Substance Abuse and Cognitive Decline: The Critical Role of Tau Protein as a Potential Biomarker

Posted on August 14, 2025 by David

“Tau protein is essential for the structural stability of neurons, particularly through its role in microtubule assembly and axonal transport. However, when abnormally hyperphosphorylated or cleaved, Tau can aggregate into insoluble forms that disrupt neuronal function, contributing to the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease (AD).

Emerging evidence suggests that similar Tau-related alterations may occur in individuals with chronic exposure to psychoactive substances. This review compiles experimental, clinical, and postmortem findings that collectively indicate a substance-specific influence on Tau dynamics.

Alcohol and opioids, for instance, promote Tau hyperphosphorylation and fragmentation through the activation of kinases such as GSK-3β and CDK5, as well as proteases like caspase-3, leading to neuroinflammation and microglial activation. Stimulants and dissociatives disrupt insulin signaling, increase oxidative stress, and impair endosomal trafficking, all of which can exacerbate Tau pathology.

In contrast, cannabinoids and psychedelics may exert protective effects by modulating kinase activity, reducing inflammation, or enhancing neuroplasticity.

Psychedelic compounds such as psilocybin and harmine have been demonstrated to decrease Tau phosphorylation and facilitate cognitive restoration in animal models. Although the molecular mechanisms differ across substances, Tau consistently emerges as a convergent target altered in substance-related cognitive disorders.

Understanding these pathways may provide not only mechanistic insights into drug-induced neurotoxicity but also identify Tau as a valuable biomarker and potential therapeutic target for the prevention or treatment of cognitive decline associated with substance use.”

https://pubmed.ncbi.nlm.nih.gov/40806766/

“Alcohol, methamphetamine, and opioids consistently elicited Tau hyperphosphorylation in cortical and subcortical regions tied to executive function, reward processing, and memory. In contrast, certain cannabinoids and psychedelics demonstrated potential neuroprotective properties, modulating Tau-related signaling in ways that reduced aberrant phosphorylation and enhanced synaptic resilience in preclinical models. “

https://www.mdpi.com/1422-0067/26/15/7638

Exploring the impact of chronic intermittent EU-GMP certified Cannabis sativa L. therapy and its relevance in a rat model of aging

Posted on August 7, 2025 by David

“Background: Aging is a multifaceted process marked by the progressive accumulation of cellular damage in various tissues, resulting in a decline in physiological functions. The primary aim of aging research is to identify compounds that can delay or mitigate these detrimental changes. As cannabis legalization becomes more widespread and with limited empirical studies on its effects in the aging human population, there is a pressing need for research into the impact of Cannabis and cannabinoids on healthy aging and age-related diseases.

Methods: Our study aims to evaluate the effects of chronic, intermittent exposure, defined as 6 weeks of use of EU-GMP certified Cannabis sativa L. (Cannabixir® Medium Flos) administration, dosed at 6.25 and 25 mg/kg on neurobiological changes in naturally aged rats and its potential efficacy in mitigating age-related alterations. The impact of the Cannabixir® Medium Flos was assessed through clinical, histopathological, immunohistochemical, and behavioral evaluations.

Results: Cannabixir® Medium Flos was found to be generally safe, with no significant effects on motor performance and a neutral effect on anxiety-like behavior. Histological analysis revealed that the hippocampus of aged rats treated with this compound-an area known for its abundance of endocannabinoids and cannabinoid receptor type 1-exhibited characteristics similar to those observed in young adult rats. Additionally, the study suggests that chronic, intermittent treatment with Cannabixir® Medium Flos may modulate astrocyte function, reduce neuroinflammation, and potentially influence cell proliferation and neuronal apoptosis in a dose-dependent manner. However, these preliminary findings should be interpreted with caution, as the study’s exploratory nature.

Conclusions: These preliminary findings suggest that cannabinoid therapy targeting the endocannabinoid system may offer potential neuroprotective benefits in aging.

While the study offers valuable preclinical insights into the effects of an EU-GMP-certified cannabinoid receptor ligand in reducing age-related cognitive decline, these effects are likely mediated by a combination of mechanisms. Given the complex phytochemical composition, the observed outcomes cannot be attributed exclusively to cannabinoid receptor activation. Accordingly, these findings should be interpreted with caution, and further studies employing more targeted methodologies are needed to elucidate the underlying mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/40770774/

“Targeting the ECS could be a promising strategy for developing therapies aimed at promoting healthy aging and longevity.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00313-8

Neural Signatures of Cannabis Use: Reversing Cognitive Aging via Whole-Brain Functional Network Connectivity

Posted on August 6, 2025 by David

“Given the growing trend toward permissive societal attitudes and the legalization of cannabis, coupled with an increasing recognition of its therapeutic potential, there has been a notable rise in cannabis consumption among older adults.

Cognitive aging, one of the most prevalent concerns in this demographic, intersects with cannabis use, which shares several neural correlates. However, the precise impact of cannabis on the aging brain and cognitive function remains poorly understood.

In this study, we leveraged large-scale data from the UK Biobank, which includes over 25,000 participants, to conduct a comprehensive examination of the relationships between cannabis use, normative aging, and cognitive function. Our focus was on how these factors correlate with brain functional network connectivity (FNC), aiming to elucidate the interactive effects underlying brain neuroimaging patterns.

Our findings reveal that cannabis usage and healthy aging are associated with overlapping brain network configurations, particularly within the FNC between subcortical and sensorimotor regions, as well as between subcortical and cerebellar areas, albeit with significantly reversed effects.

Notably, cannabis users exhibited superior performance across multiple cognitive domains, and interestingly, the effects of cannabis and cognition are presented concurrently across a range of brain systems.

In conclusion, our study offers valuable insights into the potential influence of cannabis on brain aging and cognitive performance. The results suggest that cannabis users display brain network characteristics typically associated with younger brains, along with enhanced cognitive abilities, highlighting a potential modulatory role for cannabinoids and endocannabinoids in neurodegenerative processes, as explained through neural dedifferentiation and compensation theories.”

https://pubmed.ncbi.nlm.nih.gov/40766216/

https://www.researchsquare.com/article/rs-6977015/v1

The impact of cannabis use on ageing and longevity: a systematic review of research insights

Posted on July 30, 2025 by David

“With aging emerging as a global challenge linked to chronic diseases, identifying interventions that support a healthy lifespan and health span has become imperative. Cannabinoids derived from cannabis, particularly cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), have gained attention for their potential to promote healthy aging through interactions with the endocannabinoid system. While CBD has often been highlighted for its benefits, emerging evidence indicates that THC, under certain conditions and doses, may also play a therapeutic role in aging. Despite this interest, significant knowledge gaps persist in understanding cannabis’s role in promoting healthy aging and longevity.Aim

We reviewed recent literature to investigate the effect of cannabinoid use, particularly CBD and THC on aging and longevity. By synthesizing findings from preclinical models, clinical studies, and real-world evidence, we aimed to elucidate the potential of cannabinoids, in fostering healthy aging, mitigate age-related decline, and promote well-being in older populations.Method

We conducted a systematic review guided by PRISMA to investigate the impact of cannabinoids on aging and longevity. Studies involving preclinical models (e.g., Caenorhabditis elegans, rodents, zebrafish, and mice) and clinical populations aged 50 years and older were included. Exclusion criteria targeted acute effects and mechanisms of action in different medical conditions. Aging was explicitly defined as biological and psychological changes associated with advancing age, and longevity was defined as the extension of lifespan and factors influencing healthy aging.Findings

Eighteen studies investigating the direct impact of cannabinoids on aging and longevity were identified in preclinical models (11) and human studies (7). Preclinical studies have shown promising results regarding the potential benefits of cannabinoids including improved lifespan, cognitive function, inflammation, memory, sleep quality, and social interaction. The effects of THC appear more complex, with potential benefits at low doses and drawbacks at higher doses, highlighting their complex role in aging. However, the limited number of human studies hinders a comprehensive understanding. Clinical studies also suggest potential therapeutic applications for cannabinoids in aging populations, although further research is needed to understand their mechanisms of action and long-term effects fully.”

Conclusion

“Cannabinoids hold promise for supporting healthy aging and enhancing the quality of life in older populations. While preliminary research suggests intriguing possibilities, more studies are needed to solidify the link between cannabis use, the ECS, and healthy aging in humans. Rigorous clinical trials are crucial to evaluate their safety and efficacy. Longitudinal studies and well-designed clinical trials are critical to understanding the safety, efficacy, and long-term effects of cannabis use in aging populations. Future research should optimize dosages, investigate mechanisms of action, and explore the influence of cannabis use initiated in aging as opposed to lifetime exposure. Clarifying these aspects is vital for informing public health strategies and developing targeted therapeutic interventions for age-related conditions.”

“These findings open exciting avenues for exploring novel therapeutic interventions for age-related cognitive decline and neurological disorders.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-025-00267-x

https://pubmed.ncbi.nlm.nih.gov/40731362/

Anti-Inflammatory Effects of Cannabinoids in Therapy of Neurodegenerative Disorders and Inflammatory Diseases of the CNS

Posted on July 29, 2025 by David

“Many neurodegenerative diseases are associated with immune system disorders, while neurodegenerative processes often occur in inflammatory conditions of the Central Nervous System (CNS).

Cannabinoids exhibit significant therapeutic potential due to their dual ability to modulate both neural and immune functions. These compounds have a broad spectrum of action, allowing them to target multiple pathological mechanisms underlying neurodegenerative and inflammatory CNS diseases.

The present review outlines the therapeutic potential of cannabinoids, with a focus on their anti-inflammatory properties, in the treatment of neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease, as well as inflammatory CNS disorders like multiple sclerosis and HIV-associated dementia.”

https://pubmed.ncbi.nlm.nih.gov/40724820/

“Cannabinoids, the active compounds derived from Cannabis sativa, are attracting increasing interest for their therapeutic potential in neurodegenerative disorders (Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease) and inflammatory CNS conditions (multiple sclerosis and HIV-associated dementia).

Their multimodal mechanisms of action include the following: (1) modulating pathological protein aggregation and mitochondrial dysfunction, and (2) exerting neuroprotective and anti-inflammatory effects which are mediated through microglial regulation.

The neurodegenerative diseases and inflammatory CNS disorders discussed in this work represent a serious challenge for healthcare systems due to their complex etiology or pathophysiology, severe symptoms, and the limited effectiveness of existing treatments. Consequently, improving therapeutic strategies for these disorders remains a priority.

Many studies suggest that pharmacological modulation of the endocannabinoid system could influence neurodegenerative processes, providing a basis for further research into cannabinoid-based therapies. In particular, the inhibition of FAAH in the endocannabinoid system has emerged as a potential therapeutic approach to control neuroinflammatory processes.”

https://www.mdpi.com/1422-0067/26/14/6570

Ageing, Neurodegeneration and the Endocannabinoid System

Posted on July 25, 2025 by David

“Numerous studies carried out in the last 30-40 years have strongly demonstrated that the endocannabinoid system exerts important modulatory functions in the central nervous system (CNS). These neuromodulatory functions encompass the whole life of animals, with specific activities during neurodevelopment (prenatal, postnatal and adolescent periods), adulthood and possibly senescence too. However, this is the life stage less investigated in relation with the endocannabinoid system to date.

In the aged brain, the activity of this system appears to be altered, which contributes to subtle impairments that typically occur during ageing in learning and memory, motor behaviour, social behaviour and other neurobiological functions. Some of the changes in endocannabinoid activity may represent a process to attenuate ageing-related impairment in the brain function, which is consistent with its role as a pro-homeostatic system.

An important observation is that these alterations become extreme when normal brain ageing acquires pathological characteristics, as happens in chronic neurodegenerative disorders. This includes the cannabinoid type-1 (CB₁) receptor downregulation or impairment in its signalling and the increase in endocannabinoid-inactivating enzymes, both hypothesised to contribute to pathogenic events. By contrast, elevated levels of endocannabinoids due to a reduced Fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) expression and the upregulation of cannabinoid type-2 (CB₂) receptors may in turn serve as endogenous pro-homeostatic adaptations against brain impairment.

This review synthesises information on: (i) subtle alterations in the endocannabinoid system in the senescent brain in the absence of pathology, with the purpose of demonstrating that these alterations are representative of the extreme changes experienced by this system in the brain pathological ageing; and (ii) the development of neuroprotective therapies based on the pharmacological management of specific endocannabinoid targets to combat neurodegenerative pathologies.

Together, research in this area comes at a critical time as global lifespan is increasing, incidence of age-related neurodegenerative disorders is expanding, and the unmet need for efficacious neuroprotective treatments is a public health necessity.”

https://pubmed.ncbi.nlm.nih.gov/40707697/

https://link.springer.com/chapter/10.1007/7854_2025_597

Multi-Target Protective Effects of β-Caryophyllene (BCP) at the Intersection of Neuroinflammation and Neurodegeneration

Posted on July 15, 2025 by David

“Recent advances in cannabinoid-based therapies identified the natural CB2 receptor agonist β-caryophyllene (BCP) as a promising anti-inflammatory and neuroprotective agent. To further explore its therapeutic potential on the management of neurodegenerative disorders, in the present study we investigated the ability of BCP to prevent neuroinflammation and promote neuroprotection by using both in vitro and ex vivo models of β-amyloid induced neurotoxicity.

Our data showed that BCP significantly protected human microglial HMC3 cells from Aβ_25-35-induced cytotoxicity, reducing the release of pro-inflammatory cytokines (TNF-α, IL-6) while enhancing IL-10 secretion. These effects were associated with a reduced activation of the NF-κB pathway, which emerged as a central mediator of BCP action.

Notably, the use of CB2R- or PPARγ-selective antagonists revealed that the observed NF-κB inhibition by BCP may involve the coordinated activation of both canonical (e.g., CB2R) and non-canonical (e.g., PPARγ) receptors. Moreover, BCP restored the expression of SIRT1, PGC-1α, and BDNF, indicating the involvement of neurotrophic pathways.

Clear neuroprotective properties for BCP have been highlighted in Aβ_1-42-treated brain slice preparations, where BCP demonstrated the rescue of both the amyloid-dependent depression of BDNF expression and long-term synaptic potentiation (LTP) impairment.

Overall, our results suggest that BCP constitutes an attractive natural molecule for the treatment of Aβ-induced neuroinflammation and synaptic dysfunction, warranting further exploration for its clinical application.”

https://pubmed.ncbi.nlm.nih.gov/40649806/

“In conclusion, the results of our study suggest a pleiotropic mechanism of action for the development of BCP neuroprotective effects in relation to amyloid-induced neuroinflammation and synaptic impairment, encouraging further investigations into an in vivo model of amyloid-dependent cognitive damage to clarify the exact mechanism of action of BCP and confirm whether this natural molecule may represent a novel option for the treatment of NDDs.

Furthermore, the potent anti-inflammatory effects exerted by BCP through the interaction of CB2 and PPARγ receptors support the therapeutic potential of BCP in a broad range of conditions, including neurodegenerative and metabolic diseases, neuropathic pain, and cancer. Taking into consideration the safety of BCP in humans, dietary use, and its efficacy in various experimental models of disease, BCP may be further explored as co-supplementary drug in experimental studies.”

https://www.mdpi.com/1422-0067/26/13/6027

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.” https://www.ncbi.nlm.nih.gov/pubmed/18574142

Differential metabolic pathways underlie THC- and CBD-mediated inhibition of B-cell activation in both young and aged mice

Posted on July 2, 2025 by David

“Objective: B lymphocytes play a crucial role in immunity but also contribute to the pathogenesis of various diseases. Cannabis plants produce numerous biologically active compounds, including cannabinoids. The two most studied phytocannabinoids are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids exert diverse and potent biological effects primarily through the endocannabinoid system (ECS), which also plays a key role in mature B-cell function. Both the immune system and the ECS undergo age-related changes that lead to a clinically significant decline in function.

Methods: This study compares the effects of THC and CBD on B-cell activity in young and aged mice. Murine B lymphocytes were activated using lipopolysaccharide (LPS) and interleukin-4 (IL-4), and the impact of cannabinoid treatments was assessed in terms of cell phenotype, proliferation, antibody secretion, tumor necrosis factor-alpha (TNFα) secretion, extracellular signal-regulated kinase (ERK) phosphorylation, and the cellular metabolome.

Results: Both THC and CBD exhibited dose-dependent inhibitory effects on B-cell activation in young and aged mice. However, we show here, for the first time, that the treatments induce distinct metabolic profiles. Although some metabolites, such as glucose-6-phosphate, pentose phosphate pathway (PPP) and nucleotide metabolites, were reduced by both cannabinoids, THC selectively reduced the levels of a distinct set of amino acids, while only CBD increased the levels of Citrulline and Allantoin. Additionally, the effects of THC and CBD differed between young and aged B cells, suggesting that age-related changes in the ECS may influence cannabinoid sensitivity.

Conclusions: These findings provide insights into the distinct mechanisms by which THC and CBD regulate immune activation and may open the door for investigating the mechanisms behind cannabinoids effects on the immune system. They also highlight the need for further research into phytocannabinoid-based therapies, particularly in age-specific contexts. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may enhance their clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/40599768/

“These findings emphasize the need for further investigation into phytocannabinoid-based therapies, particularly for age-specific applications. Given the immunoregulatory properties of cannabinoids, especially CBD, tailored therapeutic strategies may be developed to optimize their clinical use.”

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1605474/full

Recent Preclinical Evidence on Phytocannabinoids in Neurodegenerative Disorders: A Focus on Parkinson’s and Alzheimer’s Disease

Posted on June 27, 2025 by David

“The endocannabinoid system (ECS) is a vital biological network essential for maintaining homeostasis and supporting various physiological functions. It comprises cannabinoid receptors, endogenous lipid-based ligands, known as endocannabinoids, as well as metabolic enzymes and associated proteins responsible for regulating their levels within tissues. The ECS plays a central role in modulating processes involving the central nervous system (CNS). Recent studies have highlighted its antioxidant, anti-inflammatory, and neuroprotective properties.

The therapeutic potential of cannabinoids, particularly phytocannabinoids derived from plants, has attracted significant attention in medical and pharmaceutical research. This interest has grown in parallel with the increasing availability of cannabinoid-based food supplements on the pharmaceutical market. Given the complexity of the ECS and its broad range of interactions, the discovery of this system has spurred extensive investigations into the use of cannabinoids for various health conditions.

In this review, we examine recent preclinical evidence supporting the use of phytocannabinoids in the context of neurodegenerative diseases, particularly in Alzheimer’s disease and Parkinson’s disease. Targeting the ECS through phytocannabinoid-based pharmacological modulation offers a promising therapeutic strategy for these neurological disorders. Among these compounds, cannabidiol has emerged as a key focus of research due to its multifaceted effects and favorable safety profile. Nonetheless, continued investigation is necessary to clarify its mechanisms of action, and to develop effective, evidence-based clinical applications.”

https://pubmed.ncbi.nlm.nih.gov/40573285/

“Recent advances in cannabinoid research have shed light on the considerable therapeutic potential of phytocannabinoids, particularly CBD, in the treatment of neurodegenerative diseases.

The preclinical studies presented in this review demonstrate consistent neuroprotective, anti-inflammatory, antioxidant, and neuromodulator effects in models of AD, PD, or HD.

These effects are largely mediated through the complex interplay of phytocannabinoids with the ECS, as well as their interactions with non-cannabinoid targets, such as TRPV1, 5-HT1A receptors, and PPARs.The ECS emerges as a crucial modulator of CNS homeostasis, and its dysregulation appears to be closely linked with the pathophysiology of major neurodegenerative diseases.

Phytocannabinoid-mediated modulation of ECS activity has shown promising outcomes in various animal models, including reductions in neuroinflammation, attenuation of excitotoxicity, and preservation of cognitive and motor function.The evidence suggests that phytocannabinoids may contribute to neuronal preservation, attenuation of neuroinflammatory cascades, and improvement in motor and cognitive performance in disease models. Moreover, their favorable safety profile and ability to act on multiple molecular pathways position them as promising candidates for disease-modifying interventions.

As interest in cannabinoid pharmacotherapy continues to grow, phytocannabinoids represent a promising, multifaceted class of compounds with the potential to address unmet therapeutic needs in the field of neurodegeneration.”

https://www.mdpi.com/1424-8247/18/6/890

Cannabinol’s Modulation of Genes Involved in Oxidative Stress Response and Neuronal Plasticity: A Transcriptomic Analysis

Posted on June 26, 2025 by David

“Cannabis sativa is a remarkable source of bioactive compounds, with over 150 distinct phytocannabinoids identified to date. Among these, cannabinoids are gaining attention as potential therapeutic agents for neurodegenerative diseases.

Previous research showed that cannabinol (CBN), a minor cannabinoid derived from Δ⁹-tetrahydrocannabinol, exhibits antioxidant, anti-inflammatory, analgesic, and anti-bacterial effects.

The objective of this study was to assess the protective potential of 24 h CBN pre-treatment, applied at different concentrations (5 µM, 10 µM, 20 µM, 50 µM, and 100 µM), in differentiated neuroblastoma × spinal cord (NSC-34) cells. Transcriptomic analysis was performed using next-generation sequencing techniques.

Our results reveal that CBN had no negative impact on cell viability at the tested concentrations. Instead, it showed a significant effect on stress response and neuroplasticity-related processes. Specifically, based on the Reactome database, the biological pathways mainly perturbed by CBN pre-treatment were investigated.

This analysis highlighted a significant enrichment in the Reactome pathway’s cellular response to stress, cellular response to stimuli, and axon guidance.

Overall, our results suggest that CBN holds promise as an adjuvant agent for neurodegenerative diseases by modulating genes involved in neuronal cell survival and axon guidance.”

https://pubmed.ncbi.nlm.nih.gov/40563376/

“Aging and neurodegenerative diseases are characterized by a progressive decline in cellular functions, including genomic instability, epigenetic alterations, mitochondrial dysfunction, and chronic inflammation. Our study supports that CBN exerts pleiotropic effects by modulating key molecular pathways involved in oxidative stress response, DNA repair, and neuronal survival. These results suggest that CBN positively modulates the response to cellular damage, stimulating the antioxidant response through the Nrf2 pathway and reducing the sensitivity to programmed cell death, as demonstrated by the regulation of caspases and other genes related to neuronal survival. These effects indicate that CBN may be able to support neuronal health under conditions of chronic stress, a hallmark of neurodegenerative diseases. These findings pave the way for further research into CBN’s therapeutic potential, emphasizing the need for in vivo studies to validate its efficacy and safety profile in neurodegenerative disease models.”

https://www.mdpi.com/2076-3921/14/6/744

www.thctotalhealthcare.com

Category Archives: Alzheimer’s Disease (AD)