Harmine is an effective therapeutic small molecule for the treatment of cardiac hypertrophy.

Harmine is a ß-carboline alkaloid isolated from Banisteria caapi and Peganum harmala L with various pharmacological activities, including antioxidant, anti-inflammatory, antitumor, anti-depressant, and anti-leishmanial capabilities. Nevertheless, the pharmacological effect of harmine on cardiomyocytes and heart muscle has not been reported. Here we found a protective effect of harmine on cardiac hypertrophy in spontaneously hypertensive rats in vivo. Further, harmine could inhibit the phenotypes of norepinephrine-induced hypertrophy in human embryonic stem cell-derived cardiomyocytes in vitro. It reduced the enlarged cell surface area, reversed the increased calcium handling and contractility, and downregulated expression of hypertrophy-related genes in norepinephrine-induced hypertrophy of human cardiomyocytes derived from embryonic stem cells. We further showed that one of the potential underlying mechanism by which harmine alleviates cardiac hypertrophy relied on inhibition of NF-κB phosphorylation and the stimulated inflammatory cytokines in pathological ventricular remodeling. Our data suggest that harmine is a promising therapeutic agent for cardiac hypertrophy independent of blood pressure modulation and could be a promising addition of current medications for cardiac hypertrophy.

Neuroprotective potential of Ayahuasca and untargeted metabolomics analyses: applicability to Parkinson's disease.

ETHNOPHARMACOLOGY RELEVANCE: Ayahuasca is a tea produced through decoction of Amazonian plants. It has been used for centuries by indigenous people of South America. The beverage is considered to be an ethnomedicine, and it is traditionally used for the treatment of a wide range of diseases, including neurological illness. Besides, some scientific evidence suggests it may be applicable to Parkinson's disease (PD) treatment. Thus, Ayahuasca deserves in depth studies to clarify its potential role in this disease. AIM OF THE STUDY: This study aimed to use an untargeted metabolomics approach to evaluate the neuroprotective potential of the Ayahuasca beverage, the extracts from its matrix plants (Banisteriopsis caapi and Psychotria viridis), its fractions and its main alkaloids on the viability of SH-SY5Y neuroblastoma cells in an in vitro PD model. MATERIAL AND METHODS: The cytotoxicity of Ayahuasca, crude extracts, and fractions of B. caapi and P. viridis, as well as neuroprotection promoted by these samples in a 6-hydroxydopamine (6-OHDA)-induced neurodegeneration model, were evaluated by the MTT assay at two time-points: 48 h (T1) and 72 h (T2). The main alkaloids from Ayahuasca matrix plants, harmine (HRE) and N,N-dimethyltryptamine (DMT), were also isolated and evaluated. An untargeted metabolomics approach was developed to explore the chemical composition of samples with neuroprotective activity. Ultra-Performance Liquid Chromatography coupled to Electrospray Ionisation and Time-of-Flight (UPLC-ESI-TOF) metabolome data was treated and further analysed using multivariate statistical analyses (MSA): principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). The metabolites were dereplicated using the Dictionary of Natural Products and an in house database. The main alkaloids were also quantified by UPLC-MS/MS. RESULTS: The samples did not cause cytotoxicity in vitro and three of samples intensely increased cell viability at T1. The crude extracts, alkaloid fractions and HRE demonstrated remarkable neuroprotective effect at T2 while the hydroalcoholic fractions demonstrated this neuroprotective effect at T1 and T2. Several compounds from different classes, such as ß-carbolines and monoterpene indole alkaloids (MIAs) were revealed correlated with this property by MSA. Additionally, a total of 2419 compounds were detected in both ionisation modes. HRE showed potent neuroprotective action at 72 h, but it was not among the metabolites positively correlated with the most efficacious neuroprotective profile at either time (T1 and T2). Furthermore, DMT was statistically important to differentiate the dataset (VIP value > 1), although it did not exhibit sufficient neuroprotective activity by in vitro assay, neither a positive correlation with T1 and T2 neuroprotective profile, which corroborated the MSA results. CONCLUSION: The lower doses of the active samples stimulated neuronal cell proliferation and/or displayed the most efficacious neuroprotection profile, namely by preventing neuronal damage and improving cell viability against 6-OHDA-induced toxicity. Intriguingly, the hydroalcoholic fractions exhibited enhanced neuroprotective effects when compared to other samples and isolated alkaloids. This finding corroborates the significance of a holistic approach. The results demonstrate that Ayahuasca and its base plants have potential applicability for PD treatment and to prevent its progression differently from current drugs to treat PD.

Pesquisas com ayahuasca na psicologia: revisão de literatura sobre o potencial terapêutico / Research with ayahuasca in psychology: a literature review of its therapeutic potential

A Ayahuasca é uma bebida alucinógena utilizada em contexto religioso, sendo associada a melhorias na saúde mental dos usuários. O presente estudo teve como objetivo fazer um levantamento da produção de pesquisas que avaliam o seu potencial terapêutico no campo da Psicologia. Foi realizada uma revisão narrativa de literatura com os descritores "Psicologia" e "Ayahuasca" indexados no portal CAPES, nas plataformas Medline e Scielo. Foram obtidos 34 artigos e foram aplicados critérios de inclusão ­ serem escritos nas línguas portuguesa ou inglesa, e possuírem o descritor "Ayahuasca" no título ­ e de exclusão ­ não abordarem o uso terapêutico da ayahuasca como problema de pesquisa. Após a filtragem, obteve-se 8 artigos publicados entre 2006 e 2018, divididos em 10 estudos, sendo 7 de pesquisa básica e 3 de pesquisa aplicada. Conclui-se que a produção de estudos sobre a eficácia terapêutica da Ayahuasca e seus efeitos na saúde mental dos usuários é recente e escassa. É importante que estudos futuros abordem além de parâmetros psicopatológicos ou farmacológicos questões sociais e culturais atrelados ao uso de substâncias. É essencial que particularidades do ambiente no qual a substância foi ingerida e da história de vida do usuário sejam consideradas e investigadas minunciosamente

The Ayahuasca is a hallucinogenic drink used in religious context and its use is associated with improvements in mental health of users. This study aimed to do a survey of the researches that evaluate the therapeutic potential of Ayahuasca in Psychology. A narrative literature review was performed with the descriptors "Psychology" and "Ayahuasca" indexed on the CAPES portal, on Medline and Scielo platforms. Thirty-four articles were obtained and inclusion criteria were applied - written in Portuguese or English, and having the descriptor "Ayahuasca" in the title - and exclusion - not addressing the therapeutic use of ayahuasca as a research problem. After filtering, we obtained 8 articles published between 2006 and 2018, divided into 10 studies: 7 of basic research and 3 of applied research. It is concluded that the production of studies on the therapeutic efficacy of Ayahuasca and its effects on users' mental health is recent and scarce. It is important that future studies address beyond psychopathological or pharmacological parameters, analising social and cultural issues linked to substance use. It is essential that particularities of the environment in which the substance was taken and of the user's life history are considered and investigated in detail.

Influence of environment on the leaf morpho-anatomy and histochemical of the ayahuasca leaf: Populations cultivated in extra-Amazonian regions

Psychotria viridis Ruiz & Pav (Rubiaceae) occurs naturally throughout the Amazon and it is traditionally used by indigenous communities, being incorporated into religious use in urban contexts over the last few decades. It is known and cultivated in many regions of South America for possessing valuable bioactive alkaloids. In this paper, we described P. viridis leaf morphology, anatomy and histochemistry from three populations cultivated in the southeastern Brazil, in order to identify possible adaptations to local environment and management. All plants presented terminal stipules and basic morpho-anatomical patterns of leaves, consistent with most species of the genus, as heterogeneous dorsiventral mesophyll, uniseriate epidermis, presents large cells with prominent vacuoles and druses. Unicellular non-glandular trichomes and multicellular starry trichomes were present in the primary and secondary veins. Amphi-hypostomatic leaf pattern, not yet described for the species, was common in all studied plants. Variation in the presence of domatia in the same population indicates that this structure cannot be used for taxonomic determination of P. viridis, as already described for other species of the genus. Presence of secretory ducts and reduction in stomata density and leaf area represent the main morpho-anatomic adaptations of plants from drier and warmer climates. Histochemical tests were positive for alkaloids, polysaccharides, proteins and phenolic compounds, being negative for starch only in plants subjected to water stress. We concluded that the morpho-anatomical and histochemical alterations found in the plants of this study resulted from seasonal water deficit adaptations and to maintain or attract mutualistic organisms

Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews.

INTRODUCTION: Mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent studies suggest that serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) have anxiolytic, antidepressive, and antiaddictive effects. Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included. Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open label, and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.

Chronic intermittent exposure to ayahuasca during aging does not affect memory in mice

The Quechua term ayahuasca refers to a beverage obtained from decoctions of the liana Banisteriopsis caapi with leaves of Psychotria viridis. The ritualistic use of ayahuasca is becoming a global phenomenon, with some individuals using this beverage throughout life, including in old age. Cognitive impairment is a common manifestation during aging. There are conflicting reports on the ability of some ayahuasca compounds to exert neuroprotective or neurotoxic effects that could improve or impair learning and memory. Animal models provide a relevant and accessible means of investigating the behavioral effects of ayahuasca without the environmental conditions associated with the ritualistic use of the beverage. In this study, we investigated the influence of chronic ayahuasca exposure throughout aging on the spatial reference and habituation memories of mice. Twenty-eight male c57bl/6 mice (6 months old) received ayahuasca or water (1.5 mL/kg, orally) twice a week for 12 months and were tested in the Morris water maze (MWM), open field and elevated plus maze (EPM) tasks before and after treatment. During aging, there was significant impairment in the evocation (but not acquisition) of spatial reference memory and in habituation to the open field. There was also a decrease in locomotor activity in the open field and EPM tests, whereas the anxiety parameters were unaltered. Ayahuasca treatment did not alter any of these parameters associated with aging. These findings indicate that chronic exposure to ayahuasca during aging did not affect memory in mice.

An ontogenic study of the behavioral effects of chronic intermittent exposure to ayahuasca in mice

Ayahuasca is a beverage obtained from decoctions of the Banisteriopsis caapi plus Psychotria viridis. In religious contexts, ayahuasca is used by different age groups. However, little is known of the effects of ayahuasca during ontogenic development, particularly with regard to the functional characteristics of the central nervous system. Animal models are useful for studying the ontogenic effects of ayahuasca because they allow exclusion of the behavioral influence associated with the ritualistic use. We investigated the effects of exposure to ayahuasca (1.5 mL/kg, orally, twice a week) on memory and anxiety in C57BL/6 mice, with the post-natal day (PND) being used as the ontogenic criterion for classification: childhood (PND21 to PND35), adolescence (PND35 to PND63), adulthood (PND90-PND118), childhood-adolescence (PND21 to PND63), childhood-adulthood (PND21 to PND118) and adolescence-adulthood (PND35 to PND118). One day after the last ayahuasca exposure, the mice were subjected to the Morris water maze (MWM), open field and elevated plus maze tasks (EPM). Ayahuasca did not affect locomotion in the open field or open arms exploration in the EPM, but increased the risk assessment behavior in the childhood group. Ayahuasca did not cause any change in acquisition of spatial reference memory in the MWM task, but decreased the time spent on the platform quadrant during the test session in the adolescence group. These results suggest that, in mice, exposure to ayahuasca in childhood and adolescence promoted anxiety and memory impairment, respectively. However, these behavioral changes were not long-lasting since they were not observed in the childhood-adulthood and adolescence-adulthood groups.

Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report

Objectives: Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode. Methods: Open-label trial conducted in an inpatient psychiatric unit. Results: Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement. Conclusions: These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder. .

Ayahuasca: el encuentro de dos paradigmas / Ayahuasca: the meeting of two paradigms

La ayahuasca es una liana que crece en la Amazonía y con la cual se prepara una sustancia con potentes propiedades psicoactivas, también denominada ayahuasca. Esta sustancia está ligada con la cosmovisión de los pueblos amazónicos que la consideran una planta espiritual y medicinal por las visiones y percepción de los efectos que produce. Las investigaciones en laboratorio muestran que la ayahuasca contiene derivados betacarbolínicos como la harmina y derivados triptamínicos como la N,N-dimetiltriptamina (DMT), moléculas que intervienen en determinados fenómenos psicodislépticos de tipo alucinatorio -visiones de seres sobrenaturales- junto a alteraciones de la conciencia del yo descritas como una sensación de muerte y renacimiento que pueden llevan al usuario de la ayahuasca a un estado de éxtasis espiritual y bienestar. Estos efectos han sido descritos en la literatura y se ha considerado el potencial terapéutico de la ayahuasca frente a trastornos del estado de ánimo y problemas adictivos en los cuales se han reportado algunos resultados favorables. Sin embargo, los efectos psicoactivos que genera la ayahuasca son complejos debido a sus aspectos subjetivos, sociales y culturales y por consiguiente son difíciles de abordar objetivamente en el marco del paradigma científico actual. Por tales motivos resulta necesario el replanteamiento de formas alternativas de investigación que puedan interpretar la subjetividad presente en la experiencia psicoactiva por uso de ayahuasca.

Ayahuasca is a vine that grows in the Amazon, used to prepare a substance with high psychoactive properties also called ayahuasca. This substance is linked with the worldview of the Amazonian people who consider it a spiritual and medicinal plant due to the views and perceptions of the effects it produces. Laboratory research shows that ayahuasca contains ß-carbolinicderivates, such as harmineand tryptaminederivatives such as N,N-dimethyltryptamine (DMT), which are molecules involved in psychoactive processes related to visions of supernatural beings and the sense of death and rebirth that leads to a state of higher spirituality and wellness. These effects were studied to evaluate the therapeutic potential of ayahuasca in mood disorders and addictions, and favorable results were found. However, the psychoactive effects of ayahuasca are accompanied by subjective, social and cultural features which generate difficulties for an objective approach to the experience under the positivist paradigm. For these reasons it is necessary to rethink alternative forms of research that can interpret the subjectivity present in the psychoactive experience and, with it, a change in training and in the practice of medicine.

Determination of N,N-dimethyltryptamine in beverages consumed in religious practices by headspace solid-phase microextraction followed by gas chromatography ion trap mass spectrometry.

A novel analytical approach combining solid-phase microextraction (SPME)/gas chromatography ion trap mass spectrometry (GC-IT-MS) was developed for the detection and quantification N,N-dimethyltryptamine (DMT), a powerful psychoactive indole alkaloid present in a variety of South American indigenous beverages, such as ayahuasca and vinho da jurema. These particular plant products, often used within a religious context, are increasingly consumed throughout the world following an expansion of religious groups and the availability of plant material over the Internet and high street shops. The method described in the present study included the use of SPME in headspace mode combined GC-IT-MS and included the optimization of the SPME procedure using multivariate techniques. The method was performed with a polydimethylsiloxane/divinylbenzene (PDMS/DVB) fiber in headspace mode (70 min at 60 °C) which resulted in good precision (RSD<8.6%) and accuracy values (71-109%). Detection and quantification limits obtained for DMT were 0.78 and 9.5 mg L(-1), respectively and good linearity (1.56-300 mg L(-1), r(2)=0.9975) was also observed. In addition, the proposed method showed good robustness and allowed for the minimization of sample manipulation. Five jurema beverage samples were prepared in the laboratory in order to study the impact of temperature, pH and ethanol on the ability to extract DMT into solution. The developed method was then applied to the analysis of twelve real ayahuasca and vinho da jurema samples, obtained from Brazilian religious groups, which revealed DMT concentration levels between 0.10 and 1.81 g L(-1).

Gas chromatographic analysis of dimethyltryptamine and beta-carboline alkaloids in ayahuasca, an Amazonian psychoactive plant beverage.

INTRODUCTION: Ayahuasca is obtained by infusing the pounded stems of Banisteriopsis caapi in combination with the leaves of Psychotria viridis. P. viridis is rich in the psychedelic indole N,N-dimethyltryptamine, whereas B. caapi contains substantial amounts of beta-carboline alkaloids, mainly harmine, harmaline and tetrahydroharmine, which are monoamine-oxidase inhibitors. Because of differences in composition in ayahuasca preparations, a method to measure their main active constituents is needed. OBJECTIVE: To develop a gas chromatographic method for the simultaneous determination of dimethyltryptamine and the main beta-carbolines found in ayahuasca preparations. METHODOLOGY: The alkaloids were extracted by means of solid phase extraction (C(18)) and detected by gas chromatography with nitrogen/phosphorous detector. RESULTS: The lower limit of quantification (LLOQ) was 0.02 mg/mL for all analytes. The calibration curves were linear over a concentration range of 0.02-4.0 mg/mL (r(2 )> 0.99). The method was also precise (RSD < 10%). CONCLUSION: A simple gas chromatographic method to determine the main alkaloids found in ayahuasca was developed and validated. The method can be useful to estimate administered doses in animals and humans for further pharmacological and toxicological investigations of ayahuasca.