The therapeutic potential of harmine and ayahuasca in depression: evidence from exploratory animal and human studies

The high prevalence and the socio-functional impairment associated with depressive disorders, added to the limitations of currently available treatments, justify the search for novel pharmacological strategies for the management of depression. This chapter presents the major results of animal and human studies conducted by a group of Brazilian researchers concerning the antidepressant potential of harmine, an alkaloid belonging to the group of β-carbolines and present in Ayahuasca (AYA), a tea with hallucinogenic properties used for religious and medicinal purposes Correspondence/Reprint request: Dr. Jaime Eduardo C. Hallak, Department of Neurosciences and Behavior Ribeirão Preto Medical School, University of São Paulo, Brazil. E-mail: jechallak@rnp.fmrp. usp.br Flávia de Lima Osório et al. 76 by peoples from the Amazon. The results obtained thus far suggest that harmine and other substances present in AYA might have antidepressant-like effects in the central nervous system of animals and human patients, pointing out the possibility of the therapeutic use of AYA in humans. 1. Depressive disorders – Clinical aspects Depression is a highly frequent psychiatric disorder with a lifetime prevalence of 17%, being twice as prevalent among women as compared with men. Onset usually occurs in the third decade of life, but the disorder can affect individuals at any age. It is a recurring condition and around 20-25% of patients become chronically ill[1]. Depressive disorders are associated with intense suffering, high morbidity rates, and increased mortality[2]. According to a study of the World Health Organization (WHO), depression is currently the fourth leading cause of morbidity and, within a ten-year period, it might rank second among the disorders affecting productive life[1]. According to the current Diagnostic and Statistical Manual of Mental Disorders published by the American Psychiatric Association (DSM-IV)[3], the diagnosis of a depressive episode requires the presence of depressed mood and/or anhedonia for a minimum of two weeks, accompanied by at least four of the following symptoms: significant weight loss or gain (5% of body weight); psychomotor agitation or retardation; insomnia or hypersomnia; fatigue or diminished energy; low self-esteem or inappropriate feelings of guilt; difficulties to think, concentrate or make decisions; and thoughts of death and suicide ideation or attempt. The symptoms must be associated with significant suffering and/or impairment in social, occupational or other functional areas, cannot be caused by a general medical condition or substance use, or fulfill the criteria for a mixed episode (episode in which the diagnostic criteria for both depression and mania are simultaneously satisfied). Clinically, depressive disorders are divided into single episode (if only one episode has occurred in life), recurring (when at least two episodes occurred), and chronic (if an episode lasts for two years or more)[3]. In terms of severity, depressive episodes are divided into mild, moderate, and severe. In mild episodes, few or no additional criteria besides those necessary for diagnosis are fulfilled and functional impairment is minor; in severe episodes a variety of symptoms are present, with significant functional impairment and possible association with psychotic symptoms; in moderate episodes, both the number of symptoms and the ensuing functional impairment lie on an intermediate level between the two former categories[3]. Harmine, ayahuasca and depression 77 2. Etiologic factors and neurobiology of depression The vulnerability to develop depression is connected with environmental factors such as early parental loss, childhood history of traumatic events, personality traits, family and personal history of depression, recent traumatic events, and genetic factors[1]. One of the main hypotheses to explain the neurobiology of depression was proposed following the discovery of the mechanisms of action of early antidepressant agents, which were accidentally discovered in the 1950s during the development of antihistamine (imipramine → tricyclic antidepressant) and antituberculosis (iproniazid → monoamine oxidase (MAO) inhibitor) drugs. Added to this, the comprehension of the action of three substances on the central nervous system (CNS), namely, imipramine (inhibiting neuronal reuptake of noradrenaline and serotonin), reserpine (depleting monoamines and causing depressive symptoms), and amphetamine (releasing noradrenalin and inhibiting its neuronal reuptake, causing euphoria) led to the proposition, in the 1960s, of the classic monoamine theory of depression, according to which the disorder would be caused by decreased availability of noradrenaline and serotonin in the brain[4]. These discoveries were followed by the development of new antidepressants, with similar mechanisms of action but better side-effect profiles and easier management, which are widely used in today’s practice, such as serotonin and noradrenaline selective reuptake inhibitors[5]. The serotonergic and noradrenergic systems, which are involved in the pharmacology of antidepressants, project from nuclei located in the brain stem onto wide areas in the midbrain. Noradrenergic neurons project from the locus coeruleus, whereas serotonergic neurons project from the raphe nuclei[4]. Fourteen serotonin receptors, divided into seven classes, have been identified to date. Together with other neurotransmitters, serotonin mediates such diverse aspects as mood, anxiety, sleep, body temperature, eating and sexual behavior, gastrointestinal motility, and others[6]. Many antidepressant drugs act primarily by increasing extracellular concentrations of serotonin, which leads to alterations in many receptors, resulting in therapeutic effects secondary to late neurochemical alterations. The activation of pre-synaptic 5-HT1A receptors in the raphe nuclei normally leads to decreased serotonin release. Antidepressant drugs that act by inhibiting the reuptake of serotonin cause the desensitization of these receptors, thus stimulating the release of serotonin by neurons and increasing the serotonergic neurotransmission. This hypothesis would explain the time Flávia de Lima Osório et al. 78 required for antidepressant drugs to present their therapeutic effects, since these are dependent on neurochemical adaptations[6]. 3. Treatment of depression A number of alternatives are available today to treat depression, encompassing antidepressant drugs, psychotherapy, electroconvulsive therapy, and other somatic treatments. In respect to the pharmacological management of the disorder, it is clear that the discovery of antidepressants in the 1950s brought about a revolution in the treatment of depression, standing out among the other therapies available[2]. Currently, different classes of antidepressant agents are available, which are classified according to their effects on the neuronal synapse, their action on MAO or on their chemical structure. Tricyclic antidepressants (TCA) and MAO inhibitors (MAOI) are known as “first generation” or “classic” antidepressants. Both these groups act by increasing the extracellular availability of monoamines – TCAs via inhibition of serotonin and noradrenaline reuptake, and MAOIs via inhibition of the metabolism of these neurotransmitters[7]. Besides the action described above, which is responsible for their therapeutic effects, TCAs act upon many other receptors, presenting antimuscarinic, antihistaminic, and anti-α2 adrenergic effects that may cause undesirable reactions such as urinary retention, constipation, orthostatic hypotension, weight gain, and somnolence. Additionally, TCAs block the sodium channels, interfering on nervous transmission and being potentially arrhythmogenic[4,7]. Concerning MAOIs, their main adverse effect is the risk of hypertension crises triggered by the intake of food containing tyramine, a sympathomimetic amine occurring in large quantities in certain foods and which is metabolized by MAO[4]. Newer antidepressants have been designed to be more selective. Among these are the selective serotonin reuptake inhibitors (SSRIs: fluoxetine, paroxetine), selective noradrenaline reuptake inhibitors (reboxetine), serotonin-noradrenaline reuptake inhibitors (venlafaxine, minalcipran, duloxetine), and other antidepressants with multiple mechanisms of action, such as mirtazapine, which acts as a pre-synaptic α2-noradrenergic antagonist and as an antagonist of serotonin receptors (5-HT2 e 5-HT3), and nefazodone, which acts both by inhibiting the reuptake of serotonin and noradrenaline and by antagonizing α2 and 5-HT receptors[7]. Although the side-effects of these drugs are not as significant as those of earlier antidepressants, they are still present in more recently developed psychopharmacological agents[3]. Harmine, ayahuasca and depression 79 The efficacy of newer antidepressants is not different from the efficacy of compounds developed earlier, and although around 80% of the patients respond to the treatment with antidepressants, only 50% present full remission[5]. In summary, the limitations associated with the currently available pharmacological treatments of depression are: low response rates, sideeffects, and time required until therapeutic effects are attained. Thus, novel pharmacological strategies, especially those with acute effects, would have an important impact on the treatment of depression[8].