Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications.

“Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems.

One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells.

These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells).

This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer’s disease, Parkinson’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis.

This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression…”

http://www.ncbi.nlm.nih.gov/pubmed/26260390

Therapeutic potential of cannabis-related drugs.

“In this review, I will consider the dual nature of Cannabis and cannabinoids.

The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the ‘abuse’ of Cannabis outside the clinic.

The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma.

As with every other medicinal drug of course, the ‘trick’ will be to maximise the benefit and minimise the cost.

After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit.”

http://www.ncbi.nlm.nih.gov/pubmed/26216862

Phytocannabinoids for Cancer Therapeutics: Recent Updates and Future Prospects.

“Phytocannabinoids (pCBs) are lipid-soluble phytochemicals present in the plant, Cannabis sativa L. and non-cannabis plants which have a long history in traditional and recreational medicine.

The plant and constituents were central in the discovery of the endocannabinoid system, the most new target for drug discovery.

The endocannabinoid system includes two G protein-coupled receptors; the cannabinoid receptors-1 and -2 (CB1 and CB2) for marijuana’s psychoactive principle ∆(9)-tetrahydrocannabinol (∆9-THC), their endogenous small lipid ligands; namely anandamide (AEA) and 2-arachidonoylglycerol (2-AG), also known as endocannabinoids and the proteins for endocannabinoid biosynthesis and degradation such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

The endocannabinoid system has been suggested as a pro-homeostatic and pleiotropic signaling system activated in a time- and tissue-specific way during pathological conditions including cancer.

Targeting the CB1 receptors become a concern because of adverse psychotropic reactions. Hence, targeting the CB2 receptors or the endocannabinoid metabolizing enzyme by phytocannabinoids obtained from non-cannabis plant lacking psychotropic adverse reactions has garnered interest in drug discovery.

These pCBs derived from plants beyond cannabis appear safe and effective with a wider access and availability.

In recent years, several pCBs derived other than non-cannabinoid plants have been reported to bind to and functionally interact with cannabinoid receptors and appear promising candidate for drug development in cancer therapeutics.

Several of them also target the endocannabinoid metabolizing enzymes that control endocannabinoid levels. In this article, we summarize, critically discuss the updates and future prospects of the pCBs as novel and promising candidates for cancer therapeutics.”

http://www.ncbi.nlm.nih.gov/pubmed/26179998

http://www.thctotalhealthcare.com/category/cancer/

Selective Reduction of THC’s Unwanted Effects through Serotonin Receptor Inhibition

“While recreational marijuana users may seek the full range of its effects, broad medical use of THC—including for pain, nausea, and anxiety—is hindered by them.

In a new study, Xavier Viñals, Estefania Moreno, Peter McCormick, Rafael Maldonado, Patricia Robledo, and colleagues demonstrate that the cognitive effects of THC are triggered by a pathway separate from some of its other effects.

That pathway involves both a cannabinoid receptor and a serotonin receptor, and when this pathway is blocked, THC can still exert several beneficial effects, including analgesia, while avoiding impairment of memory.

The results of this study are potentially highly important, in that they identify a way to reduce some of what are usually thought of as THC’s unwanted side effects when used for medicinal purposes while maintaining several important benefits, including pain relief.

The widening acceptance of a role for THC in medicine may be accelerated by the option to reduce those side effects by selective pharmacological disruption or blocking of the heteromer.”

http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002193

The endocannabinoid anandamide inhibits cholangiocarcinoma growth via activation of the noncanonical Wnt signaling pathway.

Logo of ajpgi

“Cholangiocarcinomas are cancers that have poor prognosis and limited treatment options.

Marijuana and its derivatives have been used in medicine for many centuries.

…cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.

Indeed, we have recently demonstrated that the endocannabinoid anandamide (AEA) has antiproliferative effects on cholangiocarcinoma cell lines in vitro via a cannabinoid receptor-independent pathway involving the stabilization of lipid raft-membrane structures and the recruitment of death-receptor complexes into the lipid rafts.

Modulation of the endocannabinoid system may be important in cholangiocarcinoma treatment.

The antiproliferative actions of the noncanonical Wnt signaling pathway warrants further investigation to dissect the mechanism by which this may occur.

We propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system, or mimicking the mode of action of AEA, would prove beneficial for the treatment of this devastating disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2604798/

 

Opposing actions of endocannabinoids on cholangiocarcinoma growth: recruitment of Fas and Fas ligand to lipid rafts.

The Journal of Biological Chemistry

“Cholangiocarcinomas are devastating cancers of biliary origin with limited treatment options…

Marijuana and its derivatives have been used in medicine for many centuries, and presently there is an emerging renaissance in the study of the therapeutic effects of cannabinoids…

In addition, cannabinoids might be effective antitumoral agents because of their ability to inhibit the growth of various types of cancer cell lines in culture and in laboratory animals.

Modulation of the endocannabinoid system is being targeted to develop possible therapeutic strategies for a number of cancers; therefore, we evaluated the effects of the two major endocannabinoids, anandamide and 2-arachidonylglycerol, on numerous cholangiocarcinoma cell lines…

These findings suggest that modulation of the endocannabinoid system may be a target for the development of possible therapeutic strategies for the treatment of this devastating cancer.

Consistent with our observation that AEA has antiproliferative and proapoptotic properties, cannabinoids of various origins (endogenous, plant-derived, or synthetic analogues) have been shown to suppress cancer cell growth in vitro as well as in vivo.

In conclusion, we have clearly demonstrated opposing actions of the endocannabinoids AEA and 2-AG on cholangiocarcinoma cell proliferation and have shown that these actions are via a cannabinoid receptor-independent but lipid raft-mediated pathway. Furthermore we have shown that the antiproliferative/proapoptotic actions of AEA are mediated via an accumulation of ceramide and the recruitment of the Fas death receptor into the lipid rafts. Cholangiocarcinoma has a very poor prognosis and survival rate; therefore we propose that the development of novel therapeutic strategies aimed at modulating the endocannabinoid system or mimicking the mode of action of AEA would prove beneficial for the treatment of this devastating disease.”

http://www.jbc.org/content/282/17/13098.long

Cannabinoids and Tremor Induced by Motor-related Disorders: Friend or Foe?

“Tremor arises from an involuntary, rhythmic muscle contraction/relaxation cycle and is a common disabling symptom of many motor-related diseases such as Parkinson disease, multiple sclerosis, Huntington disease, and forms of ataxia.

In the wake of anecdotal, largely uncontrolled, observations claiming the amelioration of some symptoms among cannabis smokers, and the high density of cannabinoid receptors in the areas responsible for motor function, including basal ganglia and cerebellum, many researchers have pursued the question of whether cannabinoid-based compounds could be used therapeutically to alleviate tremor associated with central nervous system diseases.

In this review, we focus on possible effects of cannabinoid-based medicines, in particular on Parkinsonian and multiple sclerosis-related tremors and the common probable molecular mechanisms. While, at present, inconclusive results have been obtained, future investigations should extend preclinical studies with different cannabinoids to controlled clinical trials to determine potential benefits in tremor.”

http://www.ncbi.nlm.nih.gov/pubmed/26152606

Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury

Heart and Circulatory Physiology

“CANNABINOIDS ARE NATURAL and synthetic compounds structurally or pharmacologically related to the constituents of the plant Cannabis sativa or to the endogenous agonists (endocannabinoids) of the cannabinoid CB1 and CB2 receptors.

Cannabidiol (CBD) is a major cannabinoid constituent of Cannabis.

In contrast to tetrahydrocannabinol, CBD binds very weakly to CB1 and CB2 receptors. Contrary to most cannabinoids, CBD does not induce psychoactive or cognitive effects.

CBD has been shown to have anti-inflammatory properties. CBD (together with tetrahydrocannabinol) has been successfully tested in a few preliminary human trials related to autoimmune diseases…

Cannabidiol (CBD) is a major, nonpsychoactive Cannabis constituent with anti-inflammatory activity mediated by enhancing adenosine signaling.

Inasmuch as adenosine receptors are promising pharmaceutical targets for ischemic heart diseases, we tested the effect of CBD on ischemic rat hearts.

Our study shows that CBD induces a substantial in vivo cardioprotective effect from ischemia that is not observed ex vivo.

Inasmuch as CBD has previously been administered to humans without causing side effects, it may represent a promising novel treatment for myocardial ischemia.”

http://ajpheart.physiology.org/content/293/6/H3602

Cannabidiol causes endothelium-dependent vasorelaxation of human mesenteric arteries via CB1 activation.

“The protective effects of cannabidiol (CBD) have been widely shown in preclinical models and have translated into medicines for the treatment of multiple sclerosis and epilepsy. However, the direct vascular effects of CBD in humans are unknown.

CONCLUSION:

This study shows, for the first time, that CBD causes vasorelaxation of human mesenteric arteries via activation of CB1 and TRP channels, and is endothelium- and nitric oxide-dependent.”

http://www.ncbi.nlm.nih.gov/pubmed/26092099

Medical use of cannabis: an addiction medicine perspective.

“The use of cannabis for medical purposes, evident throughout history, has become a topic of increasing interest. Yet on the present medical evidence, cannabis-based treatments will only be appropriate for a small number of people in specific circumstances. Experience with cannabis as a recreational drug, and with use of psychoactive drugs that are prescribed and abused, should inform harm reduction in the context of medical cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/26059881

“A safer alternative: Cannabis substitution as harm reduction.”  http://www.ncbi.nlm.nih.gov/pubmed/25919477