Modulation of spatial learning and memory by cannabinoid-estrogen interaction in an AD-like cognitive impairment: The role of cannabinoid receptors and BDNF protein

A 2026 study found that a THC-standardized marijuana extract improved spatial learning and memory in an Alzheimer’s-like model of cognitive impairment. Researchers tested the extract in rats exposed to amyloid-beta, a protein closely associated with Alzheimer’s disease, and observed improvements in memory performance.

The cognitive improvements were accompanied by changes in cannabinoid receptor signaling and in BDNF, or brain-derived neurotrophic factor, a protein that supports neuron survival, brain plasticity, learning, and memory. The findings suggest that the brain’s cannabinoid system and BDNF may be involved in the neuroprotective-like effects observed with the THC-standardized extract.

The researchers also examined the interaction with estrogen and found that adding estradiol did not produce an additional synergistic improvement. As the authors concluded, “These preclinical findings suggest that a THC-standardized marijuana extract may exert neuroprotective-like effects in an AD-like cognitive impairment model.”

“Alzheimer’s disease (AD) is an increasingly prevalent neurodegenerative disorder worldwide, with women showing a higher risk of developing the disease. The decline in steroid hormones after menopause may contribute to the increased susceptibility of women to neurodegenerative conditions.

In parallel, cannabis-derived compounds have been reported to alleviate certain symptoms associated with neurological disorders. The present study was designed to investigate the effects of marijuana extract on cognitive impairment and hippocampal molecular markers in an ovariectomized AD-like rat model, and to evaluate whether co-administration with estradiol modifies these effects.

The marijuana extract used in this study was characterized by HPLC and was found to contain 8.5% Δ9-THC. AD-like cognitive impairment pathology was induced by intra-hippocampal administration of Aβ25-35 in OVX rats. Animals were treated with marijuana extract (60 mg/kg/day, corresponding to approximately 5.1 mg/kg/day Δ9-THC) either alone or in combination with 17β-estradiol (1 mg/kg every 4 days) for 28 days. Cognitive performance was evaluated using the Morris water maze (MWM). In addition, hippocampal CB1/CB2 receptor expression and BDNF protein levels were measured to examine potential molecular associations.

Our findings showed that chronic administration of the marijuana extract improved Aβ25-35-induced deficits in spatial learning and memory.

Alterations in CB1 receptor expression and BDNF levels accompanied these behavioral effects. Notably, co-treatment with estradiol did not produce a synergistic effect, suggesting a complex interaction between cannabinoid-related and estrogen-related signaling pathways.

These preclinical findings suggest that a THC-standardized marijuana extract may exert neuroprotective-like effects in an AD-like cognitive impairment model. However, because the extract was not fully phytochemically characterized and the mechanistic analyses were correlational, the results should be interpreted cautiously. Further studies are needed to clarify the underlying mechanisms and translational relevance of these findings.”

https://pubmed.ncbi.nlm.nih.gov/42756662

“In conclusion, chronic administration of THC-standardized marijuana extract improved spatial learning and memory performance in the AD-like cognitive impairment model, and these behavioral changes were accompanied by alterations in hippocampal CB1/CB2 gene expression and BDNF protein levels.”

https://www.ibroneuroreports.org/article/S2667-2421(26)00149-1/fulltext

Cannabidiol Ameliorates Blood-Brain Barrier Dysfunction and Inhibits Memory Astrocytes Activation in Mice With Sickness-Like Behaviors

A new 2026 study published in CNS Neuroscience & Therapeutics found that cannabidiol (CBD) improved blood-brain barrier dysfunction, reduced neuroinflammation, and alleviated depressive-like behaviors in mice. The researchers found that sickness-like mice showed weakened blood-brain barrier integrity, reduced protective tight-junction proteins, abnormal astrocyte activation, and increased inflammation in the brain.

A single dose of CBD improved these changes, restoring important blood-brain barrier markers while reducing abnormal astrocyte activity and neuroinflammation. The researchers also identified a particularly interesting target called “memory astrocytes”—astrocytes that can respond more rapidly and strongly when exposed to a second inflammatory challenge.

The study found that CBD inhibited this memory-astrocyte-associated secondary inflammatory response, helping protect the blood-brain barrier and improve behavior. The researchers concluded that CBD may improve blood-brain barrier dysfunction associated with depression and identified memory-astrocyte-mediated neuroinflammation as a potential therapeutic target.

“Background: Blood-brain barrier (BBB) dysfunction has been increasingly implicated in the pathophysiology of depression; however, effective therapeutic strategies targeting this pathology remain limited. This study aimed to investigate the effect of cannabidiol (CBD) on improving depressive-like behaviors and BBB impairment, as well as its underlying mechanism.

Methods: Depressive-like behaviors in mice were assessed via exploratory and despair-like tests. BBB integrity was evaluated by examining tight junction protein expression in endothelial cells and AQP4 reduction from the perivascular membrane. Astrocyte activation and neuroinflammation were also measured. The therapeutic effects of a single CBD dose were examined.

Results: Mice with depressive-like phenotypes showed reduced exploratory behavior and increased despair-like behavior. In the BBB, the expression of tight junction proteins in endothelial cells was downregulated; in astrocytes, decreased AQP4 expression was observed, abnormal activation was enhanced, and neuroinflammation was elevated. A single dose of CBD alleviated all the above pathological changes. Further studies demonstrated that CBD exerted its effects by inhibiting memory astrocyte-associated secondary neuroinflammation, thereby alleviating depressive-like behaviors in mice with depressive-like phenotypes.

Conclusion: Experimental results show that CBD treatment can improve BBB dysfunction in depression and further indicates that targeted inhibition of memory astrocytes-mediated neuroinflammation may promote the treatment of depression.”

https://pubmed.ncbi.nlm.nih.gov/42747207

“Cannabidiol (CBD), a natural extract from cannabis, possesses multiple biological functions including cardioprotection, anti-inflammation, anti-cancer, anti-oxidation, and neuroprotection. Additionally, it plays indispensable roles in relieving depression and regulating BBB function]. CBD ameliorates depression by upregulating brain-derived neurotrophic factor, inhibiting neuroinflammation, alleviating oxidative stress, and modulating neurotransmitter transmission.”

https://onlinelibrary.wiley.com/doi/10.1002/cns.71168

An Ultra-Low Dose of ∆9-Tetrahydrocannabinol Alleviates Alzheimer’s Disease-Related Cognitive Impairments and Modulates TrkB Receptor Expression in a 5XFAD Mouse Model

An ultra-low dose of Δ9-THC improved Alzheimer’s disease-related cognitive impairment in 5xFAD mice, including animals treated after memory problems were already established. The study found improvements in learning and memory without relying on repeated high-dose THC exposure.

The researchers also found changes in TrkB receptor expression, a signaling pathway closely tied to brain plasticity, learning, memory, and neuronal survival. These changes suggest that THC’s effects may involve more than temporary symptom relief and may influence mechanisms connected to cognitive function.

The findings add to a growing body of preclinical research showing that very low doses of THC can produce different biological effects than higher doses, particularly in the aging and Alzheimer’s-disease brain. In this model, a single ultra-low dose was enough to improve cognitive performance and alter a key neurotrophic signaling pathway.

“Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment.

Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent.

Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice.

Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus.

We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC.

The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.”

https://pubmed.ncbi.nlm.nih.gov/36012711

“The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset. As THC is a cheap, widely available substance already approved for use in other conditions, this research brings us closer to understanding its mechanisms and will possibly lead to new treatments.”

https://www.mdpi.com/1422-0067/23/16/9449/htm

Need this THC study explained? thcXplained.com

An Ultra-Low Dose of ∆9-Tetrahydrocannabinol Alleviates Alzheimer’s Disease-Related Cognitive Impairments and Modulates TrkB Receptor Expression in a 5XFAD Mouse Model

An ultra-low dose of Δ9-THC improved Alzheimer’s disease-related cognitive impairment in 5xFAD mice, including animals treated after memory problems were already established. The study found improvements in learning and memory without relying on repeated high-dose THC exposure.

The researchers also found changes in TrkB receptor expression, a signaling pathway closely tied to brain plasticity, learning, memory, and neuronal survival. These changes suggest that THC’s effects may involve more than temporary symptom relief and may influence mechanisms connected to cognitive function.

The findings add to a growing body of preclinical research showing that very low doses of THC can produce different biological effects than higher doses, particularly in the aging and Alzheimer’s-disease brain. In this model, a single ultra-low dose was enough to improve cognitive performance and alter a key neurotrophic signaling pathway.

“Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment.

Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent.

Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice.

Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus.

We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC.

The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.”

https://pubmed.ncbi.nlm.nih.gov/36012711/

“The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset. As THC is a cheap, widely available substance already approved for use in other conditions, this research brings us closer to understanding its mechanisms and will possibly lead to new treatments.”

https://www.mdpi.com/1422-0067/23/16/9449/htm

Need this THC study explained? thcXplained.com

Δ 9 -Tetrahydrocannabinol promotes functional remyelination in the mouse brain

Myelin is the protective coating that surrounds nerve fibers and helps electrical signals move efficiently through the brain and spinal cord. Damage to myelin is a major feature of neurological disorders involving demyelination, making the repair of this protective layer an important therapeutic target.

In this mouse study, Δ9-THC promoted the regeneration of oligodendrocytes, the cells responsible for producing myelin, and enhanced remyelination in damaged white matter. THC treatment was also associated with improved recovery of motor function.

The researchers found that these effects involved activation of the CB1 cannabinoid receptor and the maturation of oligodendrocyte precursor cells into myelin-producing cells. The findings suggest that THC may have potential as a compound capable of supporting functional repair after myelin damage.

“Background and purpose: Research on demyelinating disorders aims to find novel molecules that are able to induce oligodendrocyte precursor cell differentiation to promote central nervous system remyelination and functional recovery. Δ9 -Tetrahydrocannabinol (THC), the most prominent active constituent of the hemp plant Cannabis sativa, confers neuroprotection in animal models of demyelination. However, the possible effect of THC on myelin repair has never been studied.

Experimental approach: By using oligodendroglia-specific reporter mouse lines in combination with two models of toxin-induced demyelination, we analysed the effect of THC on the processes of oligodendrocyte regeneration and functional remyelination.

Key results: We show that THC administration enhanced oligodendrocyte regeneration, white matter remyelination and motor function recovery. THC also promoted axonal remyelination in organotypic cerebellar cultures. THC remyelinating action relied on the induction of oligodendrocyte precursor differentiation upon cell cycle exit and via CB1 cannabinoid receptor activation.

Conclusions and implications: Overall, our study identifies THC administration as a promising pharmacological strategy aimed to promote functional CNS remyelination in demyelinating disorders.”

https://pubmed.ncbi.nlm.nih.gov/34216154/

“THC administration following cuprizone-induced demyelination enhanced oligodendrocyte regeneration, white matter remyelination and motor function recovery.”

“THC administration is a promising pharmacological strategy to promote functional CNS remyelination in demyelinating disorders.”

“Our study provides a novel therapeutic advantage of THC-based interventions in multiple sclerosis by promoting remyelination and functional recovery. New clinical trials with improved designs on cannabinoids in people with multiple sclerosis are needed now, considering these compounds as potential remyelinating/disease-modifying drugs to try to overcome previous failures. Our work also suggests that at least part of the neuroprotective action of phytocannabinoids in multiple sclerosis animal models and potentially in patients as well may be due to an enhanced CNS remyelination. Finally, this study also identifies THC as a potent inductor of oligodendrocyte progenitor cell differentiation under demyelination in mice, opening the possibility for this molecule to become a candidate drug to promote oligodendrocyte regeneration and remyelination in the treatment of demyelinating disorders.”

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15608

Need this THC study explained? thcXplained.com

Cannabinoids and Neurogenesis: The Promised Solution for Neurodegeneration?

molecules-logo“The concept of neurons as irreplaceable cells does not hold true today. Experiments and evidence of neurogenesis, also, in the adult brain give hope that some compounds or drugs can enhance this process, helping to reverse the outcomes of diseases or traumas that once were thought to be everlasting.

Cannabinoids, both from natural and artificial origins, already proved to have several beneficial effects (e.g., anti-inflammatory, anti-oxidants and analgesic action), but also capacity to increase neuronal population, by replacing the cells that were lost and/or regenerate a damaged nerve cell.

Neurogenesis is a process which is not highly represented in literature as neuroprotection, though it is as important as prevention of nervous system damage, because it can represent a possible solution when neuronal death is already present, such as in neurodegenerative diseases.

The aim of this review is to resume the experimental evidence of phyto- and synthetic cannabinoids effects on neurogenesis, both in vitro and in vivo, in order to elucidate if they possess also neurogenetic and neurorepairing properties.”

https://pubmed.ncbi.nlm.nih.gov/34684894/

“The current results of cannabinoids effects on neurogenesis are encouraging, and it is expectable that the amount of evidence continues to increase in the future with other experiments.”

https://www.mdpi.com/1420-3049/26/20/6313/htm

Δ9-Tetrahydrocannabivarin (THCV): a commentary on potential therapeutic benefit for the management of obesity and diabetes

figure1“Δ9-Tetrahydrocannabivarin (THCV) is a cannabis-derived compound with unique properties that set it apart from the more common cannabinoids, such as Δ9-tetrahydrocannabinol (THC). The main advantage of THCV over THC is the lack of psychoactive effects. In rodent studies, THCV decreases appetite, increases satiety, and up-regulates energy metabolism, making it a clinically useful remedy for weight loss and management of obesity and type 2 diabetic patients. The distinctions between THCV and THC in terms of glycemic control, glucose metabolism, and energy regulation have been demonstrated in previous studies. Also, the effect of THCV on dyslipidemia and glycemic control in type 2 diabetics showed reduced fasting plasma glucose concentration when compared to a placebo group. In contrast, THC is indicated in individuals with cachexia. However, the uniquely diverse properties of THCV provide neuroprotection, appetite suppression, glycemic control, and reduced side effects, etc.; therefore, making it a potential priority candidate for the development of clinically useful therapies in the future. Hopefully, THCV could provide an optional platform for the treatment of life-threatening diseases.”

https://pubmed.ncbi.nlm.nih.gov/33526143/

“The psychoactive effects of THC in marijuana are the main reasons for its classification as a Schedule I substance, even though it is the THC that the U.S. Food and Drug Administration (FDA) approved for appetite stimulation and weight gain. In contrast to THC, clinical and therapeutic advantages of THCV regarding its lack of psychoactive effects in human studies are of great value in pharmacotherapy. It is envisioned that the unique and diverse characteristics of THCV could be explored for further development into clinically useful medicines for the treatment of life-threatening diseases.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-0016-7

Δ 9 -Tetrahydrocannabinol promotes functional remyelination in the mouse brain

British Journal of Pharmacology“Background and purpose: Research on demyelinating disorders aims to find novel molecules that are able to induce oligodendrocyte precursor cell differentiation to promote central nervous system remyelination and functional recovery.

Δ9 -Tetrahydrocannabinol (THC), the most prominent active constituent of the hemp plant Cannabis sativa, confers neuroprotection in animal models of demyelination. However, the possible effect of THC on myelin repair has never been studied.

Experimental approach: By using oligodendroglia-specific reporter mouse lines in combination with two models of toxin-induced demyelination, we analysed the effect of THC on the processes of oligodendrocyte regeneration and functional remyelination.

Key results: We show that THC administration enhanced oligodendrocyte regeneration, white matter remyelination and motor function recovery. THC also promoted axonal remyelination in organotypic cerebellar cultures. THC remyelinating action relied on the induction of oligodendrocyte precursor differentiation upon cell cycle exit and via CB1 cannabinoid receptor activation.

Conclusions and implications: Overall, our study identifies THC administration as a promising pharmacological strategy aimed to promote functional CNS remyelination in demyelinating disorders.”

https://pubmed.ncbi.nlm.nih.gov/34216154/

“Our study provides a novel therapeutic advantage of THC-based interventions in multiple sclerosis by promoting remyelination and functional recovery. New clinical trials with improved designs on cannabinoids in people with multiple sclerosis are needed now, considering these compounds as potential remyelinating/disease-modifying drugs to try to overcome previous failures. Our work also suggests that at least part of the neuroprotective action of phytocannabinoids in multiple sclerosis animal models and potentially in patients as well may be due to an enhanced CNS remyelination. Finally, this study also identifies THC as a potent inductor of oligodendrocyte progenitor cell differentiation under demyelination in mice, opening the possibility for this molecule to become a candidate drug to promote oligodendrocyte regeneration and remyelination in the treatment of demyelinating disorders.”

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15608

The impact of cannabinoid type 2 receptors (CB2Rs) in neuroprotection against neurological disorders

 Acta Pharmacologica Sinica“Cannabinoids have long been used for their psychotropic and possible medical properties of symptom relief. In the past few years, a vast literature shows that cannabinoids are neuroprotective under different pathological situations.

Most of the effects of cannabinoids are mediated by the well-characterized cannabinoid receptors, the cannabinoid type 1 receptor (CB1R) and cannabinoid type 2 receptor (CB2R). Even though CB1Rs are highly expressed in the central nervous system (CNS), the adverse central side effects and the development of tolerance resulting from CB1R activation may ultimately limit the clinical utility of CB1R agonists. In contrast to the ubiquitous presence of CB1Rs, CB2Rs are less commonly expressed in the healthy CNS but highly upregulated in glial cells under neuropathological conditions.

Experimental studies have provided robust evidence that CB2Rs seem to be involved in the modulation of different neurological disorders. In this paper, we summarize the current knowledge regarding the protective effects of CB2R activation against the development of neurological diseases and provide a perspective on the future of this field. A better understanding of the fundamental pharmacology of CB2R activation is essential for the development of clinical applications and the design of novel therapeutic strategies.”

https://pubmed.ncbi.nlm.nih.gov/33024239/

https://www.nature.com/articles/s41401-020-00530-2

A Cannabinoid Type 2 (CB2) Receptor Agonist Augments NOS-Dependent Responses of Cerebral Arterioles during Type 1 Diabetes

Microvascular Research “While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease state such as type 1 diabetes (T1D).

Our goal was to test the hypothesis that administration of a CB2 agonist (JWH-133) would improve impaired endothelial (eNOS)- and neuronal (nNOS)- dependent dilation of cerebral arterioles during T1D.

In vivo diameter of cerebral arterioles in nondiabetic and T1D rats was measured in response to an eNOS-dependent agonist (adenosine 5′-diphosphate; ADP), an nNOS-dependent agonist (N-methyl-D-aspartate; NMDA), and an NOS-independent agonist (nitroglycerin) before and 1 hour following JWH-133 (1 mg/kg IP). Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in T1D rats.

Treatment with JWH-133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and T1D rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and T1D rats, and JWH-133 did not influence responses to nitroglycerin in either group. The restoration in responses to the agonists by JWH-133 could be inhibited by treatment with a specific inhibitor of CB2 receptors (AM-630; 3 mg/kg IP).

Thus, activation of CB2 receptors can potentiate reactivity of cerebral arterioles during physiologic and pathophysiologic states. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular diseases via a mechanism that can increase cerebral blood flow.”

https://pubmed.ncbi.nlm.nih.gov/32979391/

“Activation of CB2 receptors improves cerebral vascular function. Activation of CB2 receptors improves responses in type 1 diabetes. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular disease that can contribute to the pathogenesis of stroke.”

https://www.sciencedirect.com/science/article/pii/S0026286220301370?via%3Dihub