Effects of cannabidiol interactions with Wnt/β-catenin pathway and PPARγ on oxidative stress and neuroinflammation in Alzheimer’s disease.

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“Alzheimer’s disease (AD) is a neurodegenerative disease, in which the primary etiology remains unknown. AD presents amyloid beta (Aβ) protein aggregation and neurofibrillary plaque deposits. AD shows oxidative stress and chronic inflammation.

In AD, canonical Wingless-Int (Wnt)/β-catenin pathway is downregulated, whereas peroxisome proliferator-activated receptor γ (PPARγ) is increased. Downregulation of Wnt/β-catenin, through activation of glycogen synthase kinase-3β (GSK-3β) by Aβ, and inactivation of phosphatidylinositol 3-kinase/Akt signaling involve oxidative stress in AD.

Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid from Cannabis sativa plant. In PC12 cells, Aβ-induced tau protein hyperphosphorylation is inhibited by CBD. This inhibition is associated with a downregulation of p-GSK-3β, an inhibitor of Wnt pathway. CBD may also increase Wnt/β-catenin by stimulation of PPARγ, inhibition of Aβ and ubiquitination of amyloid precursor protein.

CBD attenuates oxidative stress and diminishes mitochondrial dysfunction and reactive oxygen species generation. CBD suppresses, through activation of PPARγ, pro-inflammatory signaling and may be a potential new candidate for AD therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/28981597

https://academic.oup.com/abbs/article-abstract/49/10/853/3978657/Effects-of-cannabidiol-interactions-with-Wnt?redirectedFrom=fulltext

Photobiomodulation Therapy Improves Acute Inflammatory Response in Mice: the Role of Cannabinoid Receptors/ATP-Sensitive K+ Channel/p38-MAPK Signalling Pathway.

Molecular Neurobiology

“Although photobiomodulation therapy (PBM) has been applied clinically for the treatment of pain and inflammation, wound healing, sports and soft tissue injuries, as well as to repair injured spinal cords and peripheral nerves, it remains unclear which molecular substrates (receptor) are implicated in the cellular mechanisms of PBM.

Here, we reported that PBM (660 nm, 30 mW, 0.06 cm2, 50 J/cm2, plantar irradiation) significantly inhibited carrageenan-induced paw oedema, but not noxious thermal response, through positive modulation to both CB1 and CB2 cannabinoid receptors. The use of CB1 antagonist AM281 or CB2 antagonist AM630 significantly reversed the anti-inflammatory effect of PBM. Analysis of signalling pathway downstream of cannabinoid receptors activation reveals that anti-inflammatory effects of PBM depend, in great extent, on its ability to activate ATP-dependent K+ channels and p38 mitogen-activated protein kinase. Moreover, PBM therapy significantly reduced the levels of pro-inflammatory cytokine IL-6 in both paw and spinal cord, and restored the reduction of the level of anti-inflammatory cytokine IL-10 in spinal cord after carrageenan injection. Unlike the potent cannabinoid receptor agonist (WIN 55212-2), PBM did not exert any CNS-mediated effects in the tetrad assay. Finally, PBM does not reduce inflammation and noxious thermal response induced by LPS and zymosan, a TLR4 and TLR2/dectin-1 ligand, respectively.

Thus, cannabinoid receptors and, possibly, the endocannabinoid system, represent an important site of action of PBM that opens the possibility of complementary and nonpsychotropic therapeutic interventions in clinical practice.”

https://www.ncbi.nlm.nih.gov/pubmed/28980210

https://link.springer.com/article/10.1007%2Fs12035-017-0792-z

Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy.

European Respiratory Society

“Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity via elevation of endocannabinoids.

Primary vagal ganglia neurons, tissue bioassay, in vivoelectrophysiology and a conscious guinea pig cough model were utilised to investigate a role for fatty acid amides in modulating sensory nerve activation in vagal afferents. FAAH inhibition produced antitussive activity in guinea pigs with concomitant plasma elevation of the fatty acid amides N-arachidonoylethanolamide (anandamide), palmitoylethanolamide, N-oleoylethanolamide and linoleoylethanolamide. Palmitoylethanolamide inhibited tussive stimulus-induced activation of guinea pig airway innervating vagal ganglia neurons, depolarisation of guinea pig and human vagus, and firing of C-fibre afferents. These effects were mediated via a cannabinoid CB2/Gi/o-coupled pathway and activation of protein phosphatase 2A, resulting in increased calcium sensitivity of calcium-activated potassium channels.

These findings identify FAAH inhibition as a target for the development of novel, antitussive agents without the undesirable side-effects of direct cannabinoid receptor agonists.”

https://www.ncbi.nlm.nih.gov/pubmed/28931663

http://erj.ersjournals.com/content/50/3/1700782

Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain.

Journal of Pain and Symptom Management Home

“Prior phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.

To assess adjunctive nabiximols (Sativex®), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol and cannabidiol, in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.

Nabiximols was statistically superior to placebo on two of three quality-of-life instruments at week 3 and on all three at week 5.

The safety profile of nabiximols was consistent with earlier studies.

Although not superior to placebo on the primary efficacy endpoint, nabiximols had benefits on multiple secondary endpoints, particularly in US patients.

Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/28923526

http://www.jpsmjournal.com/article/S0885-3924(17)30465-7/fulltext

Re-visiting the Endocannabinoid System and Its Therapeutic Potential in Obesity and Associated Diseases.

 Current Diabetes Reports

“The purpose of the review was to revisit the possibility of the endocannabinoid system being a therapeutic target for the treatment of obesity by focusing on the peripheral roles in regulating appetite and energy metabolism.

Previous studies with the global cannabinoid receptor blocker rimonabant, which has both central and peripheral properties, showed that this drug has beneficial effects on cardiometabolic function but severe adverse psychiatric side effects. Consequently, focus has shifted to peripherally restricted cannabinoid 1 (CB1) receptor blockers as possible therapeutic agents that mitigate or eliminate the untoward effects in the central nervous system.

Targeting the endocannabinoid system using novel peripheral CB1 receptor blockers with negligible penetrance across the blood-brain barrier may prove to be effective therapy for obesity and its co-morbidities.

Perhaps the future of blockers targeting CB1 receptors will be tissue-specific neutral antagonists (e.g., skeletal muscle specific to treat peripheral insulin resistance, adipocyte-specific to treat fat excess, liver-specific to treat fatty liver and hepatic insulin resistance).”

https://www.ncbi.nlm.nih.gov/pubmed/28913816

https://link.springer.com/article/10.1007%2Fs11892-017-0924-x

The Clinical Significance of Endocannabinoids in Endometriosis Pain Management.

“Patients with endometriosis often suffer from diffuse and poorly localized severe pain. The current pain management strategies include medical and hormonal therapy, as well as surgery. Medical management of pain is often insufficient and is associated with high rate of recurrence. Better pain management is therefore of urgent need.

Methods: Among the various candidates, the endocannabinoid system (ECS) has recently emerged as a relevant pharmacological target for the management of endometriosis-related pain. A computerized literature search was performed to identify relevant studies combining the keywords “endometriosis,” “endocannabinoid,” “cannabinoid receptor,” “THC,” and “pain mechanisms.”

Conclusions: This review describes the multiple and complex pain mechanisms associated with endometriosis. Current data and theories concerning the link between the ECS and pain management for endometriosis patients are presented. Finally, we will discuss which aspects of endometriosis-associated pain can be targeted by modulation of the ECS.”

An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies.

Mary Ann Liebert, Inc. publishers

“This literature survey aims to extend the comprehensive survey performed by Bergamaschi et al. in 2011 on cannabidiol (CBD) safety and side effects. Apart from updating the literature, this article focuses on clinical studies and CBD potential interactions with other drugs.

Results: In general, the often described favorable safety profile of CBD in humans was confirmed and extended by the reviewed research. The majority of studies were performed for treatment of epilepsy and psychotic disorders. Here, the most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. In comparison with other drugs, used for the treatment of these medical conditions, CBD has a better side effect profile. This could improve patients’ compliance and adherence to treatment. CBD is often used as adjunct therapy. Therefore, more clinical research is warranted on CBD action on hepatic enzymes, drug transporters, and interactions with other drugs and to see if this mainly leads to positive or negative effects, for example, reducing the needed clobazam doses in epilepsy and therefore clobazam’s side effects.

Conclusion: This review also illustrates that some important toxicological parameters are yet to be studied, for example, if CBD has an effect on hormones. Additionally, more clinical trials with a greater number of participants and longer chronic CBD administration are still lacking.”

Cannabis Roots: A Traditional Therapy with Future Potential for Treating Inflammation and Pain

Image result for cannabis and cannabinoid research

“The cannabis plant is known for its multiple uses: the leaves, flowers, seeds, stalks, and resin glands have all been exploited for food, fuel, fiber, medicine, and other uses.

The roots of the cannabis plant have a long history of medical use stretching back millennia. However, the therapeutic potential of cannabis roots has been largely ignored in modern times.

In the first century, Pliny the Elder described in Natural Histories that a decoction of the root in water could be used to relieve stiffness in the joints, gout, and related conditions. By the 17th century, various herbalists were recommending cannabis root to treat inflammation, joint pain, gout, and other conditions.

Active compounds identified and measured in cannabis roots include triterpenoids, friedelin (12.8 mg/kg) and epifriedelanol (21.3 mg/kg); alkaloids, cannabisativine (2.5 mg/kg) and anhydrocannabisativine (0.3 mg/kg); carvone and dihydrocarvone; N-( p-hydroxy-b-phenylethyl)-p-hydroxy-trans-cinnamamide (1.6 mg/kg); various sterols such as sitosterol (1.5%), campesterol (0.78%), and stigmasterol (0.56%); and other minor compounds, including choline. Of note, cannabis roots are not a significant source of D9 – tetrahydrocannabinol (THC), cannabidiol, or other known phytocannabinoids.

Conclusion: The current available data on the pharmacology of cannabis root components provide significant support to the historical and ethnobotanical claims of clinical efficacy. Certainly, this suggests the need for reexamination of whole root preparations on inflammatory and malignant conditions employing modern scientific techniques.”

http://online.liebertpub.com/doi/full/10.1089/can.2017.0028

A Review of the Therapeutic Antitumor Potential of Cannabinoids.

:Image result for J Altern Complement Med.

“The aim of this review is to discuss cannabinoids from a preclinical and clinical oncological perspective and provide the audience with a concise, retrospective overview of the most significant findings concerning the potential use of cannabinoids in cancer treatment.

RESULTS:

Cannabis sativa is a plant rich in more than 100 types of cannabinoids. Besides exogenous plant cannabinoids, mammalian endocannabinoids and synthetic cannabinoid analogues have been identified. Cannabinoid receptors type 1 (CB1) and type 2 (CB2) have been isolated and characterized from mammalian cells. Through cannabinoid receptor and non-receptor signaling pathways, cannabinoids show specific cytotoxicity against tumor cells, while protecting healthy tissue from apoptosis. The dual antiproliferative and proapoptotic effects of cannabinoids and associated signaling pathways have been investigated on a large panel of cancer cell lines. Cannabinoids also display potent anticancer activity against tumor xenografts, including tumors that express high resistance to standard chemotherapeutics. Few studies have investigated the possible synergistic effects of cannabinoids with standard oncology therapies, and are based on the preclinically confirmed concept of “cannabinoid sensitizers.” Also, clinical trials aimed to confirm the antineoplastic activity of cannabinoids have only been evaluated on a small number of subjects, with no consensus conclusions regarding their effectiveness.

CONCLUSIONS:

A large number of cannabinoid compounds have been discovered, developed, and used to study the effects of cannabinoids on cancers in model systems. However, few clinical trials have been conducted on the use of cannabinoids in the treatment of cancers in humans. Further studies require extensive monitoring of the effects of cannabinoids alone or in combination with standard anticancer strategies. With such knowledge, cannabinoids could become a therapy of choice in contemporary oncology.”

Endocannabinoids in arthritis: current views and perspective.

International Journal of Rheumatic Diseases

“Preclinical and clinical studies using cannabis-based therapy have been shown to provide both analgesia and anti-inflammatory effects, with an overall alleviation of clinical symptoms in animal models of arthritis, highlighting its promising therapeutic application for humans. Despite this, the development of cannabis-based therapeutics remains in its infancy, with further investigation into its efficacy and safety profile in patients still required. This synopsis reviews the various components of the endocannabinoid system in health and disease and their potential as therapeutic targets.”

https://www.ncbi.nlm.nih.gov/pubmed/28736968

http://onlinelibrary.wiley.com/doi/10.1111/1756-185X.13146/abstract