Indications for the use of cannabinoids / Indicação do uso de canabinoides

ABSTRACT BACKGROUND AND OBJECTIVES: The increasingly widespread use of cannabinoids in the management of acute and chronic pain generates an urgent need to study how cannabinoids act on CB1 and CB2 receptors and what their effects are on the organism. It is important to understand the difference in action between natural cannabinoids (cannabidiol, delta 9-tetrahydrocannabinol, cannabigerol, cannabinoil, terpenes) and synthetic ones, so that the appropriate choice is made in each case, and depending on the pathophysiology of pain, one or the other active is more indicated. CONTENTS: Studies collected in the Pubmed, Cochrane Library and Web of Science databases were analyzed. These studies focus were on natural cannabinoids (cannabidiol, delta 9-tetrahydrocannabinol, cannabigerol, cannabinoil, terpenes) and synthetic cannabinoids in the use for the treatment of chronic pain, their action on the endocannabinoid system through the activation of the CB1 and CB2 receptor and their effect after activating this receptor, aiming to compile which cannabinoid is more indicated in the treatment of pain pathology. CONCLUSION: The subject still requires much study and new articles are being published daily. The analysis of the studies must be carried out with criteria to evaluate their seriousness. The endocannabinoid system is closely linked to the treatment of chronic pain and some cannabinoids such as: cannabidiol, delta 9-tetrahydrocannabinol, cannabigerol, cannabinoil, as well as some terpenes are already considered important in the treatment of chronic pain inferring sparing effect of opioids, anticonvulsants, antidepressants among others.

RESUMO JUSTIFICATIVA E OBJETIVOS: O uso cada vez mais disseminado dos canabinoides no controle da dor aguda e crônica gera uma necessidade urgente do estudo de como os canabinoides agem nos receptores CB1 e CB2 e quais seus efeitos no organismo. É importante entender a diferença de ação entre os canabinoides naturais (canabidiol, delta 9-tetrahidrocanabinol, canabigerol, canabinol, terpenos) e os sintéticos, para que a escolha adequada seja realizada em cada caso, sendo que dependendo da fisiopatologia da dor é mais indicado um ou outro ativo. CONTEÚDO: Foram analisados estudos coletados na Pubmed, Cochrane Library e Web of Science. Os estudos se concentram em canabinoides naturais (canabidiol, delta 9-tetrahidrocanabinol, canabigerol, canabinoil, terpenos) e canabinoides sintéticos no uso para o tratamento da dor crônica, sua ação no sistema endocanabinoide através da ativação do receptor CB1 e CB2 e seu efeito após ativar esse receptor, visando compilar qual canabinoide é mais indicado no tratamento da patologia álgica. CONCLUSÃO: O assunto ainda requer muito estudo e diariamente novos artigos vem sendo publicados. A análise dos estudos deve ser realizada com critério para avaliar sua seriedade. O sistema endocanabinoide está intimamente ligado ao tratamento da dor crônica e alguns canabinoides como: canabidiol, delta 9-tetrahidrocanabinol, canabigerol, canabinoil, assim como alguns terpenos já são considerados importantes no tratamento da dor crônica inferindo efeito poupador de opioides, anticonvulsivantes, antidepressivos entre outros.

Dispersive liquid-liquid microextraction,an effective tool for the determination of synthetic cannabinoids in oral fluid by liquid chromatography-tandem mass spectrometry / 药物分析学报

In the present work,dispersive liquid-liquid microextraction (DLLME) was used to extract six synthetic cannabinoids (JWH-018,JWH-019,JWH-073,JWH-200,or WIN 55,225,JWH-250,and AM-694) from oral fluids.A rapid baseline separation of the analytes was achieved on a bidentate octadecyl silica hydride phase (Cogent Bidentate C18;4.6 mm × 250 mm,4 μm) maintained at 37℃,by eluting in isocratic conditions (water:acetonitrile (25:75,V/V)).Detection was performed using positive electrospray ionization-tandem mass spectrometry.The parameters affecting DLLME (pH and ionic strength of the aqueous phase,type and volume of the extractant and dispersive solvent,vortex and centrifugation time)were optimized for maximizing yields.In particular,using 0.5 mL of oral fluid,acetonitrile (1 mL),was identified as the best option,both as a solvent to precipitate proteins and as a dispersing solvent in the DLLME procedure.To select an extraction solvent,a low transition temperature mixture (LTTM;composed of sesamol and chlorine chloride with a molar ratio of 1:3) and dichloromethane were compared;the latter (100 μL) was proved to be a better extractant,with recoveries ranging from 73％ to 101％ by vortexing for 2 min.The method was validated according to the guidelines of Food and Drug Administration bioanalytical methods:intra-day and inter-day precisions ranged between 4 ％ and 18 ％depending on the spike level and analyte;limits of detection spanned from 2 to 18 ng/mL;matrix-matched calibration curves were characterized by determination coefficients greater than 0.9914.Finally,the extraction procedure was compared with previous methods and with innovative techniques,presenting superior reliability,rapidity,simplicity,inexpensiveness,and efficiency.

Metabolism of New Psychoactive Substances 4F-MDMB-BUTINACA in Zebrafish / 法医学杂志

Objective To study the metabolic transformation pathways of 4F-MDMB-BUTINACA in vivo by establishing zebrafish models. Methods Six adult zebrafish were randomly divided into blank control group and experimental group, with three fish in each group. After the zebrafish in the experimental group were exposed to 1 μg/mL 4F-MDMB-BUTINACA for 24 h, they were transferred to clean water and cleaned three times, then pretreated for instrumental analysis. The zebrafish in blank control group were not exposed to 4F-MDMB-BUTINACA. Mass spectrometry and structural analysis of 4F-MDMB-BUTINACA and its metabolites were conducted by liquid chromatography-high resolution mass spectrometry and Mass Frontier software. Results A total of twenty-six metabolites of 4F-MDMB-BUTINACA were identified in zebrafish, including eighteen phase Ⅰ metabolites and eight phase Ⅱ metabolites. The main metabolic pathways of phase Ⅰ metabolites of 4F-MDMB-BUTINACA in zebrafish were ester hydrolysis, N-dealkylation, oxidative defluorination and hydroxylation, while the main metabolic pathway of phase Ⅱ metabolites was glucuronidation. Conclusion Metabolite Md24 （ester hydrolysis） and Md25 （ester hydrolysis combined with dehydrogenation） would be recommended to be potentially good biomarkers for abuse of 4F-MDMB-BUTINACA.

Identification of Synthetic Cannabinoid 5F-EDMB-PICA in Suspicious Herbal Products / 法医学杂志

Objective To study the qualitative analysis strategy for unknown synthetic cannabinoid in the suspicious herbal product when no reference substance is available. Methods The synthetic cannabinoid in herbal blend was extracted with methanol. The extract was concentrated by rotary evaporator and separated and purified by preparative liquid chromatography, to obtain high purity synthetic cannabinoid sample. Gas chromatography-mass spectrometry （GC-MS）, ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry （UPLC-QTOF-MS） and nuclear magnetic resonance （NMR） were used to determine the structure of the prepared compound. Results High purity unknown sample （10 mg） was obtained by preparative liquid chromatography. The sample was analyzed by GC-MS, UPLC-TOF-MS and NMR, and through spectrum analysis, the unknown synthetic cannabinoid was determined as 5F-EDMB-PICA. Conclusion The method to extract unknown synthetic cannabinoid from low content herbal products by preparative liquid chromatography was established, and the structure of the unknown sample was identified by comprehensive use of GC-MS, UPLC-QTOF-MS and NMR. The information will assist forensic laboratories in identifying this substance or other compounds with similar structures in their casework.

Pharmacology Of Noval Cannabinoids

Cannabis is a plant rich in various compounds that have a variety of impacts on the physiology of humans and the effects of these metabolites have a significant role in managing a variety of clinical diseases. A substantial increase in the use of SC (synthetic cannabinoids) had seen in the last few years especially infrequent cannabis users. The SCs will generate psychoactive effects that were similar to cannabis. However, the composition and pharmacological characteristics of these drugs make them possibly hazardous. Like all drugs, cannabis’ pharmacokinetics depends on the route of administration. Several studies showed that the bioavailability is less in oral administration when compared to inhalation. The main reason for this decrease in oral bioavailability is that cannabinoids undergo the first-pass metabolism before entering into the systemic circulation whereas in inhalation, it enters the circulation directly through the lungs. Cannabis sativa is a psychoactive plant that contains more than 500 components of which 104 cannabinoids had been identified. Of these, 2 components such as Δ9-THC (Δ9-tetrahydrocannabinol) and CBD (cannabidol) were under the scientific investigation. Δ9-THC is the primary cannabinoid which was responsible for the consequences of psychotrophy. The potency of cannabis is assessed based on the THC concentration of a sample that is the main psychoactive cannabinoid in cannabis. The adverse effects are in direct relation to the concentration of THC in the product after regular cannabis use. It can be assumed that several cannabinoids will find their way into the pharmacies from preclinical research within a century.

Rapid Identification of Four New Synthetic Cannabinoids in Whole Blood / 法医学杂志

Objective To establish accurate and rapid methods to identify four new synthetic cannabinoids （JWH-203, JWH-122, 5F-APINACA and AB-CHMINACA） in blood samples. Methods The whole blood samples were extracted by acetonitrile and methanol, screened by gas chromatography-mass spectrometry （GC-MS） then confirmed by liquid chromatography-tandem mass spectrometry （LC-MS/MS） method, and multiple reaction monitoring （MRM） mode was used for quantitative analysis. Results The GC-MS method needed 21 min to complete the analysis, while the LC-MS/MS method needed 5 min. The AB-CHMINACA, JWH-203, 5F-APINACA and JWH-122 all used quasi molecular ion peak as a parent ion. The precursor-product ion combinations were m/z 357.4→312.2, m/z 340.2→125.0, m/z 384.1→135.1 and m/z 356.4→169.2. The four synthetic cannabinoids in blood samples had good linearity in the 1-250 ng/mL mass concentration range （r>0.99）. The limits of detection （LODs） were in the range of 0.1-0.5 ng/mL, the recovery rate was 85.4%-95.2%, the RSD less than 10.0%, and the matrix effect was 80.3%-92.8%. Conclusion The GC-MS and LC-MS/MS chromatographic behaviors and mass spectrometry analysis information of four synthetic cannabinoids were obtained in this study, and the possible causes of differences in chromatographic behaviors were discussed preliminarily. Therefore this study has a suggestive effect on judging the development trend of synthetic cannabinoids. This method can be used for rapid identification of four synthetic cannabinoids in blood, which can provide reference for identification of new synthetic cannabinoids when they are proliferating at present.

Applications of nuclear magnetic resonance spectroscopy in the screening of new psychoactive substances / 中国药科大学学报

@#GC-MS and LC-MS are the main techniques used for the structural identification of new psychoactive substances at present. However, they are hard to give accurate structure information because of the hardly available corresponding reference standards and the quickly changing status of these compounds. This leads tremendous obstacle on the rapid identification of new psychoactive substances. Nuclear magnetic resonance spectroscopy is one of the most effective methods for structures identification. Therefore, NMR is especially suitable for the analysis and identification of new psychoactive substances even with rapid structural changes. This article summarizes the NMR applications for the structural analysis of new psychoactive substances including synthetic cannabinoids, synthetic cathinones, piperazines, phenethylamines, ketamine & phencyclidine-type substances, and fentanyls. It is found that the NMR signals of the main frame structure of each kind of the new psychoactive substances are basically the same. Hence, these frame structure NMR signals can provide scientific evidence for the rapid identification of new psychoactive substances. This article also look ahead the prospect for the application of LC-NMR and DOSY in new psychoactive substances, which provides new ideas for the screening of new psychoactive substances.

Valoración médico legal del consumo de la marihuana sintética / Legal medical evaluation of the consumption of synthetic marihuana

ResumenLa marihuana sintética es una sustancia que ha incrementado su consumo en los últimos años y que conlleva a múltiples implicaciones en la salud de las personas que la utilizan. Este artículo se basa en identificar los principales formas de uso, los síntomas de los evaluados, la fisiopatología de estas sustancias y los riesgos y consideraciones para el manejo de pacientes que consumen cannabinoides sintéticos, así como los criterios Médico Legales que se deben tener presentes en el momento de realizar una valoración de evaluados que utilizan alguna sustancia en la Clínica Médico Forense y en el momento de realizar una autopsia Médico Legal en particular cuando existe la historia reciente del consumo de la marihuana sintética.

SummarySynthetic marijuana is a substance that has increased its consumption in recent years and that leads to multiple implications on the health of people who use it. This article is based on identifying the main forms of use, the symptoms of the evaluated ones, the pathophysiology of these substances and the risks and considerations for the management of patients who use synthetic cannabinoids, as well as the Legal Medical criteria that must be kept in mind The time to make an assessment in the Forensic Medical Clinic and at the time of performing a Medical Legal autopsy in particular when there is the recent history of the consumption of synthetic marijuana

Consumo de drogas: reporte por tarjeta de enfermedad de declaración obligatoria. Municipio Plaza de la Revolución / Drugs consumption: Report on compulsory disease declaration card

Introducción:El consumo de sustancias psicoactivas es considerado un serio problema por su impacto negativo sobre la salud, la economía, la convivencia familiar y social. Objetivo: Identificar las características comportamentales relacionadas con el consumo de sustancias psicoactivas en pacientes del municipio Plaza de la Revolución. Material y Métodos: Investigación descriptiva de corte transversal en los 71 pacientes residentes en el municipio, reportados por tarjeta EDO durante el período 2013- 2015 por trastornos relacionados con el consumo de sustancias psicoactivas. Se aplicó una encuesta y una entrevista semiestructurada, previo consentimiento informado de los pacientes. Resultados: El 87.4 por ciento de los encuestados pertenecía al sexo masculino donde primaron personas en edades entre 20 y 29 años. La mayoría de las féminas eran adolescentes contando con una menor de solo 13 años. Primó el diagnóstico de abuso a múltiples sustancias siendo la marihuana, el alcohol y los fármacos los más usados. Los cuadros de intoxicación aguda fueron en su mayoría provocados por psicofármacos. Los monoconsumidores menores de 21 años prefirieron los cannabinoides sintéticos, los de mayor edad el crack. Elevada prevalencia de tabaquismo en los pacientes con incremento del consumo de cigarrillos cuando ingerían bebidas alcohólicas. Los encuestados tenían escasa percepción de riesgo del uso de la marihuana. El mayor número de reportes fue realizado por el Departamento de salud mental del municipio. Conclusiones: Teniendo en cuenta el consumo de múltiples sustancias encabezadas por la marihuana así como el uso de nuevas drogas de síntesis fundamentalmente en adolescentes y adultos jóvenes se trazaron estrategias por el equipo de salud mental(AU)

Introduction: The consumption of psychoactive substances is considered a serious problem because of its negative impact on health, economy, and family and social coexistence. Objective: To identify the behavioral characteristics related to the consumption of psychoactive substances in patients of Plaza de la Revolución Municipality. Material and methods: A descriptive cross-sectional investigation was conducted in 71 patients who live in the municipality, and were reported by compulsory disease declaration cards presenting disorders related to the consumption of psychoactive substances during the 2013-2015 period. A survey and a semi-structured interview were both applied, with a previous informed consent given by the patients. Results: the 87 percent of the inquired people were male, most of them aged 20 - 29 years. Most women were adolescents, including an underage who was only 13 years old. The aspect of great importance was the diagnosis of multiple substance abuse, being Marijuana, alcohol, and medications the most used ones. The cases of acute intoxication were mainly caused by psychopharmaceutical drugs. Monoconsumers younger than 21 years of age preferred the synthetic cannabinoids, and the older ones preferred the crack. There was a high prevalence of smoking in patients with increased cigarette consumption when they were drinking alcohol. The inquired people had a little risk perception of using Marijuana. The greatest number of reports was carried out by the Department of Mental Health of the municipality. Conclusions: Some strategies were developed by the mental health team, considering the consumption of multiple substances headed by Marijuana, as well as the use of new synthetic drugs which were mainly consumed by adolescents and young adults(AU)

Synthetic cannabinoids in the kidneys

Summary Acute kidney injury is an important cause of mortality and morbidity today and can occur due to several reasons. As time, geographic regions, and living conditions change, various etiological agents arise with nephrotoxic effects. Awareness of such nephrotoxic effects has been raised with the increasing frequency of addictive substance use, especially among young people in society.

Analysis of metabolites and metabolic pathway of 5F-AMB in vitro using UPLC-HR-MS / 药学学报

This study was designed to investigate the metabolites of 5F-AMB by human liver microsomes model in vitro. 5F-AMB was added in the reaction mixture to simulate the metabolic process in human hepatocytes in vivo, and then to determine the reaction points and pathways of metabolism by ultra performance liquid chromatography (UPLC) coupled to high resolution mass spectrum (HR-MS). 5F-AMB generated 9 metabolites in total in the human liver microsomes model. Ester hydrolysis, combination of ester hydrolysis and oxidative defluorination, combination of ester hydrolysis and hydroxylation on pentyl chain moiety and combination of ester hydrolysis and hydroxylation on indazole ring moiety reactions were its main metabolic pathways. The method is fast and efficient so that the ester hydrolysis, combination of ester hydrolysis and oxidative defluorination, combination of ester hydrolysis and hydroxylation on pentyl chain moiety and combination of ester hydrolysis and hydroxylation on indazole ring moiety metabolites of 5F-AMB can be used as the suitable and potential biomarkers in the urine samples.

Rapid screening of 3 synthetic cannabinoids in blood by direct analysis in real time mass spectrometry / 中国法医学杂志

Objective To establish a method for rapid detection of JWH-018, JWH-250 and AM-2201 in blood by direct analysis in real-time coupled with tandem mass spectrometry. Methods These samples were extracted by acetonitrile-methanol (4:1), using DART 12Dip-it automatic sampling system. They were analyzed by positive ion and MRM mode. Results The detection limits of JWH-018, JWH-250 and AM-2201 were in good linearity in the range of 0.02-5.00μg/mL. The correlation coefficients were above 0.99 and the detection limits were 0.016μg/mL, 0.003μg/ mL and 0.017μg/mL, respectively. The intra-day and inter-day RSD were less than 15%. Conclusion The method has the advantages of high sensitivity and good accuracy. The sample processing is simple and can be analyzed in short time. This method is suitable for the analysis of JWH-018, JWH-250 and AM-2201 in practical cases.

Assessment of the Abuse Liability of Synthetic Cannabinoid Agonists JWH-030, JWH-175, and JWH-176

The emergence and use of synthetic cannabinoids have greatly increased in recent years. These substances are easily dispensed over the internet and on the streets. Some synthetic cannabinoids were shown to have abuse liability and were subsequently regulated by authorities. However, there are compounds that are still not regulated probably due to the lack of abuse liability studies. In the present study, we assessed the abuse liability of three synthetic cannabinoids, namely JWH-030, JWH-175, and JWH-176. The abuse liability of these drugs was evaluated in two of the most widely used animal models for assessing the abuse potential of drugs, the conditioned place preference (CPP) and self-administration (SA) test. In addition, the open-field test was utilized to assess the effects of repeated (7 days) treatment and abrupt cessation of these drugs on the psychomotor activity of animals. Results showed that JWH-175 (0.5 mg/kg), but not JWH-030 or JWH-176 at any dose, significantly decreased the locomotor activity of mice. This alteration in locomotor activity was only evident during acute exposure to the drug and was not observed during repeated treatment and abstinence. Similarly, only JWH-175 (0.1 mg/kg) produced significant CPP in rats. On the other hand, none of the drugs tested was self-administered by rats. Taken together, the present results indicate that JWH-175, but not JWH-030 and JWH-176, may have abuse potential. More importantly, our findings indicate the complex psychopharmacological effects of synthetic cannabinoids and the need to closely monitor the production, dispensation, and use of these substances.

Canabinoides sintéticos: drogas de abuso emergentes / Synthetic cannabinoids: emerging drugs of abuse

CONTEXTO: A Cannabis sativa (cannabis, maconha, marijuana) é uma droga de abuso com efeitos psicoativos e potencial terapêutico bastante conhecidos. Um grande número de canabinoides foi sintetizado na tentativa de excluir ou minimizar os efeitos psicotrópicos e mantendo as aplicações terapêuticas. Os canabinoides sintéticos representam o mais recente avanço das designer drugs. OBJETIVOS: Este trabalho busca trazer informações sobre a utilização de canabinoides sintéticos como drogas de abuso emergentes, principalmente sob a forma de spice ou herbal blends. MÉTODOS: Foi realizada uma pesquisa bibliográfica na base de dados PubMed utilizando os descritores de assunto "synthetic cannabinoids", "spice", "legal highs", "herbal blends", "psychosis cannabis" e suas combinações. RESULTADOS: Foram encontrados canabinoides sintéticos nos produtos Spice, confirmando que os incensos herbais realmente surgiram como drogas de abuso emergentes. CONCLUSÃO: Não está claro se a utilização de canabinoides sintéticos e de Spice é uma moda passageira ou se irá se estabelecer em nossa sociedade. No entanto, o fenômeno das designer drugs, especialmente canabinoides sintéticos, representa um desafio presente para o sistemas de saúde no mundo globalizado, tornando-se necessária a pesquisa clínica e forense desses produtos.

BACKGROUND: Cannabis sativa (cannabis, marijuana) is a drug of abuse with well known psychoactive effects and therapeutic potential. A large number of cannabinoids chemically similar to Δ9-THC, the main active metabolite of marijuana, were synthesized in an attempt to exclude or minimize the psychotropic effects, maintaining the therapeutic potential. OBJECTIVES: The aim of this work was to review of the use of synthetic cannabinoids as emerging drugs of abuse, especially in the form of spice or herbal blends. METHODS: A bibliographic search was performed in PubMed employing the terms "synthetic cannabinoids", "spice", "legal highs", "herbal blends", "psychosis cannabis" and cross references. RESULTS: A number of synthetic cannabinoids can be found in Spice products, confirming that herbal incense emerged as new drugs of abuse. DISCUSSION: It is unclear whether the use of synthetic cannabinoids and Spice is a fad or will be established as common practice in our society. However, the phenomenon of designer drugs, especially synthetic cannabinoids, will remain a challenge to health authorities in the globalized world, requiring additional clinical and forensic research.