Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration.

 “The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids.

METHODS:

We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro.

RESULTS:

Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis.

CONCLUSIONS:

The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.”

https://www.ncbi.nlm.nih.gov/pubmed/30899454

https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-019-0148-x

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The Effect of Medical Marijuana Laws on the Health and Labor Supply of Older Adults: Evidence from the Health and Retirement Study

 Journal of Policy Analysis and Management banner

“Older adults are at elevated risk of reducing labor supply due to poor health, partly because of high rates of symptoms that may be alleviated by medical marijuana. Yet, surprisingly little is known about how this group responds to medical marijuana laws (MMLs). We quantify the effects of state medical marijuana laws on the health and labor supply of adults age 51 and older, focusing on the 55 percent with one or more medical conditions with symptoms that may respond to medical marijuana. We use longitudinal data from the Health and Retirement Study to estimate event study and differences‐in‐differences regression models. Three principle findings emerge from our analysis. First, active state medical marijuana laws lead to lower pain and better self‐assessed health among older adults. Second, state medical marijuana laws lead to increases in older adult labor supply, with effects concentrated on the intensive margin. Third, the effects of MMLs are largest among older adults with a health condition that would qualify for legal medical marijuana use under current state laws. Findings highlight the role of health policy in supporting work among older adults and the importance of including older adults in assessments of state medical marijuana laws.”

https://onlinelibrary.wiley.com/doi/10.1002/pam.22122

https://www.jhsph.edu/news/news-releases/2019/medical-marijuana-laws-linked-to-health-and-labor-supply-benefits-in-older-adults.html?fbclid=IwAR2X_qV1jKU4Hj41KBHAr25o20CBZrWEIqfkcxCxzepC_2NLvsSRxeCNA9g

“Medical marijuana may increase productivity in older adults, Johns Hopkins study suggests” https://www.news5cleveland.com/news/national/medical-marijuana-may-increase-productivity-in-older-adults-johns-hopkins-study-suggests

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Analyzing the role of cannabinoids as modulators of Wnt/β-catenin signaling pathway for their use in the management of neuropathic pain.

Bioorganic & Medicinal Chemistry Letters

“Neuropathic pain is a debilitating form of treatment-resistant chronic pain caused by damage to the nervous system. Cannabinoids have been known for suppressing neuropathic pain by modulating the endo cannabinoid system. Since the canonical Wnt/β-catenin signaling has recently been implicated in pain sensation, we investigated the impact of major cannabinoids (1-6) from the leaves of Cannabis sativa and an epoxy derivative of compound 2, here upon referred to as 2a, on modulating Wnt/β-catenin signaling pathway. The results presented in this study show that compound 1, 2 and 2a exhibited potent inhibitory activity against Wnt/β-catenin pathway in a dose-dependent manner. Compound 2a was seen to inhibit this pathway at slightly lower concentrations than its parent molecule 2, under similar conditions. Taken together, compound 1, 2 and 2a, by virtue of their inhibition of Wnt/β-catenin signaling pathway, could be developed as effective neuroprotective agents for the management of neuropathic pain.”

https://www.ncbi.nlm.nih.gov/pubmed/30871771

https://www.sciencedirect.com/science/article/pii/S0960894X19301428?via%3Dihub

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Illicit drug use and prescription drug misuse among young adult medical cannabis patients and non-patient users in Los Angeles

Drug and Alcohol Dependence

“Young adults have the highest rates of cannabis and other drug use, as compared to other age groups, and contribute a significant proportion to the total population of medical cannabis patients (MCP). However, little is known about the relationships between various cannabis practices and illicit drug use/prescription drug misuse among young adult cannabis users with and without legal access to medical cannabis.

RESULTS:

Illicit drug use was associated with being non-Hispanic white (AOR = 3.0, 95% CI 1.8-5.1), use of cannabis concentrates (AOR = 2.8, 95% CI 1.6-4.9), while self-reported medical cannabis use was associated with lower probability of illicit drug use (AOR = 0.5, 95% CI 0.3-0.9). The odds of prescription drug misuse were increased for participants who reported use of cannabis edibles (AOR = 2.0, 95% CI 1.1-3.5), and decreased with age (AOR = 0.9, 95% CI 0.8-1.0) and for those who used cannabis alone (AOR = 0.5, 95% CI 0.3-0.9).

CONCLUSION:

Use of alternative cannabis forms, but not cannabis use frequency, were associated with greater odds of other drug use. Self-reported medical cannabis use, but not MCP status, decreased probability of illicit drug use.”

https://www.ncbi.nlm.nih.gov/pubmed/30861391

https://www.sciencedirect.com/science/article/pii/S0376871619300596?via%3Dihub

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Cannabidiol enhances the passage of lipid nanocapsules across the blood-brain barrier both in vitro and in vivo.

 Molecular Pharmaceutics“Diseases affecting the central nervous system (CNS) should be regarded as a major health challenge due to the current lack of effective treatments given the hindrance to brain drug delivery imposed by the blood-brain barrier (BBB). Since efficient brain drug delivery should not solely rely on passive targeting, active targeting of nanomedicines into the CNS is being explored. The present study is devoted to the development of lipid nanocapsules (LNCs) decorated with non-psychotropic cannabinoids as pioneering non-immunogenic brain targeting molecules and to the evaluation of their brain targeting ability both in vitro and in vivo. Noticeably, both the permeability experiments across the hCMEC/D3 cell-based in vitro BBB model and the biodistribution experiments in mice consistently demonstrated that the highest brain targeting ability was achieved with the smallest-sized cannabinoid-decorated LNCs. Importantly, the enhancement in brain targeting achieved with the conjugation of CBD to LNCs outperformed by 6-fold the enhancement observed for the G-Technology® (the main brain active strategy that has already entered clinical trials for the treatment of CNS diseases) As the transport efficiency across the BBB certainly determines the efficacy of the treatments for brain disorders, small cannabinoid-decorated LNCs represent auspicious platforms for the design and development of novel therapies for CNS diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/30865462

https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b01344

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Does morning affect contribute to daily Cannabis use?

Addictive Behaviors

“Several theories posit that cannabis and other substances are used to reduce negative affect. This daily report study considered whether variations in positive and negative affect, reported each morning, contributed to the likelihood of cannabis use later that day. We also explored whether levels of positive and negative affect reported immediately after cannabis use improved, relative to that day’s morning levels. The sample included 183 men and 183 women representing heterosexual, cannabis-using couples from the community. Participants made independent, daily reports of affect and cannabis use episodes for 30 consecutive days. Using multilevel modeling, we modeled men’s and women’s use of cannabis on a given day as a function of morning levels of positive, hostile, and anxious affect, accounting for partner cannabis use that day, and mean levels of positive and negative affect. Men and women were more likely to use cannabis on a given day when morning positive affect was lower than typical for the person and when partner used cannabis that day. Neither hostile nor anxious affect contributed to later use of cannabis. Immediately after cannabis use, positive affect increased, and hostile and anxious affect decreased relative to that day’s morning levels. The improved affect immediately after use suggests a mechanism of positive reinforcement.”

https://www.ncbi.nlm.nih.gov/pubmed/30856545

https://www.sciencedirect.com/science/article/abs/pii/S030646031831339X?via%3Dihub

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Epidiolex as adjunct therapy for treatment of refractory epilepsy: a comprehensive review with a focus on adverse effects.

 

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“Medically refractory epilepsy remains an area of intense clinical and scientific interest since a significant porportion of patients continue to suffer from debilitating seizures despite available therapies. In this setting, recent studies have focused on assessing the benefits of cannabidiol (CBD)-enriched cannabis, a plant based product without psychoactive properties which has been shown to decrease seizure frequency in animal models. More recently, several randomized controlled and open label trials have studied the effects of Epidiolex, a 99% pure oral CBD extract, on patients with refractory epilepsy. This in turn has led to the FDA approval of and more recently, to the Drug Enforcement Administration’s placement of Epidiolex into schedule V of the Controlled Substances Act (CSA). In this review, we summarize the major findings of several recent large-scale studies using this product with a focus on its adverse effects.”

https://www.ncbi.nlm.nih.gov/pubmed/30854190

“The recent FDA approval of Epidiolex combined with the placement of this compound in schedule V of the CSA (the least restrictive schedule of the CSA) has created a much-needed opportunity for the continued study of high-concentration, regulated CBD as a potential therapy for refractory epilepsy. Although recent RCTs and open-label extended-access programs have already demonstrated significant improvement in seizure frequency and severity with a relatively well-tolerated side effect profile for this compound, continued monitoring of Epidiolex is needed to further asses the long-term safety and efficacy, particularly with regard to immune, cognitive, hormonal, and reproductive function. Furthermore, there have been no large-scale RCTs demonstrating significant seizure reduction with Epidiolex in patients with focal onset seizures. Nonetheless, to date, Epidiolex has proven to be an attractive treatment option for an otherwise devastating group of epileptic syndromes. Future studies expanding our knowledge of this compound will be helpful in better understanding its role in the future of epilepsy treatment.”  https://f1000research.com/articles/8-234/v1

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The Endocannabinoid System and Cannabidiol’s Promise for the Treatment of Substance Use Disorder.

 Related image“Substance use disorder is characterized by repeated use of a substance, leading to clinically significant distress, making it a serious public health concern. The endocannabinoid system plays an important role in common neurobiological processes underlying substance use disorder, in particular by mediating the rewarding and motivational effects of substances and substance-related cues. In turn, a number of cannabinoid drugs (e.g., rimonabant, nabiximols) have been suggested for potential pharmacological treatment for substance dependence. Recently, cannabidiol (CBD), a non-psychoactive phytocannabinoid found in the cannabis plant, has also been proposed as a potentially effective treatment for the management of substance use disorder. Animal and human studies suggest that these cannabinoids have the potential to reduce craving and relapse in abstinent substance users, by impairing reconsolidation of drug-reward memory, salience of drug cues, and inhibiting the reward-facilitating effect of drugs. Such functions likely arise through the targeting of the endocannabinoid and serotonergic systems, although the exact mechanism is yet to be elucidated. This article seeks to review the role of the endocannabinoid system in substance use disorder and the proposed pharmacological action supporting cannabinoid drugs’ therapeutic potential in addictions, with a focus on CBD. Subsequently, this article will evaluate the underlying evidence for CBD as a potential treatment for substance use disorder, across a range of substances including nicotine, alcohol, psychostimulants, opioids, and cannabis. While early research supports CBD’s promise, further investigation and validation of CBD’s efficacy, across preclinical and clinical trials will be necessary.”

https://www.ncbi.nlm.nih.gov/pubmed/30837904

https://www.frontiersin.org/articles/10.3389/fpsyt.2019.00063/full

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The Relationship between Marijuana Use Prior to Sex and Sexual Function in Women.

Sexual Medicine Open Access - Click here to go back to the homepage

“Scientific research on the effects of marijuana on sexual functioning in women, including libido, arousal, orgasm, and satisfaction, is limited.

AIM:

To evaluate women’s perceptions of the effect of marijuana use before sexual activity.

METHODS:

A cross-sectional design, from March 2016-February 2017, within a single, academic, obstetrics and gynecology practice, was performed. Patients were given a questionnaire at their visit and asked to complete it anonymously and place it in a locked box after their visit.

MAIN OUTCOME MEASURES:

The primary outcome was satisfaction in the sexual domains of drive, orgasm, lubrication, dyspareunia, and overall sexual experience. The secondary outcome was the effect of the frequency of marijuana use on satisfaction.

RESULTS:

Of the 373 participants, 34.0% (n = 127) reported having used marijuana before sexual activity. Most women reported increases in sex drive, improvement in orgasm, decrease in pain, but no change in lubrication. After adjusting for race, women who reported marijuana use before sexual activity had 2.13 higher odds of reporting satisfactory orgasms (adjusted odds ratio = 2.13; 95% CI = 1.05, 4.35) than women who reported no marijuana use. After adjusting for race and age, women with frequent marijuana use, regardless of use before sex or not, had 2.10 times higher odds of reporting satisfactory orgasms than those with infrequent marijuana use (adjusted odds ratio = 2.10; 95% CI = 1.01-4.44).

CONCLUSION:

Marijuana appears to improve satisfaction with orgasm. A better understanding of the role of the endocannabinoid system in women is important, because there is a paucity of literature, and it could help lead to development of treatments for female sexual dysfunction. ”

https://www.ncbi.nlm.nih.gov/pubmed/30833225

https://www.smoa.jsexmed.org/article/S2050-1161(19)30009-1/fulltext

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Second Cannabinoid Receptor Has the Yin to the First Receptor’s Yang

“Understanding the diverse effects that cannabis has on the human body is imperative if we hope to take advantage of its medicinal properties to treat various disorders. As such, elucidating the molecular structure of the receptors that bind endocannabinoids is a critical step toward developing selective drugs that can differentiate between the two known receptors—CB1 and CB2—for these molecules. Since the structure of the CB1 receptor was resolved a few years ago, an international team of researchers led by scientists at the iHuman Institute within ShanghaiTech University has just published the crystal structure of the human type 2 cannabinoid receptor, CB2.

Findings from the new study—published recently in Cell through an article titled “Crystal Structure of the Human Cannabinoid Receptor CB2”—should be helpful in the development of drugs against inflammatory, neurodegenerative, and other diseases. The study authors compared the newly discovered structure to that of the CB1 receptor, deeming the two receptors to be the “yin and yang” of the human endocannabinoid system.”

“Crystal Structure of the Human Cannabinoid Receptor CB1” https://www.cell.com/fulltext/S0092-8674(16)31385-X
“Crystal Structure of the Human Cannabinoid Receptor CB2” https://www.cell.com/cell/pdf/S0092-8674(18)31625-8.pdf
“This study compares newly discovered structures to those of the CB1 receptor, and deems the two receptors to be the Yin and Yang of the human endocannabinoid system, which is a signalling system that regulates biological processes such as pain, immune function, metabolism, and neuronal activities among others.” https://www.worldhealth.net/news/ying-yang-second-cannabinoid-receptor/
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