A single dose of ayahuasca acutely raised salivary cortisol and, 48 hours later, normalised the blunted awakening salivary cortisol response in treatment‑resistant depression patients to levels seen in healthy controls, without changing plasma cortisol.
Papers cited by this study that are also in Blossom
Vollenweider, F. X., Kometer, M. · Nature Reviews Neuroscience (2010)
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.
Major depressive disorder (MDD) is common and linked to dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, with studies reporting both hypercortisolism and hypocortisolism depending on factors such as depression subtype, severity, sex, illness duration and socioeconomic status. Cortisol measures, including the cortisol awakening response (CAR), have been used as biomarkers of depression and treatment response, though findings are heterogeneous. Psychedelics, and specifically ayahuasca, have recently shown rapid antidepressant effects in early clinical studies; ayahuasca contains N,N-dimethyltryptamine (N,N-DMT) plus β-carboline MAO inhibitors and has a long history of ritual medicinal use in Brazil and South America. Galvão and colleagues set out to examine how a single dose of ayahuasca affects cortisol physiology in people with treatment-resistant depression and in healthy volunteers. They tested two primary hypotheses: that patients and controls would differ at baseline in plasma cortisol and awakening salivary cortisol response (AUC), and that ayahuasca (but not placebo) would acutely raise cortisol during the dosing session and alter cortisol measures 48 hours after ingestion, with cortisol responses correlating with clinical improvement in depressive symptoms.
This was a randomised, double-blind, placebo-controlled, parallel-arm trial conducted at a university hospital in Natal, Brazil, and registered as NCT02914769. Seventy-one volunteers were enrolled: 43 healthy controls (19 men, 24 women) and 28 patients with treatment-resistant major depression (7 men, 21 women). Treatment resistance was defined as inadequate response to at least two antidepressants from different classes. Exclusion criteria included prior ayahuasca experience, certain medical or neurological disorders, bipolar or psychotic history, substance abuse and pregnancy. Selected patients were in a moderate–severe depressive episode (HAM-D ≥ 17) and underwent a pharmacological washout of about two weeks; they were not taking antidepressants during the trial but were taking benzodiazepines. Participants were randomised 1:1 to receive a single oral dose of ayahuasca or a placebo liquid designed to mimic the appearance and taste but without psychoactive properties. The ayahuasca batch averaged 0.36 mg/mL N,N-DMT, 1.86 mg/mL harmine, 0.24 mg/mL harmaline and 1.20 mg/mL tetrahydroharmine; dose was 1 mL/kg adjusted to deliver approximately 0.36 mg/kg N,N-DMT. During the dosing session subjects remained resting with eyes closed and could listen to a predefined music playlist; two researchers provided support. Biological measures comprised awakening salivary cortisol (three samples collected at awakening: +5, +30 and +45 minutes; area under the curve, AUC, calculated from these) and fasting morning total plasma cortisol collected at 07:00. Saliva and plasma were stored at −80°C and assayed by ELISA. Clinical depression severity was measured with MADRS at baseline (D0) and 48 hours after dosing (D2). Acute salivary cortisol response during the dosing session was measured immediately before dosing and at +1h40. Statistical analysis used log-transformed cortisol values; baseline group comparisons used ANCOVA with sex as covariate, correlations used Spearman tests, acute salivary responses were compared with Mann–Whitney tests, and longitudinal analyses employed General Linear Models (GLM) with Fisher post-hoc tests. Significance threshold was p < 0.05.
Baseline (D0) comparisons showed that patients with treatment-resistant depression had lower awakening salivary cortisol AUC and lower total plasma cortisol than healthy controls. Specifically, awakening salivary AUC was 49.4 ± 8.3 cm2 in patients (n=20) versus 62.5 ± 6.3 cm2 in controls (n=41); the ANCOVA main effect of group was significant (F=9.75, p=0.002) and sex had no effect. Total plasma cortisol averaged 15.12 ± 1.73 μg/dl in patients (n=28) and 19.52 ± 1.37 μg/dl in controls (n=43), with a significant group effect (F=4.71, p=0.03) independent of sex. At baseline control subjects showed a positive correlation between plasma cortisol and salivary AUC (Spearman rs=0.54, p<0.05), whereas no such correlation was found in patients. The extracted text reports that 61% of patients had ‘‘relative’’ hypocortisolemia (below 15 μg/dl) and 22.22% had ‘‘true’’ hypocortisolemia (below 10 μg/dl) using the study’s cutoff values. During the dosing session, salivary cortisol measured at +1h40 increased substantially in both healthy volunteers and patients who received ayahuasca compared with those who received placebo; the paper reports a ‘‘major acute increase’’ but the extracted text does not provide exact magnitude values. Two days after dosing (D2) the GLM reported a significant Group×Treatment×Days interaction for awakening salivary AUC (F=4.57, p=0.03). Post-hoc comparisons showed that patients who received ayahuasca had an awakening salivary AUC at D2 (59.4 ± 12.7 cm2) that was similar to healthy subjects who received ayahuasca (50.1 ± 8.2 cm2) and to controls who received placebo (61.9 ± 8.9 cm2). By contrast, patients who received placebo continued to show a lower AUC at D2 (41.2 ± 14.8 cm2) relative to placebo-treated controls (61.9 ± 8.9 cm2; Fisher post-hoc p=0.03). Sex did not influence these results according to the reported analyses. Total plasma cortisol showed no significant changes between D0 and D2 within groups or treatments and no group or treatment effects were detected in the GLM for plasma cortisol. Clinically, the extracted text reports that 77% of patients in the ayahuasca group and 64% in the placebo group met the study’s definition of response at D2 (clinical response defined as ≥50% reduction in baseline depression scale scores). The paper lists MADRS scores at D0 (32.67 ± 6.31) and reports values at D2 (55.79 ± 32.14 for ayahuasca and 61.42 ± 25.7 for placebo), but these D2 figures appear inconsistent with the baseline mean and the stated response rates; the extraction does not clarify whether these numbers represent raw scores, percent change or another metric. The investigators did not find correlations between cortisol changes (acute or at 48 hours) and clinical improvement in depressive symptoms. Individual responses in both AUC and plasma cortisol showed large variability.
Galvão and colleagues interpret their findings as evidence that patients with treatment-resistant depression displayed basal hypocortisolemia and a blunted cortisol awakening response compared with healthy controls, and that a single ayahuasca dose produced an acute rise in salivary cortisol and, by 48 hours, normalised the awakening salivary cortisol AUC in patients. The authors note that this normalisation was not observed in patients who received placebo. They discuss cortisol’s physiological role in stress adaptation and note that both excess and deficiency of cortisol have adverse effects; the presence of hypocortisolemia in their patient sample is linked in the paper to possible long-term HPA axis maladaptation, cumulative life stressors, socioeconomic disadvantage and prior chronic antidepressant exposure. The discussion situates the acute cortisol rise after ayahuasca within prior reports that serotonergic psychedelics and DMT can elevate cortisol acutely, and proposes that ayahuasca’s pharmacology (N,N-DMT and β-carbolines increasing serotonergic tone) could mediate acute CRH/ACTH and cortisol release. The authors highlight that salivary awakening AUC was more sensitive than total plasma cortisol to both baseline group differences and to the treatment effect, and therefore may be a more robust biomarker for some purposes; however, they caution against using salivary cortisol alone as a diagnostic marker because altered cortisol patterns occur across disorders and because they did not observe a correlation between cortisol shifts and symptom improvement. Key limitations acknowledged by the authors include large individual variability in cortisol measures, the complex aetiology of hypocortisolemia, potential confounding by long-term antidepressant exposure and socioeconomic factors in the sample, and the need for further and longer-term studies to establish clinical relevance. They conclude that the observed modulation of awakening salivary cortisol by ayahuasca, alongside clinical response signals, supports further clinical research into psychedelics for mood disorders.
This is a randomized double-blinded placebo-controlled trial using a parallel arm design. Patients were referred from psychiatric units of the Onofre Lopes University Hospital, in Natal/RN, Brazil, and through media and internet advertisements. All procedures took place at the University Hospital. The study was approved by the Research Ethics Committee of the University Hospital (# 579.479; see supplementary material), and all subjects provided written informed consent prior to participation. This study is registered in(NCT02914769).
Statistical analysis was conducted in Statistic 12.5 (data analysis software system), and the level of significance was set at p < 0.05 for all tests. Graphics were built in R 3.4.1 (RStudio). The area under the curve (AUC) was calculated from the 3 points of salivary cortisol at waking time. Both salivary and plasma cortisol levels were normalized by the logarithm to use parametric tests. A parametric test of Analysis of Covariance (ANCOVA) was used to analyze differences between groups (healthy and patients) at baseline, for both salivary (AUC of awakening salivary cortisol) and plasma cortisol. Sex was inserted as co-variable. At baseline, Spearman correlations were calculated across plasma cortisol and AUC of awakening salivary cortisol of patients and controls and scores of scales of depression (HAM-D and MADRS) and duration of disease of patients. General Linear Models (GLM) and Fisher post-hoc tests were used to evaluate interaction among: changes of AUC of awakening salivary cortisol response along the days (D0 and D2), which was considered as dependent variable, and sex (men and women), groups (healthy volunteers and patients) and treatment (AYA or PLA) as independent variable. For plasma cortisol, this same analysis was applied but sex was not used as independent variable, because the number of male patients who received placebo was too small (n=2). Acute response (%) of salivary cortisol during the dosing session were evaluated 1h40 after ayahuasca or placebo ingestion and assessed by Mann-Whitney test. Moreover, Spearman correlations test were calculated across acute response (%) of salivary cortisol during the dosing session for controls and patients of AYA and PLA groups, plasma cortisol and AUC of awakening salivary cortisol of D2 for patients and controls of each treatment and scores of MADRS for patients of each treatment.
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Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Sanches, R. F., Osório, F. L., Dos Santos, R. G. et al. · Journal of Clinical Psychopharmacology (2016)
Tracy, D., Baumeister, D., Barnes, G. et al. · Therapeutic Advances in Psychopharmacology (2014)
Carbonaro, T. M., Eshleman, A. J., Forster, M. J. et al. · Psychopharmacology (2014)
Frecska, E., Bokor, P., Winkelman, M. J. · Frontiers in Pharmacology (2016)
Bouso, J. C., González, D., Fondevila, S. et al. · PLOS ONE (2012)
Santos, R. G., Landeira-Fernandez, J., Strassman, R. J. et al. · Journal of Ethnopharmacology (2007)
Bouso, J. C., Fábregas, J. M., Antonijoan, R. M. et al. · Psychopharmacology (2013)
Rodríguez-Fornells, A., Ribeiro, S., Sanches, R. F. et al. · European Neuropsychopharmacology (2015)
Halpern, J. H., Sherwood, A. R., Passie, T. et al. · Medical Science Monitor (2008)
Fábregas, J. M., González, D., Fondevila, S. et al. · Drug and Alcohol Dependence (2010)
Barbosa, P., Mizumoto, S., Bogenschutz, M. P. et al. · Drug Testing and Analysis (2012)
Callaway, J. C., Mckenna, D. J., Grob, C. S. et al. · Journal of Ethnopharmacology (1999)
Dos Santos, R. G. · Journal of Psychoactive Drugs (2014)
Passie, T., Seifert, J., Schneider, U. et al. · Addiction Biology (2002)
Hasler, F., Grimberg, U., Benz, M. A. et al. · Psychopharmacology (2004)
Strajhar, P., Schmid, Y., Liakoni, E. et al. · Journal of Neuroendocrinology (2016)
Papers in Blossom that reference this study
Gukasayan, N., Narayan, S. K. · Journal of Psychoactive Drugs (2023)
Kuiperes, Z., Schreiber, R. · Neurobiology of Learning and Memory (2021)
In this study we found basal hypocortisolemia and blunted awakening salivary cortisol response in treatment-resistant patients with major depression, compared to healthy subjects. After treatment of patients and controls with ayahuasca or placebo, was observed (1 hour and 40 minutes after ingestion) major acute increases in salivary cortisol of groups that ingested ayahuasca compared to placebo-ingesting groups. Moreover, 48h after (D2) of the dosing session 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 that continued showing blunted AUC of awakening salivary cortisol response compared to the control group that ingested placebo. Two days after dosing session (D2), 77% of patients that were treated with ayahuasca showed response while 64% from the placebo group responded. Clinical response was defined as a reduction of 50% or more in baseline scores, of scales of depression. Cortisol is a steroid hormone that triggers stress response in an adaptive way: it increases cardiovascular and respiratory systems activity, mobilizes glucose to provide enough fuel needed to remove the stressor and limit acute inflammation processes. Not only the excess, but also the reduction of this hormone is believed to be harmful, major depression traditionally has been associated mainly with hypercortisolism, but an increasing number of studies have been found hypocortisolism in depression. The chronic decrease in cortisol levels induces non-specific symptoms such as general malaise, weakness, low blood pressure, muscle weakness, loss of appetite and weight, gastrointestinal complaints and immunological dysfunction. Moreover, low cortisol levels are present in some physiological diseases as Addison's diseaseand adrenal insufficiencyand some psychopathologies as post-traumatic stress disorders. Thus, these results partially corroborate our hypothesis, since control group and patients presented, at baseline, different total plasma cortisol levels and awakening salivary cortisol response, since patients showed hypocortisolemia and blunted awakening salivary cortisol response. But, unexpectedly these alterations in cortisol observed in baseline for patients not were correlated with severity or duration of disease. In literature more severe depression, marked by a chronic or recurrent disease, frequently disclose hypocortisolism. These patients often exhibit long-term exposition to stressors, which in the early phase of disease may induce a chronic upregulated activity of the HPA axis and hypercortisolemia, after this, a maladaptive regulation of the HPA function reduces cortisol to very low pathological levels. In addition, evidence suggests that prolonged use of some antidepressants may also lead to increased expression of cortisol receptors and increased sensitivity of negative feedback, thus decreasing cortisol levels to under homeostatic values. Our patients are treatment-resistants and used an average of 3.86±1.66 different types of antidepressants, which could in turns induced hypocortisolemia. Low cortisol levels in depression have also been associated with maladaptive coping styleand unfavorable socioeconomic status. Patients in this study had a particular profile: they live in Rio Grande do Norte, a state of Northeast Brazil, a region characterized by low socioeconomic status, low educated and living in a low-income household, in a stressful environment. Previous studies, of other research groups, have reported similar results. They found low levels of cortisol at awakening in patients with depression in our state (Rio Grande do Norte) compared to healthy volunteers (58), and with patients from Canada. Due to significant levels of poverty and scarce government investments in this region, this population usually is submitted to a long exposure of adverse events in life, and early in life they cope with precarious physical and physiological health, as well as with cumulative social and economic disadvantage conditions. The etiology of hypocortisolism is explained by various theories. One of them shows that a greater and decompensate sensitivity in negative feedback of the HPA axis deregulates cortisol secretion. Also, hypocortisolism is associate to adrenal insufficiency, a failure to produce cortisol and a decrease or increase in Adrenocorticotrophic hormone (ACTH) concentrations that depend on the type of failure, whether primary or secondary, respectively. New evidence also appoints the participation of paracrine and autocrine messengers in adrenal failure. While several theories try to explain the etiology of hypocortisolism, it seems that the best approach to elucidate this pathophysiological process involves the integration of all these theories. The regulation of cortisol is an important physiological aspect on the way of achieving biological health, since cortisol is an integrative hormone with large potential of body modulation, particularly involved in the etiology of depression, engaging immune and monoaminergic systems. Moreover, optimal levels of cortisol are necessary to induce neurogenesis, possibly due to its modulatory properties over brain-derived neurotrophic factor (BDNF) transcription and binding to its receptor. This relation seems an important factor in the etiology of depression, considering that the effectiveness of traditional antidepressants seems to be mediated by neuronal plasticity and neurogenesis. Here, we found that depressive patients showed basal hypocortisolemia and blunted awakening salivary cortisol response in comparison to controls. The values for diagnosis of corticosteroid insufficiency varies, some studies point cortisol levels below 15μg/dl and others under 10μg/dl as hypocortisolemia. Studies that evaluated the utility of basal morning serum cortisol measurements in the diagnosis of adrenal insufficiency showed that values below 10μg/dl had 77% of specificity, and 62 of sensitivity (as defined by a subnormal serum cortisol response to insulin-induced hypoglycemia) acting as good indicator of disease. In this study we considered 10μg/dl as value of cutoff for true hypocortisolemia. We observed that 61% of patients showed relative hypocortisolemia (below 15μg/dl) and 22.22% true hypocortisolemia (below 10μg/dl). The awakening salivary cortisol response has been less used than plasma cortisol to monitor adrenal insufficiency, because it not had been fully validated as the diagnostic test. The levels of cortisol in plasma and saliva, at baseline, was positively correlated for controls, but not for patients. It is observed correlation between total plasma and salivary cortisol in healthy subjects. Probably this correlation not occurs in patients because of the malfunction of their HPA axisor by changes in concentration of CBG (Cortisol Binding Globulin), its protein of transportation in plasma. During the acute effects of ayahuasca we found increased cortisol levels, 1h40 after intake. Previous studies in healthy subjects have also reported increased cortisol levels during the acute effects of ayahuasca, N,N-DMT, psilocybinand LSD. One should bear in mind that our patients presented, in general, hypocortisolemia and blunted awakening salivary cortisol response. It is reasonable to consider that subjects who took ayahuasca which immediately increased cortisol levels probably were acutely benefited by the ingestion of the ayahuasca, thereby leading to a direction of achieving the hormonal homeostasis. After 48 hours of dosing session, no changes with respect to baseline within each group, both treatments, were observed for AUC of awakening salivary cortisol response and plasma cortisol. Individual changes of AUC and PC between D0 and D2 showed a large variability in these responses. Some studies also faced with this large individual variability in baseline levels and response of cortisol, and these are facts that disturb the validation of cortisol as biomarker in DM. However, after 48 hours of dosing session the AUC of awakening salivary cortisol response of patients that ingested ayahuasca, and not placebo, became similar to both control that ingested ayahuasca and placebo, the initial blunted response of depressed patients disappear. This similarity of AUC between controls and patients that were treated with ayahuasca points to a beneficial modulation of ayahuasca on awakening salivary cortisol response. Some studies with animal models of depression, rodents and non-human primates, observed positive antidepressant effects with the use of ayahuasca or its specific components. Using the recently validated translational animal model of depression, young marmosets (Callithrix jacchus) were treated with nortriptyline during 7 days, a tricyclic antidepressant, or with a single dose of ayahuasca. It was observed that ayahuasca increased fecal cortisol levels until 48 hours after it ingestion and presented more notable antidepressant effects than nortriptyline, since it reverted depressive-like behaviors and regulated cortisol levels faster and during more time. The modulation of HPA axis by antidepressants depend on the type of antidepressant used and the duration of treatment, acute or chronic. Noradrenaline or serotonin (5HT) reuptake-inhibiting antidepressants, such as reboxetine and citalopram, acutely stimulate cortisol secretion in healthy volunteers, probably due the elevation in 5HT levels. On the other hand, some antidepressants, as mirtazapine, acutely inhibits cortisol release, probably due to its selective antagonism at 5-HT2 receptors. It is interesting to notice that the long-term effects of antidepressants are frequently opposite of the acute ones. In long way, reboxetine up-regulates cortisol receptors function, repairs the disturbed feedback control and normalizes HPA axis. Mirtazapine, within 1 week, markedly reduces HPA axis activity in depressed patients. If the patient is resistant to treatments, and uses antidepressants by years, the long-term effects could be disturbed and followed by a disfavorable physiological response, as cited above, the chronic use of some antidepressant could induces hypocortisolemia. Here, the acute increases of cortisol levels by the ayahuasca can be due the rise in serotonin induced by the N,N-DMT, and β-carbolinic alkaloids, likewise, literature appoints to a modulation of the secretion of CRH and ACTH both at the hypothalamic and pituitary glands by serotonin. In clinical practice the physiological variables are not used for the diagnosis of DM or for choose and evaluate treatments. The use of cortisol as a biomarker could aid in the diagnosis, prognosis and analysis of the evolution of the treatments. As discussed, DM is correlated to hyper and hypocortisolemia and antidepressants have distinct action in cortisol levels, thus the use of cortisol as biomarker could influence the choice of treatment. In this way, as ayahuasca increases cortisol levels acutely, its use as antidepressant could be favorable for depressive patients that show hypocortisolemia. However, more investigation are necessary, mainly chronic treatment studies. Again, once more, our hypothesis was partially corroborated. As was hypothesized, ayahuasca induced a large increase in acute salivary cortisol response than placebo. Although, this increase was not sustained along 48 hours, patients that ingested ayahuasca, and not placebo, presented similar AUC of awakening salivary cortisol response compared to controls (ayahuasca and placebo) in D2. This last finding, although it is different from the hypothesis, is important and corroborates with the improvement of several physiological system, emotional and cognitive aspects that was regulated by cortisol. Patients showed considerable reduction in depressive symptoms in D2, however, this progress was not correlated with cortisol changes, either acutely nor 48 hours after dosing. Our results suggest that the AUC awakening salivary cortisol response is a more robust biomarker than the PC, since it was altered in baseline and it was sensible to treatment by ayahuasca. Other studies appoint in the same way, considering the awakening salivary cortisol response as more strong marker than PC, as it is less modulatated by circadian clock and by daily stressors than PC. As well as, some prospective studies have shown that awakening salivary cortisol, and not total PC levels, could predict depressive episodesHowever, we should be cautious when trying to consider salivary cortisol, in an isolated way, as a biomarker for the diagnosis of DM, since altered cortisol patterns are also found in other mental disorders and in this study we not found correlation between improvement in depressive symptoms and in AUC of awakening salivary cortisol response. Many studies argue that, in an individual way, this biomarker fits more in the aid of prognostics and therapeutic accompaniments than in the diagnosis. On the other hand, it is suggested that a panel of neuroendocrine and immune biomarkers would be the most suitable for the aid in the diagnosis of psychopathologies, as recently proposed for depression. In the current overview, however, we emphasize that more studies are required to increase the assumption that salivary cortisol can be useful as a biomarker in order to contribute with valuable information in the diagnostic, prognostic and therapeutic results in major depression In sum, the present study appoints new evidence of improvements of depressive symptoms and of AUC of awakening salivary cortisol response by ayahuasca, 48 hours after its ingestion, in DM patients with treatment-resistant depression, which presented blunted salivary cortisol awakening response and hypocortisolemia. As cortisol act in regulation of distinct physiological, cognitive and emotional partway, the improvement of its awakening response could be important as part of the antidepressant effects. Taking these findings in account, this work contributes significantly to support the return of clinical studies with natural psychedelics applied to mental disorders.