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Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis.

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Journal of Pharmacology and Experimental Therapeutics

“Phytocannabinoids modulate inflammatory responses by regulating the production of cytokines in several experimental models of inflammation.

Cannabinoid type-2 (CB2) receptor activation was shown to reduce the production of the monocyte chemotactic protein-2 (MCP-2) chemokine in polyinosinic-polycytidylic acid [poly-(I:C)]-stimulated human keratinocyte (HaCaT) cells, an in vitro model of allergic contact dermatitis (ACD).

We investigated if nonpsychotropic cannabinoids, such as cannabidiol (CBD), produced similar effects in this experimental model of ACD.

We show that in poly-(I:C)-stimulated HaCaT cells, CBD elevates the levels of AEA and dose-dependently inhibits poly-(I:C)-induced release of MCP-2, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α in a manner reversed by CB2 and TRPV1 antagonists 6-iodopravadoline (AM630) and 5′-iodio-resiniferatoxin (I-RTX), respectively, with no cytotoxic effect.

This is the first demonstration of the anti-inflammatory properties of CBD in an experimental model of ACD.”

https://www.ncbi.nlm.nih.gov/pubmed/29632236

http://jpet.aspetjournals.org/content/365/3/652.long

Cannabis Therapeutics and the Future of Neurology.

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“Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes.

While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain.

This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE).

Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics.

The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/30405366

https://www.frontiersin.org/articles/10.3389/fnint.2018.00051/full

A Phase I, Randomized, Double-Blind, Placebo-Controlled, Single Ascending Dose, Multiple Dose, and Food Effect Trial of the Safety, Tolerability and Pharmacokinetics of Highly Purified Cannabidiol in Healthy Subjects.

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“A formal single ascending and multiple dose pharmacokinetic (PK) trial of cannabidiol (CBD) oral solution was required to determine the safety and tolerability of CBD, the maximum tolerated dose, and to examine the effect of food on CBD PK parameters.

OBJECTIVE:

This trial assessed the safety, tolerability and PK of CBD oral solution in healthy adult volunteers, as well as the effect of food on CBD PK parameters.

 CONCLUSION:

CBD was generally well tolerated. Most AEs were mild in severity; none were severe or serious. The safety and PK profile support twice-daily administration of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/30374683

https://link.springer.com/article/10.1007%2Fs40263-018-0578-5

Medical Use of Cannabinoids.

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“Cannabinoid receptors, endocannabinoids and the enzymes responsible for their biosynthesis and degradation constitute the endocannabinoid system. In recent decades, the endocannabinoid system has attracted considerable interest as a potential therapeutic target in numerous pathological conditions. Its involvement in several physiological processes is well known, such as in energy balance, appetite stimulation, blood pressure, pain modulation, embryogenesis, nausea and vomiting control, memory, learning and immune response, among others, as well as in pathological conditions where it exerts a protective role in the development of certain disorders. As a result, it has been reported that changes in endocannabinoid levels may be related to neurological diseases such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and multiple sclerosis, as well as anorexia and irritable bowel syndrome. Alterations in the endocannabinoid system have also been associated with cancer, affecting the growth, migration and invasion of some tumours. Cannabinoids have been tested in several cancer types, including brain, breast and prostate cancers. Cannabinoids have shown promise as analgesics for the treatment of both inflammatory and neuropathic pain. There is also evidence for a role of the endocannabinoid system in the control of emotional states, and cannabinoids could prove useful in decreasing and palliating post-traumatic stress disorder symptoms and anxiolytic disorders. The role of the endocannabinoid system in addictions has also been examined, and cannabinoids have been postulated as alternative and co-adjuvant treatments in some abuse syndromes, mainly in ethanol and opioid abuses. The expression of the endocannabinoid system in the eye suggests that it could be a potential therapeutic target for eye diseases. Considering the importance of the endocannabinoid system and the therapeutic potential of cannabinoids in this vast number of medical conditions, several clinical studies with cannabinoid-based medications are ongoing. In addition, some cannabinoid-based medications have already been approved in various countries, including nabilone and dronabinol capsules for the treatment of nausea and vomiting associated with chemotherapy, dronabinol capsules for anorexia, an oral solution of dronabinol for both vomiting associated with chemotherapy and anorexia, a Δ9-tetrahydrocannabinol/cannabidiol oromucosal spray for pain related to cancer and for spasticity and pain associated with multiple sclerosis, and an oral solution of cannabidiol for Dravet and Lennox-Gastaut syndromes. Here, we review the available efficacy, safety and tolerability data for cannabinoids in a range of medical conditions.”

https://www.ncbi.nlm.nih.gov/pubmed/30374797

https://link.springer.com/article/10.1007%2Fs40265-018-0996-1

What do Cochrane systematic reviews say about the use of cannabinoids in clinical practice?

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SciELO - Scientific Electronic Library Online

“The therapeutic effects of cannabinoid compounds have been the center of many investigations.

This study provides a synthesis on all Cochrane systematic reviews (SRs) that assessed the use of cannabinoids as a therapeutic approach.

CONCLUSIONS:

This review identified eight Cochrane systematic reviews that provided evidence of unknown to moderate quality regarding the use of cannabinoids as a therapeutic intervention. Further studies are still imperative for solid conclusions to be reached regarding practical recommendations.”

 https://www.ncbi.nlm.nih.gov/pubmed/30365598
http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802018005016102&lng=en&tlng=en

Acute administration of beta-caryophyllene prevents endocannabinoid system activation during transient common carotid artery occlusion and reperfusion.

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“The transient global cerebral hypoperfusion/reperfusion achieved by induction of Bilateral Common Carotid Artery Occlusion followed by Reperfusion (BCCAO/R) has been shown to stimulate early molecular changes that can be easily traced in brain tissue and plasma, and that are indicative of the tissue physiological response to the reperfusion-induced oxidative stress and inflammation.

The aim of the present study is to probe the possibility to prevent the molecular changes induced by the BCCAO/R with dietary natural compounds known to possess anti-inflammatory activity, such as the phytocannabinoid beta-caryophyllene (BCP).

CONCLUSIONS:

Collectively, the pre-treatment with BCP, likely acting as agonist for CB2 and PPAR-alpha receptors, modulates in a beneficial way the ECS activation and the lipoperoxidation, taken as indicative of oxidative stress. Furthermore, our results support the evidence that BCP may be used as a dietary supplement to control the physiological response to the hypoperfusion/reperfusion-induced oxidative stress.”

 https://www.ncbi.nlm.nih.gov/pubmed/29402275
“beta-caryophyllene (BCP), a sesquiterpene found as a common constituent of the essential oils of numerous food plants and primary component in Cannabis sativa L., is a dietary phytocannabinoid acting as selective agonist for CB2 receptor and peroxisome-proliferator activating receptor alpha (PPAR-alpha)”
https://lipidworld.biomedcentral.com/articles/10.1186/s12944-018-0661-4
“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

Up-regulation of heme oxygenase-1 expression and inhibition of disease-associated features by cannabidiol in vascular smooth muscle cells.

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“Aberrant proliferation and migration of vascular smooth muscle cells (VSMC) have been closely linked to the development and progression of cardiovascular and cancer diseases.

The cytoprotective enzyme heme oxygenase-1 (HO-1) has been shown to mediate anti-proliferative and anti-migratory effects in VSMC. This study investigates the effect of cannabidiol (CBD), a non-psychoactive cannabinoid, on HO-1 expression and disease-associated functions of human umbilical artery smooth muscle cells (HUASMC).

HO-1 protein and mRNA were significantly increased by CBD in a time- and concentration-dependent manner. Although the expression of several cannabinoid-activated receptors (CB1, CB2, G protein-coupled receptor 55, transient receptor potential vanilloid 1) was verified in HUASMC, CBD was shown to induce HO-1 via none of these targets. Instead, the CBD-mediated increase in HO-1 protein was reversed by the glutathione precursor N-acetylcysteine, indicating the participation of reactive oxygen species (ROS) signaling; this was confirmed by flow cytometry-based ROS detection.

CBD-induced HO-1 expression was accompanied by inhibition of growth factor-mediated proliferation and migration of HUASMC. However, neither inhibition of HO-1 activity nor knockdown of HO-1 protein attenuated CBD-mediated anti-proliferative and anti-migratory effects. Indeed, inhibition or depletion of HO-1 resulted in induction of apoptosis and intensified CBD-mediated effects on proliferation and migration.

Collectively, this work provides the first indication of CBD-mediated enhancement of HO-1 in VSMC and potential protective effects against aberrant VSMC proliferation and migration. On the other hand, our data argue against a role of HO-1 in CBD-mediated inhibition of proliferation and migration while substantiating its anti-apoptotic role in oxidative stress-mediated cell fate.”

https://www.ncbi.nlm.nih.gov/pubmed/30349652

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=26191&path[]=81658

Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor.

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“The cannabinoid type-1 (CB1) receptor, a G-protein-coupled receptor, is an attractive target for drug discovery due to its involvement in many physiological processes. Historically, drug discovery efforts targeting the CB1 receptor have focused on the development of orthosteric ligands that interact with the active site to which endogenous cannabinoids bind. Research performed over the last several decades has revealed substantial difficulties in translating CB1 orthosteric ligands into druggable candidates. The difficulty is mainly due to the adverse effects associated with orthosteric CB1 ligands. Recent discoveries of allosteric CB1 modulators provide tremendous opportunities to develop CB1 ligands with novel mechanisms of action; these ligands may potentially improve the pharmacological effects and enhance drug safety in treating the disorders by regulating the functions of the CB1 receptor. In this paper, we review and summarize the complex pharmacological profiles of each class of CB1 allosteric modulators, the development of new classes of CB1 allosteric modulators and the results from in vivo assessments of their therapeutic value.”

 https://www.ncbi.nlm.nih.gov/pubmed/30333554
https://www.nature.com/articles/s41401-018-0164-x

New Methods for the Comprehensive Analysis of Bioactive Compounds in Cannabis sativa L. (hemp).

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“Cannabis sativa L. is a dioecious plant belonging to the Cannabaceae family. The main phytochemicals that are found in this plant are represented by cannabinoids, flavones, and terpenes. Some biological activities of cannabinoids are known to be enhanced by the presence of terpenes and flavonoids in the extracts, due to a synergistic action.

In the light of all the above, the present study was aimed at the multi-component analysis of the bioactive compounds present in fibre-type C. sativa (hemp) inflorescences of different varieties by means of innovative HPLC and GC methods. In particular, the profiling of non-psychoactive cannabinoids was carried out by means of HPLC-UV/DAD, ESI-MS, and MS². The content of prenylated flavones in hemp extracts, including cannflavins A and B, was also evaluated by HPLC.

The study on Cannabis volatile compounds was performed by developing a new method based on headspace solid-phase microextraction (HS-SPME) coupled with GC-MS and GC-FID. Cannabidiolic acid (CBDA) and cannabidiol(CBD) were found to be the most abundant cannabinoids in the hemp samples analysed, while β-myrcene and β-caryophyllene were the major terpenes. As regards flavonoids, cannflavin A was observed to be the main compound in almost all the samples.

The methods developed in this work are suitable for the comprehensive chemical analysis of both hemp plant material and related pharmaceutical or nutraceutical products in order to ensure their quality, efficacy, and safety.”

https://www.ncbi.nlm.nih.gov/pubmed/30322208

https://www.mdpi.com/1420-3049/23/10/2639

Atypical Pharmacodynamic Properties and Metabolic Profile of the Abused Synthetic Cannabinoid AB-PINACA: Potential Contribution to Pronounced Adverse Effects Relative to Δ9-THC

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“Recreational use of marijuana is associated with few adverse effects, but abuse of synthetic cannabinoids (SCBs) can result in anxiety, psychosis, chest pain, seizures and death.

To potentially explain higher toxicity associated with SCB use, we hypothesized that AB-PINACA, a common second generation SCB, exhibits atypical pharmacodynamic properties at CB1 cannabinoid receptors (CB1Rs) and/or a distinct metabolic profile when compared to Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive cannabinoid present in marijuana.

Taken collectively, the atypical pharmacodynamic properties of AB-PINACA at CB1Rs relative to Δ9-THC (e.g., higher potency/efficacy and greater production of desensitization), coupled with an unusual metabolic profile (e.g., production of metabolically stable active phase I metabolites) may contribute to the pronounced adverse effects observed with abuse of this SCB compared to marijuana.

““K2” or “Spice” is a popular drug of abuse that is heavily marketed to young teens and first-time drug users as “safe” and/or “legal” marijuana”. Most K2 preparations consist of plant materials laced with a mixture of one or more SCB compounds possessing psychoactive properties similar to those produced by Δ9-tetrahydrocannabinol (Δ9-THC), the principal psychoactive compound found in marijuana. However, in contrast to the low incidence of adverse effects reported following use of marijuana, recreational abuse of SCBs can additionally result in anxiety, psychosis, chest pain, seizures and death.

In marked contrast to K2/Spice products, marijuana contains only a single psychoactive compound Δ9-THC and a second natural constituent known as cannabidiol, that appears to blunt adverse effects produced by Δ9-THC. In fact, the beneficial combination of cannabidiol with Δ9-THC led to development of Sativex, a drug currently in clinical trials to treat a variety of indications including spasticity associated with multiple sclerosis.

In addition to Δ9-THC and cannabidiol, the cannabis plant contains hundreds of other phytocannabinoids and constituents not present in K2/Spice products that may help mitigate harmful and/or adverse effects ”

https://www.ncbi.nlm.nih.gov/pubmed/30319418

https://www.frontiersin.org/articles/10.3389/fphar.2018.01084/full