•First clinical trial evaluating inhaled DMT's effects in a controlled setting.•No serious adverse event were observed, indicating potential safety.•Profound, yet manageable, subjective psychological ...effects reported by participants.•Inhaled DMT offers a rapid, non-invasive, and cost-efficient tool for psychiatry.
Psychedelics are being increasingly examined for their therapeutic potential in mood disorders. While the acute effects of ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) last over several hours, inhaled N,N-Dimethyltryptamine (DMT) effects last around 10 min, which might provide a cost- and time-effective alternative to the clinical application of oral psychedelics. We aimed at investigating the safety and tolerability of inhaled DMT (BMND01 candidate). We recruited 27 healthy volunteers to receive a first, lower dose and a second, higher dose (5/20 mg, 7.5/30 mg, 10/40 mg, 12.5/50 mg, or 15/60 mg) of inhaled DMT in an open-label, single-ascending, fixed-order, dose-response study design. We investigated subjective experiences (intensity, valence, and phenomenology), physiological effects (blood pressure, heart rate, respiratory rate, blood oxygen saturation, body temperature), biochemical markers (liver, kidney, and metabolic functions), and adverse events during the acute and post-acute effects of DMT. DMT dose-dependently increased intensity, valence and perceptual ratings. There was a mild, transient, and self-limited increase in blood pressure and heart rate. There were no changes in safety blood biomarkers and no serious adverse events. DMT dose-dependently enhanced subjective experiences and positive valence. Inhaled DMT might be an efficient, non-invasive, safe route of administration, which might simplify the clinical use of this substance. This is the first clinical trial to test the effects of inhaled DMT (BMND01 candidate).
Sleep disorders and changes in the profile of the cortisol awakening response (CAR) are potential predictive factors for the incidence of major depressive disorder (MDD). However, these parameters ...usually are evaluated separately, lacking information regarding the simultaneous association of sleep disorders and CAR, mainly throughout the MDD severity. This study addressed the relationship between sleep quality and CAR in patients with initial/mild depression (MD, n = 30) versus advanced/treatment-resistant (TRD, n = 28), compared with a group of healthy controls (CG, n = 49), aiming to point out in a clinical perspective which alterations in sleep and CAR have been observed along major depression severity stages. TRD patients presented a blunted CAR and poorer sleep quality comparing MD and CG groups. Additionally, MD patients showed worse sleep quality and larger CAR than CG. Taken together, both sleep quality and CAR were correlated with MDD symptoms and predictors of MDD severity, with a greater classification power for sleep quality. From sleep quality, specifically, the use of sleep medication and sleep efficiency predicted depression severity, discriminating mild and treatment-resistant depression. These results show the importance of assessing sleep quality and CAR in patients with major depression when there is a need for evaluation of the disorder’s severity in a clinical context. CAR and sleep quality can be useful complementary tools to help in the clinical identification of major depression severity and the understanding of their impact on MDD may support further studies that aim to improve intervention strategies to increase the effectiveness of treatments.
Abstract
On February 2023, the Drug Enforcement Administration (DEA) released a document to the legal team representing the Church of the Eagle and the Condor (“CEC”). This disclosure came two years ...after the church, in conjunction with Chacruna Institute, submitted two FOIA requests to the DEA and the Department of Justice requesting all records pertaining to ayahuasca. This report, titled “Ayahuasca: Risks to Public Health and Safety,” was issued in July 2020. In the present article, we challenge a number of claims made in the DEA report and highlight significant factual omissions, theoretical biases, and misinterpretations of existing data. We will demonstrate that the DEA report severely downplays the safety profile and therapeutic potential of ayahuasca and overemphasizes the risks. It also fails to include current research on ayahuasca demonstrating its potential benefits.
The physical basis of consciousness is one of the most intriguing open questions that contemporary science aims to solve. By approaching the brain as an interactive information system, complex ...network theory has greatly contributed to understand brain process in different states of mind. We study an non-ordinary state of mind by comparing resting-state functional brain networks of individuals in two different conditions: before and after the ingestion of the psychedelic brew Ayahuasca. In order to quantify the functional, statistical symmetries between brain region connectivity, we calculate the pairwise information parity of the functional brain networks. Unlike most of usual network quantification, which is done on a local or global scale, information parity quantifies the pairwise statistical similarities considering the entire network structure. We detect an increase in the average information parity on brain networks of individuals under psychedelic influences. Notably, the information parity between regions from the limbic system and frontal cortex is consistently higher for all the individuals while under the psychedelic influence.
Open problems abound in the theory of complex networks, which has found successful application to diverse fields of science. With the aim of further advancing the understanding of the brain's ...functional connectivity, we propose to evaluate a network metric which we term the geodesic entropy. This entropy, in a way that can be made precise, quantifies the Shannon entropy of the distance distribution to a specific node from all other nodes. Measurements of geodesic entropy allow for the characterization of the structural information of a network that takes into account the distinct role of each node into the network topology. The measurement and characterization of this structural information has the potential to greatly improve our understanding of sustained activity and other emergent behaviors in networks, such as self-organized criticality sometimes seen in such contexts. We apply these concepts and methods to study the effects of how the psychedelic Ayahuasca affects the functional connectivity of the human brain. We show that the geodesic entropy is able to differentiate the functional networks of the human brain in two different states of consciousness in the resting state: (i) the ordinary waking state and (ii) a state altered by ingestion of the Ayahuasca. The entropy of the nodes of brain networks from subjects under the influence of Ayahuasca diverge significantly from those of the ordinary waking state. The functional brain networks from subjects in the altered state have, on average, a larger geodesic entropy compared to the ordinary state. We conclude that geodesic entropy is a useful tool for analyzing complex networks and discuss how and why it may bring even further valuable insights into the study of the human brain and other empirical networks.
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Previous issue date: 2017-07-28
Ensaios cl?nicos recentes t?m sugerido o potencial antidepressivo de alguns psicod?licos;
seroton?rgicos, como a ayahuasca e a psilocibina. A ayahuasca ? uma subst?ncia utilizada;
h? centenas de anos por povos ind?genas da bacia amaz?nica. Essa bebida ? geralmente preparada;
a partir de duas plantas, uma contendo a triptamina psicod?lica N,Ndimetiltriptamina,;
um agonista de receptores seroton?rgicos e sigma-1. A outra planta cont?m;
potentes inibidores revers?veis da monoamina oxidase A, como a harmina, harmalina e;
tetrahidroharmina. Em um ensaio cl?nico recente, 17 pacientes com depress?o resistente ao;
tratamento foram submetidos a uma ?nica sess?o com a ayahuasca, e a severidade dos sintomas;
avaliados por escalas cl?nicas para a depress?o, nesse caso a Escala de Avalia??o de;
Depress?o de Montgomery-?sberg (MADRS) e a escala de Hamilton (HAM-D). Os resultados;
sugerem melhora significativa j? nas primeiras horas ap?s a ingest?o, efeito esse mantido;
por 21 dias. Apesar de promissor, esse estudo n?o controlou o efeito placebo, que ? alto, chegando;
a alcan?ar 40%, em ensaios cl?nicos para depress?o. Esta tese faz parte de um ensaio;
cl?nico duplo-cego randomizado placebo-controlado em 35 pacientes com depress?o unipolar;
resistente ao tratamento. Um grupo de volunt?rios controles saud?veis tamb?m foi avaliado.;
Os pacientes receberam uma ?nica dose de ayahuasca ou placebo. Um dia antes e um dia depois;
da administra??o da subst?ncia, os pacientes participaram de uma s?rie de testes e avalia??es,;
incluindo escalas psicom?tricas e imagem por resson?ncia magn?tica funcional;
(fMRI), realizados no decurso de uma sess?o experimental de quatro dias. A severidade da;
depress?o foi aferida por duas escalas cl?nicas: MADRS e HAM-D. As avalia??es foram realizadas;
um dia antes (linha de base), e um, dois e sete dias ap?s a sess?o de tratamento. Observamos;
efeitos antidepressivos significativos da ayahuasca quando comparados ao placebo;
em todos os instantes de tempo avaliados (D1, D2 e D7). Os escores da MADRS foram significativamente;
menores no grupo da ayahuasca, em compara??o com o placebo. Da mesma;
forma, as pontua??es da HAM-D foram significativamente diferentes entre os grupos no D7.;
Os tamanhos do efeito entre os grupos aumentaram de D1 para D7. As taxas de resposta;
(redu??o de 50% nos sintomas) foram elevadas para ambos os grupos nos dias D1 e D2. J?;
sete dias ap?s a sess?o, a taxa de resposta foi significativamente maior no grupo ayahuasca;
que no placebo (64% ayahuasca x 27% placebo). Nesse mesmo ponto de avalia??o, a taxa de;
remiss?o foi marginalmente maior no grupo ayahuasca que no placebo (p<0.056, 36% ayahuasca;
x 7% placebo). Al?m disso, investigamos a rela??o entre os efeitos antidepressivos e os;
efeitos psicod?licos agudos da ayahuasca, avaliados pela Escala de Avalia??o Alucin?gena;
(HRS, Hallucinogenic Rating Scale) e o Question?rio de Experi?ncia M?stica (MEQ30, Mystical;
Experience Questionnaire). Os resultados sugerem que efeitos psicod?licos mais intensos;
est?o correlacionados a taxas de resposta maiores no D7. Por fim, para investigar as bases;
neurais dos efeitos antidepressivos da ayahuasca, utilizamos dados de fMRI adquiridos durante;
a realiza??o de um protocolo de regula??o emocional um dia antes e um dia ap?s a sess?o;
de tratamento. Observamos mudan?as na am?gdala, ?nsula anterior, c?rtex pr?-frontal ventrolateral;
e na por??o subgenual do giro do c?ngulo. Este ? o primeiro ensaio cl?nico, duplocego,;
controlado, a testar o uso de uma subst?ncia psicod?lica para a depress?o resistente ao;
tratamento. Em conjunto, nossos resultados trazem novas evid?ncias que apoiam a seguran?a;
e o valor terap?utico da ayahuasca, administrada dentro de um cen?rio apropriado, para ajudar;
a tratar a depress?o.
Recent open label trials show that psychedelics hold promise as fast-onset antidepressants;
in treatment resistant depression. In Brazil, a psychedelic substance worth mentioning;
is the ayahuasca. This brew composed by the psychedelic N,N-dimethyltryptamine (N,NDMT),;
a serotonin and sigma-1 receptors agonist, and reversible monoamine oxidase A inhibitors,;
such as harmine, harmaline, and tetrahydroharmine, causes changes in perception,;
emotion and cognition. Preliminary results from our group suggest its antidepressant potential,;
in addition to demonstrating its safety and tolerability. Although promising, none of;
these studies have controlled for the placebo effect, which is high in clinical trials for depression.;
To address this issue, we conducted a parallel-arm, double-blind randomized placebocontrolled;
trial in 35 patients with treatment-resistant depression. A healthy control group of;
50 volunteers was also examined. Patients received a single dose of either ayahuasca or placebo.;
One day before dosing, and one day after dosing patients were enrolled in a series of;
tests and assessments, including psychometric scales and fMRI, conducted in the course of a;
four-day experimental session, to assess changes in different markers of depression. Two clinical;
scales for depression assessed changes in depression severity: the Montgomery??sberg;
Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale (HAM-D). Assessments;
were made at baseline, and at 1, 2 and 7 days after dosing. We observed significant;
antidepressant effects of ayahuasca when compared to placebo at all endpoints. MADRS;
scores were significantly lower in the ayahuasca group, compared to placebo. Likewise, HAMD;
scores were significantly different at D7. Between-group effect sizes increased from D1 to;
D7. Response rates were high for both groups at D1 and D2, and were significantly higher in;
the ayahuasca group at D7. Remission rate was marginally significant at D7. In addition, we;
examined the relationship between the antidepressant and acute psychedelic effects of ayahuasca.;
The psychedelic effects were assessed using the Hallucinogen Rating Scale (HRS) and;
the Mystical Experience Questionnaire (MEQ30) after the dosing session. We found that;
higher psychedelic effects measured by both HRS and MEQ30 correlated with improvements;
in clinical outcome at D7. Finally, to investigate the neural bases of the antidepressant effects;
of ayahuasca, we used fMRI data through an emotional task at baseline, and one day;
after dosing. We observed changes in key limbic regions, such as amygdala, anterior insula,;
ventrolateral prefrontal cortex, and subgenual cingulate cortex in ayahuasca group when;
compared to placebo. To our knowledge this is the first controlled trial to test a psychedelic;
substance in treatment resistant depression. Overall, this study brings new evidence supporting;
the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to;
help treat depression.
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Previous issue date: 2012-05-25
...Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
Ayahuasca is psychotropic beverage that has been used for ages by indigenous populations in South America, notably in the Amazon region, for religious and medicinal purposes. The tea is obtained by the decoction of leaves from the Psychotria viridis with the bark and stalk of a shrub, the Banisteriopsis caapi. The first is rich in N-N-dimethyltryptamine (DMT), which has an important and well-known hallucinogenic effect due to its agonistic action in serotonin receptors, specifically 5-HT2A. On the other hand, β-carbolines present in B. caapi, particularly harmine and harmaline, are potent monoamine oxidase inhibitors (MAOi). In addition, the tetrahydroharmine (THH), also present in B. caapi, acts as mild selective serotonin reuptake inhibitor and a weak MAOi. This unique composition induces a number of affective, sensitive, perceptual and cognitive changes in individuals under the effect of Ayahuasca. On the other hand, there is growing interest in the Default Mode Network (DMN), which has been consistently observed in functional neuroimaging studies. The key components of this network include structures in the brain midline, as the anterior medial frontal cortex, ventral medial frontal cortex, posterior cingulate cortex, precuneus, and some regions within the inferior parietal lobe and middle temporal gyrus. It has been argued that DMN participate in tasks involving self-judgments, autobiographical memory retrieval, mental simulations, thinking in perspective, meditative states, and others. In general, these tasks require an internal focus of attention, hence the conclusion that the DMN is associated with introspective mental activity. Therefore, this study aimed to evaluate by functional magnetic resonance imaging (fMRI) changes in DMN caused via the ingestion of Ayahuasca by 10 healthy subjects while submitted to two fMRI protocols: a verbal fluency task and a resting state acquisition. In general, it was observed that Ayahuasca causes a reduction in the fMRI signal in central nodes of DMN, such as the anterior cingulate cortex, the medial prefrontal cortex, the posterior cingulate cortex, precuneus and inferior parietal lobe. Furthermore, changes in connectivity patterns of the DMN were observed, especially a decrease in the functional connectivity of the precuneus. Together, these findings indicate an association between the altered state of consciousness experienced by individuals under the effect of Ayahuasca, and changes in the stream of spontaneous thoughts leading to an increased introspective mental activity
A Ayahusca ? uma bebida psicotr?pica que tem sido utilizada h? s?culos por popula??es originais da Am?rica do Sul, notadamente da regi?o Amaz?nica, com fins religiosos e medicinais. O ch? ? obtido pela decoc??o de folhas da Psychotria viridis com a casca e tronco de um arbusto, a Banisteriopsis caapi. A primeira ? rica em N,N-dimetiltriptamina (DMT), que tem importante e bem conhecido efeito alucin?geno devido a sua atua??o agonista nos receptores de serotonina, especificamente 5-HT2A. Por outro lado, as β-carbolinas presentes na B. caapi, particularmente a harmina e a harmalina, s?o potentes inibidores da monoamina oxidase (iMAO). Al?m disso, a tetrahidroharmina (THH), tamb?m presente na B. caapi, atua como leve inibidor seletivo da recapta??o de serotonina e um fraco inibidor de MAO. Essa composi??o ?nica provoca uma s?rie de altera??es afetivas, sensoriais, perceptuais e cognitivas em indiv?duos sob o efeito da Ayahuasca. Por outro lado, existe um interesse crescente na rede de modo padr?o, do ingl?s Default Mode Network (DMN), que tem sido consistentemente observada em estudos de neuroimagem funcional. As principais componentes dessa rede incluem estruturas da linha m?dia do c?rtex cerebral, como o c?rtex frontomedial anterior, c?rtex frontomedial ventral, o giro cingulado posterior, o pr?-cuneus e algumas regi?es do lobo parietal inferior e do giro temporal m?dio. Acredita-se que a DMN participe de tarefas que envolvem autojulgamentos, evoca??o de mem?rias autobiogr?ficas, realiza??o de simula??es mentais, pensar em perspectiva, estados meditativos, entre outros. De maneira geral, essas tarefas requerem um foco de aten??o interno, da? a conclus?o de que a DMN estaria associada ? atividade mental introspectiva. Assim, este estudo teve como objetivo avaliar, por meio de resson?ncia magn?tica funcional (fMRI), as poss?veis mudan?as da DMN causadas pela ingest?o da Ayahuasca em 10 volunt?rios saud?veis investigados enquanto se submeteram a dois protocolos: uma tarefa de flu?ncia verbal e a aquisi??o de dados cont?nuos durante estado de repouso. De maneira geral, observa-se que a Ayahuasca provoca redu??o na amplitude do sinal de fMRI nos nodos centrais da DMN, tais como o c?ngulo anterior, o c?rtex pr?-frontal medial, o c?ngulo posterior, o pr?-cuneus e o lobo parietal inferior. Al?m disso, tamb?m foram observadas altera??es no padr?o de conectividade da DMN, em particular, diminui??o da conectividade funcional no pr?-cuneus. Juntos, esses achados indicam a poss?vel associa??o entre o estado alterado de consci?ncia experimentado pelos indiv?duos sob efeito da Ayahuasca, e mudan?as no fluxo de pensamentos espont?neos ligados ao aumento da introspec??o
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