that the endocannabinoid system (ECS) is crucial for regulating inflammation, cell proliferation and pain. The ECS is composed of cannabinoid receptors such as type 1 (CBR1), type 2 (CBR2) and GPR55, endocannabinoids and enzymes. Proteins of ECS have previously been localized in the epidermal cells of the horse hooves. Given the physio-pathological role and cellular distribution of the ECS across species, the authors hypothesized that cannabinoid receptors are expressed within the inflammatory cells, fibroblasts and endothelial cells of the equine hoof laminae, going beyond the epidermal cells.

Objectives: To preliminary analyze the gene expression of Cn1r, Cn2r and GPR55 in the hoof laminae and test the specificity of the antibody against GPR55. To characterize the distribution and expression of CBRs in the inflammatory cells and fibroblasts of the laminar junction of equine healthy hooves and with laminitis.

Animals: Animals were divided into 3 groups: healthy, acute laminitis and chronic laminitis. A total of 18 samples were collected and processed from the front limb of animals slaughtered for consumption or euthanized (6 control animals, 4 acute laminitis, 8 chronic laminitis).

Methods: Analysis of CBR1, CBR2 and GPR55 protein expression was made by fluorescence microscopy with co-localization with antibodies against the macrophages marker IBA1, the T cell marker CD3, the neutrophils marker calprotectin (MAC387), the fibroblasts marker vimentin (Clove V9) and the nerve fibers marker Substance P. Preliminary analysis was performed to evaluate gene expression (Cnr1Cnr2, and Gpr55) using real-time PCR and to verify the specificity of the primary antibody (Gpr55) with Western Blotting (WB).

Results: The resident pool of inflammatory cells in the normal laminae and the inflammatory infiltrate cells of the affected equine laminae showed protein expression of CB2R and GPR55; no CB1R staining was seen at the inflammatory cells. Equine dermal fibroblast and endothelial cells exhibited protein expressions of CB1R, CBR2 and GPR55. Substance P positive nerve fibers were positive for CB1R.

Conclusions and clinical importance: Cannabinoid receptors are expressed in different immune cell types of the hoof laminae, pointing to the role of the ECS in modulating inflammatory outburst, tissue degeneration and pain. Our results serve as a foundation for the development of new veterinary pharmacotherapies that target the ECS during laminitis.”

https://pubmed.ncbi.nlm.nih.gov/41394912

“The present findings highlight the presence of cannabinoid receptors CB1, CB2, and GPR55 in the inflammatory cells, fibroblasts and endothelial cells of healthy and pathological hoof lamellar epithelial tissue. The modulation of CB1R, CB2R, and GPR55 signaling pathways could offer novel therapeutic approaches for managing hoof diseases.”

https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2025.1723160/full

Marijuana Legalization and Suicides Among Older Adults

“Suicide rates among older adults have been rising over time in the United States. At the same time, more individuals have been suffering with chronic pain and illness, which are often underlying risk factors for suicide. As self-medication with marijuana has become common, we ask whether access to legal marijuana for medical and recreational purposes reduces suicides rates among older individuals. We find that suicide rates among older age groups decline following the opening of recreational marijuana dispensaries, especially among older Whites, and middle-aged White males and females with low levels of education.”

https://www.nber.org/papers/w34519

Cannabidiol promotes fine-tuning of natural killer and monocytic cells subsets as well as cytokine storm during chikungunya virus exposure in vitro: Insights for putative therapeutic interventions

“Chikungunya virus (CHIKV) is an arbovirus that causes acute and chronic disease by strong stimulation of the immune system. It activates innate and adaptive immune cells, including monocytes, natural killer (NK) cells, and lymphocytes, as well as soluble mediators such as IL-17A, IFN-γ, IL-13, and IL-7. Despite the significant morbidity associated with CHIKV, no specific antiviral therapy is currently available.

In this context, natural compounds with immunomodulatory potential, such as cannabidiol (CBD), represent promising candidates. Here, we investigated whether CBD modulates immune responses following CHIKV stimulation. Peripheral blood mononuclear cells (PBMCs) were stimulated with inactivated CHIKV and treated with CBD. Immune cell subsets were analyzed by flow cytometry, and soluble factors were profiled by Luminex assay.

CBD treatment fine-tuned NK and monocyte subsets in vitro and attenuated key inflammatory pathways, particularly the IL-17A-IFN-γ axis, in response to CHIKV stimulation.

These findings identify CBD as a potential immunomodulatory candidate for innovative therapeutic strategies against CHIKV and other alphaviruses.”

https://pubmed.ncbi.nlm.nih.gov/41385863

“Altogether, our results show that Cannabidiol promotes fine-tuning of NK, monocytic subsets CHIKV stimuli in vitro. In addition, CBD attenuates key inflammatory pathways upon CHIKV immune recall, characterized by the IL-17A-IFN-g axis.

Overall, this study provides new insights into the immunological landscape of CHIKV-induced immunity and identifies CBD as a promising candidate for innovative immunomodulatory therapeutic strategies against the disease associated to this Alphavirus.”

“CBD could be a potential immunomodulatory agent against viral inflammation.”

“Overall, this study provides new insights into the immunological landscape of CHIKV infection and identifies CBD as a promising candidate for innovative therapeutic strategies against this disease.”

https://www.sciencedirect.com/science/article/pii/S0753332225010947?via%3Dihub