Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies

This meta-analysis (2016) examines studies on the mental health effects of ayahuasca, harmine, and harmaline within humans and animals, and shows consistent evidence for its antidepressant and anxiolytic (anxiety) effects.

Abstract

Objective: To conduct a systematic literature review of animal and human studies reporting anxiolytic or antidepressive effects of ayahuasca or some of its isolated alkaloids (dimethyltryptamine, harmine, tetrahydroharmine, and harmaline).

Methods: Papers published until 3 April 2015 were retrieved from the PubMed, LILACS and SciELO databases following a comprehensive search strategy and using a predetermined set of criteria for article selection.

Results: Five hundred and fourteen studies were identified, of which 21 met the established criteria. Studies in animals have shown anxiolytic and antidepressive effects of ayahuasca, harmine, and harmaline, and experimental studies in humans and mental health assessments of experienced ayahuasca consumers also suggest that ayahuasca is associated with reductions in anxiety and depressive symptoms. A pilot study reported rapid antidepressive effects of a single ayahuasca dose in six patients with recurrent depression.

Conclusion: Considering the need for new drugs that produce fewer adverse effects and are more effective in reducing anxiety and depression symptomatology, the described effects of ayahuasca and its alkaloids should be further investigated.”

Authors: Rafael G. dos Santos, Flávia L. Osório, José Alexandre S. Crippa & Jaime E. C. Hallak

Summary

Introduction

Ayahuasca is a botanical hallucinogen produced by boiling stems of the liana Banisteriospsis caapi with leaves of the shrub Psychotria viridis. It contains considerable amounts of the hallucinogenic tryptamine N,N-dimethyltryptamine (DMT).

A systematic review of animal and human studies on ayahuasca and its isolated alkaloids suggested that these compounds have broad therapeutic potential, especially for the treatment of substance dependence and anxiety and mood disorders.

Search strategy

The electronic PubMed, LILACS, and SciELO databases were searched for studies on ayahuasca, dimethyltryptamine, harmine, tetrahydroharmine, and harmaline, and anxiety, anxiogenic, anxilytic, depressive, and antidepressant.

Eligibility criteria

The review included animal models of anxiety and depression, experimental studies with healthy volunteers, observational studies with ayahuasca consumers, and clinical trials.

Data extraction

All studies were screened by two independent reviewers, and discrepancies were resolved by a third reviewer. Animal and human studies were divided into two categories for clarity and interpretation of results.

Study selection

A systematic review was conducted on 21 studies involving 10 animal studies, 9 human studies, and 1 clinical trial. The studies were classified according to the species, compound, and behavior/symptom assessed.

Animal studies

Mice treated with harmaline had an anxiolytic effect on the elevated plus maze test and the marble burying test.

A study in mice using the forced swim test (FST) showed that harmine reduced immobility time and reversed effects of a GABAA receptor antagonist.

Since 2009, our group has published several studies describing the antidepressive properties of harmine. The highest dose of harmine (10 mg/kg) increased climbing time and the lowest dose (3-5 mg/kg) increased swimming time in rats.

Harmine treatment reversed anhedonia and the increase in adrenal gland weight in rats using the chronic mild stress (CMS) model, and normalized adrenocorticotropic hormone (ACTH) and hippocampal BDNF levels.

Acute and chronic administration of harmine reduced lipid and protein oxidation and increased activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in the rat prefrontal cortex and hippocampus.

The effects of harmine on energy metabolism were assessed by evaluation of mitochondrial respiratory chain and creatine kinase activity. Acute and chronic treatment with harmine increased the activity of creatine kinase and of the mitochondrial respiratory chain, depending on dose and brain area.

Harmine, a substance that regulates cell energy homeostasis, reversed increased activity of an enzyme involved in mitochondrial function in the rat prefrontal cortex.

Human studies

DMT administration produced relaxation and increased positive mood in some participants. Oral DMT did not produce any psychoactive effects, while smoked DMT was fully psychoactive and increased positive mood.

In a study among first-time ayahuasca consumers, reduced psychiatric symptoms and increased serenity and tranquility were observed. Ayahuasca use was also associated with improved mental health, confidence, and optimism.

In studies with experienced members of the Unia o do Vegetal religion, ayahuasca use was not associated with any psychiatric symptoms, and members showed better neuropsychological performance and reduced psychopathology, including anxiety-and depression-related symptoms.

Ayahuasca reduced anxiety, panic-like, and hopelessness symptoms in experienced Santo Daime members, but did not modify state or trait anxiety.

Ayahuasca administration significantly reduced depressive symptoms in patients with recurrent depression in an open-label trial conducted in an inpatient psychiatric unit.

Discussion

We reviewed 21 studies on the anxiolytic and antidepressive effects of ayahuasca and its alkaloids. The results show that these compounds are effective.

Research shows that ayahuasca users do not exhibit symptoms of psychiatric disorders or neurocognitive problems, and have increased well-being and spirituality.

Studies in rodents have reported that the b-carbolines harmine and harmaline, as well as ayahuasca, produce anxiolytic or antidepressive effects. The mechanisms of action responsible for these effects are not completely understood, but may involve regulation of cell energy homeostasis, mitochondrial functions and oxidative stress, and modulation of BDNF.

DMT, psilocybin, and LSD are 5-HT1A/2A/2C receptor agonists that modulate emotional processing, reduce anxiety and depressive symptoms, and increase positive mood. However, a definite conclusion regarding the potential beneficial effects of these compounds cannot be drawn from previous investigations.

Recent studies have shown that psilocybin and LSD have anxiolytic effects in mice and rats, and have antidepressive-like effects in rats. Psilocybin and LSD may be useful for treating OCD and depression.

Ayahuasca may affect the default mode network (DMN), which is involved in introspection, meditative states, daydreaming, imagination, and mind-wandering. Ayahuasca may also affect the thickness of the posterior cingulate cortex.

Regarding other serotonergic hallucinogens, a recent functional MRI study reported decreased cerebral blood flow in several brain areas and increased functional connectivity of the DMN and the TPN, suggesting that the subjective effects of hallucinogens could be caused by disruption of DMN-TPN functional connectivity.

Ayahuasca and its alkaloids can produce anxiolytic and antidepressive effects, which are probably mediated by agonist action on 5-HT1A/2A/2C receptors. The mechanisms of action are not completely understood, but may include non-serotonergic mechanisms that regulate cell energy homeostasis, mitochondrial functions, and oxidative stress.

The results of this systematic review suggest that ayahuasca and its alkaloids have anxiolytic and antidepressive properties. Further studies are needed to replicate these findings.

The present review found few clinical trials and most evidence of its anxiolytic and antidepressive effects came from rodent studies.

The human studies included in this review were mostly experimental and observational in nature, and had small sample sizes. The results show that ayahuasca and its alkaloids have anxiolytic and antidepressive effects in rodents, healthy volunteers, and depressed patients.

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