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Ayahuasca

Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies

Abstract

Objective: To conduct a systematic review of modern-era (post-millennium) clinical studies assessing the therapeutic effects of serotonergic psychedelics drugs for mental health conditions. Although the main focus was on efficacy and safety, study characteristics, duration of antidepressants effects across studies, and the role of the subjective drug experiences were also reviewed and presented.

Method: A systematic literature search (1 Jan 2000 to 1 May 2020) was conducted in PubMed and PsychINFO for studies of patients undergoing treatment with a serotonergic psychedelic.

Results: Data from 16 papers, representing 10 independent psychedelic-assisted therapy trials (psilocybin = 7, ayahuasca = 2, LSD = 1), were extracted, presented in figures and tables, and narratively synthesized and discussed. Across these studies, a total of 188 patients suffering either cancer- or illness-related anxiety and depression disorders (C/I-RADD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD) or substance use disorder (SUD) were included. The reviewed studies established feasibility and evidence of safety, alongside promising early data of efficacy in the treatment of depression, anxiety, OCD, and tobacco and alcohol use disorders. For a majority of patients, the therapeutic effects appeared to be long-lasting (weeks-months) after only 1 to 3 treatment session(s). All studies were conducted in line with guidelines for the safe conduct of psychedelic therapy, and no severe adverse events were reported.

Conclusion: The resurrection of clinical psychedelic research provides early evidence for treatment efficacy and safety for a range of psychiatric conditions, and constitutes an exciting new treatment avenue in a health area with major unmet needs.

Andersen, K., Carhart-Harris, R., Nutt, D. J., & Erritzoe, D. (2021). Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies. Acta psychiatrica Scandinavica, 143(2), 101–118. https://doi.org/10.1111/acps.13249

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Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context

Ayahuasca is a beverage obtained from Banisteriopsis caapi plus Psychotria viridis. B. caapi contains the β-carbolines harmine, harmaline, and tetrahydroharmine that are monoamine oxidase inhibitors and P. viridis contains N,N-dimethyltryptamine (DMT) that is responsible for the visionary effects of the beverage. Ayahuasca use is becoming a global phenomenon, and the recreational use of DMT and similar alkaloids has also increased in recent years; such uncontrolled use can lead to severe intoxications. In this investigation, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to study the kinetics of alkaloids over a 24 h period in saliva and serum of 14 volunteers who consumed ayahuasca twice a month in a religious context. We compared the area under the curve (AUC), maximum concentration (Cmax ), time to reach Cmax (Tmax ), mean residence time (MRT), and half-life (t1/2 ), as well as the serum/saliva ratios of these parameters. DMT and β-carboline concentrations (Cmax ) and AUC were higher in saliva than in serum and the MRT was 1.5-3.0 times higher in serum. A generalized estimation equations (GEEs) model suggested that serum concentrations could be predicted by saliva concentrations, despite large individual variability in the saliva and serum alkaloid concentrations. The possibility of using saliva as a biological matrix to detect DMT, β-carbolines, and their derivatives is very interesting because it allows fast noninvasive sample collection and could be useful for detecting similar alkaloids used recreationally that have considerable potential for intoxication.

Lanaro, R., Mello, S. M., da Cunha, K. F., Silveira, G., Corrêa-Neto, N. F., Hyslop, S., Cabrices, O. G., Costa, J. L., & Linardi, A. (2021). Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context. Drug testing and analysis, 13(3), 664–678. https://doi.org/10.1002/dta.2955

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Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial

Abstract

Rationale: Suicidality is a major public health concern with limited treatment options. Accordingly, there is a need for innovative interventions for suicidality. Preliminary evidence indicates that treatment with the psychedelic ayahuasca may lead to decreases in depressive symptoms among individuals with major depressive disorder (MDD). However, there remains limited understanding of whether ayahuasca also leads to reductions in suicidality.

Objective: To examine the acute and post-acute effect of ayahuasca on suicidality among individuals with MDD.

Methods: We conducted a secondary analysis of an open-label trial in which individuals with recurrent MDD received a single dose of ayahuasca (N = 17). Suicidality was assessed at baseline; during the intervention; and 1, 7, 14, and 21 days after the intervention.

Results: Among individuals with suicidality at baseline (n = 15), there were significant acute (i.e., 40, 80, 140, and 180 min after administration) and post-acute (1, 7, 14, and 21 days after administration) decreases in suicidality following administration of ayahuasca. Post-acute effect sizes for decreases in suicidality were large (Hedges’ g = 1.31-1.75), with the largest effect size 21 days after the intervention (g = 1.75).

Conclusions: When administered in the appropriate context, ayahuasca may lead to rapid and sustained reductions in suicidality among individuals with MDD. Randomized, double-blind studies with larger sample sizes are needed to confirm this early finding.

Zeifman, R. J., Singhal, N., Dos Santos, R. G., Sanches, R. F., de Lima Osório, F., Hallak, J., & Weissman, C. R. (2021). Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial. Psychopharmacology, 238(2), 453–459. https://doi.org/10.1007/s00213-020-05692-9

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Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N, N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact

Abstract

Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.

Brito-da-Costa, A. M., Dias-da-Silva, D., Gomes, N., Dinis-Oliveira, R. J., & Madureira-Carvalho, Á. (2020). Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact. Pharmaceuticals (Basel, Switzerland), 13(11), 334. https://doi.org/10.3390/ph13110334

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Polypharmacology or “Pharmacological Promiscuity” In Psychedelic Research: What Are We Missing?

Abstract

Research with psychedelic drugs has mainly focused on isolated compounds. However, this approach is challenged by the “polypharmacology” paradigm. In this Viewpoint, we suggest that we may be missing something if we do not use the whole product in the case of ayahuasca or Psilocybe mushrooms. After describing how research on psychedelic drugs can be effectively combined with the polypharmacology paradigm, ethical issues are also briefly discussed.

Ona, G. S., Dos Santos, R. G., Hallak, J., & Bouso, J. C. (2020). Polypharmacology or “Pharmacological Promiscuity” In Psychedelic Research: What Are We Missing?. ACS chemical neuroscience, 11(20), 3191–3193. https://doi.org/10.1021/acschemneuro.0c00614

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N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

Abstract

N,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

Morales-Garcia, J. A., Calleja-Conde, J., Lopez-Moreno, J. A., Alonso-Gil, S., Sanz-SanCristobal, M., Riba, J., & Perez-Castillo, A. (2020). N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo. Translational psychiatry, 10(1), 331. https://doi.org/10.1038/s41398-020-01011-0

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Chemical Composition of Traditional and Analog Ayahuasca

Abstract

Traditional ayahuasca can be defined as a brew made from Amazonian vine Banisteriopsis caapi and Amazonian admixture plants. Ayahuasca is used by indigenous groups in Amazonia, as a sacrament in syncretic Brazilian religions, and in healing and spiritual ceremonies internationally. The study aimed to determine concentrations of the main bio- and psychoactive components of ayahuasca used in different locations and traditions. We collected 102 samples of brews from ayahuasca-using communities. Concentrations of N,N-dimethyltryptamine (DMT), tetrahydroharmine, harmine, and harmaline were determined by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). Qualitative analyses for non-traditional additives (moclobemide, psilocin, yuremamine) were performed by high resolution mass spectrometry. Higher and more variable concentrations of DMT in neoshamanic ayahuasca samples compared to indigenous samples may indicate use of higher and more variable proportions of DMT-containing admixture plants. From European samples, we found two related samples of analog ayahuasca containing moclobemide, psilocin, DMT, yuremamine, and very low concentrations of B. caapi alkaloids. Some analogs of ayahuasca (Peganum harmala, Mimosa tenuiflora) were used in Europe. No analogs were found from Brazil or Santo Daime ceremonies in Europe. We recommend awareness about the constituents of the brew and ethical self-regulation among practitioners of ayahuasca ceremonies.

Kaasik, H., Souza, R., Zandonadi, F. S., Tófoli, L. F., & Sussulini, A. (2021). Chemical Composition of Traditional and Analog Ayahuasca. Journal of psychoactive drugs, 53(1), 65–75. https://doi.org/10.1080/02791072.2020.1815911

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Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies

Abstract

Introduction: Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders.

Objective: To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients’ accounts, and elucidating how these affect the treatment process.

Methods: We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP).

Results: Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses.

Conclusions: This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.

Breeksema, J. J., Niemeijer, A. R., Krediet, E., Vermetten, E., & Schoevers, R. A. (2020). Psychedelic treatments for psychiatric disorders: a systematic review and thematic synthesis of patient experiences in qualitative studies. CNS drugs, 1-22; 10.1007/s40263-020-00748-y

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Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca

Abstract

Background: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients (n = 28) and healthy controls (n = 45).

Aims: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale.

Results: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed (rho = -0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed.

Conclusions: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.

Galvão-Coelho, N. L., de Menezes Galvão, A. C., de Almeida, R. N., Palhano-Fontes, F., Campos Braga, I., Lobão Soares, B., … & de Araujo, D. B. (2020). Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca. Journal of Psychopharmacology34(10), 1125-1133; 10.1177/0269881120936486
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The pharmacological interaction of compounds in ayahuasca: a systematic review

Abstract

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.

Ruffell, S., Netzband, N., Bird, C., Young, A. H., & Juruena, M. F. (2020). The pharmacological interaction of compounds in ayahuasca: a systematic review. Brazilian Journal of Psychiatry42(6), 646-656.; 10.1590/1516-4446-2020-0884
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