Category Archives: Alzheimer’s Disease (AD)

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

Posted on by

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

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

Posted on by

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

Exploring the Potential of Cannabinoid Nanodelivery Systems for CNS Disorders

Posted on by

Cannabinoids such as THC and CBD have shown therapeutic potential in neurological disorders, but poor water solubility and low bioavailability can limit their effectiveness. This review explores how nanotechnology may overcome these barriers by improving cannabinoid stability, controlled release and targeted delivery to the central nervous system, including strategies designed to enhance passage across the blood-brain barrier.

“Cannabinoids have a major therapeutic value in a variety of disorders. The concepts of cannabinoids are difficult to develop, but they can be used and are advantageous for a number of diseases that are not sufficiently managed by existing treatments. Nanoconjugation and encapsulation techniques have been shown to be effective in improving the delivery and the therapeutic effectiveness of drugs that are poorly soluble in water. Because the bioavailability of cannabinoids is low, the challenge is to explore different administration methods to improve their effectiveness. Because cannabinoids cross the blood-brain-barrier (BBB), they modify the negative effects of inflammatory processes on the BBB and may be a key factor in the improvement of BBB function after ischemic disease or other conditions. This review discusses various types of cannabinoid administration, as well as nanotechnologies used to improve the bioavailability of these compounds in CNS diseases.”

“The growing acceptance of Cannabis and cannabinoids has led to an increasing number of clinical trials testing various nanoproducts. CNS disorders are key therapeutic targets for cannabinoids, and nanoformulation platforms for cannabinoid nanoconjugates provide efficient transport across the BBB. Selected examples of cannabinoid nanoconjugates have shown enhanced bioavailability and improved bio-efficacy with promising outcomes in biomedical applications. We expect to see many results from clinical trials in the near future to evaluate the adverse effects and effectiveness of this treatment. However, precise delivery of these nanoformulations to pathological sites inside the brain remains a challenge.”

https://pmc.ncbi.nlm.nih.gov/articles/PMC9863859/

Differential Effects of Cannabidiol and Cannabigerol on Cognition, Neuroinflammation, and Blood-Brain Barrier Integrity in a Rat Model of Iron Overload

Posted on by

Researchers comparing cannabidiol (CBD) and cannabigerol (CBG) found that both cannabinoids reversed recognition-memory impairment and restored a protein important to blood-brain barrier integrity in rats exposed to excessive iron early in life.

Both CBD and CBG reduced the inflammatory marker IL-1β, although their broader effects on inflammation differed. The findings suggest that the two phytocannabinoids may protect cognitive function through distinct but complementary mechanisms involving neuroinflammation and the blood-brain barrier.

“Iron is an essential micronutrient for brain development, participating in mitochondrial respiration, myelination, and neurotransmitter synthesis. However, previous studies have demonstrated that excessive iron during early postnatal life induces oxidative reactions, leading to mitochondrial dysfunction and synaptic failure. These alterations compromise energy metabolism and neuronal integrity, contributing to long-lasting cognitive dysfunction and increased brain vulnerability later in life.

This study evaluated the effects of cannabidiol (CBD) and cannabigerol (CBG) on behavioral, neuroinflammatory, and blood-brain barrier (BBB) outcomes in rats exposed to early-life iron overload.

Male Wistar rats received iron carbonyl (30 mg/kg, intragastrically) from postnatal day 12 to 14. At three months of age, they were treated intraperitoneally with CBD, CBG (both at 10 mg/kg), or vehicle for 21 days. Cognitive performance was assessed in the open field and object recognition tasks. We examined hippocampal levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), as proinflammatory markers, and occludin, a protein known to regulate BBB permeability.

Iron-exposed animals showed impaired recognition memory, with elevated TNF-α and IL-1β, while CBD reversed memory deficits and reduced IL-1β in iron-treated animals, without affecting TNF-α.

CBG restored memory, decreased IL-1β in both iron-treated and controls, and increased TNF-α in controls. Also, iron overload reduced occludin expression in vehicle-treated rats which was reversed by both CBD and CBG.

These findings highlight inflammation and BBB disruption as mediators of iron-induced cognitive dysfunction and show that both phytocannabinoids act through distinct but complementary mechanisms, supporting their therapeutic potential in neuroinflammation linked to iron overload.”

https://pubmed.ncbi.nlm.nih.gov/42663810

https://link.springer.com/article/10.1007/s12640-026-00826-x


Cannabis and Cannabinoids: The Medical Potential of Cannabidiol in Mental and Neurological Disorders

Posted on by

Cannabidiol (CBD) has become one of the most widely studied cannabis compounds for its potential effects on the brain and nervous system.

This review examines evidence across a range of mental and neurological disorders, including anxiety, depression, psychosis, epilepsy, neurodegenerative diseases and other conditions involving altered brain signaling or inflammation.

The research highlights CBD’s broad therapeutic potential while helping clarify the biological mechanisms that may underlie its effects.

“Background/Objectives: Mental and neurological disorders contribute substantially to the global burden of disease, affecting people of all ages and backgrounds. As their prevalence increases with age, their overall impact is expected to grow in the coming decades. Although psychological and pharmacological treatments are available, many patients fail to achieve satisfactory outcomes, underscoring the need for improved therapeutic strategies. Cannabis sativa L. has been used for medicinal purposes for centuries, and cannabidiol (CBD) has attracted increasing attention because of its broad therapeutic potential. Scientific studies indicate that CBD may be beneficial in several mental and neurological disorders. 

Methods: A comprehensive literature search was conducted to identify articles investigating the therapeutic potential of CBD and cannabis in selected disorders. 

Results: Evidence from preclinical and clinical studies, together with findings from the broader cannabis literature, indicates that CBD may offer therapeutic benefits in a range of conditions, including Alzheimer’s and Parkinson’s disease, anxiety disorders, and epilepsy. Emerging data also support its potential use as an adjunctive therapy for COVID-19. Current research has improved understanding of the neurobiological mechanisms underlying these disorders and the molecular pathways through which CBD may exert its effects. CBD has demonstrated good tolerability, with predominantly mild adverse effects and a favorable safety profile. 

Conclusions: Despite promising findings, many available studies are preclinical or involve small patient cohorts, and the mechanisms underlying the therapeutic effects of CBD remain incompletely understood. Further well-designed, randomized, controlled, multicenter trials are needed to establish the efficacy and safety of CBD and support its integration into clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/42653735

“The Cannabis plant has been used for medicinal purposes for thousands of years, with therapeutic indications mentioned in the medical texts of ancient civilizations.”

“These findings support the safety and clinical applicability of CBD and further suggest its potential as a therapeutic agent.”

“CBD is a promising therapeutic candidate for several mental and neurological disorders.”,

https://www.mdpi.com/1424-8247/19/8/1238


The beneficial properties of CBDA in diet-induced neuroinflammation

Posted on by

Cannabidiolic acid (CBDA), the natural acidic precursor of CBD, is drawing increasing attention for its own biological effects.

In this study, researchers examined CBDA in a model of diet-induced neuroinflammation and found evidence that it may help reduce inflammatory changes in the brain associated with an unhealthy diet.

The findings add to growing research showing that acidic cannabinoids such as CBDA may have therapeutic properties distinct from their better-known neutral forms.

“Cannabidiolic acid (CBDA) is a phytocannabinoid found in the Cannabis plant. Understanding the effects of CBDA is essential to uncover its full potential and possible health benefits.

The study was conducted on rats receiving standard rat chow (control) and a high-fat diet (HFD).

Half of the animals in each group were administered CBDA intragastrically. The total lipid fractions and arachidonic acid (AA) contents were measured in the frontal and posterior cortex, hippocampus, and subcortical nuclei using gas-liquid chromatography. The expression of proteins involved in neurodegenerative diseases and insulin signaling pathway proteins in the frontal and posterior cortex was measured using Immunoblotting. RT-PCR was used to assess the expression of pro-inflammatory pathway proteins in the same regions. Additionally, untargeted and targeted metabolomic analyses were performed on cerebrospinal fluid (CSF).

The results showed that a decrease in arachidonic acid levels and pro-inflammatory precursor proteins after CBDA treatment in high-fat-fed rats was simultaneous with improved insulin signaling, particularly in the posterior cortex.

Inactivation of glycogen synthase kinase 3 (GSK-3β) in this region was concomitant with changes in neurodegenerative biomarkers in the cortex and CSF. Metabolomic studies revealed a significant diminishment in creatinine, phenylalanine, and sarcosine levels in the HFD+CBDA group, suggesting it plays an important role in neurological disorders.

The results suggest that CBDA has anti-inflammatory properties by reducing the synthesis of lipid inflammatory mediators, which are concomitant with improved insulin signaling and probably reduced neurodegeneration.

Thus, CBDA could be considered as a part of future clinical treatment for many inflammatory conditions.”

https://pubmed.ncbi.nlm.nih.gov/42627619

“Our study demonstrated a preliminary analysis of the impact of CBDA on the inflammatory profile of the brain under conditions of excess calories from fat. The results suggest an anti-inflammatory role for this cannabinoid, particularly in inhibiting the synthesis of lipid inflammatory mediators.”

https://link.springer.com/article/10.1007/s10787-026-02358-4

Beyond inflammation: Cannabinoid receptors as metabolic checkpoints in glial reprogramming during neurodegeneration

Posted on by

Cannabinoid receptors are increasingly being studied for roles that go beyond controlling inflammation in the brain.

This review examines how CB1 and CB2 receptors may act as metabolic checkpoints in glial cells, influencing how these cells use energy, respond to stress and change their behavior during neurodegenerative disease.

The findings highlight a broader role for the endocannabinoid system in shaping brain metabolism and glial function, with potential relevance to conditions such as Alzheimer’s, Parkinson’s and other neurodegenerative disorders.

“Cannabinoid receptors have traditionally been regarded as regulators of neuroinflammation. However, their anti-inflammatory effects alone are insufficient to fully elucidate their complicated roles in neurodegenerative diseases (NDDs).

Mounting evidence identifies disruptions in energy metabolism as key drivers of neurodegeneration, which has prompted a re-evaluation of the cannabinoid receptor system within the context of brain energy metabolism and pathophysiological processes. Accumulated findings from several independent preclinical studies have offered novel insights into the potential involvement of cannabinoid receptors in energy metabolism, mitochondrial function, and glial metabolic reprogramming.

This review focuses on the metabolic regulatory potential of classical cannabinoid receptors, including cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R), with particular attention to mitochondrial CB1 receptors (mtCB1), as well as non-classical targets such as G protein-coupled receptor 55 (GPR55), G protein-coupled receptor 119 (GPR119), and peroxisome proliferator-activated receptors (PPARs). Additionally, the review explores the mechanisms by which astrocytes maintain neuronal support through cell-type-specific metabolic specialization and how metabolic reprogramming in microglia modulates neuroinflammatory phenotypes.

Although the current evidence is predominantly derived from preclinical models and several mechanistic links remain to be experimentally validated, we propose a novel conceptual model, namely the cannabinoid receptor-glial metabolic reprogramming-neuronal metabolic support failure axis, in which the breakdown of metabolic checkpoints is viewed as a crucial event in disease progression.

At the therapeutic level, we advocate shifting from conventional anti-inflammatory approaches to metabolic repair strategies, while also exploring emerging directions in the development of cannabinoid-based medications targeting metabolism.

Collectively, a deep understanding of the complex metabolic regulatory functions of cannabinoid receptors is critical for developing next-generation treatment strategies for NDDs.”

https://pubmed.ncbi.nlm.nih.gov/42624021

“Shift from anti-inflammation to metabolic repair for cannabinoid NDD therapy.”

https://www.sciencedirect.com/science/article/abs/pii/S1567576926011458?via%3Dihub


Design, Synthesis, In Silico and In Vitro Pharmacological Profiling of Cannabidiol-like Synthetic Analogues as Multi-Target Anti-Alzheimer’s Agents

Posted on by

Alzheimer’s disease involves multiple overlapping pathological processes, making multitarget therapies especially attractive. Researchers synthesized a series of CBD-like compounds and found several with strong butyrylcholinesterase inhibition, antioxidant activity, favorable predicted brain penetration, and good neuronal-cell safety. Two compounds, 3b and 3f, emerged as particularly promising leads for further development as multi-target anti-Alzheimer’s agents.

“Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that requires therapeutic agents capable of targeting multiple pathological pathways.

In this study, a series of cannabidiol (CBD)-like hydrazone derivatives (3a–i) was synthesized and characterized by NMR, HRMS, and single-crystal X-ray diffraction for compound 3i.

In silico ADME analysis predicted favorable drug-like properties, including compliance with Lipinski’s Rule of Five, oral bioavailability, and blood-brain barrier permeability. The compounds were evaluated for cholinesterase inhibition, antioxidant activity, cytotoxicity in neuronal cell lines, and binding interactions with human butyrylcholinesterase (hBChE) by molecular docking. Biological evaluation revealed a marked preference for BChE over acetylcholinesterase (AChE).

Compound 3f was the most potent BChE inhibitor (IC50 = 1.67 ± 0.11 μM), while compounds 3b and 3f demonstrated high selectivity toward BChE. Antioxidant assays (DPPH, ABTS, FRAP, and FTC) indicated moderate, mechanism-dependent activity. Compounds 3b and 3e showed the strongest ABTS radical-scavenging effects, whereas compounds 3b and 3f provided the greatest protection against lipid peroxidation, surpassing CBD under the tested conditions. Several derivatives, particularly 3a, 3b, 3f, 3h, and 3i, exhibited favorable safety profiles in SH-SY5Y and Neuro-2a cells. Molecular docking supported the experimental findings.

Overall, compounds 3b and 3f emerged as promising multifunctional leads for the development of multitarget-directed anti-Alzheimer agents.”

https://pubmed.ncbi.nlm.nih.gov/42588505

“Cannabidiol (CBD), a non-psychoactive phytocannabinoid derived from Cannabis sativa, has emerged as a promising multitarget neuroprotective agent for Alzheimer’s disease (AD).”

https://www.mdpi.com/1420-3049/31/15/2657

Delta-9-Tetrahydrocannabinol (∆9-THC) Induce Neurogenesis and Improve Cognitive Performances of Male Sprague Dawley Rats

Posted on by

THC is often associated with impaired memory, but its effects on the brain may depend heavily on dose and context. In this rat study, Δ9-THC enhanced markers involved in multiple stages of hippocampal neurogenesis and improved learning and memory performance, with the 1.5 mg/kg dose producing particularly strong effects on both neurogenesis and cognitive function.

“Neurogenesis is influenced by various external factors such as enriched environments. Some researchers had postulated that neurogenesis has contributed to the hippocampal learning and memory.

This project was designed to observe the effect of Delta-9-tetrahydrocannabinol (∆9-THC) in cognitive performance that influenced by the neurogenesis.

Different doses of ∆9-THC were used for observing the neurogenesis mechanism occurs in the hippocampus of rats. The brains were stained with antibodies, namely BrdU, glial fibrillary acidic protein (GFAP), nestin, doublecortin (DCX) and class III β-tubulin (TuJ-1). The cognitive test was used novel-object discrimination test (NOD) while the proteins involved, DCX and brain-derived neurotrophic factor (BDNF), were measured.

Throughout this study, ∆9-THC enhanced the markers involved in all stages of neurogenesis mechanism. Simultaneously, the cognitive behaviour of rat also showed improvement in learning and memory functions observed in behavioural test and molecular perspective.

Administration of ∆9-THC was observed to enhance the neurogenesis in the brain, especially in hippocampus thus improved the cognitive function of rats.”

https://pubmed.ncbi.nlm.nih.gov/28933048

“The treatment of 1.5 mg/kg of ∆9-THC has increase all the markers for neurogenesis and cognition function while improve the cognitive performance.”

https://link.springer.com/article/10.1007/s12640-017-9806-x

“Neurogenesis is the scientific term for the birth and growth of new brain cells.”

Need this THC study explained? thcXplained.com

Δ9-Tetrahydrocannabinol Modulates Hippocampal Neurogenesis in Female Wistar Rats: Interaction with Estradiol

Posted on by

THC may influence the female brain through both neurogenic and anti-inflammatory mechanisms. In ovariectomized female rats, Δ9-THC significantly increased hippocampal cell proliferation, showed evidence of enhanced neurogenesis, and reduced the inflammatory markers COX-2 and TNF-α. The effects also interacted with estradiol, highlighting the importance of hormonal status in determining THC’s actions in the brain.

“The endocannabinoid system (ECS) plays a key role in regulating neurogenesis and inflammatory processes in the brain.

The increasing prevalence of Cannabis use among women highlights the importance of understanding sex-specific effects of cannabinoids, particularly in the context of hormonal interactions.

This study aimed to investigate the effects of delta-9-tetrahydrocannabinol (THC) and estradiol benzoate (EB) on adult hippocampal neurogenesis (AHN) and inflammation in ovariectomized female Wistar rats.

Sixteen rats were allocated to four experimental groups receiving THC, EB, both treatments, and vehicle. Immunohistochemical analyses were conducted to evaluate markers of proliferation (Ki-67), neurogenesis (doublecortin and PSA-NCAM), cannabinoid receptor expression (CB1), and inflammation (COX-2 and TNF-α) in the hippocampal formation.

The administration of THC significantly increased Ki-67 immunoreactivity, suggesting enhanced cell proliferation. A trend toward increased doublecortin expression was observed, particularly in EB-treated animals. THC also modulated CB1 receptor expression, with significant increases in the dentate gyrus and hilus following combined THC and EB treatment. Furthermore, THC reduced inflammatory markers, with region-dependent decreases in COX-2 and TNF-α expression.

These findings indicate that THC influences markers associated with hippocampal cell proliferation, neurogenesis, cannabinoid signaling and inflammation in female rats, and that some of these effects depend on estradiol status.

The interaction between cannabinoids and gonadal hormones may represent an important mechanism underlying sex-specific neurobiological responses and suggests potential targets for therapeutic intervention in neuropsychiatric disorders.”

https://pubmed.ncbi.nlm.nih.gov/42570151

https://link.springer.com/article/10.1007/s11064-026-04857-w