Use of Cannabis for Agitation in Patients With Dementia

 logo“Studies have reported changes in the endocannabinoid system in the brain of patients with Alzheimer’s disease (AD), playing a role in the pathophysiology of AD. Cannabinoids have been shown to have neuroprotective properties, reduce neuroinflammation, and enhance neurogenesis. Evidence suggests that the utilization of marijuana products containing both tetrahydrocannabinol (THC) and cannabidiol (CBD) or CBD alone have been effective and safe for use in older people with agitation associated with dementia.

A review in 2017 summarized positive findings for therapeutic benefits of cannabinoids in agitation of AD and dementia, but there was no definitive conclusion because of varying cannabinoid products. Cannabinoids were shown to be well tolerated, with few short-term side effects. This differs from first-line medications utilized for dementia behaviors, which can have unwanted side effects. Further research regarding the safety, efficacy, and variability of these products in older people is needed.”

https://pubmed.ncbi.nlm.nih.gov/32600509/

https://www.ingentaconnect.com/content/ascp/tscp/2020/00000035/00000007/art00006;jsessionid=1ivcuvrvy4g1s.x-ic-live-03

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Can Physical Activity Support the Endocannabinoid System in the Preventive and Therapeutic Approach to Neurological Disorders?

ijms-logo“The worldwide prevalence of neurological and neurodegenerative disorders, such as depression or Alzheimer’s disease, has spread extensively throughout the last decades, becoming an enormous health issue.

Numerous data indicate a distinct correlation between the altered endocannabinoid signaling and different aspects of brain physiology, such as memory or neurogenesis. Moreover, the endocannabinoid system is widely regarded as a crucial factor in the development of neuropathologies. Thus, targeting those disorders via synthetic cannabinoids, as well as phytocannabinoids, becomes a widespread research issue.

Over the last decade, the endocannabinoid system has been extensively studied for its correlation with physical activity. Recent data showed that physical activity correlates with elevated endocannabinoid serum concentrations and increased cannabinoid receptor type 1 (CB1R) expression in the brain, which results in positive neurological effects including antidepressant effect, ameliorated memory, neuroplasticity development, and reduced neuroinflammation. However, none of the prior reviews presented a comprehensive correlation between physical activity, the endocannabinoid system, and neuropathologies.

Thus, our review provides a current state of knowledge of the endocannabinoid system, its action in physical activity, as well as neuropathologies and a possible correlation between all those fields. We believe that this might contribute to finding a new preventive and therapeutic approach to both neurological and neurodegenerative disorders.”

https://pubmed.ncbi.nlm.nih.gov/32545780/

https://www.mdpi.com/1422-0067/21/12/4221

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Cannabinoid as Beneficial Replacement Therapy for Psychotropics to Treat Neuropsychiatric Symptoms in Severe Alzheimer’s Dementia: A Clinical Case Report

CrossFit | 190629“Alzheimer’s Dementia (AD) is a devastating neurodegenerative disease that affects approximately 17% of people aged 75-84. Neuropsychiatric symptoms (NPS) such as delusions, agitation, anxiety, and hallucinations are present in up to 95% of patients in all stages of dementia. To date, any approved and effective pharmacological interventions for the treatment of NPS are still not available.

We describe a clinical case of a female patient diagnosed with AD with continuous cognitive decline and dementia-related behavioral symptoms. Between 2008 and 2019, the patient was examined half-yearly at the memory clinic of the Medical University of Innsbruck. At each visit, cognitive state and pharmacological treatment were evaluated. In addition, NPs were assessed by using the neuropsychiatric inventory (NPI). In 2018, the patient progressed to severe AD stage and presented with progressive NPs (anxiety, suspected delusions, agitation, aggressive behavior, and suspected pain due to long immobility).

Consequently, off-label treatment with low-dose dronabinol was initiated, which facilitated a reduction of psychopharmacological treatment from six to three psychotropics. At the same time, the patient’s emotional state improved, while disruptive behavior, aggression, and sedation decreased significantly. This case report underpins the need for randomized, controlled trials to explore the effect of cannabinoid receptor agonists on behavioral and psychological symptoms in patients with severe AD.”

https://pubmed.ncbi.nlm.nih.gov/32477187/

“Cannabinoids have a distinct pharmacologic profile that may offer an alternative pharmacologic approach to antipsychotics and sedatives for treating NPs in patients with AD. In addition, the beneficial effect on appetite and pain may significantly improve quality of life of AD-patients and their caregivers.”

https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00413/full

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Age-dependent Alteration in Mitochondrial Dynamics and Autophagy in Hippocampal Neuron of Cannabinoid CB1 receptor-deficient Mice.

Brain Research Bulletin“Endocannabinoid system activity contributes to the homeostatic defense against aging and thus may counteract the progression of brain aging.

The cannabinoid type 1 (CB1) receptor activity declines with aging in the brain, which impairs neuronal network integrity and cognitive functions.

Altogether, these findings suggest that reduced CB1 signaling in CB1-KO mice leads to reduced mitophagy and abnormal mitochondrial morphology in hippocampal neurons during aging.

These mitochondrial changes might be due to the impairments in mitochondrial quality control system, which links age-related decline in CB1 activity and impaired memory.”

https://www.ncbi.nlm.nih.gov/pubmed/32294520

https://www.sciencedirect.com/science/article/abs/pii/S0361923020301386?via%3Dihub

“Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586121/

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From Cannabis sativa to Cannabidiol: Promising Therapeutic Candidate for the Treatment of Neurodegenerative Diseases.

frontiers in pharmacology – Retraction Watch“Cannabis sativa, commonly known as marijuana, contains a pool of secondary plant metabolites with therapeutic effects.

Besides Δ9-tetrahydrocannabinol that is the principal psychoactive constituent of Cannabiscannabidiol (CBD) is the most abundant nonpsychoactive phytocannabinoid and may represent a prototype for anti-inflammatory drug development for human pathologies where both the inflammation and oxidative stress (OS) play an important role to their etiology and progression.

To this regard, Alzheimer’s disease (AD), Parkinson’s disease (PD), the most common neurodegenerative disorders, are characterized by extensive oxidative damage to different biological substrates that can cause cell death by different pathways. Most cases of neurodegenerative diseases have a complex etiology with a variety of factors contributing to the progression of the neurodegenerative processes; therefore, promising treatment strategies should simultaneously target multiple substrates in order to stop and/or slow down the neurodegeneration.

In this context, CBD, which interacts with the eCB system, but has also cannabinoid receptor-independent mechanism, might be a good candidate as a prototype for anti-oxidant drug development for the major neurodegenerative disorders, such as PD and AD. This review summarizes the multiple molecular pathways that underlie the positive effects of CBD, which may have a considerable impact on the progression of the major neurodegenerative disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32210795

“The present review provided evidence that the nonpsychoactive phytocannabinoids CBD could be a potential pharmacological tool for the treatment of neurodegenerative disorders; its excellent safety and tolerability profile in clinical studies renders it a promising therapeutic agent.

The molecular mechanisms associated with CBD’s improvement in PD and AD are likely multifaceted, and although CBD may act on different molecular targets all the beneficial effects are in some extent linked to its antioxidant and anti-inflammatory profile, as observed in in vitro and in vivo studies. Therefore, this review describes evidence to prove the therapeutical efficacy of CBD in patients affected by neurodegenerative disorders and promotes further research in order to better elucidate the molecular pathways involved in the therapeutic potential of CBD.”

https://www.frontiersin.org/articles/10.3389/fphar.2020.00124/full

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Melatonin and cannabinoids: mitochondrial-targeted molecules that may reduce inflammaging in neurodegenerative diseases.

Image result for histology and histopathology“Generally, the development and progression of neurodegenerative diseases are associated with advancing age, so they are usually diagnosed in late adulthood. A primary mechanism underlying the onset of neurodegenerative diseases is neuroinflammation. Based on this background, the concept of “neuroinflammaging” has emerged. In this deregulated neuroinflammatory process, a variety of immune cells participate, especially glial cells, proinflammatory cytokines, receptors, and subcellular organelles including mitochondria, which are mainly responsible for maintaining redox balance at the cellular level. Senescence and autophagic processes also play a crucial role in the neuroinflammatory disease associated with aging.

Of particular interest, melatonin, cannabinoids, and the receptors of both molecules which are closely related, exert beneficial effects on the neuroinflammatory processes that precede the onset of neurodegenerative pathologies such as Parkinson’s and Alzheimer’s diseases. Some of these neuroprotective effects are fundamentally related to its anti-inflammatory and antioxidative actions at the mitochondrial level due to the strategic functions of this organelle. The aim of this review is to summarize the most recent advances in the study of neuroinflammation and neurodegeneration associated with age and to consider the use of new mitochondrial therapeutic targets related to the endocannabinoid system and the pineal gland.”

https://www.ncbi.nlm.nih.gov/pubmed/32154907

https://www.hh.um.es/Abstracts/Vol_/_/__18212.htm

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The implications of late-life cannabis use on brain health: A mapping review and implications for future research.

Ageing Research Reviews“While medical and recreational cannabis use is becoming more frequent among older adults, the neurocognitive consequences of cannabis use in this age group are unclear. The aim of this literature review was to synthesize and evaluate the current knowledge on the association of cannabis use during older-adulthood with cognitive function and brain aging.

We reviewed the literature from old animal models and human studies while focusing on the link of middle- and old-age use of cannabis with cognition. The report highlights the gap in knowledge on cannabis use in late-life and cognitive health, and discusses the limited findings in the context of substantial changes in attitudes and policies. Furthermore, we outline possible theoretical mechanisms and propose recommendations for future research.

The limited evidence on this important topic suggests that use in older ages may not be linked with poorer cognitive performance, thus detrimental effects of early-life cannabis use may not translate to use in older ages. Rather, use in old ages may be associated with improved brain health, in accordance with the known neuroprotective properties of several cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/32109605

“Cannabis use in older ages may be associated with improved brain health.”

https://www.sciencedirect.com/science/article/pii/S1568163719303204?via%3Dihub

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Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology.

Image result for frontiers in neurology“Microglia, the resident immune cells of the central nervous system, mediate brain homeostasis by controlling neuronal proliferation/differentiation and synaptic activity. In response to external signals from neuropathological conditions, homeostatic (M0) microglia can adopt one of two activation states: the classical (M1) activation state, which secretes mediators of the proinflammatory response, and the alternative (M2) activation state, which presumably mediates the resolution of neuroinflammation and tissue repair/remodeling.

Since chronic inflammatory activation of microglia is correlated with several neurodegenerative diseases, functional modulation of microglial phenotypes has been considered as a potential therapeutic strategy.

The endocannabinoid (eCB) system, composed of cannabinoid receptors and ligands and their metabolic/biosynthetic enzymes, has been shown to activate anti-inflammatory signaling pathways that modulate immune cell functions. Growing evidence has demonstrated that endogenous, synthetic, and plant-derived eCB agonists possess therapeutic effects on several neuropathologies; however, the molecular mechanisms that mediate the anti-inflammatory effects have not yet been identified.

Over the last decade, it has been revealed that the eCB system modulates microglial activation and population. In this review, we thoroughly examine recent studies on microglial phenotype modulation by eCB in neuroinflammatory and neurodegenerative disease conditions.

We hypothesize that cannabinoid 2 receptor (CB2R) signaling shifts the balance of expression between neuroinflammatory (M1-type) genes, neuroprotective (M2-type) genes, and homeostatic (M0-type) genes toward the latter two gene expressions, by which microglia acquire therapeutic functionality.”

https://www.ncbi.nlm.nih.gov/pubmed/32117037

https://www.frontiersin.org/articles/10.3389/fneur.2020.00087/full

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Chronic Treatment with 50 mg/kg Cannabidiol Improves Cognition and Moderately Reduces Aβ42 Levels in 12-Month-Old Male AβPPswe/PS1ΔE9 Transgenic Mice.

Image result for j alzheimers dis“Alzheimer’s disease (AD) is characterized by progressive cognitive decline and pathologically by the accumulation of amyloid-β (Aβ) and tau hyperphosphorylation causing neurodegeneration and neuroinflammation. Current AD treatments do not stop or reverse the disease progression, highlighting the need for more effective therapeutics.

The phytocannabinoid cannabidiol (CBD) has demonstrated antioxidant, anti-inflammatory, and neuroprotective properties. Furthermore, chronic CBD treatment (20 mg/kg) reverses social and object recognition memory deficits in the AβPPxPS1 transgenic mouse model with only limited effects on AD-relevant brain pathology.

Importantly, studies have indicated that CBD works in a dose-dependent manner. Thus, this study determined the chronic effects of 50 mg/kg CBD in male AβPPxPS1 mice. 12-month-old mice were treated with 50 mg/kg CBD or vehicle via daily intraperitoneal injections for 3 weeks prior to behavioral testing. A variety of cognitive domains including object and social recognition, spatial and fear-associated memory were evaluated. Pathological brain analyses for AD-relevant markers were conducted using ELISA and western blot.

Vehicle-treated male AβPPxPS1 mice demonstrated impaired social recognition memory and reversal spatial learning. These deficits were restored after CBD treatment. Chronic CBD tended to reduce insoluble Aβ40 levels in the hippocampus of AβPPxPS1 mice but had no effect on neuroinflammation, neurodegeneration, or PPARγ markers in the cortex.

This study demonstrates that therapeutic-like effects of 50 mg/kg CBD on social recognition memory and spatial learning deficits in AβPPxPS1 mice are accompanied by moderate brain region-specific reductions in insoluble Aβ40 levels. The findings emphasize the clinical relevance of CBD treatment in AD; however, the underlying mechanisms involved require further investigation.”

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Overview of cannabidiol (CBD) and its analogues: Structures, biological activities, and neuroprotective mechanisms in epilepsy and Alzheimer’s disease.

European Journal of Medicinal Chemistry“Herein, 11 general types of natural cannabinoids from Cannabis sativa as well as 50 (-)-CBD analogues with therapeutic potential were described. The underlying molecular mechanisms of CBD as a therapeutic candidate for epilepsy and neurodegenerative diseases were comprehensively clarified. CBD indirectly acts as an endogenous cannabinoid receptor agonist to exert its neuroprotective effects. CBD also promotes neuroprotection through different signal transduction pathways mediated indirectly by cannabinoid receptors. Furthermore, CBD prevents the glycogen synthase kinase 3β (GSK-3β) hyperphosphorylation caused by Aβ and may be developed as a new therapeutic candidate for Alzheimer’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/32109623

“For AD treatment, CBD can rescue the production of neurofibrillary tangles and inhibit neuronal apoptosis.”

https://www.sciencedirect.com/science/article/abs/pii/S0223523420301306?via%3DihubImage 1

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