Studies: How Cannabis Helps Dementia

Links to studies using cannabis for dementia

Cannabis Therapeutics and the Future of Neurology 

10/2018 [FTA] "...No current pharmacotherapy is approved for agitation in AD. Commonly used anti-psychotics, antidepressants, anxiolytics and hypnotics are often associated with increased mortality in demented patients (Kales et al., 2007), with an FDA “Black Box Warning.” Four acetylcholinesterase inhibitors are approved in the USA to improve memory: galantamine, donepezil, tacrine and rivastigmine. None show strong evidence of efficacy and are of limited benefit on a temporary basis. Various NMDA receptor antagonists in development have proven largely ineffective on disease progression or have proven toxic. In contrast, treatment with cannabinoids appears both more promising and benign. As demonstrated in 1998 (Hampson et al., 1998), and the subject of USA patent US09674028, CBD is a neuroprotective antioxidant, more potent than ascorbate or tocopherol, that works on the same NMDA target without attendant toxicity...

...In addition to its neuroprotective antioxidant effects (Iuvone et al., 2004), THC competitively inhibited acetylcholinesterase, increasing levels, and prevented Aβ aggregation via binding to the enzyme in a critical region affecting amyloid production (Eubanks et al., 2006)...

...Initial trials of herbal cannabis for AD have begun sporadically, with a more focused effort in a California nursing home [assisted living] (Hergenrather, 2017). Patients were treated with a variety of preparations: THC-predominant (2.5–30 mg/dose), CBD predominant, and THCA, mainly in tinctures and confections. Marked benefit was reported on neuroleptic drug sparing, decreased agitation, increased appetite, aggression, sleep quality, objective mood, nursing care demands, self-mutilation and pain control.

... Based on its pharmacology (Russo and Marcu, 2017), cannabis components may provide myriad benefits on target symptoms in this complex disorder:

• Agitation: THC, CBD, linalool

• Anxiety: CBD, THC (low dose), linalool

• Psychosis: CBD

• Insomnia/Restlessness: THC, linalool

• Anorexia: THC

• Aggression: THC, CBD, linalool

• Depression: THC, limonene, CBD

• Pain: THC, CBD

• Memory: alpha-pinene (Russo, 2011; Russo and Marcu, 2017) + THC

• Neuroprotection: CBD, THC

• Reduced Aβ plaque formation: THC, CBD, THCA

Thus, an extract of a Type II chemovar of cannabis (THC/CBD) with a sufficient pinene fraction would seem to be an excellent candidate for clinical trials (Lewis et al., 2018). "

Cannabinoids in late-onset Alzheimer's disease

06/2015 [FTA] “...Several in vitro and in vivo studies have demonstrated that cannabinoids can reduce oxidative stress, neuroinflammation, and the formation of amyloid plaques and neurofibrillary tangles, the key hallmarks of LOAD. In addition, in population-based studies, cannabinoids reduced dementia-related symptoms (e.g., behavioral disturbances)...”

Cannabinoids for treatment of Alzheimer's disease: moving toward the clinic

03/2014 [FTA] “...Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau phosphorylation, as well as by promoting the brain's intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress…”

Cannabis, Cannabinoids, and Sleep: a Review of the Literature

04/2017 [FTA] “...Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia…”

Mortality risk in patients with dementia treated with antipsychotics versus other psychiatric medications

10/2007 [FTA] “...Antipsychotic medications taken by patients with dementia were associated with higher mortality rates than were most other medications used for neuropsychiatric symptoms…”

Cannabidiol and (-)Delta9-tetrahydrocannabinol are neuroprotective antioxidants 

07/1998 [FTA] “...Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical (Fenton reaction) system and neuronal cultures. Cannabidiol was more protective against glutamate neurotoxicity than either ascorbate or alpha-tocopherol, indicating it to be a potent antioxidant. These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol, may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia…”

 

US Department of Health patent on Cannabinoids as Neuroprotectant 6630507B1

04/1998 [FTA] “...The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and HIV dementia…”

Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells

04/2004 [FTA] “...Our results indicate that cannabidiol exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against beta-amyloid peptide toxicity…”

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads

06/2017 [FTA] Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas.

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects

08/2011 [FTA] “...Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL(-1) . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant.”

Pharmacological Foundations of Cannabis Chemovars

03/2018 [FTA] “...Specific chemovars may produce enhanced analgesia, anti-inflammatory, anticonvulsant, antidepressant, and anti-anxiety effects, while simultaneously reducing sequelae of Δ9-tetrahydrocannabinol such as panic, toxic psychosis, and short-term memory impairment.”

Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease

08/2015 [FTA] “...The behavioural effects of ECS medications, as well as their ability to modulate neuroinflammation and oxidative stress, make targeting this system potentially relevant in AD. This article summarizes the literature to date supporting this rationale and evaluates clinical studies investigating cannabinoids for agitation and aggression in AD. Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids—dronabinol or nabilone—on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies. Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.”

The therapeutic potential of the endocannabinoid system for Alzheimer’s disease

04/2012 [FTA] “...Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects. Thus, the cannabinoid system should be a prime target for AD therapy…”

Endocannabinoid signalling in Alzheimer’s disease

12/2013 [FTA] “...The ECs, OEA and PEA have multiple physiological roles including involvement in learning and memory, neuroinflammation, oxidative stress, neuroprotection and neurogenesis. They have also been implicated in the pathology of, or perhaps protective responses to, neurodegenerative diseases. This is particularly the case with Alzheimer's disease, the most common age-related dementia associated with impairments in learning and memory accompanied by neuroinflammation, oxidative stress and neurodegeneration…”

A molecular link between the active component of marijuana and Alzheimer’s disease pathology

10/2008 [FTA] “...Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Aβ aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease…”

Neuroprotective effect of CBD… on beta-amyloid-induced toxicity in PC12 cells

04/2004 [FTA] “...Our results indicate that cannabidiol exerts a combination of neuroprotective, anti-oxidative and anti-apoptotic effects against beta-amyloid peptide toxicity, and that inhibition of caspase 3 appearance from its inactive precursor, pro-caspase 3, by cannabidiol is involved in the signalling pathway for this neuroprotection.”

The Potential Therapeutic Effects of THC on Alzheimer’s Disease

[FTA] “...From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner...We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways.”

The Role of Endocannabinoid Signaling in the Molecular Mechanisms of Neurodegeneration in Alzheimer’s Disease 

2015 [FTA] “...AD is multifaceted in nature and is linked to different multiple mechanisms in the brain...The ideal treatment for AD should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway...In this review, we recapitulate the role of endocannabinoid signaling in AD and the probable mechanisms through which modulators of the endocannabinoid system provide their effects, thus highlighting how this target might provide more advantages over other therapeutic targets.”

CBD in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression

08/2007 [FTA] “...The results of the present study confirm in vivo anti-inflammatory actions of CBD, emphasizing the importance of this compound as a novel promising pharmacological tool capable of attenuating Abeta evoked neuroinflammatory responses.”

CBD: A promising drug for neurodegenerative disorders?

2009 [FTA] “...cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.”

Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer’s disease leads to enhanced cognitive

11/2013 [FTA] “Alzheimer's disease (AD) is characterized by amyloid-β deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition...the findings indicate that CB1 deficiency can worsen AD-related cognitive deficits and support a potential role of CB1 as a pharmacologic target.”

The role of the endocannabinoid system in Alzheimer’s disease 

2008 [FTA] “...There is evidence, from in vivo studies on beta-amyloid-induced neurotoxicity, also for a possible causative role of endocannabinoids in the impairment in memory retention, which is typical of AD. This might open the way to the use of cannabinoid receptorantagonists as therapeutic drugs for the treatment of cognitive deficits in the more advanced phases of this disorder. The scant, but nevertheless important literature on the regulation and role of the endocannabinoid system in AD, and on the potential treatment of this disorder with cannabinoids and endocannabinoid-based drugs, are discussed in this mini-review.”

The role of phytochemicals in the treatment and prevention of dementia 

06/2011 [FTA] “This review presents the potential and actual therapeutic strategies for dementia in relation to the known mechanisms of dementia pathology. Phytochemicals that have shown mechanistic effects relevant to the pathological targets in dementia are discussed, with an emphasis on those showing positive clinical trial evidence... phytochemicals discussed include cannabinoids (e.g. cannabidiol) from Cannabis sativa, which are emerging as potential therapeutic agents for BPSD, and resveratrol (occurs in various plants) and curcumin (from turmeric [Curcuma longa]), which have been investigated for their pharmacological activities relevant to dementia and their potential effects on delaying dementia progression....Other plants and their extracts that have produced promising clinical data in dementia patients, with respect to cognition, include saffron (Crocus sativus), ginseng (Panax species), sage (Salvia species) and lemon balm (Melissa officinalis), although more extensive and reliable clinical data are required...most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba…”

Cannabidiol Promotes Amyloid Precursor Protein Ubiquitination and Reduction of Beta Amyloid Expression

in SHSY5YAPP+ Cells Through PPARγ Involvement

07/2014 [FTA] “...Results indicated the CBD capability to induce the ubiquitination of APP protein which led to a substantial decrease in APP full length protein levels in SHSY5Y(APP+) with the consequent decrease in Aβ production. Moreover, CBD promoted an increased survival of SHSY5Y(APP+) neurons, by reducing their long-term apoptotic rate…”

Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic 

03/2014 [FTA] “...Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau phosphorylation, as well as by promoting the brain's intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress…”

Can Marijuana Prevent Alzheimer’s? 

10/2012 [FTA] “Cognitive decline is the No. 1 fear among Americans older than 50, but while we know that exercise, proper diet and social and educational engagement can help maintain brain health, there is as yet no intervention that can fully prevent the onset of dementia or Alzheimer's disease.If no such development occurs, the number of Americans with Alzheimer's disease is expected to triple in the next 50 years...new treatments that can reproduce, through natural or synthetic means, some of the beneficial effects of cannabinoids could hold promise. In 2007, Ohio State University researchers published a paper stating that medications which can stimulate cannabinoid receptors in the brain "may provide clinical benefits in age-related diseases that are associated with brain inflammation, such as Alzheimer’s disease." In 2009, Italian and Israeli researchers found that cannabidiol (CBD), marijuana’s primary non-psychoactive cannabinoid, may also block the formation of the plaques in the brain believed to bring on Alzheimer’s...

Safety and Efficacy of Medical Cannabis Oil for Behavioral and Psychological Symptoms of Dementia

2016 [FTA] “...NPI domains of significant decrease were: Delusions, agitation/aggression, irritability, apathy, sleep and caregiver distress...Adding MCO to AD patients' pharmacotherapy is safe and a promising treatment option.”

Cannabinoids for the Treatment of Agitation and Aggression in Alzheimer’s Disease

08/2015 [FTA] “...Letters, case studies, and controlled trials from four electronic databases were included. While findings from six studies showed significant benefits from synthetic cannabinoids—dronabinol or nabilone—on agitation and aggression, definitive conclusions were limited by small sample sizes, short trial duration, and lack of placebo control in some of these studies. Given the relevance and findings to date, methodologically rigorous prospective clinical trials are recommended to determine the safety and efficacy of cannabinoids for the treatment of agitation and aggression in dementia and AD.”

Natural Phytochemicals in the Treatment and Prevention of Dementia: An Overview

04/2016 [FTA] “...In this review, we summarize the neuroprotective effects of the main phytochemicals belonging to the polyphenol, isothiocyanate, alkaloid and cannabinoid families in the prevention and treatment of the most common kinds of dementia. We believe that natural phytochemicals may represent a promising sources of alternative medicine, at least in association with therapies approved to date for dementia.”

Delineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model

10/2016 [FTA] “Previous reports have demonstrated that the combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) botanical extracts, which are the components of an already approved cannabis-based medicine, reduce the Alzheimer-like phenotype of AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Here, we provide evidence that such natural cannabinoids are still effective in reducing memory impairment in AβPP/PS1 mice at advanced stages of the disease but are not effective in modifying the Aβ processing or in reducing the glial reactivity associated with aberrant Aβ deposition as occurs when administered at early stages of the disease. The present study also demonstrates that natural cannabinoids do not affect cognitive impairment associated with healthy aging in wild-type mice. The positive effects induced by Δ9-THC and CBD in aged AβPP/PS1 mice are associated with reduced GluR2/3 and increased levels of GABA-A Rα1 in cannabinoid-treated animals when compared with animals treated with vehicle alone.”

CBD Modulates the Expression of Alzheimer’s Disease-Related Genes in Mesenchymal Stem Cells

12/2016 [FTA] “...we found that CBD led to the downregulation of genes linked to AD, including genes coding for the kinases responsible of tau phosphorylation and for the secretases involved in Aβ generation. In parallel, immunocytochemistry analysis has shown that CBD inhibited the expression of GSK3β, a central player in AD pathogenesis, by promoting PI3K/Akt signalling...In conclusion, we have found that pre-treatment with CBD prevented the expression of proteins potentially involved in tau phosphorylation and Aβ production in GMSCs. Therefore, we suggested that GMSCs preconditioned with CBD possess a molecular profile that might be more beneficial for the treatment of AD…”

In vivo Evidence for Therapeutic Properties of CBD for Alzheimer’s Disease

02/2017 [FTA] “... The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and Δ9-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone. The studies provide "proof of principle" that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies…”

Neurological aspects of medical use of CBD

2017 [FTA] “..Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy…”


The influence of cannabinoids on generic traits of neurodegeneration

[FTA] “...Neurodegenerative diseases are a heterogeneous group of age-related disorders. While AD, PD and HD have a variety of different genetic and environmental causes, the principal factor involved is the progressive and severe loss of neurons. It is widely accepted that neuroinflammation, excitotoxicity and oxidative stress are key mediators of neurodegeneration, and impaired neurogenesis as well as reduced trophic support leave neuronal systems unable to cope. The eCB system is emerging as a key regulator of many neuronal systems that are relevant to neurodegenerative disorders. Activation of CB1 receptors regulates many neuronal functions such as Ca2+ homeostasis and metabolic activity while the CB2 receptor is mainly involved in regulating the inflammatory response.

Here, we have put forward the mechanisms of neurodegeneration in the three most prevalent neurodegenerative disorders, AD, PD and HD, as well as showing the vulnerability of the brain as a result of age. We have summarized evidence of the beneficial role of modulating the cannabinoid system to reduce the burden of neurodegeneration. Pharmacological modulation of the eCB system ( Figure 3) has been shown to reduce chronic activation of the neuroinflammatory response, aid in Ca2+ homeostasis, reduce oxidative stress, mitochondrial dysfunction and the resulting proapoptotic cascade, while promoting neurotrophic support…”

Effects of Dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease

[FTA] “...These results indicate that dronabinol is a promising novel therapeutic agent which may be useful not only for treatment of anorexia but also to improve disturbed behavior in patients with Alzheimer's disease…”

https://www.ncbi.nlm.nih.gov/pubmed?Db=pubmed&Cmd=ShowDetailView&TermToSearch=9309469

These results indicate that dronabinol is a promising novel therapeutic agent which may be useful not only for treatment of anorexia but also to improve disturbed behavior in patients with Alzheimer's disease.

Delta-9-tetrahydrocannabinol for nighttime agitation in severe dementia. 

2006 [FTA] “...The study suggests that dronabinol was able to reduce nocturnal motor activity and agitation in severely demented patients. Thus, it appears that dronabinol may be a safe new treatment option for behavioral and circadian disturbances in dementia…”

VIDEO

Cannabis and the Brain: Neuroprotection vs Toxicity Gregory Gerdeman, PhD - 6/2016