The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation

Mary Ann Liebert, Inc. publishers

“Corneal injury can result in dysfunction of corneal nociceptive signaling and corneal sensitization.

Activation of the endocannabinoid system has been reported to be analgesic and anti-inflammatory.

The purpose of this research was to investigate the antinociceptive and anti-inflammatory effects of cannabinoids with reported actions at cannabinoid 1 (CB1R) and cannabinoid 2 (CB2R) receptors and/or noncannabinoid receptors in an experimental model of corneal hyperalgesia.

Topical cannabinoids reduce corneal hyperalgesia and inflammation.

The antinociceptive and anti-inflammatory effects of Δ8THC are mediated primarily via CB1R, whereas that of the cannabinoids CBD and HU-308, involve activation of 5-HT1A receptors and CB2Rs, respectively.

Cannabinoids could be a novel clinical therapy for corneal pain and inflammation resulting from ocular surface injury.”

https://www.ncbi.nlm.nih.gov/pubmed/29450258

http://online.liebertpub.com/doi/abs/10.1089/can.2017.0041

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Inhibition of aldose reductase activity by Cannabis sativa chemotypes extracts with high content of cannabidiol or cannabigerol.

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“Aldose reductase (ALR2) is a key enzyme involved in diabetic complications and the search for new aldose reductase inhibitors (ARIs) is currently very important.

The synthetic ARIs are often associated with deleterious side effects and medicinal and edible plants, containing compounds with aldose reductase inhibitory activity, could be useful for prevention and therapy of diabetic complications.

Non-psychotropic phytocannabinoids exert multiple pharmacological effects with therapeutic potential in many diseases such as inflammation, cancer, diabetes.

Here, we have investigated the inhibitory effects of extracts and their fractions from two Cannabis sativa L. chemotypes with high content of cannabidiol (CBD)/cannabidiolic acid (CBDA) and cannabigerol (CBG)/cannabigerolic acid (CBGA), respectively, on human recombinant and pig kidney aldose reductase activity in vitro.

A molecular docking study was performed to evaluate the interaction of these cannabinoids with the active site of ALR2 compared to known ARIs. The extracts showed significant dose-dependent aldose reductase inhibitory activity (>70%) and higher than fractions.

The inhibitory activity of the fractions was greater for acidic cannabinoid-rich fractions. Comparative molecular docking results have shown a higher stability of the ALR2-cannabinoid acids complex than the other inhibitors.

The extracts of Cannabis with high content of non-psychotropic cannabinoids CBD/CBDA or CBG/CBGA significantly inhibit aldose reductase activity.

These results may have some relevance for the possible use of C. sativa chemotypes based preparations as aldose reductase inhibitors.”

https://www.ncbi.nlm.nih.gov/pubmed/29427593

https://www.sciencedirect.com/science/article/pii/S0367326X17317598

“Dietary sources of aldose reductase inhibitors: prospects for alleviating diabetic complications.” https://www.ncbi.nlm.nih.gov/pubmed/19114390

“Edible vegetables as a source of aldose reductase differential inhibitors.”  https://www.ncbi.nlm.nih.gov/pubmed/28159579

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Medical Cannabis, a Beneficial High in Treatment of Blepharospasm? An Early Observation.

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“The objective of this study was to observe the effect of medical cannabis in benign essential blepharospasm (BEB) as an adjunct to botulinum toxin.

 

Three out of four patients (75%) reported symptomatic improvement.

Medical cannabis is an accepted therapy for muscle spastic disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/29339959

http://www.tandfonline.com/doi/abs/10.1080/01658107.2017.1318150?journalCode=ioph20

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Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts.

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“Approximately 65 million adults in the US have periodontitis, causing tooth loss and decreased quality of life.

 Cannabinoids modulate immune responses, and endocannabinoids are prevalent during oral cavity inflammation. Targets for intervention in periodontal inflammation are cannabinoid type 1 and 2 receptors (CB1R, CB2R), particularly CB2R because its levels increase during inflammation.

We previously demonstrated that SMM-189 (CB2R inverse agonist) decreased pro-inflammatory cytokine production in primary microglial cells. The hypothesis of this study was that cannabinoids anandamide (AEA), HU-308 (CB2R selective agonist), and SMM-189 decrease pro-inflammatory IL-6 and MCP-1 production by primary human periodontal ligament fibroblasts (hPDLFs) stimulated with P. gingivalis LPS, TNF-α, or IL-1β.

CONCLUSION:

The effective inhibition of LPS, TNF-α, IL-1β stimulated IL-6 and MCP-1 production by CB2R ligands in hPDLFs suggests that targeting the endocannabinoid system may lead to development of novel drugs for periodontal therapy, aiding strategies to improve oral health.”

https://www.ncbi.nlm.nih.gov/pubmed/29274621

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Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial

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“Research in both animals and humans indicates that cannabidiol (CBD) has antipsychotic properties.

The authors assessed the safety and effectiveness of CBD in patients with schizophrenia.

After 6 weeks of treatment, compared with the placebo group, the CBD group had lower levels of positive psychotic symptoms and were more likely to have been rated as improved and as not severely unwell by the treating clinician.

These findings suggest that CBD has beneficial effects in patients with schizophrenia. As CBD’s effects do not appear to depend on dopamine receptor antagonism, this agent may represent a new class of treatment for the disorder.”

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Pharmacotherapy of Apnea by Cannabimimetic Enhancement, the PACE Clinical Trial: Effects of Dronabinol in Obstructive Sleep Apnea.

Oxford University Press

“There remains an important and unmet need for fully effective and acceptable treatments in obstructive sleep apnea (OSA). At present, there are no approved drug treatments. Dronabinol has shown promise for OSA pharmacotherapy in a small dose-escalation pilot study.

Here, we present initial findings of the Phase II PACE (Pharmacotherapy of Apnea by Cannabimimetic Enhancement) trial, a fully-blinded parallel groups, placebo-controlled randomized trial of dronabinol in patients with moderate or severe OSA.

These findings support the therapeutic potential of cannabinoids in patients with OSA. In comparison to placebo, dronabinol was associated with lower AHI, improved subjective sleepiness and greater overall treatment satisfaction. Larger scale clinical trials will be necessary to clarify the best potential approach(es) to cannabinoid therapy in OSA”   https://www.ncbi.nlm.nih.gov/pubmed/29121334

“These findings support the therapeutic potential of cannabinoids in patients with obstructive sleep apnea (OSA).” https://academic.oup.com/sleep/article-abstract/doi/10.1093/sleep/zsx184/4600041?redirectedFrom=fulltext

Cannabinoid May Be First Drug for Sleep Apnea” https://www.medscape.com/viewarticle/891821
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The Synthetic Cannabinoid WIN 55,212-2 Elicits Death in Human Cancer Cell Lines.

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“Studies have revealed that cancer might be treated with cannabinoids since they can influence cancer cell survival. These findings suggest an alternative treatment option to chemo- and radiotherapy, that are associated with numerous adverse side-effects for the patients.

MATERIALS AND METHODS:

Viability staining was conducted on lung cancer, testicular cancer and neuroblastoma cells treated with different concentrations of the synthetic cannabinoid WIN 55,212-2 and the percentage of dead cells was compared. Activity of apoptosis-related enzymes was investigated by the presence of DNA ladder in gel electrophoresis.

RESULTS:

Treatment with different WIN 55,212-2 concentrations led to a significant dose-dependent reduction of cell viability. A DNA ladder was observed after WIN 55,212-2 treatment of testicular cancer and lung cancer cells.

CONCLUSION:

The application of WIN 55,212-2 was found to trigger cell death in the investigated cell lines. The decline in lung cancer and testicular cancer cell viability seems to have been caused by apoptosis. These findings may contribute to development of alternative cancer therapy strategies.”

https://www.ncbi.nlm.nih.gov/pubmed/29061818

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Sativex in the management of multiple sclerosis-related spasticity: An overview of the last decade of clinical evaluation.

Multiple Sclerosis and Related Disorders Home

“Spasticity is a common symptom of multiple sclerosis (MS) affecting about 80% of MS patients. Numerous lines of evidence suggest that spasticity due to its complexity is not adequately managed with conventional anti-spastic therapies. Therefore, in order to improve the outcomes for the majority of MS patients, alternative approaches are needed to be discovered. Over the last years, the use of cannabinoid compounds as a potential treatment for MS-related symptoms has aroused great interest, owing to encouraging preclinical and clinical studies. To date, Sativex, an oromucosal spray containing tetrahydrocannabinol and cannabidiol in approximately 1:1 ratio, is the only commercially available formulation containing cannabinoids used as add-on therapy for treatment of spasticity in adult MS patients who are not responding to conventional antispastic therapies.

METHODS:

Here, by performing a literature search, we provided an overview of the last decade of clinical evaluations as well as post-marketing studies about effectiveness and safety of Sativex in the management of MS-related spasticity.

RESULTS:

Sativex was proven effective in treating spasticity and also in improving the patient’s quality of life. In addition, a low incidence of adverse reactions Sativex-related supports the good safety profile and its tolerability.

CONCLUSION:

This review by recognizing the clinical effectiveness of Sativex in spasticity management, opened a new opportunity for many patients with spasticity resistant to common antispastic drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/29055461

http://www.msard-journal.com/article/S2211-0348(17)30148-7/fulltext

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Reprint of: survey of medicinal cannabis use among childbearing women: patterns of its use in pregnancy and retroactive self-assessment of its efficacy against ‘morning sickness’.

Complementary Therapies in Clinical Practice

“A majority of women experience some nausea and/or vomiting during pregnancy. This condition can range from mild nausea to extreme nausea and vomiting, with 1-2% of women suffering from the life-threatening condition hyperemesis gravidarum.

Cannabis (Cannabis sativa) may be used therapeutically to mitigate pregnancy-induced nausea and vomiting.

This paper presents the results of a survey of 84 female users of medicinal cannabis, recruited through two compassion societies in British Columbia, Canada. Of the seventy-nine respondents who had experienced pregnancy, 51 (65%) reported using cannabis during their pregnancies. While 59 (77%) of the respondents who had been pregnant had experienced nausea and/or vomiting of pregnancy, 40 (68%) had used cannabis to treat the condition, and of these respondents, 37 (over 92%) rated cannabis as ‘extremely effective’ or ‘effective.’

Our findings support the need for further investigations into cannabis therapy for severe nausea and vomiting during pregnancy.”

https://www.ncbi.nlm.nih.gov/pubmed/19880090

“Marijuana use is common in pregnancy but may not be an independent risk factor for poor neonatal outcomes in term pregnancies.”  http://www.sciencedirect.com/science/article/pii/S000293781500527X

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Activation of cannabinoid receptor type II by AM1241 protects adipose-derived mesenchymal stem cells from oxidative damage and enhances their therapeutic efficacy in myocardial infarction mice via Stat3 activation.

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“The poor survival of cells in ischemic sites diminishes the therapeutic efficacy of stem cell therapy. Previously we and others have reported that Cannabinoid receptor type II (CB2) is protective during heart ischemic injury for its anti-oxidative activity. However, whether CB2 activation could improve the survival and therapeutic efficacy of stem cells in ischemic myocardium and the underlying mechanisms remain elusive.

Here, we showed evidence that CB2 agonist AM1241 treatment could improve the functional survival of adipose-derived mesenchymal stem cells (AD-MSCs) in vitro as well as in vivo. Moreover, AD-MSCs adjuvant with AM1241 improved cardiac function, and inhibited cardiac oxidative stress, apoptosis and fibrosis. To unveil possible mechanisms, AD-MSCs were exposed to hydrogen peroxide/serum deprivation to simulate the ischemic environment in myocardium.

Results delineated that AM1241 blocked the apoptosis, oxidative damage and promoted the paracrine effects of AD-MSCs. Mechanistically, AM1241 activated signal transducers and activators of transcription 3 (Stat3) through the phosphorylation of Akt and ERK1/2. Moreover, the administration of AM630, LY294002, U0126 and AG490 (inhibitors for CB2, Akt, ERK1/2 and Stat3, respectively) could abolish the beneficial actions of AM1241.

Our result support the promise of CB2 activation as an effective strategy to optimize stem cell-based therapy possibly through Stat3 activation.”

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