“There is considerable interest in the effects of medical marijuana laws (MML) on marijuana use in the USA, particularly among youth. The article by Stolzenberg et al. (2015) “The effect of medical cannabis laws on juvenile cannabis use” concludes that “implementation of medical cannabis laws increase juvenile cannabis use”. This result is opposite to the findings of other studies that analysed the same US National Survey on Drug Use in Households data as well as opposite to studies analysing other national data which show no increase or even a decrease in youth marijuana use after the passage of MML. We provide a replication of the Stolzenberg et al. results and demonstrate how the comparison they are making is actually driven by differences between states with and without MML rather than being driven by pre and post-MML changes within states. We show that Stolzenberg et al. do not properly control for the fact that states that pass MML during 2002-2011 tend to already have higher past-month marijuana use before passing the MML in the first place. We further show that when within-state changes are properly considered and pre-MML prevalence is properly controlled, there is no evidence of a differential increase in past-month marijuana use in youth that can be attributed to state MML.”
Tag Archives: Cannabinoids
The endocannabinoid system: potential for reducing cardiometabolic risk.
“The endocannabinoid system (ECS) affects multiple metabolic pathways in the brain and other organs. The transmembrane CB receptors were cloned in the early 1990s, followed shortly thereafter by the discovery of endogenous ligands, now known as endocannabinoids.
Three general types of cannabimimetic compounds have been described: herbal CBs, which occur uniquely in the cannabis plant (Cannabis sativa); endogenous CBs (or endocannabinoids), which are produced in the brain and peripheral tissues; and synthetic CBs, which are functionally similar compounds synthesized in the laboratory.
Obesity is associated with increased risk for insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, atherogenic dyslipidemia, and cardiovascular disease. Recent studies indicate that the body protects itself from weight loss by lowering energy expenditure. Both energy consumption and energy expenditure are regulated by hormones from a number of organs that act on the brain, as well as neural signals emanating from the brain itself.
Lifestyle modification is the initial intervention for obesity, with emphasis on reducing calorie intake and increasing physical activity; pharmacotherapy may be indicated for certain cardiovascular and metabolic risk factors.
This review focuses on the link between the biology of the cannabinoid receptor type 1 (CB1 receptor) system and body-weight regulation, as well as clinical data from studies of the first CB1 receptor antagonist…”
The endocannabinoid system: a new approach to control cardiovascular disease.
“The endocannabinoid (EC) system consists of 2 types of G-protein-coupled cannabinoid receptors–cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)–and their natural ligands.
The EC system plays a key role in the regulation of food intake and fat accumulation, as well as glucose and lipid metabolism.
When overactivated, the EC system triggers dyslipidemia, thrombotic and inflammatory states, and insulin resistance.
Blocking CB1 receptors centrally and peripherally in adipose tissue can help normalize an overactivated EC system. CB1 blockade helps regulate food intake and adipose tissue metabolism, contributing to improved insulin sensitivity and other features of the metabolic syndrome.
Visceral adipose tissue is most closely associated with the metabolic syndrome, which is a constellation of conditions that place people at high risk for coronary artery disease.
Targeting the EC system represents a new approach to treating visceral obesity and reducing cardiovascular risk factors.”
Plant-Derived and Endogenous Cannabinoids in Epilepsy.
“Cannabis is one of the oldest psychotropic drugs and its anticonvulsant properties have been known since the last century.
The aim of this reveiw was to analyze the efficacy of cannabis in the treatment of epilepsy in adults and children. In addition, a description of the involvement of the endocannabinoid system in epilepsy is given in order to provide a biochemical background to the effects of endogenous cannabinoids in our body.
General tolerability and adverse events associated with cannabis treatment are also investigated. Several anecdotal reports and clinical trials suggest that in the human population cannabis has anticonvulsant properties and could be effective in treating partial epilepsies and generalized tonic-clonic seizures, still known as “grand mal.”
They are based, among other factors, on the observation that in individuals who smoke marijuana to treat epilepsy, cessation of cannabis use precipitates the re-emergence of convulsive seizures, whereas resuming consumption of this psychotropic drug controls epilepsy in a reproducible manner.
In conclusion, there is some anecdotal evidence for the potential efficacy of cannabis in treating epilepsy.
Though there has been an increased effort by patients with epilepsy, their caregivers, growers, and legislators to legalize various forms of cannabis, there is still concern about its efficacy, relative potency, availability of medication-grade preparations, dosing, and potential short- and long-term side effects, including those on prenatal and childhood development.”
Vaccenic acid suppresses intestinal inflammation by increasing the endocannabinoid anandamide and non-cannabinoid signaling molecules in a rat model of the metabolic syndrome.
“Vaccenic acid (VA), the predominant ruminant-derived trans fat in the food chain, ameliorates hyperlipidemia yet mechanisms remain elusive. We investigated whether VA could influence tissue endocannabinoids (EC) by altering the availability of their biosynthetic precursor, arachidonic acid (AA) in membrane phospholipids (PL).
Interestingly, VA increased jejunal concentrations of anandamide and those of the non-cannabinoid signaling molecules, oleoylethanolamide and palmitoylethanolamide, relative to CD (P<0.05). This was consistent with a lower jejunal protein abundance (but not activity) of their degrading enzyme, fatty acid amide hydrolase and mRNA expression TNFα and IL-1β (P<0.05).
The ability of VA to reduce 2-AG in the liver and VAT provides a potential mechanistic explanation to alleviate ectopic lipid accumulation. The opposing regulation of EC and other non-cannabinoid lipid signaling molecules by VA suggests an activation of benefit via the EC system in the intestine.”
Cannabis effects on driving longitudinal control with and without alcohol.
“Although evidence suggests cannabis impairs driving, its driving-performance effects are not fully characterized. We aimed to establish cannabis‘ effects on driving longitudinal control (with and without alcohol, drivers’ most common drug combination) relative to psychoactive ∆9 -tetrahydrocannabinol (THC) blood concentrations.
Current occasional (≥1×/last 3 months, ≤3 days per week) cannabis smokers drank placebo or low-dose alcohol, and inhaled 500 mg placebo, low (2.9%), or high (6.7%) THC vaporized cannabis over 10 min ad libitum in separate sessions (within-subject, six conditions). Participants drove (National Advanced Driving Simulator, University of Iowa) simulated drives 0.5-1.3 h post-inhalation. Blood and breath alcohol samples were collected before (0.17 and 0.42 h) and after (1.4 and 2.3 h) driving.
We evaluated the mean speed (relative to limit), standard deviation (SD) of speed, percent time spent >10% above/below the speed limit (percent speed high/percent speed low), longitudinal acceleration, and ability to maintain headway relative to a lead vehicle (headway maintenance) against blood THC and breath alcohol concentrations (BrAC).
THC was associated with a decreased mean speed, increased percent speed low and increased mean following distance during headway maintenance. BrAC was associated with increased SD speed and increased percent speed high, whereas THC was not.
Neither was associated with altered longitudinal acceleration.
A less-than-additive THC*BrAC interaction was detected in percent speed high (considering only non-zero data and excluding an outlying drive event), suggesting cannabis mitigated drivers’ tendency to drive faster with alcohol.
Cannabis was associated with slower driving and greater headway, suggesting a possible awareness of impairment and attempt to compensate.”
http://www.ncbi.nlm.nih.gov/pubmed/26889769
“Stoned Drivers Safer Than Drunk Drivers” http://americanlivewire.com/2015-02-15-stoned-drivers-safer-drunk-drivers/
Natural product modulators of transient receptor potential (TRP) channels as potential anti-cancer agents.
“Treatment of cancer is a significant challenge in clinical medicine, and its research is a top priority in chemical biology and drug discovery. Consequently, there is an urgent need for identifying innovative chemotypes capable of modulating unexploited drug targets.
The transient receptor potential (TRPs) channels persist scarcely explored as targets, despite intervening in a plethora of pathophysiological events in numerous diseases, including cancer.
Both agonists and antagonists have proven capable of evoking phenotype changes leading to either cell death or reduced cell migration.
Among these, natural products entail biologically pre-validated and privileged architectures for TRP recognition.
Furthermore, several natural products have significantly contributed to our current knowledge on TRP biology. In this Tutorial Review we focus on selected natural products, e.g. capsaicinoids, cannabinoids and terpenes, by highlighting challenges and opportunities in their use as starting points for designing natural product-inspired TRP channel modulators.
Importantly, the de-orphanization of natural products as TRP channel ligands may leverage their exploration as viable strategy for developing anticancer therapies.
Finally, we foresee that TRP channels may be explored for the selective pharmacodelivery of cytotoxic payloads to diseased tissues, providing an innovative platform in chemical biology and molecular medicine.”
Development and Pharmacological Characterization of Selective Blockers of 2-Arachidonoyl Glycerol Degradation with Efficacy in Rodent Models of Multiple Sclerosis and Pain.
“We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity.
Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol, and behaves as cannabinoid (CB1/CB2) receptor indirect agonist.
Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin.
Given these evidences, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain.”
Blockade of Nicotine and Cannabinoid Reinforcement and Relapse by a Cannabinoid CB1-Receptor Neutral Antagonist AM4113 and Inverse Agonist Rimonabant in Squirrel Monkeys.
“Nicotine, the main psychoactive component of tobacco, and (-)-Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, play major roles in tobacco and marijuana dependence as reinforcers of drug-seeking and drug-taking behavior.
Drugs that act as inverse agonists of cannabinoid CB1 receptors in the brain can attenuate the rewarding and abuse-related effects of nicotine and THC…
Recently-developed CB1-receptor neutral antagonists may provide an alternative therapeutic approach to nicotine and cannabinoid dependence.
These findings point to CB1-receptor neutral antagonists as a new class of medications for treatment of both tobacco dependence and cannabis dependence.”
Elevated Systemic Levels of Endocannabinoids and Related Mediators Across the Menstrual Cycle in Women With Endometriosis.
“Cannabinoids and modulators of the endocannabinoid system affect specific mechanisms that are critical to the establishment and development of endometriosis.
The aim of this study was to measure the systemic levels of endocannabinoids and related mediators in women with and without endometriosis and to investigate whether such levels correlated with endometriosis-associated pain.
These preliminary data suggest that the pharmacological manipulation of the action or levels of these mediators may offer an alternative option for the management of endometriosis-associated pain.”