jwh-018 and Substance-Related-Disorders

Topics: Animals; Behavior, Animal; Cannabinoids; Drug Tolerance; Humans; Hypothermia; Indoles; Mental Disorders; Naphthalenes; Seizures; Substance Withdrawal Syndrome; Substance-Related Disorders

In April and May 2015, the state of Mississippi experienced an unprecedented outbreak of severe reactions to the drug commonly referred to as "Spice." After numerous calls to the Poison Control Center, it became clear that health care providers were largely unfamiliar with the category of synthetic cannabinoids. This review article briefly highlights cannabinoid effects, chemical characteristics, and treatment for this often-dangerous category of drugs of abuse.

Topics: Cannabinoids; Designer Drugs; Humans; Illicit Drugs; Indoles; Molecular Structure; Naphthalenes; Substance-Related Disorders; United States

With new synthetic cannabinoids (SCs) appearing on the European drug market every year, early warning systems are key to detect, monitor, and respond to threats posed by them. The European Union Early Warning System (EU EWS) implemented by the European Monitoring Centre for Drugs and Drug Addiction has monitored these substances since their first European detection in 2008. Since then, national and international responses have been implemented, aimed at tackling risks posed by SCs. Throughout this time, new SCs have emerged on the European market containing diverse structural moieties, appearing to be designed in a way that circumvents existing legal controls, contributing to a complex public health scenario. This study provides an inventory of the SCs detected in the EU from 2008 to 2022, describing their structural evolution by analysing separately four structural features: their core, tail, linker, and linked groups. The range of structural changes is analysed considering key milestones, including the year of first report by the European Union Early Warning System to the key legislative changes that have occurred since. The analysis shows that from June 2021 to July 2022, 20 out of 23 newly emerged SCs evade the generic SC legislation introduced in China in May 2021. This supports the hypothesis that the protection of public health benefits from timely information exchange and careful assessment of the risks associated with these substances. Additionally, the introduction of legal responses, albeit an important instrument to reduce the availability of dangerous substances on the market, may also be accompanied by unintended consequences.

Topics: Cannabinoids; European Union; Humans; Indoles; Substance-Related Disorders

Synthetic cannabinoid receptor agonists (SCRAs) are found in illicit smoking products, such as "K2" or "Spice." Convulsions are commonly reported adverse effects of SCRAs but are poorly understood.. We determined convulsant effects of SCRAs AB-PINACA, and 5F-ADB-PINACA in adult male NIH Swiss mice, and then determined if convulsant effects of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 elicited seizure-like effects using EEG.. Mice were administered SCRAs or pentylenetetrazole (PTZ) and placed in observation chambers where convulsant effects were scored. The capacity of the CB1R antagonist rimonabant, the benzodiazepine diazepam, or the non-specific CYP450 inhibitor 1-aminobenzotriazole (1-ABT) to attenuate convulsant effects was determined. Other mice were prepared with EEG headmounts to ascertain whether observed convulsions occurred concurrently with seizure-like effects by assessing root-mean-square (RMS) power, high amplitude EEG spike analysis, and videography.. Mice receiving AB-PINACA or 5F-ADB-PINACA exhibited dose-dependent convulsant effects that were blocked by 10 mg/kg rimonabant pretreatment but not by pretreatment with 10 mg/kg diazepam; these convulsant effects were not altered in the presence of 100 mg/kg 1-ABT. Repeated administration of 10 mg/kg AB-PINACA and 3 mg/kg 5F-ADB-PINACA produced partial tolerance to convulsant effects but did not lead to cross-tolerance to PTZ-induced convulsions. In EEG studies, convulsant doses of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 did not produce seizures concomitantly with convulsions.. These data extend previous findings of convulsant effects of SCRAs and suggest that convulsant effects of AB-PINACA, 5F-AB-PINACA, 5F-ADB-PINACA, and JWH-018 are CB1R-mediated but are not associated with electroencephalographic seizures. These results further suggest that benzodiazepines may not effectively treat convulsions elicited by SCRA use in humans.

Topics: Animals; Benzodiazepines; Cannabinoid Receptor Agonists; Cannabinoids; Convulsants; Diazepam; Electroencephalography; Humans; Indazoles; Indoles; Male; Mice; Naphthalenes; Pentylenetetrazole; Receptor, Cannabinoid, CB1; Rimonabant; Seizures; Substance-Related Disorders; Valine

Topics: Cannabinoids; Crowding; Emergency Service, Hospital; Humans; Illicit Drugs; Indoles; Naphthalenes; Substance-Related Disorders

Synthetic cannabinoids, including JWH-018 and JWH-073, belong to a class of aminoalkylindoles (AAIs) that are smoked to produce an effect similar to tetrahydrocannabinol. Compounds in this class are often collectively known as 'Spice'. After ingestion, these compounds are extensively metabolized to their hydroxy and carboxylic acid metabolites. During forensic analysis, detection of these metabolites in urine is an indication of past exposure to the parent compounds. The analytical process involved hydrolysis of conjugated metabolites by glucuronidase, solvent extraction, derivatization by trifluoroacetic anhydride and hexafluoroisopropanol and GC-EIMS detection. Identification of the unknown was based on the criteria of GC retention time within ±2% and mass spectral ion ratio within ±20% of that of a standard. Deuterated internal standards of the carboxylic acid metabolites were used for quantification. The acid (JWH-018-COOH, JWH-073-COOH) and hydroxy (JWH-018-OH, JWH-073-OH) metabolites were linear over the concentration range of 0.1-10 and 0.2-10 ng/mL, respectively, with a correlation coefficient-square, R(2) > 0.999 (N = 5). Extraction recoveries of the metabolites were within 79 and 87%. The method was applied to 17 urine specimens collected as part of a military law enforcement investigation. Nine of the specimens tested positive for one or more of the metabolites. When the procedure was extended to screen other AAI compounds, two of the specimens were found to contain JWH-210, JWH-250 (JWH-302 or JWH-201) and JWH-250 (C4 isomers). The GC-EIMS method presented here was found to be suitable for detecting JWH-018 and JWH-073 metabolites and other AAI compounds in urine.

Topics: Biotransformation; Calibration; Carboxylic Acids; Chromatography, High Pressure Liquid; Forensic Toxicology; Gas Chromatography-Mass Spectrometry; Humans; Hydroxylation; Illicit Drugs; Indoles; Limit of Detection; Linear Models; Military Personnel; Naphthalenes; Predictive Value of Tests; Reference Standards; Reproducibility of Results; Smoking; Substance Abuse Detection; Substance-Related Disorders; Tandem Mass Spectrometry

With respect to the continuous emergence of new synthetic cannabinoids on the market since 2008, evaluation of the metabolism of these compounds and the development of analytical methods for the detection of these drugs including their respective metabolites in biological fluids have become essential. Other than JWH-018 or JWH-073, AM-2201 is one of the frequently identified synthetic cannabinoids in Korea. Recently, in our laboratory, several JWH-018 metabolites have been detected in some urine samples obtained from subjects who were arrested for the possession of herbal mixtures containing only AM-2201 or from those who confessed AM-2201 abuse. In the present study, we identified major urinary metabolites of AM-2201 and several metabolites of JWH-018, i.e., N-5-hydroxylated and carboxylated metabolites from rats administered AM-2201 and found that the metabolic profile in rats was similar to those in human subjects in this study. Analytical results of the urine samples from suspects who had a considerable possibility of AM-2201 or JWH-018 intake were also compared to distinguish between AM-2201 and JWH-018 abuse. The presence of 6-indole hydroxylated metabolites of each drug and N-4-hydroxy metabolite of AM-2201 was found to contribute to the decisive differences in the metabolic patterns of the two drugs. In addition, the concentration ratio of the N-(5-hydroxypentyl) metabolite to the N-(4-hydroxypentyl) metabolite of JWH-018 may be used as a criterion to differentiate between AM-2201 and JWH-018 abuse.

Topics: Animals; Biotransformation; Chromatography, Liquid; Humans; Illicit Drugs; Indoles; Male; Mass Spectrometry; Naphthalenes; Predictive Value of Tests; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Substance Abuse Detection; Substance-Related Disorders

Topics: Automobile Driving; Cannabinoids; Chromatography, Liquid; Designer Drugs; Forensic Toxicology; Germany; Humans; Indoles; Naphthalenes; Substance Abuse Detection; Substance-Related Disorders; Tandem Mass Spectrometry

Marijuana substitutes often contain blends of multiple psychoactive synthetic cannabinoids (SCBs), including the prevalent SCBs (1-pentyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-018) and (1-butyl-1H-indole-3-yl)-1-naphthalenyl-methanone (JWH-073). Because SCBs are frequently used in combinations, we hypothesized that coadministering multiple SCBs induces synergistic drug-drug interactions. Drug-drug interactions between JWH-018 and JWH-073 were investigated in vivo for Δ(9)-tetrahydrocannabinol (Δ(9)-THC)-like discriminative stimulus effects, analgesia, task disruption, and hypothermia. Combinations (JWH-018:JWH-073) of these drugs were administered to mice in assays of Δ(9)-THC discrimination, tail-immersion, and food-maintained responding, and rectal temperatures were measured. Synergism occurred in the Δ(9)-THC discrimination assay for two constant dose ratio combinations (1:3 and 1:1). A 1:1 and 2:3 dose ratio induced additivity and synergy, respectively, in the tail-immersion assay. Both 1:1 and 2:3 dose ratios were additive for hypothermia, whereas a 1:3 dose ratio induced subadditive suppression of food-maintained responding. In vitro drug-drug interactions were assessed using competition receptor-binding assays employing mouse brain homogenates and cannabinoid 1 receptor (CB1R)-mediated inhibition of adenylyl cyclase activity in Neuro2A wild-type cells. Interestingly, synergy occurred in the competition receptor-binding assay for two dose ratios (1:5 and 1:10), but not in the adenylyl cyclase activity assay (1:5). Altogether, these data indicate that drug-drug interactions between JWH-018 and JWH-073 are effect- and ratio-dependent and may increase the relative potency of marijuana substitutes for subjective Δ(9)-THC-like effects. Combinations may improve the therapeutic profile of cannabinoids, considering that analgesia but not hypothermia or task disruption was potentiated. Importantly, synergy in the competition receptor-binding assay suggests multiple CB1R-SCB binding sites.

Topics: Adenylyl Cyclase Inhibitors; Animals; Binding, Competitive; Body Temperature; Cells, Cultured; Conditioning, Operant; Discrimination, Psychological; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Female; Generalization, Psychological; Hypothermia; Illicit Drugs; In Vitro Techniques; Indoles; Male; Membranes; Mice; Naphthalenes; Pain; Pain Measurement; Psychomotor Performance; Receptor, Cannabinoid, CB1; Substance-Related Disorders

New designer drugs such as K2, Spice, and "bath salts" present a formidable challenge for law enforcement and public health officials. The following report summarizes a three-year study of 1320 law enforcement cases involving over 3000 products described as vegetable material, powders, capsules, tablets, blotter paper, or drug paraphernalia. All items were seized in Arkansas from January 2010 through December 2012 and submitted to the Arkansas State Crime Laboratory for analysis. The geographical distribution of these seizures co-localized in areas with higher population, colleges, and universities. Validated forensic testing procedures confirmed the presence of 26 synthetic cannabinoids, 12 designer stimulants, and 5 hallucinogenic-like drugs regulated by the Synthetic Drug Prevention Act of 2012 and other state statutes. Analysis of paraphernalia suggests that these drugs are commonly used concomitantly with other drugs of abuse including marijuana, MDMA, and methamphetamine. Exact designer drug compositions were unpredictable and often formulated with multiple agents, but overall, the synthetic cannabinoids were significantly more prevalent than all the other designer drugs detected. The synthetic cannabinoids JWH-018, AM2201, JWH-122, JWH-210, and XLR11 were most commonly detected in green vegetable material and powder products. The designer stimulants methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxy-N-methylcathinone (methylone), and α-methylamino-valerophenone (pentedrone) were commonly detected in tablets, capsules, and powders. Hallucinogenic drugs were rarely detected, but generally found on blotter paper products. Emerging designer drug products remain a significant problem and continued surveillance is needed to protect public health.

Topics: Benzodioxoles; Cannabinoids; Capsules; Central Nervous System Stimulants; Designer Drugs; Dronabinol; Hallucinogens; Humans; Indoles; Methamphetamine; Methylamines; Molecular Structure; Naphthalenes; Paper; Pentanones; Powders; Pyrrolidines; Substance-Related Disorders; Synthetic Cathinone; Tablets

An 18-year-old man inhaled a substance containing synthetic cannabinoids and 1 hour later developed a severe global headache. Imaging revealed a perimesencephalic subarachnoid haemorrhage. An angiogram suggested that a small superior cerebellar artery aneurysm was the culprit. This report discusses the, as yet undefined, relationship between "herbal highs" and intracranial haemorrhage.

Topics: Adolescent; Angiography, Digital Subtraction; Cannabinoids; Cerebral Angiography; Endovascular Procedures; Headache; Humans; Illicit Drugs; Indoles; Magnetic Resonance Angiography; Male; Naphthalenes; Subarachnoid Hemorrhage; Substance-Related Disorders; Tomography, X-Ray Computed

Aroma, Spice, K2 and Dream are examples of a class of new and increasingly popular recreational drugs. Ostensibly branded "herbal incense", they have been intentionally adulterated with synthetic cannabinoids such as JWH-018 in order to confer on them cannabimimetic psychoactive properties while circumventing drug legislation. JWH-018 is a potent cannabinoid receptor agonist. Little is known about its pharmacology and toxicology in humans. This is the first research considering the effects of JWH-018 on a psychiatric population and exploring the relationship between JWH-018 and psychotic symptoms.. This paper presents the results of semi-structured interviews regarding the use and effects of JWH-018 in 15 patients with serious mental illness in a New Zealand forensic and rehabilitative service.. All 15 subjects were familiar with a locally available JWH-018 containing product called "Aroma" and 86% reported having used it. They credited the product's potent psychoactivity, legality, ready availability and non-detection in drug testing as reasons for its popularity, with most reporting it had replaced cannabis as their drug of choice. Most patients had assumed the product was "natural" and "safe". Anxiety and psychotic symptoms were common after use, with 69% of users experiencing or exhibiting symptoms consistent with psychotic relapse after smoking JWH-018. Although psychological side effects were common, no one reported becoming physically unwell after using JWH-018. Three subjects described developing some tolerance to the product, but no one reported withdrawal symptoms.. It seems likely that JWH-018 can precipitate psychosis in vulnerable individuals. People with risk factors for psychosis should be counseled against using synthetic cannabinoids.

Topics: Adult; Cannabinoids; Humans; Illicit Drugs; Indoles; Interview, Psychological; Male; Middle Aged; Naphthalenes; New Zealand; Psychoses, Substance-Induced; Psychotic Disorders; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Substance-Related Disorders; Young Adult

'Spice' is an herbal blend that has been reported to produce cannabis-like effects when smoked and is marketed as an alternative to marijuana. Synthetic additives have been identified in numerous 'Spice' preparations from different sources. Common among many of the preparations were the compounds JWH018 and a dimethyloctyl variant of CP47,497 (CP47,497-C8) and, more recently JWH073. The synaptic effects of each of these compounds were uncharacterized. We previously reported that JWH018 is a potent and efficacious CB(1) cannabinoid receptor agonist. In this study we have examined the abilities of CP47,497-C8 and JWH073 to inhibit neurotransmission in cultured autaptic hippocampal neurons. Each inhibited EPSCs with an efficacy and potency similar to JWH018. We also analyzed these compounds' effects on promoting internalization of CB(1) receptors in HEK293 cells stably expressing CB(1) receptors. Similar to our neurotransmission data, CP47,497-C8 internalized CB(1) in a fashion indistinguishable from JWH018. However, JWH073 was less potent and produced slower internalization than JWH018 and CP47,497-C8. It appears that 'Spice' contains a number of cannabinoid receptor agonists that activate CB(1) receptors to inhibit synaptic transmission with similar potencies and efficacies. It is highly probable that the cannabis-like effects of 'Spice' are due to the presence of these and analogous synthetic additives acting on CB(1) receptors.

Topics: Animals; Cell Line; Cyclohexanols; Indoles; Mice; Naphthalenes; Plant Extracts; Protein Transport; Receptor, Cannabinoid, CB1; Stereoisomerism; Structure-Activity Relationship; Substance-Related Disorders; Synaptic Transmission

We describe three cases with confirmed exposure to "spice" by detection of the metabolites JWH-018 and/or JWH-073 in urine. All cases had a negative urine drug screen. Case 1. A 25-year-old male with possible seizure, tachycardia, acidosis, and unresponsiveness, presented to a local emergency department (ED) after smoking a "spice" product. His symptoms resolved with benzodiazepines, fluid, and observation. His urine tested positive for JWH-018 and negative for JWH-073 metabolites. Case 2. A 21-year-old male was found unresponsive after smoking "spice." He had hypertension, was agitated, and had a Glasgow Coma Score of 7; the patient was intubated. The skin was warm and dry. His symptoms resolved with IV fluids and he was discharged home after 24 h. His urine tested positive for metabolites of JWH-018 and JWH-073. Case 3. A 19-year-old male was brought to the ED 1 h after smoking a "spice" product and having paranoia and delusions. His urine tested positive for JWH-018 and JWH-073 metabolites. He was discharged asymptomatic after observation for a few hours.. Spice products are new and abused for their psychogenic effects and mood alteration. These cases exhibited changes consistent with either an anticholinergic or sympathomimetic agent that resolved following general supportive care.

Topics: Adult; Cannabinoids; Humans; Indoles; Male; Naphthalenes; Substance-Related Disorders

Topics: Adolescent; Emergency Service, Hospital; Female; Humans; Hypertension; Hypokalemia; Illicit Drugs; Indoles; Naphthalenes; Psychomotor Agitation; Substance-Related Disorders; Tachycardia