Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment.

Biochemical Pharmacology“Gestational methylazoxymethanol acetate (MAM) treatment produces offspring with adult phenotype relevant to schizophrenia, including positive- and negative-like symptoms, cognitive deficits, dopaminergic dysfunction, structural and functional abnormalities.

Here we show that adult rats prenatally treated with MAM at gestational day 17 display significant increase in dopamine D3 receptor (D3) mRNA expression in prefrontal cortex (PFC), hippocampus and nucleus accumbens, accompanied by increased expression of dopamine D2 receptor (D2) mRNA exclusively in the PFC. Furthermore, a significant change in the blood perfusion at the level of the circle of Willis and hippocampus, paralleled by the enlargement of lateral ventricles, was also detected by magnetic resonance imaging (MRI) techniques.

Peripubertal treatment with the non-euphoric phytocannabinoid cannabidiol (30 mg/kg) from postnatal day (PND) 19 to PND 39 was able to reverse in MAM exposed rats: i) the up-regulation of the dopamine D3 receptor mRNA (only partially prevented by haloperidol 0.6 mg/kg/day); and ii) the regional blood flow changes in MAM exposed rats. Molecular modelling predicted that cannabidiol could bind preferentially to dopamine D3 receptor, where it may act as a partial agonist according to conformation of ionic-lock, which is higly conserved in GPCRs.

In summary, our results demonstrate that the mRNA expression of both dopamine D2 and D3 receptors is altered in the MAM model; however only the transcript levels of D3 are affected by cannabidiol treatment, likely suggesting that this gene might not only contribute to the schizophrenia symptoms but also represent an unexplored target for the antipsychotic activity of cannabidiol.”

https://www.ncbi.nlm.nih.gov/pubmed/32360362

https://www.sciencedirect.com/science/article/abs/pii/S000629522030232X?via%3Dihub

SARS-CoV2 induced respiratory distress: Can Cannabinoids be added to anti-viral therapies to reduce lung inflammation?

Brain, Behavior, and Immunity“Coronavirus disease-2019 (COVID-19), caused by Severe Acute Respiratory Syndrome coronoavirus-2 (SARS-CoV2) has emerged as a global pandemic, which was first reported in Wuhan, China. Recent reports have suggested that acute infection is associated with a cytokine superstorm, which contributes to the symptoms of fever, cough, muscle pain and in severe cases bilateral interstitial pneumonia characterized by ground glass opacity and focal chest infiltrates that can be visualized on computerized tomography scans. Currently, there are no effective antiviral drugs or vaccines against SARS-CoV2. In the recent issue of BBI, Zhang et al. thoroughly summarized the current status of potential therapeutic strategies for COVID-19. One of them, anti-IL6 receptor (Tocilizumab) antibody, resulted in clearance of lung consolidation and recovery in 90% of the 21 treated patients. Although promising, it has also produced adverse effects like pancreatitis and hypertriglyceridemia, which make it imperative to explore effective alternative anti-inflammatory strategies. Here, we intend to highlight the potential effects of cannabinoids, in particular, the non-psychotropic cannabidiol (CBD), that has shown beneficial anti-inflammatory effects in pre-clinical models of various chronic inflammatory diseases and is FDA approved for seizure reduction in children with intractable epilepsy.

Like Δ9-tetrahydrocannabinol (Δ9-THC), the most well-studied cannabinoid, CBD decreased lung inflammation in a murine model of acute lung injury potentially through the inhibition of proinflammatory cytokine production by immune cells and suppressing exuberant immune responses. CBD can inhibit the production of proinflammatory cytokines like interleukin (IL)-2, IL-6, IL-1α and β, interferon gamma, inducible protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein-1α, and tumor necrosis factor-α that have been associated with SARS-CoV2 induced multi-organ pathology and mortality. In a murine model of chronic asthma, CBD reduced proinflammatory cytokine production, airway inflammation and fibrosis. Moreover, CBD can effectively inhibit the JAK-STAT pathway including the production and action of type I interferons without leading to addiction, alterations in heart rate or blood pressure and adverse effects on the gastrointestinal tract and cognition. In simian immunodeficiency virus (SIV)-infected rhesus macaques (RMs), we reported THC mediated attenuation of IFN stimulated gene expression in the intestine. Similar to CBD, chronic THC administration blocked inflammation induced fibrosis in lymph nodes of chronically SIV-infected RMs. Unlike THC, CBD has a high margin of safety and is well tolerated pharmacologically even after treatments of up to 1500 mg/day for two weeks in both animals and humans, which suggests its feasibility to reduce SARS-CoV2 induced lung inflammation/pathology and disease severity.

The many uncertainties associated with the COVID-19 pandemic such as status of the economy, employment and loss of connection can fuel depression, fear and anxiety. CBD has shown promise as an alternative therapy for the clinical management of anxiety disorders. Based on its anxiolytic and anti-depressant properties, it has been suggested that CBD could be used to improve the mental and somatic health of patients suffering from anxiety and emotional stress after recovering from Ebola disease. Like Ebola, patients recovering from COVID-19 may experience various psychological and social stressors that may be triggered by residual chronic inflammation and autoimmune reactions. Therefore, randomized clinical trials to test the efficacy of CBD on alleviating anxiety and fear associated with COVID-19 infection and its consequences on people’s physical, social and psychological well-being may be beneficial in the future. Additionally, severely ill COVID-19 patients exhibited neurological symptoms like cerebrovascular disease, headache and disturbed consciousness (Reviewed in. Brain edema, neuronal degeneration and presence of SARS-CoV2 in the cerebrospinal fluid (CSF) were confirmed at autopsy. Therefore, longitudinal CSF sampling using non-human primate (NHP) studies may help clarify whether and when SARS-CoV2 invades the brain, and if this happens, does it result in neuroinflammation and more importantly, whether cannabinoids can modulate these events.

Being a negative allosteric modulator of the cannabinoid receptor-1, CBD can counter the psychotropic effects of THC when co-administered with THC. Although Remdesivir reduced the mortality rate of seriously ill COVID-19 patients needing invasive ventilation, similar studies in rhesus macaques revealed minimal subpleural inflammatory cellular infiltrates in the lungs of clinically recovered Remdesivir treated RMs at necropsy. This suggests persistence of inflammation and may partly explain the 20–30% reduction in lung function in COVID-19 patients after recovery, which if left unresolved may lead to pulmonary fibrosis. Collectively, these findings support the investigation of cannabinoids as a plausible option to be added as an adjunct to Remdesivir or any new antivirals on SARS-CoV2 induced lung inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/32360437

https://www.sciencedirect.com/science/article/pii/S0889159120307078?via%3Dihub

“Cannabis Indica speeds up Recovery from Coronavirus”   https://www.researchgate.net/publication/339746853_Cannabis_Indica_speeds_up_Recovery_from_Coronavirus

Cannabidiol and Other Non-Psychoactive Cannabinoids for Prevention and Treatment of Gastrointestinal Disorders: Useful Nutraceuticals?

ijms-logo“Cannabis sativa is an aromatic annual flowering plant with several botanical varieties, used for different purposes, like the production of fibers, the production of oil from the seeds, and especially for recreational or medical purposes.

Phytocannabinoids (terpenophenolic compounds derived from the plant), include the well-known psychoactive cannabinoid Δ9-tetrahydrocannabinol, and many non-psychoactive cannabinoids, like cannabidiol.

The endocannabinoid system (ECS) comprises of endocannabinoid ligands, enzymes for synthesis and degradation of such ligands, and receptors. This system is widely distributed in the gastrointestinal tract, where phytocannabinoids exert potent effects, particularly under pathological (i.e., inflammatory) conditions.

Herein, we will first look at the hemp plant as a possible source of new functional food ingredients and nutraceuticals that might be eventually useful to treat or even prevent gastrointestinal conditions.

Subsequently, we will briefly describe the ECS and the general pharmacology of phytocannabinoids. Finally, we will revise the available data showing that non-psychoactive phytocannabinoids, particularly cannabidiol, may be useful to treat different disorders and diseases of the gastrointestinal tract.

With the increasing interest in the development of functional foods for a healthy life, the non-psychoactive phytocannabinoids are hoped to find a place as nutraceuticals and food ingredients also for a healthy gastrointestinal tract function.”

https://www.ncbi.nlm.nih.gov/pubmed/32357565

https://www.mdpi.com/1422-0067/21/9/3067

Novel approaches and current challenges with targeting the endocannabinoid system.

 Publication Cover“The pathophysiological relevance of the endocannabinoid system has been widely demonstrated in a variety of diseases including cancer, neurological disorders, and metabolic issues. Therefore, targeting the receptors and the endogenous machinery involved in this system can provide a successful therapeutic outcome.

Ligands targeting the canonical cannabinoid receptors, CB1 and CB2, along with inhibitors of the endocannabinoid enzymes have been thoroughly studied in diverse disease models. In fact, phytocannabinoids such as cannabidiol or Δ9-tetrahydrocannabinol are currently on the market for the management of neuropathic pain due to spasticity in multiple sclerosis or seizures in children epilepsy amongst others.

Expert opinion: Even if orthosteric CB1 and CB2 ligands are on the forefront in cannabinoid clinical research, emerging strategies such as allosteric or biased modulation of these receptors along with controlled off-targets effects may increase the therapeutic potential of cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/32336154

“Multi-target approaches could be promising strategies for the treatment of endocannabinoid system-related disorders. The authors believe that phytocannabinoids are at the forefront of future clinical research.”

https://www.tandfonline.com/doi/abs/10.1080/17460441.2020.1752178?journalCode=iedc20

Endocannabinoid-Mediated Neuromodulation in the Olfactory Bulb: Functional and Therapeutic Significance.

ijms-logo “Endocannabinoid synthesis in the human body is naturally occurring and on-demand.

It occurs in response to physiological and environmental stimuli, such as stress, anxiety, hunger, other factors negatively disrupting homeostasis, as well as the therapeutic use of the phytocannabinoid cannabidiol and recreational use of exogenous cannabis.

Together with their specific receptors CB1R and CB2R, endocannabinoids are major components of endocannabinoid-mediated neuromodulation in a rapid and sustained manner. Extensive research on endocannabinoid function and expression includes studies in limbic system structures such as the hippocampus and amygdala.

The wide distribution of endocannabinoids, their on-demand synthesis at widely different sites, their co-existence in specific regions of the body, their quantitative differences in tissue type, and different pathological conditions indicate their diverse biological functions that utilize specific and overlapping pathways in multiple organ systems.

Here, we review emerging evidence of these pathways with a special emphasis on the role of endocannabinoids in decelerating neurodegenerative pathology through neural networks initiated by cells in the main olfactory bulb.”

https://www.ncbi.nlm.nih.gov/pubmed/32325875

https://www.mdpi.com/1422-0067/21/8/2850

Cannabis Indica speeds up Recovery from Coronavirus

ResearchGate“Cannabis Indica Speeds up Recovery from Coronavirus Severe acute respiratory syndrome (SARS) is a viral respiratory disease caused by the SARS coronavirus (SARS-CoV).

Cannabis indica speeds up recovery.

Recovered individuals do not infect others.

Cannabis indica resin is antiviral and inhibits cell proliferation.

It has a higher efficacy than any single compound like THC or CBD”

https://www.researchgate.net/publication/339746853_Cannabis_Indica_speeds_up_Recovery_from_Coronavirus

Promising in vitro antioxidant, anti-acetylcholinesterase and neuroactive effects of essential oil from two non-psychotropic Cannabis sativa L. biotypes.

Phytotherapy Research“The aim of this study was to compare the micro-morphological features of two different non-drug Cannabis sativa L. biotypes (Chinese accession G-309 and one fibrante variety) and to evaluate the phytochemical profile as well as some biological properties of the essential oils (EOs) obtained by hydrodistillation of dried flowering tops. After a micro-morphological evaluation by scanning electron microscopy, the phytochemical composition was analysed by GC-FID and GC-MS analyses.

Antioxidant and anti-acetylcholinesterase properties were investigated by several in vitro cell-free assays, while neuroactive effects were evaluated on mouse cortical neuronal as well as human iPS cell-derived central nervous system cells grown on MEA chips. Both EOs showed strong antioxidant properties mainly attributable to the high content of hydroxylated compounds as well as significant anti-acetylcholinesterase activities (IC50 74.64 and 57.31 μg/ml for Chinese accession and fibrante variety, respectively).

Furthermore, they showed a concentration-dependent inhibition of spontaneous electrical activity of human and mouse neuronal networks, with the fibrante variety, which showed the best activity (MFR, IC50 0.71 and 10.60 μg/ml, respectively). The observed biological activities could be due to a synergic effect between terpenes and phytocannabinoids, although in vivo studies, which clarify the molecular mechanism, are still lacking.”

https://www.ncbi.nlm.nih.gov/pubmed/32309898

https://onlinelibrary.wiley.com/doi/abs/10.1002/ptr.6678

Epigenetic regulation of the cannabinoid receptor CB1 in an activity-based rat model of anorexia nervosa.

International Journal of Eating Disorders“Both environmental and genetic factors are known to contribute to the development of anorexia nervosa (AN), but the exact etiology remains poorly understood.

Herein, we studied the transcriptional regulation of the endocannabinoid system, an interesting target for body weight maintenance and the control of food intake and energy balance.

Among the evaluated endocannabinoid system components, we observed a selective and significant down-regulation of the gene encoding for the type 1 cannabinoid receptor (Cnr1) in ABA rats’ hypothalamus and nucleus accumbens and, in the latter area, a consistent, significant and correlated increase in DNA methylation at the gene promoter.

Our findings support a possible role for Cnr1 in the ABA animal model of AN. In particular, its regulation in the nucleus accumbens appears to be triggered by environmental cues due to the consistent epigenetic modulation of the promoter.

These data warrant further studies on Cnr1 regulation as a possible target for treatment of AN.”

https://www.ncbi.nlm.nih.gov/pubmed/32275093

https://onlinelibrary.wiley.com/doi/abs/10.1002/eat.23271

Synergistic cytotoxic activity of cannabinoids from cannabis sativa against cutaneous T-cell lymphoma (CTCL) in-vitro and ex-vivo.

 Peer-reviewed Oncology & Cancer Research Journal | Oncotarget“Cannabis sativa produces hundreds of phytocannabinoids and terpenes.

Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL), characterized by patches, plaques and tumors. Sézary is a leukemic stage of CTCL presenting with erythroderma and the presence of neoplastic Sézary T-cells in peripheral blood.

This study aimed to identify active compounds from whole cannabis extracts and their synergistic mixtures, and to assess respective cytotoxic activity against CTCL cells.

This mixture induced cell cycle arrest and cell apoptosis. Significant cytotoxic activity of the corresponding mixture of pure phytocannabinoids further verified genuine interaction between S4 and S5.

We suggest that specifying formulations of synergistic active cannabis compounds and unraveling their modes of action may lead to new cannabis-based therapies.”

https://www.ncbi.nlm.nih.gov/pubmed/32284791

“Cannabis sativa has been used by humanity for thousands of years. Various phytocannabinoids exhibit antitumor effects in a wide array of cell lines and animal models. We have shown that a certain synergistic mixture of phytocannabinoids derived from C. sativa extracts have significant cytotoxic activity against My-La and HuT-78 cell lines and against SPBL.

To conclude, active cannabis extract fractions and their synergistic combinations were cytotoxic to CTCL cell lines in in-vitro and to SPBL in ex-vivo studies. The defined S4+S5 formulation of synergistic phytocannabinoids induced cell cycle arrest and cell apoptosis, and affected multiple biological pathways, including those associated with cancer. Based on this pre-clinical study new cannabis-based products that are based on precise composition of synergistically interacting compounds may be developed.”

https://www.oncotarget.com/article/27528/text/

The effects of cannabinoids in exemestane-resistant breast cancer cells: PS181.

“Exemestane is one of the aromatase inhibitors (AI) used as first line treatment for estrogen-receptor positive breast cancer in post-menopausal women. Exemestane acts by inhibiting aromatase, the enzyme responsible for the conversion of androgens to estrogens and also by promoting apoptosis of breast cancer cells. Nevertheless, despite its therapeutic success, this AI, after prolonged treatment, can induce acquired resistance, which causes tumor relapse. Therefore, it is important to find new strategies to overcome resistance in order to improve breast cancer treatment.

Considering that the development of resistance is the main reason for endocrine treatment failure, our group decided to explore the ability of three cannabinoids, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) and anandamide (AEA), to reverse resistance to exemestane. The THC and CBD are phytocannabinoids derived from the plant Cannabis sativa (marijuana) whereas AEA is an endocannabinoid. For that, it was used LTEDaro cells, a long-term estrogen deprived ER+ breast cancer cell line that mimics resistance to exemestane. These cells were treated with exemestane in combination with two phytocannabinoids, CBD and THC, and the endocannabinoid AEA.

The presence of CB1 and CB2 in LTEDaro cells was confirmed by Western blot analysis and the effects of the combination of cannabinoids with exemestane were evaluated by MTT and LDH assays. Cell morphology was analyzed by Giemsa and Hoechst staining.

Results: Our results demonstrate that all the cannabinoids induce a decrease in viability of exemestane-resistant cells, in a dose- and time-dependent manner, without LDH release. These results indicate that the studied cannabinoids, mainly THC and AEA, revert the resistance to exemestane, probably by inducing apoptosis, as observed in Giemsa/Hoechst stain by the presence of typical morphological features of apoptosis.

Conclusion: This study highlights the efficacy of using cannabinoids as a potential adjuvant treatment to revert resistance to AIs.”

https://www.ncbi.nlm.nih.gov/pubmed/32258721

https://journals.lww.com/pbj/fulltext/2017/09000/The_effects_of_cannabinoids_in.118.aspx