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

      1 , 2 , 2 , 3 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 4 , 5 , 4 , 5 , 4 , 5 , 6 , 7 , 7 , 8 , 9 , 9 , 10 , 5 , 11 , 5 , 12 , 4 , 5 , 2 , 3 , 5 , 2 , 3 , 5 , 1 , 2
      Psychological Medicine
      Cambridge University Press
      Ayahuasca, depression, HRS, MEQ, psychedelics, randomized controlled trial (RCT)

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          Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.


          To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.


          We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 ( p = 0.04), and 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 significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054).


          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. This study is registered at http://clinicaltrials.gov (NCT02914769).

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          Most cited references29

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          Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study.

          Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms.
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            Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial.

            Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval [CI], 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively. Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
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              Antidepressant effects of ketamine in depressed patients.

              A growing body of preclinical research suggests that brain glutamate systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. This is the first placebo-controlled, double-blinded trial to assess the treatment effects of a single dose of an N-methyl-D-aspartate (NMDA) receptor antagonist in patients with depression. Seven subjects with major depression completed 2 test days that involved intravenous treatment with ketamine hydrochloride (.5 mg/kg) or saline solutions under randomized, double-blind conditions. Subjects with depression evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion (i.e., mean 25-item Hamilton Depression Rating Scale scores decreased by 14 +/- SD 10 points vs. 0 +/- 12 points, respectively during active and sham treatment). These results suggest a potential role for NMDA receptor-modulating drugs in the treatment of depression.

                Author and article information

                Psychol Med
                Psychol Med
                Psychological Medicine
                Cambridge University Press (Cambridge, UK )
                March 2019
                : 49
                : 4
                : 655-663
                [1 ]Brain Institute, Federal University of Rio Grande do Norte (UFRN) , Natal/RN, Brazil
                [2 ]Onofre Lopes University Hospital, UFRN , Natal/RN, Brazil
                [3 ]Department of Clinical Medicine, UFRN , Natal/RN, Brazil
                [4 ]Department of Neurosciences and Behaviour, University of São Paulo (USP) , Ribeirão Preto/SP, Brazil
                [5 ]National Institute of Science and Technology in Translational Medicine (INCT-TM) , Ribeirão Preto/SP, Brazil
                [6 ]Department of Medical Psychology and Psychiatry, University of Campinas , Campinas/SP, Brazil
                [7 ]Department of Clinical Analysis and Toxicology, USP , São Paulo/SP, Brazil
                [8 ]Sant Pau Institute of Biomedical Research , Barcelona, Spain
                [9 ]Department of Pharmacy, UFRN , Natal/RN, – Brazil
                [10 ]Department of Psychology, UFRN , Natal/RN, Brazil
                [11 ]Department of Physiology, UFRN , Natal/RN, Brazil
                [12 ]Department of Biophysics and Pharmacology, UFRN , Natal/RN, Brazil
                Author notes
                Author for correspondence: Dráulio B Araújo, E-mail: draulio@ 123456neuro.ufrn.br
                S0033291718001356 00135
                © Cambridge University Press 2018

                This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 13 February 2018
                : 16 April 2018
                : 24 April 2018
                Page count
                Figures: 5, Tables: 1, References: 54, Pages: 9
                Original Articles

                Clinical Psychology & Psychiatry
                ayahuasca,depression,hrs,meq,psychedelics,randomized controlled trial (rct)


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