Author Archives: David

Tetrahydrocannabivarin (THCV) Dose Dependently Blocks or Substitutes for Tetrahydrocannabinol (THC) in a Drug Discrimination Task in Rats

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“Delta-9-Tetrahydrocannabivarin (THCV), a naturally occurring cannabinoid and structural analog of THC, exhibits a dual pharmacological profile as a CB1 receptor agonist/antagonist and a partial CB2 agonist. This study evaluated the effects of THCV in a THC discrimination model in rats. Male Sprague-Dawley rats (n = 16, 300-340 g, PND60) were trained under a fixed ratio 20 (FR20) schedule to discriminate THC (3 mg/kg) from vehicle. Substitution tests were conducted with THC (0.325-3 mg/kg), THCV (0.75-6 mg/kg), and THC-THCV combinations. THCV produced an inverted U-shaped substitution curve, significantly differing from vehicle (p = 0.008). At 3 mg/kg, THCV partially substituted for THC (54.6% ± 17.82, p = 0.003). Response rate significantly increased during the substitution test with 3 mg/kg of THCV (p = 0.042). THCV (6 mg/kg) reversed THC (0.75 mg/kg)-induced responding (p = 0.040), with no significant change in response rate (p = 0.247). However, THCV combined with THC (1.5 mg/kg) affected response rates (p = 0.012), with 6 mg/kg significantly reducing rates vs. 3 mg/kg (p = 0.013). Blood THC and 11-OH-THC levels remained unchanged when THC was combined with THCV. The findings suggest THCV can partially mimic or block THC’s discriminative effects in a dose-dependent manner, possibly acting as a partial CB1 agonist.”

https://pubmed.ncbi.nlm.nih.gov/41008636/

“Taken together, our findings highlight THCV’s unique pharmacological profile, characterized by partial agonism dose-dependent substitution for THC, and antagonism at higher doses. Importantly, THCV substituted for THC in a graded manner without evidence of pharmacokinetic interactions, and it also produced stimulant-like effects that distinguish it from THC. These results suggest that THCV may act as a dose-dependent modulator of cannabinoid receptor activity, capable of both mimicking and opposing THC’s discriminative stimulus effects. Such bidirectional properties are consistent with its complex receptor pharmacology and underscore the importance of dose in determining behavioral outcomes. Future studies should expand on these findings by examining sex- and strain-dependent variability, assessing the role of CB1 and CB2 receptor mechanisms using antagonist approaches, and exploring THCV’s actions across a broader range of behavioral paradigms, including those related to reward, cognition, and feeding behavior. Together, these efforts will help to clarify the pharmacology of THCV and further delineate its position within the cannabinoid spectrum.”

https://www.mdpi.com/2218-273X/15/9/1329

Cannabizetol, a Novel Cannabinoid: Chemical Synthesis, Anti-inflammatory Activity and Extraction from Cannabis sativa L

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“We report the first isolation of a previously unknown cannabinoid, cannabizetol (CBGD, 7), from Cannabis sativa extracts, representing the third member of the rare class of methylene-bridged dimeric cannabinoids. The availability of a chemically synthesized standard was crucial for its unequivocal identification, thus confirming the natural occurrence of this new compound.

In addition to this structural discovery, we demonstrate that cannabizetol exhibits remarkable antioxidant and skin anti-inflammatory activity, significantly higher than that observed for the known dimeric cannabinoid cannabitwinol (CBDD, 6).

These results highlight cannabizetol as a promising bioactive metabolite with potential dermatological applications. To further enable its study, we developed a continuous flow approach to optimize the preparation of these dimers, achieving a substantial reduction in reaction times.”

https://pubmed.ncbi.nlm.nih.gov/40994228/

“Several cannabinoids have demonstrated biological activities, making Cannabis sativa particularly attractive as a source of potential medicinal active principles.”

https://pubs.acs.org/doi/10.1021/acs.jnatprod.5c00826

Cannabidiol attenuates heroin seeking in male rats associated with normalization of discrete neurobiological signatures within the nucleus accumbens with subregional specificity

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“Background: Opioid use disorder is a chronic relapsing condition characterized by cycles of compulsive drug use, abstinence, and relapse. Cannabidiol (CBD), a non-intoxicating cannabinoid, is under investigation as an anti-relapse treatment. CBD attenuates cue-induced heroin-seeking in a rodent model of relapse, and reduces craving and anxiety induced by drug-associated cues in abstinent individuals with heroin use disorder. The neurobiological mechanisms by which CBD may exert its anti-relapse effects are unknown.

Methods: The objective of the current study was to evaluate the effects of CBD administration on heroin-seeking behavior in conjunction with transcriptomic profiling in the nucleus accumbens core (NAcC) and shell (NAcS).

Results: Heroin-trained animals exhibited high levels of cue-induced heroin-seeking behavior. Importantly, CBD attenuated cue-induced heroin-seeking behaviors. Postmortem RNA-sequencing of the NAcC and NAcS revealed shared transcriptomic alterations the NAc subregions in response to heroin, with a more robust impact of heroin in the NAcS. Though CBD had minimal impact on the heroin-induced perturbations in the NAcC, it normalized components of the transcriptomic signature altered by heroin in both NAc subregions including transcripts that correlated with heroin-seeking behavior. In contrast, CBD normalized a particular subset of NAcS genes that correlated to heroin-seeking behavior. Those genes were specifically linked to the extracellular matrix, astrocyte function, and their upstream regulators related to immune function.

Conclusion: These findings underscore the NAc subregional signatures of heroin-induced neurobiological perturbations and provide novel biological targets relevant for CBD’s apparent anti-relapse effects.”

https://pubmed.ncbi.nlm.nih.gov/40992584/

https://linkinghub.elsevier.com/retrieve/pii/S0006322325014623

Cannabinoid treatment impacts adaptive behavior in autism patients and caregivers’ mental health: A prospective real-life cohort study

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“Introduction: Pharmacological interventions for behavioral symptoms of Autism Spectrum Disorder (ASD) are limited and recent studies point out benefits with the use of cannabinoids.

Method: This longitudinal observational study investigates ASD symptoms after 3 months of starting cannabidiol (CBD)-rich extract therapy and it’s impact on the mental health of caregivers. Assessment was based on clinical and socioeconomic questionnaire, Autism Treatment Evaluation Checklist (ATEC), Childhood Autism Rating Scale (CARS) and Vineland 3 Scale. The Brief Symptom Inventory (BSI) was applied to evaluate caregiver’s health.

Results: Sixteen patients with ASD who received cannabinoid treatment (CBD group) and seventeen patients with ASD without cannabinoid treatment (control group). CBD group was characterized as severe autism, ATEC total (SD) 85.5 ± 34.00, while controls as moderate, ATEC total (SD) 58.6 ± 25.53 (p = 0.047). After 3 months of treatment, CBD group showed a reduction in maladaptive behavior – internalizing (Vineland 3) (p = 0.008), and their caregivers a reduction in symptoms of Interpersonal Sensitivity (BSI) (p = 0.038), Global Severity Index (BSI) (p = 0.025) and Positive Symptom Distress Index (BSI) (p = 0.007), indicating reduction on mental health symptoms. For the control group, after 3 months there was a significant increase in scores for Daily Living Activities (Vineland 3) (p = 0.031) and Socialization (ATEC) (p = 0.037).

Conclusion: This study suggests that therapy with cannabidiol (CBD)-rich extract in severe ASD may have positive effects on anxious and depressive symptoms, potentially positively impacting on the mental health of their caregivers.”

https://pubmed.ncbi.nlm.nih.gov/40967683/

http://linkinghub.elsevier.com/retrieve/pii/S0079612325001311

Molecular pathogenesis of Alzheimer’s disease onset in a mouse model: effects of cannabidiol treatment

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“Introduction: Alzheimer’s disease (AD) is a common neurodegenerative condition involving a complex blend of disturbances in synaptic development and maintenance, neurovascular cross-talk, ionic and nutrient transport, and mitochondrial metabolism. The precise molecular profile of AD onset with insight for major pathological contributors remains unclear with corresponding impedances in therapeutic development. The current study sought two objectives, as (i) to resolve the molecular pathogenesis from cognitive impairment to the onset of AD-like neuropathology and (ii) whether the novel agent cannabidiol (CBD), noted for its neuroprotective effects, influences the molecular transition associated with AD onset.

Methods: Dietary CBD was administered daily (80-100 mg/kg/day) in male 3xTg-AD mice and wild-type B6129SF2/J animals from 4.5 to 6.5 mo of age with inclusion of vehicle controls. RNA sequencing encompassed longitudinal and cross-sectional blood and brain samples, respectively. Metabolomics and behavioral analyses examined brain regions (cortex, hippocampus) and associated integrated neurocircuitry.

Results and discussion: There were >1,000 differentially expressed markers of AD onset, whereby >75% were either eliminated or reversed in the direction of expression in response to CBD. Signaling pathways encompassed synaptic development and plasticity (e.g., Foxp2), neurovascular interactions (Smad9, Angptl6), receptors and ion channels (Gria4, Chrna2, Rgs7/Rgs7bp), mitochondrial genes (Ndufa7, Cox7a2), immunity (Ncr1), oxidation-reduction (Esr1), lipid synthesis (Fasn, ApoE), and carbohydrate metabolism (Mafa, Mlxipl). As potentially addressable with CBD treatment, AD onset represents molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and aberrations in developmental genes with involvement of major pathological contributors such as inflammation, oxidative signaling, dyslipidemia, and insulin resistance.”

https://pubmed.ncbi.nlm.nih.gov/40979532/

“Altogether, with all details enclosed in the primary manuscript and Supplementary Files, we hereby conclude that the onset of Alzheimer’s disease represents a molecular integration of neurovascular interactions, channelopathies, metabolic disturbances, and developmental genes gone awry with notable overlap among other neurological (e.g., Parkinson’s and frontotemporal dementia) and non-neurological (e.g., cancer) conditions. Remarkably, chronic cannabidiol treatment has the potential to widely address and almost completely disrupt molecular signatures of the onset of Alzheimer’s disease.”

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2025.1667585/full

Cannabinoids in preclinical research of sepsis: a scoping review

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“Background: Sepsis is a global health problem that ends millions of lives and costs billions of dollars in treatment and management every year. This disease is responsible for one in every five deaths worldwide, and is the third leading cause of death in hospitals. Despite decades of research, no current specific treatment or cure are available, only supportive and symptomatic care, and few preclinical studies reach human trials. Since the discovery of the endocannabinoid system (ECS), cannabinoids have been researched as a potential treatment for various diseases, including sepsis. Our review aimed to summarize what is known about the endocannabinoid system research in preclinical sepsis.

Methods: A scoping search was conducted in the databases Pubmed, Scopus and Web of Science. Articles were selected in case they studied a cannabinoid or the ECS in preclinical sepsis or septic shock, with no time limit. Data regarding animals species, model os sepsis, treatments, cannabinoids utilized and main outcomes were analyzed.

Results: We found that the most commonly used animal species was both Mus musculus and Rattus norvegicus, and the most frequently performed sepsis model was the endotoxemia induced by lipopolysaccharide (LPS). The most studied receptor was cannabinoid receptor type 2 (CB2) and among all cannabinoid types, synthetic cannabinoids were researched in the majority of the studies. We also discuss the evaluated outcomes, as well as their involvement with the endocannabinoid system and underlying molecular mechanisms. We highlight the main promising results and explore the limitations and future challenges in the field.

Conclusion: Cannabinoids are promising therapeutic targets in the treatment of sepsis, as they improved survival, and reduced inflammation and organ injury. However, deleterious adverse effects were reported, with the underlying molecular mechanisms still unknown, and further research is needed to evaluate their benefits and future use in clinical research.”

https://pubmed.ncbi.nlm.nih.gov/40956450/

https://link.springer.com/article/10.1007/s00011-025-02090-9

Cannabis Improves Metabolic Dysfunction and Macrophage Signatures in Obese Mice

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“Obesity rates continue to rise, highlighting the need for new treatments that are effective, safe, and widely accessible. Aligned with the easing of restrictions on cannabis use, interest in its therapeutic potential is evolving. As such, we examined the effects of the cannabis plant with high cannabidiol (CBD) content or high Δ9-tetrahydrocannabinol (THC) content on metabolic and immune dysregulation in obese mice.

Briefly, female C57BL/6 mice were randomized into four groups (n=15/group): 1) Lean, 2) Obese Placebo, 3) Obese CBD, and 4) Obese THC. Lean mice consumed a low-fat diet for the study duration. Obese mice consumed a high-fat diet for 16 weeks prior to a 4-week cannabis (3x/week; high CBD = ~4.2 mg/kg and high THC = ~7.3 mg/kg) intervention.

Consistent with our hypothesis, obesity increased Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and metabolic dysfunction-associated steatohepatitis (MASH) both of which were significantly mitigated by either high (10.5%) CBD or high (18.16%) THC cannabis (p<0.05). Interestingly, these changes appeared to occur independent of significant weight loss or measurable changes in food intake.

Diet-induced obesity also increased infiltrating macrophages, pan macrophages, and M1-like pro-inflammatory macrophages in adipose tissue and liver. These effects were rescued by high CBD and high THC (p<0.05), providing evidence consistent with causation for the improvements in HOMA-IR and MASH.

Despite the legal complexities surrounding cannabis use, these data suggest both CBD and THC can be a viable therapy to target macrophages and improve metabolic health and immune dysregulation with obesity.”

https://pubmed.ncbi.nlm.nih.gov/40960937/

https://journals.physiology.org/doi/abs/10.1152/ajpcell.00503.2025

Orally Administered CBD/CBG Hemp Extract Reduces Severity of Ulcerative Colitis and Pain in a Murine Model

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“Background: Ulcerative colitis (UC) is an autoimmune disorder characterized by inflammation of the mucosa that gives rise to a disrupted epithelial morphology. Persistent or recurrent inflammation and the debilitating nature of the associated symptoms make treatment of UC challenging. Cannabinoids derived from Cannabis sativa L. have been used for treatment of gastrointestinal disorders due to the wide-ranging therapeutic benefits of these compounds. 

Methods: We evaluated a commercial hemp extract, high in cannabigerol (CBG) and cannabidiol (CBD), as a novel treatment for UC symptoms using the dextran sodium sulfate (DSS) model in mice. Hemp extract was administered via two different routes of administration, intraperitoneal (i.p) and oral (p.o). 

Results: Specifically, we observed that cannabinoid treatment reduced damage to the colonic epithelium. We also observed that CBG/CBD rich hemp extracts help reduce pain-related responses in these animals. 

Conclusions: Together, the data suggest that cannabinoid administration has the potential to be an effective alternate therapeutic option for UC management.”

https://pubmed.ncbi.nlm.nih.gov/40943856/

“Our current findings suggest that minor cannabinoids, particularly CBD and CBG, may prove to be useful, novel therapies for treating IBD. These findings are important because patients already report using cannabis and cannabinoid-based products for managing their symptoms, despite little clinical data to support the use of high-THC products for treating IBD.

In conclusion, our data suggest that HE enriched for CBD and CBG may offer therapeutic potential as a treatment for IBD patients.”

https://www.mdpi.com/2077-0383/14/17/6095

Chemical Composition and Antioxidant Activity of the Stembark Essential Oils of Two Cannabis sativa L. Cultivars from Komga, South Africa

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“Cannabis sativa L. is an aromatic medicinal plant with various biologically active classes of compounds such as cannabinoids, polyphenols, and terpenes.

Unlike the widely investigated inflorescence and leaf, the stembark of C. sativa has been overlooked regarding its medicinal potential. This study, therefore, was aimed at determining the chemical composition and antioxidant activity of the essential oils (EOs) obtained from the fresh and dried stembark of two C. sativa cultivars, Lifter and Cherrywine, grown in Komga, South Africa, with a view to ascertaining the more promising cultivar.

The chemical profiles of the hydro-distilled EOs were analyzed by gas chromatography-mass spectrometry (GC-MS), while an in vitro antioxidant activity assessment of the EOs was performed using DPPH and H2O2 spectrophotometric methods. The identified constituents from the EOs were molecularly docked against NOX2, a protein implicated in oxidative stress. The afforded EOs were colorless with a mild skunk-like odor. A total of thirty-two constituents were identified in both fresh and dry oils from the Lifter cultivar while the Cherrywine cultivar contained a total of forty-two constituents.

The EOs of both cultivars contained twenty compounds, notably Cannabidiol (0.25-85.03%), Caryophyllene oxide (1.27-19.58%), Caryophyllene (0.64-16.61%), Humulene (0.37-8.15%), Octacosane (3.37-6.55%), Humulene-1,2-epoxide (0.45-5.78%), Nerolidol (0.32-4.99%), Palmitic acid (1.45-4.45%), Tetracosane (1.75-2.91%), Dronabinol (0.86-2.86%), Cannabinol (0.54-1.64%), 7-epi-γ-eudesmol (0.53-1.00%), Guaiol (0.37-0.66%), Linoleic acid (0.22-0.60%), γ-Selinene (0.15-0.48%), β-Eudesmol (0.34-0.50%), and Linalool (0.24-0.30%).

The dried Lifter stembark oil (DLSO) gave the best antioxidant activity among the four investigated cannabis oils, exhibiting the lowest IC50 values of 21.68 ± 1.71 and 26.20 ± 1.34 µg/mL against DPPH and H2O2 radicals, respectively. The notable antioxidant activity of the DLSO may be attributed to the higher number (30) of constituents compared to the fresh Lifter stembark oil (LSO) with 11 constituents. Additionally, the DLSO showed a unique chemical profile comprising monoterpenes, oxygenated and hydrocarbon sesquiterpenes. Further in silico studies on the putative constituents in the Lifter cultivar revealed Cannabinol, Cannabidiol, and Linalool as the promising constituents based on their higher binding energy scores of -9.7, -8.5, and -6.5 kcal/mol, respectively, compared to L-Ascorbic acid (-5.7 kcal/mol).

It can be inferred from this study that the EOs from the stembark of C. sativa contain promising compounds, such as Cannabinol, Cannabidiol, and Linalool, which might be responsible for the displayed antioxidant activity of the oils. Thus, the study findings underscore the biological importance of C. sativa stembark in the management of oxidative stress-related conditions.”

https://pubmed.ncbi.nlm.nih.gov/40943472/

https://www.mdpi.com/1422-0067/26/17/8552

Impact of Medical Cannabis on the Quality of Life of Cancer Patients: A Critical Review

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“Purpose: This study aimed to review the literature on the impact of medical cannabis (MC) on the quality of life (QoL) of cancer patients. 

Materials and Methods: A critical review was conducted using PubMed, Latin American and Caribbean Health Sciences Literature, Scopus, Virtual Health Library, and Embase. The inclusion criteria were access to the full content; in English, Spanish, or Portuguese; published until January 2025, relating “Cancer,” “Quality of Life,” and “Medical Cannabis.” Of the 267 articles identified, 16 were selected for the final analysis. 

Results: The studies suggest that MC can improve mental health, sleep, appetite, and pain in cancer patients and decrease nausea, vomiting, and the use of other medications, such as opioids. Increased survival time and cognitive function improvements were also observed, with mild or moderate adverse effects. Both tetrahydrocannabinol and cannabidiol (full spectrum) were commonly used, with varied intervention durations. 

Conclusion: Despite differences and methodological limitations, including only four randomized clinical trials, which precluded systematic review or meta-analysis, findings suggest that MC may improve QoL for cancer patients by alleviating physical and psychosocial symptoms associated with cancer treatment. In contrast, some mild or moderate adverse effects may be present. Moreover, the use of MC faces challenges such as the interaction with some chemotherapy treatment. More randomized controlled trials are needed to better understand the effects of MC among oncology patients.”

https://pubmed.ncbi.nlm.nih.gov/40932699/

https://www.liebertpub.com/doi/10.1177/27683605251377417