A Single Dose Of Ayahuasca Modulates Salivary Cortisol In Treatment-Resistant Depression

Major depression is a highly prevalent mood disorder, affecting about 350 million people, and around 30% of the patients are resistant to currently available antidepressant medications. Recent evidence from a randomized placebo-controlled trial supports the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol response, in the same group of treatment-resistant patients and in healthy volunteers. Subjects received a single dose of ayahuasca or placebo, and both plasma and awakening salivary cortisol response were measured at baseline (before dosing) and 48h after the dosing session. Baseline assessment (D0) showed blunted awakening salivary cortisol response and hypocortisolemia in patients (DM), both with respect to healthy controls group (C). Salivary cortisol also was measured during dosing session and we observed a large increased for both C and DM that ingested ayahuasca, than placebo groups. After 48h of the dosing session (D2) with ayahuasca, awakening salivary cortisol response (for both sexes) of treated patients became similar to levels detected in controls. This was not observed in patients that ingested placebo. No changes in plasma cortisol were observed after 48 hours of ayahuasca or placebo ingestion for both groups and sexes. Therefore, these findings point to new evidence of modulation of ayahuasca on salivary cortisol levels, as cortisol acts in regulation of distinct physiological pathways, emotional and cognitive processes related to etiology of depression, this modulation could be an important part of the antidepressant effects observed with ayahuasca. Moreover, this study highlights the importance of psychedelics in the treatment of human mental disorders.

Our hypotheses are that patients and controls will show, in baseline, different levels of 155 plasma cortisol and awakening salivary cortisol response and the cortisol levels in patients 156 will be correlated with severity and/or duration of disease. Moreover, ayahuasca, but not 157 placebo, will increase cortisol levels acutely (43), during dosing session and after 48 hours 158 of its ingestion in volunteers patients and control, but with different intensity. The 159 responses will be correlated with improvement in depression symptoms in patients group 160 (42).

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This is a randomized double-blinded placebo-controlled trial using a parallel arm design. 165 Patients were referred from psychiatric units of the Onofre Lopes University Hospital, in 166 Natal/RN, Brazil, and through media and internet advertisements. All  Rating Scale (MADRS). All patients were not using any antidepressant medication during 187 the trial, however they all were under regular use of benzodiazepines.

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Volunteers from both groups (healthy and patients) were randomly assigned (1:1) to 190 receive ayahuasca or placebo using 10-gauge blocks. Half of the patients and half of the 191 controls received ayahuasca while the other half received placebo. All investigators and 192 patients were blinded to the intervention assignment.  195 196 The substance used as placebo did not have psychoactive properties, but induced a light 197 gastrointestinal discomfort, and simulated some organoleptic properties of ayahuasca. It 198 is a brown liquid with a bitter and sour taste. It contained water, yeast, citric acid, zinc 199 sulfate and a caramel dye. Saliva was collected using a specific cotton stick called Salivette (Sarstedt, Germany).

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Volunteers were instructed to place the cotton in the mouth without touching and 212 masticating it for a period of about 1 to 2 minutes. Before and during collection subjects 213 remained at rest and no liquid or food were allowed.

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Statistical analysis was conducted in Statistic 12.5 (data analysis software system), and 268 the level of significance was set at p < 0.05 for all tests. Graphics were built in R 3.4.1 269 (RStudio).

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The area under the curve (AUC) was calculated from the 3 points of salivary cortisol at   For plasma cortisol, this same analysis was applied but sex was not used as independent 287 variable, because the number of male patients who received placebo was too small (n=2).

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Acute response (%) of salivary cortisol during the dosing session were evaluated 1h40 290 after ayahuasca or placebo ingestion and assessed by Mann-Whitney test.

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Socio-demographic characteristics of healthy volunteers, control group (C), and patients     Figure 3a shows     In this study we found basal hypocortisolemia and blunted awakening salivary cortisol Cortisol is a steroid hormone that triggers stress response in an adaptive way: it increases 473 cardiovascular and respiratory systems activity, mobilizes glucose to provide enough fuel 474 needed to remove the stressor and limit acute inflammation processes (45). Not only the 475 excess, but also the reduction of this hormone is believed to be harmful, major depression 476 traditionally has been associated mainly with hypercortisolism, but an increasing number 477 of studies have been found hypocortisolism in depression (8,46,47 In literature more severe depression, marked by a chronic or recurrent disease, frequently 491 disclose hypocortisolism (46,8,47). These patients often exhibit long-term exposition to conditions.

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The etiology of hypocortisolism is explained by various theories. One of them shows that 515 a greater and decompensate sensitivity in negative feedback of the HPA axis deregulates 516 cortisol secretion (54). Also, hypocortisolism is associate to adrenal insufficiency, a 517 failure to produce cortisol and a decrease or increase in Adrenocorticotrophic hormone 518 (ACTH) concentrations that depend on the type of failure, whether primary or secondary, 519 respectively (48). New evidence also appoints the participation of paracrine and autocrine 520 messengers in adrenal failure (59). While several theories try to explain the etiology of 521 hypocortisolism, it seems that the best approach to elucidate this pathophysiological 522 process involves the integration of all these theories.

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The regulation of cortisol is an important physiological aspect on the way of achieving  Here, we found that depressive patients showed basal hypocortisolemia and blunted 535 awakening salivary cortisol response in comparison to controls. The levels of cortisol in plasma and saliva, at baseline, was positively correlated for  However, more investigation are necessary, mainly chronic treatment studies.

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Again, once more, our hypothesis was partially corroborated. As was hypothesized, 613 ayahuasca induced a large increase in acute salivary cortisol response than placebo. the aid in the diagnosis of psychopathologies, as recently proposed for depression (93).

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In the current overview, however, we emphasize that more studies are required to increase 640 the assumption that salivary cortisol can be useful as a biomarker in order to contribute

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That research was conducted in the absence of any commercial or financial relationships 656 that could be construed as a potential conflict of interest.