A spicy kind of high: a profile of synthetic cannabinoid users

Aims: Over the last 6 years, numerous products have been made available and marketed as “legal highs.” Many of these products contain compounds similar to those within cannabis and function to create a high comparable to that of smoking marijuana. Though governments have regulated these psychoactive compounds, variants are still sold. At this point, little is known about the characteristics of users of synthetic cannabinoids. Design and Participants: A self-report survey instrument was administered to 2349 university students at a large institute in the State of Georgia. Respondents reported on their lifetime, last-year, and last-month synthetic cannabinoid use and demographic characteristics. Results: Males, Whites and Hispanics, users of other substances, and those from more affluent families were significantly more likely to report having used a synthetic cannabinoid. In addition, those that self-identified as lesbian, gay, bisexual, or transgender (LGBT) were twice as likely to have used synthetic cannabinoids. Conclusions: This research is among the first to detail characteristics of synthetic cannabinoid users in a large random sample. It appears that use of synthetic cannabinoids (synthetic marijuana analogs) continued after initial bans and that use is concentrated in affluent White and Hispanic males and in the LGBT community.     

A Case of Cannabinoid Hyperemesis Syndrome Caused by Synthetic Cannabinoids

Background

Cannabinoid hyperemesis syndrome (CHS) was initially described in 2004 and remains an under-recognized clinical entity that occurs in chronic heavy marijuana smokers.

Case Report

We describe the first report of CHS in an abuser of synthetic cannabinoids. CHS is thought to be caused by over-stimulation of the cannabinoid 1 receptor. The synthetic cannabinoids found in K2, Spice, and other commonly abused designer cannabinoids, including those used by our patient (JWH-018, JWH-073, JWH-122, AM-2201, and AM-694), are potent agonists of the cannabinoid 1 receptor.

Conclusion

Our report suggests that frequent habitual smoking of synthetic cannabinoids can cause cannabinoid hyperemesis syndrome.     

Severe Toxicity Following Synthetic Cannabinoid Ingestion

Objective. To report a case of seizures and supraventricular tachycardia (SVT) following confirmed synthetic cannabinoid ingestion. Background. Despite widespread use of legal synthetic cannabinoids, reports of serious toxicity following confirmed use of synthetic cannabinoids are rare. We report severe toxicity including seizures following intentional ingestion of the synthetic cannabinoid JWH-018 and detail confirmation by laboratory analysis. Case Report. A healthy 48 year old man had a generalized seizure within thirty minutes of ingesting an ethanol mixture containing a white powder he purchased from the Internet in an attempt to get high. Seizures recurred and abated with lorazepam. Initial vital signs were: pulse, 106/min; BP, 140/88 mmHg; respirations, 22/min; temperature, 37.7 °C. A noncontrast computed tomography of the brain and EEG were negative, and serum chemistry values were normal. The blood ethanol concentration was 3.8 mg/dL and the CPK 2,649 U/L. Urine drug screening by EMIT was negative for common drugs of abuse, including tetrahydrocannabinol. On hospital day 1, he developed medically refractory SVT. The patient had no further complications and was discharged in his normal state of health 10 days after admission. The original powder was confirmed by gas chromatography mass spectrometry to be JWH-018, and a primary JWH-018 metabolite was detected in the patient's urine (200 nM) using liquid chromatography tandem mass spectrometry. Discussion. Synthetic cannabinoids are legal in many parts of the world and easily obtained over the Internet. Data on human toxicity are limited and real-time confirmatory testing is unavailable to clinicians. The potential for toxicity exists for users mistakenly associating the dose and side effect profiles of synthetic cannabinoids to those of marijuana. Conclusion. Ingestion of JWH-018 can produce seizures and tachyarrhythmias. Clinicians, lawmakers, and the general public need to be aware of the potential for toxicity associated with synthetic cannabinoid use.     

Acute kidney injury associated with smoking synthetic cannabinoid

Context and objectives. Synthetic cannabinoids are illegal drugs of abuse known to cause adverse neurologic and sympathomimetic effects. They are an emerging health risk: 11% of high school seniors reported smoking them during the previous 12 months. We describe the epidemiology of a toxicologic syndrome of acute kidney injury associated with synthetic cannabinoids, review the toxicologic and public health investigation of the cluster, and describe clinical implications of the cluster investigation. Materials and methods. Case series of nine patients affected by the toxicologic syndrome in Oregon and southwestern Washington during May–October 2012. Cases were defined as acute kidney injury (creatinine > 1.3 mg/dL) among persons aged 13–40 years without known renal disease who reported smoking synthetic cannabinoids. Toxicology laboratories used liquid chromatography and time-of-flight mass spectrometry to test clinical and product specimens for synthetic cannabinoids, their metabolites, and known nephrotoxins. Public health alerts informed clinicians, law enforcement, and the community about the cluster and the need to be alert for toxidromes associated with emerging drugs of abuse. Results. Patients were males aged 15–27 years (median, 18 years), with intense nausea and flank or abdominal pain, and included two sets of siblings. Peak creatinine levels were 2.6–17.7 mg/dL (median, 6.6 mg/dL). All patients were hospitalized; one required dialysis; none died. No alternate causes of acute kidney injury or nephrotoxins were identified. Patients reported easily purchasing synthetic cannabinoids at convenience, tobacco, and adult bookstores. One clinical and 2 product samples contained evidence of a novel synthetic cannabinoid, XLR-11 ([1-(5-fluoropentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone). Discussion and conclusion. Whether caused by direct toxicity, genetic predisposition, or an as-yet unidentified nephrotoxin, this association between synthetic cannabinoid exposure and acute kidney injury reinforces the need for vigilance to detect new toxicologic syndromes associated with emerging drugs of abuse. Liquid chromatography and time-of-flight mass spectrometry are useful tools in determining the active ingredients in these evolving products and evaluating them for toxic contaminants.     

A case of acute cerebral ischemia following inhalation of a synthetic cannabinoid

Objective. Synthetic cannabinoids are increasingly used in the United States as marijuana substitutes. However, reports of severe toxicity, resulting from their use, are limited. We present the case of acute cerebral infarction following synthetic cannabinoid inhalation. Case report. A 33-year-old man with no significant medical history presented at the emergency department with right-sided weakness and aphasia. He had smoked a synthetic cannabinoid (SC) product called “WTF” prior to the onset of symptoms. Physical examination showed right hemiparesis, dysarthria, and aphasia. Laboratory evaluation, electrocardiography, and computed tomography (CT) of the head were unremarkable. Following administration of intravenous tissue plasminogen activator, his symptoms improved. A repeat head CT showed acute infarction in the left insular cortex. His hypercoagulability panel was unremarkable, and the patient was discharged neurologically intact. Urine toxicology results were unremarkable. Analysis of the product by gas chromatography–mass spectrometry (GC–MS) procedure confirmed the presence of a synthetic cannabinoid known as XLR-11. Conclusion. XLR-11 has previously been associated with acute kidney injury in humans. However, there are no reports of it causing acute cerebral ischemic events. The close temporal association between XLR-11 inhalation and his stroke is concerning. Acute cerebral infarction may occur after XLR-11 use in healthy patients.     

Administration of nabilone for postoperative pain control in the marijuana-addicted: Case study

Cannabis has been used for the treatment of pain for centuries. Case reports, small uncontrolled studies among health care providers suggest that cannabis and cannabinoids can be helpful for the relief of pain. However, controlled studies and systematic reviews have been less conclusive. Attempts to administer synthetic cannabinoids for postoperative pain control are disappointing. Moreover, marijuana addiction is an exclusion criterion in all published articles.We report the first, at least to our knowledge, administration of nabilone, a synthetic cannabinoid, for postoperative pain control in a marijuana-addicted patient as an adjuvant drug. The results suggest that nabilone can be considered as part of a multimodal analgesic regimen for habitual marijuana abusers. Nabilone optimizes pain control, improves sleep, decreases irritability and promotes early return of bowel function.     

Evidence for novel cannabinoid receptors

Cannabinoids, including the bioactive constituents of the marijuana plant, their synthetic analogs, and endogenous lipids with cannabinoid-like activity, produce their biological effects by interacting with specific receptors. To date, two G protein-coupled cannabinoid receptors have been identified by molecular cloning, CB1 receptors mainly expressed in the brain and mediating most of the neurobehavioral effects of cannabinoids and CB2 receptors expressed by immune and hematopoietic tissues. Recent findings indicate that some cannabinoid effects are not mediated by either CB1 or CB2 receptors, and in some cases there is compelling evidence to implicate additional receptors in these actions. These include transient receptor potential vanilloid 1 (TRPV1) receptors and as-yet-unidentified receptors implicated in the endothelium-dependent vasodilator effect of certain cannabinoids and in the presynaptic inhibition of glutamatergic neurotransmission in the hippocampus. The case for these additional receptors is being reviewed here.     

Assistive Technology for Young Children: Creating Inclusive Learning Environments,by Kathleen Curry Sadao,EdD, and Nancy B. Robinson,PhD, CCC-SLP

ABSTRACT

This study sought to compare road safety of new drivers with low vision who have followed a specific pilot bioptic training program with other groups of drivers all matched for age and driving experience. A quasi-experimental design was used two years after drivers obtained their license. Drivers were classified in the experimental group (n?=?10, they followed a pilot bioptic training program and had license restrictions: weight of the car, requirement of a yearly medical exams, requirement to wear glasses/contacts, use of a bioptic telescope), the comparison group (n?=?17, similar license restrictions except the use of a bioptic telescope) and the regional population (n?=?1,690, no license restriction). The number of new drivers involved in at least one accident and who committed at least one offense is not greater for users of a bioptic telescope than for drivers of in the other groups. The results of this study indicate that driving with a bioptic telescope does not increase the risk of accidents and offenses, with more scientific evidence than in previous studies, among drivers aged between 25 and 35 who have a congenital visual impairment and who have completed an eight-week pilot bioptic training program.     

Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects

The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, G(i/o) proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.     

Contact highs and urinary cannabinoid excretion after passive exposure to marijuana smoke

Five healthy men were passively exposed under pre- and postplacebo controlled conditions to sidestream smoke from four and 16 standard marijuana cigarettes (2.8% delta-9-tetrahydrocannabinol [delta-9-THC]) for 1 hour each day for 6 consecutive days. Subjective effects produced by the 16-cigarette exposure conditions were similar to those observed after active smoking of one 2.8% delta-9-THC marijuana cigarette. Effects after the four-cigarette condition were less pronounced. Concurrent physiologic measurements showed no clear trends or effects of smoke exposure for either condition. Daily mean plasma levels of delta-9-THC ranged from 2.4 to 7.4 ng/ml with an individual high of 18.8 ng/ml for the 16-cigarette condition. With the use of EMIT cannabinoid assays with 20 ng/ml (EMIT 20) and 100 ng/ml (EMIT 100) cutoffs, urines positive per subject under the four- and 16-cigarette passive exposure conditions were 4.6 +/- 2.2 and 35.2 +/- 3.8, respectively, for the EMIT 20 and 0.0 and 1.0 +/- 0.8, respectively, for the EMIT 100 assay. From the results of these studies, caution is clearly indicated for individuals who might be substantially exposed to heavy marijuana cigarette smoke environments and for those interpreting marijuana screening data.     

Cannabinoide und Immunsystem

The medical use of cannabis or cannabinoid compounds is controversial. Cannabinoids like the Delta(9)-THC (tetrahydrocannabinol) or the synthetic derivative Nabilone are available against cancer- and HIV-associated cachexia, nausea and vomiting. Over the last 20 years, the cannabinoid receptors CB(1) and CB(2) and their endogenous ligands have been found. The involvement of this endogenous cannabinoid signalling system in feeding, appetite, pain perception and immunomodulation could be demonstrated using animal and in vitro studies. Thus, the concern about immunosuppressive effects in humans using medical cannabinoid preparations grew. However, up to now most human studies have failed to demonstrate a well-defined and reproducible immunosuppressive cannabinoid-effect. Only the smoking of marijuana showed a significant local immunosuppression of the bactericidal activity of human alveolar macrophages.In animal studies, cannabinoids were identified as potent modulators of cytokine production, causing a shift from Th1 to Th2 cytokines. In consequence, a compromised cellular immunity was observed in these animals, resulting in enhanced tumor growth and reduced immunity to viral infections. In vitro, immunosuppressive effects were shown in all immune cells, but only at high micromolar cannabinoid concentrations not reached under normal clinical conditions. In conclusion, there is no evidence that cannabinoids induce a serious, relevant immunosuppression in humans, with the exception of marijuana-smoking which may affect local broncho-alveolar immunity.     

The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy

Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Delta9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus. Furthermore, we determined that during an short-term pilocarpine-induced seizure, levels of the endogenous CB1 ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region. These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.     

Perinatal exposure to Δ9-tetrahydrocannabinol triggers profound defects in T cell differentiation and function in fetal and postnatal stages of life, including decreased responsiveness to HIV antigens

Marijuana abuse is very prominent among pregnant women. Although marijuana cannabinoids have been shown to exert immunosuppression in adults, virtually nothing is known about the effects of marijuana use during pregnancy on the developing immune system of the fetus and during postnatal life. We noted that murine fetal thymus expressed high levels of the cannabinoid receptors CB1 and CB2. Moreover, perinatal exposure to Δ(9)-tetrahydrocannabinol (THC) had a profound effect on the fetus as evidenced by a decrease in thymic cellularity on gestational days 16, 17, and 18 and postgestational day 1 and marked alterations in T cell subpopulations. These outcomes were reversed by CB1/CB2 antagonists, suggesting that THC-mediated these effects through cannabinoid receptors. Thymic atrophy induced in the fetus correlated with caspase-dependent apoptosis in thymocytes. Thymic atrophy was the result of direct action of THC and not based on maternal factors inasmuch as THC was able to induce T cell apoptosis in vitro in fetal thymic organ cultures. It is noteworthy that perinatal exposure to THC also had a profound effect on the immune response during postnatal life. Peripheral T cells from such mice showed decreased proliferative response to T cell mitogen as well as both T cell and antibody response to HIV-1 p17/p24/gp120 antigens. Together, our data demonstrate for the first time that perinatal exposure to THC triggers profound T cell dysfunction, thereby suggesting that the offspring of marijuana abusers who have been exposed to THC in utero may be at a higher risk of exhibiting immune dysfunction and contracting infectious diseases including HIV.     

Cannabinoid-mediated elevation of intracellular calcium: a structure-activity relationship

This laboratory has reported previously that Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and cannabinol (CBN) robustly elevate intracellular calcium ([Ca(2+)](i)) in resting human and murine T cells, whereas CP55,940 [5-(1,1-dimethylheptyl)-2-(5-hydroxy-2-(3-hydroxypropyl)cyclohexyl)phenol], a high-affinity ligand for CB1 and CB2, does not. In light of our previous studies, the objective of the present investigation was to examine the ability of various cannabinoid compounds to elevate [Ca(2+)](i) in the CB2 receptor-expressing human peripheral blood acute lymphoid leukemia T cell line and the dependence of structural similarity to Delta(9)-THC therein. The present studies demonstrate that CBN and HU-210 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol], both tricyclic and in that respect structurally similar to Delta(9)-THC, elevate [Ca(2+)](i). The [Ca(2+)](i) elevation elicited by both CBN and HU-210 was attenuated upon removal of extracellular calcium and upon pretreatment with SK&F96365 [1-[beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole], an inhibitor of receptor-operated cation channels. In addition, pretreatment with either CB1 or CB2 receptor antagonists attenuated the CBN- and HU-210-mediated [Ca(2+)](i) elevation. Further investigation of the dependence of Delta(9)-THC, CBN, and HU-210 on cannabinoid receptors using splenocytes from wild-type and CB1(-/-)/CB2(-/-) mice showed that the [Ca(2+)](i) elevation elicited by all three tricyclic cannabinoids was independent of CB1 and CB2. Moreover, both the CB1 and CB2 receptor antagonists attenuated that rise in [Ca(2+)](i) elicited by the tricyclic cannabinoids in the wild-type and CB1(-/-)/CB2(-/-) mouse splenocytes. Taken together, the present results demonstrate that classic tricyclic cannabinoids with structural similarity to Delta(9)-THC elicit a robust influx of calcium in T cells putatively through receptor-operated cation channels in a manner sensitive to the cannabinoid receptor antagonists, but independent of the CB1 and CB2 receptors.     

Hyperglycemia at presentation is associated with in hospital mortality in non-diabetic patient with organophosphate poisoning

Aims: This study evaluated whether the initial venous glucose level at presentation is associated with fatality in organophosphate (OP)-poisoned patients without diabetes mellitus (DM) and whether the association between glucose and outcome differs depending on the chemical formulation of the OP ingested. Methods: This retrospective observational case series consisted of 184 patients without DM who had a history of OP poisoning. Initial glucose level at presentation, outcome and general clinical data were recorded. The patients were categorized into the following groups according to their glucose level at presentation: group 1 (<140?mg/dl, n?=?63), group 2 (140–200?mg/dl, n?=?58), group 3 (200–300?mg/dl, n?=?41), and group 4 (≥300?mg/dl, n?=?22). The most commonly ingested OPs were dichlorvos (n?=?33), fenitrothion (n?=?25), and ethyl p-nitrophenol thio-benzene phosphonate (EPN) (n?=?24). The primary outcome was case fatality. Results: Group 4 had a higher case fatality than groups 1 (p?=?0.003) and 2 (p?=?0.015), and group 3 had a higher case fatality than group 1 (p?=?0.040). Multivariate analysis revealed that age [odds ratio (OR) 1.065, 95% confidence interval (CI) 1.020–1.112, p?=?0.001], being in group 3 (OR 6.997, 95% CI 1.063–46.066, p?=?0.043) and being in group 4 (OR 9.101, 95% CI 1.380–60.044, p?=?0.022) were associated with case fatality. When using the glucose level at presentation?>?233?mg/dl, the dichlorvos group had a higher sensitivity (66.7% vs. 50.0%), specificity (90.0% vs. 86.4%), and positive (40.0% vs. 25.0%) and negative (96.4% vs. 95.0%) predictive values for predicting case fatality than the EPN group. No patient died of fenitrothion poisoning (mean glucose level at presentation?=?169.4?±?39.6?mg/dl). Conclusion: The case fatality risk independently increases as the initial venous glucose level at presentation increases in OP-poisoned patients without DM. However, because the association between the venous glucose level at presentation and case fatality varies according to the type of OP ingested, the chemical identity of the OP should be considered.     

The truth about marijuana is all rolled up in a blunt: prevalence and predictors of blunt use among young African–American adults

Several studies suggest that African–American young adults are more likely than other racial groups to smoke marijuana in blunts (i.e., hollowed-out cigars filled with marijuana). Given that tobacco content is found in the wrapper leaf of cigars that are used to make blunts, more studies are needed to assess the co-occurring use of marijuana and tobacco among African–American young adults. The present study was designed to address this gap by examining the prevalence rates and predictors of blunt usage among young African–American men and women (ages 18–25) participating in the 2012 National Survey on Drug Use and Health. Among participants who reported using marijuana in the past month, 74.4% of African–American women (N?=?246) and 82.7% of men (N?=?312) smoked marijuana in a blunt in the past 30 days (current blunt smokers). Logistic regression analyses revealed that current blunt smokers, both men and women, were approximately five times more likely to drive under the influence of illegal drugs in the past year than former and non-blunt smokers. Future marijuana research should examine the dual use of marijuana and tobacco rather than focusing solely on marijuana use, especially among young African–American men and women.     

Circulating SCCA–IgM complex is a useful biomarker to predict the outcome of therapy in hepatocellular carcinoma patients

Introduction: Hepatocellular carcinoma (HCC) develops in about 3–4% of cirrhotic patients every year. The squamous cell carcinoma antigen (SCCA) has been found elevated in liver cancer specimens by immunohistochemistry, and detected in complex with IgM (SCCA-IgM) in the serum of patients with HCC. The aim of this study was to evaluate the ability of serological SCCA-IgM levels to predict the efficacy of HCC therapy.

Materials and methods: From April 2012 to April 2014, 131 patients with a new diagnosis of HCC were enrolled. The HCC diagnosis was made according to the EASL guidelines. The patients were staged and treated according to the BCLC Staging System: BCLC stages A and B were treated with locoregional therapy, and BCLC stage C was treated with Sorafenib. Response to therapy was evaluated according to the mRECIST criteria. Serum SCCA-IgM levels were determined by a commercially available ELISA kit at basal time (T₀) and after one month of treatment (T₁).

Results: At baseline and one month into therapy, SCCA-IgM levels were significantly lower (p value <.05) in patients who responded to therapy compared to those who did not respond (median SCCA-IgM level [25th?+?75th percentile] at T₀:115.1?AU/mL [50.0?+?174.4] vs. 149.1?AU/mL [111.3?+?198.8]; median SCCA-IgM level [25th?+?75th percentile] at T₁: 113.4?AU/mL [50.0?+?194.2] vs. 170.6?AU/mL [111.7?+?344.2]).

Conclusion: Our study suggests that the SCCA-IgM determination could be helpful in predicting the response to therapy in patients with HCC.     

Differential effects of endogenous and synthetic cannabinoids on alpha7-nicotinic acetylcholine receptor-mediated responses in Xenopus Oocytes

The effects of endogenous and synthetic cannabinoid receptor agonists, including 2-arachidonoylglycerol (2-AG), R-methanandamide, WIN55,212-2 [4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenylcarbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one], and CP 55,940 [1alpha,2beta-(R)-5alpha]-(-)-5-(1,1-dimethyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl-phenol], and the psychoactive constituent of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), on the function of homomeric alpha7-nicotinic acetylcholine (nACh) receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp technique. The endogenous cannabinoid receptor ligands 2-AG and the metabolically stable analog of anandamide (arachidonylethanolamide), R-methanandamide, reversibly inhibited currents evoked with ACh (100 microM) in a concentration-dependent manner (IC50 values of 168 and 183 nM, respectively). In contrast, the synthetic cannabinoid receptor agonists CP 55,940, WIN55,212-2, and the phytochemical Delta9-THC did not alter alpha7-nACh receptor function. The inhibition of alpha7-mediated currents by 2-AG was found to be non-competitive and voltage-independent. Additional experiments using endocannabinoid metabolites suggested that arachidonic acid, but not ethanolamine or glycerol, could also inhibit the alpha7-nACh receptor function. Whereas the effects of arachidonic acid were also noncompetitive and voltage-independent, its potency was much lower than 2-AG and anandamide. Results of studies with chimeric alpha7-nACh-5-hydroxytryptamine (5-HT)3 receptors comprised of the amino-terminal domain of the alpha7-nACh receptor and the transmembrane and carboxyl-terminal domains of 5-HT3 receptors indicated that the site of interaction of the endocannabinoids with the alpha7-nAChR was not located on the N-terminal region of the receptor. These data indicate that cannabinoid receptor ligands that are produced in situ potently inhibit alpha7-nACh receptor function, whereas the synthetic cannabinoid ligands, and Delta9-THC, are without effect, or are relatively ineffective at inhibiting these receptors.     

Therapeutic Use of Synthetic Cannabinoids: Still an OpenIssue?

Cannabis sativa has a long history of use for medical purposes despite marijuana's addictive potential. The discovery of the endogenous cannabinoid system as a neuromodulatory system composed of receptors, endogenous ligands (endocannabinoids), and enzymes responsible for their synthesis and degradation, together with recent advancements in the elucidation of cannabinoid pharmacology, has renewed interest in medicines acting on the endocannabinoid system. Synthetic cannabinoid agonists have been developed and used for treatment of different human pathologic conditions, and promising potent cannabinoid antagonists are currently under clinical evaluation. During the last decade, new generations of synthetic cannabinoids appeared on the global drug market, proposed as marijuana-like compounds and sold as herbal mixture also known as spice drugs or legal highs. Because activation of cannabinoid receptors may induce central and peripheral beneficial effects, the newest synthetic cannabinoids having full agonistic activity and high potency at cannabinoid type 1 and type 2 receptors might have therapeutic potential too. However, case reports of acute and fatal intoxications are accumulating and revealing that this is not the case because adverse effects of the latest generation of synthetic cannabinoids far exceed the desired ones.     

Medical use of cannabis products

Introduction

The German government intends to reduce the barriers for the medical use of cannabis products. A discussion on the indications and contraindications of the medical use of cannabis and on the changes of the regulatory framework has already begun in Germany. It is useful to draw from the experiences of other countries with a more liberal medical use of cannabis.

Methods

The Israeli and Canadian experience is outlined by physicians who have been charged with expertise on the medical use of cannabis by their jurisdiction.

Results

In Israel, only the plant-based cannabinoid nabiximol (mixture of tetrahydrocannabinol/cannabidiol) can be prescribed for spasticity/chronic pain in multiple sclerosis and for cancer pain. The costs of nabiximole are reimbursed by some, but not by all health maintenance organizations. The medical use of marijuana is permitted; however, it is strictly regulated by the government. Selected companies are allowed to produce marijuana for medical use, and only certain physicians are licensed to prescribe marijuana as a therapeutic drug for specific indications such as chronic neuropathic, and cancer pain, inflammatory bowel diseases, or posttraumatic stress disorder if conventional treatments have failed. The costs of marijuana are not reimbursed by health insurance companies.In Canada, synthetic cannabinoids and the plant-based (nabiximol) are licensed for neuropathic and cancer pain, HIV-related anorexia and chemotherapy-associate nausea. The costs of these synthetic cannabinoids are covered by health insurance companies. The medical use of marijuana as a treatment option is allowed for individual patients suffering from any medical condition when authorized by a medical practitioner or nurse. Licensed producers are the only source for patients to newly access medical cannabis, although those with previous permission to grow may continue cultivation at the present time. The costs of marijuana are not reimbursed by health insurance companies.There are multiple contraindications for the medical use of cannabis products in both countries.

Conclusions

The use of standardized, synthetic, and plant-based cannabis products should be allowed in Germany for defined medical conditions when high-level evidence of efficacy and safety exists. The costs should be reimbursed by the health insurance companies. Contraindications for the medical use of cannabis should be defined. Growing marijuana by patients for their medical use should not be allowed.