Rapid and long-lasting effects of subcutaneous esketamine on suicidality: An open-label study in patients with treatment-resistant depression.

Therapeutics for suicide management is limited, taking weeks to work. This open-label clinical trial with 18 treatment-resistant depressive patients tested subcutaneous esketamine (8 weekly sessions) for suicidality. We noted a rapid and enduring effect of subcutaneous esketamine, lasting from one week to six months post-treatment, assessed by the Beck Inventory for Suicidality (BSI). There was an immediate drop in suicidality, 24 h following the initial dose, which persisted for seven days throughout the eight-week dosing period. Additionally, this study is the first to examine a six-month follow-up after multiple administrations of subcutaneous esketamine, finding consistently lower levels of suicidality throughout this duration. Conversely, suicidality also was measured along the 8-weeks of treatment by a psychiatrist using the Montgomery-Asberg Depression Rating Scale (MADRS), which showed significant reduction only after two treatment sessions expanding until the last session. Moreover, notably, 61% of patients achieved remission on suicidality (MADRS). These results suggest that weekly subcutaneous esketamine injections offer a cost-effective approach that induces a rapid and sustained response to anti-suicide treatment. This sets the stage for further, more controlled studies to corroborate our initial observations regarding the effects of SC esketamine on suicidality. Registered trial at: https://ensaiosclinicos.gov.br/rg/RBR-1072m6nv.

Safety and tolerability of inhaled N,N-Dimethyltryptamine (BMND01 candidate): A phase I clinical trial.

Psychedelics are being increasingly examined for their therapeutic potential in mood disorders. While the acute effects of ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) last over several hours, inhaled N,N-Dimethyltryptamine (DMT) effects last around 10 min, which might provide a cost- and time-effective alternative to the clinical application of oral psychedelics. We aimed at investigating the safety and tolerability of inhaled DMT (BMND01 candidate). We recruited 27 healthy volunteers to receive a first, lower dose and a second, higher dose (5/20 mg, 7.5/30 mg, 10/40 mg, 12.5/50 mg, or 15/60 mg) of inhaled DMT in an open-label, single-ascending, fixed-order, dose-response study design. We investigated subjective experiences (intensity, valence, and phenomenology), physiological effects (blood pressure, heart rate, respiratory rate, blood oxygen saturation, body temperature), biochemical markers (liver, kidney, and metabolic functions), and adverse events during the acute and post-acute effects of DMT. DMT dose-dependently increased intensity, valence and perceptual ratings. There was a mild, transient, and self-limited increase in blood pressure and heart rate. There were no changes in safety blood biomarkers and no serious adverse events. DMT dose-dependently enhanced subjective experiences and positive valence. Inhaled DMT might be an efficient, non-invasive, safe route of administration, which might simplify the clinical use of this substance. This is the first clinical trial to test the effects of inhaled DMT (BMND01 candidate).

A quantitative textual analysis of the subjective effects of ayahuasca in naïve users with and without depression.

Ayahuasca is a brew with psychoactive properties that has been used as an entheogen for centuries, with more recent studies suggesting it is a promising treatment for some clinical disorders. Although there is an emerging scientific literature on its effects, to the best of our knowledge no study has explored the self-reported experiences of first-time ayahuasca users with quantitative textual analysis tools. Accordingly, the current study aimed to analyze the subjective experience of naive individuals with depression and healthy controls after consuming ayahuasca. For this purpose, responses from a subsample of participants from a previous clinical trial to open-ended questions regarding their experience with ayahuasca underwent textual analysis. Data from nine patients with treatment-resistant depression and 20 healthy individuals were included, and quantitative textual analysis was performed using IRaMuTeQ 0.7 alpha 2 and R 3.1.2. The analysis identified five clusters: alterations in the state of consciousness, cognitive changes, somatic alterations, auditory experiences, and visual perceptual content. Additionally, findings suggest specific features of the experience of people with depression with ayahuasca, such as increased aversive bodily reactions. The results are consistent with previous findings indicating central axes of the psychedelic experience, and may inform therapeutic approaches using ayahuasca.

Moderators of ayahuasca's biological antidepressant action.

Introduction: The understanding of biological responses to psychedelics with antidepressant potential is imperative. Here we report how a set of acute parameters, namely emotional (depressive symptoms), cognitive (psychedelic experience), and physiological (salivary cortisol), recorded during an ayahuasca dosing session, modulated serum brain-derived neurotrophic factor (BDNF), serum cortisol (SC), serum interleukin 6 (IL-6), plasma C-reactive protein (CRP), and salivary cortisol awakening response (CAR). Methods: Results were analyzed 2 days after the psychedelic intervention (ayahuasca) versus placebo in both patients with treatment-resistant depression and healthy volunteers. These measures were assessed as part of a randomized double-blinded, placebo-controlled trial (n = 72). Results: Results revealed that larger reductions of depressive symptoms during the dosing session significantly moderated higher levels of SC in patients. Whereas lesser changes in salivary cortisol levels during the ayahuasca intervention were related to higher BDNF levels in patients with a larger clinical response in the reduction in depressive symptoms. No moderator was found for patient's CAR, IL-6, and CRP responses to ayahuasca and for all biomarker responses to ayahuasca in healthy controls and in the placebo group. Discussion: In summary, some specific emotional and physiological parameters during experimental ayahuasca session were revealed as critical moderators of the improvement of major depression biomarkers, mainly BDNF and SC two days after ayahuasca intake. These findings contribute to paving the way for future studies investigating the biological antidepressant response to psychedelic therapy.

Prophylactic action of ayahuasca in a non-human primate model of depressive-like behavior.

Observational studies of long-term users of ayahuasca, an Amazonian psychedelic brew, suggest an increase in resilience via improvements in emotion and cognition. Ayahuasca has also demonstrated clinical antidepressant effects in human and animal studies; however, its potential prophylactic action in depression has not been previously studied. Therefore, this experimental study sought to evaluate the potential prophylactic effects of repeated and long-term ayahuasca use, via the modulation of resilience, in a non-human primate animal model, Callithrix jacchus, subjected to a protocol for induction of depressive-like behavior. For the formation of the study groups, some juvenile marmosets were kept in their family groups (GF = 7), while for the two experimental groups, the animals were removed from the family and kept socially isolated. Then, part of the isolated animals made up the group in which ayahuasca was administered (AG, n = 6), while for others, no intervention was made (IG, n = 5). AG animals took ayahuasca (1.67 mL/300g body weight) at weeks 4 (before isolation), 8, and 12 (during isolation) of the study. More adaptive stress response was observed for the AG when compared to the IG. The AG showed higher cortisol reactivity and fecal cortisol levels than IG, while both measures were similar to FG. Moreover, AG animals showed no signs of anhedonia and no increase in chronic stress-related behaviors, which were expressed by the IG. Thus, ayahuasca seems to promote the expression of resilient responses, indicating a prophylactic action, buffering the emergence of depressive-like behaviors and cortisol alterations associated with major depression. These results are encouraging for further research on the prophylactic use of psychedelics to prevent psychopathologies associated with chronic stress.

Insular cortex activity during food-specific inhibitory control is associated with academic achievement in children.

BACKGROUND/OBJECTIVES: Inhibitory control (IC) is usually poorer in children with overweight and obesity and has been associated with unhealthy eating behaviors and lower academic achievement. Food-specific IC tasks depicting salient unhealthy foods may be more sensitive to predicting fat accumulation and unhealthy behaviors than traditional IC tasks. However, the neural activation patterns in response to food-specific IC remain unclear, especially in developing children`s brains. Here, we investigated brain activity associated with food-specific IC in children with accumulated fat mass. SUBJECTS/METHODS: 36 children with overweight and obesity performed a food-specific Go/No-Go task in an MRI scanner. We assessed the children's body composition with dual-energy x-ray absorptiometry, academic achievement, somatic maturation, and cardiorespiratory fitness. RESULTS: The left insular cortex was significantly activated during successful inhibition of palatable food cues and was associated with higher academic achievement. Also, linear regression showed that academic achievement correlated with insular cortex activation even when controlling for somatic maturation, cognitive performance, and cardiorespiratory fitness. CONCLUSION: Our results indicate that insular cortex activation, an area known for rational and emotional processing, is associated with successful inhibitory control in response to food images in children with overweight and obesity, while academic performance seems to play a role in the magnitude of this activation.

The impact of a brief mindfulness training on interoception: A randomized controlled trial.

Interoception is a collection of different representations of signals originating within the body. The way of perceiving these signals seems to be related to both emotion regulation and dysregulation, and its dysfunction is implicated across a variety of affective disorders. There is a growing body of research investigating the relationship between mindfulness meditation practices and interoception showing an increase in interoceptive processes with regular training. In this study, we assessed the effects of a three-day mindfulness training on interoceptive accuracy and sensibility in a young healthy adult sample. Moreover, we also performed a mediation analysis on interoceptive sensibility and anxiety. Healthy participants (n = 40) naive to mindfulness practices were randomized to a brief mindfulness training (MT) (n = 20, females = 10) or to an active control group (n = 20, females = 10). Participants were assessed before and after the 3-days intervention for both groups on measures of interoception and anxiety in a modified intention-to-treat approach. The brief mindfulness training group increased interoceptive sensibility while active control had no effects on this variable. Five out of eight subdomains of interoceptive sensibility were significantly improved after mindfulness training. There was no significant difference in interoceptive accuracy after training. The effect of a brief mindfulness training on interoceptive sensibility mediated changes in the anxiety state. To date, this is the first study showing a plausible mechanism of a brief mindfulness training to explain the anxiolytic effects of meditation practices. Trial registration: RBR-7b8yh8, March 28th 2017 http://www.ensaiosclinicos.gov.br/rg/RBR-7b8yh8/.

Nootropic effects of LSD: Behavioral, molecular and computational evidence.

The therapeutic use of classical psychedelic substances such as d-lysergic acid diethylamide (LSD) surged in recent years. Studies in rodents suggest that these effects are produced by increased neural plasticity, including stimulation of the mTOR pathway, a key regulator of metabolism, plasticity, and aging. Could psychedelic-induced neural plasticity be harnessed to enhance cognition? Here we show that LSD treatment enhanced performance in a novel object recognition task in rats, and in a visuo-spatial memory task in humans. A proteomic analysis of human brain organoids showed that LSD affected metabolic pathways associated with neural plasticity, including mTOR. To gain insight into the relation of neural plasticity, aging and LSD-induced cognitive gains, we emulated the experiments in rats and humans with a neural network model of a cortico-hippocampal circuit. Using the baseline strength of plasticity as a proxy for age and assuming an increase in plasticity strength related to LSD dose, the simulations provided a good fit for the experimental data. Altogether, the results suggest that LSD has nootropic effects.

LSD and creativity: Increased novelty and symbolic thinking, decreased utility and convergent thinking.

BACKGROUND: Controversy surrounds psychedelics and their potential to boost creativity. To date, psychedelic studies lack a uniform conceptualization of creativity and methodologically rigorous designs. AIMS: This study aimed at addressing previous issues by examining the effects of lysergic acid diethylamide (LSD) on creativity using multimodal tasks and multidimensional approaches. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 24 healthy volunteers received 50 µg of LSD or inactive placebo. Near drug peak, a creativity task battery was applied, including pattern meaning task (PMT), alternate uses task (AUT), picture concept task (PCT), creative metaphors task (MET) and figural creativity task (FIG). Creativity was assessed by scoring creativity criteria (novelty, utility, surprise), calculating divergent thinking (fluency, originality, flexibility, elaboration) and convergent thinking, computing semantic distances (semantic spread, semantic steps) and searching for data-driven special features. RESULTS: LSD, compared to placebo, changed several creativity measurements pointing to three overall LSD-induced phenomena: (1) 'pattern break', reflected by increased novelty, surprise, originality and semantic distances; (2) decreased 'organization', reflected by decreased utility, convergent thinking and, marginally, elaboration; and (3) 'meaning', reflected by increased symbolic thinking and ambiguity in the data-driven results. CONCLUSION: LSD changed creativity across modalities and measurement approaches. Three phenomena of pattern break, disorganization and meaning seemed to fundamentally influence creative cognition and behaviour pointing to a shift of cognitive resources 'away from normal' and 'towards the new'. LSD-induced symbolic thinking might provide a tool to support treatment efficiency in psychedelic-assisted therapy.

Ayahuasca for the Treatment of Depression.

Ayahuasca, the vine of the souls in Quechua, is a psychedelic brew with a few formulations that most often include the bark of a liana in the Malpighiaceae family (Banisteriopsis caapi), with leaves from a shrub in the coffee family Rubiaceae (Psychotria viridis). Mixed with water and boiled for hours or days, it produces a brownish-colored liquid with a strong and characteristic taste. Ayahuasca contains the psychedelic tryptamine N,N-Dimethyltryptamine (DMT), and Monoamine Oxidase Inhibitors (MAOi), and in the past few years, it has been tested. In recent years its antidepressant properties have been put to the test. Evidence from open and randomized placebo-controlled clinical trials has shown encouraging results, indicating significant and rapid antidepressant effects, starting as early as 1 day after the ayahuasca intervention. In addition, we have explored the nature of these effects using multivariate measures. In this article, we will review the history, pharmacology, clinical trials, and clinical and behavioral markers associated with the antidepressant effects of ayahuasca.

Low-dose LSD and the stream of thought: Increased Discontinuity of Mind, Deep Thoughts and abstract flow.

RATIONALE: Stream of thought describes the nature of the mind when it is freely roaming, a mental state that is continuous and highly dynamic as in mind-wandering or free association. Classic serotonergic psychedelics are known to profoundly impact perception, cognition and language, yet their influence on the stream of thought remains largely unexplored. OBJECTIVE: To elucidate the effects of LSD on the stream of thought. METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 24 healthy participants received 50 µg lysergic acid diethylamide (LSD) or inactive placebo. Mind-wandering was measured by the Amsterdam Resting State Questionnaire (ARSQ), free association by the Forward Flow Task (FFT) for three seed word types (animals, objects, abstract words). ARSQ and FFT were assessed at +0 h, +2 h, +4 h, +6 h, +8 h and +24 h after drug administration, respectively. RESULTS: LSD, compared to placebo, induced different facets of mind-wandering we conceptualized as "chaos" (Discontinuity of Mind, decreased Sleepiness, Planning, Thoughts under Control, Thoughts about Work and Thoughts about Past), "meaning" (Deep Thoughts, Not Sharing Thoughts) and "sensation" (Thoughts about Odours, Thoughts about Sounds). LSD increased the FFT for abstract words reflecting an "abstract flow" under free association. Overall, chaos was strongest pronounced (+2 h to +6 h), followed by meaning (+2 h to +4 h), sensation (+2 h) and abstract flow (+4 h). CONCLUSIONS: LSD affects the stream of thought within several levels (active, passive), facets (chaos, meaning, sensation, abstractness) and time points (from +2 h to +6 h). Increased chaos, meaning and abstract flow at +4 h indicate the utility of a late therapeutic window in psycholytic therapy.

Potential biomarkers of major depression diagnosis and chronicity.

BACKGROUND: Molecular biomarkers are promising tools to be routinely used in clinical psychiatry. Among psychiatric diseases, major depression disorder (MDD) has gotten attention due to its growing prevalence and morbidity. METHODS: We tested some peripheral molecular parameters such as serum mature Brain-Derived Neurotrophic Factor (mBDNF), plasma C-Reactive Protein (CRP), serum cortisol (SC), and the salivary Cortisol Awakening Response (CAR), as well as the Pittsburgh sleep quality inventory (PSQI), as part of a multibiomarker panel for potential use in MDD diagnosis and evaluation of disease's chronicity using regression models, and ROC curve. RESULTS: For diagnosis model, two groups were analyzed: patients in the first episode of major depression (MD: n = 30) and a healthy control (CG: n = 32). None of those diagnosis models tested had greater power than Hamilton Depression Rating Scale-6. For MDD chronicity, a group of patients with treatment-resistant major depression (TRD: n = 28) was tested across the MD group. The best chronicity model (p < 0.05) that discriminated between MD and TRD included four parameters, namely PSQI, CAR, SC, and mBDNF (AUC ROC = 0.99), with 96% of sensitivity and 93% of specificity. CONCLUSION: These results indicate that changes in specific biomarkers (CAR, SC, mBDNF and PSQI) have potential on the evaluation of MDD chronicity, but not for its diagnosis. Therefore, these findings can contribute for further studies aiming the development of a stronger model to be commercially available and used in psychiatry clinical practice.

Pathophysiology of Major Depression by Clinical Stages.

The comprehension of the pathophysiology of the major depressive disorder (MDD) is essential to the strengthening of precision psychiatry. In order to determine the relationship between the pathophysiology of the MDD and its clinical progression, analyzed by severity of the depressive symptoms and sleep quality, we conducted a study assessing different peripheral molecular biomarkers, including the levels of plasma C-reactive protein (CRP), serum mature brain-derived neurotrophic factor (mBDNF), serum cortisol (SC), and salivary cortisol awakening response (CAR), of patients with MDD (n = 58) and a control group of healthy volunteers (n = 62). Patients with the first episode of MDD (n = 30) had significantly higher levels of CAR and SC than controls (n = 32) and similar levels of mBDNF of controls. Patients with treatment-resistant depression (TRD, n = 28) presented significantly lower levels of SC and CAR, and higher levels of mBDNF and CRP than controls (n = 30). An increased severity of depressive symptoms and worse sleep quality were correlated with levels low of SC and CAR, and with high levels of mBDNF. These results point out a strong relationship between the stages clinical of MDD and changes in a range of relevant biological markers. This can assist in the development of precision psychiatry and future research on the biological tests for depression.

Brief mindfulness-based training and mindfulness trait attenuate psychological stress in university students: a randomized controlled trial.

BACKGROUND: Psychological distress in University settings has grown and became a public health concern. In this context, contemplative practices such as mindfulness have been proposed as a strategy to help students on stress management. METHODS: Forty university students (20 female), aged between 18 to 30 years (mean = 24.15; SD = 3.56), with no previous experience with meditation or yoga were recruited at the Federal University of Rio Grande do Norte and randomized to a mindfulness training (MT) or active control (AC) groups. We analyzed measures of anxiety, affect, stress, as well as state and trait mindfulness in order to evaluate the effects of trait mindfulness and a brief mindfulness intervention in forty healthy young students. Participants were classified as Low (n = 27, females = 13) or High (n = 13, females = 7) Trait Mindfulness by k-means clustering and compared between them using Wilcoxon sum rank test. Furthermore, the sample was randomly allocated to an AC (n = 20, females = 10) or a MT (n = 20, females = 10) group, and mixed analysis of variance was performed to analyze the effect of interventions. The mechanisms and role of trait mindfulness in the intervention was assessed by a moderated mediation analysis. RESULTS: We found that High Trait individuals have lower anxiety trait, anxiety state and perceived stress levels. Only the MT group reduced their anxiety state and perceived stress after the intervention and increased their state mindfulness. Both groups reduced negative affect and cortisol, and no change was found in positive affect. Moderated mediation analysis showed that the training-induced change in state mindfulness mediated the increase in positive affect and the decrease in perceived stress and cortisol, regardless of trait mindfulness. For anxiety state the decrease only occurred in individuals with High Trait Mindfulness. CONCLUSIONS: Together, these results suggest that higher trait mindfulness is associated with low levels of psychological distress and that a brief mindfulness-based intervention seems to be useful to reduce distress measures in university students. TRIAL REGISTRATION: ReBEC, U1111-1194-8661. Registered 28 March 2017-Retrospectively registered, http://www.ensaiosclinicos.gov.br/rg/RBR-7b8yh8.

The Dream of God: How Do Religion and Science See Lucid Dreaming and Other Conscious States During Sleep?

Lucid dreaming (LD) began to be scientifically studied in the last century, but various religions have highlighted the importance of LD in their doctrines for a much longer period. Hindus' manuscripts dating back over 2,000 years ago, for example, divide consciousness in waking, dreaming (including LD), and deep sleep. In the Buddhist tradition, Tibetan monks have been practicing the "Dream Yoga," a meditation technique that instructs dreamers to recognize the dream, overcome all fears when lucid, and control the oneiric content. In the Islamic sacred scriptures, LD is regarded as a mental state of great value, and a special way for the initiated to reach mystical experiences. The Christian theologian Augustine of Hippo (354-430 AD) mentions LD as a kind of preview of the afterlife, when the soul separates from the body. In the nineteenth century, some branches of the Spiritism religion argue that LD precedes out-of-body experiences during sleep. Here we reviewed how these religions interpret dreams, LD and other conscious states during sleep. We observed that while Abrahamic monotheisms (Judaism, Christianity, and Islam) recognize dreams as a way to communicate with God to understand the present and predict the future, the traditional Indian religions (Buddhism and Hinduism) are more engaged in cultivating self-awareness, thus developed specific techniques to induce LD and witnessing sleep. Teachings from religious traditions around the world offer important insights for scientific researchers today who want to understand the full range of LD phenomenology as it has emerged through history.

Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca.

BACKGROUND: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients (n = 28) and healthy controls (n = 45). AIMS: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale. RESULTS: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed (rho = -0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed. CONCLUSIONS: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.

Effects of Yoga Respiratory Practice (Bhastrika pranayama) on Anxiety, Affect, and Brain Functional Connectivity and Activity: A Randomized Controlled Trial.

Pranayama refers to a set of yoga breathing exercises. Recent evidence suggests that the practice of pranayama has positive effects on measures of clinical stress and anxiety. This study explored the impact of a Bhastrika pranayama training program on emotion processing, anxiety, and affect. We used a randomized controlled trial design with thirty healthy young adults assessed at baseline and after 4 weeks of pranayama practices. Two functional magnetic resonance imaging (MRI) protocols were used both at baseline and post-intervention: an emotion task as well as a resting-state acquisition. Our results suggest that pranayama significantly decreased states of anxiety and negative affect. The practice of pranayama also modulated the activity of brain regions involved in emotional processing, particularly the amygdala, anterior cingulate, anterior insula, and prefrontal cortex. Resting-state functional MRI (fMRI) showed significantly reduced functional connectivity involving the anterior insula and lateral portions of the prefrontal cortex. Correlation analysis revealed that changes in connectivity between the ventrolateral prefrontal cortex and the right anterior insula were associated with changes in anxiety. Although it should be noted that these analyses were preliminary and exploratory, it provides the first evidence that 4 weeks of B. pranayama significantly reduce the levels of anxiety and negative affect, and that these changes are associated with the modulation of activity and connectivity in brain areas involved in emotion processing, attention, and awareness. The study was registered at https://www.ensaiosclinicos.gov.br/rg/RBR-2gv5c2/(RBR-2gv5c2).

Changes in Cortisol but Not in Brain-Derived Neurotrophic Factor Modulate the Association Between Sleep Disturbances and Major Depression.

Sleep disturbance is a symptom consistently found in major depression and is associated with a longer course of illness, reduced response to treatment, increased risk of relapse and recurrence. Chronic insomnia has been associated with changes in cortisol and serum brain-derived neurotrophic factor (BDNF) levels, which in turn are also changed in major depression. Here, we evaluated the relationship between sleep quality, salivary cortisol awakening response (CAR), and serum BDNF levels in patients with sleep disturbance and treatment-resistant major depression (n = 18), and in a control group of healthy subjects with good (n = 21) and poor (n = 18) sleep quality. We observed that the patients had the lowest CAR and sleep duration of all three groups and a higher latency to sleep than the healthy volunteers with a good sleep profile. Besides, low CAR was correlated with more severe depressive symptoms and worse sleep quality. There was no difference in serum BDNF levels between groups with distinct sleep quality. Taken together, our results showed a relationship between changes in CAR and in sleep quality in patients with treatment-resistant depression, which were correlated with the severity of disease, suggesting that cortisol could be a physiological link between sleep disturbance and major depression.

Acute effects of ayahuasca in a juvenile non-human primate model of depression

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.