Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca

This double-blind, active placebo-controlled study (n=73) investigated the effects of ayahuasca (25.2mg/70kg of DMT, 130.2mg/70kg of harmine, 16.8 mg/70kg of harmaline, 84mg/70kg of tetrahydroharmine) on blood inflammatory biomarkers in patients with treatment-resistant depression (n=28) and healthy controls (n=45). Results indicate that 48 hours after treatment the concentration of the inflammatory biomarker CRP was reduced in response to ayahuasca but to placebo amongst both healthy volunteers and patients with depression and that improvements in the patients’ depressive symptoms were correlated with this trend.

Abstract

“Background: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients (n = 28) and healthy controls (n = 45).

Aims: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale.

Results: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed (rho = -0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed.

Conclusions: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.”

Authors: Nicole Leite Galvão-Coelho, Ana Cecília de Menezes Galvão, Raíssa Nóbrega de Almeida, Fernanda Palhano-Fontes, Isaac Campos Braga, Bruno Lobão Soares, João Paulo Maia-de-Oliveira, Daniel Perkins, Jerome Sarris & Draulio Barros de Araujo

Summary

Introduction

Pharmacological interventions are the most used therapeutic strategy to treat major depressive disorder (MDD), but 50% of treatments are unsuccessful in preventing relapse, leading to recurrent MDD. Some depressive patients have higher blood levels of pro-inflammatory biomarkers, such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-), and C-reactive protein (CRP).

Ayahuasca is a traditional Amazon brew that has been studied for its potential antidepressant properties. We conducted a double-blind placebo-controlled trial with treatment-resistant depression patients and healthy controls to evaluate the blood inflammatory biomarkers.

Depressive patients show lower inflammation than typical inflammatory diseases such as infections or autoimmune disorders, and so may have a lower risk of depression severity.

The relationship between inflammation and antidepressant treatment is complex. The anti-inflammatory effects of antidepressants may be influenced by the pre-treatment level of inflammation.

Chronic stress disrupts the balance between pro-inflammatory and anti-inflammatory pathways, and reduces brain-derived neurotrophic factor (BDNF), which is associated with decreased brain volume in specific areas among patients with MDD.

There is a renewal interest in the use of classic serotonergic psychedelics for treatment of MDD, due to their short latency for clinical improvement. These substances have also been identified as potential fast-acting antidepressants.

We measured blood levels of IL-6 and CRP in volunteers recruited for a randomized placebo-controlled trial of ayahuasca for treatment-resistant depression. We hypothesized that these levels would be reduced after ayahuasca intake compared to placebo, and found a negative relationship between them.

Study design

Ayahuasca was used in a randomized double-blinded placebo-controlled trial for treatment-resistant depression at the Federal University of Rio Grande do Norte. All subjects provided written informed consent prior to participation.

Sample, inclusion, and exclusion criteria

73 volunteers participated in the trial. They were naive to any classic serotonergic psychedelic that is an agonist of 5-HT2A, and had no current diagnosis or previous history of drug abuse or a substance-related disorder.

A group of 28 treatment-resistant depressive patients were included in this study. They had inadequate responses to at least two antidepressant medications from different classes and were assessed using the Hamilton Depression Scale and the Montgomery-sberg Depression Rating Scale.

Procedure

Inpatients and outpatients were administered a single oral liquid dose of 1 mL/kg of ayahuasca or placebo in a randomized 1:1 ratio. Participants listened to two curated playlists while dosing, and blood samples were collected immediately before and 2 days after dosing.

The clinical trial was focused on ayahuasca effects without a psychotherapeutic approach. Volunteers were followed up by two researchers throughout the dosing section and were given opportunities to share their experiences.

Drug and placebo preparation

A single batch of ayahuasca was used in this study. It was prepared in a Barquinha church, at Ji-Paraná, Rondônia, Brazil, and quantified at two different time points along the study to evaluate alkaloids concentrations and its stability.

Biomarker quantifications

Blood samples were collected to measure plasma CRP and serum IL-6, cortisol, BDNF, glutamic oxalacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT). All of the measured biomarkers have potential value as inflammatory biomarkers in MDD.

Statistical analysis

Groups, treatment, and phases were considered independent variables, and MADRS, CRP, IL-6, cortisol, and BDNF levels were considered dependent variables. Body mass index was used as a covariable in multivariable analyses.

At D0, the student t-test, Chi-square test, Mann-Whitney test, and CRP and IL-6 were used to compare variables between groups and to analyze personality disorders.

Multiple regression was used to test if gender, age, and number of unsuccessful previous antidepressant treatments predicted CRP and IL-6 levels.

Multiple regression and binary logistic regression were used to predict the antidepressant response and remission rates of patients treated with ayahuasca at D2.

Pre-treatment phase (D0)

The reported trial was conducted in accordance with the consolidated standards of reporting trials statement, and gender and age did not predict a patient’s MADRS scores at D0.

Patients had higher BMI and similar levels of GOT and GPT than the control group, and higher CRP and IL-6 levels than the control group, adjusting for BMI.

For patients, CRP levels correlated with cortisol levels, and IL-6 levels with any variable. The number of previous unsuccessful antidepressant treatments did not predict CRP or IL-6 levels, and no differences were found between patients with comorbid personality disorder and comorbid anxiety disorder.

Both groups administered ayahuasca and not placebo had reduced CRP levels at D2, compared with D0, adjusting for BMI. Ayahuasca reduced CRP levels 26.6%, whereas placebo increased CRP levels 20.4%.

For all patients treated with ayahuasca, lower MADRS scores were directly correlated with lower CRP levels at D2, and no significant correlations were found between CRP reduction and cortisol or BDNF changes for placebo or ayahuasca-treated patients.

IL-6 and substance (ayahuasca or placebo)

No statistically significant difference was found in IL-6 levels between treatment groups or phases, and no correlation was found between IL-6 levels and response or remission rates.

Discussion

Treatment-resistant depressive patients had higher CRP levels than healthy controls. Ayahuasca treatment reduced CRP levels and improved depressive symptoms in patients.

The pre-treatment CRP levels observed here in patients were characterized as a low-grade inflammatory profile. However, high levels of IL-6 have also been reported in MDD, which may be due to the involvement of IL-6 in the pro-inflammatory and anti-inflammatory response.

Although traditionally IL-6 and CRP are physiologically linked, some studies have shown that CRP increases independently of IL-6. The mechanisms behind such changes are not completely understood, but some hypotheses have been raised.

In this study, ayahuasca decreased CRP levels in patients and controls 48 hours after ingestion, and this decrease was moderately correlated with improvement in depressive symptoms. This result corroborates other studies that have shown an association between low-grade inflammation and treatment resistance in depressive patients.

We did not find changes in IL-6 after treatment with placebo or ayahuasca. However, ketamine, an anesthetic with psychedelic and antidepressant actions, has been proposed to have anti-inflammatory properties.

Pro-inflammatory biomarkers did not predict response or remission rates at D2. This finding may be due to suboptimal measurement points.

We observed a negative correlation between CRP and cortisol levels in patients, and we can argue that this is due to low cortisol levels, because cortisol is a potent anti-inflammatory hormone. However, no correlation was observed between inflammatory, BDNF, and cortisol responses to treatment.

The absence of expected correlations between biomarkers can be due to several factors, including the fact that patients showed alterations in these biomarkers.

The limitation of this study is that only total BDNF levels were measured, and the sample size was limited to a modest number of patients with treatment-resistant depression and comorbid personality and anxiety disorder. However, the results support the use of ayahuasca as an alternative treatment with anti-inflammatory effects for MDD.