“The increase in lifespan during the last 50 years, mainly in developed countries, has originated a progressive elevation in the incidence of chronic neurodegenerative disorders, for which aging is the key risk factor. This fact will definitively become the major biomedical challenge during the present century, in part because the expectation of a persisting elevation in the population older than 65 years over the whole population and, on the other hand, because the current lack of efficacious therapies to control these disorders despite years of intense research. This chapter will address this question and will stress the urgency of developing better neuroprotective and neurorepair strategies that may delay/arrest the progression of these disorders, reviewing the major needs to solve the causes proposed for the permanent failures experienced in recent years, e.g., to develop multitarget strategies, to use more predictive experimental models, and to identify early disease biomarkers. This chapter will propose the cannabinoids and their classic (e.g., endocannabinoid receptors and enzymes) and nonclassic (e.g., peroxisome proliferator-activated receptors, transcription factors) targets as a useful strategy for developing novel therapies for these disorders, based on their broad-spectrum neuroprotective profile, their activity as an endogenous protective system, the location of the endocannabinoid targets in cell substrates critical for neuronal survival, and their ability to serve for preservation and rescue, but also for repair and/or replacement, of neurons and glial cells against cytotoxic insults.” https://www.ncbi.nlm.nih.gov/pubmed/28750802 http://www.sciencedirect.com/science/article/pii/S0076687917301787?via%3Dihub]]>
Endocannabinoid Transport Proteins: Discovery of Tools to Study Sterol Carrier Protein-2.
“The endocannabinoid (eCB) neurotransmitter system regulates diverse neurological functions including stress and anxiety, pain, mood, and reward. Understanding the mechanisms underlying eCB regulation is critical for developing targeted pharmacotherapies to treat these and other neurologic disorders. Cellular studies suggest that the arachidonate eCBs, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), are substrates for intracellular binding and transport proteins, and several candidate proteins have been identified. Initial evidence from our laboratory indicates that the lipid transport protein, sterol carrier protein 2 (SCP-2), binds to the eCBs and can regulate their cellular concentrations. Here, we present methods for evaluating SCP-2 binding of eCBs and their application to the discovery of the first inhibitor lead molecules. Using a fluorescent probe displacement assay, we found SCP-2 binds the eCBs, AEA (Ki=0.68±0.05μM) and 2-AG (Ki=0.37±0.02μM), with moderate affinity. A series of structurally diverse arachidonate analogues also bind SCP-2 with Ki values between 0.82 and 2.95μM, suggesting a high degree of tolerance for arachidonic acid head group modifications in this region of the protein. We also report initial structure-activity relationships surrounding previously reported inhibitors of Aedis aegypti SCP-2, and the results of an in silico high-throughput screen that identified structurally novel SCP-2 inhibitor leads. The methods and results reported here provide the basis for a robust probe discovery effort to fully elucidate the role of facilitated transport mediated by SCP-2 in eCB regulation and function.” https://www.ncbi.nlm.nih.gov/pubmed/28750817 http://www.sciencedirect.com/science/article/pii/S007668791730174X?via%3Dihub ]]>
Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition.
“The endocannabinoid system plays a role in regulating bone mass and bone cell activity and inactivation of the type 1 (Cnr1) or type 2 (Cnr2) cannabinoid receptors influences peak bone mass and age-related bone loss. As the Cnr1 and Cnr2 receptors have limited homology and are activated by different ligands, we have evaluated the effects of combined deficiency of Cnr1 and 2 receptors (Cnr1/2-/- ) on bone development from birth to old age and studied ovariectomy induced bone loss in female mice. The Cnr1/2-/- mice had accelerated bone accrual at birth when compared with wild type littermates, and by 3 months of age, they had higher trabecular bone mass. They were also significantly protected against ovariectomy-induced bone loss due to a reduction in osteoclast number. The Cnr1/2-/- mice had reduced age-related bone loss when compared with wild-type due to a reduction in osteoclast number. Although bone formation was reduced and bone marrow adiposity increased in Cnr1/2-/- mice, the osteoclast defect outweighed the reduction in bone formation causing preservation of bone mass with aging. This contrasts with the situation previously reported in mice with inactivation of the Cnr1 or Cnr2 receptors individually where aged-related bone loss was greater than in wild-type. We conclude that the Cnr1 and Cnr2 receptors have overlapping but nonredundant roles in regulating osteoclast and osteoblast activities. These observations indicate that combined inhibition of Cnr1 and Cnr2 receptors may be beneficial in preventing age-related bone loss, whereas blockade of individual receptors may be detrimental.” https://www.ncbi.nlm.nih.gov/pubmed/28752643 http://onlinelibrary.wiley.com/doi/10.1111/acel.12638/abstract]]>
Going to pot? The impact of dispensary closures on crime☆
“Jurisdictions that sanction medical or, more recently, recreational marijuana use often allow retail sales at dispensaries. Dispensaries are controversial as many believe they contribute to local crime. To assess this claim, we analyze the short-term mass closing of hundreds of medical marijuana dispensaries in Los Angeles.
Contrary to popular wisdom, we find an immediate increase in crime around dispensaries ordered to close relative to those allowed to remain open. The increase is specific to the type of crime most plausibly deterred by bystanders, and is correlated with neighborhood walkability. We find a similar pattern of results for temporary restaurant closures due to health code violations. A likely common mechanism is that “eyes upon the street” deter some types of crime.”“Closing medical marijuana dispensaries increases crime, according to new study. Contrary to popular belief, medical marijuana dispensaries (MMDs) reduce crime in their immediate areas, suggests a new report.” https://www.sciencedaily.com/releases/2017/07/170711125704.htm
Integrating Endocannabinoid Signaling and Cannabinoids into the Biology and Treatment of Posttraumatic Stress Disorder.
“Exposure to stress is an undeniable, but in most cases surmountable, part of life. However, in certain individuals, exposure to severe or cumulative stressors can lead to an array of pathological conditions including posttraumatic stress disorder (PTSD), characterized by debilitating trauma-related intrusive thoughts, avoidance behaviors, hyperarousal, as well as depressed mood and anxiety. In the context of the rapidly changing political and legal landscape surrounding use of cannabis products in the United States, there has been a surge of public and research interest in the role of cannabinoids in the regulation of stress-related biological processes and in their potential therapeutic application for stress-related psychopathology. Here we review the current state of knowledge regarding the effects of cannabis and cannabinoids in PTSD and the preclinical and clinical literature on the effects of cannabinoids and endogenous cannabinoid signaling systems in the regulation of biological processes related to the pathogenesis of PTSD. Potential therapeutic implications of the reviewed literature are also discussed. Lastly, we propose that a state of endocannabinoid deficiency could represent a stress-susceptibility endophenotype predisposing to the development of trauma-related psychopathology and provide biologically plausible support for the self-medication hypotheses used to explain high rates of cannabis use in patients with trauma-related disorders.” https://www.ncbi.nlm.nih.gov/pubmed/28745306 https://www.nature.com/npp/journal/vaop/naam/abs/npp2017162a.html]]>
The endocannabinoid system expression in the female reproductive tract is modulated by estrogen.
“The endocannabinoid system (ECS) is involved in several physiological events that resulted in a growing interest in its modulation. Moreover, the uterine levels of anandamide (AEA), the major endocannabinoid, must be tightly regulated to create proper embryo implantation conditions. However, there are no evidences about the regulation of AEA in uterus by estrogen. Thus, the aim of this study is to elucidate whether estradiol benzoate (EB) and tamoxifen (TAM) administration to ovariectomized (OVX) rats can induce changes in the expression of cannabinoid receptors and AEA-metabolic enzymes in uterus by evaluating gene transcription and protein levels by qPCR, Western blot and immunohistochemistry. In summary, these data collectively indicate that the expression of ECS components, as well as, the AEA and PGE2 levels in rat uterus is modulated by EB. Thus, estradiol may have a direct regulatory role in the modulation of ECS in female reproductive tissues.” https://www.ncbi.nlm.nih.gov/pubmed/28743542 http://linkinghub.elsevier.com/retrieve/pii/S0960076017301887]]>
Cannabidiol reduces seizure frequency in Dravet syndrome
“Cannabidiol is effective in treating drug-resistant seizures in Dravet syndrome, according to a new clinical trial. For the first time, a multinational, randomized, double-blind, placebo-controlled trial has confirmed controversial anecdotal evidence supporting the efficacy of cannabinoids in epilepsy.” https://www.nature.com/nrneurol/journal/v13/n7/full/nrneurol.2017.86.html
“Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome” http://www.nejm.org/doi/10.1056/NEJMoa1611618
“Cannabinoids for Epilepsy — Real Data, at Last” http://www.nejm.org/doi/full/10.1056/NEJMe1702205
]]>Fewer Seizures With Cannabidiol in Catastrophic Epilepsy
“Cannabidiol reduced the frequency of convulsive seizures compared with placebo in Dravet syndrome, a childhood epilepsy disorder with a high mortality rate and no approved treatment in the United States, reported a clinical trial in the New England Journal of Medicine.” http://jamanetwork.com/journals/jama/fullarticle/2645099
“Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome” http://www.nejm.org/doi/full/10.1056/NEJMoa1611618#t=abstract
“EPILEPSY AND MARIJUANA: CANNABIS DRUG REDUCES DRAVET SYNDROME SEIZURES IN LARGE-SCALE CLINICAL TRIAL” http://www.newsweek.com/cannabis-marijuana-dravet-syndrome-epilepsy-clinical-trial-614982]]>The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model.
“The lipophilic phytocannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) show therapeutic efficacy in various medical conditions. Both molecules are poorly water soluble and subjected to extensive first pass metabolism in the gastrointestinal tract, leading to a limited oral bioavailability of approximately 9%. We have developed an advanced lipid based Self-Emulsifying Drug Delivery System termed Advanced Pro-NanoLiposphere (PNL) pre-concentrate. The PNL is composed of lipid and emulsifying excipients of GRAS status and are known to increase solubility and reduce Phase I metabolism of lipophilic active compounds. Advanced PNLs are PNLs with an incorporated natural absorption enhancers. These molecules are natural alkaloids and phenolic compounds which were reported to inhibit certain phase I and phase II metabolism processes. Here we use piperine, curcumin and resveratrol to formulate the Advanced-PNL formulations. Consequently, we have explored the utility of these Advanced-PNLs on CBD and THC oral bioavailability. Oral administration of CBD-piperine-PNL resulted in 6-fold in AUC compared to CBD solution, proving to be the most effective of the screened formulations. The same trend was found in pharmacokinetic experiments of THC-piperine-PNL with resulted in a 9.3-fold increase in AUC as compared to THC solution. Our Piperine-PNL can be used as a platform for synchronized delivery of piperine and CBD or THC to the enterocyte site. This co-localization provides an increase in CBD and THC bioavailability by its effect at the pre-enterocyte and the enterocyte levels of the absorption process. The extra augmentation in the absorption of CBD and THC by incorporating piperine into PNL is attributed to the inhibition of Phase I and phase II metabolism by piperine in addition to the Phase I metabolism and P-gp inhibition by PNL. These novel results pave the way to utilize piperine-PNL delivery system for other poorly soluble, highly metabolized compounds that currently cannot be administered orally.” https://www.ncbi.nlm.nih.gov/pubmed/28736128 http://www.sciencedirect.com/science/article/pii/S0928098717304025]]>
Associations between Adolescent Cannabis Use and Neuropsychological Decline: A Longitudinal Co-Twin Control Study.
“This study tested whether adolescents who used cannabis or met criteria for cannabis dependence showed neuropsychological impairment prior to cannabis initiation and neuropsychological decline from before to after cannabis initiation.