Monthly Archives: June 2016

Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

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“There is growing pressure for states and the federal government to legalize the use of cannabis products for medical purposes in the United States.

Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted Δ9 -tetrahydrocannabinol (Δ9 -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader.

The objectives of this review are to provide an overview of the pharmacology and toxicology of CBD; to summarize some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and to assess the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States.

Unlike Δ9 -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors (CB1 and CB2 ), whose activation results in the psychotropic effects characteristic of Δ9 -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use.

CBD exhibits antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties.

In combination with Δ9 -THC, CBD has received regulatory approvals in several European countries and is currently under study in U.S. Food and Drug Administration-registered trials in the United States.

A number of states have passed legislation to allow for the use of CBD-rich, limited Δ9 -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications.

Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain.”

http://www.ncbi.nlm.nih.gov/pubmed/27285147

Activation of cannabinoid CB1 receptors in the ventral hippocampus improved stress-induced amnesia in rat.

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“The ventral hippocampus (VH) has a high distribution of cannabinoid CB1 receptors which are important in modulating stress responses. Stress exposure activates the hypothalamic-pituitary-adrenal axis (HPA) which can impact hippocampal formation to change hippocampus-based memories.

The purpose of the present study was to determine the possible role of the VH cannabinoid CB1 receptors in stress-induced amnesia using a step-through passive avoidance procedure in male Wistar rats.

Taken together, it can be concluded that exposure to post-training inescapable stress impaired memory consolidation. The impairing effects of stress on memory retrieval may be mediated by the VH cannabinoid CB1 receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27282634

The effect of spinally administered WIN 55,212-2, a cannabinoid agonist, on thermal pain sensitivity in diabetic rats.

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“These data show that cannabinoids have potent antinociceptive effects through direct actions in the spinal dorsal horn of nociceptive pathway. This suggests that intrathecally administered cannabinoids may offer hopeful strategies for the treatment of diabetic neuropathic pain.”

http://www.ncbi.nlm.nih.gov/pubmed/27279983

Opioid and cannabinoid synergy in a mouse neuropathic pain model.

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“Clinical studies have reported that pan-cannabinoid receptor agonists may have efficacy in neuropathic pain states and that this might be enhanced by co-administration with opioids. While cannabinoid-opioid analgesic synergy has been demonstrated in animal models of acute pain, it has not been examined in neuropathic pain models. We examined the effect of combination treatment with cannabinoid and opioid receptor agonists on allodynia and side-effects in a nerve injury induced neuropathic pain model.

These findings indicate that combination administration of non-selective opioid and cannabinoid receptor agonists synergistically reduces nerve injury induced allodynia, while producing side-effects in an additive manner. This suggests that combination treatment has an improved anti-allodynic potency and therapeutic index in a neuropathic pain model.”

http://www.ncbi.nlm.nih.gov/pubmed/27278681

Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics.

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“Chemotherapy-induced nausea and vomiting (CINV) is one of the most common symptoms feared by patients, but may be prevented or lessened with appropriate medications.

Several antiemetic options exist to manage CINV. Corticosteroids, serotonin receptor antagonists, and neurokinin receptor antagonists are the classes most commonly used in the prevention of CINV. There are many alternative drug classes utilized for the prevention and management of CINV such as antihistamines, benzodiazepines, anticonvulsants, cannabinoids, and dopamine receptor antagonists.

Medications belonging to these classes generally have lower efficacy and are associated with more adverse effects. They are also not as well studied compared to the aforementioned agents.

This review will focus on dronabinol, a member of the cannabinoid class, and its role in CINV.

Cannabis sativa L. (also known as marijuana) contains naturally occurring delta-9-tetrahydrocannibinol (delta-9-THC). The synthetic version of delta-9-THC is the active ingredient in dronabinol that makes dronabinol an orally active cannabinoid.

Evidence for clinical efficacy of dronabinol will be analyzed in this review as monotherapy, in combination with ondansetron, and in combination with prochlorperazine.”

http://www.ncbi.nlm.nih.gov/pubmed/27274310

Pharmacological activation of cannabinoid 2 receptor attenuates inflammation, fibrogenesis, and promotes re-epithelialization during skin wound healing.

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“Previous studies showed that cannabinoid 2 (CB2) receptor is expressed in multiple effector cells during skin wound healing. Meanwhile, its functional involvement in inflammation, fibrosis, and cell proliferation in other organs and skin diseases implied CB2 receptor might also regulate skin wound healing.

These results, taken together, indicate that activating CB2 receptor could ameliorate wound healing by reducing inflammation, accelerating re-epithelialization, and attenuating scar formation.

Thus, CB2 receptor agonist might be a novel perspective for skin wound therapy.”

http://www.ncbi.nlm.nih.gov/pubmed/27268717

Medicinal cannabis: Principal cannabinoids concentration and their stability evaluated by a high performance liquid chromatography coupled to diode array and quadrupole time of flight mass spectrometry method.

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“In the last few years, there has been a boost in the use of cannabis-based extracts for medicinal purposes, although their preparation procedure has not been standardized but rather decided by the individual pharmacists.

The present work describes the development of a simple and rapid high performance liquid chromatography method with UV detection (HPLC-UV) for the qualitative and quantitative determination of the principalcannabinoids (CBD-A, CBD, CBN, THC and THC-A) that could be applied to all cannabis-based medicinal extracts (CMEs) and easily performed by a pharmacist.

In order to evaluate the identity and purity of the analytes, a high-resolution mass spectrometry (HPLC-ESI-QTOF) analysis was also carried out. Full method validation has been performed in terms of specificity, selectivity, linearity, recovery, dilution integrity and thermal stability. Moreover, the influence of the solvent (ethyl alcohol and olive oil) was evaluated on cannabinoids degradation rate.

An alternative extraction method has then been proposed in order to preserve cannabis monoterpene component in final CMEs.”

http://www.ncbi.nlm.nih.gov/pubmed/27268223

RNA-seq analysis of delta -9-tetrahydrocannabinol-treated T cells reveals altered gene expression profiles that regulate immune response and cell proliferation.

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“Marijuana has drawn significant public attention and concern both for its medicinal and recreational use. Δ9-tetrahydrocannabinol (THC), which is the main bioactive component in marijuana, has also been shown to possess potent anti-inflammatory properties by virtue of its ability to activate cannabinoid receptor-2 (CB-2) expressed on immune cells.

In this study, we used RNA-seq to quantify the transcriptomes and transcript variants that are differentially regulated by THC in super antigen-activated lymph node cells and CD4+ T cells. We found that the expressions of many transcripts were altered by THC in both total lymph node cells and CD4+ T cells. Furthermore, the abundance of many miRNA precursors and long non-coding RNAs was dramatically altered in THC treated mice. For example, the expression of miR-17/92 cluster and miR-374b/421 cluster was down regulated by THC. On the other hand miR-146a which has been shown to induce apoptosis was up regulated by THC. Long non-coding RNAs that are expressed from the opposite strand of CD27 and Appbp2 were induced by THC.

In addition, THC treatment also caused alternative promoter usage and splicing. The functions of those altered transcripts were mainly related to immune response and cell proliferation.”

http://www.ncbi.nlm.nih.gov/pubmed/27268054

Aberrant epilepsy-associated mutant Nav1.6 sodium channel activity can be targeted with cannabidiol.

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“Mutations in brain isoforms of voltage-gated sodium channels have been identified in patients with distinct epileptic phenotypes. Clinically, these patients often do not respond well to classic anti-epileptics and many remain refractory to treatment.

Exogenous as well as endogenous cannabinoids have been shown to target voltage-gated sodium channels and cannabidiol has recently received attention for its potential efficacy in the treatment of childhood epilepsies.

In this study, we further investigated the ability of cannabinoids to modulate sodium currents from wild-type and epilepsy-associated mutant voltage-gated sodium channels.

These findings suggest that cannabidiol could be exerting its anticonvulsant effects, at least in part, through its actions on voltage-gated sodium channels, and resurgent current may be a promising therapeutic target for the treatment of epilepsy syndromes.”

http://www.ncbi.nlm.nih.gov/pubmed/27267376

Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine.

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“Compared with men, women show enhanced responses to drugs of abuse, and consequently are thought to be more vulnerable to addiction.

The ovarian hormone estradiol has emerged as a key facilitator in the heightened development of addiction in females. These actions of estradiol appear mediated by estrogen receptor (ER) activation of metabotropic glutamate receptor type 5 (mGluR5). However, the downstream effectors of this ER/mGluR5 signaling pathway are unknown.

Here we investigate whether cannabinoid 1 receptor (CB1R) activation is a part of the mechanism whereby estradiol influences behavioral and synaptic correlates of addiction.

Following repeated cocaine administration, estradiol-treated ovariectomized rats exhibited both sensitized locomotor responses and decreases in the dendritic spine density of nucleus accumbens core medium-spiny neurons in comparison to oil-treated controls. Both effects of estradiol were blocked by AM251, a CB1R inverse agonist.

These results indicate that part of the signaling mechanism through which estradiol impacts behavioral and synaptic correlates of addiction in female rats requires activation of CB1Rs.”

http://www.ncbi.nlm.nih.gov/pubmed/27266915