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← Fourteen Years of Clinical Research with Ayahuasca - Jordi Riba

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  1. [Fourteen Years of
    Clinical Research]
  2. [with Ayahuasca:
    Jordi Riba]
  3. [April 20, 2013]
  4. In my talk I would like to
    show you some of the data
  5. we have obtained in these
    last 14 years, in which
  6. we have conducted a series
    of clinical trials involving
  7. the administration of ayahuasca
    to healthy humans.
  8. More recently we have also assessed
    the long-term effects of ayahuasca use.
  9. I'll be showing some data in this regard.
    First of all I would like to
  10. make an introduction or start
    telling you about how I
  11. got involved in this field.
  12. As Ken has said, I started as a
    graduate student at the pharmacy school
  13. in Barcelona, studying organic chemistry
    and doing research in
  14. the synthesis of indole alkaloids, and
    by a series of happy coincidences
  15. I had the chance of meeting this person
    here. He is an anthropologist
  16. and he had done research
    with the Shuar in Ecuador.
  17. He had written this interesting book.
    It's called, in Spanish,
  18. Los Jíbaros Cazadores de Sueños.
  19. In English this would be
    the jíbaro, or Shuar, chasers of dreams.
  20. So, in a way I found myself
    getting to know people who had done
  21. research with these Amazon tribes
    that were using substances that had
  22. a profound effect on the mind, and
    that I had always been interested in
  23. natural products, and especially
    alkaloids, that had effects on the
  24. central nervous system. And this person,
    which is María [Faricula],
  25. he is anthropologist, also
    introduced me to this lady,
  26. Ester Martinez, and to
    Josep María Fábregas,
  27. who is probably in the audience.
    You'll see a talk he'll give today.
  28. They are medical doctors and
    they were very knowledgeable
  29. about the Santo Daime religion which
    had recently arrived in Europe
  30. and in Spain, and these people
    were having regular sessions
  31. in the Barcelona area. I got in touch
    with them, I participated in
  32. the sessions, and I got to know
    first-hand what ayahuasca was about.
  33. Also, my anthropologist friend
    introduced me to this other person.
  34. He was professor of pharmacology at
    this institution. It's Saint Paul's
  35. Hospital in Barcelona. This is a venerable
    institution. It was founded
  36. in 1401, so shortly after I
    went to this hospital,
  37. we celebrated the 600th anniversary
    of the institution. And he was
  38. leading the psychopharmacology
    research team at this hospital,
  39. and I proposed that we
    might study ayahuasca. No one had
  40. conducted any studies,
    or at least to my knowledge, no one had.
  41. At that time, when I met him in 1996,
    I did not know about
  42. the Hoasca Project then. And he
    found it was very interesting.
  43. Hallucinogens had been
    studied in Barcelona,
  44. by psychiatrists 40 years
    earlier in the 1950s,
  45. and he said, "Okay, let's go ahead
    with this. I have experience with"
  46. "clinical trials, but if you're going to
    work with these controversial"
  47. "substances, we have to do this
    in a very proper manner, using"
  48. "a very good methodology.
    We'll have to submit the protocol"
  49. to the ethics committee, to the
    health authorities in Madrid.
  50. So we have to think how we're
    actually going to do this.
  51. So we put a lot of thought into
    how we could address this,
  52. how we could implement
    the best methodologies, single-blind,
  53. double-blind designs, accurately measure
    the alkaloid contents in
  54. ayahuasca, and be able to administer it
    to the participants in a consistent way,
  55. in an easy way, using a formulation
    that wouldn't degrade with time.
  56. After several years, I started working
    in this department in 1996,
  57. and two years later we finally obtained
    this formulation which was
  58. freeze-dried ayahuasca. What we did
    was import Santo Daime from Brazil.
  59. We freeze-dried it. We obtained everything
    that was in ayahuasca
  60. except for the water, and we finally
    encapsulated it. We also
  61. quantified the alkaloid contents in this
    mixture. Jay Scallaway, who had
  62. participated in the Hoasca Project,
    determined the DMT content in the powder.
  63. And all this process which I am showing
    here in one slide proved to be
  64. very tricky. This freeze-drying process
    has to take place under very
  65. specific conditions, in the absence of
    humidity. Otherwise what you obtain
  66. is a gooey product that you
    cannot use in any studies
  67. or encapsulate or do anything
    with it. So finally, in 1999,
  68. we got approval for our first
    study in St. Paul's Hospital.
  69. This was a pilot study here. We wanted
    to enroll 6 healthy volunteers.
  70. Most of the people we...all the
    people we finally enrolled were male.
  71. This was not a condition that
    we imposed. It was mere chance,
  72. but in the end we decided that
    all should be the same gender.
  73. And here we decided to administer
    3 different doses of this
  74. encapsulated, freeze-dried ayahuasca
    in increasing order. So we started
  75. with a placebo. We followed with
    a low dose, medium dose, and
  76. afterwards, a high dose. The objective
    of this study was to determine
  77. the tolerability of this product and if
    it had any effects at all, if
  78. the effects that people would be
    experiencing would be the same that
  79. we had been told people experience
    during the ayahuasca sessions,
  80. or whether this freeze-dried product
    would be totally inactive.
  81. We also obtained some initial
    electroencephalography measures and
  82. we also drew some blood samples,
    but this was not the main objective
  83. of this pilot study. So here's a picture
    of myself with less years
  84. and more hair on the left and my
    supervisor Manel Barbanoj here.
  85. We are about to start this first clinical
    trial in healthy humans
  86. administering the ayahuasca doses.
    And we thought that perhaps
  87. the people who would volunteer for
    this study would be Santo Daime
  88. members or people who were
    involved in the ayahuasca rituals,
  89. but in the end, they saw really no
    interest in coming to our lab and
  90. experiencing all the uncomfortable
    aspects of participating in
  91. a clinical trial, like having an indwelling
    catheter in your vein or having
  92. electrodes attached to your scalp.
    So in the end, the people
  93. we recruited were psychonauts.
    Very brave, all these people who
  94. decided to volunteer and experience
    the effects of ayahuasca in
  95. a clinical environment. And here is one
    of the participants who put on
  96. his lucky t-shirt this day. [laughter]
  97. Here we can see him
    about to swallow
  98. the freeze-dried ayahuasca capsules
    before we start taking measures,
  99. et cetera. And a few minutes after
    the ingestion of the capsules,
  100. we can see the first signs of
    inebriation taking place which,
  101. in his case, were an intense
    inclination to fool around.
  102. [laughter]
  103. So after these initial minutes, this
    participant was more in control of himself.
  104. After 45, 60 minutes the real trance
    set in, and here where we can see
  105. him experiencing bliss or ecstasy
    during the acute effects of ayahuasca.
  106. So, jokes apart, this initial
    pilot study worked quite well.
  107. We did get all the subjective
    effects that people reported
  108. for ayahuasca. We administered,
    for instance, this rating scale,
  109. the Hallucinogen Rating Scale. It had
    been developed by Rick Strassman
  110. to assess the effects of intravenous
    DMT. And we obtained in this
  111. pilot study a nice, dose-dependent effect.
    We found significant increases
  112. in affective modifications
    in cognitive processes,
  113. changes in perception. Also,
    an increase in intensity as we gave
  114. a higher dose. Also, somatic effects, and
    the only scale which was
  115. not significantly modified in
    this study was volition.
  116. The volition scale is measuring
    the degree to which
  117. the participant is incapacitated by
    the drug that's been administered.
  118. So, participants were able to
    interact with their surroundings.
  119. The experiences they had were
    very introspective. They closed
  120. their eyes. They concentrated on
    the mental processes that were
  121. developing while the effects of ayahuasca,
    and it was very easy to deal with
  122. them in this experimental environment,
    even though we had this initial
  123. worry that perhaps it wouldn't be possible
    at all to be able to do this
  124. in a laboratory. Also, we recorded what
    participants considered
  125. unpleasant in these different sessions
    in which they participated,
  126. and as happens with liquid
    ayahuasca, many of them reported
  127. experiencing nausea. Here after
    the placebo, no one experiences nausea,
  128. but after the low and the medium
    dose, 4 out of 6 participants or
  129. 5 out of 6 participants experienced
    nausea to varying degrees,
  130. but vomiting was very infrequent.
    This was an interesting difference
  131. with liquid ayahuasca. Only one
    subject out of 5 actually vomited
  132. despite this nausea that people were
    experiencing. This freeze-dried,
  133. encapsulated form of ayahuasca
    proved to be very convenient for
  134. studies in this clinical setting and besides,
    it seemed to be more tolerable
  135. than the original tea. We also wanted
    to assess cardiovascular safety.
  136. Was this posing an important risk
    from the cardiovascular
  137. point of view for the participants?
  138. And here you can see the graphs
    for systolic blood pressure,
  139. diastolic blood pressure, and heart rate.
    And despite these increases
  140. you see here compared to placebo,
    placebo would be the blue line,
  141. these increases were not significant,
    maybe because the sample is
  142. so small, only 6 volunteers, but the main
    increases we measured
  143. were also very moderate between
    12, 14 mmHg of increase.
  144. If you compare this to an amphetamine,
    an amphetamine in a clinical
  145. setting has been reported
    to induce increases
  146. in the order of 30, 40 mmHg. No effects
    whatsoever were observed
  147. in heart rate, only this random variation.
    This is between two, four
  148. beats per minute increase, but nothing
    significant, and we've never
  149. found significant variations in
    heart rate in subsequent studies.
  150. We also did, after each of the
    experimental sessions, a series of
  151. blood tests in order to see whether this
    was toxic from different points of view,
  152. and we saw no alterations in blood cell
    counts, in white blood cells,
  153. red blood cells, platelets, many other
    variables we assessed here,
  154. or in biochemical parameters.
    In bilirrubin, creatinin,
  155. in liver transaminases, there was
    no sign that this was
  156. being a burden for the liver
    whatsoever. So after this initial
  157. pilot study, we moved on to a
    larger study which we called the
  158. pharmacokinetics-pharmacodynamics
    study. Here we measured
  159. many different
    pharmacodynamic variables.
  160. Pharmacodynamics deals with
    the effects of drugs.
  161. Pharmacokinetics is studying the
    variations of drug concentrations
  162. in the body. And here we had a
    larger number of participants.
  163. We had 18 healthy volunteers.
    We had 2 doses, 0.6 and
  164. 0.85 mg DMT/kg body weight
    and also a placebo. Here we did all kinds

  165. of measurements. We obtained
    blood samples at many time points
  166. to be able to plot the variations in
    concentrations along time.

  167. We took many measures
    of brain electrical activity,
  168. electroencephalography, in order to...
    assess the topographical changes.
  169. That means the changes on the scalp,
    the voltage changes on the scalp.
  170. Also, to try to identify in the brain,
    which brain areas are responsible
  171. for these changes we are
    observing at the scalp level,
  172. and also a series of other
    measures like evoked potentials.
  173. I'll talk about this later. And we wanted
    also to measure in people
  174. the monoamine oxidase inhibiting
    effects of ayahuasca.
  175. Here in this larger study what we saw
    related to pharmacokinetics,
  176. to alkaloid plasma concentrations, is
    that there was a nice correlation
  177. or correspondence between the
    increase in DMT plasma levels,
  178. the time at which the peak concentration
    is reached and the decrease
  179. that's observed thereafter, with the
    subjective effects that were
  180. reporting the volunteers. We could see
    that the maximum concentrations
  181. of DMT occurred around 1.5, 2 hours
    after administration, and this
  182. coincided with the peak of subjective
    effects. And also here in
  183. this study, we observed a nice
    dose-dependent effects as
  184. we had found in the pilot study.
  185. We also determined other substances
    that are found in ayahuasca.
  186. We determined blood levels of
    harmaline, the blood levels of
  187. tetrahydroharmine. Here also,
    the levels we measured were
  188. dose-dependent. After the higher
    dose, the levels we could
  189. find in blood were higher than
    after the low dose.
  190. But what we didn't find here in
    most volunteers was harmine,
  191. and this is the main monoamine
    oxidase in ayahuasca, and it's
  192. present more or less in the same
    amounts as tetrohyrdoharmine,
  193. at least in the ayahuasca we were using.
    So we were surprised by
  194. this finding, and we decided to look
    into 2 potential derivatives
  195. of harmine and harmaline, which are
    harmal and harmalol.
  196. These compounds are also
    found in ayahuasca,
  197. but the amounts we measured
    here were larger
  198. than those that were present in the
    tea that we were administering.
  199. So the conclusion we reached, and
    we have replicated this in
  200. a subsequent study in collaboration
    with Ethan McIlhenny and
  201. Steven Barker, is that harmine
    gets very rapidly metabolized
  202. when it's ingested, at least in the
    volunteers that have participated
  203. in our studies. This is dependent
    on a series of enzymes
  204. called cytochromes. Basically what
    they do is they transform
  205. harmine into harmal and
    harmaline into harmalol.
  206. So very quickly, these monoamine
    oxidase inhibitors
  207. get wiped out of the system. So this
    monoamine oxidase inhibition
  208. that's brought about by ayahuasca
    is relatively short-lived and not
  209. very intense, or not as intense
    as we thought this would be.
  210. So...
  211. [inaudible]
  212. they are, but they are less potent
    than harmine and harmaline.
  213. [inaudible]
  214. We weren't able to measure any harmine
    in most of the participants in this study.
  215. [inaudible]
  216. How early? Half an hour maybe,
    between 15 or 30 minutes.
  217. What we did, also, based on data
    that Rick Strassman had obtained
  218. in his intravenous DMT studies and
    using a pharmacokinetic parameter
  219. that's called the apparent volume of
    distribution, we tried to estimate
  220. what the amount of DMT that had
    accessed systemic circulation in
  221. our study. We did this by calculating
    a series of ratios between our values
  222. of apparent volume of distribution and
    the volume of the distributions
  223. that we had calculated based on
    Rick Strassman's data. We found that only
  224. around 10, 14% of DMT in ayahuasca
    actually reaches systemic
  225. circulation. So most of it, even in
    the presence of these
  226. monoamine oxidase inhibitors,
    gets degraded.
  227. What we've seen in
    subsequent studies is that
  228. oxidative deamination is not
    the only pathway that's
  229. available for DMT to be degraded.
    So even if monoamine oxidase
  230. were 100% inhibited, there
    would be other pathways
  231. that DMT could follow to be
    eliminated from the system.
  232. So this combination of Banisteriopsis
    caapi and Psychotria viridis
  233. is effective; it leads to
    psychoactivity, but perhaps it's not
  234. that effective as we would have thought,
    because you are only using
  235. this 10, 15% of the DMT that's present
    in the brew. So that was the
  236. pharmacokinetics, and we wanted to
    try to understand which brain
  237. mechanisms ayahuasca was targeting.
    We wanted to study
  238. the pharmacodynamics,
    which were the effects
  239. that ayahuasca was
    exerting on the brain.
  240. In order to do this we used
    a series of measures.
  241. One of the measures was this
    paradigm. It's called P50 suppression.
  242. This is based on a theory that
    postulates that under certain
  243. circumstances, the brain is less
    able to filter out information.
  244. We thought that perhaps all
    these visions, all these thoughts,
  245. these revelations, these insights
    that people are experiencing
  246. during the effects of ayahuasca
    arise from the fact that
  247. more information access consciousness
    than during normal wakefulness.
  248. We wanted to test this, by means of
    this P50 suppression paradigm,
  249. and basically what you do here is
    present a series of pairs of stimuli,
  250. of auditory stimuli and you measure
    the event-related potentials,
  251. the brain activity that's time-locked
    to the presentation of
  252. these stimuli. What we saw here is that
    there's really, there's
  253. a certain decrease of the amplitude
    of the first of these
  254. two stimuli when you
    administer ayahuasca.
  255. After the low dose or the high dose,
    there's a slight decrease, but
  256. what's most remarkable here is that
    the activation that the second
  257. auditory stimulus, or the second click,
    elicits at the cortical level,
  258. it increases with dose. As the dose of
    ayahuasca gets larger, this
  259. filtering property, that
    the brain has to not allow
  260. certain information to
    access consciousness,
  261. actually decreases, and it does so
    in a dose-dependent manner.
  262. These decreases are statistically
    significant as you can see here.
  263. We had a first insight into which
    brain mechanisms could be involved
  264. in the genesis of the effects
    of ayahuasca on the brain.
  265. What we did also was measure,
    repeatedly, spontaneous brain
  266. electrical activity, that is, not brain
    electrical activity that's
  267. locked to the presentation of a
    given stimulus, but spontaneous
  268. activity without any external input.
    Here what is shown in this
  269. figure is the results of
    this statistical analysis.
  270. This is a multivariate analysis
    in which we have
  271. recorded the EEG signals,
    we have calculated the
  272. power spectrum at different
    time points, at 45 minutes,
  273. 1 hour, 1 and a half,
    2, 2 and a half,
  274. 6, 8 hours after
    ayahuasca administration,
  275. for the low dose, and for the high
    dose. Here these circles represent

  276. the head, the scalp. Each white dot
    is an electrode, and all the
  277. changes you see here in red or purple
    indicate statistically significant
  278. differences versus a placebo. So
    changes after the low dose are
  279. really isolated, just in certain electrodes,
    and one could think they
  280. are almost random, but after the
    high dose, we see that
  281. most changes are found
    around the peak of
  282. subjective effects between 1 and
    2 and a half hours after administration.
  283. We can see these changes on many
    different electrode or recording sites.
  284. Afterwards, what we did was look
    at the different frequency bands.
  285. This is a classic division of the
    power spectrum of the EEG into
  286. frequency bands. We have what is called
    a slow activity or
  287. a delta power, and here, what we saw was
    basically decreases in delta power.
  288. So this slow activity gets diminished.
  289. The maximum effects are observed also
  290. around 90 minutes or 2
    hours after administration.
  291. Also theta power, which is the
    frequency band that goes from
  292. 3.5 to 7.5 Hz was also showing statistically
    significant decreases, also

  293. around this time window.
  294. The same happened for
    alpha power although
  295. effects were visible a little earlier
    and lingered longer than
  296. for other variables.
  297. For beta-1, which is in
    the low range of
  298. the fast brain activity,
    we also saw decreases.
  299. When we looked at the higher
    frequencies, we saw increases
  300. in those values, but these
    findings were not as
  301. consistent as the decreases we
    find in these lower frequency bands.
  302. So in terms of if you...what's
    happening here is that there's a shift

  303. from the slow activity to the fast
    activity, and in relative terms
  304. you have increases in beta, in
    fast activity, in beta-3, in beta-4,
  305. but when you do the subsequent
    analyses that I'm going to show now,
  306. nothing survives multiple comparisons.
  307. So what analysis we did later? What
    we did was based on these changes
  308. we're seeing at scalp locations
    which are basically changes in power,
  309. in voltage, we tried to localize
    which brain areas were responsible
  310. for these changes. We have a series
    of measurements on the scalp,
  311. you have your potential values, you
    have a transform metrics, and
  312. finally, what you find is another value
    which is current density in
  313. a series of voxels, of volume elements
    throughout the brain. You can
  314. represent changes also using a series
    of statistical comparisons,
  315. and you do this in
    a standard brain atlas,
  316. which is the Talairach brain atlas.
  317. We did this for the findings we
    had found in the delta band,
  318. and we found that changes
    were located, or the areas that
  319. were thought to be related to these
    changes we were seeing were found
  320. in posterior brain areas, in the
    middle temporal gyrus, the superior
  321. temporal gyrus, the precuneus, and
    in the fusiform gyrus, basically
  322. all areas that are in the
    posterior section of the brain.
  323. When we looked at theta changes,
    here we also saw changes in
  324. the temporal lobe, and the only
    changes that we observed
  325. in frontal regions, basically located
    in the cingulate gyrus and in
  326. the medial frontal gyrus. When we
    looked at the alpha-2 band again,
  327. the sources which were responsible
    for the changes were located
  328. in posterior brain areas, temporal
    and precuneus, and for the beta-1
  329. band, also precuneus. So the majority of
    changes we were seeing here,
  330. based on the effects of ayahuasca
    on the EEG, were located
  331. in these posterior areas of the brain,
    but after all, this is not
  332. the gold standard to try to find which
    brain areas are responsible
  333. for drug changes. Most studies,
    which are considered to implement
  334. a better methodology or have a better
    localization power were at
  335. that time nuclear medicine techniques.
    So what we did later was a

  336. SPECT analysis, but before that,
    what I'm showing you here
  337. is the summary of results we
    found for the EEG findings.
  338. Basically, we found that the areas
  339. that were responsible for the
    changes were located in
  340. association cortex. This association
    cortex is responsible for
  341. the processing of auditive,
    somatosensory and visual information,
  342. and also in what's called transmodal
    areas, those areas that are
  343. connecting different areas of the brain
    that are responsible for
  344. the initial processing of information in
    the visual modality or in
  345. the auditive modality. So these transmodal
    areas, what they are doing
  346. is connect information that's
    coming from more basic areas.
  347. And basically, we found significant
    effects here in the temporal,
  348. parietal and frontal intermodal
    association cortex, and
  349. also in limbic regions, as I've
    shown you in the anterior cingulate,
  350. and in the parahippocampal gyrus.
    After this initial analysis, we
  351. went on to do a nuclear medicine study.
    We did a SPECT study. What
  352. we did here was administer a high
    dose of ayahuasca, and after
  353. around 100 minutes or 2 hours after
    drug administration, when
  354. the effects were maximum, we injected
    a tracer, and afterwards we
  355. brought the subject to the camera,
    and saw which brain areas lit up
  356. during the acute effects or the
    maximal effects of ayahuasca.
  357. And here, in this study, we found
    activations in the anterior
  358. cingulate cortex. We had seen this
    one also in the analysis of the
  359. theta power, in the EEG study,
    also in frontal regions in
  360. the medial frontal cortex.
  361. In the insula, we hadn't found any
    changes in the EEG study in this region,
  362. and in the parahippocampal gyrus
    and hippocampus, which we
  363. had found in that previous study.
    So there's partial overlap
  364. between the two techniques. We
    find that in certain transmodal
  365. areas we see changes in EEG
    activity and also in blood flow,
  366. measured by means of SPECT,
    basically in this frontal intermodal
  367. association cortex, and the limbic
    regions, but what we really
  368. didn't see using this nuclear
    medicine technique is any changes
  369. in posterior brain regions.
    These decreases in posterior areas
  370. are very stubborn, because
    we have conducted additional
  371. studies involving the administration
    of ayahuasca subsequently,
  372. like this study in which we administered
    2 different doses of ayahuasca,
  373. one at time zero and one 4 hours
    after the initial dose, and we keep
  374. seeing these decreases in posterior
    brain areas. And these changes
  375. we see here we really didn't find
    in the nuclear medicine
  376. technique, in SPECT. So maybe,
    depending on the technique
  377. you are using, you may see some
    effects of the drug and not others.
  378. So if we have to compare the
    results we obtained using the
  379. 2 different techniques, we find
    that by means of current
  380. density analysis, we can locate
    activity changes in the associating
  381. cortex pertaining to the visual and
    auditory sensory modalities,
  382. and this will be useful to explain
    the perceptual modifications
  383. that people under ayahuasca refer.
    How is it possible that you see
  384. changes in external perception, in the
    depth of objects, in the intensity of
  385. lights, in color, if areas that are
    associated with visual processing
  386. are not targeted by ayahuasca,
    if you only have changes in
  387. frontal brain areas? So based
    on current density analysis,
  388. we could be able to explain these
    perceptual modifications.
  389. Also, the changes we see using
    this technique in transmodal
  390. areas, basically this intermodal
    association cortex, would allow us
  391. to explain phenomena like synesthesia,
    which is experiencing
  392. one sensory modality affecting
    another sensory modality.
  393. All these changes we see here
    would be dependent on posterior
  394. brain regions and are only
    visible if we use this technique,
  395. current density analysis of
    the EEG. The limbic areas lit up
  396. in both techniques, using [Lareto],
    the current density analysis,
  397. and SPECT. Changes at this level
    could explain the recovery of
  398. memories that people report
    under ayahuasca, also the affective
  399. modifications, and changes in
    the frontal neocortex and insula,
  400. which we only saw using
    the nuclear medicine technique,
  401. using SPECT, could explain
    also the insights, the interception,
  402. the understanding and the revelations
    that we usually experience
  403. during the peak effects of ayahuasca.
    So this is the information
  404. I have from previous studies.
    This is already published,
  405. and here was basically a comparison
    of the two techniques,
  406. and now what I'm going to
    show you here is results I obtained
  407. very recently, just one or two
    days before I took the plane
  408. to San Francisco. Basically what
    we've been doing here is analyzing
  409. brain electrical activity, EEG,
    using a different technique.
  410. We have a team of engineers
    who are working with this analysis,
  411. this signal analysis. They are
    using transfer entropy, and this is
  412. based on information theory.
    Basically, this technique, what it
  413. allows us is to see whether
    activity changes at one location are
  414. affecting activity at other locations.
    So this is an asymmetric
  415. measure. We can establish
    causality relationships between
  416. changes we observe, and if we
    analyze the EEG signals in
  417. the repeated dose administration
    study, we see that basically,
  418. what we have here is a change
    in the way anterior and posterior
  419. regions relate to each other.
    So here, 2 hours after ayahuasca
  420. administration, we are seeing
    a decrease in anterior-posterior
  421. connectivity. We can analyze
    which areas are conditioning
  422. the effects on other areas, so
    what is causing the effects,
  423. and what is the consequence
    of the changes. So we can identify
  424. areas that we can call sources
    of this decrease
  425. we are observing, and we can
    also identify the targets of these
  426. decreases we are observing.
    So here what we have at 2 hours after
  427. ayahuasca administration is
    a decrease in the frontal-parietal
  428. transfer of information. So
    there's a decrease in causality
  429. between frontal and posterior
    areas, and here what we see
  430. is that frontal brain regions are
    decreasing the control or the influence
  431. they have over posterior
    brain regions. So using this technique,
  432. we are seeing effects at frontal
    locations and also at posterior
  433. locations, what we were unable
    to see when we used either EEG
  434. power analysis or when we
    administered a radio tracer to see
  435. changes in blood flow.
  436. These relationships are dynamic,
    and when we do this analysis
  437. not at 2 hours after ayahuasca
    administration but at 2 and a half
  438. hours after ayahuasca administration,
    what we see here is an increase
  439. in anterior-posterior connectivity.
    So this might appear shocking,
  440. or in contrast with what we were
    seeing at 2 hours, but if we take a look
  441. at the sources and the targets
    of these changes, we see now that
  442. the source areas involved in
    this increase are posterior
  443. brain areas, and the target areas
    are basically anterior. So there's
  444. also changes here, but most of
    the areas that are acting as targets
  445. here in this analysis are anterior
    brain areas. So what we saw earlier
  446. was a decrease in the information
    transfer from anterior to posterior,
  447. and here what we see is
    an increased information transfer
  448. from the parietal cortex to
    the frontal cortex. So in a way, we've seen
  449. an inversion of what would be
    normal functioning without ayahuasca,
  450. because these changes I'm
    showing you here are the statistical
  451. comparison versus placebo.
    At 3 hours after drug administration,
  452. again we see a decrease between
    anterior and posterior sites.
  453. We didn't see changes between,
    let's say, right hemisphere
  454. and left hemisphere, but it's
    always frontal and posterior.
  455. Here the source areas are again
    frontal areas and the target
  456. areas are posterior brain areas. But
    here, like what I had shown you
  457. at two hours, what we see is
    a decrease of the influence
  458. anterior brain areas or activity
    at these sites has over activity
  459. at posterior brain areas. So by
    this new technique, we haven't
  460. given still much thought into
    these results. As I am telling you,
  461. this is preliminary. I got it the same
    week I flew in. It's that
  462. perhaps we have found a way
    in which we can see this combined
  463. effect which, depending on
    the technique we used, we could only
  464. see in the back part of the brain
    or in the frontal part of the brain.
  465. So given that ayahausca is
    targeting all these areas and
  466. the frontal cortex seems to be
    a prominent hub in mediating
  467. the effects we see after ayahuasca
    administration, what we
  468. planned to do and did was see
    how acute ayahuasca administration
  469. would affect cognitive processes
    that we know that are depending
  470. on the correct functioning of
    the frontal cortex. So here we
  471. administered a battery of
    neuropsychological tests while
  472. people, subjects were under
    the influence of ayahuasca.
  473. The first test we used was
    the Sternberg test. This is a working
  474. memory task. Here, what I'm
    showing in the graphs is the total errors
  475. that subjects are committing.
    Here they are presented with a series
  476. of letters, and after a while a fixation
    cross appears on a screen,
  477. and afterwards they are shown
    a test letter, and they have to say
  478. whether this letter was in the initial
    list or not. This is a working
  479. memory test. What we saw here
    is that, compared to pre-ayahuasca,
  480. which are the bars in blue, after
    ayahuasca there's a certain increase
  481. in the errors that people are
    committing, but these errors, or
  482. the number of errors, is dependent
    on the experience people have
  483. with the tea. So we recruited
    people, we did this on purpose,
  484. that had either only occasional
    experience with ayahuasca
  485. or were very experienced users.
    Maybe people here had used
  486. ayahuasca on tens of occasions,
    while people here had used
  487. ayahuasca on hundreds of
    occasions. As you can see,
  488. the increase we see in
    the number of errors is much larger
  489. in the occasional users than in
    the experienced users, but this
  490. didn't reach statistical significance.
    But we are seeing here that
  491. ayahuasca might be affecting
    functions that are dependent
  492. on the frontal lobe, but this highly
    depends on the experience
  493. that people have with the tea.
    So there can be several explanations
  494. for this, like people are more able
    to focus on the task because
  495. they are more familiar with
    the experience, or maybe something
  496. is changing in the brain after
    several ayahuasca intakes,
  497. or after many ayahuasca intakes,
    that allow them to do this
  498. much better than the naïve
    subjects or occasional users.
  499. So we also did this more complex
    task, which involves planning.
  500. This is not only working memory;
    it is a more complex task.
  501. Here, what we saw is that
    occasional users are clearly
  502. impaired, but experienced
    users actually perform better
  503. under ayahuasca than
    after placebo.
  504. [laughter, applause]
  505. And in this case, in the Tower
    of London, this reached statistical
  506. significance. So there's a
    different behavior depending on
  507. your prior experience with
    ayahuasca. If we have a look at the
  508. number of movements they
    used to solve this test, this
  509. Tower of London, again, we
    see that the occasional users
  510. are impaired. The experienced
    users actually perform better.
  511. This again reaches
    statistical significance.
  512. So, these are effects after acute
    ayahuasca administration
  513. in people who had experience,
    varying degrees of experience,
  514. with ayahuasca, and what we did
    was also plot these lifetime
  515. ayahuasca intakes versus their
    performance on the Tower of London.
  516. Here we are correlating the
    number of times people have
  517. participated in ayahuasca
    sessions against time, against
  518. the execution time. We have
    a significant correlation here,
  519. so the greater your experience
    with ayahuasca, the better
  520. you perform this task, and the same
    with the Tower of London.
  521. So after finding these very
    interesting results, we wanted
  522. to have a look at the brains of
    our experienced users. So this
  523. was not exactly the same
    sample that had participated
  524. in the acute ayahuasca
    administration study, but here what we did
  525. was recruit a series of very
    experienced people. They had used
  526. ayahuasca for many years, and
    we did a series of studies
  527. using magnetic resonance imaging.
    We analyzed cortical
  528. thickness, diffusion tensor
    imaging and functional fMRI.
  529. I only have the results for
    the first test, for cortical thickness.
  530. This is what I'm going to
    show you now. What we saw here is
  531. that compared to controls, long-term
    ayahuasca users actually
  532. have showed changes in
    brain areas. What are the changes
  533. we observe? In certain brain areas,
    posterior brain areas, we
  534. find a decrease in cortical
    thickness, and in frontal areas
  535. we find an increase. So again,
    we are seeing these two hubs
  536. that seem to be related to
    the acute ayahuasca effects,
  537. these medial areas, one frontal,
    one more posterior, this posterior
  538. in the posterior cingulate and
    the precuneus. If we correlate
  539. these changes with lifetime
    ayahuasca use, we see that there's
  540. negative correlation for
    the decreases. There's a positive
  541. correlation for the increases
    in these areas. So the more
  542. ayahuasca you've taken,
    the greater the cortical thickness
  543. in the frontal medial areas, and
    the smaller the cortical thickness
  544. in posterior brain areas.
  545. What's the impact of these
    changes we are seeing in these
  546. brain regions? Are these people
    impaired when they're not
  547. under ayahuasca? How do they
    actually perform when we subject them
  548. to neuropsychological assessment?
    Well, here you can see,
  549. for instance, results of a
    working memory task. It is called
  550. a 2-back task. Again, users
    perform more rapidly,
  551. this is reaction time, than
    controls, and this is significant.
  552. This is the percentage of correct
    responses we are getting, and again,
  553. long-term ayahuasca users perform
    much better than controls.
  554. So at least we are not seeing any
    impairment in neuropsychological
  555. testing associated with long-term
    ayahuasca use, even though
  556. we are seeing changes in brain areas,
    in this cortical thickness
  557. measures, this is not related to
    impairment in performance.
  558. So this is all the data I wanted to
    show you today, and just
  559. a brief mention of the ongoing
    studies we have, and future studies
  560. we have planned. We are going to
    analyze the fMRI and DTI data
  561. we have gathered in this study
    with long-term ayahuasca
  562. users. We also have a collaboration
    with the State University
  563. of Louisiana, with Dr. Steven Barker
    and Dr. Ethan McIlhenny.
  564. We are studying DMT metabolism.
    We have already some data
  565. we'll publish soon. With
    the team in Brazil, led by
  566. Drs. Draulio de Araujo and Dr. Ribeiro,
    we are going to start
  567. a study assessing the potential
    benefits of ayahuasca in depression.
  568. In Barcelona, we are also planning
    to start a new study in which
  569. we are going to investigate the
    role of the serotonin 2A receptor
  570. in the effects of ayahuasca. We are
    going to administer
  571. this compound, ketanserin,
    trying to block the effects
  572. that ayahuasca brings about and
    in this way try to see to which extent
  573. this receptor plays an important
    role in all the effects we are seeing
  574. on the subjective effects, on these
    EEG changes I've shown you,
  575. and we're trying to get funding
    for this project. Hopefully
  576. we'll be successful. Yeah, the last
    thing I want to do is give thanks
  577. to all the people who have collaborated
    with us through the years.
  578. Josep María [Fericula], Esther Martinez,
    Josep María Fábregas,
  579. these people which I've mentioned
    at the beginning of my presentation,
  580. who were crucial in guiding me in
    these initial steps of my research,
  581. James Callaway from
    the Hoasca Project quantified the DMT
  582. in the ayahuasca we used. José Carlos
    Bouso and Rafael dos Santos,
  583. my Ph.D. students. They are doctors
    already. They gathered
  584. most of the information I've
    shown you, and Draulio de Araujo,
  585. Fernanda Pailano, Sidarta Ribeiro,
    have done the analysis
  586. of the cortical thickness study, and
    Steven Barker, Ethan McIlhenny,
  587. have helped me with the
    pharmacokinetics studies, and these
  588. three people, Sergio Romero,
    Miquel Angel Mañanas,
  589. Joan Francesc Alonso are
    engineers from the Polytechnical
  590. University at Barcelona, and
    they are implementing all this
  591. entropy transfer analysis that
    I've shown you. And finally,
  592. Richard Wolfe, who's in the
    audience, and Ben de Loenen,
  593. have supported us through all
    these years, have helped us
  594. financially with our research, and
    I would like to thank you all
  595. for your attention this morning. Thanks.
  596. [applause]
  597. [inaudible] about a
    half hour for questions.
  598. [inaudible]
  599. Hi, my name is Bruce Morton. I'm
    from the University of Hawaii.
  600. I think the core issue of all our
    studies is "how do psychedelics"
  601. "cause ego death and transcendence?"
    I think your studies
  602. are fascinating in that they show
    brain areas that have been
  603. associated with the generation of
    ego strengths, and in particular
  604. I applaud you for calling the attention
    to the anterior cingulate
  605. and the insula, which are key
    elements in the production
  606. of the ego, and who struggle valiantly
    against being suppressed
  607. by hallucinogens, ultimately to
    become chemically poisoned.
  608. So please continue your work, and
    I would like to keep the focus
  609. on 5HT-2 receptors in these limbic
    areas, and thank you very much.
  610. Thanks.
  611. Brian Rush, Toronto, Canada.
    Thank you for a great overview.
  612. I guess my question is: we now have
    so many years of research
  613. showing low or no toxicity, including
    other studies for sure,
  614. you know, not presented of
    your own work. For those of us now
  615. embarking on other more
    clinically-oriented studies, for example
  616. in addiction or in depression,
    should we be monitoring toxicity
  617. in those studies, or do we have
    enough? I guess it's almost
  618. a policy question. Do we have
    enough information to satisfy
  619. those people who would be
    concerned about that?
  620. Well I think you always have to
    be on the safer side, and I would
  621. recommend that you do that,
    that you test for toxicity
  622. for potential participants before
    you enroll them in the study, and also
  623. throughout the study. I'm also
    sure that if you plan to do this in
  624. a country where no previous
    studies with ayahuasca in clinical
  625. populations have been conducted,
    the health authorities
  626. will certainly require this.
  627. Thank you.
  628. [Juan Gustus], clinical psychiatrist
    from Belgium. Regarding
  629. the cardiovascular safety, what do you
    know about the increase of QT
  630. and ECG? Because, for
    cardiovascular safety, you only,
  631. the blood pressure what
    do you know about the [inaudible]?
  632. We recently did a study in which
    we monitored electrocardiogram
  633. continuously, but we still haven't
    analyzed the data yet.
  634. So during the effects we recorded
    this. But what we also did in
  635. all other studies is, when we
    included the volunteers, they also
  636. had an electrocardiogram done,
    and afterwards, before they
  637. were considered they had
    finished their participation with us,
  638. they also had this done, and no
    alterations were found
  639. in these variables.
  640. Thank you.
  641. Douglas [Call], from [Ashen],
    Oregon, I'm a psychologist,
  642. neuropsychologist. The question
    is: on the connectivity
  643. measures that you had, was that
    across all frequencies?
  644. Say, .3 to 30 Hz?
  645. Yes, in this connectivity measure,
    in transfer entropy, you use
  646. the whole signal. We didn't subdivide
    into frequency bands.
  647. It is a totally different
    kind of analysis.
  648. With conventional quantitative
    EEGs, you can look at the phase
  649. relationship. Do you guys, can you
    do that with that technique, or not?
  650. We have used other connectivity
    measures. We have explored
  651. other connectivity measures
    subdividing by frequency bands,
  652. and we didn't find systematic effects
    or something that made sense
  653. to us. So it's basically this transfer
    entropy, it's the technique
  654. that has allowed us to obtain
    more consistent results.
  655. It sort of looked like what you
    got was the deactivation
  656. of the default network, which of course
    makes sense. Does that
  657. seem reasonable to you?
  658. That could be an interpretation, but
    when we did this data processing
  659. of the EEG many years ago,
    because we published the paper
  660. in 2002, the default mode network
    was not invoked at the time,
  661. so we didn't interpret our results
    using this framework.
  662. But seen in retrospect, that
    could be a possible
  663. valid interpretation, I guess.
  664. Hi, I'm Gerald Thomas from BC,
    Canada, and I'm just wondering:
  665. the subjective effects of ayahuasca
    vary greatly in the experience,
  666. and I wonder, in this connectivity
    between the front and the back
  667. and the flip-flopping you saw
    of that, which is dominant,
  668. in those instances where people
    don't report much of an effect,
  669. because I've been in ceremony
    where that's the case, nothing
  670. really happens, were you able
    to differentiate who was having
  671. that flip-flop, and what degree,
    and how it affected their
  672. perceptions of the experience?
  673. What I'm showing here is the
    results of a statistical comparison
  674. in which I'm comparing a group
    of 22 participants in the day
  675. they received ayahuasca versus
    the day they received placebo.
  676. So you see here those interactions
    that survived the statistical
  677. comparison and the correction
    for multiple comparisons,
  678. so you don't see the individual
    changes. But what we plan to do,
  679. also, is start looking for
    relationships between the changes
  680. we observe at this level and
    subjective effects. So we are
  681. doing this right now.
  682. Kenneth Tupper, University of
    British Columbia. I understand
  683. the experimental conditions under
    which you were making
  684. your observations were stimulus-free.
    There was no audio inputs.
  685. In the experiences of most traditions,
    the environment includes
  686. singing or chanting. Music seems
    to be an integral part
  687. of the ayahuasca experience in
    almost all the traditions
  688. that use it. Have you thought
    about the role that music
  689. might play in the brain effects, and
    thought of that as an experimental
  690. control for future research?
  691. Until now, we've always conducted
    our studies in a dimly-lit
  692. ambience without any prominent
    external stimuli, except
  693. when we've measured evoked
    potentials. But that would,
  694. it is certainly something I would
    want to look at, because,
  695. yeah, I know how powerfully music
    can influence the experience,
  696. and that would certainly be
    something very interesting for
  697. a future study. I'm sure that,
    who knows, maybe the effects
  698. we see are different. But it's
    hard enough to interpret
  699. what we have now, so that would
    be another level
  700. of complexity, I guess.
  701. Thank you.
  702. Yes, the music shifts the pictures
    in the ceremonies. I've been
  703. doing brain mapping, EEG,
    of ayahuasca, and acute effects
  704. of smoked DMT also, and what
    impresses me most is how variable
  705. the changes are from one
    person to another. So I always
  706. look at a baseline and then changes
    and do that kind of comparison.
  707. Your EEG data here was
    a group comparison?
  708. It's a group comparison, and yeah,
    EEG's very tricky. You have to
  709. standardize the recording conditions
    very well, and I think that
  710. incorporating a placebo is essential,
    because you see variations
  711. as time passes, even if you don't
    administer any substance.
  712. So the EEG's going to change,
    so in the...what I'm showing
  713. here always is the comparison
    versus the placebo, so I've
  714. subtracted the effects that the
    placebo induces, so you see
  715. the net effect.
  716. So it's a group comparison.
  717. If you only do a pre- and a post-,
    you are not controlling
  718. for this variability. So I would always
    encourage or recommend
  719. to incorporate some kind of
    placebo measure to subtract.
  720. Yeah, I have this wonderful software.
    You can get a very reliable
  721. high-test/retest reliability pre-
    and post-, but what's exciting
  722. is that the EEG changes are
    reversible, with the acute changes
  723. with DMT, and the person is
    now returning to ordinary
  724. consciousness and the EEG is
    also returning and looking like
  725. the baseline now.
  726. Hopefully.
  727. So come and see the notes that I have.
    Not hopefully; it's data.
  728. It's real data.
  729. Well, I mean the effects last for
    several hours, so if you come back...
  730. I'm talking about acute...
  731. To shared reality I would expect
    the EEG to return to baseline
  732. levels, I guess.
  733. It does over hours, but acute
    tests within minutes.
  734. Hello Jordi. Thank you for your talk.
    My name is Fernando Tófoli.
  735. I am from the State University of
    Campinas, Brazil. I wonder
  736. whether these experienced users
    of ayahuasca were from
  737. an ayahuasca religion, and if so,
    how you think that might
  738. affect the results of the test? I mean,
    being a member of one of
  739. the religions is not only drinking
    ayahuasca, but being subject
  740. to a lot of other variables. How do you
    control these variables?
  741. That's my question, if we can.
  742. We haven't controlled for these
    variables. But what I can say
  743. is the less experienced ayahuasca
    participants that I've
  744. shown data for here were also
    participating in these religious
  745. ayahausca sessions.
  746. They were not participating with
    the same regularity as
  747. the experienced users, and they
    had a lower number of total
  748. intakes, but they had also been
    involved with these ayahuasca
  749. religions. So yeah, we didn't
    explicitly control for that, but
  750. most of them had, also, experience
    with religious ayahuasca groups.
  751. Thank you.
  752. You're welcome.
  753. One of your slides showed, that
    you went over very quickly
  754. and didn't talk about it, showed
    the individual differences
  755. in responsiveness to beta-carbolines.
    I myself have found
  756. an incredibly sensitivity, like when
    I have ayahuasca, I must have
  757. vomited all of four hours, 40 times,
    and I've tried it over and
  758. over again, and I think that I must
    be, not an evil person
  759. but somebody that's...
  760. Maybe you're just a slow metabolizer.
  761. There are people, there are genetic
    differences, then, between
  762. metabolizers, and I'm wondering if
    this has anything to do with
  763. the fatalities associated with
    ayahuasca in South America,
  764. or in Central America.
  765. That can always play
    a role. Individual
  766. differences, of course. If you're
    a slow metabolizer, you'll have
  767. higher levels of alkaloids, and
    they are, from person to person,
  768. this varies. So the same amount
    of ayahuasca could lead to
  769. higher alkaloid concentrations and
    if you are taking other medicines
  770. or you have heart conditions
    or whatever, then perhaps
  771. the adverse effects you may
    experience will be stronger.
  772. I was curious about the
    Tower of London test and other tests,
  773. whether those were administered
    at one time or over time,
  774. and if you noticed an improvement
    over time. I'm thinking about
  775. Rupert Sheldrake's studies on
    crossword puzzle use over time.
  776. The more people who are exposed to
    a certain crossword puzzle,
  777. the faster they get at it, and
    I wondered about statistical
  778. analysis of those sorts
    of possible effects.
  779. Yes, in that study, we had
    these 2 groups of participants,
  780. and they all did the Tower of London
    and all the neuropsychological
  781. tests prior to ayahuasca intake,
    and then afterwards. So they
  782. did the test twice. But the
    changes...everyone went
  783. through this protocol this way,
    because it was very difficult
  784. to counterbalance the administration
    of these tests. How are you
  785. going to grab people's attention
    to explain them how to solve
  786. the Tower of London, if on the first
    occasion they are under
  787. the effects of ayahuasca? So
    everyone did this prior to ayahausca
  788. intake and then afterwards. But
    of course this is an issue,
  789. and what we are currently doing
    is we are recruiting another
  790. group of people and we are
    going to administer the same tests
  791. twice to see if there are any
    learning effects involved, that
  792. could require another interpretation
    of the results we are getting.
  793. But we are currently doing this;
    we haven't finished yet.
  794. My question was about whether
    the people took the test at
  795. the same time, and whether the
    people that took the test later
  796. in time would do statistically better
    than those who had done it
  797. at the beginning of the experiment.
    Rupert [Sheldrake]'s
  798. study on crossword puzzle use or
    solving was people that had
  799. never seen that crossword puzzle
    before did better statistically
  800. than those who had done it
    yesterday versus today.
  801. Oh, you mean the time lapse
    between the first assessment
  802. and the second assessment?
    It was the same for everyone.
  803. And the time window in which
    we tested them during the acute
  804. effects of ayahuasca was the same
    for everyone. So it couldn't
  805. happen that someone was not
    experiencing ayahuasca
  806. effects anymore, or one person
    was in the initial abrupt phase
  807. in which the ayahuasca effects
    were still increasing. Everyone
  808. was in the plateau when we tested them.
  809. Okay.
  810. Hi. My name is Cory Bathfield.
    I'm from Brooklyn, New York.
  811. I'm studying shamanism in the
    Iquitos region in Peru right now,
  812. and looking at these slides,
    I noticed, as you said, that
  813. some people perform better...
    the people who are experienced
  814. users perform better on tasks
    in their regular life not under this
  815. influence. I'm wondering if you
    have thought about, or if you're
  816. interested in doing any research
    in doing that deliberately,
  817. like using ayahuasca
    as something for cognitive,
  818. or for learning enhancement.
  819. The main bias in these results
    I'm showing you is that when you
  820. test long-term users, you're testing
    people who have decided
  821. to keep taking ayahuasca, and
    probably if they've decided
  822. to keep taking ayahuasca it's
    because they find that this is
  823. positive in their lives. So what
    happened with the other person
  824. who tried ayahuasca once and
    never returned? So perhaps
  825. if you are experiencing
    deleterious effects of ayahuasca
  826. and never show up again at
    an ayahuasca meeting, then
  827. 15 years later you are obviously
    not available for testing,
  828. or if you suffered cognitive impairment
    or psychiatric consequences,
  829. whatever. I don't know. I have to
    admit, also, the weaknesses
  830. of this design. So ideally what we
    should do is contact people when
  831. they are initially interested
    in getting involved with ayahuasca,
  832. and follow them for a certain time,
    for some months or years,
  833. and see what leads some to
    carry on taking ayahuasca,
  834. and others to decide they want to
    give up, and see if anyone
  835. experiences negative consequences
    or whether this is positive
  836. for everyone. I don't know. If you can
    see cognitive improvements
  837. in a substantial number of
    individuals, why not? We could try
  838. what you are suggesting and see
    if this could be used to
  839. improve cognition. I don't know.
  840. Hi. I was curious if you had any
    ideas why the freeze-dried
  841. ayahuasca didn't cause vomiting
    in most of the patients.
  842. We found this repeatedly through
    all the studies we've conducted.
  843. I think the reason can be that
    you are not experiencing
  844. all this taste and smell
    right from the start. After a while,
  845. of course, people report feeling
    the acidity in the stomach,
  846. but they are not suffering
    the nausea right from the start.
  847. They don't have to swallow down
    something that it's not very pleasant.
  848. So I think that plays a role, perhaps.
  849. Any more questions?
  850. No? Okay, then thank you.
  851. [applause]
  852. [Presented by
    The Beckley Foundation]
  853. [Council on
    Spiritual Practices]
  854. [Heffter Research Institute]
  855. [Mutidisciplinary Assocation
    for Psychedelic Studies (MAPS)]