Cannabis: Drug of Abuse and Therapeutic Agent, Two Sides of the Same Coin

ABSTRACT The consumption of Cannabis sativa plant, known as marijuana in the Western world, for different purposes (therapeutic, intoxicating, and spiritual) due to its psychoactive effects, can be traced back to ancient times. Cannabis is the most used illicit drug worldwide; however, its legal status is changing rapidly. Cannabis regulation will allow a better understanding of its effects as a misused drug, including new challenges, such as the availability of highly potent Cannabis extracts. Furthermore, scientific research is making significant efforts to take advantage of the potential therapeutic uses of Cannabis active compounds. The science of Cannabis derivatives started with the identification of the phytocannabinoids Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), allowing the formal study of the complex set of effects triggered by Cannabis consumption and the deciphering of its pharmacology. Δ9-THC is recognized as the compound responsible for the psychoactive and intoxicating effects of Cannabis. Its study led to the discovery of the endocannabinoid system, a neuromodulatory system widespread in the human body. CBD does not induce intoxication and for that reason, it is the focus of the search for cannabinoid potential clinical applications. This review examines the current state of knowledge about contrasting perspectives on the effects of Cannabis, Δ9-THC, and CBD: their abuse liability and potential therapeutic use; two sides of the same coin.

Caracterización y seguimiento de una población de uruguayos usuarios de derivados de cannabis medicinal artesanal / Characterization and follow up of a population of Uruguayan cannabis derivatives users in artisanal medicine / Caracterização e monitoramento de uma população de usuários uruguaios de derivados artesanais de cannabis medicinal

Introducción: el conocimiento del cannabis medicinal data de hace más de 10.000 años y tiene sus orígenes en el continente asiático y en la medicina oriental. En el último tiempo ha surgido especial interés en su uso terapéutico, y Uruguay desde 2013 cuenta con una ley que regula la tenencia y uso de la planta de cannabis. Objetivo: caracterizar el uso de los derivados de cannabis medicinal (DCM) en una población de usuarios uruguayos. Metodología: se realizó un estudio observacional, prospectivo, en una población de usuarios de DCM, a través de encuestas telefónicas. Los datos obtenidos se analizaron utilizando Excel®, mediante estadística descriptiva. Resultados: se incluyeron 32 usuarios entre 29 y 78 años, la mayoría de sexo femenino. La forma farmacéutica más utilizada fue el aceite y la principal indicación fue para el tratamiento del dolor. Se observó una disminución en la intensidad del dolor postratamiento. El principal efecto adverso observado fue la sequedad de boca. Conclusiones: es el primer estudio nacional en caracterizar el uso de DCM artesanal. Se incluyeron 32 usuarios de DCM artesanal. La principal indicación de DCM fue para el tratamiento del dolor, siendo la artrosis su principal causa. Todos los usos fueron para indicaciones no aprobadas si se compara con sus equivalentes industrializados. Predominó el uso en mujeres adultas. Se destacó una gran expectativa frente al inicio del uso. Los eventos adversos observados estuvieron dentro de los esperados y de entidad leve.

Summary: Introduction: knowledge on medical cannabis is over 10,000 years old and stems from Asian and Eastern medicine. In recent years, special interest on its therapeutic use has arisen, and in 2013 Uruguay passed a law to regulate possession and use of cannabis plants. Objective: to characterize the use of medicinal cannabis derivatives in a population of Uruguayan users. Method: observational, prospective study in a population of medicinal cannabis derivatives users through telephone surveys. Data obtained were analysed with Excel®, by using descriptive statistics. Results: thirty two users were included in the study, between 29 and 78 years old, most of which were female. The most widely used pharmaceutical form was oil and the main indication was to treat pain. A decline in pain intensity after treatment was observed. The main adverse effect observed was dry mouth. Conclusions: this is the first national study to characterize the use of artisanal medicinal cannabis derivatives. Thirty two users of artisanal medicinal cannabis derivatives were included in the study. The main indication for artisanal medicinal cannabis derivatives was the treatment of pain, arthrosis being the main cause. All users followed non-approved indications if compared to industrialized equivalents. The use was more extended among women. Great expectation upon initiation of use was noticed. Adverse events observed were mild and the expected.

Introdução: o conhecimento da cannabis medicinal remonta a mais de 10.000 anos e tem suas origens no continente asiático e na medicina oriental. Nos últimos tempos, surgiu um interesse especial em seu uso terapêutico e, desde 2013, o Uruguai possui uma lei que regula a posse e o uso da planta de cannabis. Objetivo: caracterizar o uso de derivados de cannabis medicinal (DCM) em uma população de usuários uruguaios. Metodologia: Foi realizado um estudo observacional, prospectivo, em uma população de usuários de DCM, por meio de inquéritos telefônicos. Os dados obtidos foram analisados ​​no programa Excel®, por meio de estatística descritiva. Resultados: foram incluídos 32 usuários entre 29 e 78 anos, a maioria do sexo feminino. A forma farmacêutica mais utilizada foi o óleo e a principal indicação foi para o tratamento da dor. Observou-se diminuição da intensidade da dor pós-tratamento. O principal efeito adverso observado foi boca seca. Conclusões: este é o primeiro estudo nacional a caracterizar o uso de DCM artesanal. Foram incluídos 32 usuários artesanais de DCM. A principal indicação da CMD foi para o tratamento da dor, sendo a osteoartrite sua principal causa. Todos os usos foram para indicações não aprovadas quando comparados aos seus equivalentes industrializados. Predominou o uso em mulheres adultas. Houve uma grande expectativa desde o início do uso. Os eventos adversos observados estavam dentro do esperado e de entidade leve.

Retrograde inhibition of hyperactive central pathways in nociplastic pain / Inibição retrógrada das vias centrais hiperativas nas dores nociplásticas

ABSTRACT BACKGROUND AND OBJECTIVES: Nociplastic pain occurs due to a combination of hyperexcitability and decreased inhibitory activity in the central nervous system, responsible for a state of amplification of different stimuli, present in many chronic disorders. Among them: fibromyalgia, chronic migraine, irritable bowel syndrome, myofascial pain syndrome and complex regional pain syndrome. Often, several of these diseases are associated. Nociplastic pain therapy is a challenge in clinical practice, since most traditional treatments are not effective in controlling symptoms, often causing difficulty in adherence or even interruption of treatment due to undesirable adverse effects. The objective of this article was to demonstrate the importance of identifying the presence of nociplastic pain in the patient's condition, and also the pathophysiological mechanisms involved. Thus, due to retrograde neuromodulation, a unique feature of the endocannabinoid system until now, evaluate the use of pharmaceutical grade medicines based on the cannabis plant as an adjunct in the therapy of pain and other symptoms associated with this disorder. CONTENTS: This article was addressed the pathophysiology of nociplastic pain, the physiology to the endocannabinoid system, the cannabis plant with its components and its use as an adjuvant medication in the multimodal treatment of nociplastic pain (due to retrograde neuromodulation), based on published scientific articles between 1981 and 2022. CONCLUSION: Although the scientific evidence supporting the use of medical cannabis in nociplastic pain therapy is insufficient so far, it can and should be considered as a possible adjuvant medication in multimodal pain therapy, always on an individual basis, when recommended treatments fail or are not tolerated.

RESUMO JUSTIFICATIVA E OBJETIVOS: A dor nociplástica ocorre por uma combinação de hiperexcitabilidade e diminuição da atividade inibitória no sistema nervoso central, responsável por um estado de amplificação de estímulos diversos, presente em muitas doenças crônicas. Entre essas doenças estão: fibromialgia, migrânea crônica, síndrome do intestino irritável, síndrome dolorosa miofascial e síndrome de dor complexa regional. Frequentemente, várias dessas doenças se apresentam associadas. A terapia da dor nociplástica é um desafio na prática clínica, uma vez que a maioria dos tratamentos tradicionais não são eficazes no controle dos sintomas, causando muitas vezes dificuldade de adesão ou até mesmo interrupção do tratamento, devido aos efeitos adversos indesejáveis. O objetivo deste artigo foi demonstrar a importância da identificação da presença da dor nociplástica no quadro do paciente, e do conhecimento dos mecanismos fisiopatológicos envolvidos. Dessa forma, devido à neuromodulação retrógrada, característica exclusiva do sistema endocanabinoide até o momento, avaliar a utilização de fármacos de grau farmacêutico à base da planta cannabis como coadjuvante na terapia da dor e dos outros sintomas associados a essa doença. CONTEÚDO: Este artigo abordou a fisiopatologia da dor nociplástica, a fisiologia do sistema endocanabinoide, a planta cannabis com seus componentes e sua utilização como medicação coadjuvante no tratamento multimodal da dor nociplástica (decorrente da neuromodulação retrógrada), com base em artigos científicos publicados entre 1981 e 2022. CONCLUSÃO: Apesar das evidências científicas que apoiam o uso da cannabis medicinal na terapia da dor nociplástica serem insuficientes até o momento, ela pode e deve ser considerada como um possível fármaco coadjuvante na terapia multimodal da dor, sempre de forma individualizada, quando os tratamentos preconizados falharem ou não forem tolerados.

Latest advances in the diagnosis and treatment of interstitial cystitis/bladder pain syndrome / 现代泌尿外科杂志

Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by pain, oppressing sensation, or discomfort associated with the bladder, accompanied by lower urinary tract symptoms, lasting for more than 6 weeks (or 6 months). Since IC/BPS was first reported, its diagnosis and treatment have been a challenge to clinicians. This article will review its classification and phenotype, fundamental research, imaging, symptom score, cystoscopy, treatment and potential therapeutic targets.

New targeted compounds-biosynthesis of phytocannabinoids / 生物工程学报

Phytocannabinoids are bioactive terpenoids that are exclusive to Cannabis sativa L. The main pharmacologically active phytocannabinoids are Δ9-tetrahydrocannabinol and cannabidiol, both target endogenous cannabinoid receptors. Δ9-tetrahydrocannabinol and cannabidiol have extensive therapeutic potential due to their participation in many physiological and pathological processes in human body by activating the endocannabinoid system. At present, Δ9-tetrahydrocannabinol, cannabidiol and their analogues or combination preparations are used to treat epilepsy, vomiting in patients with cancer chemotherapy, spasticity in multiple sclerosis and relieve neuropathic pain and pain in patients with advanced cancer. With the further exploration of the application value of Δ9-tetrahydrocannabinol and cannabidiol as well as the increasing demand for standardization of pharmaceutical preparations, it is imminent to achieve large-scale production of Δ9-tetrahydrocannabinol and cannabidiol in the pharmaceutical industry. In this article, pharmacological research progress of phytocannabinoids in recent years, biosynthetic pathways of phytocannabinoids and the mechanism of key enzymes as well as various product development strategies of cannabinoids in pharmaceutical industry are reviewed. By exploring the potential of synthetic biology as an alternative strategy for the source of phytocannabinoids, it will provide a theoretical basis for the research and development of microbial engineering for cannabinoids synthesis, and promote the large-scale production of medicinal cannabinoids.

Cannabis: from plant condemned by prejudice to one of the greatest therapeutic options of the century / Cannabis: de planta condenada pelo preconceito a uma das grandes opções terapêuticas do século

BACKGROUNG: Cannabis sativa has a fascinating history and has been used by mankind for millennia. Many societies such as Greek, Roman, Chinese, African, Indian and Arabic take advantage of the plant's qualities, which are consumed as food, medicine, fuel, fibers or tobacco. The first reference found related to the therapeutic use of the plant data from 2700 B.C. and is present in the pharmacopoeia of the Chinese Emperor Shen-Nung, where this plant was recommended in the treatment of malaria, rheumatic pain, in irregular and painful menstrual cycles. The book "De Matéria Médica", written by the doctor Pedânio Dioscórides considered thefounder of pharmacology, exposes Cannabis as one of the natural substances that can relieve inflammatory pain. In Brazil, African slaves brought a cannabis during the colonial period, around 1549. Then, its use spread quickly among black slaves and Indians, who started to cultivate it. Once the plant was popularized among French intellectuals and English doctors in the Indian imperial army, it started to be considered in our country as an excellent medicine for men, until it was suppressed by the police authorities in the 1930s. Only 60 years later important findings were highlighted around Cannabis with the System Endocannabinoid and its receptors, neurotransmitters such as anandamide and 2-AG, revolutionizing the understanding of molecular signaling that modulates pain and analgesia, inflammation, appetite, gastrointestinal motility and sleep cycles, immune cell activity and hormones among others.We are in front of a huge revolution in the therapeutic area, in which phytocabinoids represent one of the great therapeutic options of the century. We need a widespread disclosure that CBD is not marijuana and that its use for recreational purpose has nothing to do with the use of medical cannabis. Scientific research is seriously committed to the use of the substance in various pathologies. The role of information is absolute, being the main tool to clarify a society

A cannabis sativa tem uma história fascinante e é utilizada pela humanidade há milênios. Muitas sociedades como a grega, a romana, a chinesa, a africana, indiana e árabe aproveitaram as qualidades da planta, fosse ela consumida como alimento, medicina, combustível, fibras ou fumo. A primeira referência encontrada relativa à utilização terapêutica da planta data de 2700 a.C. e está presente na farmacopeia do Imperador chinês Shen-Nung, onde esta planta era recomendada no tratamento da malária, de dores reumáticas, nos ciclos menstruais irregulares e dolorosos. O livro "De Matéria Médica", escrito pelo médico Pedânio Dioscórides considerado o fundador da farmacologia, traz a Cannabis como uma das substâncias naturais que podem aliviar dores de origem inflamatória. No Brasil, a Cannabis foi trazida por escravos africanos no período colonial, por volta de 1549. Em seguida, o seu uso disseminou-se rapidamente entre os negros escravos e índios, que passaram a cultivá-la. Devido à popularização da planta dentre intelectuais franceses e médicos ingleses do exército imperial da Índia, ela passou a ser considerada em nosso meio como excelente medicamento para muitos males, até ser reprimida pelas autoridades policiais na década de 1930. Descobertas importantes foram destaque no campo da Cannabis somente 60 anos depois com o Sistema Endocanabinoide e seus receptores, neurotransmissores como a anandamida e o 2-AG, revolucionando o entendimento da sinalização molecular que modula dor e analgesia, inflamação, apetite, motilidade gastrointestinal e ciclos de sono, atividade de células imunes, hormônios e muito mais. Estamos diante de uma enorme revolução na área terapêutica em que os fitocanabinoides representam uma das grandes opções terapêuticas do século. Precisamos de uma divulgação ampla de que o CBD não é maconha e que o uso recreativo da maconha nada tem a ver com o uso da Cannabis medicinal, que as pesquisas científicas estão seriamente empenhadas em estabelecer a eficácia da substância em várias patologias. O papel da informação é absoluto e se constitui na principal ferramenta para esclarecer a sociedade.

Cannabis and the exocannabinoid and endocannabinoid systems. Their use and controversies

Cannabis (marijuana) is one of the most consumed psychoactive substances in the world. The term marijuana is of Mexican origin. The primary cannabinoids that have been studied to date include cannabidiol and delta-9-tetrahydrocannabinol, which is responsible for most cannabis physical and psychotropic effects. Recently, the endocannabinoid system was discovered, which is made up of receptors, ligands and enzymes that are widely expressed in the brain and its periphery, where they act to maintain balance in several homeostatic processes. Exogenous cannabinoids or naturally-occurring phytocannabinoids interact with the endocannabinoid system. Marijuana must be processed in a laboratory to extract tetrahydrocannabinol and leave cannabidiol, which is the product that can be marketed. Some studies suggest cannabidiol has great potential for therapeutic use as an agent with antiepileptic, analgesic, anxiolytic, antipsychotic, anti-inflammatory and neuroprotective properties; however, the findings on cannabinoids efficacy and cannabis-based medications tolerability-safety for some conditions are inconsistent. More scientific evidence is required in order to generate recommendations on the use of medicinal cannabis.

El Sistema de Endocannabinoides como regulador de la lipogénesis y su posible modulación por la Mangiferina

RESUMEN Actualmente es innegable la participación del sistema endocannabinoides (SEC) en la regulación metabólica; ya que su sobre estimulación ha sido relacionada con varias patologías entre las que se encuentran obesidad, diabetes mellitus, retinopatía e hígado graso no alcohólico. Éstas se relacionan mutuamente a través de alteraciones del metabolismo de los lípidos, como lo es una sobre estimulación de la síntesis de ácidos grasos, una disminución en la beta-oxidación, hiperglicemia causada por un aumento de la gluconeogénesis, así como en la glucólisis; procesos en los cuales se ha descrito al SEC como un participante crucial. Por otro lado, algunos compuestos fitoquímicos, tales como la mangiferina (MGF), han probado sus efectos farmacológicos en el metabolismo de lípidos a nivel hepático y en el control glicémico. Hasta el momento se desconoce el efecto de la mangiferina sobre los receptores de endocannabinoides, por lo que esta revisión aborda la regulación a nivel sistémico (órganos y tejidos) y central (sistema nervioso) de la lipogénesis por el SEC y la regulación negativa que tiene la mangiferina sobre éste. Finalmente se sugiere, con base en la información publicada hasta el momento, una relación entre el posible efecto que pueden tener la MGF sobre el SEC.

ABSTRACT Currently, the participation of the endocannabinoid system in metabolic regulation is undeniable; because its hyperactivation has been related to several pathologies such as obesity, diabetes mellitus, retinopathy and non-alcoholic fatty liver, and others. These pathologies are related through alterations in lipid metabolism, e.g. over stimulation of fatty acid synthesis, beta-oxidation decrease, hyperglycemia increase, all these changes are caused by increase in gluconeogenesis, as well as glycolysis, processes in which the SEC has been described as a main character. On the other hand, some phytochemicals such as mangiferin (MGF) have shown their pharmacological effects on lipid metabolism, as well as glycemic control. So far, the effect of mangiferin on cannabinoid receptors is unknown. In this review, we try to demonstrate how mangiferin and these receptors participate in the opposite manner in the adaptation of lipid metabolism in many organs like as liver, tissue adipose and SN (nervous system). In addition, we suggest, based on the published information to until now, a relationship between the MGF´s effect on the SEC.

Action of ketamine and endocannabinoid system in rapid anti-depression therapy / 上海交通大学学报（医学版）

Major depression disorder (MDD) is a common but serious affective disorder in modern society. Suicide idea and suicide behaviour induced by MDD during its later stage put a heavy burden on society and family. Anti-depression drugs lack efficiency in treating a portion of MDD patients. This is referred to as treatment resistant depression (TRD). A study reported the rapid onset and long lasting anti-depression effect of ketamine, which also come into effect in TRD patients. △9-Tetrahydrocannabinol is the active substance of marijuana, which also exerts rapid anti-depression effect via targeting at brain cannabinoid receptors. The two central nerve system stimulants belonging to the tightly controlled psychoactive substances have obvious adverse effects. This article summarizes the action of ketamine and endocannabinoid system in rapid anti-depression therapy in recent researches.

Action of ketamine and endocannabinoid system in rapid anti-depression therapy / 上海交通大学学报（医学版）

Major depression disorder (MDD) is a common but serious affective disorder in modern society. Suicide idea and suicide behaviour induced by MDD during its later stage put a heavy burden on society and family. Anti-depression drugs lack efficiency in treating a portion of MDD patients. This is referred to as treatment resistant depression (TRD). A study reported the rapid onset and long lasting anti-depression effect of ketamine, which also come into effect in TRD patients. Δ9-Tetrahydrocannabinol is the active substance of marijuana, which also exerts rapid anti-depression effect via targeting at brain cannabinoid receptors. The two central nerve system stimulants belonging to the tightly controlled psychoactive substances have obvious adverse effects. This article summarizes the action of ketamine and endocannabinoid system in rapid anti-depression therapy in recent researches.

Neurobiología de las adicciones / Neurobiology of addictions

Resumen La proporción de usuarios de una droga de abuso que desarrolla dependencia sólo representa una parte de ellos. Es decir, hay una proporción de usuarios que no presentan un trastorno por consumo de sustancias (TCS). Por ejemplo, en Mexico sólo el 15% de quienes consumen alcohol desarrollan un trastorno por consumo de alcohol (ТСА). Este 15% sugiere una vulnerabilidad en esta población, por lo que determinar los mecanismos que predisponen a estos sujetos a la adicción es indispensable para la prevención о para la rehabilitación del TCS. Se ha sugerido la participación de factores genéticos y medioambientales en el desarrollo de dicha vulnerabilidad al TCS. Por ejemplo, se ha demostrado que los sujetos que son psicópatas o sociópatas у que son agresivos, que presentan falta de atención y son impulsivos, entre otras características clínicas, presentan comorbilidad con el abuso y dependencia a sustancias. Por otro lado, se ha observado que existe una relación entre las experiencias adversas en los primeros años de vida y el consumo de sustancias de abuso. En estudios preclínicos, hemos demostrado que las ratas privadas de cuidado materno en los días posnatales 2 al 16 (DPN2-DPN16), al llegar a la edad adulta (DPN90) consumen más alcohol que las que han recibido cuidado materno todo el tiempo. Además, presentan una desregulación en la expresión de los receptores para canabinoides del tipo ו (CB1R) en algunas zonas del cerebro, por ejemplo, el núcleo accumbens y la corteza prefrontal. En breve, podríamos suponer que un sujeto es vulnerable a tener una adicción si nace psicópata o desarrolla una personalidad antisocial, o bien, si durante la infancia ha contendido con situaciones adversas, como son un pobre cuidado parental o el abuso verbal, fisco o sexual. Cabe señalar que estos no son los únicos factores que han sido asociados a este trastorno, pero para los fines de esta revisión, sólo discutiremos esta vulnerabilidad con base en los mecanismos epigenéticos que afectan al sistema endocanabinérgico (seCB) e interfieren con la función del sistema de inhibición de la conducta.

Abstract The proportion of drug abuse users that develop dependence does not represent the totality of users. Therefore, there is a substantial proportion of users that does not develop a substance use disorder (SUD). For example, in Mexico, only 15% of all alcohol consumers develop alcohol use disorder (AUD). Determining the mechanisms that predispose individuals to AUD or SUD is crucial for its prevention or rehabilitation. The involvement of genetic and environmental factors to the development of SUD has been suggested. For example, psychopaths or sociopaths that have a strong genetic predisposition have comorbidity with SUD. On the other hand, a relationship between adverse experiences in the early years of and substance abuse has been documented. In pre-clinical studies, we have shown that rats deprived of maternal care from postnatal day (PND)2 to PND16, and tested once they reach adulthood (PND90) consume more alcohol than those that were under materna care at all times. In addition, we observed a dysregulation in the expression of cannabinoid receptors type 1 (CBIR)in some areas of the brain, i.e. nucleus acumens and prefrontal cortex. In short, we presume that a subject who is vulnerable to addiction has either been born with a psychopathic disorder, developed an antisocial personality, experienced adverse situations such as neglected parental care, or verbal, physical or sexual abuse. These are not the only factors that have been associated with SUD, but for the purposes of this review we will discuss vulnerability based only on epigenetic mechanisms affecting the endocannabinergic system and interfering with the functioning of the behavior inhibition system.

Novel therapeutic targets for post-traumatic stress disorder:endocannabinoid system / 中国病理生理杂志

Post-traumatic stress disorder (PTSD) is a kind of mental disorder that usually occurs after life-threatening and strong mental traumas .Clinical studies showed that the PTSD patients are 3 times more likely to have can-nabis as compared with the healthy people .The use of cannabinoids has a close relationship with the occurrence and clini-cal manifestations of PTSD .Experimental studies revealed that endocannabinoid ( eCB) signal alterations in animal models of PTSD influenced fear memory of the animals , suggesting a close correlation between the eCB system and the pathogenesis of PTSD.Given that the eCB system was reported to regulate affective states and participate in memory consolidation , re-trieval and extinction , targeting the eCB system may improve the emotional and cognitive features of PTSD , thereby holding out great promise for the development of novel approaches for clinical treatment of PTSD .

Potential Therapeutic Targets of the Endocannabinoid System in Common Neurodegenerative Disorders and Organic Acidemias

Abstract The cannabinoid chemistry is currently being addressed in preclinical approaches as a viable therapeutic alternative for the management of a wide range of signs, symptoms, and some biochemical hallmarks of many neurological pathologies (such as neuroinflammation and neurodegeneration). This clinical orientation is grounded on the consistent promissory profile that cannabinoid compounds have shown, and the great necessity of feasible options to undergo such disorders. Even though at early research stages, metabolic disorders are starting to rise as potential targets of cannabinoid alternatives; approaches in this term could, in turn, aim to modulate the endocannabinoid response for therapeutic purposes. This review recalls the pathologic scenarios endured in the course of neurological diseases of high occurrence and the most typical metabolic disorders, while discussing the neuroprotective mechanisms of cannabinoid agonists in the central nervous system, and the potential targets of the endocannabinoid system and metabolic disorders.

Avaliação da atividade muscular mastigatória, nocicepção associada e participação do sistemaendocanabinoide no comportamento bruxismo-símile em ratos

O aumento da atividade muscular mastigatória é considerado uma resposta física de mudanças no estado emocional. O estresse e a ansiedade aumentam a atividade mioelétrica dos músculos do sistema estomatognático, com resultante aumento das parafunções, como apertamento dos dentes.O bruxismo é uma atividade parafuncional diurna ou noturna, incluindo apertamento ou ranger os dentes. Tem forte associação com a dor miofascial mastigatória, uma dor facial crônica dos músculos mastigatórios com possível bloqueio e limitação da abertura de boca.Osistema endocanabinoide é composto pelos receptores canabinoides, pelos ligantes endógenos (endocanabinoides) e proteínas responsáveis pelo seu metabolismo.Os endocanabinoides estão envolvidos em diferentes funções fisiológicas e patológicas, como imunomodulação, inflamação e analgesia.A ação antinociceptiva dos canabinoides tem sido demonstrada em vários modelos experimentais de dor, porém, não há relatos na literatura do envolvimento dos canabinoides na nocicepção associada à hiperatividade muscular emsituações de hábitos parafuncionais. O objetivo da presente pesquisafoi estudar a atividade muscular mastigatóriae a nocicepção associada em modelo de estresse emocional em ratos e o envolvimento do sistema endocanabinoide. O estudo foi aprovado pela Comissão de Ética em Pesquisa Animal da Universidade Federal do Ceará (nº 35/13)...

The increased masticatory muscle activity is considered a physical response to changes in emotional state. Stress and anxiety increase the myoelectric activity of the stomatognathic system muscles, with resulting parafunctions increase, as teeth clenching.Bruxism is a diurnal or nocturnal parafunctional activity including clenching or teeth grinding.Bruxism is strongly associated with the masticatory myofascial pain, a chronic facial pain of the masticatory muscles with possible blockage and limited mouth opening.The endocannabinoid system consists of cannabinoid receptors by the endogenous ligands (endocannabinoids) and proteins responsible for its metabolism.Endocannabinoids are involved in different physiological and pathological functions. The antinociceptive action of cannabinoids has beeshown in several experimental models of pain, but there are no literature reports of cannabinoids involvement in nociception associated with muscle hyperactivity in parafunctional habits situations. The aim of this study was to study the masticatory muscle activity and nociception associated in emotional stress model in rats and the endocannabinoid system involvement. The study was approved by the Animal Research Ethics Committee of the Federal University of Ceará (N° 35/13)...

Inibição do transito gastrintestinal por antipsicoticos: estudo experimental da clozapina

A eficácia da clozapina(CLZ)como um agente antipsicótico atípico foi reconhecida desde o início dos anos 1960, sendo ainda nos dias atuais a droga de escolha no tratamento de casos de esquizofrenia refratários a outros antipsicóticos. Dentre os efeitos adversos da CLZ, a constipaçãoé relatada com frequência, podendo progredir para obstruçãointestinal, necrose intestinal,sepse intrabdominale morte. O presente estudoavaliou o mecanismo de ação da CLZsobre a motilidade gastrintestinalatravés da análise da taxa de trânsito intestinal (TI) e da excreção de pelotas fecais em camundongos. Foram utilizados camundongos Swiss, machos, peso 25-30g, provenientes do Biotério Central da UFC e o projeto foi aprovado pela CEPA/UFC (Proc. No. 57/2014).As drogas utilizadas foram: CLZ (2,5; 5; 10; 20mg/kg), neostigmina (NEO, 1mg/kg i.p.), serotonina (5-HT, 10mg/kg v.o.), alilisitiocianato (AITC 10mg/kg v.o.), domperidona (DOM, 20mg/kg v.o.), L-NAME (80 mg/kg i.p.), naloxona (2mg/kg s.c.), glibenclamida (5mg/kg i.p.) e AM251 (1mg/kg i.p.).A administração oral de CLZ 10 e 20 mg/kgreduziusignificativamente(p<0,05) o transito gastrintestinal (TI) em relação ao veículoa partir desse resultado optou-se pela menor dose efetiva de CLZ sobre a função motora intestinal para as avaliações subsequentes...

Clozapine (CLZ)an atypicalantipsychotic agentrecognized for its efficacy since the early 1960s stillsnowadays the drug of choice in treating refractory schizophrenia cases to other antipsychotics. Among the adverse effects of CLZ, constipation, often reported, may progress to bowel obstruction, intestinal necrosis, intraabdominal sepsis and death. This study evaluated the mechanism of action of CLZ on gastrointestinal motility by analyzingthe intestinal transit rate (IT) and excretionof fecal pellets in mice. Animals usedwereSwiss males, weight 25-30g, from the UFC Central Animal Facility and the project approved by the CEPA / UFC (Proc. No. 57/2014). The drugs used were: CLZ (2.5, 5, 10, 20mg/kgp.o.), neostigmine (NEO 1mg /kg i.p.), serotonin (5-HT, 10mg/kg p.o.), alilisotiocianate(AITC 10mg/kg p.o.) , domperidone (DOM 20mg/kg p.o.), L-NAME (80 mg/kg i.p.), naloxone (2 mg/kg s.c.), glibenclamide (5 mg/kg i.p.) and AM251 (1 mg/kg i.p.). Oral administration of CLZ 10 and 20 mg/kg significantly (p <0.05) inhibited ITfrom the vehicle.Based on the results we decided forthe smallest effective dose of CLZ active on intestinal motor function(10mg/kg)for subsequent evaluations...

Repercussões de variantes genéticas em componentes do sistema endocanabinoide e no receptor PPAR-α sobre o perfil de risco cardiometabólico, adipocitocinas e níveis plasmáticos de endocanabinoides em indivíduos com diferentes graus de adiposidade / Effects of genetic variants in components of the endocannabinoid system and the PPAR-α receptor on the cardiometabolic risk profile, adipocytokines and plasma endocannabinoid levels in subjects with varying degrees of adiposity

Analisar a associação recíproca entre fatores de risco cardiometabólico, níveis de adipocitocinas (leptina e adiponectina de alto peso molecular), endocanabinoides (anandamida [AEA] e 2-araquidonoilglicerol [2-AG]), compostos canabimiméticos (N-oleoiletanolamina [OEA] e N-palmitoiletanolamina [PEA]) e polimorfismos em genes codificadores de componentes do sistema endocanabinoide (enzima de degradação de endocanabinoides FAAH [gene FAAH] e receptor endocanabinoide CB1 [gene CNR1]) e do receptor PPAR-α[genePPARA], em indivíduos com diferentes graus de adiposidade. Duzentos indivíduos, entre 18 e 60 anos, com diferentes graus de índice de massa corporal (IMC) compuseram a amostra, dividida em dois grupos: cem eutróficos (IMC < 25 kg/m2) e 100 obesos (IMC ≥30 kg/m2), com 50 homens e 50 mulheres em cada grupo. Os obesos ficaram assim distribuídos: grau 1, com IMC < 35 kg/m2(n=54), 27 homens e 27 mulheres; grau 2, com IMC < 40 kg/m2 (n=32), 16 homens e 16 mulheres e grau 3, com IMC ≥40 kg/m2(n=14), 7 homens e 7 mulheres. Todos os indivíduos foram recrutados entre funcionários, estudantes e residentes do Hospital Universitário Pedro Ernesto, bem como voluntários do quadro da Polícia Militar do Estado do Rio de Janeiro e selecionados com base em amostra de conveniência. Todos foram avaliados por parâmetros antropométricos, determinação da pressão arterial, análises laboratoriais e genotipagem, para determinar seu perfil metabólico, níveis de endocanabinoides e adipocitocinas e rastreamento dos polimorfismos FAAH385C>A, CNR13813A>G e PPARA484C>G. Foram excluídos do estudo aqueles com história de comorbidades crônicas, doenças inflamatórias agudas, dependência de drogas de qualquer natureza e em uso de medicação nos dez dias anteriores à entrada no estudo. A atividade inflamatória, avaliada pela proteína C reativa ultrassensível (PCRUS), acompanhou o grau de resistência insulínica...

To analyze the reciprocal association of cardiomet abolic risk factors, levels of adipocytokines (leptin and high molecular weight adiponectin), endocannabinoids (anandamide [AEA] and 2-arachidonoylglycerol [2-AG]), cannabimimetic compounds (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]) and polymorphisms in genes encoding components of the endocannabinoid system (endocannabinoid degradation enzyme FAAH [FAAHgene] and endocannabinoid receptor CB1 [CNR1gene]) and the PPAR-α receptor (PPARAgene) in subjects with varying degrees of adiposity. Two hundred individuals between 18 and 60 years with varying degrees of body mass index (BMI) comprised the sample, divided in two groups: one hundred eutrophic (BMI < 25 kg/m2) and 100 obese (BMI ≥30 kg/m2), 50 men and 50 women per group. The obese were distributed as follows: grade 1, with BMI < 35 kg/m2(n = 54), 27 men and 27 women; grade 2, with BMI between ≥35 and < 40 kg/m2 (n = 32), 16 men and 16 women and grade 3, with BMI ≥40 kg/m2(n = 14), 7 men and 7 women. All subjects were recruited from staff, students and residents of Pedro Ernesto University Hospital, as well as volunteers from Military Police of Rio de Janeiro State and selected based on a convenience sample. All were evaluated by anthropometric parameters, blood pressure determination, laboratory analysis and genotyping, to determine their metabolic profile, endocannabinoid and adipocytokine levels and investigate the polymorphisms FAAH385C>A, CNR1 3813G>A and PPARA484C>G. Those with a history of chronic comorbidities, acute inflammatory diseases, drug addiction of any kind and on medication in the ten days prior to study entry were withdrawn from the study.The inflammatory activity as assessed by high sensitive C reactive protein (hsCRP), accompanied the degree of insulin resistance...

Los productos de Cannabis sativa: situación actual y perspectivas en medicina / Cannabis sativa products: current status and perspectives in medicine

Psychoactive preparations of Cannabis sativa, such as marijuana and hashish, have been used for centuries for medicinal, religious and recreational purposes. Today marijuana is the most widely used illegal drug worldwide, particularly among teenagers and young adults. Adolescence is a critical phase in Central Nervous System development, characterized by neuronal maturation and rearrangement processes. Marijuana is very complex in its chemistry due to the large number of active constituents capable of interacting with each other. With inhaled marihuana, subjects experience euphoria, a feeling of relaxation, and intensification of ordinary sensory experiences. Chronic consumption results in tolerance, dependence, withdrawal syndrome, cognitive deterioration, and increased risk of psychiatric illnesses. The discovery of an endogenous cannabinoid system renewed the medical interest in marijuana and data from the last 20 years have shown that, in the postnatal brain, endocannabinoids regulate the function of many synapses and play an important role in brain development; also, that chronic consumption of marijuana early in life negatively affects Central Nervous System development. Recently, interest on marijuana has centered on its medicinal properties, and a good number of controlled clinical studies support its use in certain medical conditions; however, safety and efficacy of marijuana remains controversial. In this article we analyze the pharmacological knowledge on marijuana, the risks of its consumption, data on its medicinal properties and, based on the available evidence, we conclude that its legalization should be discouraged. Finally, we postulate that marijuana in its herbal form, by the enteral route, could be of a great value in mitigating suffering in patients with terminal illness.

Los productos psicoactivos de la Cannabis sativa, como marihuana y hachís, se han usado desde hace varios siglos con fines medicinales, religiosos y recreativos. Ahora, la marihuana es la droga ilegal de mayor consumo en el mundo, particularmente por adolescentes y adultos jóvenes. La adolescencia es una etapa crítica en el desarrollo y maduración del Sistema Nervioso Central. La marihuana está constituida por un gran número y variedad de substancias químicas que pueden interactuar entre sí. Sus efectos agudos se caracterizan por euforia, relajación e intensificación de las experiencias sensoriales ordinarias. Su consumo crónico induce tolerancia, dependencia, síndrome de carencia, déficit cognitivo y aumenta el riesgo de enfermedades psiquiátricas. El descubrimiento de un sistema cannabinoide endógeno renovó el interés médico por la marihuana y los datos de los últimos 20 años indican que el sistema endocannabinoide regula la función de diversos tipos de sinapsis y juega un papel importante en el desarrollo cerebral extrauterino. Recientemente el interés sobre la marihuana se centró en sus propiedades medicinales y existe un buen número de ensayos clínicos controlados que apoyan su uso en ciertas condiciones médicas; sin embargo, su eficacia y seguridad siguen siendo motivo de controversia. En este artículo se analizan los conocimientos farmacológicos sobre la marihuana, se establecen los riesgos de su consumo, la información sobre sus propiedades medicinales y, con base en la evidencia disponible, se opina contra su legalización. Finalmente, aquí se postula que la marihuana en su forma herbaria, por vía enteral, puede ser de gran valor para mitigar el sufrimiento de pacientes con enfermedad terminal.

Effects of cannabinoid receptors and their ligands on gastrointestinal motility and secretion / 国际外科学杂志

Endocannabinoid system has several kinds of receptors, all of which have correspondence ligands and pathways of synthesis and degradation, and they belong to G-protein coupled receptors family. Recently studies show that stimulation of cannabinoid receptors has inhibitory effects on gastrointestinal motility and secretion. In this article, we introduce the compositions of the cannabinoid family members, includingtheir receptors, ligands, and antagonists, and their effects on the gastrointestinal motility and secretion. Useful information can be provided for the further study on the effects of endocannabinoid system on gastrointestinal motility and secretion, providing theoretic evidences for clinical use of cannabinoid.

Neurobiologia da Cannabis: do sistema endocanabinoide aos transtornos por uso de Cannabis / Neurobiology of Cannabis: from the endocannabinoid system to cannabis-related disorders

OBJETIVOS: Diante das lacunas na efetividade das terapêuticas para transtornos por uso de Cannabis, a droga ilícita mais consumida no mundo, este trabalho propõe-se a rever os conhecimentos sobre o substrato neuroanatômico, biomolecular e celular do sistema endocanabinoide, descrever os mecanismos de neuroplasticidade dependente dos canabinoides e relacioná-los com a neurobiologia dos transtornos por uso de Cannabis (abuso e dependência). MÉTODOS: Recorreu-se às bases de dados Medline, Scopus e ISI Web of Knowledge; as palavras-chave pesquisadas foram "Cannabis", "neurobiology", "endocannabinoid system", "endocannabinoids", "receptors, cannabinoid", "neuronal plasticity", "long-term synaptic depression", "long-term potentiation", "marijuana abuse" e "tetrahydrocannabinol". Foram incluídos 80 trabalhos nesta revisão. DISCUSSÃO: A distribuição neuroanatômica, celular e biomolecular do sistema endocanabinoide adequa-se perfeitamente às suas funções de neuromodulação (via neuroplasticidade e metaplasticidade), nomeadamente em vias relacionadas aos transtornos por uso de substâncias. Os canabinoides exógenos perturbam essas funções. CONCLUSÃO: O sistema endocanabinoide contribui para a definição de setpoints em diversas vias neuronais, incluindo vias cruciais na instalação de transtornos por uso de substâncias; com o uso de Cannabis, esses setpoints tornar-se-ão mais permissivos, facilitando os transtornos por uso de Cannabis. Os avanços no entendimento da neurobiologia da Cannabis abrem uma janela de oportunidades para novas estratégias terapêuticas nos transtornos por uso de Cannabis.

OBJECTIVES: Given the challenges arising from the poor effectiveness of therapies for Cannabis-related disorders, the most commonly used illicit drug in the world, this paper aims to review the present knowledge about the neuroanatomic, biomolecular and cellular substrate of the endocannabinoid system, describing the mechanisms of cannabinoid-dependent neuronal plasticity and relating them with the neurobiology of Cannabis-related disorders (abuse and dependence). METHODS: Medline, Scopus and ISI Web of Knowledge were searched for the keywords "Cannabis", "neurobiology", "endocannabinoid system", "endocannabinoids", "receptors, cannabinoid", "neuronal plasticity", "long-term synaptic depression", "long-term potentiation", "marijuana abuse" and "tetrahydrocannabinol". Eighty studies were included in this review. DISCUSSION: The neuroanatomical, cellular and biomolecular characterization of the endocannabinoid system serves perfectly its neuromodulatory neuroplastic and metaplastic functions, particularly in pathways related to substance-related disorders. Exogenous cannabinoids disrupt these functions. CONCLUSION: The endocannabinoid system contributes to the definition of setpoints in several neuronal pathways, including pathways critical for the development of substance-related disorders; with Cannabis use these setpoints become more permissive, facilitating Cannabis-related disorders. The advances in understanding the neurobiology of Cannabis open a window of opportunities for new therapeutic strategies in Cannabis-related disorders.

Antagonismo del Sistema Endocanabinoide: Implicaciones en el tratamiento de la obesidad, síndrome metabólico y adición a drogas

Rimonabant (SR141716, Acomplia®) ha sido catalogado como un antagonista/agonista inverso del receptor canabinoide tipo 1 (CB1). Dicho compuesto ha sido ampliamente utilizado como una herramienta para evaluar los mecanismos mediante los cuales los agonistas canabinoides producen sus efectos farmacológicos y adicionalmente dilucidar los respectivos roles fisiológicos y fisiopatológicos del receptor CB1. Aparte del antagonismo a nivel del receptor CB1 reciente evidencia ha demostrado cada vez mas que rimonabant también es capaz de ejercer acciones por si mismo. Estas acciones pueden ser vistas como agonismo inverso o como antagonismo de un tono endocanabinoide endógeno que tiende variar según las circunstancias. Actualmente, dentro de los diferentes efectos de rimonabant, los que poseen mayor relevancia clínica son sus propiedades anti-obesidad y su capacidad de atenuar la dependencia a la nicotina. Los resultados obtenidos en estudios clínicos recientes han demostrado que el tratamiento con rimonabant produce perdida de peso en pacientes obesos. Adicionalmente rimonabant produce una normalización de los parámetros metabólicos y disminuye los trastornos cardiovasculares asociados con la obesidad en humanos. Rimonabant también es efectivo en la dependencia al cigarrillo y posee un perfil toxicológico relativamente seguro. Esta revisión considerara los principales efectos obtenidos con rimonabant haciendo especial énfasis en sus aplicaciones más promisorias.

Rimonabant (SR141716, Acomplia®) has been described as an antagonist/inverse agonist at the cannabinoid receptor type 1 (CB1). It has been widely used as a tool to evaluate the mechanisms by which cannabinoid agonists produce their pharmacological effects and to elucidate the respective physiological or pathophysiological roles of the CB1 receptor. In addition of being a CB1 antagonist, it has become increasingly clear that rimonabant can exert its own intrinsic actions. These may be viewed as evidence of either the inverse agonist nature of rimonabant or of tonic activity of the endocannabinoid system that tends to change according to the circumstances. Amongst the several effects of rimonabant, the most clinically relevant are its anti obesity properties and its ability to attenuate nicotine dependence. To date, data obtained from clinical trials (RIO North America, RIO Europe and RIO Lipid) indicate that rimonabant may have major clinical benefits in relation to its anti-obesity properties and as a novel candidate for the treatment of metabolic and cardiovascular disorders associated with overweight and obesity. Other clinical trials, such as the STRATUS study, have also shown that rimonabant may be effective in smoking cessation, and that the drug has a reasonable safety profile. This review will focus on the main effect obtained to date with rimonabant.