“Cannabidiol (CBD) has shown potential for treating schizophrenia (SCZ) by targeting its positive and negative cognitive symptoms. In this study, we investigated if CBD could reverse the memory impairment observed after chronic administration of the NMDA receptor antagonist MK-801.
Chronic treatment with MK-801 (0.5 mg/kg i.p., twice a day, for 14 days) resulted in short- and long-term memory deficits and decreased relative power of γ oscillations in freely moving animals. CBD administration (30 mg/kg i.p. daily for seven days after the MK-801 treatment period) reversed these changes. The cognitive effects of CBD were prevented by blocking 5-HT1A but not CB2 receptors.
At the cellular level, the depletion of parvalbumin-positive neurons and their associated perineuronal nets in the prelimbic medial prefrontal cortex (mPFC) and ventral hippocampus (vHip) induced by MK-801 was reversed by CBD. This neuroprotective effect was mediated by 5-HT1A and CB2 receptors in the vHip but was independent of these receptors in the mPFC. Additionally, CBD reversed MK-801-induced microglial activation in both mPFC and vHip, again through 5-HT1A and CB2 receptors.
These findings suggest that CBD modulates multiple pathways affected in SCZ-like conditions, offering a promising therapeutic avenue for SCZ treatment.”
“We previously found that enhancing the levels of 2-arachidonoylglycerol (2-AG) and anandamide (AEA) could improve autism spectrum disorder (ASD) symptoms. This study investigated the effect of cannabinoid type 1 receptor (CB1R) in ASD with pharmacological, genetic and brain-targeted intervention and the underlying mechanisms.
Results showed that blocking CB1R counteracted the beneficial effects of boosting 2-AG or AEA on ASD-like behaviors in valproic acid (VPA)-exposed mice. Besides, CB1R knockout mice exhibited ASD-like behaviors and synaptic deficits.
In CB1R-specific brain-targeted regulation, activating CB1R ameliorated synaptic dysfunction, including neuronal complexity, spine density, dendritic integrity, synaptic protein expression, and neuronal damage. Moreover, activating CB1R enhanced the expression and current density of Kir4.1, indicating that CB1R may influence synaptic activity by modulating Kir4.1.
Collectively, our findings indicated a critical role for CB1R in the improvement of ASD-like behavior and synaptic dysfunction, which may offer promising avenues for developing effective treatments for ASD.”
“Background: Cancer remains a major global health issue, prompting the need for innovative treatment approaches that extend beyond conventional methods such as chemotherapy and radiation. The endocannabinoid system (ECS), primarily the cannabinoid receptors CB1R and CB2R, presents a promising opportunity for cancer therapy by selectively targeting cell signaling pathways. This systematic review intends to explore the mode of action of synthetic cannabinoids as potential anticancer agents and their impact on tumor growth in various cancer cell lines.
Methods: Of the 287 articles identified between January 1990 and July 2024, 27 studies met strict criteria focusing on their anticancer effects. Data extraction and quality assessment were conducted using GRADE criteria and the Cochrane Risk of Bias tool, ensuring robust evaluation of the studies’ reliability.
Results: Various pharmacological actions of synthetic cannabinoids function as agonists, antagonists, and inverse agonists at the CB1R and CB2R receptors. Key findings indicate that CB2R agonists significantly reduce cancer cell proliferation through diverse mechanisms, with selective CB2R agonists effectively inhibiting cancer cell growth and survival. Studies involving CB1R antagonists, particularly in conjunction with CB2R agonists, highlight their role in blocking CB1R to either validate or enhance the efficacy of CB2R agonists in mitigating tumor growth. Inverse agonists targeting CB2R have shown moderate success in inducing cancer cell death by disrupting survival pathways. Notably, synthetic cannabinoid agonists display significant potential in targeting CB1 and CB2 receptors to inhibit tumor proliferation and promote apoptosis across various cancer types.
Conclusion: The systematic review concludes that CB2R agonists can effectively inhibit tumor growth while inducing apoptosis in various cancers. Although CB1R agonists show potential in modulating cancer pathways, there is a notable lack of research on CB1 inverse agonists, emphasizing the need for further investigation. Additionally, the study advocates for greater exploration of mixed receptor agonist and receptor mode of action to validate these promising therapeutic approaches.”
“Phytocannabinoids, which are the natural cannabinoids found in Cannabis sativa, have been extensively studied for their potential anticancer effects. These compounds act as agonists for cannabinoid receptor 1 and cannabinoid receptor 2, facilitating their therapeutic applications through the activation of these CBRs. By activating CB1R and CB2R, phytocannabinoids produce various therapeutic effects, including anti-nociception, anti-inflammation, anticonvulsant, and anti-emetic properties.”
“Background: Alzheimer’s Disease (ad) patients often experience clinically significant agitation, leading to distress, increased healthcare costs and earlier institutionalisation. Current treatments have limited efficacy and significant side effects. Cannabinoid-based therapies, such as the nabiximols oral spray (Sativex®; 1:1 delta-9-tetrahydrocannabinol and cannabidiol), offer potential alternatives. We aimed to explore the feasibility and safety of nabiximols as a potential treatment for agitation in ad.
Methods: The ‘Sativex® for Agitation & Aggression in Alzheimer’s Dementia’ (STAND) trial was a randomised, double-blind, placebo-controlled, feasibility study conducted in UK care homes. Participants with probable ad and predefined clinically significant agitation were randomised to receive placebo or nabiximols for 4 weeks on an up-titrated schedule, followed by a 4-week observation period. To be considered feasible, we prespecified the following thresholds that needed to be met: randomising 60 participants within 12 months, achieving a ≥ 75% follow-up rate at 4 weeks, maintaining ≥80% adherence to allocation and estimating a minimum effect size (Cohen’s d ≥ 0.3) on the Cohen-Mansfield Agitation Inventory. This trial is registered with ISRCTN 7163562.
Findings: Between October 2021 and June 2022, 53 candidates were assessed; 29 met eligibility criteria and were randomised. No participants withdrew, and adherence was high (100%) and was generally feasible to deliver. The intervention was well tolerated (0 adverse reactions), with no safety concerns reported.
Interpretation: Despite significant COVID-19 pandemic related challenges, administering nabiximols through oral mucosa to advanced ad patients with agitation demonstrated feasibility and safety. These findings support a larger confirmatory efficacy trial to evaluate the potential therapeutic efficacy of nabiximols for agitation in ad.”
“In conclusion, this study demonstrates the feasibility of a pilot randomised, placebo-controlled trial of nabiximols oral spray for agitation in AD patients in care homes, with no safety concerns observed.”
“Low-dose mixed delta-9-tetrahydrocannabinol and cannabidiol showed favourable safety profile and high tolerability.”
“Recent work has shown that people with HIV (PWH) exhibit deficits in cognitive control and altered brain responses in the underlying cortical networks, and that regular cannabis use has a normalizing effect on these neural responses.
However, the impact of regular cannabis use on the neural oscillatory dynamics underlying motor control deficits in PWH remains less understood. Herein, 102 control cannabis users, control nonusers, PWH who regularly use cannabis, and PWH who do not use cannabis performed a motor control task with and without interference during high-density magnetoencephalography. The resulting neural dynamics were examined using whole-brain, voxel-wise statistical analyses that examined the impact of HIV status, cannabis use, and their interaction on the neural oscillations serving motor control, spontaneous activity during the baseline period, and neurobehavioral relationships.
Our key findings revealed cannabis-by-HIV group interactions in oscillatory gamma within the prefrontal cortices, higher-order motor areas, and other regions, with the non-using PWH typically exhibiting the strongest gamma interference responses. Cannabis-by-HIV interactions were also found for oscillatory beta in the dorsal premotor cortex. Spontaneous gamma during the baseline was elevated in PWH and suppressed in cannabis users in all regions exhibiting interaction effects and the left primary motor cortex, with spontaneous levels being correlated with behavioral performance.
These findings suggest that regular cannabis use has a normalizing effect on the neural oscillations serving motor control and the abnormally elevated spontaneous gamma activity that has been widely replicated in PWH, which may suggest that cannabis has at least some therapeutic utility in PWH.”
“Further, these findings corroborate multiple recent studies showing elevated spontaneous gamma activity in PWH, and that regular cannabis use is associated with a marked suppression in such spontaneous activity.”
“Despite effective combination antiretroviral therapy (cART), chronic neuroinflammation and glial dysfunction continues to be an important yet understudied issue with people living with HIV (PLWH).
The endocannabinoid system is increasingly recognized as a potential therapeutic target for modulating neuroimmune environments, given its role in regulating synaptic plasticity, immune responses, and neuroinflammatory cascades. However, the extent to which cannabinoids influence HIV-associated neuroinflammation remains unclear.
This study investigates the impact of Δ9-tetrahydrocannabinol (THC) on astrocyte growth characteristics, viability, and senescence-associated cytokine release following exposure to HIV Tat protein using primary mixed glial cultures derived from rhesus macaques. Real-time impedance-based cellular integrity assessments were conducted using the xCELLigence system, while morphological analyses and cytokine quantification were performed using phase-contrast microscopy and multiplex immunoassays.
Treatment of macaques with THC protected the astrocytes from virus-induced senescence.
Further, THC facilitated a rapid recovery from Tat-induced decline in astrocyte adhesion, suggesting a compensatory effect. THC promoted glial process elongation and morphological complexity, indicative of a shift toward a neuroprotective phenotype. Furthermore, THC significantly reduced inflammatory cytokine secretion, including TNF-α, IL-6, and IL-1β, in an apparently dose-dependent manner.
These findings suggest that THC may modulate neuroinflammation in PLWH by promoting astrocytic survival, suppressing inflammatory cytokine secretion, and enhancing neurotrophic signaling. However, prolonged exposure to high-dose THC may negatively impact glial survival.
The results underscore the complexity of cannabinoid signaling in the CNS and highlight the potential of cannabinoid-based interventions to mitigate HIV-associated neuroinflammation.”
“Introduction: Marijuana use is associated with HPV-positive head and neck squamous cell carcinoma (HNSCC). However, cannabinoid use continues to increase in the US general population for recreational purposes as well as in cancer patients for palliative care. In this study, we explored the role of cannabidiol (CBD) in promoting anti-tumor activity by modulating immune response in HPV-positive HNSCC by using pre-clinical models.
Methods: The anti-proliferative effect of CBD on HPV-positive HNSCC cells was evaluated through BrdU, apoptosis and migration analyses, followed by western blot analysis to assess its role in activating the MAPK pathway. Next, the anti-tumor immune response of CBD was evaluated in immunocompetent syngeneic mouse as well as in immune-deficient B6.129S7-Rag1tm1Mom/J or Rag 1 Knockout mice (Rag1 -/-) and athymic nude mouse. Immune cell infiltration was measured by flow cytometry, IHC and multiplex IHC analysis after subcutaneous injection of mEER cells. Furthermore, the anti-tumor activity of CBD on the tumor microenvironment was evaluated after the depletion of CD4+T cells and CD8+T cells in murine models.
Results: We observed CBD treatment inhibited cell proliferation and migration by promoting apoptosis in HPV-positive HNSCC cells through activation of the MAPK pathway and its associated markers like ERK1/2, JNK/SAPK and MK2. CBD significantly inhibited tumor growth in immunocompetent mice but had no effect in immune-deficient models, indicating an immune-dependent mechanism. CBD enhanced infiltration of CD4+T and CD8+T cells, CD19+B cells, NK cells, and M1-like macrophages into the primary tumors of immunocompetent syngeneic mice models, implicating an enhanced anti-tumor immune response. Interestingly, we observed a significant increase in tumor volume in CD4-depleted mice treated with CBD as compared to CBD-treated wild-type mice suggesting the importance of CD4+T cells in CBD-mediated anti-tumor activity. Finally, multiplex IHC analysis demonstrated co-localization of CD4+T and CD8+ T cells with the activated MAPK marker phospho-p38 in CBD-treated tumors.
Discussion: CBD inhibits tumor cell proliferation in HPV-positive HNSCC by activating the MAPK pathway. It also enhances anti-tumor activity by modulating the tumor immune microenvironment, promoting co-localization of p38 MAPK-activated CD4+ and CD8+ T cells.”
“In conclusion, our study suggests that CBD inhibits tumor cell proliferation in HPV-positive HNSCC by activating MAPK pathway and exhibits anti-tumor activity by modulating the CD4+T and CD8+T cells in the tumor immune microenvironment. Therefore, CBD may potentially provide a supportive role in cancer therapy through immune-mediated mechanisms.”
“As such, specific cannabinoids may become an integral component of comprehensive cancer treatment regimens, offering new hope to patients with HPV-positive head and neck cancer.”
“Fungal infections pose a major threat to human health with increasing incidence of antifungal resistance globally. Despite the need for novel antifungal drugs, few are currently in clinical development.
Here we evaluate the antifungal activity of five phytocannabinoids against several clinically relevant fungal pathogens, with a focus on the priority pathogen Cryptococcus neoformans.
Our results demonstrate that Cannabidiol (CBD), and particularly Cannabidivarin (CBDV), have broad activity against C. neoformans and other fungal pathogens, including dermatophytes that cause common tinea. We found that both CBD and CBDV acted in a fungicidal manner and prevented biofilm formation in C. neoformans.
Phytocannabinoid treatment impeded factors important for virulence and antifungal resistance, including reduced capsule size and disruption of mature biofilms. Proteomics analysis revealed that the antifungal activity of CBD and CBDV was linked to destabilisation of the membrane, alterations in ergosterol biosynthesis, disruption of metabolic pathways, as well as selective involvement of mitochondrial-associated proteins. We next tested the ability of CBD to topically clear a C. neoformans fungal infection in vivo using the Galleria mellonella burn wound model, and we observed greatly improved survival in the CBD treated larvae.
This study illustrates the potential of phytocannabinoids as antifungal treatments and opens up new routes towards development of novel antifungal drugs.”
“Fungal infections are a major public health issue affecting over a billion people globally. Current antifungal treatments are increasingly compromised by drug resistance and show adverse side effects, underscoring the urgent need for novel therapies.
Phytocannabinoids like Cannabidiol (CBD) and Cannabidivarin (CBDV), which have established safety profiles and are approved or under investigation for neurological conditions, may hold promise in this domain. Despite this, their antifungal properties remain underexplored.
Here we show that CBD and CBDV exhibit in vitro antifungal activity against various fungi, including common dermatophytes causing “jock itch” and “athlete’s foot”, as well as WHO Critical Priority pathogens, such as Cryptococcus neoformans. Further investigation in C. neoformans revealed that CBD and CBDV appear to work by disrupting biofilms, altering fungal cell morphology, and impacting metabolic pathways and membrane integrity, as observed through comparative proteomics. Further, in vivo experiments using Galleria mellonella infected with C. neoformans revealed significantly improved survival with CBD treatment.
The in vitro and in vivo antifungal efficacy of CBD and CBDV established in this study highlights the potential of phytocannabinoids to address the pressing need for effective and new treatments for fungal infections.”
“Overall, this study highlights promising antifungal properties of the phytocannabinoids CBD and CBDV against select fungal pathogens. We demonstrated not only their fungicidal activity against C. neoformans, but also their potential effectiveness against wider Cryptococcus strains, various other yeasts, and moulds including common dermatophytes, emphasizing their potential broader applicability in the clinic and the community.
We demonstrated that the phytocannabinoids appear to work via disrupting biofilms and altering cell morphology, while clear impacts on metabolism and membrane production could be observed with comparative proteomics. We finally showed that for the commonly available CBD, in vivo survival of G. mellonella was significantly boosted after C. neoformans infection, emphasizing the clear potential of CBD as an antifungal.
Taken together, the demonstrated efficacy of CBD and CBDV as broad antifungal agents, coupled with their established safety profile, makes them an exciting resource as a foundation for the development of future therapeutic interventions.”
“Introduction: As opioid-related drug overdoses remain a public health crisis, there is a critical need for innovative approaches to developing safer analgesics with improved safety profiles. BDH-001 is a fixed-dose combination of low-dose buprenorphine (BUP) and cannabidiol (CBD) being developed as a safer analgesic than currently available opioids. The purpose of this study was to examine the analgesic and opioid-sparing effects of BDH-001 and to complete an in vivo safety assessment in rats.
Methods: Analgesic effect of BDH-001 was assessed using the chronic constriction injury model of chronic neuropathic pain with pain threshold assessed via Von Frey testing. Drug-drug interaction effects on pharmacokinetic (PK) parameters were assessed in a single dose PK study in rodents. The effects on respiratory depression were also assessed and confirmed in two separate rodent studies performing blood gas analysis and measuring O2 saturation.
Results: BDH-001 (combination of subanalgesic BUP dose and CBD) resulted in statistically significant increases in pain threshold compared to saline (p < 0.001), CBD alone (p < 0.01), and BUP alone (p < 0.05). The half-life of BUP was significantly shorter in the presence of CBD compared to BUP alone (p = 0.008), with no significant changes in any other BUP pharmacokinetic parameter assessed. CBD was found to attenuate BUP-induced respiratory depression in rats when assessing blood gases (p < 0.05) and O2 saturation (p < 0.05) over several time bins.
Conclusions: Data obtained in the present study indicate the addition of CBD to BUP was opioid-sparing and attenuated BUP- but not morphine-induced respiratory depression. There was no evidence these findings were the result of a PK interaction. Results support the hypothesis that BDH-001, a fixed-dose combination of BUP and CBD, may provide effective analgesia with a more favorable safety profile.”
“Buprenorphine is a medication that plays a crucial role in treating opioid use disorder (OUD), also known as opioid addiction. It works by partially activating the same receptors in the brain as opioids, helping to reduce withdrawal symptoms and cravings without producing the intense euphoria or dangerous side effects associated with full opioid agonists like heroin or fentanyl.”
“Background: People with Parkinson’s disease (PD) may use cannabis-based products for symptom management. In France, products containing tetrahydrocannabinol (THC) are prohibited, while cannabidiol (CBD)-products are readily available. However, data on cannabinoid use in French people with PD are lacking.
Objectives: To identify correlates of the use of cannabis-based products and to document their patterns of use and perceived effects. Methods: A French nationwide online survey was conducted from May to July 2023. Regression analyses helped identify factors associated with current cannabis and CBD use (regardless of their form). Patterns of use and self-reported effects were also documented.
Results: The study sample comprised 1136 participants, with a median age of 68 years. Six percent (5.9%) and 17.9% reported using cannabis and CBD, respectively. Both substances were associated with better knowledge of cannabinoids and a poor self-perceived household economic situation. The most common routes of cannabis administration were oral ingestion (44.8%) and smoking (41.4%); for CBD, they were oral ingestion (82.8%) and smoking (6.4%). Users reported that cannabis and CBD were very effective for sleep disorders, pain, and rigidity/cramps. The satisfaction level for both substances was also high.
Conclusion: Cannabis and CBD use among people with PD was associated with better knowledge about cannabinoids and a poor self-perceived household economic situation. Furthermore, users reported high levels of satisfaction for both substances. An enhanced communication with healthcare providers and facilitated access to safe cannabis/CBD products are needed in France to enable people with PD to maximize the benefits of cannabinoids when clinically appropriate.”
“Users commonly reported improvements in sleep disorders, pain, and rigidity/cramps. An enhanced communication with healthcare providers and facilitated access to safe products are needed in France so that people with PD can maximize the benefits of cannabinoids when clinically appropriate.”
