Revista Brasileira de Psiquiatria.

ß 2015 Associação Brasileira de Psiquiatria


Antidepressant effects of a single dose of ayahuasca in
patients with recurrent depression: a preliminary report
Flávia de L. Osório,1,2 Rafael F. Sanches,1,3 Ligia R. Macedo,1 Rafael G. dos Santos,1
João P. Maia-de-Oliveira,4 Lauro Wichert-Ana,1 Draulio B. de Araujo,5,6 Jordi Riba,3,7,8,9
José A. Crippa,1,2 Jaime E. Hallak1,2
Department of Neurosciences and Behavior, Ribeirão Preto Medical School, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.
National Science and Technology Institute for Translational Medicine (INCT-TM), Brazil. 3Centre d’Investigació de Medicaments, Servei de
Farmacologia Clı́nica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. 4Department of Clinical Medicine, Universidade Federal do Rio
Grande do Norte (UFRN), Natal, RN, Brazil. 5Hospital Universitário Onofre Lopes, UFRN, Natal, RN, Brazil. 6Brain Institute, UFRN, Natal, RN,
Brazil. 7Human Experimental Neuropsychopharmacology, Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Department of Pharmacology and Treatment, Universitat Autònoma de Barcelona, Spain. 9Centro de Investigación Biomédica en Red de
Salud Mental, CIBERSAM, Barcelona, Spain.

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.
Keywords: Psychedelic agents; dimethyltryptamine; harmine; monoamine oxidase inhibitors;
therapeutic use

Introduction low response rates, as well as adverse effects and
latency to onset of therapeutic action.3 Thus, new
Depression is a highly prevalent disorder and is associated interventions, particularly those that with the potential
with intense personal suffering, increased mortality, and for acute effect, would have a huge impact on the
high morbidity.1,2 Although its etiology is unknown, some treatment of depression. The N-methyl-D-aspartate
theories suggest that biological factors may be implicated.3 (NMDA) receptor antagonist ketamine, for example, has
One such theory is the monoamine hypothesis, which rapid and potent antidepressant effects in treatment-
suggests that an imbalance in cerebral monoamines such resistant major depressive disorder (MDD) and bipolar
as dopamine, norepinephrine, and, especially, serotonin is depression, and its use is considered one of the most
responsible for depressive symptomatology.3 The mono- exciting areas in contemporary psychiatric research.4,5
amine hypothesis is the theory on which the leading Ayahuasca (AYA), a botanical hallucinogen tradition-
commercially available antidepressants are based.3 ally used by indigenous groups of the Northwest Amazon
Currently available treatments have limitations that can region for ritual and medicinal purposes,6,7 is a potential
lead to low therapeutic effectiveness, especially related to candidate for this new generation of antidepressant
research focusing on new pharmacological treatments
that produce immediate and more pronounced effects.
Correspondence: Jaime E. C. Hallak, Departamento de Neurociências AYA is prepared by prolonged decoction of the bark of the
e Ciências do Comportamento, Faculdade de Medicina de Ribeirão vine Banisteriopsis caapi with the leaves of the shrub
Preto, Universidade de São Paulo, Hospital das Clı́nicas, 36 andar,
Av. Bandeirantes, 3900, Ribeirão Preto, SP, Brazil.
Psychotria viridis.6,7 B. caapi contains the b-carboline
E-mail: alkaloids harmine, tetrahydroharmine (THH), and harma-
Submitted Jun 20 2014, accepted Aug 08 2014. line, which act as monoamine oxidase A inhibitors

None of 2000 ion trap mass spectrometer (Varian Inc. the general psycholo- chological. preliminary. The residue 44.e. Rev Bras Psiquiatr. 2015. a laboratory workup AYA. bilirubin.25 mm i. while P. given gave their written informed consent to participate. The volunteers received detailed does not present evidence of psychological. and potassium.55 years) with a diagnosis of recurrent MDD was dissolved in 1 mL methanol and 1 mL of the resulting participated in the study. most with a limited number of participants. and no produce an acute antidepressant effect. Universidade de São Paulo.13-15 Nevertheless.d.). in splitless mode and oven temperature program 806C for Volunteers were not taking any psychopharmaceuticals 1 min. they were patients that did not and then to 3006C for 5 min. A capillary the volunteers were experiencing depressive episodes column (DB-5MS. and centrifuged at 3. ramped at 56C/min to 2206C and held for 10 min. two volunteers solution was analyzed by gas chromatography/mass were experiencing a current mild depressive episode. and one CP3800 gas chromatograph coupled to a Varian Saturn was experiencing a severe depressive episode. performed using a Varian three were experiencing a moderate episode. a previous history of mania or hypomania induced by and an electrocardiogram were performed.16613. evaluation of evidence of current clinical conditions or pregnancy. All volunteers health problems in AYA users.02 mg/mL. spectrometry (GC/MS). THH. and its possible adverse fact. The organic phase was collected Six volunteers (two men and four women. 30 m 6 0. information on the nature of AYA.8-11 sion criteria. The chromatographic Participants were recruited through local advertise. urea. as assessed by a medical interview.26 temperature at the Santo Daime community and sub- The agonist action of AYA alkaloids on serotonergic sequently in a refrigerator in the Department of receptors and its inhibitory effects on MAO-A. open-label study was to evaluate the acute Each subject drank 120-200 mL of AYA (2.8 mg/mL DMT. Thus.21 mg/mL harmine.37(1) . years or decades) members of religious Paulo. and more studies on the potential long-term toxicity of AYA are required.. neuropsy. thickness. The psychoactive effects of AYA are produced by a The study was conducted in accordance with the combined action of peripheral (gastrointestinal and liver) Declarations of Helsinki and Tokyo concerning human monoamine oxidase A (MAO-A) inhibition by harmine and subject research and approved by the Research Ethics central 5-HT1A/2A/2C agonist action of DMT on frontal and Committee of Hospital das Clı́nicas da Faculdade de paralimbic brain areas.25 and preliminary data in resulting brew was stored in plastic bottles at room humans also support an antidepressive action for AYA. Brazil (HC-RP groups that use AYA ritually suggest that this population process no. Within this group. and harmaline) a double-blind. AYA was stored under refrigeration until the day that this substance could be useful in the treatment of of the experimental session. N-dimethyltryptamine (DMT). a 1-mL sample of AYA was homogenized with sodium Methods acetate buffer solution (pH = 9). A diagnosis of bipolar disorder and women of childbearing age). harmaline at the chromatography detection threshold of 0. Patients participated in the study before the Medical interview and laboratory tests introduction of the new medication. We obtained a standard sample of AYA prepared by An increasing number of studies report antidepressive members of the Santo Daime community. there are several reports describing reduced mental effects. viridis (rich in reduced hopelessness and panic-related signs after DMT). placebo-controlled animal study reported combined with the washed leaves of P. causes a sensation of well-being. medication and were in the process of switching to a new agent. physical examination. the small number of studies. Agilent) was used. associated Neurosciences and Behavior. Ribeirão Preto. consisting of the potential for AYA alkaloids in animals. All AYA used in the present depression in humans. state of São Paulo. and liver enzymes. The AYA batch used in the experiment depression and to test whether AYA administration could contained 0. as blood glucose levels. measurement of plasma sodium assessed by medical interview. caapi (rich in harmine. 6 0.12 Studies conducted among Medicina de Ribeirão Preto da Universidade de São long-term (i.6. Ribeirão Preto. urinary beta-HCG (in and laboratory tests. led to the hypothesis Brazil. at the time of recruitment.13-15 In gical effects of hallucinogens. None of the participants had ever used illicit drugs or A general clinical examination. (MAOI). there is insufficient information to allow a Drug definitive conclusion on this topic. 2484/2008). The acute AYA administration. 0. the objective of the present study was from this original batch.8. or psychiatric harm caused by AYA. To quantify the content of each alkaloid. Ribeirão Preto Medical with field and laboratory evidence suggesting that AYA School.000 rpm for 15 min.8 exhibit a significant therapeutic response to their latest mL/min was used as carrier gas. boiled and concentrated for several hours. and had no consisting of a complete blood cell count. as reported in the psychiatric literature. stalks of B.14 FL Osório et al. viridis is rich in the psychedelic antidepressants/substance use were considered exclu- tryptamine N.2 mL/kg effects of a single dose of AYA in patients diagnosed with body weight).25 mm film with psychotic symptoms. mean age and evaporated under a nitrogen stream. extracted with 5 mL Volunteers diethyl ether in a shaker (20 min).9.16-24 Furthermore. conditions were as follows: injector temperature 2506C ments and by referrals from private psychiatric clinics. creatinine. Helium at a flow rate of 0.

5611. the most significant score changes seated in a comfortable recliner in a quiet. The experimental session.29. which was 0. a significant increase in symptoms was performed individually. and difficulties at Dysphoric effects were recorded by means of sponta. this difference was not statistically significant (p = (+140).28 completed by a psychiatrist with clinical experience and training in the use of these scales. 140 min line.37(1) . Montgomery-Åsberg Depression Rating Scale (MADRS) Regarding depressive symptoms. On D1. This decrease Systolic blood pressure (SBP) and diastolic blood was even more pronounced by D7 (72%. On D21. Brazil).14 points.34 The clinical and demographic characteristics of the study participants are presented in Table 1. The average baseline score of the volunteers was 23. Regarding MADRS scores. dimly lit room. YMRS.11). HAM-D and MADRS scales were patients met the inclusion and exclusion criteria. mood. 2015. results were similar to Experimental procedure those observed for the HAM-D scale. Significance was set at Hamilton Rating Scale for Depression (HAM-D) p . 80 min (+80). As observed with the scales. work/activities. Antidepressant effects of ayahuasca 15 Psychometric instruments After the end of the session.01) (Figures 1 and 3). although a subsequent significant consisted of AYA intake followed by administration of decrease occurred on D21 (p = 0.27.5667. the average baseline This clinician-administered scale was used to assess the HAM-D score of the volunteers was 17. i.01). 7 (D7). volunteers were not robust decrease was observed (p = 0. On D14. were observed for items related to apparent and Table 1 Clinical and demographic characteristics of patients with recurrent major depressive disorder (n=6) Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Age (years)/sex 47/female 61/female 28/female 58/male 31/female 36/male Severity of current depressive episode Moderate Mild Severe Mild Moderate Moderate HAM-D score 16 11 29 7 20 20 MADRS score 18 16 39 9 27 32 HAM-D = Hamilton Rating Scale for Depression.05. MADRS = Montgomery-Åsberg Depression Rating Scale.009). on D14. 140 min (+140). pressure (DBP) were measured at the following time However. Rev Bras Psiquiatr.31. 3) Anxious-Depression. lasted on average 4 h and observed (p = 0.30 Data analysis Young Mania Rating Scale (YMRS) This clinician-administered scale was used to assess After verification of data distribution.73. there was a significant decrease in MADRS for 2 weeks prior to AYA administration as part of an scores (38%. During this time. and 21 (D21) after AYA 2) Thinking Disorder. 0.01). changes were observed for items related to depressed Adverse effects were not systematically assessed.34. p = 0. descriptive statistics manic symptoms. 80 min (+80). the level of symptoms increased. and 180 min (+180) after AYA administration.e. This clinician-administered scale was used to assess and quantify depressive symptoms in patients with a previous Results diagnosis of mood disorder. and points: 10 minutes (-10) before AYA administration although the symptom score remained 45% below base- (baseline) and 40 min (+40). which was statistically significant (p = 0.001). feelings of guilt. a more open-label trial. p = 0. which severity of depressive symptoms. at the following time points: 10 minutes (-10) before AYA administration Brief Psychiatric Rating Scale (BPRS) (baseline). patients remained under observation for 24 h. This interview was used to assess whether potential The BPRS. those associated with typical depres- neous verbal reports.32 and repeated-measures analysis of variance (ANOVA) were used for statistical analysis. volunteers remained the HAM-D scale.35 was classified according to the scale guidelines as a moderate level of depression. suicidal ideation. there was a 62% Assessment of tolerability decrease in the mean score. and the under the influence of any psychiatric medication or average score on D7 was 82% below baseline (p = recreational drugs. if no complications were observed.33. During measurements. The greatest score momanometer (Becton Dickinson. depressive symptoms (p = 0. At D1.002).003). and administration.01) (Figures 1 and 2). and on four symptom dimensions: 1) Withdrawal-Retardation. 4) Activation. sive symptoms. there was a further significant decrease in Blood pressure was measured using a mercury sphyg. 14 (D14).. 0. Structured Clinical Interview for DSM-IV (SCID-IV) they were discharged. Volunteers were admitted to an inpatient psychiatric unit At +180. days 1 (D1). This clinician-administered scale was used to evaluate and 180 min (+180) after AYA administration. 40 min (+40).

and none reported dysphoric mani- AD).05. Generally. With the nonsignificant. than baseline values (Figure 4).37(1) . volunteers were generally began to increase but still remained significantly lower asymptomatic on the withdrawal-retardation (BPRS-WR).05. remained so (72% below baseline) until D7. Rev Bras Psiquiatr. psy. Error bars denote one standard error of the mean. However. when they Regarding the BPRS scale. symptoms were significantly reduced (p = 0. and Young Mania Rating Scale (YMRS). and difficulty concentrating. mild and short-lived. with effect peaking at 80 min. but values However. and psychic anxiety. and activation (BPRS-A) Regarding the YMRS scale. the underlying psychopathology. MADRS: { p . 0. jective effects of AYA. 0. Figure 1 Temporal distribution of scores (means from six volunteers) on the Hamilton Rating Scale for Depression (HAM-D). effects of AYA on thought content and sensory perception On the Anxious-Depression BPRS subscale (BPRS. HAM-D: * p . Montgomery-Åsberg Depression Rating Scale (MADRS). Volunteers considered the AYA produced mild psychoactive effects. patients were informed before the experimental remained lower as compared to baseline. scores decreased and returned to baseline at 180 the first 80 minutes following AYA administration. and emotional withdrawal. Throughout the experi. irritability and decreased subscales. the increase in the scores of these sub. likely due to the presence of depressed mood. ment. Vomiting was reported by 50% of the volunteers. pessimistic thinking. these session that AYA could induce vomiting. expressed sadness. festations associated with the psychoactive effects of AYA. volunteers demonstrated higher scores at baseline. suicidal idea. conceptual disorganization.16 FL Osório et al. thinking disorder (BPRS-TD). AYA administration significant changes in symptoms throughout the experi- produced nonsignificant increases in the scores of these ment (Figure 1). 0. the symptoms expressed referred to was likely associated with the peak period of the sub- disorientation/confusion. { p . chomotor retardation.01. exception of vomiting. which min. the presence of these symptoms varied. volunteers exhibited no subscales at baseline (Figure 4). After this time capacity for insight and sleep were more prevalent during point.02) and tion. At +140. and this emetic Figure 2 Temporal distribution of individual scores on the Hamilton Rating Scale for Depression (HAM-D) (n=6). 2015. volunteers did not spontaneously scales at 80 min after AYA administration suggests that report any other adverse effect. feelings of Blood pressure increased moderately and nonsignificantly guilt. Although AYA was well tolerated by all patients. which are typical symptoms of (Table 2).

harmine. pressive effects.19. selective. * p . and harmaline are potent may provide faster reductions in depressive symptoms.21 the fast antidepressant action of AYA is promising. natural. as it Furthermore. Antidepressant effects of ayahuasca 17 Figure 3 Temporal distribution of individual scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) (n=6). regardless of the prior level of depression. The and are associated with increased synaptogenesis and antidepressant potential of AYA was previously demon.05. effect was considered by patients as an integral part of Moreover. the antidepressant effects of AYA alkaloids the effects produced by AYA. AD = Anxious-Depression. Score reductions were observed in both The decreases and increases in depressive symptoms the HAM-D and MADRS scales on D1 and D7. On the other hand. reversible. although a subsequent significant decrease occurred on D21 in both scales. HAM-D scores still remained 45% below baseline values.25 Studies conducted in rodents by our group and by others The average time necessary for the onset of therapeu. spine formation. Error bars denote one standard error of the mean. which were 2 weeks. THH. and A = Activation).17. brain-derived neurotrophic factor (BDNF) protein levels. but this difference was nonsignifi- The results of the present investigation demonstrate that cant. 2015. It is noteworthy that these events that remain active after the acute effects of AYA changes showed a profile that was very similar across have subsided. using doses of 10-15 mg/kg harmine have demonstrated tic action of commercially available antidepressants is antidepressive effects for this compound. significantly increased. MADRS scores on D14 were AYA has significant and quite impressive acute antide. Patients did not consider may inspire a new area of depression research. 0. Rev Bras Psiquiatr.3 Considering currently available medications. The acute antidepressive effects of keta- volunteers. and competitive inhibitors of Figure 4 Temporal distribution of scores (means from six volunteers) on the Brief Psychiatric Rating Scale (BPRS) subscales (WR = Withdrawal-Retardation. TD = Thinking Disorder.4. for instance. Discussion Although increased..37(1) . vomiting as causing severe discomfort. may be sustained for weeks to months the severity of the current depressive episode.5 lessness symptoms after acute AYA intake. i. mine. and these after AYA administration could reflect complex intracellular effects lasted for several days. Interestingly.e. which seem to be related with increases in strated in a study that reported a decrease in hope. associated with increases in BDNF levels. symptoms increased on D14 as measured by the HAM-D and MADRS scales.

08 mg/mL).40 well as an MAOI. * Data missing for one patient.25.9.11. Although patients did not result corroborates previous studies reporting a good spontaneously report adverse effects other than vomiting. as do DMT plasma levels. and immunological parameters.18 FL Osório et al.25. Another possibility could be to BPRS-TD scores could be explained by the DMT con. AYA in clinical populations by using other subjective ficant increases in blood pressure replicate previous measures. suggesting that systematic inquiry about side effects. or affective modifications as tion to healthy volunteers. allowing therapeutic indication. a result that AYA administration did not produce statistically sig. 2015.74 80 60 90 HR (baseline) 78611. these BPRS-TD subscale suggest that changes in sensory purgative effects are considered positive and cleansing.267. the absence of a AYA was well tolerated by all patients. tolerability profile for AYA administration to healthy the lack of a systematic assessment of adverse effects volunteers. dimly lit room throughout the experimental receive a placebo. which is AYA appears to produce less vomiting than oral lower than DMT doses used in previous studies that AYA. and. corroborating the nonsignificant studies should assess the possible adverse effects of effect of AYA on the BPRS-TD subscale. which is the time point when the the emetic effect of AYA by premedicating with an subjective effects of AYA are peaking.4613. This safe with a 5-HT2A receptor antagonist to investigate possible Rev Bras Psiquiatr. such as was designed considering the powerful influences of set neuropsychological.39 In the present study.02 120 85 150 DBP (baseline) 79.11.15. or AYA preceded by pretreatment patients to concentrate on the effects of AYA. The nonsigni. the MAO enzyme. such as visual analogue scales and other findings in human studies suggesting that AYA produces scales that measure hallucinogenic effects. Patients did not consider intake. in the present study volunteers were kept as patients or other clinical populations should also be comfortable as possible.15.8-12 with caution. reported significant psychotropic effects of AYA (0. HR values expressed in beats per minute. which reported that most assessed by the BPRS and YMRS scales.9. A previous study apparently did not have a significant influence on the reported decreased panic-related signs after acute AYA antidepressive effects of AYA.39 Interestingly. Future mild and short-lived. as nausea and vomiting are the most frequently The statistically significant reductions in BPRS-AD reported adverse effects in clinical trials of acute AYA scores from D1 to D21 suggest that AYA produced anti.48 78 68 96 HR (140 min) 72. autonomic. cognitive. considering that AYA alkaloids could interact The absence of statistically significant effects on with antiemetic drugs. HR = heart rate. Investigator interference was minimal. the psychoac.38 of AYA. Patients were informed before the brain serotonin and other monoamines. and by moderate cardiovascular effects.40 Considering this Ideally.8-12. however. Freeze-dried centration found in our AYA batch (0. as are DMT antiemetic. a comparator drug with an established session. such as impacts on cognition.8-12. experimental session that vomiting was a possible effect depressant effects.39 observed during a period ranging from 80 to 140 min after In future studies. SD = standard deviation. include the small sample size.10. This placebo and control groups. simultaneous diarrhea are mL DMT). this possibility should be explored plasma levels.36 environment may have reduced the probability of THH acts as a selective serotonin reuptake inhibitor as dysphoric reactions.25. However.12 The nonsignificant effects of AYA on the common in AYA rituals. variable degrees of nausea. is in line with previous studies of acute AYA administra- nificant sensory.15. This group could in a quiet.8-12.39 In the present study.8. in the present study these effects were despite the occurrence of vomiting.15 effects of this class of substances. vomiting depressive and anxiolytic effects.69 70 64 84 DBP = diastolic blood pressure.37(1) . In these contexts.15.8-12 All blood pressure values expressed in mmHg.8-12. and the lack of it can be safely administered to depressed patients. occasionally.39 exploring other variables that could be modified by AYA Early academic research on classical hallucinogens administration as reported in previous studies.37 Inhibition of both systems – MAO Vomiting was the only adverse effect reported by and serotonin reuptake – may result in elevated levels of volunteers (50%).31 80 70 90 DBP (140 min) 76. The 140-min time point was chosen because the subjective effects of AYA peak around this time. administration. neu- (psychological state) and setting (environment) on the roendocrine. Table 2 Systolic/diastolic blood pressure measurements in patients with recurrent major depressive disorder (n=5)* Mean 6 SD Median Minimum Maximum SBP (baseline) 118614.53 mg/ vomiting.15. future studies involving AYA and depressed background.83 120 100 140 SBP (140 min) 119623. remaining seated in a recliner designed to include a control group. it would be interesting to try to reduce AYA administration.14.9.469. may have reduced the likelihood of registering more tive effects of AYA were considered by participants as subtle effects. especially of the MAO-A subtype.7 perception and thought content may not be essential for Important limitations of the present open-label study therapeutic effects.9.25 this emetic effect to be a severe discomfort. SBP = systolic blood pressure. administer AYA in different formulations. Although participants regarded their AYA experience as pleasant nonsignificant.8. neurophysiological. producing anti.

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