“Cannabinoid-mediated memory impairment is a concern in cannabinoid-based therapies. Caffeine exacerbates cannabinoid CB1receptor (CB1R)-induced memory deficits through an adenosine A1 receptor-mediated mechanism. We now evaluated how chronic or acute blockade of adenosine A2A receptors (A2ARs) affects long-term episodic memory deficits induced by a single injection of a selective CB1R agonist. The finding that CB1R-mediated memory disruption is prevented by antagonism of adenosine A2ARs, highlights a possibility to prevent cognitive side effects when therapeutic application of CB1R drugs is desired.” https://www.ncbi.nlm.nih.gov/pubmed/28235548]]>
Category Archives: Uncategorized
FAAH inhibition produces antidepressant-like efforts of mice to acute stress via synaptic long-term depression.
“Recent studies have shown that inhibition of fatty acid amide hydrolase (FAAH), the major degradative enzyme of the endocannabinoid N-arachidonoylethanolamine (AEA), produced antidepressant behavioral responses, but its underlying mechanism is not clear. Here we find that a systemic administration of the FAAH inhibitor PF3845 or an intra-CA1 application of AEA elicits an in vivo long-term depression (LTD) at excitatory glutamatergic CA3-CA1 synapses of the hippocampus. The PF3845- and/or AEA-elicited LTD are abolished by the LTD-blocking peptide Tat-GluR2. PF3845 significantly decreases passive behavioral coping of naïve mice to acute inescapable stress, which is also abolished by Tat-GluR2 peptide. However, PF3845 does not significantly affect sucrose assumption ratio of mice receiving chronic administration of corticosterone. These results suggest that FAAH inhibitors are able to produce antidepressant effects in naïve animals in response to acute stress through LTD at hippocampal glutamatergic CA3-CA1 synapses.” https://www.ncbi.nlm.nih.gov/pubmed/28193523]]>
Leaner and greener analysis of cannabinoids
“There is an explosion in the number of labs analyzing cannabinoids in marijuana (Cannabis sativa L., Cannabaceae) but existing methods are inefficient, require expert analysts, and use large volumes of potentially environmentally damaging solvents. The objective of this work was to develop and validate an accurate method for analyzing cannabinoids in cannabis raw materials and finished products that is more efficient and uses fewer toxic solvents. An HPLC-DAD method was developed for eight cannabinoids in cannabis flowers and oils using a statistically guided optimization plan based on the principles of green chemistry. A single-laboratory validation determined the linearity, selectivity, accuracy, repeatability, intermediate precision, limit of detection, and limit of quantitation of the method. Amounts of individual cannabinoids above the limit of quantitation in the flowers ranged from 0.02 to 14.9% w/w, with repeatability ranging from 0.78 to 10.08% relative standard deviation. The intermediate precision determined using HorRat ratios ranged from 0.3 to 2.0. The LOQs for individual cannabinoids in flowers ranged from 0.02 to 0.17% w/w. We developed an optimized HPLC-DAD method with reduced extraction time and greener solvents for adoption into cannabis testing laboratories. Sample turnaround is significantly reduced, while method validation confirmed that the method produces repeatable, accurate results. The sample preparation eliminates the use of chloroform, which has been routinely used in cannabinoid analysis, reducing material costs, use of greener solvents, and improved laboratory safety for personnel. This method can be used in a variety of settings from clinical studies, research, quality control, and regulatory evaluation of this growing industry. This is a significant improvement over previous methods and is suitable for a wide range of applications including regulatory compliance, clinical studies, direct patient medical services, and commercial suppliers.” https://link.springer.com/article/10.1007/s00216-017-0256-3]]>
Cannabidiol: State of the art and new challenges for therapeutic applications.
“Over the past years, several lines of evidence support a therapeutic potential of Cannabis derivatives and in particular phytocannabinoids. Δ9-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in Cannabis plants and therapeutic application for both compounds have been suggested. However, CBD is recently emerging as a therapeutic agent in numerous pathological conditions since devoid of the psychoactive side effects exhibited instead by Δ9-THC. In this review, we highlight the pharmacological activities of CBD, its cannabinoid receptor-dependent and -independent action, its biological effects focusing on immunomodulation, angiogenetic properties, and modulation of neuronal and cardiovascular function. Furthermore, the therapeutic potential of cannabidiol is also highlighted, in particular in nuerological diseases and cancer.” https://www.ncbi.nlm.nih.gov/pubmed/28232276]]>
Regulation of Adult Neurogenesis by Cannabinoids
“In the adult mammalian brain, new neurons are born throughout life, and these new cells may influence learning, memory, olfaction, and even mood. The putative function of these new neurons suggests that manipulation of adult neurogenesis could be used therapeutically in the future, and emphasizes the importance of understanding how neurogenesis is regulated. Voluntary exercise and antidepressants are examples of factors that increase neurogenesis, while stress and drugs of abuse – alcohol, nicotine, psychostimulants, opiates – decrease neurogenesis. In contrast to the clear negative influence of these drugs of abuse, cannabinoids have mixed influence, with some marijuana-like compounds actually enhancing neurogenesis.” https://www.researchgate.net/publication/264424221_Regulation_of_Adult_Neurogenesis_by_Cannabinoids
“The role of cannabinoids in adult neurogenesis” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543605/
“Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects” http://www.jci.org/articles/view/25509
]]>Childhood academic ability in relation to cigarette, alcohol and cannabis use from adolescence into early adulthood: Longitudinal Study of Young People in England (LSYPE).
“Our aim was to determine the association between childhood academic ability and the onset and persistence of tobacco, alcohol and cannabis use across adolescence in a representative sample of English schools pupils. High academic ability was also positively associated with occasional and persistent cannabis use in late adolescence. In a sample of over 6000 young people in England, high childhood academic at age 11 is associated with a reduced risk of cigarette smoking but an increased risk of drinking alcohol regularly and cannabis use. These associations persist into early adulthood, providing evidence against the hypothesis that high academic ability is associated with temporary ‘experimentation’ with substance use.” https://www.ncbi.nlm.nih.gov/pubmed/28228447
“Looking for Pot Smokers? Check the Gifted-Students Class” http://www.medpagetoday.com/pediatrics/generalpediatrics/63354
“Which Teens Are Most Likely to Smoke Pot? The Smart Ones, Study Finds” http://time.com/4678433/brainy-teens-smoke-tobacco-pot-study/
“Smart kids more likely to smoke cannabis” http://www.theaustralian.com.au/news/latest-news/smart-kids-more-likely-to-smoke-cannabis/news-story/76122f3d7e0bbe84167bb2bea4e61e8f
Pregnenolone blocks cannabinoid-induced acute psychotic-like states in mice.
“Cannabis-induced acute psychotic-like states (CIAPS) represent a growing health issue, but their underlying neurobiological mechanisms are poorly understood. The use of antipsychotics and benzodiazepines against CIAPS is limited by side effects and/or by their ability to tackle only certain aspects of psychosis. Thus, safer wide-spectrum treatments are currently needed. Although the blockade of cannabinoid type-1 receptor (CB1) had been suggested as a therapeutical means against CIAPS, the use of orthosteric CB1 receptor full antagonists is strongly limited by undesired side effects and low efficacy. The neurosteroid pregnenolone has been recently shown to act as a potent endogenous allosteric signal-specific inhibitor of CB1 receptors. Thus, we tested in mice the potential therapeutic use of pregnenolone against acute psychotic-like effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis. We found that pregnenolone blocks a wide spectrum of THC-induced endophenotypes typically associated with psychotic-like states, including impairments in cognitive functions, somatosensory gating and social interaction. Overall, this work reveals that signal-specific inhibitors mimicking pregnenolone effects can be considered as promising new therapeutic tools to treat CIAPS.” https://www.ncbi.nlm.nih.gov/pubmed/28220044
“Pregnenolone can protect the brain from cannabis intoxication. The administration of the main active principle of Cannabis sativa (marijuana), Δ(9)-tetrahydrocannabinol (THC), substantially increases the synthesis of pregnenolone in the brain via activation of the type-1 cannabinoid (CB1) receptor. Pregnenolone then, acting as a signaling-specific inhibitor of the CB1 receptor, reduces several effects of THC. This negative feedback mediated by pregnenolone reveals a previously unknown paracrine/autocrine loop protecting the brain from CB1 receptor overactivation that could open an unforeseen approach for the treatment of cannabis intoxication and addiction.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057431/
]]>Effects of tetrahydrocannabinol on glucose uptake in the rat brain.
“Δ9-Tetrahydrocannabinol (THC) is the psychoactive component of the plant Cannabis sativa and acts as a partial agonist at cannabinoid type 1 and type 2 receptors in the brain.
The goal of this study was to assess the effect of THC on the cerebral glucose uptake in the rat brain.
Low blood THC levels of <1 ng/ml corresponded to an increased glucose uptake while blood THC levels > 10 ng/ml coincided with a decreased glucose uptake. The effective concentration in this region was estimated 2.4 ng/ml.
This glucose PET study showed that stimulation of CB1 receptors by THC affects the glucose uptake in the rat brain, whereby the effect of THC is regionally different and dependent on dose – an effect that may be of relevance in behavioural studies.”
https://www.ncbi.nlm.nih.gov/pubmed/28219717]]>
Human Cannabinoid Receptor 2 Ligand-interaction Motif: Transmembrane Helix 2 Cysteine, C2.59(89), as Determinant of Classical Cannabinoid Agonist Activity and Binding Pose.
“Cannabinoid receptor 2 (CB2R)-dependent signaling is implicated in neuronal physiology and immune surveillance by brain microglia. Selective CB2R agonists hold therapeutic promise for inflammatory and other neurological disorders.
Information on human CB2R (hCB2R) ligand-binding and functional domains is needed to inform the rational design and optimization of candidate drug-like hCB2R agonists.
These data constitute initial evidence that TMH2 cysteine C2.59(89) is a component of the hCB2R binding pocket for classical cannabinoids.
The results further demonstrate how interactions between classical cannabinoids and specific amino acids within the hCB2R* ligand-binding domain act as determinants of agonist pharmacological properties and the architecture of the agonist-hCB2R* conformational ensemble, allowing the receptor to adopt distinct activity states, such that interaction of classical cannabinoids with TMH6 cysteine C6.47(257) favors a binding pose more advantageous for agonist potency than does their interaction with TMH2 cysteine C2.59(89).”
The Inhibitory Effect of S-777469, a Cannabinoid Type 2 Receptor Agonist, on Skin Inflammation in Mice.
“We investigated the effects of S-777469 (1-[[6-Ethyl-1-[4-fluorobenzyl]-5-methyl-2-oxo-1, 2-dihydropyridine-3-carbonyl]amino]-cyclohexanecarboxylic acid), a novel cannabinoid type 2 receptor (CB2) agonist, on 1-fluoro-2,4-dinitrobenzene (DNFB)-induced ear inflammation and mite antigen-induced dermatitis in mice. The oral administration of S-777469 significantly suppressed DNFB-induced ear swelling in a dose-dependent manner. In addition, S-777469 significantly alleviated mite antigen-induced atopic dermatitis-like skin lesions in NC/Nga mice. A histological analysis revealed that S-777469 significantly reduced the epidermal thickness and the number of mast cells infiltrating skin lesions. We demonstrated that S-777469 inhibited mite antigen-induced eosinophil accumulation in skin lesions and an endogenous CB2 ligand, 2-arachidonoylglycerol (2-AG)-induced eosinophil migration in vitro. Moreover, we confirmed that 2-AG levels significantly increased in skin lesions of mite antigen-induced dermatitis model. Together, these results suggest that S-777469 inhibits skin inflammation in mice by blocking the activities of 2-AG.” https://www.ncbi.nlm.nih.gov/pubmed/28214870]]>