Category Archives: THC (Delta-9-Tetrahydrocannabinol)

Natural cannabinoids effects on glutamatergic and dopaminergic neurotransmission in a transgenic model of Alzheimer’s disease

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“Background: Previous results demonstrated that chronic treatment with a combination of two natural cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), at non-psychotropic doses reduces cognitive decline, as well as the extracellular glutamate levels and the basal excitability in the hippocampus of APP/PS1 mice. In the present study, we aimed to elucidate whether this modulation of hippocampal excitability exerted by natural cannabinoids could affect the dopaminergic activity in limbic areas related to non-cognitive symptoms of Alzheimer’s disease (AD) in our animal model.

Method: We used glutamate and dopamine biosensors, along with fiber photometry techniques, to evaluate the levels of these neurotransmitters in the hippocampus and nucleus accumbens (NAcc), respectively. Experiments were conducted in anaesthetized animals for recording under an electrical hippocampal stimulation protocol, or in awake animals for recording during behavioral evaluations (novel object recognition, open field, sociability and prepulse inhibition tests).

Result: Chronic treatment with THC and CBD reversed the increased prominence and frequency of glutamate peaks observed in the hippocampus of APP/PS1 animals during the novel object recognition test at early stages of the AD-like process. At more advanced stages, APP/PS1 mice exhibited alterations in dopamine dynamics in the NAcc, which were compatible with psychotic-like traits observed in this animal model of AD. Interestingly, these alterations were partially modulated by chronic treatment with these natural cannabinoids.

Conclusion: Our results reveal that the combination of THC and CBD modulates glutamatergic activity in the hippocampus at early stages of the AD process and that, likely related to this, reduces dopaminergic alterations in limbic areas at advanced stages. Thus, these natural cannabinoids may alleviate both cognitive and non-cognitive symptoms occurring in AD, supporting their clinical development as a pleiotropic therapeutic alternative for this neurodegenerative disease.”

https://pubmed.ncbi.nlm.nih.gov/41454444

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70855_102846

Therapeutic potential of chronic CBD:THC co-treatment on disease-relevant behaviors of female TAU58/2 mice

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“Background: Limited therapeutic success and side effect profile of traditional but also novel antibody-based therapies for Alzheimer’s disease (AD) underline the need for alternatives. Cannabinoids have anti-inflammatory effects, are easily accessible and generally well tolerated. A dosage-dependent “entourage” effect has been described for phytocannabinoids such as cannabidiol (CBD) administered in combination with delta-9-tetrahydrocannabinol (THC). The effects of cannabinoid combination treatment on tau pathology, one of the major neuropathological hallmarks of AD, is poorly understood. Here, the effects of chronic treatment with CBD and THC on disease-relevant behaviors of female TAU58/2 transgenic mice were evaluated for the first time.

Method: Six-month-old TAU58/2 transgenic females (n = 28) and wild type-like control littermates (n = 22) were chronically treated with CBD+THC (50:3 mg/kg/day, i.p.) or vehicle for five weeks. Behavioral testing started after three weeks of treatment and included assessment of motor function, spatial and social recognition memory, anxiety and sensorimotor gating.

Result: Treatment and genotype effects on individual behavioral tests are summarized in Table 1. TAU58/2 transgenic females exhibited pronounced deficits in motor function, sensorimotor gating impairments, a prominent anxiolytic-like phenotype and subtle spatial memory deficits. Chronic CBD:THC co-treatment significantly improved aspects of motor function in pole test and accelerod. Moreover, anxiolytic-like behavior of TAU58/2 mice was partially reduced by cannabinoid treatment. Cannabinoids also showed the potential to improve spatial memory impairment of transgenic mice, though not confirmed by a significant treatment effect. Social recognition memory and sensorimotor gating were not affected by the treatment.

Conclusion: Here, long-term CBD:THC treatment at 50:3 mg/kg/day shows subtle but promising therapeutic effects in middle-aged TAU58/2 mice. Thereby, this study is the first to provide evidence for the therapeutic potential of CBD:THC co-treatment on tauopathy-related behavioral symptoms. Since CBD alone did not improve deficits of adult TAU58/2 mice in a previous study, these findings underline the potential of multi-cannabinoid therapy for the treatment of AD and contribute to the evaluation of the most efficient cannabinoid ratio. Ongoing tissue analysis addressing tau and inflammatory markers will reveal further insights into the underlying molecular mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41447176

https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz70859_099683

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

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“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

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

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“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

Selective anti-cancer effects of cannabidiol and Δ9-tetrahydrocannabinol via PI3K/AKT/mTOR inhibition and PTEN restoration in ovarian cancer cells

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“Introduction: Ovarian cancer is a highly lethal gynecological malignancy, often diagnosed at advanced stages. Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) demonstrate anti-tumor activity in various cancers including ovarian cancer through multiple signaling pathways and are increasingly explored as adjuncts to chemotherapy. However, the effects of CBD and THC combination treatment and its specific mechanisms remain unclear. This study evaluated the anti-tumor effects of CBD, THC, and their combination on SKOV3 and A2780 ovarian cancer cells, focusing on phosphorylation-dependent regulation of the PI3K/AKT/mTOR pathway.

Methods: SKOV3, A2780, and IOSE cells were treated with CBD, THC, and equimolar CBD: THC combinations. Cytotoxicity was assessed using Sulforhodamine B assay, while synergistic interactions were analyzed by the Chou-Talay method using CompuSyn. Cell cycle distribution and apoptosis were evaluated, and phosphorylation of PI3K, AKT, mTOR, and PTEN was examined by Western blotting.

Results: The CBD: THC combination treatment showed potent, selective cytotoxicity at 48 h, with lower IC50 values than in non-tumor IOSE80 cells. The Chou–Talalay method validated a synergistic effect between CBD and THC. The combination treatment induced cell cycle arrest and enhanced apoptosis. Western blot analysis exhibited that equimolar CBD: THC (2.5:2.5 μM) markedly reduced phosphorylation of PI3K, AKT, and mTOR, while increasing phosphorylation of PTEN, thereby reactivating tumor-suppressive signaling.

Conclusion: These findings highlight that CBD: THC combination treatment effectively inhibited ovarian cancer cell growth and invasion via oncogenic PI3K/AKT/mTOR signaling and reactivates PTEN. The combination may represent a promising targeted therapeutic approach, warranting further in vivo validation to elucidate its clinical potential.”

“Our study elucidated the multi-faceted anti-cancer properties of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), particularly in their combination treatment, by demonstrating potent and selective anti-cancer activities against ovarian cancer cells without harming non-tumor IOSE cells, establishing a favorable therapeutic index.

The combination treatment of CBD and THC exhibited concentration- and ratio-dependent synergy, inhibiting proliferation, and hindering metastatic potential through impaired migration and invasion while inducing apoptosis and attributing to mitochondrial membrane depolarization.

Mechanistically, we revealed that CBD and THC, particularly the CBD: THC combination effectively suppresses the PI3K/AKT/mTOR signaling axis by downregulating the phosphorylation of p-PI3K, p-Akt, and p-mTOR, whereas restoring the function of the tumor suppressor PTEN. This dual modulation of oncogenic and tumor-suppressive pathways endorses the therapeutic potential of CBD: THC treatment as a targeted anti-cancer strategy.

Our findings warrant further in functional phosphatase activity to confirm the reactivation of PTEN lipid phosphatase enzyme, and vivo validation and clinical exploration to optimize cannabinoid-based regimens for ovarian cancer treatment, especially considering the precise concentration- and ration-dependent nature of their interactions.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1693129/full

“Cannabis compounds show unexpected power against ovarian cancer”

“Scientists have discovered that key compounds from cannabis—CBD and THC—show surprisingly strong effects against ovarian cancer cells. Used together, they slow cell growth, reduce colony formation, and may even block the cancer’s ability to spread. Even more promising, the treatment caused minimal harm to healthy cells and appears to work by restoring a disrupted signaling pathway that fuels tumor growth”

https://www.sciencedaily.com/releases/2025/12/251215025315.htm

Treatment with a botanical mixture of cannabidiol:Δ9-tetrahydrocannabinol enhances microglial phagocytosis and shapes amyloid plaques in a mouse model of Alzheimer’s disease

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“The potential use of phytocannabinoids in neurodegenerative disorders is currently under intense investigation based on their potential anti-inflammatory, antioxidant, and neuroprotective effects.

Here, we tested the effects of chronic (28 days) treatment with a complex botanical mixture of purified cannabidiol:Δ9-tetrahydrocannabinol (CBD:THC, 99:1) in male 5xFAD mice, a murine model of Alzheimer’s disease that recapitulates amyloid pathology. Effects of exposure to this cannabinoid mixture were evaluated using behavioral tests (elevated plus maze for anxiety, tail suspension for depression-like behavior, rotarod for motor coordination, open field for locomotor activity, and novel object recognition for memory), quantification of protein expression (IL-1β, CD40, TREM2, COX2), assessment of functional parameters (microglial phagocytic activity by flow cytometry), and in vivo multiphoton microscopy (time-course of changes of neuritic plaque structural features). Twice daily dosing with 50 mg/kg subcutaneously (s.c.) significantly reduced locomotion, increased anxiety- and depression-like behaviors and had no effect on memory and motor coordination.

In vivo imaging experiments suggest that the CBD:THC treatment enhanced microglial phagocytic activity on amyloid plaques; this effect was observed both in plaque features (multiphoton microscopy measurements) as well as in microglia (flow cytometry data). Exposure to CBD:THC induced significant changes in in vivo microglia-amyloid interactions, increasing phagocytic activity and reducing the amyloid peptide accumulation in the neuritic plaques.

Thus, CBD:THC (99:1) may be a promising treatment to reduce amyloid pathology, though caution should be noted due to the behavioral alterations observed, i.e., increased anxiety- and depression-like behaviors as well as decreased locomotion.”

https://pubmed.ncbi.nlm.nih.gov/41389629

https://www.sciencedirect.com/science/article/pii/S0753332225010960?via%3Dihub


Investigating the effectiveness and adverse events of medicinal cannabis for patients with muscle spasticity or spasms

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“Appropriate treatment of muscle spasticity and spasms is important as these conditions may significantly impair patients’ quality of life. Conventional pharmacological treatments for these conditions have poor effectiveness and/or tolerability.

Cannabis is being explored as a treatment.

This was a longitudinal study of patient use of different cannabis products. Data was collected from patient surveys, clinic records, and changes in Patient Reported Outcome Measures Information System 29-Item scores over time. Patient-reported responses on health-related quality of life adverse events (n = 150) and outcomes (n = 78) from treatment for spasticity or spasms were analyzed. No improvements in physical functioning were observed for either group of patients across all product types. However, patients with spasticity who were using cannabidiol-only products experienced an improvement in sleep disturbance, fatigue, pain interference, and pain intensity.

Patients with spasms who were using balanced, cannabidiol-dominant, or tetrahydrocannabinol-dominant products also experienced improvements in these 4 outcomes. Commonly reported adverse events were dry mouth, drowsiness, fatigue, dizziness, and nausea. Despite no observation of improvement in physical functioning, the results suggest that cannabis may help relieve some of the secondary complications associated with these conditions, such as poor sleep and pain.

SIGNIFICANCE STATEMENT: This longitudinal study highlights differential benefits across cannabis product types, with cannabidiol-only formulations aiding spasticity-related symptoms and tetrahydrocannabinol- or cannabidiol-dominant products benefiting those with spasms.

These findings support the potential of cannabis as a potential therapy to improve health-related quality of life in patients with limited options from conventional pharmacological treatments.”

https://pubmed.ncbi.nlm.nih.gov/41386046

https://jpet.aspetjournals.org/article/S0022-3565(25)40293-6/abstract


Cannabis Use and Nicotine Vaping Cessation Outcomes: A Secondary Analysis of a Randomized Clinical Trial

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“Importance: Cannabis use is prevalent among adolescents and young adults who vape nicotine. It is not known if cannabis use affects nicotine vaping cessation success.

Objective: To assess whether baseline frequency of cannabis use or cannabis use disorder (CUD) symptom severity was associated with nicotine vaping cessation in a randomized clinical trial.

Design, setting, and participants: This secondary analysis of a randomized clinical trial with youth who vaped nicotine recruited at a single site in Massachusetts from June 2022 to May 2024. The trial included 3 groups receiving 12 weeks of varenicline treatment and placebo (both double-masked, paired with counseling), as well as single-masked referral to texting-app-based nicotine vaping cessation support (enhanced usual care [EUC]). Eligible participants were aged 16 to 25 years who reported vaping nicotine regularly and did not smoke tobacco.

Exposure: Baseline cannabis use was assessed via self-reported number of days of cannabis use per week and with Cannabis Use Disorder Identification Test (CUDIT) scores.

Main outcomes and measures: Biochemically verified 7-day point prevalence nicotine vaping abstinence at week 12. Logistic regression models estimated associations between baseline cannabis use and vaping abstinence. Interaction terms were evaluated to examine whether cannabis use moderated the effect of varenicline on nicotine abstinence.

Results: Among the 261 participants randomized to nicotine vaping cessation treatment (mean [SD] age, 21.5 [2.0] years; 139 female [53%]), 28% (73 participants) reported no past-month cannabis use, 38% (100 participants) reported using cannabis more than 0 and less than 4 d/wk, and 30% (78 participants) reported using cannabis 4 to 7 d/wk. Cannabis use frequency was not significantly associated with nicotine vaping cessation (eg, 4 to 7 d/wk use vs no use: adjusted odds ratio [aOR], 1.14; 95% CI, 0.51-2.57; overall P = .20). Nor did cannabis frequency modify the effect of varenicline (eg, abstinence varenicline vs placebo or EUC among those with 4 to 7 d/wk use: aOR, 8.47; 95% CI, 2.78-28.25; vs among those with no use: aOR, 5.60; 95% CI, 1.97-17.06; overall interaction P = .32). Findings were similar for CUD symptom severity.

Conclusions and relevance: Among adolescents and young adults attempting to reduce or stop nicotine vaping, baseline cannabis use was not associated with nicotine vaping abstinence. Varenicline proved helpful for nicotine vaping cessation regardless of cannabis use, indicating that co-use of cannabis may not represent a barrier to successful nicotine vaping cessation treatment.”

https://pubmed.ncbi.nlm.nih.gov/41385228

“Findings indicate that regular cannabis or alcohol use is not expected to diminish the effectiveness of offering varenicline for nicotine vaping cessation in youth.”

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2842688

Cannabis use and cardiometabolic risk in schizophrenia

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“Purpose: Metabolic syndrome (MetS) is common in schizophrenia and drives cardiovascular risk. While cannabis use and potency are increasing, the impact of cannabis on cardiometabolic health in schizophrenia remains unclear. This study assessed the association between objectively measured cannabis use and MetS prevalence in a large schizophrenia cohort.

Methods: We conducted a cross-sectional analysis of 988 participants with DSM-IV schizophrenia from the CATIE study. Cannabis use was measured via hair testing for tetrahydrocannabinol (THC), the gold standard for long-term use detection. MetS was defined per International Diabetes Federation criteria using physical and biochemical data. Multivariable logistic regression, adjusting for demographic, clinical, and lifestyle confounders, assessed the association between THC use and MetS.

Results: THC-positive participants (14.8 %) exhibited a significantly lower prevalence of MetS compared to non-users (42.5 % vs. 60.5 %, p < 0.001). After adjusting for confounders including age, sex, ethnicity, smoking, and other substance use, cannabis use remained independently associated with reduced odds of MetS (adjusted OR 0.64, 95 %CI 0.44-0.93, p = 0.02). Among MetS components, cannabis users had significantly lower odds of elevated waist circumference after adjustment (adjusted OR 0.61, 95 %CI 0.41-0.91, p = 0.02). Cannabis use was also associated with lower weight, BMI and triglycerides and higher HDL in unadjusted analyses. No significant differences were found in blood pressure or fasting glucose.

Conclusions: In schizophrenia, cannabis use was associated with lower rates of both metabolic syndrome and central obesity. While these findings support emerging evidence of metabolic differences in cannabis users, the cross-sectional design precludes conclusions regarding causality. Longitudinal studies are needed to clarify long-term metabolic effects and guide targeted interventions.”

https://pubmed.ncbi.nlm.nih.gov/41265115

“Cannabis use is associated with better cardiometabolic health in the general population, with users showing lower fasting insulin and glucose levels, reduced waist circumference, lower BMI, reduced systolic blood pressure (SBP) and higher high-density lipoprotein (HDL) cholesterol compared to non-users.”

“Growing evidence suggests cannabis users with psychotic disorders may have better metabolic health compared to non-users.”

“In summary, our findings demonstrate a significant association between cannabis use and a lower prevalence of metabolic syndrome in individuals with schizophrenia.”

https://linkinghub.elsevier.com/retrieve/pii/S0920996425004037

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

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

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

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

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

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

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