This animal study (n=15) investigated the efficacy of ayahuasca (0.6mg DMT, 3.1mg harmine, 0.4mg harmaline, and 0.34mg tetrahydroharmine /300g) to treat depressed marmoset monkeys exposed to 8 weeks of social isolation. They found that ayahuasca reduced scratching and depression-like behaviors, increased the feeding rate, and restored body weight and fecal cortisol to baseline levels, particularly within male monkeys.

Abstract

“Objective: The incidence rate of major depression in adolescents reaches approximately 14%. This disorder is usually recurrent, without remission of symptoms even after pharmacological treatment, and persists throughout adult life. Since the effects of antidepressants take approximately 2 weeks to begin, new pharmacological therapies are under continuous exploration. Recent evidence suggests that psychedelics could produce rapid antidepressant effects. In this study, we evaluated the potential antidepressant effects of ayahuasca in a juvenile non-human primate model of depression.

Methods: While living with their families, juvenile marmosets (8 males; 7 females) were observed on alternate days for four weeks during a baseline phase. This was followed by 8 weeks of an induced depressive state protocol, the social isolated context (IC), in which the animals were monitored in the first and last weeks. Subsequently, five males and four females were randomly selected for treatment, first with a single administration of saline vehicle (1.67 mL/300 g of body weight, via gavage), followed by a single dose of ayahuasca (1.67 mL/300 g of body weight, via gavage). Both phases lasted 1 week and the animals were monitored daily. A third week of sampling was called the tardive-pharmacological effects phase. In all phases the marmosets were assessed for behavior, fecal cortisol levels, and body weight.

Results: After IC, the animals presented typical hypocortisolemia, but cortisol recovered to baseline levels 24 h after an acute dose of ayahuasca; this recovery was not observed in vehicle-treated animals. Additionally, in males, ayahuasca, but not the vehicle, reduced scratching, a stereotypic behavior, and increased feeding. Ayahuasca treatment also improved body weight to baseline levels in both sexes. The ayahuasca-induced behavioral response had long-term effects (14 days). Thus, in this translational juvenile animal model of depression, ayahuasca presented beneficial effects.

Conclusions: These results can contribute to the validation of ayahuasca as an antidepressant drug and encourage new studies on psychedelic drugs as a tool for treating mood disorders, including for adolescents with early-onset depression.”

Authors: Flávia S. da Silva, Erick A.S. Silva, Geovan M. de Sousa Jr., João P. Maia-de-Oliveira, Vanessa de Paula Soares-Rachetti, Draulio B. de Araujo, Maria B.C. Sousa, Bruno Lobão-Soares, Jaime Hallak & Nicole L. Galvão-Coelho

Summary

Introduction

MDD has been associated with physiological dysregulation and monoaminergic imbalance. However, antidepressant drugs that target these systems do not totally relieve depressive symptoms and take around 2 weeks before onset of the desired therapeutic effects.

Ayahuasca is a decoction of two plants from the Amazon rainforest that acts on several biological systems involved in the etiology of depression. Tetrahydroharmine, harmine, and harmaline are reversible MAO inhibitors that increase monoamine half-life in vivo and, consequently, residence time in the synaptic cleft space.

The influence of sexual steroids on the nervous system at puberty makes the brain particularly susceptible to environmental influences, increasing the probability of mood disorders that persist into adulthood.

Ayahuasca may be effective in treating depression in adolescents. This study evaluated the effects of ayahuasca on body weight, physiological, and behavioral parameters in a juvenile model of depression.

Animal maintenance

All animals were housed according to IBAMA guidelines and CONCEA standards, and the study was approved by the animal research ethics committee of UFRN, Natal, state of Rio Grande do Norte, Brazil.

All juvenile animals used in this study were randomly selected from 10 different families within a group of approximately 150 marmosets living in captivity at the LEAP laboratory at UFRN.

All of the animals were conditioned to the presence of the researchers, and were fed a diet of seasonal fruits, potatoes, and a protein mixture. They were weighed every 15 days to monitor their health.

Study design

Eight males and seven females were observed and their fecal cortisol was measured on alternate days during the baseline phase, eight weeks of social isolated context, and five males and four females were randomly selected for treatment with ayahuasca.

Ayahuasca treatment consisted of a single dose, and behavioral and physiological parameters were investigated 24 and 48 h after administration.

Treatments

A single batch of ayahuasca was used throughout the study for all animals. It was prepared using plants collected in a single day from the same area and contained 0.3660.01 mg/mL DMT, 1.8660.11 mg/mL harmine, 0.2460.03 mg/mL harmine, and 0.2060.05 mg/mL THH.

Ayahuasca was administered via gavage. The animals were fed a small portion of fruit on the day of administration, and were adapted to the handling procedure and apparatus prior to the study.

Behavioral recording

The behavioral data were the same as those validated by Galva o-Coelho et al.16 for juvenile marmosets and included species-specific behaviors, depressive-like behaviors, and locomotion, sleep, feeding, and anhedonia.16

Fecal samples were collected between 6:30 and 8:30 a.m. and stored at – 4 oC until cortisol extraction and quantification.

Statistical analysis

Hormonal data were normalized by logarithmic transformation, and a generalized linear model and Fisher’s post-hoc tests were used to analyze variations in behavior, cortisol, and body weight between sexes.

Results

At the end of the social IC, cortisol levels decreased, autogrooming and somnolence increased, and feeding and sucrose ingestion decreased, which indicates anhedonia. These changes were independent of sex.

Only males showed increased scent marking and reduced body weight after the IC protocol, while both males and females increased scratching. No significant statistical variations were observed in locomotion or individual piloerection.

Males showed decreased scratching and increased feeding after ayahuasca, but not after vehicle. The PH-induced reduction lasted 7 days more and was also observed in the tPE.

After PH, but not after VE, body weight increased, and it was sustained throughout tPE. This allowed recovery to baseline weight levels.

No significant alterations were observed in fecal cortisol, autogrooming, scent marking, locomotion, ingestion of sucrose, or somnolence.

Cortisol levels increased 24 h and 48 h after ayahuasca ingestion, but not after vehicle, and cortisol levels returned to baseline values at D1 and D2, independent of sex. No significant behavior alterations were found in D1 or D2 in response to vehicle or ayahuasca.

Discussion

Ayahuasca reduced scratching and depression-like behaviors, increased feeding rate and restored body weight and fecal cortisol to baseline levels in juvenile common marmosets, although this did not occur after placebo.

After treatment with vehicle alone, no changes regarding behavior or body weight were observed. A single dose of ayahuasca improved some of these depressive-like behaviors, mainly in males, and increased feeding rates indicated a positive effect.

Ayahuasca may act as an anorectic agent through the serotonin, s1R, or cortisol pathways, although the exact mechanism is unclear. It is also considered to have an anorectic effect after treating common marmosets with nortriptyline.

Ayahuasca treatment improved depressive-like behaviors in male and female common marmosets, probably due to the organizational and/or activational effects of sexual hormones on the serotonergic system and hypothalamus-pituitary-adrenal (HPA) axis, which may induce sexual dimorphism in these functions and the behaviors they control.

Non-human primate models have not been used in studies on ayahuasca, particularly those involving juveniles. However, the single dose of ayahuasca used in the present study led to improved body weight and depression-like behaviors, which remained significant for at least 14 days.

Ayahuasca’s antidepressant effect may be due to its pharmacological action on the serotoninergic system, its agonist action on the 5-HT2 receptor and s1R, and its stimulation of transcription factors, brain-derived neurotrophic factor and protein kinase B activity.

In this study, ayahuasca treatment did not improve behaviors in juvenile marmosets, and alternative protocols should be tested to determine whether substantial behavioral improvement is possible.

Marmosets have lower cortisol levels after exposure to strong stressors, and lower cortisol levels have also been reported in patients with atypical unipolar major depression and major depression with remittent conditions.

During a prolonged stress response, the HPA axis is imbalanced, which reduces cortisol synthesis, deregulating all adaptation systems, and leading to weakness, weight loss, and immunological dysfunction.

Ayahuasca treated animals with depression increased cortisol levels faster and more finely than nortriptyline, and recovered to baseline levels in only one day.

Antidepressants affect the HPA axis differently depending on the drug class (e.g. MAOi, tricyclics, SSRI, etc.). Ayahuasca and nortriptyline might modulate the secretion of both CRH and/or adrenocorticotropic hormones at the levels of the hypothalamus and pituitary gland, respectively.

Although this study used a standard traditional preparation protocol, subtle differences among preparations are probable. Further follow-up studies are necessary to evaluate the safety and tolerability of ayahuasca in humans as a basis for its use as an effective antidepressant in adolescents.

Juvenile male and female common marmosets exposed to chronic social isolation for 8 weeks showed depressive-like behaviors and changes in body weight and cortisol, which were ameliorated by a single dose of ayahuasca.