Is Cannabidiol a Promising Substance for New Drug Development? A Review of its Potential Therapeutic Applications.

Critical Reviews™ in Eukaryotic Gene Expression

“The pharmacological importance of cannabidiol (CBD) has been in study for several years.

CBD is the major nonpsychoactive constituent of plant Cannabis sativa and its administration is associated with reduced side effects.

Currently, CBD is undergoing a lot of research which suggests that it has no addictive effects, good safety profile and has exhibited powerful therapeutic potential in several vital areas.

It has wide spectrum of action because it acts through endocannabinoid receptors; CB1 and CB2 and it also acts on other receptors, such as GPR18, GPR55, GPR 119, 5HT1A, and TRPV2.

This indicates its therapeutic value for numerous medical conditions because of its neuroprotective and immunomodulatory properties.

Potential therapeutic applications of CBD include, analgesic, anti-inflammatory, anxiolytic, anti-arthritic, anti-depressant, anti-Alzheimer disease, anti-ischemic, neuroprotective, and anti-fibrotic.

More promising areas appear to include diabetes and cancer where CBD exhibits lesser side effects and more therapeutic benefits as compared to recent available medical therapies.

Hence, CBD is a promising substance for the development of new drug. However further research and clinical studies are required to explore its complete potential.”

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Review of the neurological benefits of phytocannabinoids.

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“Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

METHODS:

In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.

RESULTS:

Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.

CONCLUSIONS:

In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/29770251

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

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Activation of the Cannabinoid Type 2 Receptor by a Novel Indazole Derivative Normalizes the Survival Pattern of Lymphoblasts from Patients with Late-Onset Alzheimer’s Disease.

CNS Drugs

“Alzheimer’s disease is a multifactorial disorder for which there is no disease-modifying treatment yet.

CB2 receptors have emerged as a promising therapeutic target for Alzheimer’s disease because they are expressed in neuronal and glial cells and their activation has no psychoactive effects.

OBJECTIVE:

The aim of this study was to investigate whether activation of the CB2 receptor would restore the aberrant enhanced proliferative activity characteristic of immortalized lymphocytes from patients with late-onset Alzheimer’s disease. It is assumed that cell-cycle dysfunction occurs in both peripheral cells and neurons in patients with Alzheimer’s disease, contributing to the instigation of the disease.

METHODS:

Lymphoblastoid cell lines from patients with Alzheimer’s disease and age-matched control individuals were treated with a new, in-house-designed dual drug PGN33, which behaves as a CB2 agonist and butyrylcholinesterase inhibitor. We analyzed the effects of this compound on the rate of cell proliferation and levels of key regulatory proteins. In addition, we investigated the potential neuroprotective action of PGN33 in β-amyloid-treated neuronal cells.

RESULTS:

We report here that PGN33 normalized the increased proliferative activity of Alzheimer’s disease lymphoblasts. The compound blunted the calmodulin-dependent overactivation of the PI3K/Akt pathway, by restoring the cyclin-dependent kinase inhibitor p27 levels, which in turn reduced the activity of the cyclin-dependent kinase/pRb cascade. Moreover, this CB2 agonist prevented β-amyloid-induced cell death in neuronal cells.

CONCLUSION:

Our results suggest that the activation of CB2 receptors could be considered a useful therapeutic approach for Alzheimer’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/29736745

https://link.springer.com/article/10.1007%2Fs40263-018-0515-7

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Prolonged Cannabidiol Treatment Effects on Hippocampal Subfield Volumes in Current Cannabis Users.

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“Chronic cannabis use is associated with neuroanatomical alterations in the hippocampus. While adverse impacts of cannabis use are generally attributed to Δ9-tetrahydrocannabinol, emerging naturalistic evidence suggests cannabidiol (CBD) is neuroprotective and may ameliorate brain harms associated with cannabis use, including protection from hippocampal volume loss. This study examined whether prolonged administration of CBD to regular cannabis users within the community could reverse or reduce the characteristic hippocampal harms associated with chronic cannabis use.

Results: No change was observed in left or right hippocampus as a whole. However, left subicular complex (parasubiculum, presubiculum, and subiculum) volume significantly increased from baseline to post-treatment (p=0.017 uncorrected) by 1.58% (Cohen’s d=0.63; 2.83% in parasubiculum). Heavy cannabis users demonstrated marked growth in the left subicular complex, predominantly within the presubiculum, and right cornu ammonis (CA)1 compared to lighter users. Associations between greater right subicular complex and total hippocampal volume and higher plasma CBD concentration were evident, particularly in heavy users.

Conclusions: Our findings suggest a restorative effect of CBD on the subicular and CA1 subfields in current cannabis users, especially those with greater lifetime exposure to cannabis. While replication is required in a larger, placebo-controlled trial, these findings support a protective role of CBD against brain structural harms conferred by chronic cannabis use. Furthermore, these outcomes suggest that CBD may be a useful adjunct in treatments for cannabis dependence and may be therapeutic for a range of clinical disorders characterized by hippocampal pathology (e.g., schizophrenia, Alzheimer’s disease, and major depressive disorder).”

https://www.ncbi.nlm.nih.gov/pubmed/29682609

“In conclusion, our findings are the first to demonstrate an ameliorating effect of CBD treatment upon brain structural harms characteristic of regular cannabis use. Furthermore, these results speak to the potential for CBD treatment to restore hippocampal pathology in a range of clinical populations (e.g., schizophrenia, Alzheimer’s disease, and major depressive disorder).”

https://www.liebertpub.com/doi/10.1089/can.2017.0047

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Medical Marijuana Use in Older Adults.

Journal of the American Geriatrics Society banner“Symptom management in older adults, including pain and distressing non-pain symptoms, can be challenging. Medications can cause side effects that worsen quality of life or create other symptoms, and polypharmacy itself can be detrimental in older adults. 

Cannabinoids may offer a way of managing selected symptoms with fewer side effects.

Medical marijuana is an important area of study for older adults because of the side effects of other medications. It is also important for Baby Boomers, who are likely to have more experience with marijuana than older adults of previous generations. Therefore, geriatricians should understand medical marijuana’s clinical indications, adverse effects, and legal context.

This article reviews the evidence regarding indications for and risks of medical marijuana use in older adults.”

https://www.ncbi.nlm.nih.gov/pubmed/29668039

https://onlinelibrary.wiley.com/doi/abs/10.1111/jgs.15346

“Our study finds that the therapeutic use of cannabis is safe and efficacious in the elderly population.” https://www.ncbi.nlm.nih.gov/pubmed/29398248

“Medical cannabis significantly safer for elderly with chronic pain than Opioids”  https://www.sciencedaily.com/releases/2018/02/180213111508.htm

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Biphasic Effects of THC in Memory and Cognition.

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“A generally undesired effect of cannabis smoking is a reversible disruption of short term memory induced by delta-9-tetrahydrocannabinol (THC), the primary psychoactive component of cannabis.

However, this paradigm has been recently challenged by a group of scientists who have shown that THC is also able to improve neurological function in old animals when chronically administered at low concentrations.

Moreover, recent studies demonstrated that THC paradoxically promotes hippocampal neurogenesis, prevents neurodegenerative process occurring in Alzheimer Disease, protects from inflammation-induced cognitive damage and restores memory and cognitive function in old mice.

With the aim to reconcile these seemingly contradictory facts, the present work will show that such paradox can be explained within the framework of hormesis, defined as biphasic dose responses. ”

https://www.ncbi.nlm.nih.gov/pubmed/29574698

https://onlinelibrary.wiley.com/doi/abs/10.1111/eci.12920

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Cannabidiol Reverses Deficits in Hippocampal LTP in a Model of Alzheimer’s Disease.

Neurochemical Research

“Here we demonstrate for the first time that cannabidiol (CBD) acts to protect synaptic plasticity in an in vitro model of Alzheimer’s disease (AD).

The non-psycho active component of Cannabis sativa, CBD has previously been shown to protect against the neurotoxic effects of beta amyloid peptide (Aβ) in cell culture and cognitive behavioural models of neurodegeneration. Hippocampal long-term potentiation (LTP) is an activity dependent increase in synaptic efficacy often used to study cellular mechanisms related to memory.

Here we show that acute application of soluble oligomeric beta amyloid peptide (Aβ1-42) associated with AD, attenuates LTP in the CA1 region of hippocampal slices from C57Bl/6 mice. Application of CBD alone did not alter LTP, however pre-treatment of slices with CBD rescued the Aβ1-42 mediated deficit in LTP.

We found that the neuroprotective effects of CBD were not reversed by WAY100635, ZM241385 or AM251, demonstrating a lack of involvement of 5HT1A, adenosine (A2A) or Cannabinoid type 1 (CB1) receptors respectively. However in the presence of the PPARγ antagonist GW9662 the neuroprotective effect of CBD was prevented.

Our data suggests that this major component of Cannabis sativa, which lacks psychoactivity may have therapeutic potential for the treatment of AD”

https://www.ncbi.nlm.nih.gov/pubmed/29574668

https://link.springer.com/article/10.1007%2Fs11064-018-2513-z

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Glial expression of cannabinoid CB(2) receptors and fatty acid amide hydrolase are beta amyloid-linked events in Down’s syndrome.

Neuroscience

“Recent data suggest that the endocannabinoid system (ECS) may be involved in the glial response in different types of brain injury. Both acute and chronic insults seem to trigger a shift in the pattern of expression of some elements of this system from neuronal to glial. Specifically, data obtained in human brain tissue sections from Alzheimer’s disease patients showed that the expression of cannabinoid receptors of the CB(2) type is induced in activated microglial cells while fatty acid amide hydrolase (FAAH) expression is increased in reactive astrocytes. The present study was designed to determine the time-course of the shift from neuronal to glial induction in the expression of these proteins in Down‘s syndrome, sometimes referred to as a human model of Alzheimer-like beta-amyloid (Abeta) deposition. Here we present immunohistochemical evidence that both CB(2) receptors and FAAH enzyme are induced in Abeta plaque-associated microglia and astroglia, respectively, in Down‘s syndrome. These results suggest that the induction of these elements of the ECS contributes to, or is a result of, amyloid deposition and subsequent plaque formation. In addition, they confirm a striking differential pattern of distribution of FAAH and CB(2) receptors.”

https://www.ncbi.nlm.nih.gov/pubmed/18068305

https://www.sciencedirect.com/science/article/abs/pii/S0306452207012924

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β-Amyrin, the cannabinoid receptors agonist, abrogates mice brain microglial cells inflammation induced by lipopolysaccharide/interferon-γ and regulates Mφ1/Mφ2 balances.

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“Inflammation is a primary response to infection that can pathologically lead to various diseases including neurodegenerative diseases.

The purpose of this study was to evaluate the effect of β-Amyrin, a naturally occurring pentacyclic triterpenoid compound, on inflammation induced by lipopolysaccharide (LPS) and interferone-γ (IFN-γ) in rat microglial cells.

CONCLUSION:

β-Amyrin reduces inflammation in microglial cells and can be used as a potential anti-inflammatory agent in central nervous system neurodegenerative diseases such as Alzheimer and multiple sclerosis, by affecting the inflammatory cytokine and differentiation of microglia as resident CNS macrophages.”

https://www.ncbi.nlm.nih.gov/pubmed/29501766

“Amyrin and the endocannabinoid system. The canonical triterpene amyrin was recently suggested to bind to CB1 receptors and to significantly mediate cannabimimetic effects in animal models of pain.”   http://gertschgroup.com/blog/entry/3188293/amyrin-and-the-endocannabinoid-system

“The antinociceptive triterpene β-amyrin inhibits 2-arachidonoylglycerol (2-AG) hydrolysis without directly targeting CB receptors”   https://www.researchgate.net/publication/225079976_The_antinociceptive_triterpene_b-amyrin_inhibits_2-arachidonoylglycerol_2-AG_hydrolysis_without_directly_targeting_CB_receptors

“Finally, pentacyclic triterpenes such as β-amyrin and cycloartenol have been shown to possess numerous biological activities including anti-bacterial, anti-fungal, anti-inflammatory and anti-cancer properties.” https://www.linkedin.com/pulse/cannabis-has-terpenes-say-what-pure-hempnotics

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Innovative Therapeutic Potential of Cannabinoid Receptors as Targets in Alzheimer’s disease and Less Well-Known Diseases.

“The discovery of cannabinoid receptors at the beginning of the 1990s, CB1 being cloned in 1990 and CB2 cloned in 1993, and the availability of selective and potent cannabimimetics could only be justified by the existence of endogenous ligands that are capable of binding to them. Thus, the characterisation and cloning of the first cannabinoid receptor (CB1) led to the isolation and characterisation of the first endocannabinoid, arachidonoylethanolamide (AEA), two years later and the subsequent identification of a family of lipid transmitters known as the fatty acid ester 2-arachidonoylglycerol (2-AG). The endogenous cannabinoid system is a complex signalling system that comprises transmembrane endocannabinoid receptors, their endogenous ligands (the endocannabinoids), the specific uptake mechanisms and the enzymatic systems related to their biosynthesis and degradation. The endocannabinoid system has been implicated in a wide diversity of biological processes, in both the central and peripheral nervous systems, including memory, learning, neuronal development, stress and emotions, food intake, energy regulation, peripheral metabolism, and the regulation of hormonal balance through the endocrine system. In this context, this article will review the current knowledge of the therapeutic potential of cannabinoid receptor as a target in Alzheimer’s disease and other less well-known diseases that include, among others, multiple sclerosis, bone metabolism, and Fragile X syndrome. The therapeutic applications will be addressed through the study of cannabinoid agonists acting as single drugs and multi-target drugs highlighting the CB2 receptor agonist.”

https://www.ncbi.nlm.nih.gov/pubmed/29484980

http://www.eurekaselect.com/160083/article

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