Effects of Banisteriopsis caapi extract on Parkinson's disease

Article (PDF Available)inScientific Review of Alternative Medicine 5(3):127-132 · June 2001with 1,657 Reads 
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A substance extracted from the Amazonian vine Banisteriopsis caapi was shown in the 1920s to alleviate parkinsonism. These pioneering studies were criticized and forgotten for a number of reasons, including questions as to the identity of the active agent and failure to conduct strictly controlled studies. We now report the first double-blind, randomized placebo-controlled trial of a Banisteriopsis caapi (BC) extract for treatment of Parkinson's disease (PD). A single dose of BC administered to de novo PD patients resulted in significant improvement in motor function evidenced by decline in the Unified Parkinson's Disease Rating Scale (UPDRS) score. The beneficial effects were maximal by the second hour and persisted until the last evaluation of the patients at 4 hours. However, tremor was not improved and in some patients tremor was exacerbated. All patients also experienced a degree of transient nausea or vomiting. We measured the concentrations of the putative active agents (harmine, harmaline, and tetrahydroharmaline), and hypothesize that the beneficial effects were primarily due to glutamate receptor antagonist actions of the harmalines.
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Abstract. A substance extracted from the Amazonian
vine Banisteriopsis caapi was shown in the 1920s to alle-
viate parkinsonism. These pioneering studies were crit-
icized and forgotten for a number of reasons, including
questions as to the identity of the active agent and
failure to conduct strictly controlled studies. We now re-
port the first double-blind, randomized placebo-con-
trolled trial of a Banisteriopsis caapi (BC) extract for treat-
ment of Parkinson’s disease (PD). A single dose of BC
administered to de novo PD patients resulted in signifi-
cant improvement in motor function evidenced by de-
cline in the Unified Parkinson’s Disease Rating Scale
(UPDRS) score. The beneficial effects were maximal by
the second hour and persisted until the last evaluation of
the patients at 4 hours. However, tremor was not im-
proved and in some patients tremor was exacerbated.
All patients also experienced a degree of transient
nausea or vomiting. We measured the concentrations of
the putative active agents (harmine, harmaline, and
tetrahydroharmaline), and hypothesize that the benefi-
cial effects were primarily due to glutamate receptor an-
tagonist actions of the harmalines.
Marcos Serrano-Dueñas, MD, is in the Neurology Service of Carlos Andrade
Marín Hospital in Quito, Ecuador. Fernando Cardozo-Pelaez, PhD, and Juan R.
Sánchez-Ramos, PhD, MD, are in the Department of Neurology at the Univer-
sity of South Florida in Tampa, Florida. E-mail: jsramos@hsc.usf.edu.
Supported in part by the Helen Ellis Research Fund.
Vol. 5, No. 3 (Summer 2001)
Marcos Serrano-Dueñas, Fernando Cardozo-Pelaez,
and Juan R. Sánchez-Ramos
combination of two plants, the vine Banisteri-
opsis caapi (BC) and the leaves of other plants, most
commonly Psychotria viridis, which contains the hallu-
cinogen dimethyltryptamine (DMT). Ayahuasca
(known as hoasca in Brazil, Yage in Colombia, and Caapi
in other parts of the Amazon basin), has a long history
of use in medico-magical-religious ceremonies by natives
of the Amazonian rain forests.1,2 More recently,
ayahuasca has been used as a religious sacrament by two
state-approved churches in Brazil (Uniao do Vegetal and
Church of Santo Daime). The banisteriopsis vine con-
tains contains
-carbolines such as harmine, harmaline,
and tetrahydroharmine,3,4,5 which normally do not pro-
duce the desired psychotropic effects unless they are used
with the DMT-containing plant. When taken orally,
DMT is metabolized by monoamine oxidase (MAO) and
is inactive, but the combination of DMT and the MAO
inhibitor banisterine results in psychotropic effects.
The active agent of the banisteriopsis vine was iden-
tified by Louis Lewin, who named it banisterine. Based on
the subjective sensations experienced by Lewin following
self-adminstration, he recommended it for treatment of
rigid-akinetic syndromes in the late 1920s in Germany;4
all the reports mention improvement in rigidity, but con-
flicting results regarding tremor. Rustige also noted im-
provement in mood and affect. Later, Halpern studied
the subjective effects on herself, and noted a sensation of
lightness of body and a belligerent, aggressive mood.
Original Research
From the 1930s to the present, the use of banisterine in
treatment of PD has been virtually forgotten.
One of us (MS-D) had previously evaluated 13 pa-
tients who admitted use of ayahuasca occasionally (every
5 or 6 months), and who felt it helped alleviate the signs
and symptoms of PD. In 4 of these patients we were able
to directly observe the effects of consumption of
ayahuasca. In one of these, extract of Banisteriopsis caapi
(BC) was taken alone (no admixture of plants) and in
the other 3 patients, the admixture of plants was in-
gested. Approximately 20 minutes after ingestion of the
beverage, there was an improvement in rigidity with ex-
acerbation of tremor and appearance of abnormal invol-
untary movements as well as the induction of a halluci-
natory state. The motor effects and hallucinations were
much less evident in the single patient who took only
the BC extract.
L-dopa is the gold standard of PD treatment, but its
use is limited by the development of motor complica-
tions, including dyskinesias, in 30 to 80% of chronically
treated patients.6As a result, additional therapies have
been developed that increase and stabilize synaptic
levels of dopamine without augmenting the adminis-
tered dosage of L-dopa, as for example by inhibiting
dopamine metabolism with MAO inhibitors or with cat-
echol-O-methyl transferase inhibitors.7,8
Based on the remarkable effects of banisterine re-
ported in the late 1920s and the dramatic effects noted
in the few patients described above, we undertook a
double-blind, randomized, placebo-controlled study of
the acute effects of a single dose of BC extract in a co-
hort of 30 de novo PD patients.
Thirty consecutive patients with newly diagnosed PD
were selected (using diagnostic criteria of Calne et al.9)
from the Neurology Service of Carlos Andrade Marín
Hospital in Quito, Ecuador. The patients were randomly
assigned to receive either banisteriopsis extract or
placebo tea (Figure 1).
All patients underwent assessment of higher cor-
tical functions with the Short Test of Mental Status
(STMS);10the Hamilton test for depression (HT);11cra-
nial CT; serum chemistry (urea, creatinine, and glucose);
hepatic enzymes (GOT, GPT, GGT); and cardiac eval-
uation including EKG.
Patients who scored more than 50% on the HT, who
scored less than 29 points on the STMS, or who exhib-
ited anomalies on the serum tests or cardiac evaluation
were excluded from the study.
BC was prepared as a liquid extract 12 hours before
administration in a standard manner: 50 g (dry weight)
of the vine was chopped into small fragments, and added
to 1500 mL of water, brought to boiling for four hours
Figure 1. Double-Blind, Placebo-Controlled Trial of a Single Dose of
Banisteriopsis caapi Extract for Treatment of Parkinson’s Disease
Consecutive de novo patients (n = 30)
Not Randomized (n= 0)
Single dose placebo tea (n= 15) Single dose banisteriopsis extract (n= 15)
Examined at 1, 2, and 4 hrs (n= 15) Examined at 1, 2, and 4 hrs (n= 15)
Withdrawn from study (n= 0) Withdrawn from study (n= 0)
until the volume was reduced to 200 mL. The solution
was filtered and adminstered in that form.
All patients came to the clinic fasting and received
200 mL of either the BC solution (BC) or placebo (P),
which consisted of 200 mL of manzanilla tea. Patients
were not allowed to eat or drink anything but water
during the course of the session.
Patients were evaluated using the motor component
of the Unified Parkinson’s Disease Rating Scale
(UPDRS)12before (baseline) and 60, 120, and 240 min-
utes after ingesting the test infusions (questions 3, 4, 9,
11, 14, 17, 32–39, and 41 of the UPDRS were not in-
cluded). Analysis of variance (ANOVA) of the data fol-
lowed by Bonferroni corrections for multiple compar-
isons was performed. An value of 0.05 was chosen and
p< 0.0125 was considered statistically significant.13
This protocol was approved by the Department of
Docencia and Research of the Andrade Marín Hospital
in Quito, Ecuador. All patients provided informed con-
Measurement of harmala alkaloids
in Banisteriopsis caapi extract
Analysis of the levels of harmala alkaloids (harmine,
harmaline, and tetrahydroharmine) present in the ban-
isteriopsis extract was performed as described previously3
with certain modifications. HPLC system: The mobile
phase was 100 mM ammonium acetate, pH 6.9, with
20% methanol and 20% acetonitrile. Flow rate was kept
at 1 mL/min using a BAS 200 series pump (BAS, W.
Lafayette, Ind, USA). The mixture of harmala alkaloids
was separated using a reverse phase YMCbasic HPLC
column (4.6 ×150 mm) with a 3-micron particle size
(YMC Inc., Wilmington, NC, USA). Harmine and har-
maline were purchased from Sigma Chemical Co. (St.
Louis, Mo, USA). Tetrahydroharmine was produced
from the reduction of harmaline with sodium borohy-
dride, as described previously.3Harmine, harmaline, and
tetrahydroharmine were detected using a LS-3B fluores-
cent detector (Perkin Elmer, Norwalk, Conn, USA).
Harmine was detected using a wavelength of 300 nm for
excitation and 360 nm for emission. Harmaline and
tetrahydroharmine were detected with wavelengths of
340 nm and 480 nm for excitation and emission, re-
spectively. A calibration curve was constructed with
known amounts of the 3 compounds and the area of the
peaks was recorded and compared to the areas produced
by the injection of the Banisteriopsis caapi extract. Levels
of harmala alkaloids were expressed as micrograms per
milliliter of extract.
The average age of the BC group was 67 ± 8.3 years and
the P group averaged 62.9 ± 7 years of age. Median du-
ration of disease was 24.8 ± 12 months in the BC group
and 25 ± 7.7 months in the P group. Fifteen patients
were male and 15 female (Table 1).
At baseline, the mean UPDRS score in the BC
group was 54.4, and 53.8 for the P group (p < 0.4). The
UPDRS scores at 60, 120, and 240 minutes were 41.4 in
the BC group compared to 46.4 in the P group; 22.4 in
the BC group compared to 52.5 in the P group; and 25.6
in the BC group compared to 53 in the P group, respec-
tively. These differences were statistically significant (p
< 0.0004; p< 0.0001; p< 0.0001) (Table 2).
Side effects were noted only in the BC group.
Nausea or vomiting was noted in 100% of the BC pa-
tients, diarrhea in 53.3%, agitation in 26.6%, and 1 pa-
tient experienced transient hallucinations. All of the
patients in the BC group experienced an exacerbation of
their resting tremor and, in addition, postural and action
tremor. Abnormal involuntary movements, choreiform
in nature, were also noted (Table 3).
Analysis of the Banisteriopsis caapi extract yielded
the following levels of harmala alkaloids (mean ± sem):
harmine 418.44 ± 11.78 mg/mL, harmaline 173.03 ±
4.13 mg/mL, and tetrahydroharmine 382.40 ± 8.38
Serrano-Dueñas, Cardozo-Pelaez, and Sánchez-Ramos: Effects of Banisteriopsis caapi Extract on Parkinson’s Disease
Table 1. Patient Characteristics
# of patients 15 15
Age mean 67 62.9
(years) SD 8.3 7
range 49–81 53–76
Duration mean 24.8 25
(months) SD 12.7 7.7
range 14–36 15–38
Depression mean 35.3 33
HT SD 10.5 10.4
(%) range 15–50 15–50
Dementia mean 34.2 33.9
STMS SD 2.4 2.3
(points) range 30–38 30–38
HT = Hamilton Scale
STMS = Short Test of Mental Status
BC = Banisteriopsis caapi Group
P = Placebo Group
In this double-blind, randomized, placebo-controlled
trial, we demonstrated that a single dose of BC adminis-
tered to de novo PD patients resulted in significant im-
provement in motor function evidenced by decline in
the motor component of the UPDRS score. The benefi-
cial effects were noted by 1 hour and motor function
continued to improve for the 4 hours during which the
patients were studied. However, all patients who re-
ceived BC experienced a worsening of resting tremor
and the development of action and postural tremors,
with some abnormal choreiform movements. All pa-
tients also experienced a degree of transient nausea or
vomiting. With the exception of the single patient who
experienced confusion and hallucinations, these side ef-
fects were much less severe than those experienced by
users of the complete ayahuasca beverage.
The levels of harmaline in the banisteriopsis extract
ingested by the subjects in this study were almost iden-
tical to those measured by Callaway and colleagues in
the preparations of ayahusaca used by members of the
Uniao de Vegetal in Brazil.3However, the mean harmine
and tetrahydroharmine levels were 25% and 35%, re-
spectively, of the levels measured in their Brazilian sub-
Table 2. Analysis of Variance of UPDRS (Baseline versus 1st, 2nd and 3rd in BC compared to P)
Evaluations Evaluations
B 1st 2nd 3rd B 1st 2nd 3rd
Mean 54.4 41.4 22.4 25.6 53.8 46.4 52.5 53
DS 3.8 2.9 3.6 0.7 2.8 2.8 4.2 1.4
Range 47–61 37–46 16–28 19–33 49–57 40–52 46–57 47–57
Variance 14.6 8.6 13.4 13.9 4.6 14.5 8.9 7.1
B vs. 1st B vs. 2nd B vs. 3rd B vs. 1st B vs. 2nd B vs. 3rd
F statistic 109.2 548.5 436.5 6.5 1.8 0.8
p< 0.001 0.0001 0.0001 0.01 0.1 0.3
BC vs. P
B vs. B 1st vs. 1st 2nd vs. 2nd 3rd vs. 3rd
F statistic 0.5 15.5 609 536.2
p< 0.4 0.0004 0.0001 0.0001
UPDRS (items excluded: 3, 4, 9, 11, 13, 14, 17, 32, 33, 34, 35, 36, 37, 38, 39, and 41)
p< 0.01 is statistically significant
BC = Banisteriopsis caapi group
P = Placebo group
B = baseline
Table 3. Adverse Effects
Nausea or vomiting m 8 of 15
s 7 of 15
total 15 of 15 = 100%
Dizziness m 6 of 15
s 6 of 15
total 12 of 15 = 80%
Diarrhea m 3 of 15
s 5 of 15
total 8 of 15 = 53.3 %
Pyschomotor agitation m 2 of 15
s 2 of 15
total 4 of 15 = 26.6%
Confusion 1 of 15 = 6.6%
Hallucinations 1 of 15 = 6.6%
AIMs m 8 of 15
Exacerb. Tremor s 7 of 15
m= moderate, s= severe
AIMS = abnormal involuntary movements
jects, who ingested the complete brew prepared from a
combination of plants.3The proportion of banisteriopsis
vine to Psychtria viridis leaves and the exact methods for
preparation of the brew were not noted in the Callaway
In the shamanic use of ayahuasca for religious, mag-
ical, or healing purposes, the infusion is prepared from a
mixture of plants. A critical component of the shamanic
beverage is the presence of the DMT-containing Psy-
chotria viridis.1,2,3 DMT is a potent hallucinogen when
given systemically or when smoked; when taken orally,
it is inactive due to its metabolism by gut and liver
MAO. BC is an inhibitor of MAO and, when ingested
orally with DMT-containing plants, allows the DMT to
produce a range of psychotropic effects, with prominent
visions, hallucinations, and illusions.1,2,5
The dramatic improvement in signs and symptoms
of PD produced by the extract of BC may be due to a
combination of two known mechanisms of action of the
harmalines, the putative active agents. Harmaline, a b-
carboline compound with a structural resemblance to
serotonin, is a known nonselective inhibitor of MAO.14
MAO inhibitors can potentiate the actions of endoge-
nous dopamine, but the symptomatic benefits in PD are
very mild, as evidenced by the study of deprenyl in de
novo patients.15 It is difficult to conceive that the dra-
matic improvement produced by BC can be due solely to
MAO inhibition. It is possible that the interaction of
harmaline at glutamatergic receptors plays a significant
role in restoring motor function in PD. Harmaline has
been shown to be an NMDA receptor antagonist.16 Har-
maline displaces [3H]MK-801, which binds to the cation
channel of the NMDA receptor, from membranes pre-
pared from rabbit brain tissue.16
Glutamate is an excitatory amino acid that plays a
role in the symptomatic expression of PD17 and that has
also been implicated in the process of neurodegeneration
of dopaminergic neurons of the substantia nigra.18 When
dopamine deficiency develops, the adaptive changes in
the striatal outflow pathways result in disinhibition of
the subthalamic nucleus. In turn, the hyperactive sub-
thalamic-pallidal glutamate projection results in de-
creased outflow from globus pallidus internal segment
(GP-int) to thalamus, to produce the clinical manifes-
tations of slowness and rigidity.19 Blockage of gluta-
matergic receptors corrects the imbalance that results
from dopamine deficiency and helps restore normal
motor function.20 In the rat, local infusion of NMDA re-
ceptor antagonists to the GP-int/SNr has been shown to
reverse the signs of parkinsonism.21 In both rats and pri-
mates, the NMDA receptor antagonist LY235959 has
been shown to potentiate the antiparkinson effects of
L-dopa, to stabilize the motor fluctuations and to alle-
viate choreiform dyskinesias. However, MK-801, a glu-
tamate NMDA receptor antagonist with hallucinogenic
side effects (similar to phencyclidine and ketamine) has
been reported to induce dystonia when used with L-dopa
in a primate model of parkinsonism.21In naive rats, MK-
801 increases locomotor activity and potentiates the
motor effects of L-dopa.23The AMPA antagonist NBZX
(2,3- dihydroxy-6-intro-7-sulfamoil-benzo-9[f]quinoxa -
line) im proved tremor, posture, and manual dexterity in
parkinsonian monkeys.24When glutamate antagonists
are given together with L-dopa, the dosage of L-dopa can
be greatly reduced without lessening motor function.20,24
To conclude, we suggest that the antiglutamate actions
of harmaline are most likely responsible for the anti -
parkinson effects observed in the BC group of patients.
The transient worsening of tremor and induction of
postural and action tremor by banisterine has been been
noted before by early investigators and, in fact, harma-
line was used in the 1960s to study the mechanism of ac-
tion tremor that could be induced by harmaline in pri-
Interestingly, L-dopa-induced dyskinesias are associ-
ated with a decrease in the activity of the glutamatergic
projection to the GP-int. Paradoxically, glutamatergic
receptors are apparently involved in these dyskinesias,
since adminstration of glutamate antagonists (of the
NMDA receptor subtype) have been shown to be useful
in controlling L-dopa-induced dyskinesias.20
There is little concern for the possibility that the
harmalines in the ayahuasca tea are cytotoxic at con-
centrations found in the tea. Harmaline and a related b-
carboline, ibogaine, are cytotoxic in rats only following
extremely high doses of 100 mg/kg or 100 mg/kg ×3.
Two recent studies clearly demonstrated that even lower
doses (25 and 40 mg/kg) given to rats did not produce
Purkinje cell degeneration.25,26
To summarize, extracts of BC were shown to have
remarkable symptomatic benefit in drug-naive de novo
patients. This was the first double-blind, randomized,
placebo-controlled trial of a BC extract for treatment of
PD. Studies with banisterine done in the late 1920s were
criticized because the benefits were believed by many to
be psychological. We measured the concentrations of
the putative active agents, and hypothesize that the ben-
eficial effects were primarily due to glutamate receptor
antagonist actions of the harmalines. The most common
side effect was transient nausea/vomiting, which could in
the future be prevented by pretreatment with domperi-
done. Hallucinations in a single case may reflect a higher
Serrano-Dueñas, Cardozo-Pelaez, and Sánchez-Ramos: Effects of Banisteriopsis caapi Extract on Parkinson’s Disease
sensitivity in that patient to the NMDA receptor an-
tagonists. A complete dose-response study needs to be
done in human volunteers in order to determine the op-
timal concentrations of b-carbolines to produce max-
imal symptomatic relief and minimal side effects.
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  • ... caapi) is a liana, endemic to the Amazon, basin known to contain a number of β-carbolines such as harmine, harmaline, and tetrahydroharmine that possess MAO inhibitory properties (Schwarz, Houghton, Rose, Jenner, & Lees, 2003). Extracts of B. caapi have been shown to be effective in treating PD when used in combination with L-DOPA by extending its duration of action possibly as a result of reduced dopamine metabolism and enhanced release of dopamine from dopaminergic neurons (Serrano-Duenas, Cardozo-Pelaez, & Sanchez-Ramos, 2001a, 2001b. It is thought that these effects of B. caapi are mediated through its constituent β-carbolines 90 years ago, Lewin and Beringer both reported the successful use of harmine as monotherapy in the pre-L-DOPA era for the treatment of PD and although marketed in the 1920s for this purpose, it fell out of use because of low efficacy (see Djamshidian, Bernschneider-Reif, Poewe, & Lees, 2016). ...
    ... Importantly, the doses of the extract of B. caapi were clinically relevant as the lowest dose was equivalent to drinking approximately 150 ml of the original tea in humans. This is consistent with a study in patients with PD where a significant improvement in motor function was reported following a single dose (200 ml) of B. caapi tea (Sanchez-Ramos, 1991;Serrano-Duenas et al., 2001a, 2001b. ...
    ... This was surprising as previously it has been reported that harmaline is present in the vine; however, levels of harmaline have previously been reported as low (10% of that of harmine; Callaway, Brito, & Neves, 2005).The reason for this difference is not clear but may be due to differences in the extraction processes involved in the analysis. Indeed, in this study, we prepared the B. caapi as a tea as it was prepared in water as for earlier clinical trials (Serrano-Duenas et al., 2001a, 2001b, which was freeze-dried and then reconstituted with methanol, whereas in the analysis by Callaway et al. (2005), the samples were solely extracted by methanol. ...
    Full-text available
    Banisteriopsis caapi (B. caapi) contains harmine, harmaline, and tetrahydroharmine, has monoamine oxidase inhibitory activity, and has reported antiparkinsonian activity in humans when imbibed as a tea; however, its effects are poorly documented. For this reason, motor function was assessed in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets following administration of B. caapi extract (28.4–113.6 mg/kg; po), harmine (0.1 and 0.3 mg/kg; sc), and selegiline (10 mg/kg; sc), alone or with a submaximal dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 4–7 mg/kg). L-DOPA reversed motor disability, increased locomotor activity, and induced moderate dyskinesia. B. caapi did not increase locomotor activity or induce dyskinesia but at 56.8 and 113.6 mg/kg improved motor disability. The L-DOPA response was unaltered by co-administration of B. caapi. Harmine (0.1 and 0.3 mg/kg) produced a mild improvement in motor disability without affecting locomotor activity or dyskinesia but had no effect on the L-DOPA-induced antiparkinsonian response. Selegiline (10 mg/kg) alone improved motor function to the same extent as L-DOPA, but with only mild dyskinesia, and did not alter the response to L-DOPA, although dyskinesia was reduced. The findings suggest that B. caapi alone has a mild antiparkinsonian effect but does not enhance the L-DOPA response or reduce dyskinesia.
  • ... Additionally, it is frequently used by the community to handle their social issues and to engage into traditional spiritual healing rituals (Antonio et al., 2019;Coe and McKenna, 2017;Faber and Groot, 2007;Frecska et al., 2016;). The beverage is recognised as an ethnomedicine to improve mood changes and treat physiological conditions and mental illnesses (Antonio et al., 2019;Domínguez-Clavé et al., 2016;Serrano-Dueñas et al., 2001). ...
    ... Indeed, the way indigenous people understand and use Ayahuasca is often different from those of nonindigenous populations (Dos . Thus, there is evident historical ethnopharmacological activity for Ayahuasca in the central nervous system (CNS) that can link it to the clinical and scientific evidence of its use to treat neurodegenerative diseases like Parkinson's disease -PD (Dos Serrano-Dueñas et al., 2001;Wang et al., 2010). ...
    ... Indole alkaloids are by far the most investigated class of molecules in the plants used for Ayahuasca, namely due to their structural diversity and great medicinal potential. The Ayahuasca chemical composition is known to possess β-carbolines derivatives, such as harmine (HRE), tetrahydroharmine (THH), harmaline (HRL) and norharmine, as well as tryptamine derivatives, including N,N-dimethyltryptamine -DMT (Brierley and Davidson, 2012;Callaway et al., 2005;Frecska et al., 2016;Gaujac et al., 2012;Pic-Taylor et al., 2015;Serrano-Dueñas et al., 2001). ...
    Ethnopharmacology relevance: Ayahuasca is a tea produced through decoction of Amazonian plants. It has been used for centuries by indigenous people of South America. The beverage is considered to be an ethnomedicine, and it is traditionally used for the treatment of a wide range of diseases, including neurological illness. Besides, some scientific evidence suggests it may be applicable to Parkinson's disease (PD) treatment. Thus, Ayahuasca deserves in depth studies to clarify its potential role in this disease. Aim of the study: This study aimed to use an untargeted metabolomics approach to evaluate the neuroprotective potential of the Ayahuasca beverage, the extracts from its matrix plants (Banisteriopsis caapi and Psychotria viridis), its fractions and its main alkaloids on the viability of SH-SY5Y neuroblastoma cells in an in vitro PD model. Material and methods: The cytotoxicity of Ayahuasca, crude extracts, and fractions of B. caapi and P. viridis, as well as neuroprotection promoted by these samples in a 6-hydroxydopamine (6-OHDA)-induced neurodegeneration model, were evaluated by the MTT assay at two time-points: 48 h (T1) and 72 h (T2). The main alkaloids from Ayahuasca matrix plants, harmine (HRE) and N,N-dimethyltryptamine (DMT), were also isolated and evaluated. An untargeted metabolomics approach was developed to explore the chemical composition of samples with neuroprotective activity. Ultra-Performance Liquid Chromatography coupled to Electrospray Ionisation and Time-of-Flight (UPLC-ESI-TOF) metabolome data was treated and further analysed using multivariate statistical analyses (MSA): principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). The metabolites were dereplicated using the Dictionary of Natural Products and an in house database. The main alkaloids were also quantified by UPLC-MS/MS. Results: The samples did not cause cytotoxicity in vitro and three of samples intensely increased cell viability at T1. The crude extracts, alkaloid fractions and HRE demonstrated remarkable neuroprotective effect at T2 while the hydroalcoholic fractions demonstrated this neuroprotective effect at T1 and T2. Several compounds from different classes, such as β-carbolines and monoterpene indole alkaloids (MIAs) were revealed correlated with this property by MSA. Additionally, a total of 2419 compounds were detected in both ionisation modes. HRE showed potent neuroprotective action at 72 h, but it was not among the metabolites positively correlated with the most efficacious neuroprotective profile at either time (T1 and T2). Furthermore, DMT was statistically important to differentiate the dataset (VIP value > 1), although it did not exhibit sufficient neuroprotective activity by in vitro assay, neither a positive correlation with T1 and T2 neuroprotective profile, which corroborated the MSA results. Conclusion: The lower doses of the active samples stimulated neuronal cell proliferation and/or displayed the most efficacious neuroprotection profile, namely by preventing neuronal damage and improving cell viability against 6-OHDA-induced toxicity. Intriguingly, the hydroalcoholic fractions exhibited enhanced neuroprotective effects when compared to other samples and isolated alkaloids. This finding corroborates the significance of a holistic approach. The results demonstrate that Ayahuasca and its base plants have potential applicability for PD treatment and the possibility to prevent its progression differently from current drugs to treat PD.
  • ... The β-carbolines present in B. caapi were shown to stimulate neurogenesis in vitro and the modulation of brain plasticity could contribute to the antidepressant effects of ayahuasca [15] and harmine [16,17]. B. caapi extracts showed to act against neurodegenerative diseases, such as Parkinson's disease [18][19][20][21]. Furthermore, various studies have investigated the therapeutic potential of ayahuasca for depression and addiction in experimental animals [22][23][24][25] and humans [26][27][28]. ...
    ... In spite of the globalization of ayahuasca use and the substantial number of studies showing a broad spectrum of therapeutic potential of ayahuasca, B. caapi, and β-carbolines [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]39], there are very few studies that examined the chemical profile of the beverage and the plant obtained from different sources. The first studies that investigated the levels of β-carbolines in B. caapi were conducted in the late 1960s to the 1980s and analyzed 6-7 plant samples collected in the Peruvian Amazon [4,33,34,40]. ...
    Full-text available
    Ayahuasca is a psychoactive infusion with a large pharmacological application normally prepared with Banisteriopsis caapi, which contains the monoamine oxidase inhibitors β-carbolines, and Psichotria virids, which contains the serotonin receptor agonist N,N dimethyltryptamine (DMT). The objectives of this study were to investigate the chemical profile of B. caapi and of ayahuasca collected in various Brazilian regions. In total, 176 plant lianas, of which 159 B. caapi and 33 ayahuasca samples were analyzed. Dried liana samples were powdered, extracted with methanol, diluted, and analyzed by LC-MS/MS. Ayahuasca samples were diluted and analyzed. Mean concentrations in B. caapi were 4.79 mg/g harmine, 0.451 mg/g harmaline, and 2.18 mg/g tetrahydroharmine (THH), with a high variability among the samples (RSD from 78.9 to 170%). Native B. caapi samples showed significantly higher harmine concentrations than cultivated ones, and samples from the Federal District/Goiás had higher THH content than those collected in the State of Acre. The other Malpighiaceae samples did not contain β-carbolines, except for one D. pubipetala sample. Concentrations in ayahuasca samples ranged from 0.109 to 7.11 mg/mL harmine, 0.012 to 0.945 mg/mL harmaline, 0.09 to 3.05 mg/mL THH, and 0.10 to 3.12 mg/mL DMT. The analysis of paired ayahuasca/B. caapi confirmed that harmine is reduced to harmaline and to THH during the brew preparation. This is the largest study conducted with Malpighiaceae samples and showed a large variability in the main β-carbolines present in B. caapi. This biodiversity is a challenge for standardization of the material used in ethnopharmacological studies of B. caapi and ayahuasca.
  • ... Kwestia zastosowania go w celach terapeutycznych podejmowana jest w licznych publikacjach [75][76][77][78][79]. Zwraca się szczególną uwagę na właściwości przeciwbólowe mikstury, jak również przeciwbakteryjne i przeciwmalaryczne [75]. Wskazuje się na pozytywne rezultaty stosowania naparu w terapii uzależnień [76,77], leczeniu nowotworów [75,78] oraz redukowaniu objawów choroby Parkinsona [75,79,80]. Podstawę do przyrządzenia wywaru stanowi Banisteriopsis caapi-roślina porastająca rozległe południowoamerykańskie obszary. ...
    ... Należy ona do rodziny kwitnących krzewów i pnączy występujących głównie na terenie deszczowych lasów w dorzeczu Amazonki. Spotkać ją można we wschodniej części Brazylii, w Ekwadorze, Boliwii, Peru, Kolumbii oraz na Karaibach [11,61,75,79,80]. W pełnej fazie rozwoju roślina tworzy imponujących rozmiarów liany o długich pędach wijących się po pobliskim drzewostanie. ...
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    The article presents two plant hallucinogens-jimsonweed (Datura stramonium) and Ayahuasca which consists of Banisteriopsis caapi and Psychotria viridis. As is apparent from the observation of pop culture and of web portals addressed to people interested in the use of psychoactive substances in the past few years there has been an increase of interest in their use. W artykule zaprezentowane zostały dwa roślinne halucynogeny-bieluń dziędzierzawa (Datura stramonium) oraz ayahuasca w skład której wchodzą Banisteriopsis caapi i Psychotria viridis. Jak wynika z obserwacji wytworów kultury popularnej oraz portali internetowych skierowanych do osób zainteresowanych zażywaniem środków psychoaktywnych, w ostatnich kilku latach obserwuje się wzrost zainteresowania ich używaniem.
  • ... Interestingly, harmine was used to treat symptoms of Parkinson's disease in the late 1920s and early 1930s [63]. Evidence from recent preclinical studies using B. caapi extract has corroborated this hypothesis [64], which is also supported by a controlled clinical trial involving the administration of a B. caapi extract to patients with Parkinson's disease, where the extract improved motor function compared with placebo [65]. Therefore, future clinical trials should further explore the effects of ayahuasca on Parkinson's disease and other motor disorders, and observational studies could also improve our knowledge regarding the effects of ayahuasca in other clinical populations, such as people diagnosed with autoimmune and neuroinflammatory diseases, and also with chronic pain. ...
    Ayahuasca is a botanical hallucinogenic preparation traditionally used for ritual and therapeutic purposes by native populations of the Northwestern Amazon. In the last decades, ayahuasca use has spread to Europe, the United States, Asia, and Africa, and interest in the possible therapeutic uses of ayahuasca for treating anxiety and mood disorder and substance-use disorders has increased both among the general public and the scientific community. Indeed, preclinical, observational, and preliminary clinical studies have corroborated some of these findings. In the present article, we present an overview of these studies and highlight the current uses of ayahuasca in neuroscience, such as a tool in the investigation of the neural basis of introspection and other complex cognitive processes.
  • ... La inhibición de la MAO por harmina y harmalina proporciona protección contra la neurodegeneración, y tiene potencial valor terapéutico para el tratamiento de la enfermedad de Parkinson (Serrano, Cardozo y Sánchez, 2001). Estos resultados en conjunto apoyan los potenciales usos del ayahuasca, la cual contiene B. caapi, en el tratamiento de la enfermedad de Parkinson (Serrano et al., 2001;Schwarz et al., 2003). Se sugiere que el extracto estandarizado de B. caapi puede ser útil para las enfermedades neurodegenerativas por su efecto combinado de proantocianidinas y alcaloides de βcarbolinas, las cuales le proporcionan efectos inhibitorias de la MAO-B, propiedades antioxidantes y antineurodegenerativas (Heo y Lee, 2005), mientras que la inhibición de la MAO aumenta la liberación de dopamina en las células del cerebro (Schwarz et al., 2003), lo cual podría evitar su deterioro. ...
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    RESUMEN Se describe las características químicas y los efectos del consumo del ayahuasca para conocer el estado actual de los descubrimientos existentes hasta la fecha sobre sus propiedades farmacocinéticas y farmacodinámicas. Se realizó una revisión bibliográfica sobre estudios del ayahuasca hasta el año 2013 en inglés, español y portugués en las bases de datos de PubMed, PsycINFO, Psyke, Psicodoc y Redalyc, así como en capítulos de libros y bibliografía relacionada obtenida de investigaciones afines. Se concluye que uno de los componentes del ayahuasca, la harmina, puede ser utilizada para tratar diferentes patologías. ABSTRACT It describes the chemical characteristics and the effects of Ayahuasca consumption, in order to know the current status of the discoveries to date regarding their pharmacological properties. A literature review was performed on studies of ayahuasca until 2013 in English, Spanish, and Portuguese in the databases of PubMed, PsycINFO, Psyke, Psicodoc, and Redalyc; as well as chapters in books and literature obtained from related research. It is concluded that one of the components of ayahuasca-harmina-can be used to treat different pathologies. Introducción Los alucinógenos o psicodélicos son un grupo de sustancias psicoactivas que producen intensos efectos sobre la mente, que se adaptan bien a la fisiología humana, y no son consideradas drogas de adicción, pues no promueven su consumo compulsivo ni inducen un síndrome de abstinencia (Quirce-Balma, Badilla-Baltodano, Badilla-Chaves, Martínez-Herrera y Rodríguez, 2010). La ayahuasca es una preparación psicoactiva a base de plantas alucinógenas, que generalmente tiene como ingredientes a la Banisteriopsis caapi, rica en β-carbolinas, especialmente harmina, tetrahidroharmina (THH) y harmalina. Puede ser preparada también con Psychotria viridis, rica en dimetiltriptamina (DMT), que es un agonista de los receptores de serotonina 2A, 2C/1A con efectos alucinógenos. Como se sabe, las β-carbolinas funcionan como inhibidores reversibles de la enzima monoamino oxidasa A (MAO-A), involucrada en la inhibición del metabolismo de la DMT en el intestino, facilitando así su llegada al sistema nervioso central (Dos Santos, 2011). Debido al desconocimiento sobre los efectos del consumo del ayahuasca a corto y a largo plazo en los seres humanos, a que ha sido utilizada por décadas con fines rituales por las poblaciones mestizas del Perú y
  • ... In rats submitted to cerebral ischemia, harmine attenuated the cerebral infarct volume and reduced neuronal death (Sun et al. 2014). In addition, a double-blind, randomized, placebo-controlled trial study of B. caapi, using a single dose, revealed a significant improvement in motor function of patients with Parkinson's disease (Serrano-Dueñas, Cardozo-Pelaez, and Sánchez-Ramos 2001). An extract of B. caapi stem and harmine showed concentration-dependent inhibition of MAO-A in liver homogenates and, consequently, an increase in the release of dopamine from rat striatal slices (Schwarz et al. 2003). ...
    Ayahuasca is a beverage obtained from decoctions of the liana Banisteriopsis caapi plus the shrub Psychotria viridis. This beverage contains a combination of monoamine oxidase inhibitors (harmine, harmaline, and tetrahydroharmine) and N,N-dimethyltryptamine, the main substance responsible for its visionary effect. The ritualistic use of ayahuasca is becoming a global phenomenon. Most members of ayahuasca churches consume this beverage throughout their life, and many reports have discussed the therapeutic potential of this beverage. Ayahuasca is consumed orally, and the liver, as the major organ for the metabolism and detoxification of xenobiotics absorbed from the alimentary tract, may be susceptible to injury by compounds present in the ayahuasca decoction. In this study, we evaluated biochemical parameters related to hepatic damage in the serum of 22 volunteers who consumed ayahuasca twice a month or more for at least one year. There was no significant alteration in the following parameters: alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, urea, lactate dehydrogenase, alkaline phosphatase, and gamma glutamyl transferase. These findings indicate that chronic ayahuasca consumption in a religious context apparently does not affect hepatic function.
  • ... Schenberg (2013) published a review about ayahuasca administration in the treatment of some types of cancer and, in general, an improvement was observed in the patient's conditions. It was also reported that the B. caapi extract presented beneficial effects on patients with Parkinson´s disease (Sanchez-Ramos 1991;Serrano-Dueñas et al. 2001). ...
    Ayahuasca is a beverage used in religious rituals of indigenous and nonindigenous groups, and its therapeutic potential has been investigated. Ayahuasca is obtained by decoction of the Banisteriopsis caapi that contains β‐carbolines (harmine, harmaline, and tetrahydroharmine) plus Psychotria viridis that contains N,N‐dimethyltryptamine. Although plants used in folk medicine are recognized as safe, many of them have genotoxic potential. The Salmonella/microsome assay is usually the first line of the mutagenicity evaluation of products intended for therapeutic use. Our objective was to evaluate the mutagenicity of ayahuasca beverage and their constituents using the Salmonella/microsome assay with TA98 and TA100. We analyzed two ayahuasca samples, and also beverage samples prepared each individual plant P. viridis and B. caapi. Harmine and harmaline were also tested. All beverage samples were chemically characterized and both ayahuasca samples could be considered representative of the beverages consumed in religious rituals. Both ayahuasca samples were mutagenic for TA98 and TA100 with and without S9, with similar potencies. The beverage obtained from P. viridis was not mutagenic, and beverage obtained from B. caapi was mutagenic for TA98 with and without S9. Harmine was nonmutagenic and harmaline was mutagenic only for TA98 without S9. Harmaline fully explain the mutagenicity observed with TA98 without S9 of both ayahuasca samples and the B. caapi beverage samples. We conclude that the ayahuasca samples are mutagenic and this effect is partially explained by harmaline, one of the β‐carbolines present in the beverage. Other mutagenic compounds seem to be present and need to be further investigated. Environ. Mol. Mutagen. 2018.
  • ... In the specific case of Parkinson's disease, early evidence shows that harmine was used to treat symptoms of this disease in the late 1920s and early 1930s 66 . Evidence supporting this use has been recently reported in preclinical studies using B. caapi extract 67 and also in a double-blind, randomized, placebo-controlled trial in which B. caapi extracts improved motor function in these patients 68 . The benefits obtained by the use of B. caapi were more significant than the results showed by harmine alone, which may suggest and "entourage" effect that should also be considered in ayahuasca research. ...
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    Background Ayahuasca is a psychoactive ethnobotanical concoction that has been used for decades by indigenous groups of the Northwestern Amazon and by syncretic religious organizations for ritual and therapeutic purposes. In the last two decades, it is being used worldwide in evolving practices. Ayahuasca seem to therapeutic effects, but controlled studies are lacking. Moreover, its safety and toxicity are not completely understood. Objectives To present an overview of the effects of ayahuasca based on the most recent human studies. Methods Narrative review. Results Ayahuasca administration in controlled settings appears to be safe from a subjective and physiological perspective, with few adverse reactions being reported. More frequent adverse reactions occur in non-controlled settings. Prolonged psychotic reactions are rare and seem to occur especially in susceptible individuals. Ayahuasca showed antidepressive, anxiolytic, and antiaddictive effects in animal models, observational studies, and in open-label and controlled studies. Discussion Ayahuasca administration in controlled settings appear to be safe. Moreover, ayahuasca seem to have therapeutic effects for treatment-resistant psychiatric disorders that should be further investigated in randomized controlled clinical trials. However, medical complications and cases of prolonged psychotic reactions have been reported, and people with personal or family history of psychotic disorders should avoid ayahuasca intake.
  • ... Interestingly, in the late 1920s and early 1930s, harmine was used to treat symptoms of Parkinson's disease, such as muscular rigidity, depression, memory deficits, apathy, phobias, fatigue, and attention problems (Costa and Faria 1936;Sanchez-Ramos 1991). More recently, the potential therapeutic use of B. caapi extract in Parkinson's disease has been described in preclinical studies (Samoylenko et al. 2010;Schwarz et al. 2003), and a double-blind, randomized, placebocontrolled trial reported that B. caapi extracts improved motor function in Parkinson's patients (Serrano-Dueñas, Cardozo-Pelaez, and Sánches-Ramos 2001). However, B. caapi has other constituents, including other β-carbolines and different compounds, so the role of harmine should be better investigated. ...
    Harmine is a natural β-carboline alkaloid found in several botanical species, such as the Banisteriopsis caapi vine used in the preparation of the hallucinogenic beverage ayahuasca and the seeds of Syrian rue (Peganum harmala). Preclinical studies suggest that harmine may have neuroprotective and cognitive-enhancing effects, and retrospective/observational investigations of the mental health of long-term ayahuasca users suggest that prolonged use of this harmine-rich hallucinogen is associated with better neuropsychological functioning. Thus, in order to better investigate these possibilities, we performed a systematic literature review of preclinical studies analyzing the effects of harmine on hippocampal neurons and in memory-related behavioral tasks in animal models. We found two studies involving hippocampal cell cultures and nine studies using animal models. Harmine administration was associated with neuroprotective effects such as reduced excitotoxicity, inflammation, and oxidative stress, and increased brain-derived neurotrophic factor (BDNF) levels. Harmine also improved memory/learning in several animal models. These effects seem be mediated by monoamine oxidase or acetylcholinesterase inhibition, upregulation of glutamate transporters, decreases in reactive oxygen species, increases in neurotrophic factors, and anti-inflammatory effects. The neuroprotective and cognitive-enhancing effects of harmine should be further investigated in both preclinical and human studies.
  • Article
    Background and Methods In 1987 we began a multicenter controlled clinical trial of deprenyl (a monoamine oxidase inhibitor) and tocopherol (a component of vitamin E that traps free radicals) in the treatment of early Parkinson's disease. We randomly assigned 800 patients to one of four treatments: placebo, active tocopherol and deprenyl placebo, active deprenyl and tocopherol placebo, or both active drugs. The primary end point was the onset of disability prompting the clinical decision to begin administering levodopa. An interim analysis showed that deprenyl was beneficial . We report the results of tocopherol treatment after a mean (±SD) follow-up of 14 ±6 months, as well as the follow-up results for deprenyl. Results There was no beneficial effect of tocopherol or any interaction between tocopherol and deprenyl. The beneficial effects of deprenyl, which occurred largely during the first 12 months of treatment, remained strong and significantly delayed the onset of disability requiring levodopa therapy (hazard ratio, 0.50; 95 percent confidence interval, 0.41 to 0.62; P<0.001). The difference in the estimated median time to the end point was about nine months. The ratings for Parkinson's disease improved during the first three months of deprenyl treatment; the motor performance of deprenyl-treated patients worsened after the treatments were withdrawn. Conclusions Deprenyl (10 mg per day) but not tocopherol (2000 IU per day) delays the onset of disability associated with early, otherwise untreated Parkin-son's disease. The action of deprenyl that accounts for its beneficial effects remains unclear.
  • Article
    Harmaline and related compounds have been shown to be potent inhibitors of monoamine oxidase effecting 50 per cent inhibition of serotonin metabolism at 10−6 M. Inhibition is reversible both in vitro and in vivo. Procedures have been presented for evaluating the effectiveness of monoamine oxidase inhibitors bothin vitro and in vivo.
  • Article
    Full-text available
    Banisteriopsis caapi, Brugmansia suaveolens, andNicotiana tabacum are the principal hallucinogens used by the Shuar and related ethnic groups in Amazonian Ecuador and Peru. These three species are common hallucinogens throughout northwestern Amazonia.Banisteriopsis caapi (natem) is the hallucinogen most frequently employed by the Shuar. The Shuar drink the juice ofN. tabacum duringnatem healing ceremonies. They also believe that smoke fromN. tabacum cigarettes repel evil spirits.Brugmansia suaveolens is the strongest Shuar hallucinogen. Considered very dangerous, it sometimes is added tonatem mixtures or it may be taken alone. Other plants used in hallucinogens or in narcotic beverages includeBrunfelsia grandiflora, Cyperus spp.,Diplopterys cabrerana, Heliconia stricta, Herrania spp., andIlex guayusa.
  • Article
    There are few first-hand reports of drinking ayahuasca by residents of Amazonia, where use is widespread. One of us (F.A.F. ), who lives in Iquitos, took ayahuasca 30 times during a three-year period between 1972 and 1974 in an attempt to experience all levels of hallucination. Although unable to achieve the ultimate goal of telepathy and extrasensory perception, this author clearly relates his repeated experiences within the three other levels of hallucination and also correlates these experiences with those of others he observed who drank ayahuasca at the same time.
  • Article
    It has been suggested that the excitatory amino acid glutamate, acting as both a neurotoxin and a neurotransmitter, might play a central role in the pathophysiology of Parkinson's disease (PD). Intrinsic energetic defects of the neurons of the substantia nigra pars compacta, the brain area where the degenerative process of PD takes place, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. Degeneration of dopamine nigral neurons and striatal dopaminergic denervation cause a cascade of functional modifications in the activity of basal ganglia nuclei. Due to the close relationship that links dopaminergic and glutamatergic neurotransmission, glutamate is directly involved in the functional alterations of basal ganglia circuitry that lead to the development of parkinsonian motor symptoms. Drugs counteracting the effects of glutamate might therefore provide new protective and symptomatic strategies for therapy of PD.
  • Article
    Parkinson's disease evolves slowly, and there is current interest in exploring the earliest stages of the disorder, because of new approaches to studying pathogenesis and developing potential neuroprotective treatment. Recognizing early Parkinson's disease is not easy. The certainty of diagnosis increases as the disease advances. To address the problem of identifying Parkinson's disease in its initial phases of clinical expression, we propose the following designated levels of confidence for the diagnosis: (1) clinically possible, (2) clinically probable, and (3) clinically definite. Laboratory support for the diagnosis may be applied to each category. Criteria are provided as a framework underpinning this classification.
  • Article
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    It is of historical interest that 63 years ago Louis Lewin reported the use of a hallucinogenic compound prepared from the South American vine, Banisteria Caapi, to treat Parkinson's disease (PD). This psychoactive compound, named banisterine, proved to be identical to harmine, but 30 years were to pass before it was shown to be a reversible monoamine oxidase (MAO) inhibitor. The first reports of the use of banisterine to treat postencephalitic parkinsonism in 1929 created a stir in the popular press and banisterine was hailed as a "magic drug." Despite continued studies of the harmala alkaloids by other researchers, interest in the therapeutic value of these compounds vanished during the 1930's. The story of banisterine is reviewed because it was the first MAO inhibitor to be used in parkinsonism, and illustrates the historical role of psychoactive drugs in the development of effective therapies, and in elucidating the pathophysiology of PD.