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

Life Threatening Idiopathic Recurrent Angioedema Responding to Cannabis.

“We present a case of a 27-year-old man with recurrent episodes of angioedema since he was 19, who responded well to treatment with medical grade cannabis.

Initially, he responded to steroids and antihistamines, but several attempts to withdraw treatment resulted in recurrence. In the last few months before prescribing cannabis, the frequency and severity of the attacks worsened and included several presyncope events, associated with scrotal and neck swelling. No predisposing factors were identified, and extensive workup was negative.

The patient reported that he was periodically using cannabis socially and that during these periods he was free of attacks.

Recent data suggest that cannabis derivatives are involved in the control of mast cell activation. Consequently, we decided to try a course of inhaled cannabis as modulators of immune cell functions.

The use of inhaled cannabis resulted in a complete response, and he has been free of symptoms for 2 years.

An attempt to withhold the inhaled cannabis led to a recurrent attack within a week, and resuming cannabis maintained the remission, suggesting a cause and effect relationship.”

http://www.ncbi.nlm.nih.gov/pubmed/26257969

“Angioedema is swelling (edema) under the skin. It can happen in different parts of your body, and it’s usually caused by an allergic reation. When you have hereditary angioedema (HAE), a rare genetic condition causes the swelling, not allergies. You are born with this condition and will always have it. Treatment can help you live with it, though. Over the years, there have been big improvements in therapies, and researchers are still looking for more and better treatment options.” http://www.webmd.com/skin-problems-and-treatments/hereditary-angioedema

On the effects of CP 55-940 and other cannabinoid receptor agonists in C6 and U373 cell lines.

“Cannabinoid receptor (CBs) agonists affect the growth of tumor cells via activation of deadly cascades. The spectrum of action of these agents and the precise role of the endocannabinoid system (ECS) on oncogenic processes remain elusive.

Herein we compared the effects of synthetic (CP 55-940 and WIN 55,212-2) and endogenous (anandamide or AEA) CBs agonists (10-20 μM) on morphological changes, cell viability, and induction of apoptosis in primary astrocytes and in two glioblastoma cell lines (C6 and U373 cells) in order to characterize their possible differential actions on brain tumor cells.

None of the CBs agonist tested induced changes in cell viability or morphology in primary astrocytes.

In contrast, CP 55-940 significantly decreased cell viability in C6 and U373 cells at 5 days of treatment, whereas AEA and WIN 55,212-2 moderately decreased cell viability in both cell lines. Treatment of U373 and C6 for 3 and 5 days with AEA or WIN 55,212-2 produced discrete morphological changes in cell bodies, whereas the exposure to CP 55-940 induced soma degradation. CP 55-940 also induced apoptosis in both C6 and U373 cell lines.

Our results support a more effective action of CP 55-940 to produce cell death of both cell lines through apoptotic mechanisms. Comparative aspects between cannabinoids with different profiles are necessary for the design of potential treatments against glial tumors.”

http://www.ncbi.nlm.nih.gov/pubmed/26255146

Microinjection of orexin-A into the rat locus coeruleus nucleus induces analgesia via cannabinoid type-1 receptors.

“Locus coeruleus (LC) nucleus is involved in noradrenergic descending pain modulation.

LC receives dense orexinergic projections from the lateral hypothalamus. Orexin-A and -B are hypothalamic peptides which modulate a variety of brain functions via orexin type-1 (OX1) and orexin type-2 (OX2) receptors.

Previous studies have shown that activation of OX1 receptors induces endocannabinoid synthesis and alters synaptic neurotransmission by retrograde signaling via affecting cannabinoid type-1 (CB1) receptors.

In the present study the interaction of orexin-A and endocannabinoids was examined at the LC level in a rat model of inflammatory pain…

This data show that, activation of OX1 receptors in the LC can induce analgesia and also the blockade of OX1 or CB1 receptors is associated with hyperalgesia during formalin test.

Our findings also suggest that CB1 receptors may modulate the analgesic effect of orexin-A.

These results outline a new mechanism by which orexin-A modulates the nociceptive processing in the LC nucleus.”

http://www.ncbi.nlm.nih.gov/pubmed/26254729

The Use of Styrene Maleic Acid Nanomicelles Encapsulating the Synthetic Cannabinoid Analog WIN55,212-2 for the Treatment of Cancer.

“Synthetic cannabinoid WIN55,212-2 (WIN) has shown a promise as an anticancer agent but causes psychoactive side-effects.

In the present study, nano-micelles of styrene maleic acid (SMA)-conjugated WIN were synthesized to reduce side-effects and increase drug efficacy…

SMA-WIN demonstrated characteristics theorized to improve in vivo drug biodistribution.

Potent cytotoxicity was found against breast and prostate cancer cells in vitro, showing promise as a novel treatment against breast and prostate cancer.”

http://www.ncbi.nlm.nih.gov/pubmed/26254360

Cannabinoids Regulate Intestinal Motor Function and Electrophysiological Activity of Myocytes in Rodents.

“This study aims to investigate the effects of cannabinoid (CB)-1 and CB2 receptor ligands on intestinal motor function and muscular electrophysiological activity in rodent gastrointestinal (GI) tract…

This is one of the first reports on neuronal regulation of intestinal motility through CB-dependent pathways with potential application in the treatment of inflammatory and functional GI disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/26254701