Effect of MCH1, a fatty-acid amide hydrolase inhibitor, on the depressive-like behavior and gene expression of endocannabinoid and dopaminergic-signaling system in the mouse nucleus accumbens

Abstract MCH1 is a synthetic macamide that has shown in vitro inhibitory activity on fatty acid amide hydrolase (FAAH), an enzyme responsible for endocannabinoid metabolism. This inhibition can modulate endocannabinoid and dopamine signaling in the nucleus accumbens (NAc), potentially having an antidepressant-like effect. The present study aimed to evaluate the effect of the in vivo administration of MCH1 (3, 10, and 30 mg/kg, ip) in 2-month-old BALB/c male mice (n=97) on forced swimming test (FST), light-dark box (LDB), and open field test (OFT) and on early gene expression changes 2 h after drug injection related to the endocannabinoid system (Cnr1 and Faah) and dopaminergic signaling (Drd1 and Drd2) in the NAc core. We found that the 10 mg/kg MCH1 dose reduced the immobility time compared to the vehicle group in the FST with no effect on anxiety-like behaviors measured in the LDB or OFT. However, a 10 mg/kg MCH1 dose increased locomotor activity in the OFT compared to the vehicle. Moreover, RT-qPCR results showed that the 30 mg/kg MCH1 dose increased Faah gene expression by 2.8-fold, and 10 mg/kg MCH1 increased the Cnr1 gene expression by 4.3-fold compared to the vehicle. No changes were observed in the expression of the Drd1 and Drd2 genes in the NAc at either MCH1 dose. These results indicated that MCH1 might have an antidepressant-like effect without an anxiogenic effect and induces significant changes in endocannabinoid-related genes but not in genes of the dopaminergic signaling system in the NAc of mice.

Correlación entre la adicción a la comida y niveles del ácido araquidónico en adultos con obesidad tras intervenciones nutricionales

Introducción: Los endocannabinoides son una diana en el tratamiento de la obesidad y se producen a partir de ácidos grasos esenciales, los derivados del ácido linoleico actúan como agonistas de los receptores cannabinoides tipo 1 (CB1), asimismo, los derivados del ácido linolénico ejercen efectos de antagonistas de dichos receptores, por lo cual se plantea que modificar el consumo dietario de los ácidos grasos omega 3 y 6 podría modular la activación del sistema endocannabinoide, lo que podría ser favorable para personas con adicción a la comida, considerando cómo este sistema promueve la actividad de las vías dopaminérgicas que se alteran en la adicción a sustancias psicoactivas. Objetivo: Analizar la correlación entre el puntaje de adicción a la comida por la escala mYFAS 2.0 y los niveles plasmáticos de ácido araquidónico en adultos con obesidad tras modular la ingesta de alimentos fuente de ácidos grasos esenciales. Metodología: Se desarrolló un estudio piloto con diseño de ensayo clínico cruzado en dos tiempos, en donde los participantes recibieron los tratamientos estándar y experimental, en estos se brindaron planes siguiendo recomendaciones para el manejo nutricional de la obesidad, adicionalmente, el tratamiento experimental contó con pautas para disminuir el consumo del Omega 6 y aumentar el consumo de Omega 3 para obtener una relación menor a 5:1 entre estos ácidos grasos. Resultados: Se observó una disminución significativa en el puntaje de adicción a la comida y los niveles plasmáticos de ácido araquidónico en los participantes tras recibir el tratamiento experimental, presentando una correlación directamente proporcional entre estas, por otro lado, el tratamiento estándar estuvo asociado a una correlación inversamente proporcional entre estos. Conclusiones: El descenso en las concentraciones plasmáticas del ácido araquidónico fue asociado a un menor puntaje en la escala mYFAS 2.0 de adicción a la comida en los participantes de este estudio tras su exposición al tratamiento experimental.

Introduction: Endocannabinoids are a target in obesity treatment and they are produced from the essential fatty acids, the metabolites of linoleic acid act as agonists of the cannabinoid receptors type 1 (CB1), likewise, the metabolites of the linolenic acid act as inverse agonists of such receptors, hence, it is proposed that modifying the dietary intake of the essential fatty acids (Omega 6 and 3) may modulate the activation of the endocannabinoid system, this could be favorable for people with food addiction, considering how this system promotes the activity of the dopaminergic pathways that are altered in the psychoactive substances addiction. Objective: To analyze the correlation between the food addiction score and plasmatic levels of arachidonic acid in adults with obesity following a modulation of the dietary intake of essential fatty acids n-6 and n-3 food sources. Methods: A pilot study was carried out with a two-period crossover clinical trial design, in which the participants received standard and experimental treatments, in these programs, plans were provided following guidelines for the nutritional management of obesity, in addition, the experimental treatment included recommendations to reduce the intake of linoleic acid and to increase the intake of linolenic acid to obtain a ratio lower to 5:1 between these fatty acids. Results: A significant decrease in the food addiction score and plasmatic levels of arachidonic acid was observed in the participants exposed to the experimental treatment, showing a directly proportional correlation, moreover, the standard treatment was associated to inverse correlations between these variables. Conclusion: The decrease in plasmatic arachidonic acid levels was associated with lower scores on the mYFAS 2.0 of food addiction in the participants of this study following their exposure to the experimental treatment.

Tumor necrosis factor α, and agonist and antagonists of cannabinoid receptor type 1 and type 2 alter the immunophenotype of stem cells from human exfoliated deciduous teeth

ABSTRACT Objective To verify the involvement of the endocannabinoid system in the immunomodulatory profile of stem cells from human exfoliated deciduous teeth, in the presence or absence of TNF-α, and agonist and antagonists of CB1 and CB2. Methods Stem cells from human exfoliated deciduous teeth were cultured in the presence or absence of an agonist, anandamide, and two antagonists, AM251 and SR144528, of CB1 and CB2 receptors, with or without TNF-α stimulation. For analysis of immunomodulation, surface molecules linked to immunomodulation, namely human leukocyte antigen-DR isotype (HLA-DR), and programmed death ligands 1 (PD-L1) and 2 (PD-L2) were measured using flow cytometry. Results The inhibition of endocannabinoid receptors together with the proinflammatory effect of TNF-α resulted in increased HLA-DR expression in stem cells from human exfoliated deciduous teeth, as well as, in these cells acquiring an anti-inflammatory profile by enhancing the expression of PD-L1 and PD-L2. Conclusion Stem cells from human exfoliated deciduous teeth respond to the endocannabinoid system and TNF-α by altering key immune response molecules.

Chronic headache and cannabinoids use: myths and truths / Cefaleia crônica e uso de canabinoides: mitos e verdades

ABSTRACT BACKGROUND AND OBJECTIVES: The use of cannabis for medical purposes is known since ancient times. The endocannabinoid system is present throughout central and peripheral nervous system and plays a role in many important regulatory physiological processes like immune function, synaptic plasticity, pain and regulation of stress and emotion, among others. Due to its wide distribution and according to researches, cannabis can be indicated for symptoms management in different disorders such as chronic pain, headache, epilepsy, anxiety and other psychiatric disorders. The primary cannabinoids studied to date include delta-9-tetrahydrocannabinol (THC), cannabinol (CBN), cannabigerol (CBG), and tetrahydrocannabivarin (THCV). The active ingredients in cannabis include flavonoids, terpenes, delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and they are able to act within the endocannabinoid system and decrease nociception and also the frequency of the symptoms. The purpose of the article is to document the validity of how medical cannabis can be utilized as an alternative therapy for chronic headache management and enlighten about false beliefs regarding its use. CONTENTS: Sixty-four relevant articles were selected after a thorough screening process using PubMed and Google Scholar databases. The following keywords were used: "Cannabis", "Medical Marijuana", "Headache", "Migraine", "Cannabis and Migraine", "Cannabis and Headache". This literature study demonstrates that medical cannabis use decreases migraine duration and frequency and headaches of unknown origin. CONCLUSION: Patients suffering from migraines and related conditions may benefit from medical cannabis therapy due to its convenience and efficacy.

RESUMO JUSTIFICATIVA E OBJETIVOS: O uso da cannabis medicinal é conhecido desde a antiguidade. O sistema endocanabinoide está distribuído no sistema nervoso central e periférico e atua como importante regulador em processos fisiológicos como função imune, plasticidade sináptica, regulação da dor e das emoções/estresse, entre outros. Devido à sua ampla distribuição e, de acordo com pesquisas, a cannabis pode ser indicada no manejo de sintomas em diferentes condições, como dor crônica, cefaleias, epilepsia, ansiedade e outras doenças psiquiátricas. Os canabinoides primários estudados são o 9-tetrahydrocannabinol (THC), cannabinol (CBN), canabigeral (CBG), e a tetrahidrocannabivarina (THCV). Os ingredientes ativos da cannabis incluem flavonoides, terpenos, delta-9- tetrahydrocannabinol (THC), canabidiol (CBD), e eles são capazes de agir dentro do sistema endocanabinoide e diminuir a nocicepção e a frequência dos sintomas. O objetivo deste estudo foi documentar a validade de como a cannabis medicinal pode ser utilizada como terapia alternativa para o manejo da cefaleia crônica, além de esclarecer sobre falsas crenças ligadas a seu uso. CONTEÚDO: Sessenta e quatro artigos foram selecionados por meio de pesquisa nas bases de dados Pubmed e Google Scholar. As seguintes palavras-chave foram usadas: "Cannabis", "Maconha Medicinal", "Cefaleia", "Enxaqueca", "Cannabis e Enxaqueca", "Cannabis e Cefaleia". A literatura mostra que o uso da cannabis medicinal reduz a duração e a frequência da enxaqueca e das cefaleias de origens não conhecidas. CONCLUSÃO: Pacientes sofrendo com enxaqueca e condições relacionadas podem se beneficiar da terapia com cannabis devido à sua conveniência e eficácia.

Cannabis versus neuromodulators in chronic pain / Cannabis versus neuromoduladores na dor crônica

ABSTRACT BACKGROUND AND OBJECTIVES: The change of paradigm in relation to the medical use of cannabis and its components in the treatment of pain is undeniable nowadays. Understanding the functioning of the endocannabinoid system and its interaction with drugs already available on the market is necessary for professionals who care for patients with chronic pain. The aim of this study was to show the mechanisms by which cannabinoids act, not only on CB1 and CB2 receptors, but also on various other receptors, modulating chronic pain, and encourage health professionals to recognize the need to expand the knowledge about its functioning and synergism with several medications so that the safe use of cannabis occurs in the treatment of multiple diseases, especially chronic pain. CONTENTS: The action of cannabinoids on the endocannabinoid system has the ability to neuro and immunomodulate pain transmission in a multifactorial and extremely complex way, acting simultaneously on multiple targets, in the peripheral, spinal and supraspinal nervous system. The analgesia mechanisms determined by cannabinoids include the inhibition of the release of neurotransmitters and neuropeptides in presynaptic nerve terminals, modulation of postsynaptic neuronal excitability, activation of the descending inhibitory pathway and reduction of neural inflammation. There is also the possibility that the interaction of cannabinoids with opioid and serotonergic receptors has an amplifying effect on the analgesic effect of drugs belonging to the opioid class. CONCLUSION: The endocannabinoid system plays a key role in pain control and its pathophysiology. It is expected that this system will continue to be studied for a better understanding of its signaling pathways and metabolism, and also that more clinical trials of greater size and duration will be carried out to understand to what extent this approach can be beneficial in the treatment of chronic pain.

RESUMO JUSTIFICATIVA E OBJETIVOS: A mudança de paradigma, em nível mundial, em relação ao uso medicinal de cannabis e seus respectivos componentes no tratamento da dor é indiscutível nos tempos atuais. Entender o funcionamento do sistema endocanabinoide e sua interação com fármacos já disponíveis no mercado se faz necessário aos profissionais que cuidam de pacientes com dor crônica. O objetivo deste estudo foi mostrar os mecanismos pelos quais os canabinoides atuam, não somente nos receptores CB1 e CB2, mas também em diversos outros receptores, agindo na modulação da dor crônica, bem como incentivar os profissionais da saúde a reconhecerem a necessidade de ampliar o conhecimento acerca desse funcionamento e sinergismo com diversos fármacos para que ocorra o uso seguro da cannabis no tratamento de múltiplas doenças, sobretudo dores crônicas. CONTEÚDO: A ação dos canabinoides no sistema endocanabinoide tem a capacidade de neuro e imunomodulação da transmissão da dor de forma multifatorial e extremamente complexa, atuando simultaneamente em múltiplos alvos, no sistema nervoso periférico, espinhal e supraespinhal. Os mecanismos de analgesia determinados pelos canabinoides incluem a inibição de liberação de neurotransmissores e neuropeptídeos nos terminais nervosos pré-sinápticos, a modulação da excitabilidade neuronal pós-sináptica, a ativação da via inibitória descendente e a redução da inflamação neural. Existe ainda a possibilidade de que a interação dos canabinoides com receptores opioides e serotoninérgicos tenha uma ação amplificadora do efeito analgésico de fármacos pertencentes à classe opioide. CONCLUSÃO: O sistema endocanabinoide desempenha um papel fundamental no controle da dor e na sua fisiopatologia. Espera-se que esse sistema continue a ser estudado para uma melhor compreensão das suas vias de sinalização e metabolismo. É preciso também que se realizem mais ensaios clínicos, de maior dimensão e duração, para compreender até que ponto essa abordagem poderá ser benéfica no tratamento da dor crônica.

The endocannabinoid system and orofacial pains: updates and perspectives / O sistema endocanabinoide e as dores orofaciais: atualidades e perspectivas

ABSTRACT BACKGROUND AND OBJECTIVES: Since the relatively recent discovery of the endocannabinoid system (ECS) and its fundamental role in regulating other systems, the subject has aroused interest in all areas of health, including Dentistry. Among the possible uses and benefits of cannabinoids are their performance in pain and its predisposing or perpetuating factors, such as bruxism and sleep disorders. Although the literature is still scarce, the mechanisms of action and satisfactory results of cannabinoids and other cannabis derivatives in these situations already allow their safe prescription. The objective of this study was to verify the current evidence on the use of cannabis derivatives in orofacial pain (OFP), reviewing what is known, to date, about the ECS and the prospects for its use with support and criteria. CONTENTS: This research carried out a brief review of the cannabis plant history, addressing issues such as prejudice, prohibitions and interests, as well as its therapeutic use. Then, a review on ECS and its mechanisms of interest in OFP was presented. Next, the products derived from the plant and their effects, indications, contraindications, adverse effects, drug interactions, peculiarities and perspectives were discussed. CONCLUSION: The more knowledge is gained about the ECS and the therapeutic benefits of cannabis components and derivatives, the greater the conviction that a new therapeutic frontier has indeed emerged. The growing number of good outcomes, including cases of OFP, obtained through well-conducted studies, brings a mixture of satisfaction and excitement. No therapy will achieve good results if it does not start from an accurate diagnosis. Thus, it is of the utmost importance to know the ECS, the products and derivatives of the plant, the synthetic cannabinoids, their indications and effects. New studies are necessary and, at this moment, it can be said that the perspectives are very good and a new and challenging horizon is emerging.

RESUMO JUSTIFICATIVA E OBJETIVOS: Desde a descoberta relativamente recente do sistema endocanabinoide (SEC) e seu papel fundamental da regulação de outros sistemas, o assunto tem despertado interesse de todas as áreas da saúde, incluindo-se a Odontologia. Dentre as possíveis utilizações e benefícios dos canabinoides, está sua atuação na dor e seus fatores predisponentes ou perpetuadores, como o bruxismo e os distúrbios do sono. Embora a literatura seja ainda escassa, os mecanismos de ação e resultados satisfatórios dos canabinoides e demais derivados da cannabis nessas situações já permitem sua prescrição com segurança. O objetivo deste estudo foi verificar as atuais evidências sobre a utilização de derivados da cannabis nas dores orofaciais (DOFs), revisando o que se sabe, até o momento, sobre o SEC e as perspectivas de sua utilização com respaldo e critério. CONTEÚDO: Esta pesquisa realizou uma breve revisão da história da planta cannabis, abordando temas como preconceito, proibições e interesses, além de sua utilização terapêutica. Em seguida, foi apresentada uma revisão sobre o SEC e seus mecanismos de interesse na DOF. Na sequência, foram discutidos os produtos derivados da planta e seus efeitos, indicações, contraindicações, efeitos adversos, interações farmacológicas, peculiaridades e perspectivas. CONCLUSÃO: Quanto mais são adquiridos conhecimentos sobre o SEC e os benefícios terapêuticos dos componentes e derivados da cannabis, mais há um convencimento de que surgiu, de fato, uma nova fronteira terapêutica. O número crescente de bons desfechos, incluindo casos de DOF, obtidos através de estudos bem conduzidos, traz um misto de satisfação e empolgação. Nenhuma terapia obterá bons resultados se não partir de um diagnóstico preciso. Assim, é de suma importância que se conheça o SEC, os produtos e derivados da planta, os canabinoides sintéticos, suas indicações e efeitos. Novos estudos são necessários e, nesse momento, pode-se afirmar que as perspectivas são muito boas e um novo e desafiador horizonte está despontando.

Integrative approach to the therapeutic use of cannabis for orofacial pain / Abordagem integrativa do uso terapêutico da cannabis nas dores orofaciais

ABSTRACT BACKGROUND AND OBJECTIVES: Faced with the difficulty of treating chronic orofacial pain and seeking an approach that aims at the health and well-being of the patient in a broader way, cannabinoid therapy appears as an adjunct to pharmacological approaches. CONTENTS: Cannabinoid therapy generates analgesia through the activation of the endocannabinoid system, as well as the use of palmitoylethanolamide (PEA), curcumin, grape seed extract, aromatherapy, acupuncture, laser therapy and the practice of physical exercise. In this way, these therapies allow a reduction in the use of analgesic drugs. CONCLUSION: Cannabinoid therapy is part of this integrative approach and the combination of cannabinoids with other forms of activation of the endocannabinoid system contributes to a better therapeutic outcome and a better quality of life for countless patients suffering from chronic orofacial pain.

RESUMO JUSTIFICATIVA E OBJETIVOS: Diante da dificuldade de tratamento das dores orofaciais crônicas e buscando uma abordagem que vise a saúde e o bem-estar do paciente de uma forma mais ampla, surge a terapia canabinoide como coadjuvante nas abordagens farmacológicas. CONTEÚDO: A terapia canabinoide promove analgesia através da ativação do sistema endocanabinoide, assim como o uso da palmitoiletanolamida (PEA), curcumina, extrato de semente de uva, aromaterapia, acupuntura, laserterapia e a prática de exercício físico. Desta forma, essas terapias permitem redução do uso de fármacos analgésicos. CONCLUSÃO: A terapia canabinoide faz parte dessa abordagem integrativa e a combinação dos canabinoides com outras formas de ativação do sistema endocanabinoide contribui para melhores resultados terapêuticos e melhor qualidade de vida para inúmeros pacientes que sofrem de dores orofaciais crônicas.

Endocannabinoids are potential inhibitors of glioblastoma multiforme proliferation / 中西医结合学报

Globally, it is evident that glioblastoma multiforme (GBM) is an aggressive malignant cancer with a high mortality rate and no effective treatment options. Glioblastoma is classified as the stage-four progression of a glioma tumor, and its diagnosis results in a shortened life expectancy. Treatment options for GBM include chemotherapy, immunotherapy, surgical intervention, and conventional pharmacotherapy; however, at best, they extend the patient's life by a maximum of 5 years. GBMs are considered incurable due to their high recurrence rate, despite various aggressive therapeutic approaches which can have many serious adverse effects. Ceramides, classified as endocannabinoids, offer a promising novel therapeutic approach for GBM. Endocannabinoids may enhance the apoptosis of GBM cells but have no effect on normal healthy neural cells. Cannabinoids promote atypical protein kinase C, deactivate fatty acid amide hydrolase enzymes, and activate transient receptor potential vanilloid 1 (TRPV1) and TRPV2 to induce pro-apoptotic signaling pathways without increasing endogenous cannabinoids. In previous in vivo studies, endocannabinoids, chemically classified as amide formations of oleic and palmitic acids, have been shown to increase the pro-apoptotic activity of human cancer cells and inhibit cell migration and angiogenesis. This review focuses on the biological synthesis and pharmacology of endogenous cannabinoids for the enhancement of cancer cell apoptosis, which have potential as a novel therapy for GBM. Please cite this article as: Duzan A, Reinken D, McGomery TL, Ferencz N, Plummer JM, Basti MM. Endocannabinoids are potential inhibitors of glioblastoma multiforme proliferation. J Integr Med. 2023; 21(2): 120-128.

Cannabis medicinal: puntos críticos para su uso clínico / Medical cannabis: Critical points for clinical application

El cannabis se ha utilizado desde la antigüedad con fines recreativos y medicinales. Es una fuente muy rica de compuestos químicos, la mayoría denominados fitocannabinoides, que tienen una variedad de efectos fisiológicos, principalmente por su unión a receptores cannabinoides endógenos como el CB1 y CB2, entre otros. El cannabis tiene propiedades terapéuticas potenciales y sus preparaciones se han utilizado como remedios tradicionales para tratar el dolor y la emesis. Los cannabinoides sintéticos se utilizan clínicamente como analgésicos, antiespasmódico, antieméticos y estimulantes del apetito. La toxicidad significativa del cannabis es poco común en los adultos, sin embargo, puede tener múltiples efectos adversos agudos y crónicos. La calidad de la evidencia en este campo se ha visto limitada por la corta duración de los estudios, los reducidos tamaños de las muestras, la falta de grupos de control y la existencia de sesgos en la mayoría de los estudios revisados. En este contexto, son necesarios más estudios de mejor calidad metodológica para apoyar el uso seguro de esta terapia en otras enfermedades. La decisión de incorporar los cannabinoides como terapia en alguna de las condiciones descritas depende de la evidencia, el uso de terapias previas y el tipo de paciente.

Since ancient times cannabis has been used for recreational and medicinal purposes. It is a significant source of chemical compounds, most of them called phytocannabinoids. These compounds have several physiological effects and produce their effects primarily by binding to endogenous cannabinoid receptors such as CB1 and CB2, among others. Cannabis has potential therapeutic properties and its preparations have been used as traditional remedies to treat pain and emesis. Synthetic cannabinoids are used clinically as analgesics, antispastics, antiemetics, and appetite stimulants. Significant cannabis toxicity is rare in adults; however, it can produce countless acute and chronic side effects. The quality of the evidence in this field is limited by the short duration of the trials, poor sample sizes, lack of a control group, and the existence of bias in most of the reviewed studies. Therefore, a larger number of studies with better methodological quality is required to support the safe use of this therapy. The decision to include cannabinoids as a treatment for any of the conditions described will depend on the evidence, the use of previous therapies, and the type of patient.

O emprego da Cannabis medicinal no enfrentamento à doenças / The use of medicinal Cannabis in fighting diseases

A Cannabis possui como subespécie a Cannabis sativa. As plantas do gênero Cannabis possuem propriedades terapêuticas que são oriundas de compostos denominados canabinoides. O objetivo do presente artigo foi evidenciar como procede o uso terapêutico da Cannabis para enfrentamento das doenças. Realizou-se revisão narrativa da literatura com busca nas bases de dados: PubMED, Google Acadêmico com levantamento de artigos que tratavam acerca do uso da Cannabis medicinal para o tratamento de algumas doenças. Canabinoides correlacionam-se a receptores do nosso corpo, influindo nos mecanismos que regulam o organismo. Cannabis possibilita abordar e intervir em determinadas patologias presentes nos pacientes advindo de possuir ações benéficas anticonvulsivantes, anti-inflamatórias, analgésicas, ansiolíticas, antipsicóticas e antitumorais. Em nosso corpo existem os canabinoides ou endocanabinoides, que são similares aos canabinoides naturais ou fitocanabinoides estruturados na Cannabis. O canabidiol e o tetra-hidrocarbinol constituem canabinoides provenientes da Cannabis que podem tecer relação com os canabinoides configurados por nosso próprio corpo. O sistema de endocanabinoides possibilitou averiguar-se acerca do emprego do canabidiol para tratamento de patologias, como: Doença de Parkinson, Autismo e Epilepsia. Concluiu-se que o emprego terapêutico da Cannabis medicinal pode representar recurso que será válido para resolução do problema de saúde, podendo propiciar melhores condições e qualidade de vida aos pacientes portadores de determinadas patologias em que essa droga pode ser utilizada para tratamento.

Cannabis has Cannabis sativa as a subspecies. Cannabis plants have therapeutic properties that come from compounds called cannabinoids. The aim of this article was to show how the therapeutic use of Cannabis to cope with diseases proceeds. A narrative review of the literature was carried out with a search in the following databases: PubMED, Google Scholar with a survey of articles that dealt with the use of medicinal Cannabis for the treatment of some diseases. Cannabinoids correlate to our body's receptors, influencing the mechanisms that regulate the body. Cannabis makes it possible to address and intervene in certain pathologies present in patients arising from having beneficial anticonvulsant, anti-inflammatory, analgesic, anxiolytic, antipsychotic and antitumor actions. In our body there are cannabinoids or endocannabinoids, which are similar to natural cannabinoids or phytocannabinoids structured in Cannabis. Cannabidiol and Tetrahydrocannabinol are cannabinoids derived from Cannabis that can be related to cannabinoids configured by our own body. The endocannabinoid system made it possible to investigate the use of cannabidiol for the treatment of pathologies, such as: Parkinson's Disease, Autism and Epilepsy. It was concluded that the therapeutic use of medicinal Cannabis can represent a resource that will be valid for solving the health problem, providing better conditions and quality of life for patients with certain pathologies in which this drug can be used for treatment.

Cannabinoid receptor gene polymorphisms and cognitive performance in patients with schizophrenia and controls

Objective: To test the hypothesis that genetic variations of cannabinoid receptors contribute to the pathophysiology of cognitive deficits in schizophrenia. Methods: In this genetic association case-control study, cannabinoid receptor polymorphisms CNR1 rs12720071 and CNR2 rs2229579 were tested for association with neurocognitive performance in 69 patients with schizophrenia and 45 healthy controls. Neurocognition was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS). Results: We found a consistent association between CNR1 rs12720071 polymorphism and the cognitive performance of patients in several cognitive domains. Patients with C/C polymorphism presented significantly worse performance in motor speed, verbal fluency, attention/processing speed and reasoning/problem solving. Conclusion: Although limited, our data support the hypothesis that CNR1 variations may be associated with the pathogenesis of cognitive deficits of schizophrenia.

The endocannabinoid system in social anxiety disorder: from pathophysiology to novel therapeutics

Social anxiety disorder (SAD) is a highly prevalent psychiatric disorder that presents with an early age of onset, chronic disease course, and increased risk of psychiatric comorbidity. Current treatment options for SAD are associated with low response rates, suboptimal efficacy, and possible risk of adverse effects. Investigation of new neurobiological mechanisms may aid in the identification of more specific therapeutic targets for the treatment of this disorder. Emerging evidence suggests that the endogenous cannabinoid system, also referred to as the endocannabinoid system (ECS), could play a potential role in the pathophysiology of SAD. This review discusses the known pathophysiological mechanisms of SAD, the potential role of the ECS in this disorder, current drugs targeting the ECS, and the potential of these novel compounds to enhance the therapeutic armamentarium for SAD. Further investigational efforts, specifically in human populations, are warranted to improve our knowledge of the ECS in SAD.

Hypothesis on ontogenesis and pathophysiology of Alzheimer's disease

Abstract Alzheimer's disease is a neurodegenerative condition that causes changes in memory and cognition, in addition to behavioral disorders, and most commonly affects the elderly. Several studies in the literature have presented therapeutic measures in an attempt to interfere with the pathogenic mechanisms of the disease and to mitigate its clinical manifestations. Some factors, such as excitotoxicity, cholinergic dysfunctions, oxidative stress, tau protein hyperphosphorylation, changes in amyloid-beta peptide metabolism, herpes viruses, apolipoprotein E, glycogen synthase kinase 3, insulin resistance, and the endocannabinoid system seem to be related to pathophysiology of Alzheimer's disease. Given this, a literature review was carried out to address the molecular mechanisms associated with the pathophysiological hypotheses previously mentioned, aiming to better understanding their underlying causes and contributing to possible pharmacological strategies about treatment of the disease.

Cannabinoid CB2 receptors and spinal microglia are implicated in tingenone-mediated antinociception in mice

Objective:To investigate the antinociceptive effect of tingenone on inflammatory pain, as well as and the involvement of the cannabinoid receptors type 2 (CB2) and spinal microglia in this process. Methods:Male Swiss mice were subjected to inflammatory pain induced by intraplantar injection of carrageenan. The nociceptive threshold was measured by von Frey filaments test. Tingenone was administered orally 60 min before carrageenan injection. To evaluate the involvement of CB2 receptor, endocannabinoids, and microglia, AM630 (a CB2 receptor antagonist), MAFP (an inhibitor of an enzyme that hydrolyses endocannabinoids), and minocycline (a microglial inhibitor) were given intrathecally 20 min before tingenone administration. In addition, an immunofluorescence assay was used to evaluate CB2 receptor and CD11B (a microglial marker) expression in the spinal cord dorsal horn. Results:Tingenone significantly reduced carrageenan-induced hyperalgesia, which was reversed by pretreatment with AM630. MAFP and minocycline potentiated and prolonged the tingenone-induced antinociception. CD11B expression was increased in the spinal cord dorsal horn of mice with inflammatory pain pretreated with tingenone, which was reduced by AM630, MAFP, and minocycline. Conclusions:CB2 receptors and endocannabinoids participate in the tingenone-induced antinociception which may involve the inhibition of microglia at spinal level.

Genome-wide analysis of hippocampal transfer RNA-derived small RNAs identifies new potential therapeutic targets of Bushen Tiansui formula against Alzheimer's disease / 中西医结合学报

OBJECTIVE@#Bushen Tiansui formula (BSTSF), a traditional Chinese medicine prescription, has been widely used to treat Alzheimer's disease (AD). However, the mechanisms underlying its effects remain largely unknown. In this study, a rat AD model was used to study the effects of BSTSF on cognitive performance and expression of transfer RNA-derived small RNAs (tsRNAs) in the hippocampus, to determine whether treatment of AD with BSTSF could regulate the expression of tsRNAs, a novel small non-coding RNA.@*METHODS@#To generate a validated AD model, oligomeric amyloid-β@*RESULTS@#The learning and memory deficits of Aβ@*CONCLUSION@#This study identified a previously uncharacterized mechanism underlying the effects of BSTSF in alleviating the learning and memory deficits in Aβ

The Psychiatric Effects of Cannabis / 생물치료정신의학

With the recent legalization of recreational cannabis in Canada and 11 states of the U.S., the interest surrounding cannabis use is increasing. However, many people and even clinicians in Korea do not have exact knowledge about the psychiatric consequences of cannabis use. In this narrative review, the characteristics of cannabis, the endocannabinoid system, and the psychiatric consequences of cannabis use were provided. Cannabis contains more than 80 cannabinoids in the native plant. Psychotropic properties of Δ-9-tetrahydrocannabinol and cannabidiol are most well studied. The two main receptors are cannabinoid-1 receptor and cannabinoid-2 receptor. Several endocannabinoids, such as anandamide and 2-arachidonoylglycerol, act on the receptors as the endogenous ligands. Cannabis influences mood, cognitive functions, and psychomotor functions in acute phase responses, increasing the odds ratio for motor vehicle crashes. Long-term cannabis use is associated with various psychotic outcomes, including the development of schizophrenia, although there is interindividual variability. Cannabis adversely influences learning, memory, and attention. More frequent, persistent, and earlier onset cannabis use is associated with greater cognitive impairment. The chronic cognitive effects of cannabis are complex and controversial. Cannabis has addictive potential, and cannabis use disorder is common. Clinicians should have evidence-based knowledge about the consequences of cannabis use and communicate accurate information about cannabis use and its associated risks to the public.

An integrative overview of the cannabinergic system and mental health / Una revisión exhaustiva del sistema cannabinérgico y la salud mental

Abstract Background The endocannabinoid system (eCBs) is one of the modulatory systems widely expressed in the brain. It consists of receptors expressed in the cytoplasmic (CB1 and CB2), the mitochondrial membrane (CB1), and the endogenous ligands known as endocannabinoids, such as anandamide, 2AG and oleamide. CB1 has been found in excitatory and inhibitory neurons in the pre- and post-synaptic membranes. It is expressed in several brain areas such as the hippocampus, dorsal, and ventral striatum, amygdala and prefrontal cortex. The eCBs has been involved in the regulation of learning and memory, mood, energy balance, sleep, and drug addiction. Objective Integrate existing information about the eCBs and its role in brain function and mental health. Method Review of the information of basic and clinical relevance obtained from indexed scientific journals (PubMed/Medline, Scopus). Results Basic and clinical research on eCBs related to central nervous system function is described. Discussion and conclusion At present, the study of eCBs is of importance. The development of drugs that affect this system may be clinically useful to control different debilitating diseases. This is an area of interest to the scientific community and health care providers.

Resumen Antecedentes El sistema de endocannabinoides (eCBs) es uno de los sistemas moduladores más ampliamente expresados en el cerebro. Se compone de receptores expresados en la membrana citoplasmática (CB1 y CB2) y en la membrana mitocondrial (CB1) y ligandos endógenos conocidos como endocannabinoides, como anandamida, 2AG y oleamida. El CB1 se ha encontrado en neuronas excitadoras e inhibidoras, en las membranas pre- y pos-sináptica, en varias áreas cerebrales como el hipocampo, el estriado dorsal y ventral, y en la amígdala y la corteza prefrontal. El eCBs se ha relacionado con la regulación del aprendizaje y la memoria, del estado afectivo, del equilibrio energético, del sueño y del proceso de la adicción a las drogas. Objetivo Integrar la información existente sobre el eCBs y su función sobre los procesos cerebrales y la salud mental. Método Revisión de la información de relevancia básica y clínica obtenida de revistas científicas indexadas (PubMed/Medline, Scopus). Resultados Se describe de manera concisa información de interés básico y clínico de la investigación sobre el eCBs relacionada con la función del sistema nervioso central. Discusión y conclusión En la actualidad, el estudio del eCBs es indispensable debido a su potencial terapéutico. El desarrollo de fármacos que afecten este sistema puede ser clínicamente útil para controlar diferentes enfermedades debilitantes. Ésta es un área de interés para la comunidad científica y los proveedores de salud.

Breve reseña sobre la farmacología de los cannabinoides / Brief review on the pharmacology of cannabinoids

Intensa resulta la controversia entre los que promueven el uso de los cannabinoides con fines terapéuticos y quienes consideran que es temprana aún la introducción de estos en la clínica, por sus efectos deletéreos para la salud humana en las diferentes etapas y condicionales del desarrollo biológico. Paralelamente se debate, entre las autoridades encargadas de velar por la salud de sus conciudadanos, la polémica de legalizar o no el consumo de la Cannabis sativa en cualquiera de sus formas y derivados naturales. Ambas polémicas han fundamentado el estudio de todas las formas de presentación y consumo de esta planta, así como de sus derivados sintéticos dados sus efectos sobre la salud de enfermos y sanos. En esta breve reseña se exponen aspectos relevantes de su farmacología, debido al interés y enorme caudal de información generado por un sinnúmero de investigadores dedicados al estudio de dicha planta y sus derivados

The controversy among those that promote the use of cannabinoids with therapeutic aims is intense and who consider that it is still early for their introduction in the clinic, due to their lethal effects for the human health in the different stages and conditionals of the biological development. In parallel it is debated, among the authorities in charge of looking after the health of their fellow citizens, the polemic of legalizing or not the consumption of the Cannabis sativa in any of their forms and natural derived. Both polemics have based the study of all the forms of presentation and consumption of this herb, as well as of its synthetic derived due to their effects on the health of sick and healthy people. In this brief review outstanding aspects of their pharmacology are exposed, due to the interest and enormous flow of information generated by a large number of investigators dedicated to the study of this herb and its derived elements

Roles of endocannabinoid system in treatment of neuropsychiatric diseases and regulation of arousal from general anesthesia / 中国药理学与毒理学杂志

The endocannabinoid(eCB)system has attracted attention for its role in various behav-ioral and brain functions, and as a therapeutic target in neuropsychiatric disease states,including anxiety disorders and other conditions resulting from dysfunctional responses to stress. Brain eCB signaling seems to harmonize appropriate behavioral responses, which are essential for the long-term viability and homeostasis of organisms. Dysregulation of eCB signaling contributes to negative emotional states and increases stress responsivity. A better understanding of the underlying neural cell popula-tions and neural circuitsregulation enables the development of therapeutic strategies to mitigate behav-ioral maladaptation and provides insight into the eCB influence on neural circuits of arousal from general anesthesia.This review focuses on recent evidence that has added a new layer of complexity to the idea of targeting the eCB system for therapeutic benefit in neuropsychiatric diseases and regulation of arousal after anesthesia.

Derivados canabinóides e o tratamento farmacológico da dor / Cannabinoid derivatives and the pharmacological management of pain

RESUMO JUSTIFICATIVA E OBJETIVOS: As propriedades medicinais da Cannabis sativa têm sido relatadas por muitos séculos para o tratamento de diversos distúrbios e, mais recentemente, para o tratamento da dor. O objetivo deste estudo foi revisar os principais avanços na farmacologia do sistema endocanabinóide e no potencial uso terapêutico de alguns compostos canabinóides no tratamento de diversas formas de dor. CONTEÚDO: Foi realizada uma busca nos bancos de dados Pubmed, Scielo e Lilacs, identificando-se estudos e revisões da literatura sobre a farmacologia e o uso terapêutico de substâncias canabinóides em dor. Nessa busca foram utilizadas as seguintes palavras-chaves: Cannabis sativa, tetra-hidrocanabinol, canabidiol, sativex®, cannador®, canabinóides, endocanabinóide, dor e dor neuropática. Os canabinóides sintéticos e os extratos de Cannabis sativa apresentaram efeito analgésico em diversos ensaios clínicos, sugerindo um potencial papel no tratamento da dor, em particular naquela de origem neuropática. Os canabinóides sintéticos e os extratos de Cannabis sativatambém apresentaram efeitos ansiolíticos quando usados como adjuvantes no tratamento da dor no câncer, na artrite reumatoide e na esclerose múltipla. Porém, efeitos adversos significativos, como euforia, depressão e sedação limitam o uso clínico desses agentes canabinóides. CONCLUSÃO: Um melhor conhecimento sobre a farmacologia do sistema endocanabinóide, juntamente com os resultados dos estudos envolvendo o tratamento da dor com substâncias de natureza canabinóide, podem ser de grande valor para o desenvolvimento de fármacos que permitam um avanço significativo na terapêutica de pacientes portadores de síndromes dolorosas, em particular nos casos de difícil controle. Porém, mais estudos são necessários para confirmar esses resultados e determinar a segurança desses compostos.

ABSTRACT BACKGROUND AND OBJECTIVES: Medical properties of Cannabis sativa have been reported for centuries for the treatment of diff ent disorders and, more recently, to manage pain. Th study aimed at reviewing major pharmacological advances of the endocannabinoid system and the potential therapeutic use of some cannabinoid compounds to manage diff ent types of pain. CONTENTS: A search was carried out in Pubmed, Scielo and Lilacs databases to identify studies and literature reviews on the pharmacology and therapeutic use of cannabinoids for pain. The following keywords were used: Cannabis sativa, tetra-hydrocannabinol, cannabidiol, sativex®, cannador®, cannabinoids, endocannabinoid, pain and neuropathic pain. Synthetic cannabinoids and Cannabis sativa extracts have shown analgesic effects in several clinical trials, suggesting their potential role for pain management, especially neuropathic pain. Synthetic cannabinoids and CS extracts have also induced anxiolytic effects when used as adjuvants to treat cancer pain, rheumatoid arthritis and multiple sclerosis. However, significant adverse effects, such as euphoria, depression and sedation limit the clinical use of such cannabinoids. CONCLUSION: Further understanding of endocannabinoid system pharmacology, together with study results involving pain management with cannabinoid substances may be very useful for the development of drugs allowing a significant advance in the treatment of patients with painful syndromes, especially difficult to control. However, further studies are needed to confirm such findings and to determine the safety of such compounds.