“Twenty-eight states in the U.S have legalized medical marijuana, yet its impacts on severe health consequences such as hospitalizations remain unknown. Meanwhile, the prevalence of opioid pain reliever (OPR) use and outcomes has increased dramatically. Recent studies suggested unintended impacts of legalizing medical marijuana on OPR, but the evidence is still limited. This study examined the associations between state medical marijuana policies and hospitalizations related to marijuana and OPR.
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The Ratio of 2-AG to Its Isomer 1-AG as an Intrinsic Fine Tuning Mechanism of CB1 Receptor Activation.
“Endocannabinoids are pleiotropic lipid messengers that play pro-homeostatic role in cellular physiology by strongly influencing intracellular Ca2+ concentration through the activation of cannabinoid receptors. One of the best-known endocannabinoid ‘2-AG’ is chemically unstable in aqueous solutions, thus its molecular rearrangement, resulting in the formation of 1-AG, may influence 2-AG-mediated signaling depending on the relative concentration and potency of the two isomers.
To predict whether this molecular rearrangement may be relevant in physiological processes and in experiments with 2-AG, here we studied if isomerization of 2-AG has an impact on 2-AG-induced, CB1-mediated Ca2+ signaling in vitro.
We found that the isomerization-dependent drop in effective 2-AG concentration caused only a weak diminution of Ca2+ signaling in CB1 transfected COS7 cells. We also found that 1-AG induces Ca2+transients through the activation of CB1, but its working concentration is threefold higher than that of 2-AG. Decreasing the concentration of 2-AG in parallel to the prevention of 1-AG formation by rapid preparation of 2-AG solutions, caused a significant diminution of Ca2+ signals. However, various mixtures of the two isomers in a fix total concentration – mimicking the process of isomerization over time – attenuated the drop in 2-AG potency, resulting in a minor decrease in CB1 mediated Ca2+ transients.
Our results indicate that release of 2-AG into aqueous medium is accompanied by its isomerization, resulting in a drop of 2-AG concentration and simultaneous formation of the similarly bioactive isomer 1-AG. Thus, the relative concentration of the two isomers with different potency and efficacy may influence CB1 activation and the consequent biological responses.
In addition, our results suggest that may play role in stabilizing the strength of cannabinoid signal in case of prolonged 2-AG dependent cannabinoid mechanisms.”
Does Cannabidiol Protect Against Adverse Psychological Effects of THC?
“Tetrahydrocannabinol (THC) is the main psychoactive substance in cannabis. Cannabidiol (CBD) is a cannabinoid that appears in cannabis resin but rarely in herbal cannabis. In recent years, many positive attributes have been ascribed to CBD. Is cannabis that contains CBD less harmful than cannabis without CBD? Are people who smoke cannabis resin, therefore, less susceptible to psychosis or less likely to become addicted than are people who smoke herbal marijuana?
Delta-9-tetrahydrocannabinol (THC) is the main psychoactive constituent of cannabis, and most, if not all, of the effects associated with the use of cannabis are caused by THC. Recent studies have suggested a possible protective effect of another cannabinoid, cannabidiol (CBD).
Most recreational users will never be faced with persistent mental illness, but in some individuals cannabis use leads to undesirable effects: cognitive impairment, anxiety, paranoia, and increased risks of developing chronic psychosis or drug addiction.
Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.
Few or no adverse effects of CBD have been proffered, and where CBD has been found to have an effect, it is usually in a “positive” (i.e., salubrious) direction. The evidence favoring a beneficial effect of CBD therefore merits further investigation in studies in which the amounts and ratios of CBD and THC correspond to the daily practices of recreational cannabis use.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/
“Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.” https://www.ncbi.nlm.nih.gov/pubmed/24137134
“CBD may also potentiate some of Δ9-THC’s beneficial effects as it reduces Δ9-THC’s psychoactivity to enhance its tolerability and widen its therapeutic window.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707667/
Can we make cannabis safer?
“Cannabis use and related problems are on the rise globally alongside an increase in the potency of cannabis sold on both black and legal markets. Additionally, there has been a shift towards abandoning prohibition for a less punitive and more permissive legal stance on cannabis, such as decriminalisation and legalisation. It is therefore crucial that we explore new and innovative ways to reduce harm.
Research has found cannabis with high concentrations of its main active ingredient, δ-9-tetrahydrocannabinol (THC), to be more harmful (in terms of causing the main risks associated with cannabis use, such as addiction, psychosis, and cognitive impairment) than cannabis with lower concentrations of THC. By contrast, cannabidiol, which is a non-intoxicating and potentially therapeutic component of cannabis, has been found to reduce the negative effects of cannabis use.
Here, we briefly review findings from studies investigating various types of cannabis and discuss how future research can help to better understand and reduce the risks of cannabis use.” https://www.ncbi.nlm.nih.gov/pubmed/28259650
“Studies examining the protective effects of CBD have shown that CBD can counteract the negative effects of THC.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797438/
“CBD may also potentiate some of Δ9-THC’s beneficial effects as it reduces Δ9-THC’s psychoactivity to enhance its tolerability and widen its therapeutic window.” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707667/
Cannabinoid signaling in health and disease.
“Cannabis sativa has long been used for medicinal purposes.
To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids.
Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain.
More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection.
The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear.
In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects.
This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.”
Inflammatory Regulation by Driving Microglial M2 Polarization: Neuroprotective Effects of Cannabinoid Receptor-2 Activation in Intracerebral Hemorrhage.
“The cannabinoid receptor-2 (CB2R) was initially thought to be the “peripheral cannabinoid receptor.” Recent studies, however, have documented CB2R expression in the brain in both glial and neuronal cells, and increasing evidence suggests an important role for CB2R in the central nervous system inflammatory response.
Intracerebral hemorrhage (ICH), which occurs when a diseased cerebral vessel ruptures, accounts for 10-15% of all strokes. Although surgical techniques have significantly advanced in the past two decades, ICH continues to have a high mortality rate.
The aim of this study was to investigate the therapeutic effects of CB2R stimulation in acute phase after experimental ICH in rats and its related mechanisms.
These findings demonstrated that CB2R stimulation significantly protected the brain damage and suppressed neuroinflammation by promoting the acquisition of microglial M2 phenotype in acute stage after ICH.
Taken together, this study provided mechanism insight into neuroprotective effects by CB2R stimulation after ICH.”
CB1 receptor-mediated respiratory depression by endocannabinoids.
“Endocannabinoids (ECs) are bioactive lipid mediators acting on two distinct cannabinoid receptors (CB1 and CB2), which are ubiquitously expressed in many tissues including the respiratory system. Despite numerous experimental data showing that cannabinomimetics influence respiration, the role of endogenously produced ECs in respiratory control has not been verified yet. Pulse oximetry was used in the present study to directly measure changes in respiratory parameters during elevation of EC levels. The cannabinoid reuptake inhibitor AM-404 (10mgkg-1, i.v.), but not its vehicle, induced a transient reduction of respiratory rate with a concomitant depression of arterial oxygen saturation and increase in breath distension in wild-type mice. In contrast, CB1 knock-out mice showed no alteration in any of these parameters upon administration of AM-404. Our results imply that the EC system has an important role in the physiological control of respiration by modulating the respiratory rate and consequently influencing arterial oxygen saturation. Furthermore, this mechanism is entirely dependent on CB1 receptors.”
Flexible Bionanocomposites from Epoxidised Hemp Seed Oil Thermosetting Resin Reinforced with Halloysite Nanotubes.
“Hempseed (Cannabis sativa L.) oil comprises a variety of beneficial unsaturated triglycerides with well-documented nutritional and health benefits.
However, it can become rancid over a relatively short time period leading to increased industrial costs and waste of a valuable product. The development of sustainable polymers is presented as a strategy where both the presence of unsaturation and perox-ide content could be affectively utilised to alleviate both this waste and financial burden.
After reaction with peroxyacetic acid, incorporation of halloysite nanotubes (HNTs) and sub-sequent thermal curing, without the need for organic sol-vents or interfacial modifiers, flexible transparent materials with a low glass transition temperature were developed. The improvement in thermal stability and both the static and dynamic mechanical properties of the bionanocomposites were significantly enhanced with the well-dispersed HNT filler. At an optimum concentration of 0.5 wt.% HNTs, a simultaneous increase in stiffness, strength, ductility and toughness was observed in comparison to the unfilled cured resin.
These sustainable food-waste derived bionanocompo-sites may provide an interesting alternative to petroleum-based materials, particularly for low-load bearing applica-tions, such as packaging.”
Dietary ω-3 Polyunsaturated Fatty Acids Inhibit Tumor Growth in Transgenic ApcMin/+ Mice, Correlating with CB1 Receptor Up-Regulation.
“Mediterranean diet components, such as olive oil and ω-3 polyunsaturated fatty acids (ω-3 PUFAs), can arrest cell growth and promote cell apoptosis.
Recently, olive oil has been demonstrated to modulate type-1 cannabinoid (CB1) receptor gene expression in both human colon cancer cells and rat colon. The aim of this study was to investigate a possible link between olive oil and ω-3 PUFAs effects and CB1 receptor expression in both intestinal and adipose tissue of ApcMin/+ mice.
To confirm the role for the CB1 receptor as a negative modulator of cell proliferation in human colon cancer, CB1 receptor gene expression was also detected in tumor tissue and in surrounding normal mucosa of patients with colorectal cancer (CRC).
Dietary ω-3 PUFAs significantly inhibited intestinal polyp growth in mice, correlating with CB1 receptor gene and protein expression induction. CB1 receptor gene up-regulation was also detected in adipose tissue, suggesting a close communication between cancer cells and the surrounding environment. Tissue CB1 receptor induction was associated with a concurrent inactivation of the Wnt/β-catenin pathway.
Moreover, there was a significant reduction in CB1 receptor gene expression levels in cancer tissue compared to normal surrounding mucosa of patients with CRC, confirming that in cancer the “protective” action of the CB1 receptor is lost.”
The endocannabinoid system modulating levels of consciousness, emotions and likely dream contents.
“Cannabinoids are derivatives that are either compounds occurring naturally in the plant, Cannabis sativa or synthetic analogs of these molecules. The first and most widely investigated of the cannabinoids is ∆9-tetrahydrocannabinol (Δ9-THC), which is the main psychotropic constituent of cannabis and undergoes significant binding to cannabinoid receptors.
These cannabinoid receptors are seven-transmembrane receptors that received their name from the fact that they respond to cannabinoid compounds, including Δ9-THC. The cannabinoid receptors have been described in rat, human and mouse brains and they have been named as the CB1 and CB2 cannabinoid receptors.
Later, an endogenous molecule that exerts pharmacological effects similar to those described by ∆9-THC and binds to the cannabinoid receptors was discovered. This molecule, named anandamide, was the first of five endogenous cannabinoid receptor agonists described to date in the mammalian brain and other tissues. Of these endogenous cannabinoids or endocannabinoids, the most thoroughly investigated to date have been anandamide and 2-arachidonoylglycerol (2-AG).
Over the years, a significant number of articles have been published in the field of endogenous cannabinoids, suggesting a modulatory profile in multiple neurobiological roles of endocannabinoids. The general consensus accepts that the endogenous cannabinoid system includes natural ligands (such as anandamide and 2-AG), receptors (CB1 and CB2), and the main enzymes responsible for the hydrolysis of anandamide and 2-AG (fatty acid amide hydrolase [FAAH] and monoacylglycerol lipase [MAGL], respectively) as well as the anandamide membrane transporter (AMT).
To date, diverse pieces of evidence have shown that the endocannabinoid system controls multiple functions such as feeding, pain, learning and memory and has been linked with various diseases, such as Parkinson´s disease. Among the modulatory properties of the endocannabinoid system, current data indicate that the sleep-wake cycle is under the influence of endocannabinoids since the blocking of the CB1 cannabinoid receptor or the pharmacological inhibition of FAAH activity promotes wakefulness whereas the obstruction of AMT function enhances sleep. However, no solid evidence is available regarding the role of the endocannabinoid system in an unquestionable emotional component of the sleep: Dream activity.
Since dreaming is a mental activity that occurs during sleep (characterized by emotions, sensory perceptions, and bizarre components) and the endocannabinoid system modulates neurobiological processes involving consciousness, such as learning and memory, attention, pain perception, emotions and sleep, it is acceptable to hypothesize that the endocannabinoid system might be modulating dream activity. In this regard, an accumulative body of evidence in human and animal models has been reported regarding the role of the endocannabinoid system in the control of emotional states and dreams.
Moreover, preliminary studies in humans have indicated that treatment with cannabinoids may decrease post-traumatic stress disorder symptoms, including nightmares. Thus, based on a review of the literature available in PubMed, this article hypothesizes a conceptual framework within which the endocannabinoid system might influence the generation of dream experiences.”