Tag Archives: Cannabinoids

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

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“A link between the endocannabinoid system and Alzheimer’s disease has been discovered which has provided a new therapeutic target for the treatment of patients suffering from Alzheimer’s disease. These studies have demonstrated the ability of cannabinoids to provide neuroprotection against β-amyloid peptide (Aβ) toxicity.

Here, we demonstrate that the active component of marijuana, Δ9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid β-peptide (Aβ) aggregation, the key pathological marker of Alzheimer’s disease. 

 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.

Since the characterization of the Cannabis sativa-produced cannabinoid, Δ9-tetrahydrocannabinol (THC), in the 1960’s,1 this natural product has been widely explored as an anti-emetic, anti-convulsive, anti-inflammatory, and analgesic.”

Read more: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2562334/

 

Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration.

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“The endocannabinoid system, including endogenous ligands (‘endocannabinoids’ ECs), their receptors, synthesizing and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. ECs are bioactive lipids, which comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied ECs, and act as agonists of cannabinoid receptors.

Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol (Delta(9)-THC), the psychoactive principle of cannabis sativa preparations like hashish and marijuana. Recently, however, several lines of evidence have suggested that the EC system may play an important role in early neuronal development as well as a widespread role in neurodegeneration disorders. Many of the effects of cannabinoids and ECs are mediated by two G protein-coupled receptors (GPCRs), CB1 and CB2, although additional receptors may be implicated. Both CB1 and CB2 couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. This new system is briefly presented in this review, in order to put in a better perspective the role of the EC pathway from neurodevelopment to neurodegenerative disorders, like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis.

In addition, the potential exploitation of antagonists of CB1 receptors, or of inhibitors of EC metabolism, as next-generation therapeutics is discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/19356123

The role of phytochemicals in the treatment and prevention of dementia.

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Drugs & Aging

“Dementia pathologies such as Alzheimer’s disease (AD) are reaching epidemic proportions, yet they are not successfully managed by effective symptomatic treatments. Only five drugs have been developed to alleviate cognitive symptoms, and more effective and safe treatments are needed for both the cognitive symptoms and behavioural and psychological symptoms of dementia (BPSD). As two of these licensed drugs (cholinesterase inhibitors [ChEIs]) are naturally derived (galantamine and rivastigmine), the potential for plants to yield new therapeutic agents has stimulated extensive research to discover new ChEIs together with plant extracts, phytochemicals and their derivatives with other mechanistic effects relevant to dementia treatment. 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. Those phytochemicals discussed include the alkaloid physostigmine, a ChEI from the calabar bean (Physostigma venenosum), which has been used as a template for the development of synthetic derivatives that inhibit acetylcholinesterase, including the drug rivastigmine. Also discussed are other ChEI alkaloids including huperzine A, from Huperzia serrata, and galantamine, originally from the snowdrop (Galanthus woronowii); both alkaloids improve cognitive functions in AD patients.

Other 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. The review also discusses plant extracts, and their known constituents, that have shown relevant mechanistic effects for dementia and promising clinical data, but require more evidence for their clinical efficacy and safety. Such plants include Ginkgo biloba, which has been extensively studied in numerous clinical trials, with most outcomes showing positive effects on cognitive functions in dementia patients; however, more reliable and consistent clinical data are needed to confirm efficacy. 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. Other plants that are used in traditional practices of medicine have been suggested to improve cognitive functions (e.g. Polygala tenuifolia) or have been associated with alleviation of BPSD (e.g. the traditional prescription yokukansan); such remedies are often prescribed as complex mixtures of different plants, which complicates interpretation of pharmacological and clinical data and introduces additional challenges for quality control. Evidence for the role of natural products in disease prevention, the primary but considerably challenging aim with respect to dementia, is limited, but the available epidemiological and clinical evidence is discussed, with most studies focused on ChEIs, nicotine (from Nicotiana species), curcumin, wine polyphenols such as resveratrol and G. biloba. Challenges for the development of phytochemicals as drugs and for quality control of standardized plant extracts are also considered.”

http://www.ncbi.nlm.nih.gov/pubmed/21639405

https://link.springer.com/article/10.2165%2F11591310-000000000-00000

Cannabis May Offer Alzheimer’s Hope, Study Says

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“Marijuana compounds offer an alternative approach for treating the neurodegeneration associated with Alzheimer’s disease (AD)…

Investigators at the Trinity College, Institute for Neuroscience, in Dublin report that cannabinoids have been shown to protect neurons from the deleterious effects of amyloid plaque – the primary pathological hallmark of Alzheimer’s. Cannabinoids also demonstrate a propensity to reduce oxidative stress and inflammation, while also promoting neurogenesis (the birth of new neuronal cells), authors report.

Authors write: “In recent years the proclivity of cannabinoids to exert a neuroprotective influence has received substantial interest as a means to mitigate the symptoms of neurodegenerative conditions. … [C]annabinoids offer a multi-faceted approach for the treatment of Alzheimer’s disease by providing neuroprotection and reducing neuroinflammation, whilst simultaneously supporting the brain’s intrinsic repair mechanisms by augmenting neurotrophin expression and enhancing neurogenesis. … Manipulation of the cannabinoid pathway offers a pharmacological approach for the treatment of AD that may be efficacious than current treatment regimens.”

Preclinical studies have demonstrated that cannabinoids can delay disease progression in animal models of several neurodegenerative diseases, including multiple sclerosis and amyotrophic lateral sclerosis (Lou Gehrig’s disease).”-

Paul Armentano, NORML  http://norml.org/news/2007/09/20/cannabis-may-offer-alzheimers-hope-study-says

Full text of the study, “Alzheimer’s disease; taking the edge off with cannabinoids?” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190031/

Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease.

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“Microglial activation is an invariant feature of Alzheimer’s disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo… the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms…

Cannabinoids, whether plant-derived, synthetic, or endocannabinoids, exert their functions through activation of cannabinoid receptors, two of which have been well characterized to date: CB1 and CB2. Cannabinoids are neuroprotective against excitotoxicity and acute brain damage, both in vitro and in vivo. Several mechanisms account for the neuroprotection afforded by this type of drug such as blockade of excitotoxicity, reduction of calcium influx, antioxidant properties of the compounds, or enhanced trophic factor support. A decrease in proinflammatory mediators brought about by cannabinoids may be also involved in their neuroprotection… Cannabidiol (CBD), the major plant-derived nonpsychotropic constituent of marijuana, is of potential therapeutic interest in different disease conditions (e.g., inflammation)…

…this kind of drug with neuroprotective and anti-inflammatory effects may be of interest in the prevention of AD inflammation, in particular CB2-selective agonists, which are devoid of psychoactive effects…

Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo…

CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD.

Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102548/

Differential transcriptional profiles mediated by exposure to the cannabinoids cannabidiol and Δ9-tetrahydrocannabinol in BV-2 microglial cells.

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“Apart from their effects on mood and reward, cannabinoids exert beneficial actions such as neuroprotection and attenuation of inflammation. The immunosuppressive activity of cannabinoids has been well established. We previously showed that the psychoactive cannabinoid Δ(9) -tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) differ in their anti-inflammatory signalling pathways.

CONCLUSIONS AND IMPLICATIONS:

These observations indicated that CBD, but much less than THC, induced a cellular stress response in microglial cells and suggested that this effect could underlie its anti-inflammatory activity.”

http://www.ncbi.nlm.nih.gov/pubmed/21542829

Cannabinoids Δ9-Tetrahydrocannabinol and Cannabidiol Differentially Inhibit the Lipopolysaccharide-activated NF-κB and Interferon-β/STAT Proinflammatory Pathways in BV-2 Microglial Cells

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“Cannabinoids have been shown to exert anti-inflammatory activities in various in vivo and in vitro experimental models as well as ameliorate various inflammatory degenerative diseases. Δ9-Tetrahydrocannabinol (THC)is a major constituent of Cannabis and serves as an agonist of the cannabinoid receptors CB1 and CB2.

The second major constituent of Cannabis extract is cannabidiol (CBD). CBD lacks the psychoactive effects that accompany the use of THC. Moreover, CBD was demonstrated to antagonize some undesirable effects of THC, including intoxication, sedation, and tachycardia, while sharing neuroprotective, anti-oxidative, anti-emetic, and anti-carcinogenic properties. Both THC and CBD have been shown to exert anti-inflammatory properties and to modulate the function of immune cells…

In summary, our results show that although both THC and CBD exert anti-inflammatory effects, the two compounds engage different, although to some extent overlapping, intracellular pathways. Both THC and CBD decrease the activation of proinflammatory signaling…

 The cannabinoids by moderating or disrupting these signaling networks may show promise as anti-inflammatory agents.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804319/

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

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Psychopharmacology

“Nighttime agitation occurs frequently in patients with dementia and represents the number one burden on caregivers today. Current treatment options are few and limited due to substantial side effects.

OBJECTIVES:

The aim of the study was to measure the effect of the cannabinoid dronabinol (THC) on nocturnal motor activity.

RESULTS:

Compared to baseline, dronabinol led to a reduction in nocturnal motor activity. These findings were corroborated by improvements in Neuropsychiatric Inventory total score as well as in subscores for agitation, aberrant motor, and nighttime behaviors . No side effects were observed.

CONCLUSIONS:

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

http://www.ncbi.nlm.nih.gov/pubmed/16521031

https://link.springer.com/article/10.1007%2Fs00213-006-0343-1

Regulation of cannabinoid CB1 receptors in the central nervous system by chronic cannabinoids.

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“The potential therapeutic benefits of certain cannabinoid-mediated effects, as well as the use of marijuana for its psychoactive properties, has raised interest in understanding the cellular adaptations produced by chronic administration of this class of drugs.”

http://www.ncbi.nlm.nih.gov/pubmed/14977366

Cannabinoids and neurodegenerative diseases.

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“Although significant advances have taken place in recent years on our understanding of the molecular mechanisms of different neurodegenerative diseases, its translation into effective therapeutic treatments has not been as successful as could be expected. There is still a dramatic lack of curative treatments for the most frequent disorders and only symptomatic relief for many others. Under this perspective, the search for novel therapeutic approaches is demanding and significant attention and efforts have been directed to studying additional neurotransmission systems including the endocannabinoid system (ECS).

The neuroprotective properties of exogenous as well as endogenous cannabinoids have been known for years and the underlying molecular mechanisms have been recently unveiled. As discussed later, antioxidative, antiglutamatergic and antiinflammatory effects are now recognized as derived from cannabinoid action and are known to be of common interest for many neurodegenerative processes.

 Thus, these characteristics make cannabinoids attractive candidates for the development of novel therapeutic strategies.

 The present review will focus on the existing data regarding the possible usefulness of cannabinoid agents for the treatment of relevant neurological pathologies for our society such as Alzheimer’s disease, multiple sclerosis, Huntington’s disease and amyotrophic lateral sclerosis.”

http://www.ncbi.nlm.nih.gov/pubmed/19839933