Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression a SPECT study
This open-label study (n=17) found that a single dose of ayahuasca (100-200ml) had significant antidepressant effects up to 21 days later (MADRS-scale and others).
Authors
- Jordi Riba
- Jamie Hallak
- Rafael dos Santos
Published
Abstract
Ayahuasca is an Amazonian botanical hallucinogenic brew which contains dimethyltryptamine, a 5-HT2A receptor agonist, and harmine, a monoamine-oxidase A inhibitor. Our group recently reported that ayahuasca administration was associated with fast-acting antidepressive effects in 6 depressive patients. The objective of the present work was to assess the antidepressive potentials of ayahuasca in a bigger sample and to investigate its effects on regional cerebral blood flow. In an open-label trial conducted in an inpatient psychiatric unit, 17 patients with recurrent depression received an oral dose of ayahuasca (2.2 mL/kg) and were evaluated with the Hamilton Rating Scale for Depression, the Montgomery-Åsberg Depression Rating Scale, the Brief Psychiatric Rating Scale, the Young Mania Rating Scale, and the Clinician Administered Dissociative States Scale during acute ayahuasca effects and 1, 7, 14, and 21 days after drug intake. Blood perfusion was assessed eight hours after drug administration by means of single photon emission tomography. Ayahuasca administration was associated with increased psychoactivity (Clinician Administered Dissociative States Scale) and significant score decreases in depression-related scales (Hamilton Rating Scale for Depression, Montgomery-Åsberg Depression Rating Scale, Brief Psychiatric Rating Scale) from 80 minutes to day 21. Increased blood perfusion in the left nucleus accumbens, right insula and left subgenual area, brain regions implicated in the regulation of mood and emotions, were observed after ayahuasca intake. Ayahuasca was well tolerated. Vomiting was the only adverse effect recorded, being reported by 47% of the volunteers. Our results suggest that ayahuasca may have fast-acting and sustained antidepressive properties. These results should be replicated in randomized, double-blind, placebo-controlled trials.
Research Summary of 'Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression a SPECT study'
βBlossom's Take
Introduction
Ayahuasca is an Amazonian botanical brew combining Banisteriopsis caapi, which provides reversible monoamine oxidase A (MAO-A) inhibitors (β-carbolines such as harmine), and Psychotria viridis, a source of N,N-dimethyltryptamine (DMT), a 5-HT1A/2A/2C receptor agonist. Because DMT is normally metabolised by MAO-A in the gut and liver, co‑administration with β-carbolines allows DMT to reach the systemic circulation and the brain. Earlier preclinical, observational and experimental studies in healthy volunteers suggested potential antidepressant effects of ayahuasca, and the authors previously reported rapid and lasting antidepressant effects in six patients with recurrent major depressive disorder (MDD).
Methods
This was an open‑label inpatient study of 17 patients with recurrent MDD (14 women; mean age 42.7 years, SD 12.11) who had an inadequate response to their current antidepressant and were undergoing a medication change. Three patients had a mild current episode, 13 had a moderate episode and one had a severe episode. After a 2‑week washout, volunteers underwent medical screening including clinical examination, laboratory tests, electrocardiogram and a diagnostic interview using the Structured Clinical Interview for DSM‑IV (SCID‑IV). Exclusion criteria included bipolar or psychotic disorder, active psychotic symptoms, pregnancy and a history of antidepressant- or substance‑induced mania/hypomania. All participants gave written informed consent and the protocol was approved by a local ethics committee.
Results
Seventeen patients received a single oral dose of ayahuasca at 2.2 mL/kg (individual doses 120–200 mL), from a sample containing 0.8 mg/mL DMT and 0.21 mg/mL harmine; individual alkaloid doses therefore ranged approximately 96–160 mg DMT and 25–42 mg harmine. Psychiatric measures were taken at baseline (10 minutes before dosing), at 40, 80, 140 and 180 minutes after dosing, and at days 1, 7, 14 and 21 for the HAM‑D, MADRS and BPRS. Baseline mean HAM‑D was 19.24 (SD 5.52) and MADRS 25.6 (SD 7.6), consistent with moderate depression. After ayahuasca administration, significant reductions in HAM‑D and MADRS scores were observed from 80 to 180 minutes (P < 0.01) and sustained from day 1 through day 21 (P = 0.000). By day 21 mean HAM‑D had fallen to 7.56 (SD 4.7), a mild level of depression. Dissociative-type psychoactivity measured with the CADSS increased at 40–80 minutes (P < 0.01), consistent with the time of peak subjective effects; no significant changes were noted on the Young Mania Rating Scale (YMRS). On the BPRS, the Anxious‑Depression subscale decreased from 40 to 180 minutes (P < 0.01) and from day 1 to day 21 (P = 0.000). Improvements were also reported on Thinking Disorder and Withdrawal‑Retardation BPRS subscales (Thinking Disorder: 180 minutes, P < 0.05, and at day 1, day 14 and day 21; the extracted text is incomplete for the exact statistics of some later time points).
Discussion
Sanches and colleagues interpret their findings as indicating rapid and sustained antidepressant effects after a single ayahuasca dose in patients with recurrent MDD, with similar patterns across patients regardless of baseline episode severity. The authors link clinical improvement to increased regional cerebral blood flow measured by SPECT eight hours after dosing: significant perfusion increases were observed in the left nucleus accumbens (peak intensity 7.179; voxels 45; MNI -8, 6, -10), right insula (peak 4.695; voxels 43; MNI 32, 24, -10) and left subgenual area (peak 4.523; voxels 30; MNI -10, 32, -8), regions implicated in mood and emotion regulation. Mechanistically, the investigators propose that DMT’s agonism at 5‑HT1A/2A/2C receptors may contribute to anxiolytic and antidepressant effects, and they note potential modulation of the default mode network and rumination as a complementary pathway. The discussion contrasts these SPECT/PET findings with some fMRI reports that show decreases in blood flow, suggesting that differences in timescale and tracer half‑life between modalities may explain discrepancies. In terms of safety, ayahuasca was generally well tolerated in this controlled setting: blood pressure and heart rate showed non‑significant increases and vomiting was the only recorded adverse effect (reported by 47%); no dysphoric or manic symptoms were observed. The authors acknowledge several important limitations: the study was open‑label, non‑randomised and lacked a placebo or active comparator, preventing causal attribution; the controlled inpatient environment differs from ritual contexts in which ayahuasca is typically consumed and this may limit generalisability; and patients with bipolar disorder were excluded, with the authors noting case reports of manic episodes after ayahuasca and advising caution in that population. They conclude that randomized, double‑blind, placebo‑controlled trials are necessary, and recommend investigating the role of ceremonial or ritual context in therapeutic outcomes.
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RESULTS
After verification of data distribution, descriptive statistics and repeated-measures analysis of variance (ANOVA) were used for statistical analysis. When a significant effect was observed, pairwise comparisons were performed by means of Student t tests. Significance was set at P < 0.05.
CONCLUSION
Administration of ayahuasca was associated with rapid and sustained antidepressive effects. Results were similar across volunteers, regardless of the severity of the current depressive episode. Ayahuasca administration was also associated with increased blood perfusion in the nucleus accumbens, insula, and subgenual area, brain regions involved in the regulation of mood and emotional states. Significant score decreases in HAM-D, MADRS, and Anxious-Depression BPRS subscale scores were observed during acute drug effects and from D1 to D21 and were related to depressed mood, sadness, anxiety, feelings of guilt, suicidal ideation, difficulties at work/activities, pessimistic thinking, and difficulty concentrating. Improvements in emotional withdrawal and blunted affect were (Thinking Disorder and Withdrawal-Retardation BPRS subscales) were also observed. Ayahuasca induced significant score increases in the CADSS scale at 40 to 80 minutes, suggesting increased psychoactivity in the same time point previously associated with peak ayahuasca psychoactive effects and DMT plasma levels.No significant changes in YMRS and Activation BPRS subscale scores were observed after ayahuasca intake, suggesting an absence of maniac-like effects. However, it is important to note that in our study a diagnosis of bipolar disorder and a previous history of mania or hypomania induced by antidepressant or substance use were considered exclusion criteria. Ayahuasca may be contraindicated for bipolar disorders patients, since a recent case report described a man with bipolar disorder that developed a manic episode after ayahuasca consumption.Increased blood perfusion in the subgenual area, nucleus accumbens, and insula were observed after ayahuasca intake. Hypoactivation of these brain regions is usually associated with depression, while increased activation is usually associated with antidepressive effects.Interestingly, ayahuasca increased blood perfusion in the anterior insula of healthy volunteers, but no significant changes were observed in the subgenual area or nucleus accumbens.These data suggest that our results may be specific to depressive patients. The potential antidepressant effects of ayahuasca appear to be mediated by the agonist action of DMT on 5-HT 1A/2A/2C receptors, since agonists of these receptors produce anxiolytic and antidepressive effects.Indeed, administration of DMT and other 5-HT 1A/2A/2C receptor agonists such as psilocybin and LSD is associated with increases in positive mood in healthy volunteersand in patients suffering life-threatening diseases.Functional alterations in the default mode network (DMN), a group of brain regions associated with self-perception, could also mediate the observed effects. Rumination, a core depressive symptom, is associated with increased DMN activity, and ayahuascaand psilocybin 26 may reduce this activity.Theoretically, by changing one's self-perception, hallucinogens may reduce excessive attention to repetitive and pathological thoughts.Interestingly, decreases in brain blood flow observed in functional magnetic resonance imaging (fMRI) studiesare inconsistent with our results and previous SPECT/positron emission tomography (PET) studies.These discrepancies may be related to different timescales involved in fMRI and SPECT/PET studies, which use radiotracers with long half-lives. Thus, phasic or short-term decreases in blood flow measured with fMRI may show some rebound effects and longer-term changes that are detected by SPECT/PET.Ayahuasca was well tolerated. No significant cardiovascular effects were observed after ayahuasca intake, and vomiting was the only adverse effect recorded. However, patients did not consider vomiting as causing severe discomfort. Moreover, ayahuasca psychoactive effects were considered mild and short-lived, and no dysphoric effects were reported. Indeed, volunteers were calm and relaxed under the effects of ayahuasca, considering it as a pleasant experience. Although described results are promising, because treatment was not randomized or double-blind, and there was no placebo or other comparator group, we cannot conclude that the observed changes were in fact caused by ayahuasca. Moreover, it is important to note that the controlled clinical setting in which the experiments took place is different from the typical ritual context of ayahuasca consumption, which may impact the generalizability of our findings.Our results should be replicated in randomized, double-blind, placebo-controlled trials, and future research should investigate whether or how a ceremonial/ritual context may impact therapeutic outcomes.
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Study Details
- Study Typeindividual
- Populationhumans
- Characteristicsopen labelfollow up
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