Tetrahydrocannabinol Modulates in Vitro Maturation of Oocytes and Improves the Blastocyst Rates after in Vitro Fertilization.

 

Image result for Cellular Physiology & Biochemistry“Among the assisted reproductive techniques, the in vitro maturation of oocytes (IVM) is less developed than other techniques, but its implementation would entail a qualitative advance.

This technique consists in the extraction of immature oocytes from antral ovarian follicles with the patient under low hormone stimulation or without hormone to mature exogenously in culture media supplemented with different molecules to promote maturation.

In this sense, we are interested in the role that cannabinoids could have as IVM promoters because cannabinoid’s molecular pathway is similar to the one by which oocyte’s meiosis resumption is activated.

With the intention of advancing in the possible use of cannabinoids as supplements for the media for in vitro maturation of oocytes, we intend to deepen the study of the function of the phytocannabinoid Δ-9-tetrahydrocannabinol (THC) in the IVM process.

RESULTS:

This study confirms that the incubation of oocytes with THC during IVM accelerated some events of that process like the phosphorylation pattern of ERK and AKT and was able to increase the blastocyst rate in response to IVF. Moreover, it seems that both CB1 and CB2 are necessary to maintain a healthy oocyte maturation.

CONCLUSION:

Our data suggest that THC may be useful IVM supplements in clinic as is more feasible and reliable than any synthetic cannabinoid.”

https://www.ncbi.nlm.nih.gov/pubmed/31436397

https://www.cellphysiolbiochem.com/Articles/000149/

The effectiveness of self-directed medical cannabis treatment for pain

Complementary Therapies in Medicine“The prior medical literature offers little guidance as to how pain relief and side effect manifestation may vary across commonly used and commercially available cannabis product types. We used the largest dataset in the United States of real-time responses to and side effect reporting from patient-directed cannabis consumption sessions for the treatment of pain under naturalistic conditions in order to identify how cannabis affects momentary pain intensity levels and which product characteristics are the best predictors of therapeutic pain relief.

Between 06/06/2016 and 10/24/2018, 2987 people used the ReleafApp to record 20,513 cannabis administration measuring cannabis’ effects on momentary pain intensity levels across five pain categories: musculoskeletal, gastrointestinal, nerve, headache-related, or non-specified pain. The average pain reduction was –3.10 points on a 0–10 visual analogue scale (SD = 2.16, d = 1.55, p < .001).

Whole Cannabis flower was associated with greater pain relief than were other types of products, and higher tetrahydrocannabinol (THC) levels were the strongest predictors of analgesia and side effects prevalence across the five pain categories. In contrast, cannabidiol (CBD) levels generally were not associated with pain relief except for a negative association between CBD and relief from gastrointestinal and non-specified pain.

These findings suggest benefits from patient-directed, cannabis therapy as a mid-level analgesic treatment; however, effectiveness and side effect manifestation vary with the characteristics of the product used.

The results suggest that Cannabis flower with moderate to high levels of tetrahydrocannabinol is an effective mid-level analgesic.”

https://www.ncbi.nlm.nih.gov/pubmed/31519268

https://www.sciencedirect.com/science/article/abs/pii/S0965229919308040

“UNM study confirms cannabis flower is an effective mid-level analgesic medication for pain treatment. Cannabis likely has numerous constituents that possess analgesic properties beyond THC, including terpenes and flavonoids, which likely act synergistically for people that use whole dried cannabis flower, Cannabis offers the average patient an effective alternative to using opioids for general use in the treatment of pain with very minimal negative side effects for most people.”  https://news.unm.edu/news/unm-study-confirms-cannabis-flower-is-an-effective-mid-level-analgesic-medication-for-pain-treatment

Emerging role of cannabinoids and synthetic cannabinoid receptor 1/cannabinoid receptor 2 receptor agonists in cancer treatment and chemotherapy-associated cancer management

Journal of Cancer Research and Therapeutics“Cannabis was extensively utilized for its medicinal properties till the 19th century. A steep decline in its medicinal usage was observed later due to its emergence as an illegal recreational drug.

Advances in technology and scientific findings led to the discovery of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, that further led to the discovery of endogenous cannabinoids system consisting of G-protein-coupled receptors – cannabinoid receptor 1 and cannabinoid receptor 2 along with their ligands, mainly anandamide and 2-arachidonoylglycerol.  Endocannabinoid (EC) is shown to be a modulator not only for physiological functions but also for the immune system, endocrine network, and central nervous system.

Medicinal research and meta-data analysis over the last few decades have shown a significant potential for both THC and cannabidiol (CBD) to exert palliative effects. People suffering from many forms of advanced stages of cancers undergo chemotherapy-induced nausea and vomiting followed by severe and chronic neuropathic pain and weight loss.

THC and CBD exhibit effective analgesic, anxiolytic, and appetite-stimulating effect on patients suffering from cancer. Drugs currently available in the market to treat such chemotherapy-induced cancer-related ailments are Sativex (GW Pharmaceutical), Dronabinol (Unimed Pharmaceuticals), and Nabilone (Valeant Pharmaceuticals).

Apart from exerting palliative effects, THC also shows promising role in the treatment of cancer growth, neurodegenerative diseases (multiple sclerosis and Alzheimer’s disease), and alcohol addiction and hence should be exploited for potential benefits.

The current review discusses the nature and role of CB receptors, specific applications of cannabinoids, and major studies that have assessed the role of cannabinoids in cancer management.

Specific targeting of cannabinoid receptors can be used to manage severe side effects during chemotherapy, palliative care, and overall cancer management. Furthermore, research evidences on cannabinoids have suggested tumor inhibiting and suppressing properties which warrant reconsidering legality of the substance.

Studies on CB1 and CB2 receptors, in case of cancers, have demonstrated the psychoactive constituents of cannabinoids to be potent against tumor growth.

Interestingly, studies have also shown that activation of CB1 and CB2 cannabinoid receptors by their respective synthetic agonists tends to limit human cancer cell growth, suggesting the role of the endocannabinoid system as a novel target for treatment of cancers.

Further explorations are required to exploit cannabinoids for an effective cancer management.”

http://www.cancerjournal.net/preprintarticle.asp?id=263538

“Could Cannabis Kill Cancer Cells? A New Study Looks Promising”  https://www.portlandmercury.com/blogtown/2019/08/15/26977361/could-cannabis-kill-cancer-cells-a-new-study-looks-promising

“Study Reviews How Marijuana Compounds Inhibit Tumor Growth And Kill Cancer Cells” https://www.marijuanamoment.net/study-reviews-how-marijuana-compounds-inhibit-tumor-growth-and-kill-cancer-cells/

Cannabinoids and inflammation: Implications for People Living with HIV.

Image result for wolters kluwer “Thanks to the success of modern antiretroviral therapy (ART), people living with HIV (PLWH) have life expectancies which approach that of persons in the general population. However, despite the ability of ART to suppress viral replication, PLWH have high levels of chronic systemic inflammation which drives the development of comorbidities such as cardiovascular disease, diabetes and non-AIDS associated malignancies.

Historically, cannabis has played an important role in alleviating many symptoms experienced by persons with advanced HIV infection in the pre-ART era and continues to be used by many PLWH in the ART era, though for different reasons.

Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) are the phytocannabinoids which have received most attention for their medicinal properties. Due to their ability to suppress lymphocyte proliferation and inflammatory cytokine production, there is interest in examining their therapeutic potential as immunomodulators.

CB2 receptor activation has been shown in vitro to reduce CD4 T-cell infection by CXCR4-tropic HIV and to reduce HIV replication.

Studies involving SIV-infected macaques have shown that Δ-THC can reduce morbidity and mortality and has favourable effects on the gut mucosal immunity. Furthermore, ΔTHC administration was associated with reduced lymph node fibrosis and diminished levels of SIV proviral DNA in spleens of rhesus macaques compared with placebo-treated macaques.

In humans, cannabis use does not induce a reduction in peripheral CD4 T-cell count or loss of HIV virological control in cross-sectional studies. Rather, cannabis use in ART-treated PLWH was associated with decreased levels of T-cell activation, inflammatory monocytes and pro-inflammatory cytokines secretion, all of which are related to HIV disease progression and co-morbidities.

Randomized clinical trials should provide further insights into the ability of cannabis and cannabinoid-based medicines to attenuate HIV-associated inflammation. In turn, these findings may provide a novel means to reduce morbidity and mortality in PLWH as adjunctive agents to ART.”

https://www.ncbi.nlm.nih.gov/pubmed/31408029

https://insights.ovid.com/crossref?an=00002030-900000000-96855

Analysis of Terpenes in Cannabis sativa L. Using GC/MS: Method Development, Validation, and Application.

“Terpenes are the major components of the essential oils present in various Cannabis sativa L. varieties.

These compounds are responsible for the distinctive aromas and flavors. Besides the quantification of the cannabinoids, determination of the terpenes in C. sativa strains could be of importance for the plant selection process.

At the University of Mississippi, a GC-MS method has been developed and validated for the quantification of terpenes in cannabis plant material, viz., α-pinene, β-pinene, β-myrcene, limonene, terpinolene, linalool, α-terpineol, β-caryophyllene, α-humulene, and caryophyllene oxide.”

https://www.ncbi.nlm.nih.gov/pubmed/30646402

https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-0828-8387

The Acute Activation of the CB1 Receptor in the Hippocampus Decreases Neurotoxicity and Prevents Spatial Memory Impairment in Rats Lesioned with β-Amyloid 25-35.

Neuroscience“Given their anti-inflammatory properties, cannabinoids have been shown to be neuroprotective agents and to reduce excitotoxicity, through the activation of the Cannabinoid receptor type 1 (CB1r).

These properties have led to CB1r being proposed as pharmacological targets for the treatment of various neurodegenerative diseases.

This study aimed to evaluate the neuroprotective effect of an acute activation of CB1r on spatial memory and its impact on iNOS protein expression, NO● levels, gliosis and the neurodegenerative process induced by the injection of Aβ(25-35) into the CA1 subfield of the hippocampus.

The data obtained in the present research suggest that the acute early activation of CB1r is crucial for neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31400487

https://www.sciencedirect.com/science/article/abs/pii/S0306452219305433?via%3Dihub

Application device for THC:CBD oromucosal spray in the management of resistant spasticity: pre-production testing.

 Publication Cover“Patients with multiple sclerosis spasticity (MSS) and upper limb/hand impairment who are taking 9-delta-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®) may have difficulty self-administering their medication, possibly limiting adherence and treatment effectiveness.

A Class I EU device is available to support administration of THC:CBD spray. Pre-production testing was undertaken in a patient sample.

Results: Fifteen patients participated. Mean treatment time with THC:CBD spray was 4 (range: 0.1-6.1) years. 87% of participants ‘always’, ‘often’ or ‘sometimes’ had hand impairment, and 53% reported difficulty administering THC:CBD spray. Participants reported better application using the device (73%), with less strength required (54%). Most participants (93%) considered the instruction leaflet to be clear and many (66%) expressed interest in using the device. Most HCPs (93%) did not foresee any difficulties in use of the device.

Conclusion: The proposed adherence device was useful to address self-application difficulties with THC:CBD spray in our sample. Providing the device to MSS patients with upper limb/hand spasticity impairment may restore autonomy and support adherence to THC:CBD spray.”

https://www.ncbi.nlm.nih.gov/pubmed/31393179

https://www.tandfonline.com/doi/abs/10.1080/17434440.2019.1653182?journalCode=ierd20

Cannabinoid CB2 Receptor Modulation by the Transcription Factor NRF2 is Specific in Microglial Cells.

 “Nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor that has neuroprotective and anti-inflammatory effects, regulating more than 250 genes. As NRF2, cannabinoid receptor type 2 (CB2) is also implicated in the preservation of neurons against glia-driven inflammation. To this concern, little is known about the regulation pathways implicated in CB2 receptor expression. In this study, we analyze whether NRF2 could modulate the transcription of CB2 in neuronal and microglial cells. Bioinformatics analysis revealed an antioxidant response element in the promoter sequence of the CB2 receptor gene. Further analysis by chemical and genetic manipulations of this transcription factor demonstrated that NRF2 is not able to modulate the expression of CB2 in neurons. On the other hand, at the level of microglia, the expression of CB2 is NRF2-dependent. These results are related to the differential levels of expression of both genes regarding the brain cell type. Since modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neurodegeneration, our findings will contribute to disclose the potential of CB2 as a novel target for treating different pathologies.”

https://www.ncbi.nlm.nih.gov/pubmed/31385133

https://link.springer.com/article/10.1007%2Fs10571-019-00719-y

Δ9-Tetrahydrocannabinol suppresses monocyte-mediated astrocyte production of MCP-1 and IL-6 in a TLR7-stimulated human co-culture.

Journal of Pharmacology and Experimental Therapeutics“Cannabis is widely used in the United States with an estimated prevalence of 9.5%. Certain cannabinoids in Cannabis sativa, in particular, Δ9-tetrahydrocannabinol (THC), possess immune modulating and anti-inflammatory activity. Depending on the context, the anti-inflammatory activity of cannabinoids may be beneficial, such as in treating inflammatory diseases, or detrimental to normal immune defense against pathogens. The potential beneficial impact of cannabinoids on chronic neuroinflammation has gained recent attention. Monocyte migration to the brain has been implicated as a key event in chronic neuroinflammation and in the etiology of central nervous system diseases including viral infection (e.g., HIV-associated neurocognitive disorder). In the brain, monocytes can contribute to neuroinflammation through interactions with astrocytes, including inducing astrocyte secretion of cytokines and chemokines. In a human co-culture system, monocyte-derived IL-1β due to toll-like receptor 7 (TLR7)-activation, has been identified to promote astrocyte production of MCP-1 and IL-6. THC treatment of TLR7-stimulated co-culture suppressed monocyte secretion of IL-1β resulting in decreased astrocyte production of MCP-1 and IL-6. Furthermore, THC displayed direct inhibition of monocytes, as TLR7-stimulated monocyte monocultures treated with THC also showed suppressed IL-1β production. The cannabinoid receptor 2 (CB2) agonist, JWH-015, impaired monocyte IL-1β production similar to that of THC, suggesting THC is, in part, acting through CB2. THC also suppressed key elements of the IL-1β production pathway, including IL1B mRNA levels and caspase-1 activity. Collectively, this study demonstrates that the anti-inflammatory properties of THC suppress TLR7-induced monocyte secretion of IL-1β, through CB2, which results in decreased astrocyte secretion of MCP-1 and IL-6.

SIGNIFICANCE STATEMENT: As cannabis use is highly prevalent in the United States and has putative anti-inflammatory properties, it is important to investigate the effect of cannabinoids on immune cell function. Furthermore, cannabinoids have garnered particular interest due to their potential beneficial effects on attenuating viral-induced chronic neuroinflammation. This study utilized a primary human co-culture system to demonstrate that the major psychotropic cannabinoid in cannabis, Δ9-tetrahydrocannabinol (THC) and a cannabinoid receptor-2 (CB2) selective agonist, suppress specific monocyte-mediated astrocyte inflammatory responses. In the context of viral-induced chronic neuroinflammation, the findings presented here suggest that cannabinoids via CB2 ligation may have beneficial anti-inflammatory effects.”

https://www.ncbi.nlm.nih.gov/pubmed/31383729

http://jpet.aspetjournals.org/content/early/2019/08/05/jpet.119.260661

THE EFFECTS OF MEDICAL MARIJUANA DISPENSARIES ON ADVERSE OPIOID OUTCOMES

 Publication cover image“As more states enact laws liberalizing marijuana use and the U.S. opioid epidemic surges to unprecedented levels, understanding the relationship between marijuana and opioids is growing increasingly important.

Using a unique self‐constructed marijuana dispensary dataset, I estimate the impact of increased marijuana access on opioid‐related harms.

I exploit within‐ and across‐state variation in dispensary openings and find county‐level prescription opioid‐related fatalities decline by 11% following the opening a dispensary.

The estimated dispensary effects are qualitatively similar for opioid‐related admissions to treatment facilities. These results are strongest for males and suggest a substitutability between marijuana and opioids.”

https://onlinelibrary.wiley.com/doi/full/10.1111/ecin.12825

“I find that core-based statistical areas (CBSAs) with dispensary openings experience a 20 percentage point relative decrease in painkiller treatment admissions over the first two years of dispensary operations.”

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3012381

Access to medical marijuana reduces opioid prescriptions”  https://www.health.harvard.edu/blog/access-to-medical-marijuana-reduces-opioid-prescriptions-2018050914509