Neuropeptide VF Enhances Cannabinoid Agonist WIN55,212-2-Induced Antinociception in Mice.

“Cannabinoids produce analgesia in several pain models, but the undesirable side effects from high doses of cannabinoid drugs limit their clinic use.

Our recent results indicate that cannabinoid-induced antinociception was enhanced by neuropeptide VF (NPVF).

Here, we investigate whether low-dose cannabinoid agonists combined with NPVF can produce effective antinociception with limited side effects…

These data suggest that the cannabinoid agonist combined with NPVF produces effective antinociception-lacking tolerance via both cannabinoid receptor type 1 and neuropeptide FF receptors in the brain.”

http://www.ncbi.nlm.nih.gov/pubmed/26273748

HU-444, A Novel, Potent Anti-Inflammatory, Non-Psychotropic Cannabinoid.

“Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas.

In contrast to Δ9-tetrahydrocannabinol (Δ9-THC) it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of TNF-α, a proinflammatory cytokine, and was found to be an oral anti-arthritic therapeutic in murine collagen-induced arthritis in vivo.

However in acidic media it can cyclize to the psychoactive Δ9-THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a Δ9-THC-like compound.

In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-a production by macrophages); in vivo it led to suppression of production of TNF-α and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause Δ9-THC- like effects in mice.

We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/26272937

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

“Alzheimer’s disease (AD) is frequently associated with neuropsychiatric symptoms (NPS) such as agitation and aggression, especially in the moderate to severe stages of the illness. The limited efficacy and high-risk profiles of current pharmacotherapies for the management of agitation and aggression in AD have driven the search for safer pharmacological alternatives.

Over the past few years, there has been a growing interest in the therapeutic potential of medications that target the endocannabinoid system (ECS).

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 Endocannabinoid System and its Modulation by Phytocannabinoids

“The endocannabinoid system is currently defined as the ensemble of the two 7-transmembrane-domain and G protein-coupled receptors for Δ9-tetrahydrocannabinol (but not for most other plant cannabinoids or phytocannabinoids)—cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R); their two most studied endogenous ligands, the “endocannabinoids” N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG); and the enzymes responsible for endocannabinoid metabolism.

However, anandamide and 2-AG, and also the phytocannabinoids, have more molecular targets than just CB1R and CB2R.

Furthermore, the endocannabinoids, like most other lipid mediators, have more than just one set of biosynthetic and degrading pathways and enzymes, which they often share with “endocannabinoid-like” mediators that may or may not interact with the same proteins as Δ9-tetrahydrocannabinol and other phytocannabinoids.

In some cases, these degrading pathways and enzymes lead to molecules that are not inactive and instead interact with other receptors.

Finally, some of the metabolic enzymes may also participate in the chemical modification of molecules that have very little to do with endocannabinoid and cannabinoid targets.

Here, we review the whole world of ligands, receptors, and enzymes, a true “endocannabinoidome”, discovered after the cloning of CB1R and CB2R and the identification of anandamide and 2-AG, and its interactions with phytocannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/26271952

http://link.springer.com/article/10.1007%2Fs13311-015-0374-6

Early Phase in the Development of Cannabidiol as a Treatment for Addiction: Opioid Relapse Takes Initial Center Stage.

“Multiple cannabinoids derived from the marijuana plant have potential therapeutic benefits but most have not been well investigated, despite the widespread legalization of medical marijuana in the USA and other countries.

Therapeutic indications will depend on determinations as to which of the multiple cannabinoids, and other biologically active chemicals that are present in the marijuana plant, can be developed to treat specific symptoms and/or diseases.

Such insights are particularly critical for addiction disorders, where different phytocannabinoids appear to induce opposing actions that can confound the development of treatment interventions. Whereas Δ9-tetracannabinol has been well documented to be rewarding and to enhance sensitivity to other drugs, cannabidiol (CBD), in contrast, appears to have low reinforcing properties with limited abuse potential and to inhibit drug-seeking behavior.

Other considerations such as CBD’s anxiolytic properties and minimal adverse side effects also support its potential viability as a treatment option for a variety of symptoms associated with drug addiction.

However, significant research is still needed as CBD investigations published to date primarily relate to its effects on opioid drugs, and CBD’s efficacy at different phases of the abuse cycle for different classes of addictive substances remain largely understudied.

Our paper provides an overview of preclinical animal and human clinical investigations, and presents preliminary clinical data that collectively sets a strong foundation in support of the further exploration of CBD as a therapeutic intervention against opioid relapse.

As the legal landscape for medical marijuana unfolds, it is important to distinguish it from “medical CBD” and other specific cannabinoids, that can more appropriately be used to maximize the medicinal potential of the marijuana plant.”

http://www.ncbi.nlm.nih.gov/pubmed/26269227

Safety and Toxicology of Cannabinoids.

“There is extensive research on the safety, toxicology, potency, and therapeutic potential of cannabis.

However, uncertainty remains facilitating continued debate on medical and recreational cannabis policies at the state and federal levels.

This review will include a brief description ofcannabinoids and the endocannabinoid system; a summary of the acute and long-term effects of cannabis; and a discussion of the therapeutic potential of cannabis.

The conclusions about safety and efficacy will then be compared with the current social and political climate to suggest future policy directions and general guidelines.”

http://www.ncbi.nlm.nih.gov/pubmed/26269228

[Clinical pharmacology of medical cannabinoids in chronic pain].

“In Switzerland, medical cannabinoids can be prescribed under compassionate use after special authorization in justified indications such as refractory pain. Evidence of efficacy in pain is limited and the clinical benefit seems to be modest. Their drug-drug interactions (DDI) profile is poorly documented. Cytochromes P450 (CYP) 2C9 and 3A4 are involved in the metabolism of tetrahydrocannabinol and cannabidiol, which implies possible DDI with CYP450 inhibitor and inducer, such as anticonvulsivants and HIV protease inhibitors, which may be prescribed in patients with neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/26267945

Dissecting the cannabinergic control of behavior: The where matters.

“The endocannabinoid system is the target of the main psychoactive component of the plant Cannabis sativa, the Δ9 -tetrahydrocannabinol (THC).

This system is composed by the cannabinoid receptors, the endogenous ligands, and the enzymes involved in their metabolic processes, which works both centrally and peripherally to regulate a plethora of physiological functions.

This review aims at explaining how the site-specific actions of the endocannabinoid system impact on memory and feeding behavior through the cannabinoid receptors 1 (CB1 R).

Centrally, CB1 R is widely distributed in many brain regions, different cell types (e.g. neuronal or glial cells) and intracellular compartments (e.g. mitochondria).

Interestingly, cellular and molecular effects are differentially mediated by CB1 R according to their cell-type localization (e.g. glutamatergic or GABAergic neurons).

Thus, understanding the cellular and subcellular function of CB1 R will provide new insights and aid the design of new compounds in cannabinoid-based medicine.”

http://www.ncbi.nlm.nih.gov/pubmed/26260530

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

HU-446 and HU-465, derivatives of the non-psychoactive cannabinoid cannabidiol, decrease the activation of encephalitogenic T cells.

“Cannabidiol (CBD), the non-psychoactive cannabinoid, has been previously shown by us to decrease peripheral inflammation and neuroinflammation in mouse experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS).

Here we have studied the anti-inflammatory effects of newly synthesized derivatives of natural (-)-CBD ((-)-8,9-dihydro-7-hydroxy-CBD; HU-446) and of synthetic (+)-CBD ((+)-8,9-dihydro-7-hydroxy-CBD; HU-465)…

These results suggest that HU-446 and HU-465 have anti-inflammatory potential in inflammatory and autoimmune diseases. ”

http://www.ncbi.nlm.nih.gov/pubmed/26259697