Classic serotonergic psychedelics for mood and depressive symptoms: a meta-analysis of mood disorder patients and healthy participants

This meta-analytic review (2021, n=257) found that psychedelics provide improvements in mood for patients with mood disorders (and healthy subjects), both short (3h to 1d) and long-term (up to 60d).

Abstract

“Rationale: Major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option.

Objective: We present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately).

Results: Our search revealed 12 eligible studies (n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin (n = 8), lysergic acid diethylamide ([LSD]; n = 3), and ayahuasca (n = 1). The meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. For patients with mood disorder, significant effect sizes were detected on the acute, medium (2-7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms.

Conclusion: Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.”

Authors: Nicole L. Galvão-Coelho, Wolfgang Marx, Maria Gonzalez, Justin Sinclair, Michael de Manincor, Daniel Perkins & Jerome Sarris

Notes

“All studies included were randomized, placebo-controlled, and double-blind trials, which had either a cross-over or parallel design, with outcomes between 3 h and 60 days after dosing session.”

The 12 studies that were included are the following (see table 2 in the paper for an overview):

• Griffiths et al (2016) – LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects
• Griffiths et al (2006) – Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance
• Grob et al (2011) – Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer
• Hasler et al (2004) – Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose–effect study
• Kometer et al (2012) – Psilocybin biases facial recognition, goal-directed behavior, and mood state toward positive relative to negative emotions through different serotonergic subreceptors
• Kraehenmann et al (2015) – Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers
• Ross et al (2016) – Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial
• Wittmann et al (2007) – Effects of psilocybin on time perception and temporal control of behaviour in humans
• Dolder et al (2016) – LSD acutely impairs fear recognition and enhances emotional empathy and sociality
• Gasser et al (2014) – Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases
• Schmid et al (2015) – Acute effects of lysergic acid diethylamide in healthy subjects
• Palhano-Fontes et al (2019) – Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial

“We observed a significant moderate effect size for reduction of acute negative mood outcomes in healthy volunteers, compared to placebo, as well as significant moderate effects sizes for acute and long-term reductions of negative mood state in patients with mood disorders. For depressive symptoms, a significant large effect size was detected from a medium-term assessment, and a moderate effect size for both acute and long-term outcomes was observed for patients, compared to placebo.”

The review ends with a reflection on the methodology of the studies. It presents a fair critique regarding the difficulty in blinding participants, no apparent publication bias, and possible issues of the methodology by using different measures and timescales.

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.