[Fourteen Years of
Clinical Research]
[with Ayahuasca:
Jordi Riba]
[April 20, 2013]
In my talk I would like to
show you some of the data
we have obtained in these
last 14 years, in which
we have conducted a series
of clinical trials involving
the administration of ayahuasca
to healthy humans.
More recently we have also assessed
the long-term effects of ayahuasca use.
I'll be showing some data in this regard.
First of all I would like to
make an introduction or start
telling you about how I
got involved in this field.
As Ken has said, I started as a
graduate student at the pharmacy school
in Barcelona, studying organic chemistry
and doing research in
the synthesis of indole alkaloids, and
by a series of happy coincidences
I had the chance of meeting this person
here. He is an anthropologist
and he had done research
with the Shuar in Ecuador.
He had written this interesting book.
It's called, in Spanish,
Los Jíbaros Cazadores de Sueños.
In English this would be
the jíbaro, or Shuar, chasers of dreams.
So, in a way I found myself
getting to know people who had done
research with these Amazon tribes
that were using substances that had
a profound effect on the mind, and
that I had always been interested in
natural products, and especially
alkaloids, that had effects on the
central nervous system. And this person,
which is María [Faricula],
he is anthropologist, also
introduced me to this lady,
Ester Martinez, and to
Josep María Fábregas,
who is probably in the audience.
You'll see a talk he'll give today.
They are medical doctors and
they were very knowledgeable
about the Santo Daime religion which
had recently arrived in Europe
and in Spain, and these people
were having regular sessions
in the Barcelona area. I got in touch
with them, I participated in
the sessions, and I got to know
first-hand what ayahuasca was about.
Also, my anthropologist friend
introduced me to this other person.
He was professor of pharmacology at
this institution. It's Saint Paul's
Hospital in Barcelona. This is a venerable
institution. It was founded
in 1401, so shortly after I
went to this hospital,
we celebrated the 600th anniversary
of the institution. And he was
leading the psychopharmacology
research team at this hospital,
and I proposed that we
might study ayahuasca. No one had
conducted any studies,
or at least to my knowledge, no one had.
At that time, when I met him in 1996,
I did not know about
the Hoasca Project then. And he
found it was very interesting.
Hallucinogens had been
studied in Barcelona,
by psychiatrists 40 years
earlier in the 1950s,
and he said, "Okay, let's go ahead
with this. I have experience with"
"clinical trials, but if you're going to
work with these controversial"
"substances, we have to do this
in a very proper manner, using"
"a very good methodology.
We'll have to submit the protocol"
to the ethics committee, to the
health authorities in Madrid.
So we have to think how we're
actually going to do this.
So we put a lot of thought into
how we could address this,
how we could implement
the best methodologies, single-blind,
double-blind designs, accurately measure
the alkaloid contents in
ayahuasca, and be able to administer it
to the participants in a consistent way,
in an easy way, using a formulation
that wouldn't degrade with time.
After several years, I started working
in this department in 1996,
and two years later we finally obtained
this formulation which was
freeze-dried ayahuasca. What we did
was import Santo Daime from Brazil.
We freeze-dried it. We obtained everything
that was in ayahuasca
except for the water, and we finally
encapsulated it. We also
quantified the alkaloid contents in this
mixture. Jay Scallaway, who had
participated in the Hoasca Project,
determined the DMT content in the powder.
And all this process which I am showing
here in one slide proved to be
very tricky. This freeze-drying process
has to take place under very
specific conditions, in the absence of
humidity. Otherwise what you obtain
is a gooey product that you
cannot use in any studies
or encapsulate or do anything
with it. So finally, in 1999,
we got approval for our first
study in St. Paul's Hospital.
This was a pilot study here. We wanted
to enroll 6 healthy volunteers.
Most of the people we...all the
people we finally enrolled were male.
This was not a condition that
we imposed. It was mere chance,
but in the end we decided that
all should be the same gender.
And here we decided to administer
3 different doses of this
encapsulated, freeze-dried ayahuasca
in increasing order. So we started
with a placebo. We followed with
a low dose, medium dose, and
afterwards, a high dose. The objective
of this study was to determine
the tolerability of this product and if
it had any effects at all, if
the effects that people would be
experiencing would be the same that
we had been told people experience
during the ayahuasca sessions,
or whether this freeze-dried product
would be totally inactive.
We also obtained some initial
electroencephalography measures and
we also drew some blood samples,
but this was not the main objective
of this pilot study. So here's a picture
of myself with less years
and more hair on the left and my
supervisor Manel Barbanoj here.
We are about to start this first clinical
trial in healthy humans
administering the ayahuasca doses.
And we thought that perhaps
the people who would volunteer for
this study would be Santo Daime
members or people who were
involved in the ayahuasca rituals,
but in the end, they saw really no
interest in coming to our lab and
experiencing all the uncomfortable
aspects of participating in
a clinical trial, like having an indwelling
catheter in your vein or having
electrodes attached to your scalp.
So in the end, the people
we recruited were psychonauts.
Very brave, all these people who
decided to volunteer and experience
the effects of ayahuasca in
a clinical environment. And here is one
of the participants who put on
his lucky t-shirt this day. [laughter]
Here we can see him
about to swallow
the freeze-dried ayahuasca capsules
before we start taking measures,
et cetera. And a few minutes after
the ingestion of the capsules,
we can see the first signs of
inebriation taking place which,
in his case, were an intense
inclination to fool around.
[laughter]
So after these initial minutes, this
participant was more in control of himself.
After 45, 60 minutes the real trance
set in, and here where we can see
him experiencing bliss or ecstasy
during the acute effects of ayahuasca.
So, jokes apart, this initial
pilot study worked quite well.
We did get all the subjective
effects that people reported
for ayahuasca. We administered,
for instance, this rating scale,
the Hallucinogen Rating Scale. It had
been developed by Rick Strassman
to assess the effects of intravenous
DMT. And we obtained in this
pilot study a nice, dose-dependent effect.
We found significant increases
in affective modifications
in cognitive processes,
changes in perception. Also,
an increase in intensity as we gave
a higher dose. Also, somatic effects, and
the only scale which was
not significantly modified in
this study was volition.
The volition scale is measuring
the degree to which
the participant is incapacitated by
the drug that's been administered.
So, participants were able to
interact with their surroundings.
The experiences they had were
very introspective. They closed
their eyes. They concentrated on
the mental processes that were
developing while the effects of ayahuasca,
and it was very easy to deal with
them in this experimental environment,
even though we had this initial
worry that perhaps it wouldn't be possible
at all to be able to do this
in a laboratory. Also, we recorded what
participants considered
unpleasant in these different sessions
in which they participated,
and as happens with liquid
ayahuasca, many of them reported
experiencing nausea. Here after
the placebo, no one experiences nausea,
but after the low and the medium
dose, 4 out of 6 participants or
5 out of 6 participants experienced
nausea to varying degrees,
but vomiting was very infrequent.
This was an interesting difference
with liquid ayahuasca. Only one
subject out of 5 actually vomited
despite this nausea that people were
experiencing. This freeze-dried,
encapsulated form of ayahuasca
proved to be very convenient for
studies in this clinical setting and besides,
it seemed to be more tolerable
than the original tea. We also wanted
to assess cardiovascular safety.
Was this posing an important risk
from the cardiovascular
point of view for the participants?
And here you can see the graphs
for systolic blood pressure,
diastolic blood pressure, and heart rate.
And despite these increases
you see here compared to placebo,
placebo would be the blue line,
these increases were not significant,
maybe because the sample is
so small, only 6 volunteers, but the main
increases we measured
were also very moderate between
12, 14 mmHg of increase.
If you compare this to an amphetamine,
an amphetamine in a clinical
setting has been reported
to induce increases
in the order of 30, 40 mmHg. No effects
whatsoever were observed
in heart rate, only this random variation.
This is between two, four
beats per minute increase, but nothing
significant, and we've never
found significant variations in
heart rate in subsequent studies.
We also did, after each of the
experimental sessions, a series of
blood tests in order to see whether this
was toxic from different points of view,
and we saw no alterations in blood cell
counts, in white blood cells,
red blood cells, platelets, many other
variables we assessed here,
or in biochemical parameters.
In bilirrubin, creatinin,
in liver transaminases, there was
no sign that this was
being a burden for the liver
whatsoever. So after this initial
pilot study, we moved on to a
larger study which we called the
pharmacokinetics-pharmacodynamics
study. Here we measured
many different
pharmacodynamic variables.
Pharmacodynamics deals with
the effects of drugs.
Pharmacokinetics is studying the
variations of drug concentrations
in the body. And here we had a
larger number of participants.
We had 18 healthy volunteers.
We had 2 doses, 0.6 and
0.85 mg DMT/kg body weight
and also a placebo. Here we did all kinds
of measurements. We obtained
blood samples at many time points
to be able to plot the variations in
concentrations along time.
We took many measures
of brain electrical activity,
electroencephalography, in order to...
assess the topographical changes.
That means the changes on the scalp,
the voltage changes on the scalp.
Also, to try to identify in the brain,
which brain areas are responsible
for these changes we are
observing at the scalp level,
and also a series of other
measures like evoked potentials.
I'll talk about this later. And we wanted
also to measure in people
the monoamine oxidase inhibiting
effects of ayahuasca.
Here in this larger study what we saw
related to pharmacokinetics,
to alkaloid plasma concentrations, is
that there was a nice correlation
or correspondence between the
increase in DMT plasma levels,
the time at which the peak concentration
is reached and the decrease
that's observed thereafter, with the
subjective effects that were
reporting the volunteers. We could see
that the maximum concentrations
of DMT occurred around 1.5, 2 hours
after administration, and this
coincided with the peak of subjective
effects. And also here in
this study, we observed a nice
dose-dependent effects as
we had found in the pilot study.
We also determined other substances
that are found in ayahuasca.
We determined blood levels of
harmaline, the blood levels of
tetrahydroharmine. Here also,
the levels we measured were
dose-dependent. After the higher
dose, the levels we could
find in blood were higher than
after the low dose.
But what we didn't find here in
most volunteers was harmine,
and this is the main monoamine
oxidase in ayahuasca, and it's
present more or less in the same
amounts as tetrohyrdoharmine,
at least in the ayahuasca we were using.
So we were surprised by
this finding, and we decided to look
into 2 potential derivatives
of harmine and harmaline, which are
harmal and harmalol.
These compounds are also
found in ayahuasca,
but the amounts we measured
here were larger
than those that were present in the
tea that we were administering.
So the conclusion we reached, and
we have replicated this in
a subsequent study in collaboration
with Ethan McIlhenny and
Steven Barker, is that harmine
gets very rapidly metabolized
when it's ingested, at least in the
volunteers that have participated
in our studies. This is dependent
on a series of enzymes
called cytochromes. Basically what
they do is they transform
harmine into harmal and
harmaline into harmalol.
So very quickly, these monoamine
oxidase inhibitors
get wiped out of the system. So this
monoamine oxidase inhibition
that's brought about by ayahuasca
is relatively short-lived and not
very intense, or not as intense
as we thought this would be.
So...
[inaudible]
they are, but they are less potent
than harmine and harmaline.
[inaudible]
We weren't able to measure any harmine
in most of the participants in this study.
[inaudible]
How early? Half an hour maybe,
between 15 or 30 minutes.
What we did, also, based on data
that Rick Strassman had obtained
in his intravenous DMT studies and
using a pharmacokinetic parameter
that's called the apparent volume of
distribution, we tried to estimate
what the amount of DMT that had
accessed systemic circulation in
our study. We did this by calculating
a series of ratios between our values
of apparent volume of distribution and
the volume of the distributions
that we had calculated based on
Rick Strassman's data. We found that only
around 10, 14% of DMT in ayahuasca
actually reaches systemic
circulation. So most of it, even in
the presence of these
monoamine oxidase inhibitors,
gets degraded.
What we've seen in
subsequent studies is that
oxidative deamination is not
the only pathway that's
available for DMT to be degraded.
So even if monoamine oxidase
were 100% inhibited, there
would be other pathways
that DMT could follow to be
eliminated from the system.
So this combination of Banisteriopsis
caapi and Psychotria viridis
is effective; it leads to
psychoactivity, but perhaps it's not
that effective as we would have thought,
because you are only using
this 10, 15% of the DMT that's present
in the brew. So that was the
pharmacokinetics, and we wanted to
try to understand which brain
mechanisms ayahuasca was targeting.
We wanted to study
the pharmacodynamics,
which were the effects
that ayahuasca was
exerting on the brain.
In order to do this we used
a series of measures.
One of the measures was this
paradigm. It's called P50 suppression.
This is based on a theory that
postulates that under certain
circumstances, the brain is less
able to filter out information.
We thought that perhaps all
these visions, all these thoughts,
these revelations, these insights
that people are experiencing
during the effects of ayahuasca
arise from the fact that
more information access consciousness
than during normal wakefulness.
We wanted to test this, by means of
this P50 suppression paradigm,
and basically what you do here is
present a series of pairs of stimuli,
of auditory stimuli and you measure
the event-related potentials,
the brain activity that's time-locked
to the presentation of
these stimuli. What we saw here is that
there's really, there's
a certain decrease of the amplitude
of the first of these
two stimuli when you
administer ayahuasca.
After the low dose or the high dose,
there's a slight decrease, but
what's most remarkable here is that
the activation that the second
auditory stimulus, or the second click,
elicits at the cortical level,
it increases with dose. As the dose of
ayahuasca gets larger, this
filtering property, that
the brain has to not allow
certain information to
access consciousness,
actually decreases, and it does so
in a dose-dependent manner.
These decreases are statistically
significant as you can see here.
We had a first insight into which
brain mechanisms could be involved
in the genesis of the effects
of ayahuasca on the brain.
What we did also was measure,
repeatedly, spontaneous brain
electrical activity, that is, not brain
electrical activity that's
locked to the presentation of a
given stimulus, but spontaneous
activity without any external input.
Here what is shown in this
figure is the results of
this statistical analysis.
This is a multivariate analysis
in which we have
recorded the EEG signals,
we have calculated the
power spectrum at different
time points, at 45 minutes,
1 hour, 1 and a half,
2, 2 and a half,
6, 8 hours after
ayahuasca administration,
for the low dose, and for the high
dose. Here these circles represent
the head, the scalp. Each white dot
is an electrode, and all the
changes you see here in red or purple
indicate statistically significant
differences versus a placebo. So
changes after the low dose are
really isolated, just in certain electrodes,
and one could think they
are almost random, but after the
high dose, we see that
most changes are found
around the peak of
subjective effects between 1 and
2 and a half hours after administration.
We can see these changes on many
different electrode or recording sites.
Afterwards, what we did was look
at the different frequency bands.
This is a classic division of the
power spectrum of the EEG into
frequency bands. We have what is called
a slow activity or
a delta power, and here, what we saw was
basically decreases in delta power.
So this slow activity gets diminished.
The maximum effects are observed also
around 90 minutes or 2
hours after administration.
Also theta power, which is the
frequency band that goes from
3.5 to 7.5 Hz was also showing statistically
significant decreases, also
around this time window.
The same happened for
alpha power although
effects were visible a little earlier
and lingered longer than
for other variables.
For beta-1, which is in
the low range of
the fast brain activity,
we also saw decreases.
When we looked at the higher
frequencies, we saw increases
in those values, but these
findings were not as
consistent as the decreases we
find in these lower frequency bands.
So in terms of if you...what's
happening here is that there's a shift
from the slow activity to the fast
activity, and in relative terms
you have increases in beta, in
fast activity, in beta-3, in beta-4,
but when you do the subsequent
analyses that I'm going to show now,
nothing survives multiple comparisons.
So what analysis we did later? What
we did was based on these changes
we're seeing at scalp locations
which are basically changes in power,
in voltage, we tried to localize
which brain areas were responsible
for these changes. We have a series
of measurements on the scalp,
you have your potential values, you
have a transform metrics, and
finally, what you find is another value
which is current density in
a series of voxels, of volume elements
throughout the brain. You can
represent changes also using a series
of statistical comparisons,
and you do this in
a standard brain atlas,
which is the Talairach brain atlas.
We did this for the findings we
had found in the delta band,
and we found that changes
were located, or the areas that
were thought to be related to these
changes we were seeing were found
in posterior brain areas, in the
middle temporal gyrus, the superior
temporal gyrus, the precuneus, and
in the fusiform gyrus, basically
all areas that are in the
posterior section of the brain.
When we looked at theta changes,
here we also saw changes in
the temporal lobe, and the only
changes that we observed
in frontal regions, basically located
in the cingulate gyrus and in
the medial frontal gyrus. When we
looked at the alpha-2 band again,
the sources which were responsible
for the changes were located
in posterior brain areas, temporal
and precuneus, and for the beta-1
band, also precuneus. So the majority of
changes we were seeing here,
based on the effects of ayahuasca
on the EEG, were located
in these posterior areas of the brain,
but after all, this is not
the gold standard to try to find which
brain areas are responsible
for drug changes. Most studies,
which are considered to implement
a better methodology or have a better
localization power were at
that time nuclear medicine techniques.
So what we did later was a
SPECT analysis, but before that,
what I'm showing you here
is the summary of results we
found for the EEG findings.
Basically, we found that the areas
that were responsible for the
changes were located in
association cortex. This association
cortex is responsible for
the processing of auditive,
somatosensory and visual information,
and also in what's called transmodal
areas, those areas that are
connecting different areas of the brain
that are responsible for
the initial processing of information in
the visual modality or in
the auditive modality. So these transmodal
areas, what they are doing
is connect information that's
coming from more basic areas.
And basically, we found significant
effects here in the temporal,
parietal and frontal intermodal
association cortex, and
also in limbic regions, as I've
shown you in the anterior cingulate,
and in the parahippocampal gyrus.
After this initial analysis, we
went on to do a nuclear medicine study.
We did a SPECT study. What
we did here was administer a high
dose of ayahuasca, and after
around 100 minutes or 2 hours after
drug administration, when
the effects were maximum, we injected
a tracer, and afterwards we
brought the subject to the camera,
and saw which brain areas lit up
during the acute effects or the
maximal effects of ayahuasca.
And here, in this study, we found
activations in the anterior
cingulate cortex. We had seen this
one also in the analysis of the
theta power, in the EEG study,
also in frontal regions in
the medial frontal cortex.
In the insula, we hadn't found any
changes in the EEG study in this region,
and in the parahippocampal gyrus
and hippocampus, which we
had found in that previous study.
So there's partial overlap
between the two techniques. We
find that in certain transmodal
areas we see changes in EEG
activity and also in blood flow,
measured by means of SPECT,
basically in this frontal intermodal
association cortex, and the limbic
regions, but what we really
didn't see using this nuclear
medicine technique is any changes
in posterior brain regions.
These decreases in posterior areas
are very stubborn, because
we have conducted additional
studies involving the administration
of ayahuasca subsequently,
like this study in which we administered
2 different doses of ayahuasca,
one at time zero and one 4 hours
after the initial dose, and we keep
seeing these decreases in posterior
brain areas. And these changes
we see here we really didn't find
in the nuclear medicine
technique, in SPECT. So maybe,
depending on the technique
you are using, you may see some
effects of the drug and not others.
So if we have to compare the
results we obtained using the
2 different techniques, we find
that by means of current
density analysis, we can locate
activity changes in the associating
cortex pertaining to the visual and
auditory sensory modalities,
and this will be useful to explain
the perceptual modifications
that people under ayahuasca refer.
How is it possible that you see
changes in external perception, in the
depth of objects, in the intensity of
lights, in color, if areas that are
associated with visual processing
are not targeted by ayahuasca,
if you only have changes in
frontal brain areas? So based
on current density analysis,
we could be able to explain these
perceptual modifications.
Also, the changes we see using
this technique in transmodal
areas, basically this intermodal
association cortex, would allow us
to explain phenomena like synesthesia,
which is experiencing
one sensory modality affecting
another sensory modality.
All these changes we see here
would be dependent on posterior
brain regions and are only
visible if we use this technique,
current density analysis of
the EEG. The limbic areas lit up
in both techniques, using [Lareto],
the current density analysis,
and SPECT. Changes at this level
could explain the recovery of
memories that people report
under ayahuasca, also the affective
modifications, and changes in
the frontal neocortex and insula,
which we only saw using
the nuclear medicine technique,
using SPECT, could explain
also the insights, the interception,
the understanding and the revelations
that we usually experience
during the peak effects of ayahuasca.
So this is the information
I have from previous studies.
This is already published,
and here was basically a comparison
of the two techniques,
and now what I'm going to
show you here is results I obtained
very recently, just one or two
days before I took the plane
to San Francisco. Basically what
we've been doing here is analyzing
brain electrical activity, EEG,
using a different technique.
We have a team of engineers
who are working with this analysis,
this signal analysis. They are
using transfer entropy, and this is
based on information theory.
Basically, this technique, what it
allows us is to see whether
activity changes at one location are
affecting activity at other locations.
So this is an asymmetric
measure. We can establish
causality relationships between
changes we observe, and if we
analyze the EEG signals in
the repeated dose administration
study, we see that basically,
what we have here is a change
in the way anterior and posterior
regions relate to each other.
So here, 2 hours after ayahuasca
administration, we are seeing
a decrease in anterior-posterior
connectivity. We can analyze
which areas are conditioning
the effects on other areas, so
what is causing the effects,
and what is the consequence
of the changes. So we can identify
areas that we can call sources
of this decrease
we are observing, and we can
also identify the targets of these
decreases we are observing.
So here what we have at 2 hours after
ayahuasca administration is
a decrease in the frontal-parietal
transfer of information. So
there's a decrease in causality
between frontal and posterior
areas, and here what we see
is that frontal brain regions are
decreasing the control or the influence
they have over posterior
brain regions. So using this technique,
we are seeing effects at frontal
locations and also at posterior
locations, what we were unable
to see when we used either EEG
power analysis or when we
administered a radio tracer to see
changes in blood flow.
These relationships are dynamic,
and when we do this analysis
not at 2 hours after ayahuasca
administration but at 2 and a half
hours after ayahuasca administration,
what we see here is an increase
in anterior-posterior connectivity.
So this might appear shocking,
or in contrast with what we were
seeing at 2 hours, but if we take a look
at the sources and the targets
of these changes, we see now that
the source areas involved in
this increase are posterior
brain areas, and the target areas
are basically anterior. So there's
also changes here, but most of
the areas that are acting as targets
here in this analysis are anterior
brain areas. So what we saw earlier
was a decrease in the information
transfer from anterior to posterior,
and here what we see is
an increased information transfer
from the parietal cortex to
the frontal cortex. So in a way, we've seen
an inversion of what would be
normal functioning without ayahuasca,
because these changes I'm
showing you here are the statistical
comparison versus placebo.
At 3 hours after drug administration,
again we see a decrease between
anterior and posterior sites.
We didn't see changes between,
let's say, right hemisphere
and left hemisphere, but it's
always frontal and posterior.
Here the source areas are again
frontal areas and the target
areas are posterior brain areas. But
here, like what I had shown you
at two hours, what we see is
a decrease of the influence
anterior brain areas or activity
at these sites has over activity
at posterior brain areas. So by
this new technique, we haven't
given still much thought into
these results. As I am telling you,
this is preliminary. I got it the same
week I flew in. It's that
perhaps we have found a way
in which we can see this combined
effect which, depending on
the technique we used, we could only
see in the back part of the brain
or in the frontal part of the brain.
So given that ayahausca is
targeting all these areas and
the frontal cortex seems to be
a prominent hub in mediating
the effects we see after ayahuasca
administration, what we
planned to do and did was see
how acute ayahuasca administration
would affect cognitive processes
that we know that are depending
on the correct functioning of
the frontal cortex. So here we
administered a battery of
neuropsychological tests while
people, subjects were under
the influence of ayahuasca.
The first test we used was
the Sternberg test. This is a working
memory task. Here, what I'm
showing in the graphs is the total errors
that subjects are committing.
Here they are presented with a series
of letters, and after a while a fixation
cross appears on a screen,
and afterwards they are shown
a test letter, and they have to say
whether this letter was in the initial
list or not. This is a working
memory test. What we saw here
is that, compared to pre-ayahuasca,
which are the bars in blue, after
ayahuasca there's a certain increase
in the errors that people are
committing, but these errors, or
the number of errors, is dependent
on the experience people have
with the tea. So we recruited
people, we did this on purpose,
that had either only occasional
experience with ayahuasca
or were very experienced users.
Maybe people here had used
ayahuasca on tens of occasions,
while people here had used
ayahuasca on hundreds of
occasions. As you can see,
the increase we see in
the number of errors is much larger
in the occasional users than in
the experienced users, but this
didn't reach statistical significance.
But we are seeing here that
ayahuasca might be affecting
functions that are dependent
on the frontal lobe, but this highly
depends on the experience
that people have with the tea.
So there can be several explanations
for this, like people are more able
to focus on the task because
they are more familiar with
the experience, or maybe something
is changing in the brain after
several ayahuasca intakes,
or after many ayahuasca intakes,
that allow them to do this
much better than the naïve
subjects or occasional users.
So we also did this more complex
task, which involves planning.
This is not only working memory;
it is a more complex task.
Here, what we saw is that
occasional users are clearly
impaired, but experienced
users actually perform better
under ayahuasca than
after placebo.
[laughter, applause]
And in this case, in the Tower
of London, this reached statistical
significance. So there's a
different behavior depending on
your prior experience with
ayahuasca. If we have a look at the
number of movements they
used to solve this test, this
Tower of London, again, we
see that the occasional users
are impaired. The experienced
users actually perform better.
This again reaches
statistical significance.
So, these are effects after acute
ayahuasca administration
in people who had experience,
varying degrees of experience,
with ayahuasca, and what we did
was also plot these lifetime
ayahuasca intakes versus their
performance on the Tower of London.
Here we are correlating the
number of times people have
participated in ayahuasca
sessions against time, against
the execution time. We have
a significant correlation here,
so the greater your experience
with ayahuasca, the better
you perform this task, and the same
with the Tower of London.
So after finding these very
interesting results, we wanted
to have a look at the brains of
our experienced users. So this
was not exactly the same
sample that had participated
in the acute ayahuasca
administration study, but here what we did
was recruit a series of very
experienced people. They had used
ayahuasca for many years, and
we did a series of studies
using magnetic resonance imaging.
We analyzed cortical
thickness, diffusion tensor
imaging and functional fMRI.
I only have the results for
the first test, for cortical thickness.
This is what I'm going to
show you now. What we saw here is
that compared to controls, long-term
ayahuasca users actually
have showed changes in
brain areas. What are the changes
we observe? In certain brain areas,
posterior brain areas, we
find a decrease in cortical
thickness, and in frontal areas
we find an increase. So again,
we are seeing these two hubs
that seem to be related to
the acute ayahuasca effects,
these medial areas, one frontal,
one more posterior, this posterior
in the posterior cingulate and
the precuneus. If we correlate
these changes with lifetime
ayahuasca use, we see that there's
negative correlation for
the decreases. There's a positive
correlation for the increases
in these areas. So the more
ayahuasca you've taken,
the greater the cortical thickness
in the frontal medial areas, and
the smaller the cortical thickness
in posterior brain areas.
What's the impact of these
changes we are seeing in these
brain regions? Are these people
impaired when they're not
under ayahuasca? How do they
actually perform when we subject them
to neuropsychological assessment?
Well, here you can see,
for instance, results of a
working memory task. It is called
a 2-back task. Again, users
perform more rapidly,
this is reaction time, than
controls, and this is significant.
This is the percentage of correct
responses we are getting, and again,
long-term ayahuasca users perform
much better than controls.
So at least we are not seeing any
impairment in neuropsychological
testing associated with long-term
ayahuasca use, even though
we are seeing changes in brain areas,
in this cortical thickness
measures, this is not related to
impairment in performance.
So this is all the data I wanted to
show you today, and just
a brief mention of the ongoing
studies we have, and future studies
we have planned. We are going to
analyze the fMRI and DTI data
we have gathered in this study
with long-term ayahuasca
users. We also have a collaboration
with the State University
of Louisiana, with Dr. Steven Barker
and Dr. Ethan McIlhenny.
We are studying DMT metabolism.
We have already some data
we'll publish soon. With
the team in Brazil, led by
Drs. Draulio de Araujo and Dr. Ribeiro,
we are going to start
a study assessing the potential
benefits of ayahuasca in depression.
In Barcelona, we are also planning
to start a new study in which
we are going to investigate the
role of the serotonin 2A receptor
in the effects of ayahuasca. We are
going to administer
this compound, ketanserin,
trying to block the effects
that ayahuasca brings about and
in this way try to see to which extent
this receptor plays an important
role in all the effects we are seeing
on the subjective effects, on these
EEG changes I've shown you,
and we're trying to get funding
for this project. Hopefully
we'll be successful. Yeah, the last
thing I want to do is give thanks
to all the people who have collaborated
with us through the years.
Josep María [Fericula], Esther Martinez,
Josep María Fábregas,
these people which I've mentioned
at the beginning of my presentation,
who were crucial in guiding me in
these initial steps of my research,
James Callaway from
the Hoasca Project quantified the DMT
in the ayahuasca we used. José Carlos
Bouso and Rafael dos Santos,
my Ph.D. students. They are doctors
already. They gathered
most of the information I've
shown you, and Draulio de Araujo,
Fernanda Pailano, Sidarta Ribeiro,
have done the analysis
of the cortical thickness study, and
Steven Barker, Ethan McIlhenny,
have helped me with the
pharmacokinetics studies, and these
three people, Sergio Romero,
Miquel Angel Mañanas,
Joan Francesc Alonso are
engineers from the Polytechnical
University at Barcelona, and
they are implementing all this
entropy transfer analysis that
I've shown you. And finally,
Richard Wolfe, who's in the
audience, and Ben de Loenen,
have supported us through all
these years, have helped us
financially with our research, and
I would like to thank you all
for your attention this morning. Thanks.
[applause]
[inaudible] about a
half hour for questions.
[inaudible]
Hi, my name is Bruce Morton. I'm
from the University of Hawaii.
I think the core issue of all our
studies is "how do psychedelics"
"cause ego death and transcendence?"
I think your studies
are fascinating in that they show
brain areas that have been
associated with the generation of
ego strengths, and in particular
I applaud you for calling the attention
to the anterior cingulate
and the insula, which are key
elements in the production
of the ego, and who struggle valiantly
against being suppressed
by hallucinogens, ultimately to
become chemically poisoned.
So please continue your work, and
I would like to keep the focus
on 5HT-2 receptors in these limbic
areas, and thank you very much.
Thanks.
Brian Rush, Toronto, Canada.
Thank you for a great overview.
I guess my question is: we now have
so many years of research
showing low or no toxicity, including
other studies for sure,
you know, not presented of
your own work. For those of us now
embarking on other more
clinically-oriented studies, for example
in addiction or in depression,
should we be monitoring toxicity
in those studies, or do we have
enough? I guess it's almost
a policy question. Do we have
enough information to satisfy
those people who would be
concerned about that?
Well I think you always have to
be on the safer side, and I would
recommend that you do that,
that you test for toxicity
for potential participants before
you enroll them in the study, and also
throughout the study. I'm also
sure that if you plan to do this in
a country where no previous
studies with ayahuasca in clinical
populations have been conducted,
the health authorities
will certainly require this.
Thank you.
[Juan Gustus], clinical psychiatrist
from Belgium. Regarding
the cardiovascular safety, what do you
know about the increase of QT
and ECG? Because, for
cardiovascular safety, you only,
the blood pressure and...so what
do you know about the [inaudible]?
We recently did a study in which
we monitored electrocardiogram
continuously, but we still haven't
analyzed the data yet.
So during the effects we recorded
this. But what we also did in
all other studies is, when we
included the volunteers, they also
had an electrocardiogram done,
and afterwards, before they
were considered they had
finished their participation with us,
they also had this done, and no
alterations were found
in these variables.
Thank you.
Douglas [Call], from [Ashen],
Oregon, I'm a psychologist,
neuropsychologist. The question
is: on the connectivity
measures that you had, was that
across all frequencies?
Say, .3 to 30 Hz?
Yes, in this connectivity measure,
in transfer entropy, you use
the whole signal. We didn't subdivide
into frequency bands.
It is a totally different
kind of analysis.
With conventional quantitative
EEGs, you can look at the phase
relationship. Do you guys, can you
do that with that technique, or not?
We have used other connectivity
measures. We have explored
other connectivity measures
subdividing by frequency bands,
and we didn't find systematic effects
or something that made sense
to us. So it's basically this transfer
entropy, it's the technique
that has allowed us to obtain
more consistent results.
It sort of looked like what you
got was the deactivation
of the default network, which of course
makes sense. Does that
seem reasonable to you?
That could be an interpretation, but
when we did this data processing
of the EEG many years ago,
because we published the paper
in 2002, the default mode network
was not invoked at the time,
so we didn't interpret our results
using this framework.
But seen in retrospect, that
could be a possible
valid interpretation, I guess.
Hi, I'm Gerald Thomas from BC,
Canada, and I'm just wondering:
the subjective effects of ayahuasca
vary greatly in the experience,
and I wonder, in this connectivity
between the front and the back
and the flip-flopping you saw
of that, which is dominant,
in those instances where people
don't report much of an effect,
because I've been in ceremony
where that's the case, nothing
really happens, were you able
to differentiate who was having
that flip-flop, and what degree,
and how it affected their
perceptions of the experience?
What I'm showing here is the
results of a statistical comparison
in which I'm comparing a group
of 22 participants in the day
they received ayahuasca versus
the day they received placebo.
So you see here those interactions
that survived the statistical
comparison and the correction
for multiple comparisons,
so you don't see the individual
changes. But what we plan to do,
also, is start looking for
relationships between the changes
we observe at this level and
subjective effects. So we are
doing this right now.
Kenneth Tupper, University of
British Columbia. I understand
the experimental conditions under
which you were making
your observations were stimulus-free.
There was no audio inputs.
In the experiences of most traditions,
the environment includes
singing or chanting. Music seems
to be an integral part
of the ayahuasca experience in
almost all the traditions
that use it. Have you thought
about the role that music
might play in the brain effects, and
thought of that as an experimental
control for future research?
Until now, we've always conducted
our studies in a dimly-lit
ambience without any prominent
external stimuli, except
when we've measured evoked
potentials. But that would,
it is certainly something I would
want to look at, because,
yeah, I know how powerfully music
can influence the experience,
and that would certainly be
something very interesting for
a future study. I'm sure that,
who knows, maybe the effects
we see are different. But it's
hard enough to interpret
what we have now, so that would
be another level
of complexity, I guess.
Thank you.
Yes, the music shifts the pictures
in the ceremonies. I've been
doing brain mapping, EEG,
of ayahuasca, and acute effects
of smoked DMT also, and what
impresses me most is how variable
the changes are from one
person to another. So I always
look at a baseline and then changes
and do that kind of comparison.
Your EEG data here was
a group comparison?
It's a group comparison, and yeah,
EEG's very tricky. You have to
standardize the recording conditions
very well, and I think that
incorporating a placebo is essential,
because you see variations
as time passes, even if you don't
administer any substance.
So the EEG's going to change,
so in the...what I'm showing
here always is the comparison
versus the placebo, so I've
subtracted the effects that the
placebo induces, so you see
the net effect.
So it's a group comparison.
If you only do a pre- and a post-,
you are not controlling
for this variability. So I would always
encourage or recommend
to incorporate some kind of
placebo measure to subtract.
Yeah, I have this wonderful software.
You can get a very reliable
high-test/retest reliability pre-
and post-, but what's exciting
is that the EEG changes are
reversible, with the acute changes
with DMT, and the person is
now returning to ordinary
consciousness and the EEG is
also returning and looking like
the baseline now.
Hopefully.
So come and see the notes that I have.
Not hopefully; it's data.
It's real data.
Well, I mean the effects last for
several hours, so if you come back...
I'm talking about acute...
To shared reality I would expect
the EEG to return to baseline
levels, I guess.
It does over hours, but acute
tests within minutes.
Hello Jordi. Thank you for your talk.
My name is Fernando Tófoli.
I am from the State University of
Campinas, Brazil. I wonder
whether these experienced users
of ayahuasca were from
an ayahuasca religion, and if so,
how you think that might
affect the results of the test? I mean,
being a member of one of
the religions is not only drinking
ayahuasca, but being subject
to a lot of other variables. How do you
control these variables?
That's my question, if we can.
We haven't controlled for these
variables. But what I can say
is the less experienced ayahuasca
participants that I've
shown data for here were also
participating in these religious
ayahausca sessions.
They were not participating with
the same regularity as
the experienced users, and they
had a lower number of total
intakes, but they had also been
involved with these ayahuasca
religions. So yeah, we didn't
explicitly control for that, but
most of them had, also, experience
with religious ayahuasca groups.
Thank you.
You're welcome.
One of your slides showed, that
you went over very quickly
and didn't talk about it, showed
the individual differences
in responsiveness to beta-carbolines.
I myself have found
an incredibly sensitivity, like when
I have ayahuasca, I must have
vomited all of four hours, 40 times,
and I've tried it over and
over again, and I think that I must
be, not an evil person
but somebody that's...
Maybe you're just a slow metabolizer.
There are people, there are genetic
differences, then, between
metabolizers, and I'm wondering if
this has anything to do with
the fatalities associated with
ayahuasca in South America,
or in Central America.
That can always play
a role. Individual
differences, of course. If you're
a slow metabolizer, you'll have
higher levels of alkaloids, and
they are, from person to person,
this varies. So the same amount
of ayahuasca could lead to
higher alkaloid concentrations and
if you are taking other medicines
or you have heart conditions
or whatever, then perhaps
the adverse effects you may
experience will be stronger.
I was curious about the
Tower of London test and other tests,
whether those were administered
at one time or over time,
and if you noticed an improvement
over time. I'm thinking about
Rupert Sheldrake's studies on
crossword puzzle use over time.
The more people who are exposed to
a certain crossword puzzle,
the faster they get at it, and
I wondered about statistical
analysis of those sorts
of possible effects.
Yes, in that study, we had
these 2 groups of participants,
and they all did the Tower of London
and all the neuropsychological
tests prior to ayahuasca intake,
and then afterwards. So they
did the test twice. But the
changes...everyone went
through this protocol this way,
because it was very difficult
to counterbalance the administration
of these tests. How are you
going to grab people's attention
to explain them how to solve
the Tower of London, if on the first
occasion they are under
the effects of ayahuasca? So
everyone did this prior to ayahausca
intake and then afterwards. But
of course this is an issue,
and what we are currently doing
is we are recruiting another
group of people and we are
going to administer the same tests
twice to see if there are any
learning effects involved, that
could require another interpretation
of the results we are getting.
But we are currently doing this;
we haven't finished yet.
My question was about whether
the people took the test at
the same time, and whether the
people that took the test later
in time would do statistically better
than those who had done it
at the beginning of the experiment.
Rupert [Sheldrake]'s
study on crossword puzzle use or
solving was people that had
never seen that crossword puzzle
before did better statistically
than those who had done it
yesterday versus today.
Oh, you mean the time lapse
between the first assessment
and the second assessment?
It was the same for everyone.
And the time window in which
we tested them during the acute
effects of ayahuasca was the same
for everyone. So it couldn't
happen that someone was not
experiencing ayahuasca
effects anymore, or one person
was in the initial abrupt phase
in which the ayahuasca effects
were still increasing. Everyone
was in the plateau when we tested them.
Okay.
Hi. My name is Cory Bathfield.
I'm from Brooklyn, New York.
I'm studying shamanism in the
Iquitos region in Peru right now,
and looking at these slides,
I noticed, as you said, that
some people perform better...
the people who are experienced
users perform better on tasks
in their regular life not under this
influence. I'm wondering if you
have thought about, or if you're
interested in doing any research
in doing that deliberately,
like using ayahuasca
as something for cognitive,
or for learning enhancement.
The main bias in these results
I'm showing you is that when you
test long-term users, you're testing
people who have decided
to keep taking ayahuasca, and
probably if they've decided
to keep taking ayahuasca it's
because they find that this is
positive in their lives. So what
happened with the other person
who tried ayahuasca once and
never returned? So perhaps
if you are experiencing
deleterious effects of ayahuasca
and never show up again at
an ayahuasca meeting, then
15 years later you are obviously
not available for testing,
or if you suffered cognitive impairment
or psychiatric consequences,
whatever. I don't know. I have to
admit, also, the weaknesses
of this design. So ideally what we
should do is contact people when
they are initially interested
in getting involved with ayahuasca,
and follow them for a certain time,
for some months or years,
and see what leads some to
carry on taking ayahuasca,
and others to decide they want to
give up, and see if anyone
experiences negative consequences
or whether this is positive
for everyone. I don't know. If you can
see cognitive improvements
in a substantial number of
individuals, why not? We could try
what you are suggesting and see
if this could be used to
improve cognition. I don't know.
Hi. I was curious if you had any
ideas why the freeze-dried
ayahuasca didn't cause vomiting
in most of the patients.
We found this repeatedly through
all the studies we've conducted.
I think the reason can be that
you are not experiencing
all this taste and smell
right from the start. After a while,
of course, people report feeling
the acidity in the stomach,
but they are not suffering
the nausea right from the start.
They don't have to swallow down
something that it's not very pleasant.
So I think that plays a role, perhaps.
Any more questions?
No? Okay, then thank you.
[applause]
[Presented by
The Beckley Foundation]
[Council on
Spiritual Practices]
[Heffter Research Institute]
[Mutidisciplinary Assocation
for Psychedelic Studies (MAPS)]
14 años de ensayos clinicos
con ayahuasca: Jordi Riba
Durante mi charla me gustaría mostrarles algunos datos
que hemos obtenido durante los 14 años, en los que hemos
llevado a acabo una serie de ensayos clinicos que consitian en administrar
ayahuasca a humanos sanos.
Mas recientemente hemos valorado los efectos de la ayahuasca tras el uso prolongado.
Les mostrare unos datos al respecto. Antes de nada quisiera
hacer una introducción o explicarles como me
involucre en este campo.
Como comentó Ken, empece como estudiante de post grado en la escuela de farmacia
en Barcelona, estudiando química orgánica y investigando
la síntesis de los alcaloides de índole, y una serie de felices coincidencias
me llevaron a conocer a un hombre aquí. Es un antropologo
había investigado a los Shuar en Ecuador.
Habia escrito un libro interesante. En español, se llama
Los Jíbaros Cazadores de Sueños.
En ingles, los jibaros o shaur, cazadores de sueños.
[Catorze anos de
Pesquisa Clínica]
[com a Ayahuasca:
Jordi Riba;]
[20 de abril de 2013]
Na minha palestra eu gostaria
de lhes mostrar alguns dados
que nós obtivemos nesses últimos
14 anos, durante os quais
nós conduzimos uma série de
ensaios clínicos envolviendo
a administração de ayahuasca
a humanos saudáveis.