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Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial

Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias, Katia C. Andrade, Morgana Novaes, Jessica A. Pessoa, Sergio A. Mota-Rolim, Flavia Osório, Rafael Sanches, Rafael G. dos Santos, LuÍs F. Tófoli, Silveira Gabriela de Oliveira, Mauricio Yonamine, Jordi Riba, Francisco RR Santos, Antonio A. Silva-Junior, João Alchieri, Nicole L. Galvão-Coelho, Brunoj Lobão-Soares, Jaime Hallak, Emerson Arcoverde, João P. Maia-de-Oliveira, Dráulio B. Araújo
doi: https://doi.org/10.1101/103531
Fernanda Palhano-Fontes
1Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil,
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Dayanna Barreto
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
3Dept. of Clinical Medicine, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Heloisa Onias
1Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil,
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Katia C. Andrade
1Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil,
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Morgana Novaes
1Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil,
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Jessica A. Pessoa
1Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil,
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Sergio A. Mota-Rolim
1Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil,
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Flavia Osório
4Dept. of Neurosciences and Behaviour, University of Sao Paulo (USP), Ribeirão Preto, Brazil;
5National Institute of Science and Technology in Translational Medicine (INCT-TM), Brazil;
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Rafael Sanches
4Dept. of Neurosciences and Behaviour, University of Sao Paulo (USP), Ribeirão Preto, Brazil;
5National Institute of Science and Technology in Translational Medicine (INCT-TM), Brazil;
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Rafael G. dos Santos
4Dept. of Neurosciences and Behaviour, University of Sao Paulo (USP), Ribeirão Preto, Brazil;
5National Institute of Science and Technology in Translational Medicine (INCT-TM), Brazil;
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LuÍs F. Tófoli
6Dept. of Psychiatry, University of Campinas (UNICAMP), Campinas, Brazil;
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Silveira Gabriela de Oliveira
7Dept. of Clinical Analysis and Toxicology, University of Sao Paulo (USP), São Paulo, Brazil;
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Mauricio Yonamine
7Dept. of Clinical Analysis and Toxicology, University of Sao Paulo (USP), São Paulo, Brazil;
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Jordi Riba
8Sant Pau Institute of Biomedical Research, Barcelona, Spain;
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Francisco RR Santos
9Dept. of Pharmacy, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Antonio A. Silva-Junior
9Dept. of Pharmacy, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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João Alchieri
10Dept. of Psychology, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Nicole L. Galvão-Coelho
5National Institute of Science and Technology in Translational Medicine (INCT-TM), Brazil;
11Dept. of Physiology, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
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Brunoj Lobão-Soares
5National Institute of Science and Technology in Translational Medicine (INCT-TM), Brazil;
12Dept. of Biophysics and Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil.
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Jaime Hallak
4Dept. of Neurosciences and Behaviour, University of Sao Paulo (USP), Ribeirão Preto, Brazil;
5National Institute of Science and Technology in Translational Medicine (INCT-TM), Brazil;
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Emerson Arcoverde
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
3Dept. of Clinical Medicine, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
5National Institute of Science and Technology in Translational Medicine (INCT-TM), Brazil;
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João P. Maia-de-Oliveira
2Onofre Lopes University Hospital, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
3Dept. of Clinical Medicine, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil;
5National Institute of Science and Technology in Translational Medicine (INCT-TM), Brazil;
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Dráulio B. Araújo
1Brain Institute, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil,
12Dept. of Biophysics and Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, Brazil.
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  • For correspondence: draulio@neuro.ufrn.br
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Abstract

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double-blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery–Åsberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0·019; Cohen’s d=0·98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0·04; at D7, p<0·0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’s d=0·84; D2: Cohen’s d=0·84; D7: Cohen’s d=1·49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4·95; p = 0·04; NNT = 2·66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.

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Posted January 27, 2017.
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Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial
Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias, Katia C. Andrade, Morgana Novaes, Jessica A. Pessoa, Sergio A. Mota-Rolim, Flavia Osório, Rafael Sanches, Rafael G. dos Santos, LuÍs F. Tófoli, Silveira Gabriela de Oliveira, Mauricio Yonamine, Jordi Riba, Francisco RR Santos, Antonio A. Silva-Junior, João Alchieri, Nicole L. Galvão-Coelho, Brunoj Lobão-Soares, Jaime Hallak, Emerson Arcoverde, João P. Maia-de-Oliveira, Dráulio B. Araújo
bioRxiv 103531; doi: https://doi.org/10.1101/103531
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Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial
Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias, Katia C. Andrade, Morgana Novaes, Jessica A. Pessoa, Sergio A. Mota-Rolim, Flavia Osório, Rafael Sanches, Rafael G. dos Santos, LuÍs F. Tófoli, Silveira Gabriela de Oliveira, Mauricio Yonamine, Jordi Riba, Francisco RR Santos, Antonio A. Silva-Junior, João Alchieri, Nicole L. Galvão-Coelho, Brunoj Lobão-Soares, Jaime Hallak, Emerson Arcoverde, João P. Maia-de-Oliveira, Dráulio B. Araújo
bioRxiv 103531; doi: https://doi.org/10.1101/103531

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