The pharmacological interaction of compounds in ayahuasca: a systematic review

Ayahuasca is a South American psychoactive plant brew used as traditional medicine in spiritual and in cultural rituals. This is a review of the current understanding about the pharmacological mechanisms that may be interacting in ayahuasca. Searches were performed using PubMed, PsycINFO, and Web of Science databases and 16 papers were selected. As hypothesized, the primary narrative in existing research revolved around prevention of deamination of N,N-dimethyltryptamine (N,N-DMT, also referred to as DMT) by monoamine oxidase inhibitors (MAOIs) in ayahuasca. Two of the constituents, DMT and harmine, have been studied more than the secondary harmala alkaloids. At present, it is unclear whether the pharmacological interactions in ayahuasca act synergistically or additively to produce psychoactive drug effects. The included studies suggest that our current understanding of the preparation's synergistic mechanisms is limited and that more complex processes may be involved; there is not yet enough data to determine any potential synergistic interaction between the known compounds in ayahuasca. Our pharmacological understanding of its compounds must be increased to avoid the potential risks of ayahuasca use.

Ayahuasca no tratamento da farmacodependência à cocaína: possíveis intervenções terapêuticas? / Ayahuasca in the treatment of cocaine addiction: possible therapeutic interventions?

Alucinógenos (ALU) são substâncias psicoativas que não induzem o indivíduo à dependência, possuem perfil de segurança de uso mais alto quando comparado a outras drogas e baixa capacidade de causar tolerância ao uso. Estudos recentes propõem o uso de ALU como tratamento a algumas doenças e transtornos relacionados ao sistema nervoso central, como a depressão, ansiedade e dependência. Dentre os ALU, a ayahuasca (AYA), cujo princípio ativo é a dimetiltriptamina (DMT), é uma bebida psicoativa amplamente utilizada pelas populações indígenas em rituais religiosos. Existem evidências de que pode ser eficaz no tratamento de dependência relacionada ao álcool e nicotina. No entanto, para a cocaína, a segunda droga ilícita mais utilizada no Brasil e na Europa, não existem muitos estudos. O objetivo deste trabalho foi avaliar o potencial da AYA em prevenir a expressão da sensibilização comportamental (SC) induzida pela cocaína e as repercussões neuroquímicas do tratamento em camundongos C57Bl/6. Para tanto, foi avaliada a influência da administração aguda de AYA (1,76; 3,0; 17,6; 30,0 mg/kg de DMT v.o.) na atividade locomotora dos animais em campo aberto (CA). Como não houve diferença estatística na distância percorrida durante a análise, as duas menores doses (1,76 e 3,0 mg/kg de DMT v.o.) foram escolhidas como doses iniciais para a realização do protocolo de prevenção à expressão da SC induzida pela cocaína. Inicialmente, os animais foram habituados no CA durante 3 dias consecutivos após a administração de solução salina 0,9% i.p. No 4o dia experimental, os animais receberam, durante 10 dias alternados, cocaína 10 mg/kg ou salina 0,9% i.p. e foram submetidos diretamente à avaliação da atividade locomotora no CA por 30 minutos. Vinte e quatro horas depois, receberam, durante 8 dias consecutivos, água ou AYA (1,76 ou 3,0 mg/kg de DMT v.o.) e após 30 minutos da administração, foram colocados no CA por 30 minutos para análise da atividade locomotora. No dia seguinte, os camundongos foram desafiados com uma administração de salina. E, no último dia experimental, foi realizado um desafio com cocaína, sempre colocando o animal no CA por 30 minutos. Nessas doses, a AYA não foi eficaz em prevenir a expressão da SC induzida pela cocaína. Dessa forma, avaliamos doses superiores de AYA (15, 30 e 45 mg/kg de DMT v.o.), as quais foram capazes de prevenir a expressão da SC à cocaína. Assim, o protocolo experimental foi novamente realizado com a menor dose (15 mg/kg de DMT v.o.), ao término do protocolo experimental, os animais foram eutanasiados e tiveram seu córtex pré-frontal, estriado e hipocampo dissecados para análise por immunoblotting dos receptores serotoninérgicos 5-HT1A e 5-HT2A. No entanto, não foram não observadas diferenças significativas ao comparar o nível proteico dos receptores nos grupos experimentais. Dessa forma, esses resultados sugerem que a AYA pode ser uma boa estratégia terapêutica para a dependência em cocaína, abrindo caminho para novos estudos

Psychedelics (PSY) are psychoactive substances that do not induce the individual to addiction, have a higher use safety profile when compared to other drugs and low ability to cause tolerance to use. Recent studies propose the use of PSY as a treatment for some diseases and disorders related to the central nervous system, such as depression, anxiety and addiction. Among the PSY, ayahuasca (AYA), whose active component is dimethyltryptamine (DMT), is a psychoactive drink widely used by indigenous populations in religious rituals. There is evidence that it may be effective in treating alcohol and nicotine addiction. However, for cocaine, the second most widely used illicit drug in Brazil and Europe, there are not many studies. The aim of this study was to evaluate the potential of AYA in preventing cocaine-induced behavioral sensitization (BS) expression and the neurochemical repercussions of this treatment in C57Bl/6 mice. Thus, we evaluated the influence of acute administration of AYA (1.76; 3.0; 17.6; 30.0 mg/kg of DMT, orally) on the locomotor activity of animals in the open field (OF). As there was no statistical difference in the distance travelled during the analysis, the two lowest doses (1.76 and 3.0 mg/kg of DMT, orally) were chosen as initial doses to perform the cocaine-induced expression prevention protocol. First, animals were habituated to OF for 3 consecutive days following administration of saline 0.9% i.p. On the fourth experimental day, the animals received for 10 alternate days cocaine 10 mg/kg or saline 0,9% i.p. and were directly submitted to the evaluation of locomotor activity in OF for 30 minutes. Twenty-four hours later they received, for 8 consecutive days, water or AYA (1.76 or 3.0 mg/kg of DMT, orally), and 30 minutes after administration, they were placed in the OF for 30 minutes for analysis of locomotor activity. The next day, the mice were challenged with saline administration. On the last experimental day, a cocaine challenge was performed, always placing the animal in the OF for 30 minutes. At these doses, AYA was not effective in preventing cocaine-induced expression of BS. Thus, we evaluated higher doses of AYA (15, 30 and 45 mg/kg of DMT, orally), which were able to prevent the expression of cocaine-induced BS. Thus, the experimental protocol was again performed with the lowest dose (15 mg/kg of DMT, orally). At the end of the experimental protocol, the animals were euthanized and their prefrontal cortex, striatum and hippocampus were dissected for serotonergic receptor 5-HT1A and 5-HT2A by immunoblotting. However, no significant differences were observed when comparing receptor protein level in the experimental groups. Thus, these results suggest that AYA may be a good therapeutic strategy for cocaine addiction, paving the way for further studies

Psychotria viridis: Chemical constituents from leaves and biological properties

ABSTRACT The phytochemical study of hexane, chloroform and methanol extracts from leaves of Psychotria viridis resulted in the identification of: the pentacyclic triterpenes, ursolic and oleanolic acid; the steroids, 24-methylene-cycloartanol, stigmasterol and β-sitosterol; the glycosylated steroids 3-O-β-D-glucosyl-β-sitosterol and 3-O-β-D-glucosyl-stigmasterol; a polyunsaturated triterpene, squalene; the esters of glycerol, 1-palmitoylglycerol and triacylglycerol; a mixture of long chain hydrocarbons; the aldehyde nonacosanal; the long chain fat acids hentriacontanoic, hexadecanoic and heptadenoic acid; the ester methyl heptadecanoate; the 4-methyl-epi-quinate and two indole alkaloids, N,N-dimethyltryptamine (DMT) and N-methyltryptamine. The chemical structures were determined by means of spectroscopic (IR, 1H and 13C NMR, HSQC, HMBC and NOESY) and spectrometric (CG-MS and LCMS-ESI-ITTOF) methods. The study of biologic properties of P. viridis consisted in the evaluation of the acetylcholinesterase inhibition and cytotoxic activities. The hexane, chloroform, ethyl acetate and methanol extracts, the substances 24-methylene-cycloartanol, DMT and a mixture of 3-O-β-D-glucosyl-β-sitosterol and 3-O-β-D-glucosyl-stigmasterol showed cholinesterase inhibiting activity. This activity induced by chloroform and ethyl acetate extracts was higher than 90%. The methanol and ethyl acetate extracts inhibit the growth and/or induce the death of the tumor cells strains B16F10 and 4T1, without damaging the integrity of the normal cells BHK and CHO. DMT also demonstrated a marked activity against tumor cell strains B16F10 and 4T1.

Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies

Objective: To conduct a systematic literature review of animal and human studies reporting anxiolytic or antidepressive effects of ayahuasca or some of its isolated alkaloids (dimethyltryptamine, harmine, tetrahydroharmine, and harmaline). Methods: Papers published until 3 April 2015 were retrieved from the PubMed, LILACS and SciELO databases following a comprehensive search strategy and using a predetermined set of criteria for article selection. Results: Five hundred and fourteen studies were identified, of which 21 met the established criteria. Studies in animals have shown anxiolytic and antidepressive effects of ayahuasca, harmine, and harmaline, and experimental studies in humans and mental health assessments of experienced ayahuasca consumers also suggest that ayahuasca is associated with reductions in anxiety and depressive symptoms. A pilot study reported rapid antidepressive effects of a single ayahuasca dose in six patients with recurrent depression. Conclusion: Considering the need for new drugs that produce fewer adverse effects and are more effective in reducing anxiety and depression symptomatology, the described effects of ayahuasca and its alkaloids should be further investigated.

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. .

Usos terapéuticos de sustancias prohibidas: LSD, MDMA, THC, GHB, DMT, psilocybina y mescalina / Therapeutic uses of prohibited substances: LSD, MDMA, THC, GHB, DMT, psilocybin, mescaline

El presente texto hace un breve recorrido sobre los usos terapéuticos que han tenido la LSD, MDMA, THC, GHB, DMT, Psilocybina y Mescalina en la historia, así como también refiere algunos de los beneficios para la salud física y mental que se considera tienen en la actualidad. Esta información científica se contrapone a la normativa internacional en materia de drogas, que las clasifica como sustancias prohibidas en la Lista I, debido a su falta de uso médico aceptado por Estados Unidos y a su alto potencial de abuso. En este trayecto también se intenta comprender a qué hace referencia dicho potencial, así como las motivaciones que podrían existir detrás de la prohibición del uso terapéutico de estas drogas. En este marco, se consideran consecuencias para la salud de la población, las que atentan contra los Derechos Humanos de las personas que podrían requerir alguna de estas sustancias.

This paper makes a brief of the therapeutic uses have had the LSD, MDMA, THC, GHB, DMT, Psilocybin and Mescaline in history, as well as some of the benefits referred to physical and mental health that are considered today. This scientific information seems contrary to international legislation on drugs, which classifies as prohibited substances in Schedule I, due to its lack of acceptance medical use by the United States and its high potential for abuse. In this way also try to understand what makes this potential reference, and the reasons that could be behind the ban on therapeutic use of these drugs. In this framework, we consider health consequences of the population, which violate the human rights of people who may require some of these substances.

Hallucinogen Rating Scale (HRS) - Versão brasileira: tradução e adaptação transcultural / Hallucinogen Rating Scale (HRS) - A Brazilian version: translation and cross-cultural adaptation

CONTEXTO: Existe um crescente interesse científico pelos efeitos de alucinógenos em geral e, particularmente, pelo uso religioso da bebida psicoativa ayahuasca no Brasil. Todavia, não há no Brasil um instrumento padronizado para avaliar os efeitos de alucinógenos. A Hallucinogen Rating Scale (HRS) é um questionário amplamente usado nos Estados Unidos e na Europa para avaliar os efeitos de diversas substâncias psicoativas, incluindo as alucinógenas. OBJETIVO: Traduzir e adaptar a HRS para o português brasileiro. MÉTODO: A adaptação foi realizada em três etapas: 1) os autores do artigo traduziram a HRS para o português, visando à elaboração de uma versão-síntese inicial; 2) foi feita retrotradução dessa versão para o inglês por dois tradutores independentes; 3) foi elaborada uma versão final em português brasileiro por um comitê de revisão. Esta versão final foi desenvolvida pela comparação entre as traduções iniciais e as retrotraduções, por um processo dialógico com o autor do instrumento. RESULTADOS: Produção da versão final da HRS em português. Observaram-se as diretrizes para equivalência semântica e conceitual entre o português e inglês na descrição de estados subjetivos induzidos por alucinógenos. CONCLUSÃO: Uma versão brasileira da HRS - instrumento largamente empregado em todo o mundo para quantificar os efeitos de psicoativos - fornece um instrumento sensível para a avaliação de efeitos de substâncias alucinógenas no Brasil.

BACKGROUND: There is a growing scientific interest in the effects of hallucinogens in general and the religious use of psychoactive brew ayahuasca in Brazil in particular. However, there is not yet a standard instrument used in Brazil to evaluate the effects of hallucinogens. The Hallucinogen Rating Scale (HRS) is a questionnaire widely used in the U.S. and Europe to evaluate the effects of several psychoactive substances, including hallucinogens. OBJECTIVE: To translate and adapt the HRS to Brazilian Portuguese. METHOD: We followed three steps: 1) the authors of the article translated the HRS into Portuguese, in order to establish an initial version; 2) two independent translators back-translated this version into English; 3) a revision committee produced a final version of the Brazilian Portuguese version. This final version was developed comparing the initial translations and back-translations, through a dialogic process with the author of the instrument. RESULTS: A final Portuguese version of the HRS, following the guidelines for semantic and conceptual equivalence between English and Portuguese to describe hallucinogen-induced subjective states. DISCUSSION: A Brazilian version of the HRS - an instrument widely used throughout the world to quantify effects of psychoactive drugs - provides a sensitive instrument for evaluation of the effects of hallucinogenic substances in Brazil.

Ayahuasca: uma revisão dos aspectos farmacológicos e toxicológicos / Ayahuasca: a review of pharmacological and toxicological aspects

A ayahuasca é uma bebida psicoativa originariamente utilizada em rituais de tribos indígenas da região amazônica. Esta bebida é preparada pela infusão de caules da Banisteriopsis caapi Morton, que contém Beta-carbolinas que são inibidoras da monoaminoxidase (MAO), e de folhas da Psychotria viridis Ruiz & Pavón, que contém o alucinógeno N,N-dimetiltriptamina (DMT). A enzima MAO degrada a DMT no fígado e intestino. No Brasil, a ayahuasca tem sido incorporada em rituais de grupos sincréticos religiosos e seu uso dentro do contexto religioso é amparado por lei federal. Atualmente, esses grupos têm se espalhado na Europa e Estados Unidos, chamando a atenção de pesquisadores internacionais quanto aos efeitos da ayahuasca. Estudos têm indicado que a ayahuasca poderia ter aplicações terapêuticas como no tratamento da farmacodependência e até sugerem seu uso seguro por adultos sadios. Entretanto, poucos estudos têm sido conduzidos para melhor avaliação de suas propriedades. O objetivo do artigo é mostrar uma revisão geral da história até as recentes descobertas envolvendo a farmacologia e a toxicologia da ayahuasca.

Ayahuasca (or caapi in Brazil) is a psychoactive plant beverage initially used by shamans in religious rituals practiced by indigenous peoples in the Amazon region. It is prepared by infusing the pounded stems of Banisteriopsis caapi Morton, a liana which contains beta-carbolines, alkaloids that are potent monoamine oxidase (MAO) inhibitors, together with the leaves of Psychotria viridis Ruiz & Pavón, which contains the psychedelic agent N,N-dimethyltryptamine (DMT). The enzyme MAO normally degrades DMT in the liver and gut. In Brazil, the use of ayahuasca within religious ceremonies is protected by law and it has been incorporated into rituals of syncretic religious groups. Some of these groups have established themselves in the United States and European countries, attracting international research interest in the effects of ayahuasca. Studies suggest that it may have therapeutic applications, such as in the treatment of drug addiction, and that it can be used safely by healthy adults. However, too few studies have been performed for a good assessment of its properties to be made. The aim of this article is to present a review of the history of ayahuasca, up to the recent discoveries concerning its pharmacology and toxicology.

Eliminación de N, N-dimetiltriptamina por la orina / Elimination of N, N-dimethyltryptamine by urine

Se dosó la N, N-dimetiltriptamina (DMT) en la orina de 83 pacientes psiquiátricos. En el estudio se incluyeron pacientes que habían estado en algún momento en tratamiento con enurolépticos y pacientes con determinada sintomatología asociada a cuadros psicóticos: alucinaciones, delusiones, trastornos de la percepción, etc. En 36 casos (43,3//) se hallaron valores anormalmente altos de DMT urinaria (0,9-13,5 mcg/24 h). Estos valores se encontraron con mayor frecuencia en pacientes esquizofrénicos y en pacientes no esquizofrénicos tanto con alucinaciones o delusiones, como también anorexia o bulimia. La mayoría de los pacientes con valores normales de DMT (<0,5 mcg/24 h) presentaba retardo mental, atrofia cerebral o disritmias. Se encontró un muy buen correlato entre valores elevado de DMT urinária, mejoría clínica y el tratamiento con enurolépticos