The Therapeutic Potentials of Ayahuasca in the Treatment of Depression, Fernanda Palhano-Fontes et al., 2014

The Therapeutic Potentials of Ayahuasca in the Treatment of Depression

Fernanda Palhano-Fontes, Joao C. Alchieri, Joao Paulo M. Oliveira, Bruno Lobao Soares, Jaime E. C. Hallak, Nicole Galvao-Coelho and Draulio B. de Araujo

Chapter 2, in B. C. Labate and C. Cavnar (eds.), “The Therapeutic Use of Ayahuasca”, Springer-Verlag Berlin Heidelberg, 2014

Doi : 10.1007/978-3-642-40426-9_2, 



Major depressive disorder (MDD) is generally classified as a mood disorder with a profound effect on the individual’s behavior and quality of life. According to the World Health Organization, in about 20 years, depression will be the disorder with the most significant repercussions, both socially and economically. Despite the substantial progress in the development of new antidepressants, their effectiveness remains low, with remission of about 50 % after a single regime of treatment. The most common form of pharmacological treatment of MDD is based on selective serotonin reuptake inhibitors (SSRIs), designed to increase extracellular levels of the neurotransmitter serotonin. Unfortunately, antidepressants currently available based on SSRIs may take several weeks to achieve the desired therapeutic effects. Therefore, massive effort has been devoted to find alternative treatments for MDD.For example, the use of ketamine, of (±)-1-(2,5-Dimethoxy-4-iodophenyl)-2- aminopropane (DOI), and b-carbolines is under current investigation. Based on evidence from the literature and a pilot study conducted by our group, we speculate about the possible therapeutic potential of ayahuasca for MDD. In part, such conjecture is based on the fact that ayahuasca combines N,N-dimethyltryptamine (DMT), acting particularly on serotonin neurotransmission through 5-HT2A receptors and monoamine oxidase inhibitors (MAOI), both involved, at least indirectly, with pharmacological formulations intended for MDD treatment. In this chapter, we will review the major aspects of MDD such as diagnosis, current pharmacological treatments, and the motivations to use ayahuasca as a novel alternative.

Major Depressive Disorder: Causes and Diagnosis

Major depressive disorder (MDD) is generally classified as a mood disorder with a profound effect on the individual’s behavior and quality of life. It has a prevalence of 17 % throughout life, being twice as common in women as it is in men and usually begins in the third decade of life. For most people, MDD presents itself in recurrent episodes. However, about 20–25 % of patients are chronically ill. According to the World Health Organization (WHO), MDD is the fourth leading cause of morbidity, and they predict that by 2020, it will be ranked second disease burden worldwide (Fava and Kendler 2000).

MDD is associated with intense personal suffering, high morbidity, and increased mortality (Ebmeier et al. 2006). The Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (DSM-IV-TR) defines this condition based on the presence of depressed mood (irritable mood in children and adolescents) and/or loss of interest or pleasure (anhedonia) for at least 2 weeks,
accompanied by at least four of the following symptoms: (a) considerable change in weight (5 % of body weight), (b) frequent insomnia or hypersomnia, (c) psychomotor agitation or retardation, (d) fatigue or loss of energy, (e) low self-esteem or inappropriate guilt, (f) diminished capacity to think, concentrate, or make decisions, (g) recurrent thoughts of death, suicidal ideation, or suicide attempts. In addition, the diagnosis requires that the symptoms cause significant distress and/or impairment in social, occupational, or other areas of life, and should not be directly caused by another general medical condition or psychoactive substance use and must not meet the criteria for mixed episode (in which the diagnostic criteria of depression and mania occur concurrently) (American Psychiatric Association [APA] 2000b).

Multiple theories attempt to explain the etiology of depression, but the most widely accepted one is the monoamine hypothesis. This theory suggests that MDD is a result of decreased brain levels of monoamines, such as dopamine, norepinephrine, and serotonin (Wong and Licinio 2001). Among these, serotonin has received the most attention. Besides the reduction of serotonin levels found in depression, studies also point to an altered expression of 5HT1A autoreceptors and heteroreceptors. The most consistent finding is an increase in pre-synaptic 5HT1A autoreceptors, which inhibit the release of serotonin, and consequently reduce serotonin levels in the synaptic cleft. A reduced number of postsynaptic 5HT1A heteroreceptors in the hippocampus and prefrontal cortex, presumably induced by high cortisol levels also found in these patients, is also associated with MDD.

On the other hand, the monoamine hypothesis does not explain important matters such as the causes of the monoaminergic disturbance and the elevated refractoriness to the treatment of MDD with antidepressant drugs that target the increase of the monoamine levels in the synaptic cleft. In this scenario, several alternative hypotheses were brought to focus such as hypothalamic–pituitary–adrenal (HPA) axis dysfunctions and the inflammatory and neurodegenerative hypotheses.

One of the most common HPA abnormalities observed in depressed patients is an increase in reactivity of this axis. Scientific evidence indicates that MDD patients have impaired glucocorticoid receptor (GR) function, which results in reduced negative feedback in the HPA system, leading to chronically high levels of adrenocorticotrophic hormone-releasing factor (CRF), and increased cortisol in the plasma, urine, and cerebrospinal fluid (Zunszain et al. 2011).

Complementarily, the inflammatory theory is based on the strong mutual regulation and communication between the immune and HPA systems (Leuchter et al. 2010). Chronic activation of the HPA axis also provokes GR resistance in immune cells (Leonard 2007). Normally, basal cortisol induces the production of lymphocytes T CD4 Th2, but chronicle GR resistance leads to an imbalance in the immune system, displacing the production of these lymphocytes to a Th1 subtype, thus reducing the concentration of anti-inflammatory cytokines (IL-4, IL-10), and increasing the pro-inflammatory cytokines (IL-1, IL-6, TNF-a) (Leuchter et al. 2010; Li et al. 2011). In turn, the massive liberation of pro-inflammatory cytokines induces a decrease in GR function (Pace et al. 2007).