Modulation of Serum Brain-Derived Neurotrophic Factor by a Single Dose of Ayahuasca: Observation From a Randomized Controlled Trial

This placebo-controlled, double-blind randomized trial study (n=73) investigated the impact of BDNF (a protein related to the growth of neurons) on patients with depression who were administrated ayahuasca. The trial results observed a potential link between the changes in serum BDNF levels and the antidepressant effects of ayahuasca and also supported using psychedelics as an antidepressant.

Abstract

“Introduction: Serotonergic psychedelics are emerging as potential antidepressant therapeutic tools, as suggested in a recent randomized controlled trial with ayahuasca for treatment-resistant depression. Preclinical and clinical studies have suggested that serum brain-derived neurotrophic factor (BDNF) levels increase after treatment with serotoninergic antidepressants, but the exact role of BDNF as a biomarker for diagnostic and treatment of major depression is still poorly understood.

Methods: Here we investigated serum BDNF levels in healthy controls (N = 45) and patients with treatment-resistant depression (N = 28) before (baseline) and 48 h after (D2) a single dose of ayahuasca or placebo.

Results: In our sample, baseline serum BDNF levels did not predict major depression and the clinical characteristics of the patients did not predict their BDNF levels. However, at baseline, serum cortisol was a predictor of serum BDNF levels, where lower levels of serum BDNF were detected in a subgroup of subjects with hypocortisolemia. Moreover, at baseline we found a negative correlation between BDNF and serum cortisol in volunteers with eucortisolemia. After treatment (D2) we observed higher BDNF levels in both patients and controls that ingested ayahuasca (N = 35) when compared to placebo (N = 34). Furthermore, at D2 just patients treated with ayahuasca (N = 14), and not with placebo (N = 14), presented a significant negative correlation between serum BDNF levels and depressive symptoms.

Discussion: This is the first double-blind randomized placebo-controlled clinical trial that explored the modulation of BDNF in response to a psychedelic in patients with depression. The results suggest a potential link between the observed antidepressant effects of ayahuasca and changes in serum BDNF, which contributes to the emerging view of using psychedelics as an antidepressant. This trial is registered at http://clinicaltrials.gov (NCT02914769).”

Authors: Raíssa Nóbrega de Almeida, Ana Cecília de Menezes Galvão, Flávia Santos Da Silva, Erick Allan dos Santos Silva, Fernanda Palhano-Fontes, João Paulo Maia-de-Oliveira, Lobão-Soares Barros de Araújo, Bruno Lobão-Soares & Nicole Leite Galvão-Coelho

Summary

INTRODUCTION

There has been some recent debate about the efficacy of currently available antidepressants. Some patients have a reduced benefit after drug treatment, while others have pseudo-resistance to treatment.

Several research groups have intensified their search for new antidepressants, including psychedelic substances, such as psilocybin and ayahuasca. These studies have shown that regular intake of micro-doses of psychedelics leads to benefits in mood, health and cognition.

Ayahuasca is a brew created by Amerindians that acts as a reversible monoamine oxidase inhibitor, serotonin reuptake inhibitor, and 5-HT2A and 1R receptor agonist.

Despite the peculiarity of each psychedelic, it is known that several pathways of neuronal plasticity are activated by these compounds. This is a relevant aspect of their action as potential antidepressants.

The activation of the 5-HT2A and TrkB receptors by some psychedelics induces neuroplasticity through the rapamycin (mTOR) signaling pathway, while the activation of the 1R receptor by intracellular calcium-dependent signal increases neuroplasticity by brain-derived neurotrophic factor.

Ayahuasca compounds induce proliferation, migration and differentiation of neurons and induce cascades involved in neuroplasticity. Furthermore, harmine increases brain-derived neurotrophic factor (BDNF) in rodent animal models.

Brain-derived neurotrophic factor (BDNF) is a neurotrophin synthesized by neurons and glial cells. Patients with depression present neurodegeneration and smaller hippocampal and prefrontal cortex volume, which may be reversed after antidepressant drug treatment. Baseline alterations in serum BDNF levels in depressive patients are not a consensus in the literature, but novel antidepressants increase hippocampal BDNF level and of BDNF positive neurons in an animal model of depression.

In this study, we investigated whether serum BDNF levels predict major depression, whether serum BDNF levels depend on individual clinical characteristics, and whether serum BDNF levels predict the improvements observed in depression severity.

Study Design

The study was conducted at the psychiatry clinic of University Hospital Onofre Lopes of the Federal University of Rio Grande do Norte and complied with all ethical standards.

Seventy-three volunteers participated in the trial: 45 healthy individuals and 28 patients with treatment-resistant major depression. All patients were at least 18 years old, were naive to ayahuasca, and had no previous experience with any other psychedelic substance or history of drug abuse or substance dependency.

The volunteers were admitted to the hospital for a sleep-in 1 day before the dosing session, and were assessed with the MADRS scale before and 48 h after the dosing session.

Volunteers were placed in a comfortable living room at HUOL and were instructed with strategies to help eventual difficulties. They listened to a predefined music playlist and focused on their body, thoughts and emotions.

Ayahuasca was prepared by a branch of the Barquinha church and used throughout the trial. A placebo was used to simulate the effects of ayahuasca.

Dosage of Molecules

Blood samples were analyzed in the Laboratory of Hormone Measurements (UFRN) using a spectrophotometer microplate reader and a CYT306 ELISA kit for BDNF dosage and a DGR-SLV 1887 ELISA kit for serum cortisol dosage.

Baseline Statements

All volunteers were categorized according to their serum cortisol levels: hypocortisolemia, eucortisolemia, and hypercortisolemia. BDNF and cortisol serum concentrations were converted to fit the logarithm scale.

A binary logistic regression was used to find the best model that predicts the presence of major depression in our sample. The following potential predictor variables were added in the model: baseline serum BDNF levels, sex, income, age, and serum cortisol levels.

A multi-linear regression model was used to predict the baseline serum BDNF levels of all volunteers. The best model was decided according to Lowest Akaike’s Information Criteria (AIC), and the model with the least number of predictors was considered the best model.

A multi-linear regression model was used to test the potential modulation of clinical characteristics of patients on their baseline serum BDNF levels. The median age and median serum BDNF levels were analyzed as well as the relationship between serum BDNF and serum cortisol.

After-Dosing Assessments

After the second treatment session, patients were classified as remitters (R) or non-remitters (NR). The levels of serum BDNF were analyzed between-group and between-treatment and possible changes of serum BDNF levels before and after treatment.

A logistic regression was used to find the best model that explained the remission rates at D2. The potential predictor variables were the type of treatment and sex.

Baseline Assessments

All volunteers were Brazilians adults, most were women, most had secondary education, most had lower income than controls, most had been previously treated with at least 2 different antidepressants without remission, and 25% had tried 5 or more.

Baseline serum BDNF alone could not predict depression severity, but when the sex, income, age and cortisol level were included as potential predictors, the model turned statistically significant. Age was the variable that best predicted the model.

Several models were tested to predict baseline serum BDNF levels in volunteers. Cortisol levels were found to be the best predictor of baseline serum BDNF levels.

Volunteers with hypocortisolemia showed lower levels of baseline serum BDNF when compared to volunteers with eucortisolemia, and a negative correlation between serum BDNF and serum cortisol was observed in volunteers with eucortisolemia.

After-Dosing Assessments

We found that volunteers treated with ayahuasca had higher levels of BDNF at D2 than those treated with placebo, and that there was a negative correlation between BDNF and MADRS in patients treated with AYA, but not in patients treated with PLA.

The number of previous unsuccessful antidepressant treatments was found to be the best predictor of remission rates at D2. Patients in remission at D2 presented a smaller number of previous unsuccessful antidepressant treatments than patients that did not achieve remission.

We explored models with two possible predictors and found that the number of previous unsuccessful antidepressant treatments was the best fit with a 78.6% prediction of D2 remission rate.

DISCUSSION

In this study, we found an interaction between serum BDNF and serum cortisol levels at baseline. Patients treated with ayahuasca presented higher serum BDNF levels compared to those treated with placebo, and a negative significant correlation between serum BDNF levels and MADRS scores.

Results corroborate in part our initial hypotheses that the glucocorticoid cortisol regulates the expression of brain-derived neurotrophic factor (BDNF) in the central nervous system. This relationship is inverted U-shaped, with intermediate levels of cortisol being most suitable for BDNF expression.

The literature suggests that allostatic levels of cortisol are important to adequate BDNF expression and function. This hypothesis is corroborated by the negative correlation between BDNF and cortisol found only for eucortisolemic volunteers.

Brain-derived neurotrophic factor (BDNF) is a broad-acting neurotrophin that plays important roles in protection, differentiation, viability and growth of new neurons. Psychedelic compounds have been shown to induce neuroplasticity and neurogenesis, which may be a relevant aspect of their action as potential antidepressants.

Even though most studies suggest that patients with depression have lower serum BDNF levels than healthy controls, our study did not find any clinical characteristics that predict baseline levels of BDNF in the group of patients.

The reduction of BDNF levels in depression is most consistently observed after a 4-week wash-out period or in severe untreated patients. However, the baseline serum BDNF levels did not predict major depression in our study.

Three isoforms of BDNF have been identified, including pre-pro-BDNF, pro-BDNF, and mature BDNF. Pro-BDNF is the major secreted form, not m-BDNF.

BDNF is cleaved by plasmin and the pro-BDNF/m-BDNF ratio is critical for the determination of physiological or pathological conditions. The pro-BDNF/m-BDNF ratio is increased in the prefrontal cortex and ventral tegmental area in animal models of depression. BDNF pro-peptide and pro-BDNF can interact with Trk and p75NTR receptors, but BDNF pro-peptide and pro-BDNF have different biological activities.

Ayahuasca increased levels of brain-derived neurotrophic factor (BDNF) in individuals treated with ayahuasca compared to placebo, and this effect was correlated with lower depression symptomatology.

Ayahuasca activates 5-HT2A and 1R pathways, induces an acute increase of cortisol levels, and may be involved in the modulation of BDNF. This study suggests higher levels of BDNF in volunteers treated with ayahuasca than those treated with placebo.

We did not observe a significant difference in remission rates between treatments at D2 in our original clinical trial, but the number of previous unsuccessful antidepressant treatments predicted remission rates at D2.

Despite previous findings indicating a positive correlation between antidepressant effects and the expression of BDNF, few studies using double-blind placebo-controlled design have investigated BDNF in major depression. Ketamine has been tested in MD patients and animal models.

In addition to the limitations discussed above, the study did not consider the genetic factor related to BDNF, and serum cortisol and BDNF were measured only once. Sequential measurements throughout the day and for different days could point to more precise results.

The results point to important observations, such as higher BDNF levels in volunteers treated with ayahuasca than placebo, and a clear association between higher serum BDNF and lower symptoms of depression at D2.

ETHICS STATEMENT

The study was approved by the Ethics Committee on Medical Research of HUOL and was registered at http://clinicaltrials.gov.