Tag Archives: preclinical research

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

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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

Delta-8-tetrahydrocannabinol ameliorates murine autoimmune hepatitis and is associated with epigenetic modulation of immune responses

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A new 2026 study published in International Immunopharmacology found that delta-8-tetrahydrocannabinol (Δ8-THC) significantly reduced autoimmune hepatitis in mice while altering the immune responses responsible for liver inflammation. Researchers found that Δ8-THC reduced inflammatory immune cells and helped preserve immune cells involved in protecting the liver.

The researchers also uncovered a possible mechanism. Δ8-THC increased two microRNAs, miR-100-5p and miR-199a-3p, which suppressed mTOR signaling and shifted CD4+ T-cell development away from inflammatory Th1 and Th17 cells and toward regulatory T cells that help control excessive immune activity.

The authors concluded that Δ8-THC showed both hepatoprotective and anti-inflammatory activity and highlighted its potential therapeutic value for autoimmune and inflammatory disorders. The study adds new evidence that cannabinoids may influence disease not only by reducing inflammation, but by changing the molecular and epigenetic pathways that regulate immune responses.

“Aim of the study: Cannabinoids have gained attention for their ability to modulate immune responses and suppress inflammation. However, the effect of Δ8-THC, a minor cannabinoid found in Cannabis, has not been explored in autoimmune hepatitis. To address knowledge gap, the present study aimed to investigate the hepatoprotective and immunoregulatory properties of Δ8-THC in experimental autoimmune hepatitis and to identify molecular and epigenetic mechanisms underlying its immunoregulatory effects.

Methods: miRNA sequencing and flow cytometric analysis were performed using hepatic immune cells from female C57BL/6 mice treated with ConA (12.5 mg/kg, i.v.) and Δ8-THC (20 mg/kg, i.p.). Differential miRNA expressions were analyzed using the edgeR, and miRNA targets were predicted using Ingenuity Pathway Analysis. Target gene expression was validated by qRT-PCR and Western blot. Functional assays including miRNA mimic/inhibitor transfection and CD4+ T-cell differentiation were performed to validate target gene regulation by miRNAs and its role in CD4+ T-cell differentiation.

Results: Δ8-THC markedly suppressed ConA-induced autoimmune hepatitis by restoring immune homeostasis within the liver through suppression of inflammatory monocytes, neutrophils, and natural killer cells, and preservation of tolerogenic Kupffer cells. In addition, Δ8-THC reshaped the hepatic lymphoid compartment, diminishing inflammatory CD4+ T-cell responses while favoring regulatory T-cell expansion. These effects were associated with the preservation of miR-100-5p and miR-199a-3p expression in the liver, whereas both miRNAs were markedly downregulated following ConA treatment. mTOR, a central regulator of T-cell differentiation, was identified as a target of these miRNAs. Consistent with these findings, Δ8-THC reduced mTOR expression and upregulated hepatoprotective miRNAs in both in vivo and in vitro models. Functional analyses with miRNA overexpression and inhibition approaches verified the direct regulation of mTOR by these miRNAs in T cells and RAW 264.7 cells. In naïve CD4+ T cells, miRNA gain- and loss-of-function experiments demonstrated that miR-100-5p/miR-199a-3p-mediated suppression of mTOR promotes regulatory T-cell differentiation while limiting Th1 and Th17 polarization.

Conclusion: Our results identify Δ8-THC as a promising hepatoprotective and anti-inflammatory compound that ameliorates ConA-induced autoimmune hepatitis by influencing CD4+ T-cell differentiation potentially through the miR-100-5p/miR-199a-3p-mTOR axis, highlighting its potential therapeutic value in autoimmune and inflammatory disorders.”

https://pubmed.ncbi.nlm.nih.gov/42753324

“In conclusion, our findings suggest that Δ8-THC can mitigate ConA-induced hepatitis, potentially through epigenetic regulation involving microRNAs. Specifically, Δ8-THC improved liver function and reduced systemic and intrahepatic inflammation in ConA-exposed mice. These effects were associated with increased expression of miR-100-5p and miR-199a-3p in the liver, suggesting that these miRNAs may regulate mTOR signaling and contribute to the suppression of proinflammatory responses and promotion of anti-inflammatory pathways. Functional studies supported the involvement of these miRNAs in the regulation of mTOR signaling, CD4+ T-cell differentiation, and inflammatory responses.”

https://www.sciencedirect.com/science/article/pii/S1567576926012518?via%3Dihub

A chronic low dose of Δ9-tetrahydrocannabinol (3 mg / kg / 21 d) reorganizes the disturbed wound healing process and accelerates wound closure in old female mice

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A chronic low dose of Δ9-THC accelerated wound closure in old female mice and helped reorganize an age-disrupted healing process. The biggest improvement occurred during the inflammatory phase, when aged wounds normally heal more slowly and remain inflamed longer.

THC changed the timing and amount of immune-cell activity in the wound, reduced inflammatory cytokines, and significantly increased infiltration of mesenchymal stem cells (MSCs) involved in tissue repair. The treatment did not increase growth-factor release, suggesting the benefit came mainly from better coordination of inflammation and cell migration.

The researchers concluded that THC improved wound healing by restoring a more normal sequence of immune-cell infiltration and cytokine release. The findings suggest that stimulating the aging endocannabinoid system may help support skin regeneration and tissue repair in older organisms.

“Wound healing in old mice is characterized by disturbed tissue homeostasis, manifested by delayed immune cell infiltration and reduced growth factor secretion, leading to a delayed onset and prolonged duration of the inflammatory phase.

The endocannabinoid system (ECS) is an important regulator of tissue homeostasis and cell migration and is also considered to be subject to aging processes, which may contribute to observable aging phenomena. Therefore, stimulating the aged ECS could represent a therapeutic option to support tissue regeneration in aging.

Female old mice received a low-dose of medical THC daily for 3 weeks, before four excisional full skin wounds were created. At day 1, 3 and 7 post-surgery, the wound closure rate was analyzed and wound samples were examined immunohistochemically for the numbers of granulocytes, M1-macrophages and mesenchymal stem cells (MSCs). The concentrations of inflammatory cytokines and regenerative growth factors were determined by ELISA.

Administration of THC improved the wound healing rate of old mice between day 1 and 7, which was associated with an altered timing and quantity of infiltrating immune cells and decreased levels of inflammatory cytokines in wound tissue on days 1 and 3 post-injury.

THC treatment significantly increased MSC infiltration but had no effect on the growth factor release.

The present study confirmed the anti-inflammatory activity of THC in vivo.

The THC-treatment improved wound healing in old mice by coordinating the temporal sequence of immune cell infiltration and cytokine release. Thus, restoration of ECS signaling could be an effective strategy to support age-related skin regeneration.”

https://pubmed.ncbi.nlm.nih.gov/40653209/

“A chronic low dose of THC accelerates the wound closure rate during the inflammatory phase in old mice.”

https://www.sciencedirect.com/science/article/pii/S0531556525001615?via%3Dihub

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∆9-Tetrahydrocannabinol Increases Growth Factor Release by Cultured Adipose Stem Cells and Adipose Tissue in vivo

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Δ9-THC increased the release of growth factors from cultured adipose-derived stem cells and from adipose tissue in vivo. These growth factors are involved in processes such as cell survival, tissue repair, blood-vessel formation, and regeneration.

The researchers found that THC changed the secretory activity of adipose stem cells rather than simply affecting their growth. This suggests that THC may influence how these cells communicate with surrounding tissue and support repair through the factors they release.

The findings point to a potential role for THC in regenerative signaling and tissue-healing biology, particularly through adipose-derived stem cells and the local tissue environment. The study adds another dimension to cannabinoid research by showing that THC can affect not just mature cells, but also the reparative signals produced by stem-cell populations.

“Background: Because of its biocompatibility and its soft and dynamic nature, the grafting of adipose tissue is regarded an ideal technique for soft-tissue repair. The adipose stem cells (ASCs) contribute significantly to the regenerative potential of adipose tissue, because they can differentiate into adipocytes and release growth factors for tissue repair and neovascularization to facilitate tissue survival. The present study tested the effect of administering a chronic low dose of ∆9-tetrahydrocannabinol (THC) on these regenerative properties, in vitro and in vivo.

Methods: Human ASCs were exposed to increasing concentrations of THC. Resazurin conversion was applied to investigate the effect on metabolic activity, cell number was assessed by crystal violet staining, tri-linear differentiation was evaluated by specific colorimetric approaches, and the release of growth factors was analyzed by ELISA. Two groups of mice were treated daily either with a low dose of THC (3 mg/kg) or a vehicle solution. After 3 weeks, adipose tissue was obtained from excised fat deposits, homogenized and tested for growth factor contents.

Results: THC decreased ASC proliferation but increased metabolic activity as well as adipogenic and chondrogenic differentiation. A low concentration of THC (1 µM) enhanced the growth factor release by ASCs. The concentration of these cytokines was also increased in adipose tissue of mice treated with THC.

Conlusion: Our results indicate that chronic activation of the endocannabinoid system promoted differentiation and growth factor release of ASCs, which could be of specific value for enhancing the regenerative potential of adipose tissue.”

https://pubmed.ncbi.nlm.nih.gov/39825991/

“Our findings may offer a new approach for improved application of adipose tissue in regenerative medicine.”

https://link.springer.com/article/10.1007/s13770-024-00692-8

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Δ 9 -Tetrahydrocannabinol alleviates hyperalgesia in a humanized mouse model of sickle cell disease

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Δ9-THC reduced pain hypersensitivity in a humanized mouse model of sickle cell disease. In mice expressing more than 99% human sickle hemoglobin, acute THC treatment dose-dependently reduced both mechanical and cold hypersensitivity and also produced substantial antinociceptive effects in a tail-flick pain test.

At 1 mg/kg, THC reduced pain sensitivity without altering anxiety-like behavior or long-term memory. With repeated treatment, THC continued to provide sustained relief from mechanical hypersensitivity, although tolerance developed to its effects on cold hypersensitivity.

The researchers concluded that THC may represent a potential option for managing chronic pain associated with sickle cell disease. These findings are especially notable because sickle cell pain is often severe and difficult to control, while current treatment frequently depends on opioid analgesics.

“People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affect their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects.

Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of Δ9-tetrahydrocannabinol (THC), cannabis’ intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control.

Acute THC administration (0.1-3 mg-kg-1, intraperitoneal, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in HbSS, but not HbAA mice. In the tail-flick assay, THC (1 and 3 mg-kg-1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg-kg-1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-h novel object recognition). Subchronic THC treatment (1 and 3 mg-kg-1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice.

Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents. 

Significance Statement The study explores THC’s efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC’s potential as an alternative pain management option in SCD, highlighting both its benefits and limitations.”

https://pubmed.ncbi.nlm.nih.gov/38955494/

“The results indicate that acute THC administration alleviates mechanical and cold hypersensitivity in HbSS mice in a dose-dependent manner without affecting emotional and cognitive dysfunction also present in these mice.”

https://www.sciencedirect.com/science/article/abs/pii/S0022356524178147

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Impacts of delta 9-tetrahydrocannabinol against myocardial ischemia/reperfusion injury in diabetic rats: Role of PTEN/PI3K/Akt signaling pathway

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In diabetic rats with myocardial ischemia/reperfusion injury, Δ9-THC significantly reduced heart damage and improved cardiac function. THC pretreatment decreased infarct size as well as blood markers of heart injury, including LDH and cardiac troponin-I.

THC also reduced myocardial apoptosis and oxidative stress, two major contributors to tissue damage when blood flow returns to the heart after a period of ischemia. These protective effects were accompanied by reduced PTEN expression and activation of the PI3K/Akt signaling pathway, which is involved in cell survival.

When researchers blocked PI3K signaling, THC’s cardioprotective effect disappeared, strengthening the evidence that this pathway played an important role in the response. The findings show that THC protected the diabetic rat heart against ischemia/reperfusion injury through multiple measurable effects on cardiac damage, oxidative stress, cell death, and survival signaling.

“Despite the current optimal therapy, patients with myocardial ischemia/reperfusion (IR) injury still experience a high mortality rate, especially when diabetes mellitus is present as a comorbidity. Investigating potential treatments aimed at improving the outcomes of myocardial IR injury in diabetic patients is necessary.

Our objective was to ascertain the cardioprotective effect of delta 9-tetrahydrocannabinol (THC) against myocardial IR injury in diabetic rats and examine the role of phosphatase and tensin homolog (PTEN)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway in mediating this effect.

Diabetes was induced in male Wistar rats (8-10 weeks old, 200-250 g; n = 60) by a single injection of streptozotocin. The duration of the diabetic period was 10 weeks. During the last 4 weeks of diabetic period, rats were treated with THC (1.5 mg/kg/day; intraperitoneally), either alone or in combination with LY294002, and then underwent IR intervention. After 24 h of reperfusion, infarct size, cardiac function, lactate dehydrogenase (LDH) and cardiac-specific isoform of troponin-I (cTn-I) levels, myocardial apoptosis, oxidative stress markers, and expression of PTEN, PI3K, and Akt proteins were evaluated.

THC pretreatment resulted in significant improvements in infarct size and cardiac function and decreases in LDH and cTn-I levels (P < 0.05). It also reduced myocardial apoptosis and oxidative stress, accompanied by the downregulation of PTEN expression and activation of the PI3K/Akt signaling pathway (P < 0.05). LY294002 pretreatment abolished the cardioprotective action of THC.

This study revealed the cardioprotective effects of THC against IR-induced myocardial injury in diabetic rats and also suggested that the mechanism may be associated with enhanced activity of the PI3K/Akt signaling pathway through the reduction of PTEN phosphorylation.”

https://pubmed.ncbi.nlm.nih.gov/38149557/

“Delta 9-tetrahydrocannabinol (THC) is the main psychoactive component of cannabis and has been shown to have potential therapeutic effects in various medical conditions. THC has been shown to have anti-inflammatory and antioxidant properties, which may reduce the inflammation and oxidative stress associated with myocardial IR injury. Recent studies have suggested that THC improves glucose metabolism and insulin sensitivity and reduces blood glucose concentrations, oxidative stress, and inflammation associated with diabetic cardiomyopathy.”

https://www.cjphysiology.org/article.asp?issn=0304-4920;year=2023;volume=66;issue=6;spage=446;epage=455;aulast=Zhao

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Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain.

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In a mouse model of endometriosis, daily treatment with Δ9-THC reduced abdominal mechanical hypersensitivity and the unpleasantness associated with pain. THC also restored cognitive function in animals that had developed substantial memory deficits associated with endometriosis.

The effects went beyond pain relief. THC altered uterine innervation and, most notably, inhibited the development of endometrial cysts, suggesting a potential disease-modifying effect rather than simply masking symptoms.

These findings are important because endometriosis is a chronic condition in which pain, abnormal tissue growth, and neurological effects can all contribute to disease burden. The researchers concluded that the results support clinical investigation of THC as a potential treatment for women with endometriosis.

“Endometriosis is a chronic painful disease highly prevalent in women that is defined by growth of endometrial tissue outside the uterine cavity and lacks adequate treatment.

Medical use of cannabis derivatives is a current hot topic and it is unknown whether phytocannabinoids may modify endometriosis symptoms and development.

Here we evaluate the effects of repeated exposure to Δ9-tetrahydrocannabinol (THC) in a mouse model of surgically-induced endometriosis.

In this model, female mice develop mechanical hypersensitivity in the caudal abdomen, mild anxiety-like behavior and substantial memory deficits associated with the presence of extrauterine endometrial cysts.

Interestingly, daily treatments with THC (2 mg/kg) alleviate mechanical hypersensitivity and pain unpleasantness, modify uterine innervation and restore cognitive function without altering the anxiogenic phenotype. Strikingly, THC also inhibits the development of endometrial cysts.

These data highlight the interest of scheduled clinical trials designed to investigate possible benefits of THC for women with endometriosis.”

https://www.ncbi.nlm.nih.gov/pubmed/31931958

“These experiments suggest that THC may be a useful treatment for patients with endometriosis.”

https://elifesciences.org/articles/50356

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