Cannabidivarin mitigates motor and cognitive impairments in a female mouse model of Rett syndrome

Posted on July 10, 2025 by David

“Rett Syndrome (RTT, #312750 – OMIM) is a rare, progressive neurodevelopmental X-linked disorder, caused mostly by mutations in the gene for the methyl CpG binding protein 2 (MECP2). MECP2 is a transcriptional and epigenetic regulator that has been proposed to modulate neuronal development and adult neurogenesis, processes disrupted in both RTT patients and mouse models.

Cannabidivarin (CBDV), a non-psychotropic cannabinoid, has recently been shown to promote adult neurogenesis through a mechanism mediated by transient receptor potential cation channel subfamily V member 1 (TRPV1).

This study aimed to investigate the effects of chronic CBDV administration in a female RTT mouse model.

Pre-symptomatic Mecp2^tm1.1Bird/J female mice underwent a chronic CBDV treatment (3 mg/kg/day), followed by behavioral tests to assess potential therapeutic effects.

While CBDV did not prevent deficits in locomotor activity, it mitigated motor coordination impairments in RTT mice. Furthermore, the novel object recognition test suggested that CBDV treatment contributed to the preservation of cognitive function in these animals. Moreover, CBDV administration induced genotype-dependent differences in neural stem cell proliferation, indicating a potential vulnerability in adult hippocampal neurogenesis in Mecp2-deficient contexts.

Taken together, these findings provide new insights into the role of CBDV in RTT and support for future research, highlighting its potential as a repurposed therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/40633901/

“The data presented in this manuscript demonstrates the therapeutic potential of CBDV in improving behavioral and phenotypic abnormalities in a female mouse model of RTT. Additionally, CBDV differentially affects adult hippocampal neurogenesis in this model.”

https://www.sciencedirect.com/science/article/pii/S0024320525004813?via%3Dihub

Acute Effects of Oral Cannabinoids on Sleep and High-Density EEG in Insomnia: A Pilot Randomised Controlled Trial

Posted on July 10, 2025 by David

“Cannabinoids, particularly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have gained popularity as alternative sleep aids; however, their effects on sleep architecture and next-day function remain poorly understood.

Here, in a pilot trial, we examined the effects of a single oral dose containing 10 mg THC and 200 mg CBD (THC/CBD) on objective sleep outcomes and next-day alertness using 256-channel high-density EEG in 20 patients with DSM-5 diagnosed insomnia disorder (16 female; mean (SD) age, 46.1 (8.6) years).

We showed that THC/CBD decreased total sleep time (-24.5 min, p = 0.05, d = -0.5) with no change in wake after sleep onset (+10.7 min, p > 0.05) compared to placebo. THC/CBD also significantly decreased time spent in REM sleep (-33.9 min, p < 0.001, d = -1.5) and increased latency to REM sleep (+65.6 min, p = 0.008, d = 0.7). High-density EEG analysis revealed regional decreases in gamma activity during N2 sleep, and in delta activity during N3 sleep, and a regional increase in beta and alpha activity during REM sleep. While there was no observed change in next-day objective alertness, a small but significant increase in self-reported sleepiness was noted with THC/CBD (+0.42 points, p = 0.02, d = 0.22). No changes in subjective sleep quality, cognitive performance, or simulated driving performance were observed.

These findings suggest that a single dose of cannabinoids, particularly THC, may acutely influence sleep, primarily by suppressing REM sleep, without noticeable next-day impairment (≥ 9 h post-treatment).”

https://pubmed.ncbi.nlm.nih.gov/40631525/

“This study is the first to use high-density EEG to explore the acute effects of oral THC/CBD on objective sleep outcomes in individuals with insomnia. A single oral dose significantly reduced total sleep time and REM sleep, without impairing next-day alertness.”

https://onlinelibrary.wiley.com/doi/10.1111/jsr.70124

Long-term cannabinoid therapy can ameliorate chronic sleep deprivation-induced behavioral and neuroinflammatory changes in mice

Posted on July 9, 2025 by David

“Endocannabinoid system is an important contributor to body’s immune responses which are significantly impaired by chronic sleep deprivation (cSD). Although cannabinoids can modulate the endocannabinoid system, most are understudied, especially regarding cSD.

To investigate the therapeutic potential of CBD, CBG, CBC and their combinations, current study analyzed cSD-induced memory impairment, depression, microglial responses, cytokine profile and therapeutic effects of cannabinoid treatments using behavioral test and ELISA. Furthermore, molecular docking of these cannabinoids was performed to deduce the binding affinity with cannabinoid receptors and possible entrouge effects.

The results showed that memory impairment and depression were more evident in cSD groups. Moreover, microglial activation and pro-inflammatory polarization was also more evident and was supported by increased pro-inflammatory cytokine concentrations in cSD groups.

These changes were significantly reversed the cannabinoid groups but the combination of CBD + CBC was more effective than other treatments in reversing these cSD-induced behavioral and neuroinflammatory changes. Whereas, the molecular docking results also corroborated with the neuroimmunological changes observed in the current study, pointing towards the possible therapeutic role.

SIGNIFICANCE STATEMENT: Chronic SD employs microglial activation/polarization, to exert behavioral impairments and neuroinflammation.

This study signifies the therapeutic potential of proper sleep and cannabinoid intake.”

https://pubmed.ncbi.nlm.nih.gov/40628367/

“This study demonstrates the therapeutic efficacy of cannabinoid treatments in ameliorating cSD-induced behavioral and neuroinflammatory alterations. Notably, a multiple-compound treatment of CBD and CBC exhibited superior effectiveness compared to single-compound treatments. These findings suggest potential avenues for developing effective interventions against cSD-induced detrimental changes.”

https://www.sciencedirect.com/science/article/abs/pii/S0304394025002022?via%3Dihub

Treatment of Migraine With Phytocannabinoids, the Involvement of Endocannabinoids in Migraine, and Potential Mechanisms of Action

Posted on July 9, 2025 by David

“The American Migraine Foundation estimates that over 39 million Americans and over 1 billion people worldwide suffer from some form of migraine. Treatment of migraine generally falls into two categories: treatment of attacks once they have begun, and prophylactic prevention, including lifestyle changes. The use of phytocannabinoids to reduce both the frequency and severity of migraine is widely documented in scientific, grey, and popular literature. This review provides descriptions of both preclinical and clinical studies involving the treatment of migraines with phytocannabinoids as well as the involvement of endocannabinoids and endocannabinoid-like compounds in migraine pathology, including the receptors and associated mechanisms. Currently unanswered questions and areas for further exploration are discussed.”

https://pubmed.ncbi.nlm.nih.gov/40630421/

“The clinical studies published to date strongly suggest that phytocannabinoids are useful for mitigating migraine pain and for migraine prophylaxis. Further, studies show the potential for endocannabinoid and endocannabinoid-like compounds in migraine treatment.”

https://onlinelibrary.wiley.com/doi/10.1155/prm/7181066

“Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.”

https://pubmed.ncbi.nlm.nih.gov/15159679/

Acute and chronic effects of medicinal cannabis use on anxiety and depression in a prospective cohort of patients new to cannabis

Posted on July 8, 2025 by David

“Introduction: Medicinal cannabis has mixed evidence for treating anxiety and depression, yet patients frequently use it as a treatment. This observational study evaluated the effects of medicinal cannabis initiation in adults with clinically significant anxiety and/or depression over a 6-month period.

Methods: Adults with clinically significant anxiety and/or depression initiating medicinal cannabis use in Maryland, USA completed ecological momentary assessment (EMA) and longitudinal follow-up evaluations. Hospital Anxiety and Depression Scale (HADS) assessments were completed at baseline and 1, 3, and 6 months after medicinal cannabis initiation. EMA measures were completed at baseline and daily for 8 weeks after cannabis initiation with measures collected before each cannabis use and at time of expected peak effect. Changes in anxiety and depression were evaluated using linear mixed effect models.

Results: Significant decreases from baseline in anxiety and depression were observed, with mean scores dropping below clinically significant levels within three months of initiation. EMA data indicated that most participants selected THC-dominant cannabis and acute reductions in anxiety, depression, and perceived driving ability along with increased ratings of feeling “high”. Acute effects were dose-dependent: 10-15 mg of oral THC and at least 3 puffs of vaporized cannabis yielded the most robust reductions in anxiety and depression.

Conclusions: Initiation of THC-dominant medicinal cannabis was associated with acute reductions in anxiety and depression, and sustained reductions in overall symptom severity over a 6-month period. Controlled clinical trials are needed to further investigate the efficacy and safety of medicinal cannabis for acute anxiety and depression symptom management.”

https://pubmed.ncbi.nlm.nih.gov/40623642/

“In this prospective, observational study, medicinal cannabis use was associated with significant decreases in self-reported anxiety and depression compared with pre-cannabis use initiation baseline assessments among individuals with clinically significant anxiety and/or depression. Reductions in anxiety and depression were observed acutely following individual episodes of cannabis use and overall symptom reductions were sustained over the six-month period of observation.”

https://www.sciencedirect.com/science/article/abs/pii/S0165032725012716?via%3Dihub

Prevention of Allodynia and Hyperalgesia by Cannabidiol in a Rat Model of Chemotherapy-Induced Peripheral Neuropathy

Posted on July 8, 2025 by David

“This study demonstrates the utility of a rat model of chemotherapy-induced peripheral neuropathy (CIPN) to assess the ability of the non-psychoactive cannabinoid cannabidiol (CBD) to modulate the development of this syndrome in vivo. The method utilizes the chemotherapeutic agent paclitaxel to generate an allodynic phenotype in the animals.

This study describes how to handle and solubilize CBD, administer the chemotherapeutic agent, assess mechanical and cold sensitivity, and apply high-speed videography to measure nocifensive behavior in animals.

Using the procedures outlined, the data support that CBD prevents the allodynic phenotype from developing in the treated animals. No difference was observed in the CBD-treated animals from day 0 (pre-paclitaxel baseline) to day 7 (post-sensitization) in mechanical or thermal sensitivity, while the vehicle-treated animals became significantly more sensitive.

This response to treatment is durable up to the latest time point where data were collected (7 weeks). The addition of high-speed videography allows for a more granular and unbiased assessment of this behavioral phenotype (e.g., classification of analgesia and anti-allodynia).

This demonstrates both the utility of this model for cannabinoid drug characterization and the potential role of CBD in mitigating neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/40622941/

“Co-administration of CBD with paclitaxel prevents the development of chemotherapy-induced peripheral neuropathy in rats. This protocol describes cannabinoid handling, inducing an allodynic phenotype in rats via chemotherapeutic administration, assessing mechanical and thermal allodynia, and using high-speed videography to distinguish allodynia and hyperalgesia.”

https://app.jove.com/t/68079/prevention-allodynia-hyperalgesia-cannabidiol-rat-model-chemotherapy

Impact of minor cannabinoids on key pharmacological targets of estrogen receptor-positive breast cancer

Posted on July 5, 2025 by David

“Endocrine therapy for estrogen receptor-positive (ER⁺) breast cancer has significantly improved over the last decades. However, it presents some limitations that make the search for novel therapeutic options mandatory.

Several studies have been conducted to understand the anti-tumor potential of cannabinoids in breast cancer. Yet, most of them are focused on the major phytocannabinoids Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). However, Cannabis has other minor phytocannabinoids whose anti-cancer properties are still to be elucidated.

Here, we investigated the mechanisms of action of four minor cannabinoids, cannabigerol (CBG), cannabidivarin (CBDV), cannabinol (CBN), and cannabichromene (CBC), in 2D and 3D ER⁺ breast cancer models.

These cannabinoids dysregulate MCF-7aro cell cycle progression, induce apoptosis by different mechanisms, and inhibit the growth of MCF-7aro spheroids. CBG exerts its effects through a down-regulation of both ER and AR protein levels, while CBDV reduces aromatase protein levels. CBN and CBC simultaneously affect the three targets, ER, aromatase, and AR.

In fact, CBN and CBC present an AR-dependent cell death, down-regulate aromatase levels, and act as ER negative regulators impairing cancer cell growth. CBN caused the most pronounced effects.

Overall, this study highlights the anti-cancer properties and the therapeutic potential of these minor cannabinoids in ER⁺ breast cancer.”

https://pubmed.ncbi.nlm.nih.gov/40615070/

https://www.sciencedirect.com/science/article/pii/S1388198125000666?via%3Dihub

A 1:1 combination of cannabidiol and Δ9-tetrahydrocannabinol inhibit toll-like receptor 7- and 8-mediated inflammation in human immune cells

Posted on July 5, 2025 by David

“Cannabinoid regulation of endosomal signalling via innate immune toll-like receptors (TLRs) is understudied. Endosomal cell signalling via TLR7 and TLR8 governs cellular responses to infection with viral and bacterial single-stranded RNA. TLR7/8 activation is associated with neuroinflammation, with inappropriate activation of TLR7/8 linked to the propagation of autoimmune disease. Following activation, TLR7 and TLR8 control the cellular production of cytokines, chemokines and type I interferons (IFNs).

In this study we focused on two clinically relevant plant-derived (phyto) cannabinoids, cannabidiol (CBD) and Δ⁹-tetrahydrocannabinol (THC), given that cannabinoid-based therapeutics containing these compounds are currently available in the form of sativex® (nabiximols) and epidiolex®. The study aim was to determine the anti-inflammatory effects of CBD and THC, when delivered in isolation and in a sativex-like combination (1:1), on TLR7/8-induced inflammation in immune cells.

We employed the use of CL075 (3M-002), a thiazoloquinolone derivative that acts as an agonist of both TLR7 and TLR8. Using THP-1-derived macrophages and primary peripheral blood mononuclear cells (PBMCs) from healthy control subjects, we demonstrate that TLR7/8 activation promoted the time- and concentration-dependent production of the chemokine CXCL10, cytokine TNFα and type I IFNs in both macrophages and PBMCs. TLR7/8 activation promoted nuclear factor (NF)-κB activation, p38 MAPK phosphorylation and the transcription of interferon regulator factor 7 (IRF7).

We assessed the anti-inflammatory effects of CBD and THC, when delivered alone and in a 1:1 combination, on CL075-stimulated inflammatory mediator production in macrophages/PBMCs. Data presented herein indicate that CBD and THC, particularly when delivered in a 1:1 combination, can act as TLR7/8 immunomodulatory drugs to dampen inflammation in macrophages and PBMCs.

This study provides evidence that phytocannabinoids target TLR7/8-induced viral signalling on endosomal compartments to control inflammation in immune cells.”

https://pubmed.ncbi.nlm.nih.gov/40615103/

“The significant finding is that CBD and THC can differentially ameliorate TLR7/8-induced inflammation in immune cells, depending on whether the cannabinoids are administered alone or in combination. In particular, the 1:1 combination of CBD:THC (at 10 μM) was consistently anti-inflammatory in immune cells stimulated with CL075. The CB₁, CB₂, PPAR-γ and A_2A receptors do not mediate the anti-inflammatory propensity of the phytocannabinoids in our cell models of inflammation.

Overall, data presented herein identifies TLR7/8-mediated inflammation as a phytocannabinoid target, and gives important insight regarding the cellular mechanisms by which CBD and THC regulate inflammation.”

https://www.sciencedirect.com/science/article/pii/S0014299925006326?via%3Dihub

Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1

Posted on July 4, 2025 by David

“Objective: Developmental and epileptic encephalopathy type 1 (DEE1) is a rare drug-resistant pediatric epilepsy caused by trinucleotide repeat expansions in the X-linked ARX gene, leading to elongation of the first polyalanine tract. It presents with early onset tonic seizures or spasms, developmental and cognition delay, and high risk of premature mortality. We evaluated the therapeutic potential of highly purified cannabidiol (CBD) in Arx^(GCG)7/Y mice, a genetic DEE1 model that replicates key features of the human condition.

Methods: Arx^(GCG)7/Y mice received daily intraperitoneal CBD (100 mg/kg) for 7 days. The epileptic phenotype was evaluated via video monitoring and a scoring matrix. In Arx-DEE1 male cortex, real-time polymerase chain reaction and Western blotting assessed CBD effects on proinflammatory and neuronal markers. Microglial morphology was analyzed by Iba1 immunostaining and Sholl analysis. In vitro patch-clamp recordings tested CBD activity on Arx^(GCG)7/Y cortical neurons.

Results: CBD reduced the severity and frequency of spontaneous recurrent seizures and significantly extended the lifespan of epileptic mice. In mutant symptomatic mice, CBD activated peroxisome Pparg expression and the concurrent desensitization/inactivation of TRPV1 channels. Additionally, CBD counteracted the dysregulated expression of the proinflammatory genes Ptgs2, Mmp9, Il12, Cd68, Ccl2, and Irf3, while also restoring normal microglial morphology. Further molecular analysis demonstrated that CBD effectively offsets normal alternative splicing for the presynaptic receptor genes Nrnx1 and Nrnx3. Consistent with this, CBD rescued proper Nrnx1 splicing in mutant cortical neurons after K⁺-induced depolarization. Finally, we found that CBD reduced neuronal excitability by inducing hyperpolarization, raising the action potential threshold, and reducing the frequency and mean charge of inhibitory postsynaptic currents and the mean charge of excitatory postsynaptic currents.

Significance: These findings represent the first preclinical evidence of CBD efficacy in a murine model of genetic DEE1, identifying CBD-sensitive downstream targets and paving the way to further exploration of CBD effects in this disease for future clinical consideration.”

https://pubmed.ncbi.nlm.nih.gov/40608247/

https://onlinelibrary.wiley.com/doi/10.1111/epi.18522

Evaluating the impact of cannabis oil for autistic children with and without concomitant medications: Insights from an open-label study

Posted on July 4, 2025 by David

“Background: Although only two drugs are FDA approved for autism spectrum disorder (ASD), clinical practice treatment includes off-label use of medications to address the troubling symptoms of ASD. Several trials showed the beneficial effects of medical cannabis for alleviating symptoms of ASD. However, data are lacking regarding its safety and effectiveness as a single agent compared to add-on therapy.

Aims: To compare the safety and effectiveness of medical cannabis as a monotherapy and add-on therapy in autistic children.

Methods: An open-label trial recruiting autistic children was performed and treated with medical cannabis oil with a THC:CBD ratio of 1:20, respectively. Tests were conducted at baseline and after 6 months of therapy. A secondary analysis was done to compare physical and behavior parameters, using tests such as Autism Diagnostic Observation Schedule and Wechsler tests in the two groups.

Results: Out of 109 participants, 81 completed the treatment. Thirty received cannabis as add-on therapy to a pre-existing treatment, whereas 51 received cannabis as monotherapy, with no observed differences in baseline characteristics between the groups. The mean maximal CBD dose was 3.1 mg/kg/day in the monotherapy group, compared to 2.8 mg/kg/day in the add-on group (p = 0.40). In patients treated with drugs for psychosis, the mean maximal dose was 2.48 mg/kg/day (p = 0.12). No differences were observed in most physical and behavioral parameters. In addition, no differences in CBD blood levels were observed.

Conclusions: Add-on cannabis therapy is as safe as monotherapy treatment, without significant differences in efficacy.”

https://pubmed.ncbi.nlm.nih.gov/40613426/

https://journals.sagepub.com/doi/10.1177/02698811251332841