Phase I Hydroxylated Metabolites of the K2 Synthetic Cannabinoid JWH-018 Retain In Vitro and In Vivo Cannabinoid 1 Receptor Affinity and Activity

K2 products are synthetic cannabinoid-laced, marijuana-like drugs of abuse, use of which is often associated with clinical symptoms atypical of marijuana use, including hypertension, agitation, hallucinations, psychosis, seizures and panic attacks. JWH-018, a prevalent K2 synthetic cannabinoid, is structurally distinct from Δ(9)-THC, the main psychoactive ingredient in marijuana. Since even subtle structural differences can lead to differential metabolism, formation of novel, biologically active metabolites may be responsible for the distinct effects associated with K2 use. The present study proposes that K2's high adverse effect occurrence is due, at least in part, to distinct JWH-018 metabolite activity at the cannabinoid 1 receptor (CB1R).JWH-018, five potential monohydroxylated metabolites (M1-M5), and one carboxy metabolite (M6) were examined in mouse brain homogenates containing CB1Rs, first for CB1R affinity using a competition binding assay employing the cannabinoid receptor radioligand [(3)H]CP-55,940, and then for CB1R intrinsic efficacy using an [(35)S]GTPγS binding assay. JWH-018 and M1-M5 bound CB1Rs with high affinity, exhibiting K(i) values that were lower than or equivalent to Δ(9)-THC. These molecules also stimulated G-proteins with equal or greater efficacy relative to Δ(9)-THC, a CB1R partial agonist. Most importantly, JWH-018, M2, M3, and M5 produced full CB1R agonist levels of activation. CB1R-mediated activation was demonstrated by blockade with O-2050, a CB1R-selective neutral antagonist. Similar to Δ(9)-THC, JWH-018 and M1 produced a marked depression of locomotor activity and core body temperature in mice that were both blocked by the CB1R-preferring antagonist/inverse agonist AM251.Unlike metabolites of most drugs, the studied JWH-018 monohydroxylated compounds, but not the carboxy metabolite, retain in vitro and in vivo activity at CB1Rs. These observations, combined with higher CB1R affinity and activity relative to Δ(9)-THC, may contribute to the greater prevalence of adverse effects observed with JWH-018-containing products relative to cannabis

Ventricular Dysrhythmias Associated with Poisoning and Drug Overdose: A 10-Year Review of Statewide Poison Control Center Data from California

Background: Ventricular dysrhythmias are a serious consequence associated with drug overdose and chemical poisoning. The risk factors for the type of ventricular dysrhythmia and the outcomes by drug class are not well documented. Objective: The aim of this study was to determine the most common drugs and chemicals associated with ventricular dysrhythmias and their outcomes. Methods: We reviewed all human exposures reported to a statewide poison control system between 2002 and 2011 that had a documented ventricular dysrhythmia. Cases were differentiated into two groups by type of arrhythmia: (1) ventricular fibrillation and/or tachycardia (VT/VF); and (2) torsade de pointes (TdP). Results: Among the 300 potential cases identified, 148 cases met the inclusion criteria. Of these, 132 cases (89 %) experienced an episode of VT or VF, while the remaining 16 cases (11 %) had an episode of TdP. The most commonly involved therapeutic classes of drugs associated with VT/VF were antidepressants (33/132, 25 %), stimulants (33/132, 25 %), and diphenhydramine (16/132, 12.1 %). Those associated with TdP were antidepressants (4/16, 25 %), methadone (4/16, 25 %), and antiarrhythmics (3/16, 18.75 %). Drug exposures with the greatest risk of death in association with VT/VF were antidepressant exposure [odds ratio (OR) 1.71; 95 % confidence interval (CI) 0.705–4.181] and antiarrhythmic exposure (OR 1.75; 95 % CI 0.304–10.05), but neither association was statistically significant. Drug exposures with a statistically significant risk for TdP included methadone and antiarrhythmic drugs. Conclusions: Antidepressants and stimulants were the most common drugs associated with ventricular dysrhythmias. Patients with suspected poisonings by medications with a high risk of ventricular dysrhythmia warrant prompt ECG monitoring

An overview of recent developments in the analytical detection of new psychoactive substances (NPSs)

New psychoactive substances (NPSs), sometimes referred to as “legal highs” in more colloquial environments/ the media, are a class of compounds that have been recently made available for abuse (not necessarily recently discovered) which provide similar effects to the traditional well studied illegal drugs but are not always controlled under existing local, regional or international drug legislation. Following an unprecedented increase in the number of NPSs in the last 5 years (with 101 substances discovered for the first time in 2014 alone) its, occasionally fatal, consequences have been extensively reported in the media. Such NPSs are typically marketed as ‘not for human consumption’ and are instead labelled and sold as plant food, bath salts as well as a whole host of other equally nondescript aliases in order to bypass legislative controls. NPSs are a new multi-disciplinary research field with the main emphasis in terms of forensic identification due to their adverse health effects, which can range from minimal to life threatening and even fatalities. In this mini-review we overview this recent emerging research area of NPSs and the analytical approaches reported to provide detection strategies as well as detailing recent reports towards providing point-of-care/in-the-field NPS (“legal high”) sensors

The Effect of the FDA VVarning on the Use of Droperidol by U.S. Emergency Physicians

Objectives: To determine if emergency physicians' (EP) use droperidol has changed since the United States Food and Drug Administration (FDA) warning of December 2001 concerning QT interval prolongation, torsade de pointes, and sudden death; and to query EP opinions regarding droperidol before and after the FDA warning and regarding potential alternative drugs.Methods: An internet-based survey was designed with questions regarding droperidol use in the emergency department (ED). Data collected included EP demographics, use of droperidol before and after the FDA warning, use of alternative drugs, and incidence of arrhythmias. A representative sample of EPs were contacted by e-mail and asked to complete the survey.Results: A total of 2,000 e-mails resulted in 506 (25%) completed surveys. There was no second mailing. Responders' average years practicing was 12.6 +_ 9.2. EP responders worked in private/community (n=278, 55%), academic/county (n=187, 37%), and HMO (n=41,8%) hospitals. The majority (n=455, 90%) used droperidol and were aware of the FDA warning (n=460, 91%). Droperidol was no longer available at 122 (24%) of the respondents' EDs as a result of the FDA warning. Prior to the FDA warning, EPs who had used droperidol used it as an antiemetic (n=408, 90%), for control of agitation (n=330, 73%), for treatment of headache (n=247, 54%), and for treatment of vertigo (n=106, 23%). After the FDA warning, 387 (85%) of EPs reported their use of droperidol had decreased or ceased altogether, and 68 (15%) always obtained an electrocardiogram prior to administration. Of those who used droperidol for agitation, 137 (42%) felt there were no other drugs with greater efficacy. Haloperidol was the most cited alternative agent (n=160, 79%) followed by benzodiazepines (n=223, 68%). Of those who used droperidol for antiemesis, 116 (28%) felt there were no other drugs with greater efficacy than droperidol; promethazine was the most cited alternative agent (n=26O, 64%). Two (0.4%) EPs reported arrhythmias in patients who received droperidol. Only 37 (8%) EPs reported they were unconcerned with potential loss of droperidol from the market.Conclusion: Based on this survey, EP use of droperidol has decreased dramatically as a result of the FDA warning. However, EPs believe that there are few or no alternative antiemetic drugs that have an improved adverse effect profile