Effects of phytocannabinoids, synthetic and semi-synthetic cannabinoids on microglia and astrocytes: Review of neuroinflammatory mechanisms.

Synthetic Cannabinoid Use in a Transitional Housing Shelter: A Survey to Characterize Awareness of Risks and Reasons for Use

Receptor-dependent and receptor-independent endocannabinoid signaling: A therapeutic target for regulation of cancer growth

Differential Expression of Cannabinoid Receptors in the Human Colon: Cannabinoids Promote Epithelial Wound Healing

Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components-tetrahydrocannabinol (THC) and cannabidiol (CBD)-or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.

Patient: Female, 19-year-oldFinal Diagnosis: Status epilepticus and stress induced cardiomyopathySymptoms: SeizureMedication: —Clinical Procedure: —Specialty: ToxicologyObjective:Unusual clinical courseBackground:Synthetic cannabinoids have a higher affinity for the cannabinoid receptors CB1 and CB2 than natural cannabinoids. Their use can be associated with cardiovascular disease and neurological complications. A case is reported of status epilepticus and stress cardiomyopathy following the recreational use of the synthetic cannabinoid, UR-144.Case Report:A 19-year-old woman presented to the emergency department in status epilepticus after smoking the synthetic cannabinoid known as ‘space’. Recurring seizure activity was controlled after three hours. On hospital day 3, the patient developed severe biventricular failure. Cardiac magnetic resonance imaging (MRI) confirmed the diagnosis of stress cardiomyopathy. A comprehensive urine drug screen was performed using gas chromatography-mass spectrometry (GC-MS), which was positive for UR-144, or (1-pentyl-1H-indol-3-yl) (2,2,3,3-tetramethylcyclopropyl)-methanone, and negative for all other illicit recreational drugs. The patient improved at one week following admission, with a left ventricular ejection fraction (LVEF) of 40%. She was discharged home on hospital day 10.Conclusions:The use of the synthetic cannabinoid, UR-144, may be associated with prolonged status epilepticus and stress cardiomyopathy. Physicians should be aware of these potentially lethal complications associated with the recreational use of this and other illicit synthetic cannabinoids.

Synthetic cannabinoids are, typically, full agonists at the cannabinoid CB1 receptor, and therefore considerably more potent than natural cannabis and may have correspondingly more serious psychological effects. Despite government sanctions against their production they continue to be available in ever-increasing varieties over the Internet. The psychological consequences of synthetic cannabinoid use are relatively unknown. The purpose of this study was to synthesise the available research on the psychological consequences of synthetic cannabinoid use. A literature search of three databases was conducted in February 2018, including the following keywords: Spice, synthetic cannabis, cognition, affect, behaviour, psychosis, depression and anxiety. Seventeen studies involving a variety of participants were eligible for inclusion: one controlled administration study, seven cross-sectional studies, five Internet surveys and four qualitative studies. The controlled administration study showed that, compared to placebo, synthetic cannabinoids acutely affected some aspects of cognitive functioning and subjective psychological ratings. Non-controlled, cross-sectional studies generally showed that synthetic cannabinoid users had lower performance on cognitive tasks and showed elevated symptomatology (e.g. paranoia) compared to both natural cannabis and non-cannabis users. Methodological limitations were noted across different study designs. There is limited research on how doses, frequency or type of synthetic cannabinoid influence outcomes. Acute synthetic cannabinoid use can result in a range of psychological outcomes and, when non-intoxicated, synthetic cannabinoid users appear to differ from natural cannabis and non-users on various affective and cognitive domains. As synthetic cannabinoid use is increasing in at-risk populations there is an urgent need for more and better research to inform users, professionals and policymakers.

Prenatal substance abuse is a major public health concern. Much research has been focused on alcohol and other drug use, but there is a lack of information about prenatal cannabinoid use. Nevertheless, marijuana use during pregnancy increases the risk of a stillbirth by approximately 2.3X. Synthetic cannabinoids (SCB) are a group of heterogeneous compounds which were developed to understand the endogenous cannabinoid system and as potential therapeutics. SCBs are legally available for purchase in several places, and the use of natural and synthetic cannabinoids is high among women of reproductive age. Combined with the prevalence of unplanned pregnancies, the high use of cannabinoids may lead to an increase in prenatal exposure to cannabinoids. Early studies have shown morphological and behavioral anomalies similar to fetal alcohol syndrome. Even though the mechanisms of Δ9 -tetrahydrocannabinol (Δ9 -THC), the major psychoactive component of marijuana, and SCB are similar, there are several important differences. Subsequently, some SCBs have a 40 to 600 fold higher potency than Δ9 -THC. However, there is paucity of research focused on the prenatal effects of SCBs. This study uses correlation mapping optical coherence tomography (cm-OCT) to evaluate acute changes in the murine fetal brain vasculature in utero after exposure to CP-55,940, a well-characterized and commonly used reference compound in cannabinoid research. Our results showed a rapid decrease in parameters quantifying vasculature, i.e., vessel area density, and vessel length fraction, as compared to the sham group, demonstrating a dramatic and rapid effect of cannabinoids on fetal brain vasculature. Our work shows the need for further research on the effects of cannabinoids on fetal development.

Is there something more about synthetic cannabinoids?

Cannabis use among the younger population in Japan has been steadily increasing. The aim of the present review is to highlight recent knowledge regarding the molecular mechanisms of action and health risks associated with cannabis and synthetic cannabinoid consumption. We investigated the effects of Δ9-tetrahydrocannabinol (THC) and synthetic cannabinoids on place conditioning in ICR mice. Both Δ9-THC and synthetic cannabinoids produce a significant conditioned place preference. These rewarding effects were completely suppressed by the cannabinoid CB1 receptor type antagonist AM251. The cytotoxicological effects of Δ9-THC and synthetic cannabinoids were also characterized in the limbic forebrain of mice in primary culture in vitro. Δ9-THC and synthetic cannabinoids caused cell death in a dose-dependent manner. The rank order of cytotoxicological potency was synthetic cannabinoids>Δ9-THC and related to the agonistic activities of the CB1 receptor. A recent review on the harmful effects of cannabis use in humans reported that behavioral impairments, especially in terms of attention, memory, and complex information-processing ability, can last for many weeks after cessation of cannabis use among heavy users. In addition, cannabis use could be a risk factor for drug dependence and later psychosis among adolescents. The results of animal and human studies suggest that CB1 receptors play an important role in the expression of harmful effects of cannabis and synthetic cannabinoid use. Moreover, concern regarding increasing concentrations of Δ9-THC in cannabis in many countries has been noted, because more potent cannabis may be associated with worse adverse effects.

(1) Background: Synthetic cannabinoids (SCs) are emerging drugs of abuse sold as ‘K2’, ‘K9’ or ‘Spice’. Evidence shows that using SCs products leads to greater health risks than cannabis. They have been associated with greater toxicity and higher addiction potential unrelated to the primary psychoactive component of marijuana, Δ9-tetrahydrocannabinol (Δ9-THC). Moreover, early cases of intoxication and death related to SCs highlight the inherent danger that may accompany the use of these substances. However, there is limited knowledge of the toxicology of Spice ingredients. This systematic review intends to analyze the toxicity of SCs compounds in Spice/K2 drugs. (2) Methods: Studies analyzing synthetic cannabinoid toxicity and dependence were included in the present review. We searched the PubMed database of the US National Library of Medicine, Google Scholar, CompTox Chemicals, and Web of Science up to May 2022. (3) Results: Sixty-four articles reporting the effects of synthetic cannabinoids in humans were included in our review. Ten original papers and fifty-four case studies were also included. Fourteen studies reported death associated with synthetic cannabinoid use, with AB-CHMINACA and MDMB-CHMICA being the main reported SCs. Tachycardia and seizures were the most common toxicity symptoms. The prevalence of neuropsychiatric symptoms was higher in third-generation SCs. (4) Conclusion: SCs may exhibit higher toxicity than THC and longer-lasting effects. Their use may be harmful, especially in people with epilepsy and schizophrenia, because of the increased risk of the precipitation of psychiatric and neurologic disorders. Compared to other drugs, SCs have a higher potential to trigger a convulsive crisis, a decline in consciousness, and hemodynamic changes. Therefore, it is crucial to clarify their potential harms and increase the availability of toxicology data in both clinical and research settings.

Introduction: Synthetic cannabinoids (SCs) are commonly found in preparations used as recreational drugs. Although severe adverse health effects are not generally associated with cannabis use, a rising number of studies document seizures and even death after SC use. In this study, a mouse model is used to investigate the hypothesis that SCs are more toxic than Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis.Materials and Methods: Beginning with the SCs, JWH-073 and AM-2201, dose–response curves were generated to find the dose of each drug that was similarly efficacious to 50 mg/kg THC. Mice were given daily intraperitoneal (IP) injections of vehicle, 50 mg/kg THC, 30 mg/kg JWH-073, or 1 mg/kg AM-2201 until tolerance to the antinociceptive and hypothermic effects was complete, and then were assessed for spontaneous and antagonist-precipitated withdrawal and potential organ damage. No differences in tolerance were noted, but AM-2201 showed more rearing in the spontaneous and antagonist-precipitated withdrawal phases than either vehicle or the other two drug treatments. Histopathological examination of these mice revealed no drug-induced lesions. In a subsequent set of experiments, various doses of THC, methanandamide (mAEA), and of a variety of SCs (HU-210, CP55940, JWH-073, AM-2201, and PB-22) were given IP, and convulsions and change in body temperature were quantified.Discussion: The treatments yielded varying numbers of convulsions and a range of changes in body temperature. JWH-073 and AM-2201 produced significantly more convulsions than THC, HU-210, mAEA, or cannabidiol (CBD) (the latter two producing none). HU-210, CP55940, JWH-073, and mAEA produced greater hypothermia than THC or CBD. Convulsions and hypothermia induced by several agonists were prevented by pretreatment with a CB1 antagonist, but not a CB2 antagonist.Conclusions: In agreement with human studies and case reports, this study found that SCs generally produced more seizures than THC. Of particular significance was the finding that mAEA produced far greater hypothermia than THC (similar to most SCs), but unlike the SCs and THC, produced no seizures.

Evaluation of carboxamide-type synthetic cannabinoids on the functional activities at cannabinoid receptors and biological effects via inhalation exposure test

There is a growing use of novel psychoactive substances (NPSs) including synthetic cannabinoids. Synthetic cannabinoid products have effects similar to those of natural cannabis but the new synthetic cannabinoids are more potent and dangerous and their use has resulted in various adverse effects. The purpose of the study was to assess whether persistent use of synthetic cannabinoids is associating with impairments of executive function in chronic users. A total of 38 synthetic cannabinoids users, 43 recreational cannabis users, and 41 non-user subjects were studied in two centers in Hungary and Israel. Computerized cognitive function tests, the classical Stroop word-color task, n-back task, and a free-recall memory task were used. Synthetic cannabinoid users performed significantly worse than both recreational and non-cannabis users on the n-back task (less accuracy), the Stroop task (overall slow responses and less accuracy), and the long-term memory task (less word recall). Additionally, they have also shown higher ratings of depression and anxiety compared with both recreational and non-users groups. This study showed impairment of executive function in synthetic cannabinoid users compared with recreational users of cannabis and non-users. This may have major implications for our understanding of the long-term consequences of synthetic cannabinoid based drugs.

Rationale: Synthetic cannabinoids are increasingly used as recreational drugs and have been associated with adverse cardiovascular effects. However, reports of synthetic cannabinoids accompanied by constrictive pericarditis are limited. Patient’s concern: A 28-year-old male with a history of synthetic cannabinoid (Bonzai) abuse presented with chest discomfort, dyspnea, and lower extremity edema. Investigations revealed reduced left ventricular ejection fraction, elevated inflammatory markers, low electrocardiogram voltages, and atrial fibrillation. Diagnosis: Chest spiral computerized tomography scan and chest X-ray demonstrated pericardial calcification. Cardiac magnetic resonance imaging and right heart catheterization were done to confirm the possibility of constrictive pericarditis. Based on the patient’s addiction history and exclusion of rheumatologic and infectious causes, it was supposed that constrictive pericarditis and cardiomyopathy may be accompanied by synthetic cannabinoid use. Interventions: The patient received standard medical therapy, including loop diuretics for cardiomyopathy and constrictive pericarditis. Catheter ablation was recommended for his rhythm control, and he was planned for close monitoring of clinical and echocardiographic response and evaluation of the need for surgical pericardiectomy in the future. Outcomes: After 6 months follow-up, echocardiographic exam revealed no significant improvement in ventricular function. However, due to the high surgical risk, the patient’s poor compliance, and the continuation of drug abuse, he was not a good candidate for surgery according to our heart team’s decision. Lessons: Synthetic cannabinoids can trigger constrictive pericarditis, and clinicians should consider them when evaluating patients with compatible symptoms and exposure history. Further research on the cardiovascular effects of synthetic cannabinoids is needed and public education on potential harms is warranted.

Despite the ongoing political debate regarding the legality of medical marijuana, clinical investigations of the therapeutic use of cannabinoids are now more prevalent than at any time in history. Cannabinoids have been shown to have analgesic, anti-spasmodic, anticonvulsant, anti-tremor, anti-psychotic, anti-inflammatory, anti-oxidant, anti-emetic and appetite-stimulant properties. There are mainly two well known cannabinoid receptors, CB1 and CB2, located in the central and peripheral nervous systems as well as immune system, respectively. More recently, endocannabinoids (ligands) and their receptors have also been found in the skeleton which appears as the main body system physiologically regulated by CB2. The purpose of this investigation was to study the rate of wound healing using a scratch assay wound model created on MG63 bone cell-line monolayer and also to investigate proliferation and migration with and without the presence of cannabinoid WIN55, 212-2. Wounds were made (with average scratch width of 300|am±10-30|am SD, 1.7-5|am SEM) on confluent monolayers. After wounding, culture flasks were treated with the synthetic cannabinoid (WIN 55,212-2) with concentrations of 0.6|ag/ml and 0.9|ag/ml and a non-treated control and ethanol (as solvent). It was found that addition of synthetic cannabinoid closed the wound completely after 30 hours whereas the control showed no sign of complete wound closure after 30 hours with 25% of wound still remained open. The rate of wound closure wasfound to be higher with cannabinoid additions. These findings suggest the potential use of synthetic cannabinoid (WIN 55,212-2) for achieving complete wound closure at a faster rate.