Psychological Medicine
June 15, 2018
Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias et al.
827 citations
A single dose of ayahuasca reduced depression severity more than placebo in patients with treatment-resistant depression. Over seven days, depression scores on the Montgomery-Åsberg Depression Rating Scale were significantly lower in the ayahuasca group at days 1 and 2, and even more so at day 7. Response rates at day 7 were 64% for ayahuasca versus 27% for placebo, and remission rates showed a trend toward significance (36% vs. 7%). Effect sizes grew from day 1 to day 7, indicating sustained improvement. This is the first controlled trial to test a psychedelic substance in treatment-resistant depression, supporting ayahuasca's safety and therapeutic value when used in an appropriate setting.
PLoS ONE
February 18, 2015
Fernanda Palhano-Fontes, Kátia C. Andrade, Luís Fernando Tófoli et al.
461 citations
Ayahuasca, a psychedelic brew used traditionally by Amazonian Amerindians, significantly reduces activity in key hubs of the Default Mode Network (DMN), specifically the Posterior Cingulate Cortex (PCC)/Precuneus and medial Prefrontal Cortex (mPFC), as measured by fMRI in ten experienced subjects. Functional connectivity within the PCC/Precuneus also decreased after intake, while the orthogonality between the DMN and task-positive network showed no significant change. These findings suggest that the altered state of consciousness induced by Ayahuasca, similar to effects from psilocybin, meditation, and sleep, involves modulation of DMN activity and connectivity.
European Neuropsychopharmacology
January 16, 2015
José Carlos Bouso, Fernanda Palhano-Fontes, Antoni Rodrı́guez-fornells et al.
221 citations
Regular use of the psychedelic brew ayahuasca is associated with thinning of the posterior cingulate cortex (PCC), a key hub of the default mode network. In a comparison of 22 regular ayahuasca users and 22 matched controls, MRI scans revealed significant cortical thinning in midline brain structures among users. The degree of thinning correlated with both the intensity and duration of ayahuasca use and with scores on self-transcendence, a personality trait linked to spirituality and transpersonal feelings. While direct causation cannot be established, the findings suggest that sustained psychedelic use may induce structural brain changes underlying attentional processes, self-referential thought, and previously reported personality shifts in long-term users.
Frontiers in Psychology
June 4, 2019
Raíssa Nóbrega de Almeida, Ana Cecília de Menezes Galvão, Flávia Santos Da Silva et al.
173 citations
A single dose of ayahuasca increased serum brain-derived neurotrophic factor (BDNF) levels in both healthy controls and patients with treatment-resistant depression 48 hours after ingestion, compared with placebo. Baseline BDNF levels did not predict major depression or clinical characteristics, but lower BDNF was linked to hypocortisolemia. Among patients, only those who received ayahuasca showed a negative correlation between BDNF levels and depressive symptoms at 48 hours. The findings suggest a potential link between ayahuasca's antidepressant effects and changes in BDNF, supporting further investigation into psychedelics for depression.
Scientific Reports
August 1, 2017
Aline Viol, Fernanda Palhano-Fontes, Heloisa Onias et al.
154 citations
The entropic brain hypothesis suggests that psychedelic experiences arise from increased randomness in the brain's functional connectivity. Analyzing resting-state fMRI data from human subjects before and after ingesting ayahuasca, a psychedelic beverage used in Amazonian religious and scientific contexts, researchers found that the Shannon entropy of the brain's degree distribution increased, indicating greater disorder in network connections. Local integration within brain networks increased while global integration decreased. These findings align with the entropic brain hypothesis and relate to users' reports of 'mind-expansion.'
Journal of Psychopharmacology
July 10, 2020
Nicole Leite Galvão‐coelho, Ana Cecília de Menezes Galvão, Raíssa Nóbrega de Almeida et al.
124 citations
In a double-blind placebo-controlled trial, people with treatment-resistant depression had higher baseline levels of C-reactive protein than healthy controls, and a negative correlation between C-reactive protein and cortisol was observed. Ayahuasca, but not placebo, reduced C-reactive protein levels in both patients and healthy controls 48 hours after ingestion. Among patients treated with ayahuasca, larger reductions in C-reactive protein correlated with lower depressive symptoms. No significant changes were found for interleukin 6 or brain-derived neurotrophic factor, and these biomarkers did not predict antidepressant response or remission. The findings clarify biological mechanisms underlying ayahuasca's antidepressant effects.
Frontiers in Psychiatry
May 8, 2018
Ana Cecília de Menezes Galvão, Raíssa Nóbrega de Almeida, Erick Allan Dos Santos Silva et al.
102 citations
In treatment-resistant depression, a single dose of ayahuasca normalizes the blunted awakening salivary cortisol response observed in patients, bringing it to levels similar to those in healthy controls. During the dosing session, both patients and healthy volunteers who received ayahuasca showed higher increases in salivary cortisol than those who received placebo. No significant changes in plasma cortisol were detected 48 hours after dosing. These findings suggest that ayahuasca modulates salivary cortisol, a hormone involved in depression's etiology, and support further investigation into its antidepressant potential.
Frontiers in Pharmacology
November 19, 2019
Richard J. Zeifman, Fernanda Palhano-Fontes, Jaime E. C. Hallak et al.
79 citations
A single dose of ayahuasca, compared with placebo, was associated with medium-to-large reductions in suicidality among 29 adults with treatment-resistant depression. Suicidality was assessed by a psychiatrist before the intervention and at one, two, and seven days afterward. The between-group effect sizes (ayahuasca versus placebo) were medium at each time point (Cohen's d = 0.58, 0.56, and 0.67), and the within-group effect sizes for those receiving ayahuasca were large (Cohen's d = 1.33, 1.42, and 1.19). The group-by-time interaction was not statistically significant, suggesting the findings should be interpreted cautiously. The authors conclude that ayahuasca may hold potential as an intervention for suicidality, while noting important limitations and the need for further research.
Psychological medicine
March 1, 2023
Isabel Wießner, Marcelo Falchi, Fernanda Palhano-Fontes et al.
53 citations
In a randomized, double-blind, placebo-controlled, crossover study, 24 healthy volunteers received 50 μg LSD or placebo. LSD produced psychedelic experiences, including altered consciousness, mystical experiences, ego-dissolution, and mildly challenging experiences, and increased aberrant salience and suggestibility, but not mindfulness. LSD-induced aberrant salience correlated strongly with complex imagery, mystical experiences, and ego-dissolution. Suggestibility changes from LSD did not correlate with other effects. The results suggest the LSD state resembles psychosis and may offer a therapeutic tool, with mystical experiences linking the psychosis model and therapeutic potential. Meaning attribution appears important for the LSD psychosis model, and psychedelic-assisted therapy might benefit from suggestions that foster mystical experiences.
Journal of Psychopharmacology
February 1, 2022
Isabel Wießner, Marcelo Falchi-Carvalho, Lucas Oliveira Maia et al.
43 citations
A randomized, double-blind, placebo-controlled crossover study gave 24 healthy volunteers 50 micrograms of LSD or an inactive placebo and tested creativity near the drug's peak using multiple tasks. LSD changed creativity in three ways: it increased novelty, surprise, originality, and semantic distances (pattern break); decreased utility, convergent thinking, and marginally elaboration (disorganization); and increased symbolic thinking and ambiguity (meaning). The findings suggest LSD shifts cognitive resources away from normal patterns toward new ones, and that LSD-induced symbolic thinking might aid psychedelic-assisted therapy.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
May 1, 2022
Isabel Wießner, Rodolfo Olivieri, Marcelo Falchi et al.
42 citations
A low dose of LSD (50 μg) produces both beneficial and detrimental cognitive effects 24 hours after administration. Compared to placebo, LSD sub-acutely improved visuospatial memory and phonological verbal fluency but impaired cognitive flexibility, as measured by fewer categories achieved and more perseveration on the Wisconsin Card Sorting Test. The findings suggest that LSD-assisted therapy might be explored for conditions involving memory and language decline, such as brain injury, stroke, or dementia, while also indicating a mixed 'afterglow and hangover' profile.
Entropy
January 30, 2019
Aline Viol, Fernanda Palhano-Fontes, Heloisa Onias et al.
37 citations
A new network metric, geodesic entropy, measures the Shannon entropy of distances from one node to all others in a network, characterizing how much influence a node has based on the overall network structure. Applied to resting-state functional brain networks of humans, the metric differentiates ordinary consciousness from the altered state induced by Ayahuasca ingestion. On average, functional networks from subjects in the altered state show larger geodesic entropy than those in the ordinary state, suggesting the metric can reveal differences in brain network organization across states of consciousness.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
May 1, 2025
Marcelo Falchi-Carvalho, Fernanda Palhano-Fontes, Isabel Wießner et al.
35 citations
Vaporized DMT, a short-acting psychedelic, rapidly reduced depression symptoms in patients with treatment-resistant depression. In an open-label trial, 14 patients received inhaled DMT at 15 mg and then 60 mg. The treatment was safe and well-tolerated, with no serious adverse events. By day 7, depression scores on the Montgomery-Asberg Depression Rating Scale dropped by an average of 21.14 points. The response rate was 85.71%, and the remission rate was 57.14%, with effects lasting up to 3 months. Suicidal ideation also decreased significantly, with no severe ideation the day after dosing. Vaporized DMT offers a non-invasive, time-efficient alternative to longer-acting psychedelics and traditional antidepressants.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
March 1, 2024
Marcelo Falchi-Carvalho, Isabel Wießner, Sérgio Ruschi B Silva et al.
25 citations
Inhaled N,N-Dimethyltryptamine (DMT) produces dose-dependent increases in the intensity, positive valence, and perceptual effects of subjective experiences, with only mild, transient, and self-limited increases in blood pressure and heart rate. No changes in safety blood biomarkers or serious adverse events occurred. The acute effects last around 10 minutes, offering a potentially cost- and time-effective alternative to longer-acting oral psychedelics for clinical use in mood disorders. This open-label, single-ascending, fixed-order, dose-response study in 27 healthy volunteers tested five dose pairs (5/20 mg through 15/60 mg) of inhaled DMT (BMND01 candidate).
Current topics in behavioral neurosciences
January 1, 2022
Fernanda Palhano-Fontes, Bruno Lobão Soares, Nicole Leite Galvão-Coelho et al.
25 citations
Ayahuasca, a psychedelic brew containing DMT and MAOIs, shows rapid antidepressant effects in clinical trials. Evidence from open and placebo-controlled studies indicates significant improvement starting as early as one day after administration. This article reviews the history, pharmacology, clinical trials, and behavioral markers of ayahuasca's antidepressant properties.
medRxiv
September 29, 2019
Lorenzo Pasquini, Fernanda Palhano-Fontes, Draulio B. Araujo
24 citations
preprint
One day after a single session with the psychedelic ayahuasca, connectivity within and between brain networks that support interoception, emotion, and self-related thought is altered compared to placebo. In a randomized trial with 22 participants receiving ayahuasca and 21 receiving placebo, the ayahuasca group showed increased connectivity within the salience network, decreased connectivity within the default mode network, and increased connectivity between these two networks. Primary sensory networks were not affected. These connectivity changes correlated with acute subjective effects such as altered body awareness, volition, and affect. The findings suggest that ayahuasca induces subacute functional reorganization of higher-order cognitive brain networks.
Psychopharmacology
June 1, 2022
Isabel Wießner, Marcelo Falchi, Fernanda Palhano-Fontes et al.
22 citations
LSD alters the stream of thought in multiple ways, increasing chaos, meaning, and abstractness at different times after ingestion. In a randomized, double-blind, placebo-controlled crossover study with 24 healthy participants, 50 μg LSD compared to placebo induced facets of mind-wandering labeled 'chaos' (discontinuity of mind, decreased sleepiness and planning), 'meaning' (deep thoughts), and 'sensation' (thoughts about odors and sounds). LSD also increased free association for abstract words, reflecting an 'abstract flow.' Chaos was strongest from 2 to 6 hours after dosing, meaning from 2 to 4 hours, sensation at 2 hours, and abstract flow at 4 hours. The findings suggest a late therapeutic window around 4 hours for psycholytic therapy.
bioRxiv (Cold Spring Harbor Laboratory)
January 27, 2017
Fernanda Palhano-Fontes, Dayanna Barreto, Heloisa Onias et al.
22 citations
preprint
A single dose of ayahuasca produced significant antidepressant effects in patients with treatment-resistant depression compared to placebo. Depression severity, measured by the Montgomery–Åsberg Depression Rating Scale (MADRS), was significantly lower in the ayahuasca group at one, two, and seven days after dosing. Effect sizes increased over time, reaching a Cohen's d of 1.49 at day seven. Response rates were significantly higher in the ayahuasca group at day seven (64% vs. 27%), and remission rates were marginally significant (36% vs. 7%). This controlled trial supports the safety and therapeutic value of ayahuasca in treating depression.
Psychedelic medicine (New Rochelle, N.Y.)
March 1, 2025
Marcelo Falchi-Carvalho, Handersson Barros, Raynara Bolcont et al.
16 citations
Vaporized N,N-dimethyltryptamine (DMT) produced rapid and sustained antidepressant effects in a small open-label trial of six people with treatment-resistant depression. Depression severity, measured by the Montgomery-Asberg depression rating scale (MADRS) and Patient Health Questionnaire-9 (PHQ-9), decreased significantly from the first day through one month after dosing. The average MADRS score dropped by 22 points at day 7 and 17 points at one month. By day 7, 83.33% of patients responded to treatment and 66.67% achieved remission; at one month, 66.67% maintained response and 50% maintained remission. The short-acting, noninvasive vaporized route may improve accessibility to psychedelic treatments.
Frontiers in Psychiatry
December 5, 2022
Geovan Menezes de Sousa, Vagner Deuel de Oliveira Tavares, Ana Cecília de Menezes Galvão et al.
14 citations
In a double-blind, placebo-controlled trial with 72 participants, ayahuasca's effects on depression-related biomarkers were examined two days after dosing. Larger reductions in depressive symptoms during the session were linked to higher serum cortisol levels in patients with treatment-resistant depression. Smaller changes in salivary cortisol during ayahuasca use were associated with higher brain-derived neurotrophic factor (BDNF) levels in patients who showed greater clinical improvement in depressive symptoms. No moderating effects were found for the cortisol awakening response, interleukin-6, or C-reactive protein in patients, nor for any biomarker in healthy controls or the placebo group. The findings suggest that acute emotional and physiological responses during ayahuasca sessions may influence key biomarkers of depression.
Frontiers in behavioral neuroscience
January 1, 2022
Maria Lara Porpino de Meiroz Grilo, Geovan Menezes de Sousa, Lilían Andrade Carlos de Mendonça et al.
12 citations
Repeated ayahuasca administration before and during social isolation prevented depressive-like behaviors and cortisol alterations in common marmosets. Animals given ayahuasca showed higher cortisol reactivity and fecal cortisol levels similar to family-group controls, no signs of anhedonia, and no increase in chronic stress-related behaviors, unlike isolated animals that received no intervention. The findings suggest ayahuasca promotes resilient responses and may have a prophylactic action against depression.
January 1, 2021
Fernanda Palhano-Fontes, Sérgio Mota‐rolim, Bruno Lobão‐soares et al.
11 citations
Ayahuasca shows promise as a potent alternative medicine for treating depression and anxiety. In a study involving 100 participants, 70% reported significant mood improvements after just one session, outperforming traditional antidepressants. Biochemical analysis revealed that ayahuasca influences neurotransmitter receptors, potentially reshaping behavior and emotional well-being. Participants also noted reduced symptoms of anxiety, highlighting its potential in psychiatry. This suggests psychedelics could play a vital role in future drug studies, offering new avenues for mental health treatment beyond conventional methods.
Nature communications
August 13, 2025
William Wong, Rubén Herzog, Kátia Cristine Andrade et al.
10 citations
A new open database, the DREAM database, combines standardized sleep magneto/electroencephalography (M/EEG) recordings with dream reports from 505 participants across 20 datasets, totaling 2,643 awakenings. Each awakening includes at least 20 seconds of high-resolution sleep EEG (≥100 Hz, ≥2 electrodes) and a classification of the sleeper's reported experience. Analyses showed that reports of conscious experiences during sleep can be predicted from objective EEG features in both REM and NREM sleep. The database aims to overcome limitations of small sample sizes and methodological variability in dream research, enabling larger-scale investigations of the neurocognitive basis of dreaming.
Journal of psychiatric research
August 1, 2024
Eduardo Igor Torquato Cardoso Lopes, Patrícia Cavalcanti-Ribeiro, Fernanda Palhano-Fontes et al.
9 citations
Subcutaneous esketamine injections given weekly for eight weeks produced a rapid and lasting reduction in suicidality among 18 adults with treatment-resistant depression. Suicidal thoughts dropped within 24 hours after the first dose and remained low throughout the eight-week treatment period. At six months after treatment ended, suicidality was still consistently lower. Clinician ratings showed significant improvement only after two sessions, and 61% of patients achieved remission from suicidal ideation. The findings suggest that weekly subcutaneous esketamine may be a cost-effective way to achieve fast and sustained anti-suicide effects, but controlled studies are needed to confirm these initial observations.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
June 17, 2025
Isabel Wießner, Marcelo Falchi-Carvalho, Sophie Laborde et al.
7 citations
Inhaled vaporized DMT (60 mg) produces profound altered states of consciousness and is safe and well-tolerated in healthy adults. In a randomized, double-blind, placebo-controlled crossover trial with 25 participants, DMT significantly increased subjective intensity and most measures on the 5D-ASC, HRS, and MEQ questionnaires compared to an active placebo (0.6 mg DMT). Physiological parameters such as blood pressure and heart rate rose transiently within safe limits. Adverse events were predominantly mild and temporary. Biochemical changes were not clinically relevant. Physiological increases correlated with subjective experiences, suggesting a link between bodily responses and the psychedelic state.