Although not observed under controlled conditions, MDMA use beyond research settings has been associated with SS in case reports and toxicology studies . The vast majority of SS clinical case reports in published literature include a combination of two or more serotonergic agents including various classes of antidepressants, and other medications with serotonergic activity such as opioids , antibiotics , antihistamines , and atypical antipsychotics . Given the high percentage of the PTSD population for whom serotonin modulating therapeutics are prescribed and the high prevalence of other PTSD comorbid conditions, including substance use , depression , anxiety , sleep , and pain disorders treated by serotonergic drugs, further exploration of MDMA related Adverse Events reports from the drug safety surveillance database in the FDA Adverse Event Reporting System is warranted. In this study, we evaluated individual cases listing MDMA use associated with SS and reported to FAERS through MedWatch . We evaluated reports for the presence of MDMA as the sole reported compound, and for the presence of any additional substances or medications, particularly those that might increase the risk of SS due to their inherent serotonergic activity.The kidneys play a central role in normal body homeostasis through a variety of functions, including removal of byproducts of metabolism, clearance of toxins, regulation of body volume status, electrolytes and systemic hemodynamics, and production of hormones such as erythropoietin and active vitamin D. Hence, it is not surprising that kidney damage is associated with significant morbidity and mortality. The latter is true whether the decline in renal function is part of an acute process such as acute kidney injury due to tubular necrosis,growing cannabis indoors or a more chronic process such as chronic kidney disease caused by hypertension or diabetes. Furthermore, the mechanisms responsible for renal injury are complex and can be varied.
While these mechanisms are regularly categorized based on the type of injury and anatomic part of the nephron affected , there is significant overlap between these categories. For instance, there is evidence indicating that AKI can result in CKD. In addition, there is frequent overlap between the different anatomic sites of injury given that damage to one part of the nephron over a period of time can result in injury to other sites. For example, while diabetic kidney disease often manifests with glomerular injury and proteinuria, over an extended period of time it also results in tubulointerstitial damage and fibrosis leading to progressive CKD and end-stage kidney disease. Therefore, understanding the underlying pathways whose alterations can result in various forms of renal damage and injury can play an important role in devising effective therapies to prevent and treat kidney disease. In this regard, there is accumulating evidence that indicates that the endocannabinoid system plays a major role in normal renal physiology. In addition, there are data demonstrating that alterations of this pathway can lead to the pathogenesis of both acute and chronic kidney disease. Therefore, evaluation of the EC system can be a promising area of discovery, which may result in the generation of potentially novel therapies aimed at treating various forms of kidney disease. The EC system comprises endogenous fatty acidderived ligands, their receptors, and the enzymes required for their biosynthesis and degradation.The most wellcharacterized ECs are N-arachidonoyl ethanolamide, also known as anandamide , and 2-arachidonoylsn-glycerol .These lipid-derived molecules are generated on-demand by the metabolism of membrane phospholipids in response to various stimuli, including elevated intracellular calcium or metabotropic receptor activation.After production, they bind to the local cannabinoid receptors in an autocrine or paracrine manner, although measurable concentrations of these ligands can also be found in the blood, cerebrospinal fluid, and lymph.While the potential endocrine actions of these ECs remain an area of active research, it is well established that they act locally by binding with two widely studied cannabinoid receptors, cannabinoid subtype-1 and subtype-2 .
AEA and 2-AG can subsequently be taken up by cells through a high-affinity uptake mechanism and rapidly degraded through the action of the enzymes, fatty acid amide hydrolase , and monoacylglycerol lipase , respectively.While the role of the EC system has been initially a focus of extensive research in the central nervous system, over the course of the past two decades, a significant number of studies have confirmed its presence and importance in the peripheral organs, including the kidneys. In this regard, substantial concentrations of ECs, the machinery required for their biosynthesis and degradation, as well as CB receptors have been detected in kidney tissue.The effects produced by the actions of this system in the normal and pathological conditions of the kidney, however, have not been fully delineated given the many complexities involved in the production and breakdown of EC ligands.In addition, the differential distribution and actions of the CB1 and CB2 receptors in various structures and cell subtypes in the kidney can ultimately result in varied signaling outcomes whose overall impact will be difficult to predict. Accordingly, identifying the physiologic and pathophysiologic roles of the EC system in the field of nephrology remains an active area of exploration.It has been shown that CB1 and CB2 belong to a class of seven transmembrane domain G-protein-coupled receptors that are functionally dependent on the activation of heterotrimeric Gi /G0 proteins.Although the activation of both receptors results in the inhibition of adenylyl cyclase enzyme and increased activity of mitogen-activated protein kinase , CB1 activation has also been shown to stimulate nitric oxide synthase and directly control the activation of ion channels. The latter include the inwardly rectifying and A-type outward potassium channels, D-type outward potassium channels, and Ntype and P/Q-type calcium channels.Despite the common G-protein subunit shared between CB1 and CB2 receptors, their activation can produce opposing biological effects in normal and diseased states, in part due to the abundance and localization of these cannabinoid receptors and their EC ligands. While the CB1 receptor was initially thought to be localized to the central and peripheral nervous system,it has been shown to be present in peripheral organs such as the kidneys.For instance, the presence of functional CB1 receptor has been demonstrated in proximal convoluted tubules, distal tubules, and intercalated cells of the collecting duct in the human kidney.
Furthermore, CB1 receptor expression has also been found in other parts of the nephron in rodents, such as the afferent and efferent arterioles,thick ascending limbs of the loop of Henle,and glomeruli,as well as in various kidney cell sub-types such as glomerular podocytes, tubular epithelial cells,and cultured mesangial cells Similarly, the expression of CB2 receptors, although previously thought to be predominantly in immune cells,has also been demonstrated in renal tissue.For example, CB2 receptor expression has been localized to podocytes,proximal tubule cells, and mesangial cells in human and rat renal cortex samples. In addition to differential expression of CB receptors in different tissues and cells, the complex regulation of the biosynthesis and degradation of the kidney’s high basal levels of ECs through downstream enzymes contributes to the varied signaling effects of these ligands.While the renal cortex displayed similar levels of AEA and 2-AG, AEA was demonstrated to be enriched in the kidney medulla compared with the cortex,growing indoor cannabis while the levels of 2-AG in the medulla were similar to those of both ECs in the cortex.Moreover, AEA is present in cultured renal endothelial and mesangial cells at low levels and can be synthesized from arachidonic acid and ethanolamine and catabolized by AEA amidase in these kidney cell sub-types.The expression of FAAH was shown to be augmented in the renal cortex in comparison to its low expression levels in the medulla.Considering the diverse localization of the ECs and their receptors, as well as the complexities involved in their synthesis and catabolism, this system can play various roles in kidney function. Under normal conditions, the EC system is capable of regulating renal homeostasis as demonstrated by its control over renal hemodynamics, tubular sodium reabsorption, and urinary protein excretion. These effects are largely imparted through the activation of the CB1 receptor. In the following sections, we describe some effects of EC system activation on renal physiologic function .Under normal physiologic conditions, the EC system plays a critical role in the regulation of renal hemodynamics. For instance, it was shown that intravenous administration of AEA decreased glomerular filtration rate and increased renal blood flow in rodents, independent of changes in blood pressure.In vitro studies showed that AEA can vasodilate juxtamedullary afferent or efferent arterioles through a CB1-dependent process, normally inhibited by nitric oxide synthase,to regulate glomerular filteration rate . The actions of the AEA signaling system are likely conducted through endothelial and mesangial cells, which are capable of producing and metabolizing AEA,as well as through the hyperpolarization of smooth muscle cells via the activation of potassium channels.It should be noted that there are also non-CB1 receptor–dependent mechanismsby which ECs can mediate a vasodilatory effect and thereby regulate renal hemodynamics.Future studies need to further elucidate the role of the latter mechanisms in normal renal physiologic homeostasis.It is well known that diabetes has major renal complications, including progressive kidney disease and pathology, a condition known as diabetic nephropathy.
Diabetic nephropathy is characterized by glomerular hypertrophy and hyper filtration, which can result in albuminuria, renal fibrosis, GFR decline, and end-stage renal disease.Several studies have examined the role of the EC system in diabetes-related podocyte, mesangial and tubular cell injury, as well as the function of CB receptor activation on the adverse outcomes of diabetic nephropathy . The evaluation of mouse models of diabetic kidney disease and renal tissue from humans with advanced diabetic nephropathy have shown elevated levels of CB1 receptor expression in the kidney, and in particular in glomerular podocytes and mesangial cells.In addition, in vitro studies have shown CB1 receptor upregulation with exposure to increased glucose and albumin concentrations in mesangial cells andproximal tubule cells, respectively.Furthermore, the CB1 receptor has been found to be over expressed in glomerular podocytes in experimental mice with diabetic nephropathy.The potential consequences of the latter changes were shown in another study that found that hyperlipidemia, as induced by diabetic nephropathy, can be associated with palmitic acid–induced apoptosis in proximal tubular cells. These actions are mediated through upregulated CB1 receptor expression.Given the evidence indicating a deleterious role for the CB1 receptor in diabetic nephropathy, several studies have investigated the utility of CB1 antagonist/inverse agonists as a potential therapeutic option for diabetic kidney disease.In a streptozotocin -induced mouse model of diabetic nephropathy, albuminuria was reduced as a result of CB1 receptor blockade through a selective CB1 receptor antagonist.It was found that a marked reduction in proteinuria occurred through the preservation of glomerular podocytes and restoration of the expression of podocyte proteins nephrin, podocin, and zonula occludens-1. In addition, CB1 antagonism was also found to be associated with decreased glomerular and proximal tubular apoptosis, ultimately leading to improvements in renal function.In Zucker diabetic fatty rats, which develop type 2 diabetes due to obesity caused by a dysfunctional leptin receptor, chronic administration of a CB1 receptor inverse agonist restored GFR, reduced proteinuria, and improved the markers of podocyte health through modulation of the renin–angiotensin system and inhibition of apoptosis.While diabetic kidney disease is associated with increased expression of the CB1 receptor in various parts of the nephron, there is also evidence that CB2 receptor expression is significantly reduced. For example, STZ induced diabetic nephropathy in mice is associated with the down regulation of glomerular podocyte CB2 receptor expression.Similarly, there is decreased expression of the CB2 receptor in proximal tubule cells following exposure to elevated concentrations of albumin and glucose.Furthermore, CB2 receptor activation has been shown to ameliorate albuminuria, restore podocyte protein expression, reduce monocyte infiltration, and decrease the expression of renal profibrotic markers in rats with obesity-related nephropathy. CB2 agonism in obese diabetic nephropathy BTBR ob/ob mouse strain also reduced albuminuria, ameliorated dysfunctional nephrin expression in podocytes, and reduced mesangial matrix expansion, fibronectin accumulation, and sclerotic damage.These studies demonstrate that antagonism of CB1 receptors and activation of CB2 receptors using selective pharmacological ligands is associated with the restoration of renal structure and function, specifically albuminuria and the expression of inflammatory markers, in genetic and experimental models of diabetic nephropathy.Obesity is associated with and acts as a risk factor for the development of diabetic nephropathy,with obese individuals possessing a higher risk of progressing to end-stage renal disease.