Ayahuasca Increases Salivary Cortisol Levels in Patients with Treatment-Resistant Major Depression and Healthy Controls

Researchers are investigating the antidepressant effect of several psychedelic substances, including ayahuasca. Ayahuasca is a psychedelic beverage that has medicinal, religious, and ceremonial uses among the indigenous peoples of the Amazon basin. It is a decoction of two plants, caapi (Banisteriopsis caapi, Malpighiaceae) stem, and chacruna (Psychotria Viridis, Rubiaceae) leaf. Ayahuasca contains the hallucinogenic constituent N, N-dimethyltryptamine (N, N-DMT), which has a structure similar to serotonin, and harmala alkaloids, which are monoamine oxidase inhibitors. Compared to the general population, regular ayahuasca users have a much lower incidence of mood disorders such as major depression (MD). In clinical studies, ayahuasca has exhibited significant antidepressant effects and the onset of therapeutic benefit (24 h) was much more rapid compared to conventional antidepressants (2 wks). MD is associated with depressed levels of the steroid hormone cortisol. The purpose of this four-arm, randomized, double-blind, placebo-controlled trial was to evaluate the effect of a single dose of ayahuasca on salivary and plasma cortisol levels in patients with treatment-resistant MD and in healthy controls. The authors hypothesized that an acute dose of ayahuasca would increase cortisol levels in both groups.

Patients with treatment-resistant MD (n = 28, mean age 41 years) and healthy controls (n = 43, mean age 31 years) were enrolled in this study conducted at Onofre Lopes University Hospital (HUOL) in Natal/RN, Brazil from January 2014 to June 2016. The inclusion criteria for the MD group were moderate to severe depression (Hamilton Depression Rating Scale score ≥ 17) and poor response to at least two different classes of antidepressant drugs. Patients excluded from the MD group had previous experience with ayahuasca; had a current medical disease; were pregnant; had a history of bipolar disorder, schizophrenia, mania, hypomania, neurological disorders, or substance abuse; or were at risk of suicide. Participants excluded from the control group (C) had a history of a major illness or psychiatric disorders.

All participants (n = 71) were randomly assigned to receive an acute single dose of either 1 ml/kg ayahuasca (A) or a matching placebo beverage (P). The allocation to the four treatment arms was as follows: n = 10 MD+A, n= 12 MD+P, n =21 C+A, and n =20 C+P). The ayahuasca beverage was prepared by the Barquinha church in the city of Ji-Paraná, Brazil. It contained 0.36 mg/ml N,N-DMT, 1.86 mg/ml harmine, 0.24 mg/ml harmaline, and 1.20 mg/ml tetrahydroharmine. All participants were admitted to the psychiatric division of HUOL on the evening before the treatment. On the treatment day, saliva samples were collected for measurement of salivary cortisol early in the morning (upon awakening), immediately before treatment, 100 min post-treatment, and 48 h post-treatment. Fasting blood samples were collected for measurement of plasma cortisol upon awakening, pre-treatment, and 48 h post-treatment. The MD group completed the Montgomery-Åsberg Depression Rating Scale (MADRS) pretreatment and 48 h post-treatment.

Comparison of baseline sociodemographic characteristics showed that the MD group was older than the control group and had lower income and education levels. The majority of the MD group had another psychiatric condition, such as personality disorder or anxiety disorder. Patients in the MD group were previously treated with a mean of 3.86 different antidepressants. The authors hypothesized that baseline cortisol levels would be correlated with the severity (MADRS score) and/or duration of depression in the MD group; however, no significant correlations between these variables were found. At baseline, awakening salivary and plasma cortisol levels were significantly lower in the MD group compared to the control group (P = 0.002 and P = 0.03, respectively) and analysis showed these findings were independent of sex. At baseline, plasma cortisol levels were positively correlated with salivary cortisol levels in the control group but not in the MD group.

In both groups, those who received ayahuasca had significant increases in salivary cortisol levels 100 min post-treatment compared to those receiving placebo (P = 0.03 for MD+A; P = 0.01 for C+A). At 48 h post-treatment, none of the four treatment arms had significant changes in cortisol levels compared to baseline. However, patients with MD and controls who received ayahuasca had a comparable area under the curve (AUC) of salivary cortisol response while the patients with MD who received the placebo had significantly lower AUC of salivary cortisol response compared to controls. At 48 h, there was no correlation between cortisol levels and MADRS score in the MD group. Adverse effects associated with ayahuasca consumption were not reported.

The authors conclude that ayahuasca can modulate cortisol levels in both patients with MD and healthy people. They speculate that the lack of correlations between cortisol levels and improvement in depressive symptoms may be due to the high heterogeneity of patients and the small sample size. Given the fact that regulation of cortisol levels is considered an important part of depression treatment and the positive effect of an acute dose of ayahuasca on cortisol levels observed in this study, the authors “argue that ayahuasca should be further investigated as a treatment for depression.”

The authors state that there were no conflicts of interest.


Galvão ACM, de Almeida RN, Silva EADS, et al. Cortisol modulation by ayahuasca in patients with treatment-resistant depression and healthy controls. Front Psychiatry. May 2018;9:185. doi: 10.3389/fpsyt.2018.00185.