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

BACKGROUND: Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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).

Self-Reported Mood and Lifestyle-Related Physical Activity of Young Adults With Major Depressive Disorder.

We investigated whether mood and lifestyle-related indicators of physical health are differentially expressed according to self-reported levels of depressive symptoms among young adults with a current episode of major depression. In a cross-sectional study, we recruited 94 young adults (females = 67, 71.3%; males = 27, 28.7%; aged 18-35 years) with a current episode of major depression. We assessed their mood with the Profile of Mood States (POMS), and Beck Anxiety Inventory-(BAI), sleep with the Pittsburgh Sleep Quality Index (PSQI), physical activity with the Simple Physical Activity Questionnaire (SIMPAQ), and their cardiorespiratory fitness. Participants' depression levels were classified as follows using established cut-points: (a) Mild Depressive Symptoms (MIDS, BDI-II 14-19 points, n = 17), (b) Moderate Depressive Symptoms (MODS, BDI-II 20-28 points, n = 37) or (c) Severe Depressive Symptoms (SEDS, BDI-II 29-63 points, n = 40). As expected, we found that young adults with SEDS, when compared to those with MODS and MIDS, showed higher depressive mood on the POMS, and they exhibited greater anxiety symptoms, lower reported 'vigor' on physical activity measures, worse sleep quality as expressed by their global score sleep; daytime dysfunction; and sleep disturbance, and they showed lower cardiorespiratory fitness. Those with moderate depressive symptoms only differed from those with mild symptoms with respect to hostility, fatigue and mood disturbance. Although there was a gradient whereby worse mental and physical health indicators were more closely related to the SEDS depression categorization, while healthier indicators were associated with the MIDS category, some parameters were not different between the MDD severity groups, particularly when comparing MIDS and MODS. Clinicians treating patients with MDD should consider these factors when designing lifestyle-based interventions.

Safety and tolerability of inhaled N,N-Dimethyltryptamine (BMND01 candidate): A phase I clinical trial.

Psychedelics are being increasingly examined for their therapeutic potential in mood disorders. While the acute effects of ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) last over several hours, inhaled N,N-Dimethyltryptamine (DMT) effects last around 10 min, which might provide a cost- and time-effective alternative to the clinical application of oral psychedelics. We aimed at investigating the safety and tolerability of inhaled DMT (BMND01 candidate). We recruited 27 healthy volunteers to receive a first, lower dose and a second, higher dose (5/20 mg, 7.5/30 mg, 10/40 mg, 12.5/50 mg, or 15/60 mg) of inhaled DMT in an open-label, single-ascending, fixed-order, dose-response study design. We investigated subjective experiences (intensity, valence, and phenomenology), physiological effects (blood pressure, heart rate, respiratory rate, blood oxygen saturation, body temperature), biochemical markers (liver, kidney, and metabolic functions), and adverse events during the acute and post-acute effects of DMT. DMT dose-dependently increased intensity, valence and perceptual ratings. There was a mild, transient, and self-limited increase in blood pressure and heart rate. There were no changes in safety blood biomarkers and no serious adverse events. DMT dose-dependently enhanced subjective experiences and positive valence. Inhaled DMT might be an efficient, non-invasive, safe route of administration, which might simplify the clinical use of this substance. This is the first clinical trial to test the effects of inhaled DMT (BMND01 candidate).

Ayahuasca for the Treatment of Depression.

Ayahuasca, the vine of the souls in Quechua, is a psychedelic brew with a few formulations that most often include the bark of a liana in the Malpighiaceae family (Banisteriopsis caapi), with leaves from a shrub in the coffee family Rubiaceae (Psychotria viridis). Mixed with water and boiled for hours or days, it produces a brownish-colored liquid with a strong and characteristic taste. Ayahuasca contains the psychedelic tryptamine N,N-Dimethyltryptamine (DMT), and Monoamine Oxidase Inhibitors (MAOi), and in the past few years, it has been tested. In recent years its antidepressant properties have been put to the test. Evidence from open and randomized placebo-controlled clinical trials has shown encouraging results, indicating significant and rapid antidepressant effects, starting as early as 1 day after the ayahuasca intervention. In addition, we have explored the nature of these effects using multivariate measures. In this article, we will review the history, pharmacology, clinical trials, and clinical and behavioral markers associated with the antidepressant effects of ayahuasca.

The Impact of Ayahuasca on Suicidality: Results From a Randomized Controlled Trial.

Suicide is a major public health problem. Given increasing suicide rates and limitations surrounding current interventions, there is an urgent need for innovative interventions for suicidality. Although ayahuasca has been shown to target mental health concerns associated with suicidality (i.e., depression and hopelessness), research has not yet explored the impact of ayahuasca on suicidality. Therefore, we conducted secondary analyses of a randomized placebo-controlled trial in which individuals with treatment-resistant depression were administered one dose of ayahuasca (n = 14) or placebo (n = 15). Suicidality was assessed by a trained psychiatrist at baseline, as well as 1 day, 2 days, and 7 days after the intervention. A fixed-effects linear mixed model, as well as between and within-groups Cohen's d effect sizes were used to examine changes in suicidality. Controlling for baseline suicidality, we found a significant effect for time (p < .05). The effect of the intervention (i.e., ayahuasca vs. placebo) trended toward significance (p = .088). At all time points, we found medium between-group effect sizes (i.e., ayahuasca vs. placebo; day 1 Cohen's d = 0.58; day 2 d = 0.56; day 7 d = 0.67), as well as large within-group (ayahuasca; day 1 Cohen's d = 1.33; day 2 d = 1.42; day 7 d = 1.19) effect sizes, for decreases in suicidality. Conclusions: This research is the first to explore the impact of ayahuasca on suicidality. The findings suggest that ayahuasca may show potential as an intervention for suicidality. We highlight important limitations of the study, potential mechanisms, and future directions for research on ayahuasca as an intervention for suicidality. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02914769.

Cortisol Modulation by Ayahuasca in Patients With Treatment Resistant Depression and Healthy Controls.

Major depression is a highly prevalent mood disorder, affecting about 350 million people, and around 30% of the patients are resistant to currently available antidepressant medications. Recent evidence from a randomized controlled trial (RCT) supports the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol response, in the same group of treatment-resistant patients (MD) and in healthy volunteers (C). Subjects received a single dose of ayahuasca or placebo (dosing session), and both plasma and awakening salivary cortisol response were measured at baseline (before dosing session) and 48 h after the dosing session. Baseline assessment (D0) showed blunted awakening salivary cortisol response and hypocortisolemia in patients, with respect to healthy controls. Salivary cortisol was also measured during dosing session, and we observed higher increases for both C and MD that ingested ayahuasca than placebo. After 48 h from the dosing session with ayahuasca, patients' awakening salivary cortisol response is similar to the ones detected in controls. No significant changes in plasma cortisol levels were observed 48 h after the sessions. Therefore, these findings point to new evidence on the modulation of salivary cortisol levels as a result of an ayahuasca session, both in healthy and depressive volunteers. Considering that cortisol acts in regulation of distinct physiological pathways, emotional and cognitive processes, it is assumed to be critically involved to the etiology of depression and its regulation seems to be important for the treatment and remission of major depression, ayahuasca use as antidepressant should be further investigated. Moreover, this study highlights the importance of psychedelics in the treatment of human mental disorders.