Effects of four doses of ayahuasca or dextrocetamine on major treatment-resistant depression: a randomized, double-blind study

• Grant number: 21/04600-9
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2021
• End date: May 31, 2025
• Field of knowledge: Health Sciences - Medicine - Psychiatry
• Principal Investigator: Jaime Eduardo Cecilio Hallak
• Grantee: Giordano Novak Rossi
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 23/10516-6 - Sleep quality on ayahuasca drinkers, BE.EP.DR

Abstract

Major Depressive Disorder (MDD) is a psychopathology with a high rate of non-responders to the drugs that exist on the market today. Despite that, these drugs may take weeks to start producing their effects. Ayahuasca and ketamine have shown rapid (hours/days) and persistent (weeks) therapeutic effects on MDD. The main active ingredient of ayahuasca is dimethyltryptamine (DMT), a psychedelic tryptamine that acts as an agonist for 5-HT2A serotonergic receptors, in the same way as LSD and psilocybin. In the case of ayahuasca, two clinical trials (one open and one placebo-controlled) with a single dose in volunteers with treatment-resistant MDD showed a significant reduction in depressive symptoms and anxiety. Therapeutic effects appear to start in the first hours after consumption and last between one and three weeks. In the case of ketamine, although its intranasal use was approved for treatment-resistant MDD in 2019, only three clinical studies (one open and two placebo-controlled) have been conducted with oral ketamine to treat this disorder. As with ayahuasca, its effects start quickly and last up to two weeks. In addition, the antidepressant and anxiolytic effects of serotonergic hallucinogens have never been directly compared to ketamine. Thus, the main objective of this project is to evaluate the effects of four doses of ayahuasca or dextroketamine on depressive and anxiety symptoms in patients with treatment-resistant MDD. 50 volunteers will participate in this randomized, double-blind study with parallel groups where they will receive one of the following treatments: four doses of ayahuasca (1 mL/kg) with an interval of one week between doses or four doses of oral dextroketamine (2 mg/kg) with the same time interval. The main variables will be the variations in depressive symptoms (BDI) and anxiety (BAI) assessed in the eighth week after starting the treatment. Secondary variables include subjective effect scales (VAMS, HADS, VAS, HRS e ESS), social cognition tasks (recognition of emotions in facial expressions, empathy) and biochemical measures (BDNF). These scales and tests will be applied during the acute (0-5h) and prolonged (fifth and eighth week after the first experimental session) effects of ayahuasca and dextroketamine. The safety and tolerability of treatments will be assessed with subjective (UKU, CADSS e BPRS) and cardiovascular (blood pressure and heart rate) measures. (AU)