This open-label study (n=6) found that a single dose of ayahuasca has fast-acting anxiolytic and antidepressant effects (up to 21 days later, MADRS) in patients with a current depressive episode.
“Objectives: Ayahuasca (AYA), a natural psychedelic brew prepared from Amazonian plants and rich in dimethyltryptamine (DMT) and harmine, causes effects of subjective well-being and may therefore have antidepressant actions. This study sought to evaluate the effects of a single dose of AYA in six volunteers with a current depressive episode.
Methods: Open-label trial conducted in an inpatient psychiatric unit.
Results: Statistically significant reductions of up to 82% in depressive scores were observed between baseline and 1, 7, and 21 days after AYA administration, as measured on the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). AYA administration resulted in nonsignificant changes in Young Mania Rating Scale (YMRS) scores and in the thinking disorder subscale of the BPRS, suggesting that AYA does not induce episodes of mania and/or hypomania in patients with mood disorders and that modifications in thought content, which could indicate psychedelic effects, are not essential for mood improvement.
Conclusions: These results suggest that AYA has fast-acting anxiolytic and antidepressant effects in patients with a depressive disorder.”
Authors: Flavia de L. Osorio, Rafael F. Sanches, Ligia R. Macedo, Rafael G. dos Santos, Joao P. Maia-de-Oliveira, Lauro Wichert-Ana, Draulio B. de Araujo, Jordi Riba, Jose A. Crippa & Jaime E. Hallak
Depression is a highly prevalent disorder that is associated with intense personal suffering, increased mortality, and high morbidity. New interventions, particularly those that have the potential for acute effect, would have a huge impact on the treatment of depression.
Ayahuasca (AYA), a botanical hallucinogen traditionally used by indigenous groups of the Northwest Amazon region for ritual and medicinal purposes, is a potential candidate for this new generation of antidepressant research.
AYA is a psychoactive drug produced by the combination of peripheral MAO-A inhibition by harmine and central 5-HT1A/2A/2C agonist action of DMT on frontal and paralimbic brain areas. Long-term AYA users report no mental health problems.
The agonist action of AYA alkaloids on serotonergic receptors and its inhibitory effects on MAO-A led to the hypothesis that AYA could be useful in the treatment of depression in humans.
Six volunteers with a diagnosis of recurrent MDD participated in the study. None of them were experiencing depressive episodes with psychotic symptoms.
Patients were recruited through local advertisements and referrals from private psychiatric clinics. They were not taking any psychopharmaceuticals at the time of recruitment.
None of the participants had ever used illicit drugs or AYA, and none had a history of pregnancy or clinical conditions.
AYA was tested on volunteers in accordance with the Declarations of Helsinki and Tokyo concerning human subject research. All volunteers gave their written informed consent to participate.
We obtained a standard sample of AYA from the Santo Daime community, which was stored at room temperature and then in a refrigerator until the day of the experimental session.
Each subject drank 120-200 mL of AYA (2.2 mL/kg body weight), which was extracted with 5 mL diethyl ether in a shaker (20 min), and centrifuged at 3,000 rpm for 15 min. The residue was dissolved in 1 mL methanol and analyzed by gas chromatography/mass spectrometry (GC/MS).
Medical interview and laboratory tests
A clinical examination, laboratory workup, and interview were performed on potential patients to determine whether they met the inclusion and exclusion criteria.
The Young Mania Rating Scale, Hamilton Rating Scale for Depression, Montgomery-A sberg Depression Rating Scale were used to assess depressive symptoms.
Assessment of tolerability
Blood pressure was measured before, 40, 80, 140, and 180 minutes after AYA administration. Adverse effects were not systematically assessed.
In an open-label trial, volunteers were admitted to an inpatient psychiatric unit for 2 weeks prior to AYA administration. The experimental session lasted on average 4 h and consisted of AYA intake followed by administration of the scales.
A psychiatrist completed the BPRS, YMRS, HAM-D and MADRS scales before, 40 minutes after, 80 minutes after, 140 minutes after, and 180 minutes after AYA administration.
The clinical and demographic characteristics of the study participants are presented in Table 1. The mean HAM-D score of the volunteers was 17.5667.73 at baseline, and decreased by 62% at D1, 72% at D7, and 45% at D21.
Regarding MADRS scores, a significant decrease was observed at +180, a more robust decrease was observed on D1, and a significant increase was observed on D14, although a subsequent significant decrease occurred on D21.
AYA administration produced nonsignificant increases in the scores of the BPRS scale for withdrawal-retardation, thinking disorder, and activation subscales, with effect peaking at 80 min.
At baseline, volunteers demonstrated higher scores on the Anxious-Depression BPRS subscale (BPRS-AD), but these scores were significantly reduced at +140 and remained so until D7.
Volunteers exhibited no significant changes in symptoms throughout the experiment, but experienced irritability and decreased capacity for insight and sleep.
All patients tolerated AYA well, and did not spontaneously report any other adverse effects. Blood pressure increased moderately and nonsignificantly, and vomiting was reported by 50% of the volunteers.
AYA has significant and quite impressive acute antidepressive effects, which were observed in both the HAM-D and MADRS scales on D1 and D7. These effects lasted for several days and were similar across volunteers, regardless of the prior level of depression.
Symptoms increased on D14, but decreased on D21. MADRS scores were significantly increased on D14.
The decreases and increases in depressive symptoms after AYA administration could reflect complex intracellular events that remain active after the acute effects of AYA have subsided.
Harmine, THH, and harmaline are potent natural inhibitors of the MAO enzyme, especially of the MAO-A subtype. They may also produce antidepressant effects.
AYA produced antidepressive and anxiolytic effects, and decreased panic-related signs after acute intake. However, AYA did not produce statistically significant sensory, cognitive, or affective modifications, and these effects were observed during a period ranging from 80 to 140 min after AYA administration.
AYA was well tolerated by all patients, and had mild and short-lived psychoactive effects. It produced moderate cardiovascular effects in human studies.
Early academic research on classical hallucinogens considered the powerful influences of set (psychological state) and setting (environment) on the effects of this class of substances. In the present study, volunteers were kept as comfortable as possible, and vomiting was the only adverse effect reported by 50% of volunteers.
Future studies should explore the possibility of reducing the emetic effect of AYA by premedicating with an antiemetic, or administering AYA in different formulations.
The present open-label study has several limitations, such as a small sample size, the absence of a systematic inquiry about side effects, and the lack of placebo and control groups.
Future studies involving AYA and depressed patients should also include a control group, and should use neuroimaging techniques to investigate possible mechanisms of action. The results of this study may prompt novel research into substances with faster therapeutic actions than currently available pharmacological resources.
This preliminary study suggests that AYA may represent a powerful new substance for the treatment of depressive and anxiety symptoms. However, further studies are needed to replicate these preliminary observations.
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Institutes associated with this publicationUniversity of São Paulo
The University of São Paulo has been conducting research with psychedelics for many years, with a focus on ayahuasca given its traditional use in Brazil.
The psychedelics given at which dose and how many timesAyahuasca 120 - 200
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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).