[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.