Author Archives: David Worrell

Cannabidiol alleviates hemorrhagic shock-induced neural apoptosis in rats by inducing autophagy through activation of the PI3K/AKT pathway.

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Publication cover image“Recently, several studies have reported that the pharmacological effects exerted by cannabidiol (CBD) are partially related to the regulation of autophagy. Increasing evidence indicates that autophagy provides protection against ischemia-induced brain injury. However, the protective effect of CBD against mitochondrial-dependent apoptosis in hemorrhagic shock (HS)-induced brain injury has not been studied.

In the present study, we observed the protective effects of CBD against neural mitochondrial-dependent apoptosis in a rat model of HS. In addition, CBD increased Beclin-1 and LC3II expression and reduced P62 expression, which were indicative of autophagy. CBD treatment attenuated the neural apoptosis induced by HS, as reflected by restoring mitochondrial dysfunction, downregulation of BAX, neuro-apoptosis ratio and NF-κB signaling activation, and upregulation of BCL2 in the cerebral cortex.

Such protective effects were reversed by 3-Methyladenine, a specific autophagy inhibitor, indicating that the protective effects of CBD treatment involved autophagy. LY294002, a PI3K inhibitor, significantly inhibited CBD-induced autophagy, demonstrating that PI3K/AKT signaling is involved in the CBD’s regulation of autophagy. Furthermore, we found that CBD treatment upregulated PI3K/AKT signaling via cannabinoid receptor 1.

Therefore, these findings suggested that CBD treatment protects against cerebral injury induced by HS-mediated mitochondrial-dependent apoptosis by activating the PI3K/AKT signaling pathway to reinforce autophagy.”

https://www.ncbi.nlm.nih.gov/pubmed/32215966

https://onlinelibrary.wiley.com/doi/abs/10.1111/fcp.12557

“Hemorrhagic shock occurs when the body begins to shut down due to large amounts of blood loss.” https://www.healthline.com/health/hemorrhagic-shock

Cannabidiol in sport : ergogenic or else?

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Pharmacological Research“In the sports domain, cannabis is prohibited by the World Anti-Doping Agency (WADA) across all sports in competition since 2004. The few studies on physical exercise and cannabis focused on the main compound i.e. Δ9-tetrahydrocannabinol. Cannabidiol (CBD) is another well-known phytocannabinoid present in dried or heated preparations of cannabis. Unlike Δ9-tetrahydrocannabinol, CBD is non-intoxicating but exhibits pharmacological properties that are interesting for medical use.

The worldwide regulatory status of CBD is complex and this compound is still a controlled substance in many countries. Interestingly, however, the World Anti-Doping Agency removed CBD from the list of prohibited substances – in or out of competition – since 2018. This recent decision by the WADA leaves the door open for CBD use by athletes.

In the present opinion article we wish to expose the different CBD properties discovered in preclinical studies that could be further tested in the sport domain to ascertain its utility. Preclinical studies suggest that CBD could be useful to athletes due to its anti-inflammatory, analgesic, anxiolytic, neuroprotective properties and its influence on the sleep-wake cycle. Unfortunately, almost no clinical data are available on CBD in the context of exercise, which makes its use in this context still premature.”

https://www.ncbi.nlm.nih.gov/pubmed/32205233

“Athletes could benefit from CBD to manage pain, inflammation and the swelling processes associated with injury. CBD could be useful to manage anxiety, fear memory process, sleep and sleepiness in athletes. CBD could be interesting for the management of mild traumatic brain injury and chronic traumatic encephalopathy.”

https://www.sciencedirect.com/science/article/abs/pii/S1043661819326143?via%3Dihub

Effects of dietary hemp seed oil to sows on fatty acid profiles, nutritional and immune status of piglets.

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Image result for journal of animal science and biotechnology“The oil from industrial hemp seeds (Cannabis sativa) is an ideal source of stearidonic acid, which is a precursor fatty acid for the long-chained n-3 polyunsaturated fatty acids. These fatty acids are important for neonatal development, health and immunity.

Hemp seed oil has been investigated for the influence on human health, but research on the impact in pig nutrition is scarce. The aim of our research was to study the effect of dietary hemp seed oil relative to soybean oil to lactating sows on the transfer of fatty acids to the off-spring and the effect on piglets’ immune and nutritional status.

The hemp seed oil resulted in direct maternal supply with n-3 long-chain polyunsaturated fatty acids (LCPUFA), especially ALA and SDA, and piglets were able to convert these fatty acids obtained via the sow milk intake to C20:5n-3 and C22:5n-3. Furthermore, some interesting effects of the 5% hemp seed oil was obtained with regard to piglet initial body weight gain and glucose, which could be of interest for further research, i.e., the capability of hemp seed oil to benefit piglets during early life.”

https://www.ncbi.nlm.nih.gov/pubmed/32206310

“Our research demonstrated that colostrum and milk fatty acid composition and immunoglobulin concentration, as well as fatty acid profile of sows’ and piglets’ plasma, were influenced by the fatty acid composition of the maternal diets provided during late gestation and lactation. The hemp seed oil resulted in direct maternal supply with n-3 LCPUFAs, especially ALA and SDA, and piglets were able to convert these fatty acids obtained via the sow milk intake to C20:5n-3 and C22:5n-3.”

https://jasbsci.biomedcentral.com/articles/10.1186/s40104-020-0429-3

CSF levels of the endocannabinoid anandamide are reduced in patients with untreated narcolepsy type 1: a pilot study.

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“The endocannabinoid system (ECs) is involved in excitatory/inhibitory balance mechanisms within the CNS.

Growing evidence shows that endocannabinoids may influence both hypothalamic orexinergic and histaminergic neurons involved in narcolepsy physiopathology, thus indicating that endocannabinoids may play an intrinsic role modulating sleep and wake.

We hypothesize that the endocannabinoid system is dysregulated in narcolepsy type 1 (NT1).”

https://www.ncbi.nlm.nih.gov/pubmed/32148204

http://www.eurekaselect.com/180033/article

“Taking together, these findings suggest that CBD might prevent sleepiness in narcolepsy.” https://www.ncbi.nlm.nih.gov/pubmed/31642794

Endocannabinoid system and cardiometabolic risk factors: A comprehensive systematic review insight into the mechanistic effects of omega-3 fatty acids.

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Life Sciences“Increased levels of endocannabinoids, 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamide (AEA) have a pathophysiological role in the setting of cardiometabolic diseases. This systematic review was carried out to appraise the effect of omega-3 on cardiometabolic risk factors by highlighting the mediating effect of endocannabinoids.

Eleven animal studies and two human studies showed a marked reduction in 2-AG and AEA levels following intake of omega-3 which correlated with decreased adiposity, weight gain and improved glucose homeostasis. Moreover, endocannabinoids were elevated in three studies that replaced omega-3 with omega-6.

Omega-3 showed anti-inflammatory properties due to reduced levels of inflammatory cytokines, regulation of T-cells function and increased levels of eicosapentaenoyl ethanolamide, docosahexaenoyl ethanolamide and oxylipins; however, a limited number of studies examined a correlation between inflammatory cytokines and endocannabinoids following omega-3 administration.

In conclusion, omega-3 modulates endocannabinoid tone, which subsequently attenuates inflammation and cardiometabolic risk factors. However, further randomized clinical trials are needed before any recommendations are made to target the ECS using omega-3 as an alternative therapy to drugs for cardiometabolic disease improvement.”

https://www.ncbi.nlm.nih.gov/pubmed/32184122

“Endocannabinoid system (ECS) may mediate favorable effects of omega-3 fatty acids in cardiometabolic disorders. Omega-3 fatty acids showed anti-inflammatory effects due to increased levels of ethanolamide and oxylipins. Plant-derived omega-3 may be as effective as animal-derived omega-3 in ECS modulation. Omega-3 may have a potential to be an alternative to drugs for cardiometabolic disease improvement.”

https://www.sciencedirect.com/science/article/abs/pii/S0024320520303040?via%3Dihub

The molecular mechanisms that underpin the biological benefit of full spectrum cannabis extract in the treatment of neuropathic pain and inflammation.

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Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease“Cannabis has been shown to be beneficial in the treatment of pain and inflammatory diseases.

The biological effect of cannabis is mainly attributed to two major cannabinoids, tetrahydrocannabinol and cannabidiol. In the majority of studies to-date, a purified tetrahydrocannabinol and cannabidiol alone or in combination have been extensively examined in many studies for the treatment of numerous disorders including pain and inflammation. However, few studies have investigated the biological benefits of full-spectrum cannabis plant extract.

Given that cannabis is known to generate a large number of cannabinoids along with numerous other biologically relevant products including terpenes, studies involving purified tetrahydrocannabinol and/or cannabidiol may not precisely consider the potential biological benefits of the full-spectrum cannabis extracts. This may be especially true in the role of cannabis as a treatment of pain and inflammation. Herein, we review the pre-clinical physiological and molecular mechanisms in biological systems that are affected by cannabis.”

https://www.ncbi.nlm.nih.gov/pubmed/32201189

“Full-spectrum cannabis extract demonstrates several convincing beneficial anti-inflammatory and analgesic effects in preclinical studies. Full-spectrum cannabis extract may represent a promising therapeutic agent that seems to benefit a variety of conditions associated with pain and inflammation.”

https://www.sciencedirect.com/science/article/abs/pii/S0925443920301162?via%3Dihub

The endocannabinoid system modulates the ovarian physiology and its activation can improve in vitro oocyte maturation.

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Publication cover image“The present study investigated the effect of the lack of CB1 and CB2 receptors in mice ovarian morphology, folliculogenesis, oocyte retrieval, and oocyte maturation and evaluated the use of Δ9-tetrahydrocannabinol (THC) on oocyte in vitro maturation (IVM) by comparing classical IVM and two-step IVM by analyzing the meiotic competence of the oocytes and their evolution toward embryos.

Thus, when CB1 and CB2 receptors were missed, the ovary area and volume was significantly less and the action of the equine chorionic gonadotropin (eCG) hormone was diminished.

In addition, the mutant genotypes had fewer ovarian follicles and they were less competent after eCG administration compared with wild-type mice, and this lack of CB receptors showed a mismatch of oocyte maturation.

However, the in vitro use of THC showed improvements in oocytes IVM after a Pre-IVM step for 48 hr, as those oocytes reached a significantly higher polar body rate, a larger diameter and the best result on blastocysts rate was achieved when THC was used during the IVM step.”

https://www.ncbi.nlm.nih.gov/pubmed/32198753

https://onlinelibrary.wiley.com/doi/abs/10.1002/jcp.29663

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

2-Arachidonoylglycerol Modulation of Anxiety and Stress Adaptation: From Grass Roots to Novel Therapeutics.

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Biological Psychiatry Home“Over the past decade there has been a surge of interest in the development of endocannabinoid-based therapeutic approaches for the treatment of diverse neuropsychiatric conditions. Although initial preclinical and clinical development efforts focused on pharmacological inhibition of fatty acid amide hydrolase to elevate levels of the endocannabinoid anandamide, more recent efforts have focused on inhibition of monoacylglycerol lipase (MAGL) to enhance signaling of the most abundant and efficacious endocannabinoid ligand, 2-arachidonoylglycerol (2-AG). We review the biochemistry and physiology of 2-AG signaling and preclinical evidence supporting a role for this system in the regulation of anxiety-related outcomes and stress adaptation. We review preclinical evidence supporting MAGL inhibition for the treatment of affective, trauma-related, and stress-related disorders; describe the current state of MAGL inhibitor drug development; and discuss biological factors that could affect MAGL inhibitor efficacy. Issues related to the clinical advancement of MAGL inhibitors are also discussed. We are cautiously optimistic, as the field of MAGL inhibitor development transitions from preclinical to clinical and theoretical to practical, that pharmacological 2-AG augmentation could represent a mechanistically novel therapeutic approach for the treatment of affective and stress-related neuropsychiatric disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/32197779

https://www.biologicalpsychiatryjournal.com/article/S0006-3223(20)30049-4/fulltext

Phytocannabinoids: Useful Drugs for the Treatment of Obesity? Special Focus on Cannabidiol.

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Image result for frontiers in endocrinology

“Currently, an increasing number of diseases related to insulin resistance and obesity is an alarming problem worldwide. It is well-known that the above states can lead to the development of type 2 diabetes, hypertension, and cardiovascular diseases. An excessive amount of triacylglycerols (TAGs) in a diet also evokes adipocyte hyperplasia and subsequent accumulation of lipids in peripheral organs (liver, cardiac muscle). Therefore, new therapeutic methods are constantly sought for the prevention, treatment and alleviation of symptoms of the above mentioned diseases.

Currently, much attention is paid to Cannabis derivatives-phytocannabinoids, which interact with the endocannabinoid system (ECS) constituents. Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the most abundant compounds of Cannabis plants and their therapeutic application has been suggested. CBD is considered as a potential therapeutic agent due to its anti-inflammatory, anti-oxidant, anti-tumor, neuroprotective, and potential anti-obesity properties. Therefore, in this review, we especially highlight pharmacological properties of CBD as well as its impact on obesity in different tissues.”

https://www.ncbi.nlm.nih.gov/pubmed/32194509

“A well-known ancient plant Cannabis sativa has been a subject of scientific interest for over 50 years. Moreover, it has been used for recreational and medical purposes for thousands of years. The plant comprises about 100 phytocannabinoids, which are C21 terpenophenolic constituents. Nowadays, the most-studied phytocannabinoids are: Δ9– tetrahydrocannabinol (Δ9-THC), Δ9-tetrahydrocannabivarin (Δ9-THCV), cannabinol (CBN), cannabidiol (CBD), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC). So far, many studies have shown therapeutic properties of the above mentioned Cannabis compounds. Therefore, the aim of the current review is to focus on the emerging potential of CBD and other phytocannabinoids, which act as novel therapeutic agents in obesity treatment. From the existing data, we can conclude that CBD has the promising potential as a therapeutic agent and might be effective in alleviating the symptoms of insulin resistance, type 2 diabetes and metabolic syndrome.”

https://www.frontiersin.org/articles/10.3389/fendo.2020.00114/full

Marijuana, Ondansetron, and Promethazine Are Perceived as Most Effective Treatments for Gastrointestinal Nausea.

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 SpringerLink“Many anti-nausea treatments are available for chronic gastrointestinal syndromes, but data on efficacy and comparative effectiveness are sparse.

AIMS:

To conduct a sectional survey study of patients with chronic nausea to assess comparative effectiveness of commonly used anti-nausea treatments.

RESULTS:

One hundred and fifty-three patients completed the survey. The mean efficacy score of all anti-nausea treatments evaluated was 1.73. After adjustment, three treatments had scores statically higher than the mean, including marijuana (2.75, p < 0.0001), ondansetron (2.64, p < 0.0001), and promethazine (2.46, p < 0.0001). Several treatments, including many neuromodulators, complementary and alternative treatments, erythromycin, and diphenhydramine had scores statistically below average. Patients with more severe nausea responded better to marijuana (p = 0.036) and diphenhydramine (p < 0.001) and less so to metoclopramide (p = 0.020). There was otherwise no significant differential response by age, gender, nausea localization, underlying gastrointestinal cause of nausea, and GCSI.

CONCLUSIONS:

When treating nausea in patients with chronic gastrointestinal syndromes, clinicians may consider trying higher performing treatments first, and forgoing lower performing treatments. Further prospective research is needed, particularly with respect to highly effective treatments.”

https://www.ncbi.nlm.nih.gov/pubmed/32185665

https://link.springer.com/article/10.1007%2Fs10620-020-06195-5