Potencial uso terapêutico da ayahuasca: Uma revisão da literatura

COSTA, Salvana Priscylla Manso; CARVALHO, Keith Cardoso; GOMES, Isabella Nunes; CALAZANS, Carine Lopes; SILVA, Morganna Thinesca Almeida; MIRANDA, Joseneide de Alves; BARRETO, Ighor Costa; MELO, Matheus Vinícius Guimarães de; HOLANDA, Keyla Emanuelle Ramos de; ALENCAR FILHO, José Marcos Teixeira de

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CHEMISTRY AND PHARMACOLOGY | REVIEW • Acta Amaz. 54 (2) • Apr-Jun 2024 • https://doi.org/10.1590/1809-4392202301821 copiar

Potencial uso terapêutico da ayahuasca: Uma revisão da literatura

Autoria SCIMAGO INSTITUTIONS RANKINGS

RESUMO

Ayahuasca é uma decocção psicoativa originalmente usada na cultura indígena amazônica. É constituída por um líquido denso e marrom que resulta mais frequentemente da decocção de duas plantas nativas da floresta amazônica, Psychotria viridis (Rubiaceae) e Banisteriopsis caapi (Malpighiaceae). A composição da decocção é variável, pois diversas espécies vegetais podem ser utilizadas em seu preparo. Seu efeito psicoativo ocorre devido à presença de N,N-dimetiltriptamina (DMT), agonista dos receptores serotoninérgicos (5-HT_1A/2A/2C), que é metabolizado pela enzima monoamina oxidase tipo A (MAO-A), e também à presença de β-carbolinas, que são inibidores reversíveis da MAO-A. Essa interação conjunta promove uma sequência de efeitos neuroquímicos psicodélicos. Devido à atual expansão das pesquisas sobre substâncias psicodélicas e ao crescente interesse público nos benefícios da ayahuasca, além do seu uso tradicional na Amazônia, as pesquisas acadêmicas sobre sua capacidade terapêutica têm aumentado. Este estudo teve como objetivo realizar uma revisão de literatura sobre as evidências científicas do potencial terapêutico da ingestão de ayahuasca. A revisão abrangeu o período 2012-2022, e resultou em evidências sobre os efeitos terapêuticos da ayahuasca na depressão/ansiedade, dependência química/alcoolismo e doença de Parkinson, bem como efeitos neuropsicológicos, e possíveis efeitos tóxicos na reprodução/desenvolvimento embrionário, entre outros efeitos adversos. O maior número de publicações no período pesquisado tratou dos efeitos da ayahuasca sobre a depressão e a ansiedade. Estudos futuros precisam abordar o mecanismo detalhado de ação da ayahuasca, bem como sua potencial toxicidade, a fim de demonstrar sua segurança.

PALAVRAS-CHAVE:
Psychotria viridis; Banisteriopsis caapi; efeitos medicinais; N,N-dimetiltriptamina

Substance	Molecular formula	Classification	Structural similarity	Mechanism of action
Dimethyltryptamine (DMT)	C₁₂H₁₆N₂	Indole alkaloid with psychedelic effects	Similar to serotonin and melatonin, derivatives of the amino acid tryptophan. Chemical structure similar to sumatriptan (Schripsema and Dagnino 2017Schripsema, J.; Dagnino, D. 2017. Alcaloides indólicos. In: Simões, C.M.O.; Schenkel, E.P.; De Mello, J.P.C.; Mentz, L.A.; Petrovick, P.R. (Eds.). Farmacognosia: Do Produto Natural ao Medicamento. Artmed, Porto Alegre. p.368-387.)	Non-selective serotonin receptor agonist (Brito-da-Costa et al. 2020Brito-da-Costa, A.; Dias-da-Silva, D.; Gomes, N.; Dinis-Oliveira, R.; Madureura-Carvalho, R. 2020. Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: Clinical and forensic impact. Pharmaceuticals 13: 334. doi.org/10.3390/ph13110334. https://doi.org/10.3390/ph13110334... )
Harmine (HRM)	C₁₃H₁₂N₂O	ꞵ-carboline	Similar to indole amines such as serotonin (Schripsema and Dagnino 2017Schripsema, J.; Dagnino, D. 2017. Alcaloides indólicos. In: Simões, C.M.O.; Schenkel, E.P.; De Mello, J.P.C.; Mentz, L.A.; Petrovick, P.R. (Eds.). Farmacognosia: Do Produto Natural ao Medicamento. Artmed, Porto Alegre. p.368-387.)	MAO inhibitors (inhibit the intestinal desamination of DMT, allowing it to reach the brain). Increase in serotonin, dopamine and norepinephrine levels in the brain. (Brito-da-Costa et al. 2020Brito-da-Costa, A.; Dias-da-Silva, D.; Gomes, N.; Dinis-Oliveira, R.; Madureura-Carvalho, R. 2020. Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: Clinical and forensic impact. Pharmaceuticals 13: 334. doi.org/10.3390/ph13110334. https://doi.org/10.3390/ph13110334... )
Harmaline (HRL)	C₁₃H₁₄N₂O	ꞵ-carboline
Tetrahydroharmine (THH)	C₁₃H₁₆N₂O	ꞵ-carboline		Serotonin reuptake transporter inhibitor (Brito-da-Costa et al. 2020Brito-da-Costa, A.; Dias-da-Silva, D.; Gomes, N.; Dinis-Oliveira, R.; Madureura-Carvalho, R. 2020. Toxicokinetics and toxicodynamics of ayahuasca alkaloids N,N-dimethyltryptamine (DMT), harmine, harmaline and tetrahydroharmine: Clinical and forensic impact. Pharmaceuticals 13: 334. doi.org/10.3390/ph13110334. https://doi.org/10.3390/ph13110334... )

Evaluated aspect	Type of study	Effects	Identified substances	Concentration (mg mL^-1)	Source
Acute effects on neuropsychological performance (memory)	Clinical trial	Mixed effects, negatively affecting work memory, but not interfering with stimulus response.	-	-	*Bouso et al. (2013*Bouso, J.C.; Fábregas, J.M.; Antonijoan, R.M.; Fornells, A.; Riba, J. 2013. Acute effects of ayahuasca on neuropsychological performance: differences in executive function between experienced and occasional users. Psychopharmacology 3: 415-424. )
Toxicity and behavioral functions	Animal models (rats)	Decrease in locomotor activity and activation of brain areas involved in interpretation and emotional process.	-	-	*Pic-Taylor et al. (2015*Pic-Taylor, A.; Motta, L.G.; Morais, J.A.; Júnior, W.M.; Santos, A.D.F.A.; Campos, L.A.; et al. 2015. Behavioural and neurotoxic effects of ayahuasca infusion (Banisteriopsis caapi and Psychotria viridis) in female Wistar rats. Behavioural Processes 118: 102-110. )
Alcoholism	Animal models	Inhibition in ethanol-induced hyperlocomotion.	-	-	*Oliveira-Lima et al. (2015*Oliveira-Lima, A.J.; Santos, R.; Hollais, A.W.; Gerardi-Junior, C.A.; Baldaia, M.A.; Wuo-Silva, R.; et al. 2015. Effects of ayahuasca on the development of ethanol-induced behavioral sensitization and on a post-sensitization treatment in mice. Physiology & Behavior 142: 28-36. )
Depression	Open preliminary study	Significant and fast reduction of depressive symptoms and hopelessness.	DMT HRM	0.8 0.21	*Osório et al. (2015*Osório, F.L.; Sanches, R.F.; Macedo, L.R.; Santos, R.G.; Maia-Oliveira, J.P.; Wichert-Ana, L.; et al. 2015. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Brazilian Journal of Psychiatry 37: 13-20.)
Depression	Clinical trial	Increase in brain blood perfusion and fast sustained antidepressive effects regardless of severity of patient current depressive episode.	DMT HRM	0.8 0.21	*Sanches et al. (2016*Sanches, R.F.; Osório, F.L.; Santos, RG.; Macedo, L.R.H.; Maia-De-Oliveira, J.P.; Wichert-Ana, L.; et al. 2016. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: A SPECT study. Journal of Clinical Psychopharmacology 36: 77-81. )
Effects on animal reproduction	Animal models (rats)	Significant increase in total serum testosterone, decrease in spermatic transit time and spermatic reserves in the epididymis caudae with 4× dose (13.2 mg kg^-1 harmine, 1.04 mg kg^-1 harmaline, 1.24 mg kg^-1 DMT), but not with highest dose. No significant changes in other reproductive endpoints (spermatozoid motility and morphology, total spermatozoid count, daily sperm production), and histology of testis and epididymis.	DMT HRM HRL	0.146 1.56 0.12	*Santos et al. (2017*Santos, A.D.F.A.; Vieira, A.L.S.; Taylor, A.; Caldas, E.D. 2017. Reproductive effects of the psychoactive beverage ayahuasca in male Wistar rats after chronic exposure. Revista Brasileira de Farmacognosia 27: 353-360.)
Chemical dependency	Qualitative ethnographic analysis	Effectiveness in treatment of substance dependency was demonstrated.	-	-	Talin and Sanabriab (2017Talin, P.; Sanabria, E. 2017. Ayahuasca’s entwined efficacy: An ethnographic study of ritual healing from ‘addiction’. International Journal of Drug Policy 44: 23-30. )
Toxicity and behavioral evaluation	Animal models (zebrafish)	Anomalies in embryos at highest concentration, including hatching delay, loss of equilibrium, edema and accumulation of red blood cells. Embryo significantly decreased locomotor activity.	DMT HRM HRL	0.141 1.56 0.122	*Andrade et al. (2018*Andrade, T.S.; Oliveira, R.; Silva, L.M.; Zuben, M.V.V.; Grisolia, C.K.; Domingues, I.; Caldas, E.D. et al. 2018. Exposure to ayahuasca induces developmental and behavioral alterations on early life stages of zebrafish. Chemico-Biological Interactions 293: 133-140. )
Fetal toxicity and embryonic development	Animal models (rats)	50% mortality at higher doses, and neuronal loss, kidney injuries, intrauterine growth retardation, embryo death and anomalies in fetuses.	DMT HRM HRL	0.141 1.56 0.122	*Motta et al. (2018*Motta, L.G.; Morais, J.A.; Tavares, A.C.A.; Vianna, L.M.S.; Mortari, M.R.; Amorim, R. F.B.; et al 2018. Maternal and developmental toxicity of the hallucinogenic plant-based beverage ayahuasca in rats. Reproductive Toxicology 77: 143-153. )
Depression	Animal models	Behavioral and physiological improvements. Increase in cortisol levels (hormone involved in depression etiology).	DMT HRM HRL THH	0.01 0.11 0.03 0.05	*Silva et al. (2019*Silva, F.S.; Silva, E.A.; Souza, G.M.D.; Maia-De-Oliveira, J.P.; Soares-Rachetti, V.P.; Araujo, D.B.; et al. 2019. Acute effects of ayahuasca in a juvenile non-human primate model of depression. Brazilian Journal of Psychiatry 4: 280-288. )
Depression	Double- blinded placebo- controlled study	Rapid antidepressant effect after single dosing session compared with placebo. Depression severity changed significantly but differently for ayahuasca and placebo groups. Significantly higher improvement in psychiatric scales in the ayahuasca group compared to placebo at all time points.	DMT HRM HRL THH	0.01 0.11 0.24 0.05	*Palhano-Fontes et al. (2019*Palhano-Fontes, F.; Barreto, D.; Onias, H.; Andrade, K.C.; Novaes, M.M.; Pessoa, J.A.; et al. 2019. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychological Medicine 49: 655-663.)
Prolonged grief disorder	Observational study (no control)	Significant decrease in grief symptoms and severity with ceremonial use. Improvement in psychosocial well-being. Participants responded to online survey that included the Texas Revised Inventory of Grief, Symptom Assessment-45, WHO Quality of Life-Bref, Acceptance and Action Questionnaire, and Decentering.	DMT HRM HRL THH	2.0 2.0 0.37 1.0	Gonzales et al. (2020)
Suicidal tendency in individuals with major depressive disorder (MDD)	Open-label trial	Rapid and sustained reductions in suicidality among individuals with major depressive disorder (MDD). Decrease in suicidality highest 21 days after intervention.	DMT HRM	0.8 0.21	*Zeifman et al. (2020*Zeifman, R.J.; Singhal, N.; Santos, R.G.; Sanches, R.F.; Osório, F.L.; Hallak, J.E.; et al. 2020. 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: 453-459.)
Inflammatory biomarkers of depression	Double- blinded placebo- controlled study	Significant reduction of C-reactive protein levels across time in patients and controls, but not in placebo. Significant correlation between decrease in C-reactive protein and decrease in depressive symptoms 48 h after substance ingestion (Montgomery-Åsberg Depression Rating Scale).	DMT HRM HRL THH	0.36 1.86 0.24 1.20	*Galvao-Coelho et al. (2020*Galvão-Coelho, N.L.; Galvão, A.C.M.; Almeida, R.N.; Fontes, F.; Braga, I.C.; Soares, B.L.; et al. 2020. Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca. Journal of Psychopharmacology 34: 1125-1133. )
Mental health	Observational study	Associatuon of mental health with non-pharmacological factors that cause placebo response and dose-dependent pharmacological contribution of AYA.	DMT HRM HRL	2.01 5.57 0.38	*Uthaug et al. (2021*Uthaug, M.V.; Mason, N.L.; Toennes, S.W.; Reckweg, J.T.; Sousa Fernandes Perna, E.B.; Kuypers, K.P.C.; et al. 2021. Placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats. Psychopharmacology 238: 1899-1910. )
Adverse effects	Transversal study	Mild and tolerable adverse effects in individuals after AYA use, pending care with drug interactions.	-	-	*Durante et al. (2021*Durante, I.; Santos, R.G.; Bouso, J.C.; Hallak, J.E. 2021. Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects. Brazilian Journal of Psychiatry 43: 362-369. )
Depression and anxiety	Observational study	Most participants believed that they were cured or became better after AYA ingestion. A small part reported worsening of the symptoms.	-	-	*Sarris et al. (2021*Sarris, J.; Perkins, D.; Cribb, L.; Schubert, V.; Opaleye, E.; Bouso, J.C.; et al. 2021. Ayahuasca use and reported effects on depression and anxiety symptoms: An international cross-sectional study of 11,912 consumers. Journal of Affective Disorders Reports 4: 100098. )
State of conciousness	Observational study	Unbalance in circulating concentrations of aromatic amino acids involved in neurotransmission.	DMT HRM HRL THH	0.14 4.5 0.51 2.10	*Madrid-Gambin et al. (2022*Madrid-Gambin, F.; Gomez-Gomez, A.; Busquets-Garcia, A.; Haro, N.; Marco, S.; Mason, N. L.; et al. 2022. Metabolomics and integrated network analysis reveal roles of endocannabinoids and large neutral amino acid balance in the ayahuasca experience. Biomedicine & Pharmacotherapy 149: 112-845. )
Chemichal dependency	Animal models	Increase in locomotor activity relative to control during acquisition of sensitization.	DMT	1.76 mg kg^-1	*Almeida et al. (2022*Almeida, C.A.F.; Junior, A.A.P.; Rangel, J.G.; Pereira, B.P.; Costa, K.C.M.; Bruno, V.; et al. 2022. Ayahuasca, a psychedelic beverage, modulates neuroplasticity induced by ethanol in mice. Behavioural Brain Research, 416: 113546. )
Parkinson’s disease	In vitro model	MAO inhibitory activity by β-carbolines with potential to treat parkinsonism due to dopamin degradation prevention in brain cells.	DMT HRM	4.5 1.5	*Katchborian-Neto et al. (2020*Katchborian-Neto, A.; Santos, W.T.; Nicácio, K.J.; Corrêa, J.O.A.; Murgu, M.; Martins, T.M.M.; et al. 2020. Neuroprotective potential of Ayahuasca and untargeted metabolomics analyses: applicability to Parkinson’s disease. Journal of Ethnopharmacology 225: 1-16. doi.org/10.1016/j.jep.2020.112743 https://doi.org/10.1016/j.jep.2020.11274... )

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[1] *Corresponding author: salvanacosta@gmail.com