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A Systematic Review of Human Studies Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14040-900, Brazil ICEERS-International Center for Ethnobotanical Education, Research, and Service, 08015 Barcelona, Spain Medical Anthropology Research Center (MARC), Universitat Rovira i Virgili, 43005 Tarragona, Spain National Institute for Translational Medicine (INCT-TM), CNPq, Ribeirão Preto, Brazil Abstract Background: Ayahuasca is a serotoninergic hallucinogen that plays a central role in the Amazonian traditional medicine. Its psychoactive effects are associated with the presence of N,N-dimethyltryptamine (DMT), and monoamine oxidase inhibitors (MAO-A). Advances in neuroimaging investigations have provided insight into ayahuasca’s neurobiological mechanisms of action. Methods: Selecting only studies with neuroimaging results related to human ayahuasca consumption, we included six articles from a previous systematic review of serotoninergic hallucinogen neuroimaging studies up to 2016. Furthermore, we updated the data with a new systematic search from 2016 to 2022. We searched the PubMed, SciELO, and LILACS databases using the search terms “(ayahuasca OR DMT) AND (MRI OR fMRI OR PET OR SPECT OR imaging OR neuroimaging)”. Results: Our updated search provided five new articles for a total of 11 included in this review. The results on the Default Mode Network (DMN) are evident and may indicate a path to short term neuromodulation. Acutely, local neural networks appeared to become expanded, while overall brain connectivity declined. On chronic consumers, anatomical changes were reported, most notably related to cingulate cortex. Conclusion: Ayahuasca seems to change acute brain connectivity similarly to other psychedelics. The results are preliminary and further studies are warranted. Keywords: hallucinogens; ayahuasca; DMT; neuroimaging; SPECT; fMRI; Default Mode Network; psychedelics 1. Introduction Ayahuasca is a decoction traditionally used by Indigenous people from the Amazonian rainforest and in syncretic religious rituals in South America and around the world [1]. In Brazil, since the regulation of its use for religious and scientific purposes in 2010, it is officially prepared by the decoction of two plants, Psychotria viridis and Banisteriopsis caapi. Pharmacologically, ayahuasca is classified as a serotoninergic hallucinogen due to the presence of N,N-dimethyltryptamine (DMT, contained in P. viridis). It also contains monoamine oxidase type A inhibitors (MAO-A, contained in B. caapi) in its composition, namely harmine, tetrahydroharmine, and harmline [2]. Other substances considered serotonergic hallucinogens (or psychedelics) are lysergic acid diethylamide (LSD), mescaline, and psilocybin since they all share the agonism for serotonin 5-HT2A receptor as their main mechanism of action. On one hand, serotonergic hallucinogens have a long tradition of use in their original cultures and in the recreational context for their mind-altering effects. On the other, preliminary scientific evidence suggests that they possess anxiolytic, antidepressant, and anti-addictive properties, which has generated a growing interest regarding their possible therapeutic potential for treating mental disorders [1,3]. Concerning the modulation of neural networks, ayahuasca’s (and other similar drugs) mechanisms of action on affecting mood and self-perception remain to be fully elucidated. However, the literature points to a possible relationship between these effects with modulation of the Default Mode Network (DMN) [4], although it is still unknown how central the DMN is for the mechanisms of action of hallucinogens [5]. The DMN is a network composed of the medial prefrontal cortex, cingulate/precuneus cortex, and angular gyrus. It is involved with self-perception and self-awareness and is active when a person is not focused on the outside world, such as during daydreams, remembering the past, self-judgment, and divagation [6]. Its hyperactivation is associated with various psychiatric disorders, such as depression, anxiety, post-traumatic stress disorder, and attention deficit/hyperactivity disorder [5,6]. Furthermore, frontocortical activation of glutamate receptors, a downstream effect secondary to 5-HT2A agonism, seems to be a common pathway through which serotonergic and other hallucinogens act [7,8], but more investigations are necessary. In one of our previous articles [1], we conducted a systematic review of human trials applying neuroimaging techniques to analyze the effects of serotonergic hallucinogens. In the present study, we focused on neural network modulation by ayahuasca exclusively. Thus, this systematic review aimed to assess changes in brain anatomy and neural networks activation with acute, subacute, or chronic use of ayahuasca through neuroimaging techniques. 2. Materials and Methods The data of the present systematic review was collected according to the Systematic Reviews and Meta-Analyses guidelines (PRISMA) [9]. This study was not registered in PROSPERO. After extracting from our previous review all citations that reported results evaluating the effects of ayahuasca with any neuroimaging technique [1], we conducted a new search in the PubMed, SciElO, and LILACS databases from 2016 (the last year included in our previous review) to 1 December 2022, using the search terms “(ayahuasca OR DMT) AND (MRI OR fMRI OR PET OR SPECT OR imaging OR neuroimaging)”. Inclusion criteria consisted of any observational, case-series, and clinical trial studies with humans that analyzed acute, subacute, or prolonged effects of ayahuasca using any type of neuroimaging technique. Only studies written in English, Spanish, or Portuguese were included. Single case reports, letters to the editor, reviews, and pre-clinical studies were excluded. 2.1. Data Extraction Two independent reviewers screened and selected studies for inclusion, with discrepancies resolved by a third reviewer. From the articles included, we recorded the names of authors, year of publication, study location (city and country), study design (open-label and controlled trials, observational studies, case-series), sample characteristics (size, age, and gender), drug used, dosage, neuroimaging techniques, and main outcomes. Quality Evaluation of Selected Studies To evaluate the quality of the studies selected from our search in a standardized manner, we have utilized the National Heart, Lung, and Blood Institute (NIH) checklists [10]. Per each study design, we used three checklists: “Quality assessment for observational cohort”, “Quality assessment of controlled interventions studies”, and “Quality Assessment Tool for Before-After (Pre-Post) Studies With No Control Group”. All articles were analyzed independently by 2 reviewers to verify whether they contained or not the items presented in the respective checklist. Items from the checklists that were present within each article provided one positive point for the respective article. The overall grade of each article was calculated by dividing the positive points by the difference between the total number of points less the not applicable points. Grades go from 0 to 1, with 0 being the worst and 1 being the best. In the case of the “Quality assessment for observational cohort”, there were a total of 14 points applicable; in the “Quality Assessment Tool for Before-After (Pre-Post) Studies With No Control Group”, there were a total of 12 points; and in the “Quality assessment of controlled interventions studies”, 14 points. In cases of disagreement on scoring, the reviewers discussed their reasons for giving positive, negative, or not applicable points, and if a consensus was not reached, a third author/reviewer was consulted. 3. Results 3.1. Article Screening and Inclusion From our previous systematic review [1], six articles met our selection criteria [11,12,13,14,15,16]. We further searched the databases to include studies that were published after our previous review, resulting in 470 articles, of which none were duplicates. From these, 466 were excluded according to our inclusion and exclusion criteria. Thus, four articles were selected for full reading, and all of them were included in this review. Moreover, during the citation search one more article was also screened and selected. Therefore, a total of five new articles that were not present in our last review were included. Of these included papers, one used magnetic resonance spectroscopy (MRS) [17], three used functional magnetic resonance imaging (fMRI) [18,19,20], and one used magnetic resonance imaging (MRI) [21]. A flow diagram illustrating the different phases of the systematic search update from 2016 to 2022 is presented in Figure 1. The Cohen’s kappa coefficient for selecting the studies was 0.95. Figure 1. PRISMA flowchart for the selection of the studies. 3.2. Results from Selected Studies In this review, we worked with 11 studies that investigated the effects of ayahuasca combined with different neuroimaging techniques. Results were divided into neuroimaging techniques (SPECT, MRS, MRI, and fMRI). In 10 articles, the volunteers were healthy, with previous experience with ayahuasca [11,12,13,14,15,17,18,19,21] or without previous experience [20]. One article [16] evaluated the effects of ayahuasca in patients with major depressive disorder and did not specify previous use by the volunteers. Acute effects were investigated in 8 studies [11,12,13,15,16,17,18,19], subacute effects in 1 study [20], and long-term effects in 2 studies [14,21]. The results found are consistent in demonstrating that there were brain anatomical and functional changes caused by ayahuasca in acute or chronic consumption. Regarding clinical trials, four different articles used the same sample of volunteers, differing in the types of data analyzed [13,15,18,19]. Concerning observational studies, two articles used the same sample of volunteers [14,21]. We will discuss the results in detail in the following paragraphs. A summary figure with the main results discussed is presented in Figure 2. Figure 2. Main results from current evidence regarding brain activation and connectivity changes caused by ayahuasca ingestion. Blue areas show decreased activity while red areas show increased activity. Blue arrows show decreased connectivity while red arrows show increased connectivity. ACC: Anterior Cingulate Cortex; LS: Limbic Structures; mPFC: Medial Prefrontal Cortex; NAc: Nucleus Accumbens; PC: Precuneus; PCC: Posterior Cingulate Cortex; sFG: Superior Frontal Gyrus. 3.2.1. Single Photon Emission Computed Tomography (SPECT) Acute Effects (Molecular Imaging) Riba et al., 2006 [11] performed a double-blind, randomized clinical study involving 15 healthy male volunteers with previous experience with psychedelics. They administered a sin