Conference Highlights: Hallucinogenic Drugs in Experimental Psychiatric
Research
Vaals, Netherlands - March 13-15, 1997
Julie Holland, M.D.
Bellevue Hospital, NYC
Faculty, New York University Hospital Medical Center
March 13th through 15th, 1997 at the Hotel Casteel Bloemendal in Vaals,
Netherlands, I attended a three day workshop entitled Hallucinogenic Drugs
in Experimental Psychiatric Research. Having a long standing interest in
MDMA (Ecstasy), psychedelics, and schizophrenia, this was one conference I
was not about to miss. The workshop was quite small and limited to forty
people, so I felt relieved when, after some petitioning, I was allowed to
attend. The "Tryptic-Workshop" was organized by the Depar tment
of Psychiatry and Psychotherapy, Technical University of Aachen, Germany
in collaboration with the Department of Psychiatry and Neuropsychology,
University of Limburg, Maastricht, Netherlands and the Service de
Psychiatrie, Centre Hospitalier Univer sitaire, Liege, Belgium.
The most impressive feature of this gathering, for me, was the
professionality of the presentations. Serious scientific studies had been
performed or were in progress, and their findings were presented in a
manner similar to many pharmacologic conferences which I have
attended - totally above board, with no excuses or innuendos. The data
presented was geared to a doctorate level of understanding, with the
majority of the presentors and audience members being M.D.'s and Ph.D.'s.
Opening Event
The weekend opened with a wine and cheese 'getting to know you' party on
Friday evening. At this point in the weekend I met some recent MAPS
Bulletin contributors (Alex Gamma from Switzerland and John Halpern at
Harvard) as well as the MAPS networks coordinator, Sylvia Thyssen. It was
a pleasure to meet Sylvia after years of seeing her picture and carrying
on an E-mail correspondence. I think it is important for MAPS members and
other researchers to get a sense of what studies are going on, where, and
by whom, and I found Sylvia to be a very able diplomat within the
international psychedelic research community.
Saturday Morning
The proceedings were opened by Prof. Sass, who introduced the history of the tradition in Germany of experimental work with hallucinogens. Dr. Sass, a psychiatrist and psychopathologist, is not a specialist in psychedelics, but he is interested in the cha
nges brought about by them. He described how the research tradition of working with hallucinogens has its roots in Heidelberg, with Kurt Beringer. Beringer described the effects of mescaline in detail in the 1927 Künstlisches Psychomodell which estab
lished the groundwork for the experimental psychosis model.
Dr. Efi Gouzoulis-Mayfrank, a remarkable woman who is in the midst of
performing MDE (methylene-dioxy-ethamphetamine, "Eve"),
psilocybin and methamphetamine experiments, gave the first presentation.
She reviewed the historical context of halluci nogen research, citing the
mescaline phase of research as beginning in the late eighteen hundreds and
giving way to the LSD phase beginning in 1943, and then finally describing
research with PCP in the nineteen fifties.
Gouzoulis-Mayfrank discussed the problems and challenges of interpreting
symptoms in schizophrenia, which are quite complex and which represent a
wide variability of sub-syndromes. She stressed that her research seeks to
shed light on the onset of psychot ic episodes, not schizophrenia as a
whole, which she and others feel may be a syndrome, and not a disease.
1943-1960's: The LSD Phase
This phase of research was characterized by LSD, psilocybin, DMT,
mescaline, phencyclidine and the anti-cholinergics. At the time, areas of
interest in psychiatry were the model psychosis and the use of
psychedelics for screening for latent schizophrenia. There was also a
prevalence of psychoanalytically oriented research on consciousness and
personality, research on religious experience and psychotherapy research.
In 1962, Hollister argued against the hallucinogen experience as a model
for psychosis, des cribing the ongoing debate of the appropriateness of
hallucinogens as psychotomimetics (mimicking psychosis). This phase of
research thrived until research was restricted in 1966 following the wide
use and abuse of these drugs in non-research contexts.
On the Term "Hallucinogen"
I see that the term hallucinogen has come up more than once already, so I
suppose I must acknowledge the ever present nomenclature debate: please
understand that psychedelics are most frequently called hallucinogens in
medicine, as in the title of the weekend conference. Hallucinogen is the
accepted terminology in the American psychiatric diagnostic manual, for
example. It is also an accepted legal term and the one used to group many
scheduled drugs. The older term psychotomimetic was also used in both law
and medicine, but much less so now. I, too, prefer the less pejorative
term psychedelic, but the scientific research community at large, for the
most part, seems only willing to discuss these neuromodulators as capable
of creating models of psychosis, replete with hallucinations. Most of the
presentations during the conference had to do with comparing acute drug
intoxications with psychotic states found in illness, usually
schizophrenia, and sometimes mania. There was some attention given to
using these substances as treatments, certainly this was discussed with
more enthusiasm privately than what was publically presented.
Classification Systems
Dr. Karl-Artur Kovar delineated the different classes of psychotropes to
be discussed over the weekend: under the heading of phenethylamines are
stimulants like amphetamine and methamphetamine, hallucinogens such as
mescaline, 2CB, DOM and entactogens suc h as MDMA, MDE, MDA and MBDB. Dr.
Kovar referred to MDMA, MDA and MDE as the "Ecstasy group" and
described the complexity of their mode of action. Of course, there are
many other psychedelics which fall under different headings, such as
tryptami nes (DMT, 5 MeO-DMT, and others), phencyclohexylamines (PCP,
ketamine and others), and indolalkylamines (LSD, psilocybin, ibogaine,
bufotenine, and DMT). To confuse matters slightly, it should be noted that
most of these indolalkylamines can also be class ified as tryptamines, as
there is a tryptamine subclass of indole derivatives. Psilocybin is
4-phosphoryloxy-DMT, and bufotenine is 5-hydroxy-N,N,DMT, and LSD,
although not a tryptamine, does have a molecular structure that includes a
tryptamine molecule. During the Q&A after Kovar's presentation, the
fluoxetine effect on reversing the "neurotoxic effect" of MDMA
seen in laboratory animals was brought up.
Prepulse Inhibition (PPI) Research
The next presenter was Mark Geyer, Ph.D., UC San Diego, who explained the
effects of various compounds on a measurement called prepulse inhibition
(PPI) of startle response. PPI is a great, non-invasive way to measure
something called sensorimotor gating, which could show a deficit in how
someone filters out stimuli. Habituation, the process of 'tuning out' a
repetitive stimulus, is a precursor of selective attention. Most
schizophrenics show deficits in habituating to stimuli and in learning
from a cue ( like a prepulsea smaller stimulus given before the larger
one, to warn the subject of an impending cause for startle). In rats,
hallucinogens such as LSD, and glutamate antagonists (also called NMDA
antagonists for the type of glutamate receptor they interact with) like
PCP and ketamine all disrupt prepulse inhibition and retard the process of
habituation. In contrast, the amphetamines enhance the startle response,
and low dose MDMA enhances prepulse inhibition in rats. A member of the
audience, Franz Vollenweider, who was to present his MDMA findings the
next day, reported the information that MDMA has enhanced prepulse
inhibition in human volunteers as well, at a dose of 1.7 milligrams per
kilogram body weight. (This comes out to 119 mg. for a 150 poun d
individual. The commonly accepted 'recreational' dose of MDMA is 125 mg.
initially, with an optional delayed 50 or 75 mg. "boost" dose.)
These findings reported by Geyer and Vollenweider help to make the case
that there may be a place for huma n studies with MDMA in the context of
schizophrenia research. I have great hopes that low dose MDMA may help
people with schizophrenia to pay closer attention, be less socially
withdrawn and suspicious, perhaps talk more and connect with others. I
have ce rtainly seen and read of these effects when MDMA is used in people
without this disease. Research was conducted in the past to suggest that
schizophrenics can benefit from low dose amphetamines to combat their
negative symptoms. The concern is, will MDMA make people with
schizophrenia more psychotic? I am in the process of collecting case
studies of people with schizophrenia who have experimented with MDMA, if
anyone reading this would like to contact me, I would appreciate any
leads.
The APZ
Later in the morning of the first day, we heard about various ways
to measure altered states of consciousness (ASC), with special attention
paid to the German APZ questionnaire as described by Adolf Dittrich of
Basel, Switzerland.
Dittrich developed the APZ in 1975. It is a 159 item survey, designed to
assess specific states of consciousness rather than personality. Questions
are presented in the first person singular. It measures feelings of
oceanic boundlessness, dread of ego-dissolution and visionary
restructuralization. Dittrich drew parallels of these three to Huxley's
Heaven and Hell and Visions. He went over the definition of altered state
of consciousness and commonalities between ASCs achieved by different
methods. He cite d a recent study done with 339 subjects tested with DMT,
psilocybin, THC, NO2, perceptual deprivation, hypnagogic states, autogenic
training, sensory overload and hypnosis. Subjective reports, keyed by
independent reviewers, correlated well with APZ results.
The instrument itself has been rigorously tested, and it is the standard
in Europe for assessing ASC. It has been translated into English.
Psychometrically improved versions have been designed that utilize visual
analog scales. Several of the European pre senters were using the APZ
questionnaire as an outcome measurement of the subjects' experiences with
study drugs. Unfortunately, no one was using Rick Strassman's Hallucinogen
Rating Scale (HRS). According to Dittrich, the items in the HRS are not
interna tionally accepted criteria and were tested in too few subjects. It
has not been translated into German.
On Semantic Networks
After lunch there were two lectures on comparing
schizophrenia with a psilocybin model of psychosis, with one looking at
the analysis of facial expression and the other focusing on semantic
networks and "loose associations," as tested by priming cues
(related vs. unrelated words given before a test word, with the subject
having to decide if it was a real or nonsense word). The results showed
that in "psychosis" whether schizophrenic or psilocybin-induced,
people widen their association s between words, so an indirect semantic
primer will hasten the word choice much as a direct primer would ('lemon'
before 'sweet' as opposed to 'black' before 'white'). This last study was
eloquently presented by Dr. Manfred Spitzer, soon to be leaving He
idelberg to become the chairman of a different psychiatric department
elsewhere in Germany. Dr. Spitzer also capped the conference with an
intriguing and somewhat daring summary including the possibility of an
actual beneficial state from these substances , specifically the
evolutionary advantage of "loosened associations." He feels that
a decreased anxiety state is conducive to inducing change via these new
pathways, created by broader activations. His capping lecture did seem to
allude to the h orizons ahead, offering the possibility of treatment
modalities involving psychedelics, and admitting that it was not fully
discussed over the weekend but it was possible that "the use of
hallucinogenic agents may actually have psychotherapeutic effe cts."
The Glutamate Hypothesis
The last two lectures of the first day covered familiar ground for me, the
glutamate hypothesis of schizophrenia and experiments with NMDA type
glutamate antagonists, specifically ketamine. Glutamate is the most
abundant excitatory neurotransmitter in the brain, and the resulting
intoxicated state that ketamine brings is felt to be reminiscent of many
symptoms of schizophrenia, creating not only paranoia, delusions,
hallucinations (all positive symptoms) and disorganized speech, but also
negative symptoms - the group of behaviors manifest by social and
emotional withdrawal. It is felt by many schizophrenia researchers that
the glutamate antagonists ketamine and especially PCP, offe r the best
model for schizophrenic psychosis, since they combine both positive and
negative symptoms. One thing intriguing was that when discussing other
drugs such as psilocybin or mescaline, the European researchers routinely
specified the correlation o f their intoxications with the acutely
psychotic state, but not the chronic residual phase, of schizophrenia.
This is a differentiation not routinely made in American schizophrenia
research, where we tend to clump schizophrenics into either "positive
symptoms" or "negative symptoms" groups, and often
specifically seek out one group or another for research subjects.
Ketamine
Two American M.D.'s, John Krystal from Yale and Henry Holcombe from
University of Maryland, spoke of their clinical studies giving ketamine to
healthy volunteers and schizophrenics. This is pretty much standard
schizphrenia research fare, but was included in the conference due to
ketamine's 'psychedelic' status, I presume. Dr. Krystal also tied in some
prepulse inhibition data, reporting that in healthy volunteers, ketamine
attenuates the sensory gating, and decreases the prepulse inhibition, thus
mimicki ng results seen in schizophrenics. Dr Holcombe, commenting on work
begun by Carol Tamminga, also correlated an area with the most increase in
cerebral blood flow during the ketamine induced state, with the same brain
region recently identified in PET stud ies during active auditory
hallucination - the left superior temporal cortex. He brought up a repeated
question for researchers: what does it mean when an area of the brain is
turned on under pharmacological conditions?
Mescaline and SPECT Brainmapping
Sunday morning gave us four lectures. Leo Hermle, a researcher from
Göppingen, Germany presented some data from a 1989 study of twelve
healthy volunteers (nine of which were M.D.'s) who had ingested 500
milligrams of mescaline and underwent cerebral blood flow studies
utilizing SPECT analysis (single positron emission computed tomography: it
gives you the pretty color pictures of the brain's blood flow like PET
does, but with less resolution). His results showed an increased frontal
uptake and decreased occipital uptake with mescaline, as well as an
improved left hemisphere performance over right on a facial recognition
task. Mescaline seemed to reverse normal hemispheric assymetry, but the
phenomenon did not attain statistical significance.
The face/non-face decision picture was presented to one side of the brain
or another with a specialized projection system called a tachistoscope.
Dr. Hermle also presented some more recent data of eight male subjects who
had ingested 140 milligrams of MDE and underwent sleep EEG's
(electroencephalograph, a non-invasive brain wave study) and multiple
psychological tests and assessments. All subjects showed an increased
desire to communicate verbally, and seven out of eight showed a decrease
in anxiety. One subject noted a "good, deep sadness" and
unfortunately, one subject was noted to have hallucinations, delusions,
and increased anxiety.
REM Suppression
Efi Gouzoulis-Mayfrank followed Dr. Hermle's lecture with more details of
the experiments she had performed with him (published in 1992) and new
data from an ongoing study begun in Summer 1995 comparing MDE,
methamphetamine, psilocybin, and a placebo. Are as that were studied were
some that are relevant in the study of endogenous psychosis: working
memory, gating mechanism, alteration in psychological effects (thought
disturbances) and brain metabolism. In this large study, eight subjects
are needed for ea ch compound, and each subject takes the compound on two
different occassions, once at noon and another time at eleven p.m. Of
note, those subjects taking the entactogen MDE at night experienced
complete rapid eye movement (REM) suppression, as shown by th eir sleep
EEGs. Few of these patients slept through the night after the eleven p.m.
dose, as one might imagine. A similar picture of REM suppression was seen
with the amphetamine group. The significance of this is not fully known,
but it should be noted t hat antidepressant therapies often supress REM
stage sleep, and people with untreated depression show a faster onset of
REM when going to sleep than healthy normal volunteers. There are also
abnormalities of REM sleep in schizophrenics, one being that eve n after
sleep deprivation they do not compensate with more REM once allowed to
sleep, as healthy volunteers do.
PET Brainmapping
Franz Vollenweider, M.D. from Zürich, Switzerland, presented his PET
data (cerebral glucose utilization studies) obtained under three
experimental conditions: during exposure to ketamine, psilocybin and
amphetamine. Dr. Vollenweider attempted to corr elate different brain
regions whose blood flow and glucose metabolism changed as a result of the
intoxication, and map this onto various parameters or clusters of the APZ
scale, such as oceanic boundlessness, dread of ego dissolution, or
visionary restruc turalization. Dr. Vollenweider had mentioned from the
audience during Holcombe's talk, that the area of interest that showed
increased cerebral blood flow during mania, the anterior cingulate gyrus,
also showed increased flow at a higher amphetamine dose. Other research
of his that is currently underway, with the help of Alex Gamma, is PET and
MDMA research, however, these results were not yet available.
Receptor Antagonists
The last presentation by Dr. Schneider of Hanover, Germany involved
intoxication of delta 9 THC (tetrahydrocannabinol) in healthy volunteers.
He compared their results on a visual perception task of 3D inversion of
familiar photographs with results from a group of schizophrenics, and
found similarities in the groups' disturbances of internal regulation of
perceptual processes. Also discussed was the concept of endogenous
cannabis receptors, and the recently discovered (1992) endogenous ligand
for these receptors, anandamide, and the current development of newer
schizophrenic medications based on antagonizing these receptors, such as
SR14166A, a CB1 receptor antagonist. Another promising new treatment for
schizophrenia which was mentioned in an earlier talk by Mark Geyer was
the compound MDL 100,907, currently undergoing clinical trials nationwide
(including my home away from home, Bellevue). This is a specific 5HT2A
antagonist, thus theoretically antagonizing such psychedlics as psilocybin
( a presumed 2A and 2C agonist) and completely blocking the effects of
DOI, a serotonin agonist which disrups pre-pulse inhibition. MDL 100,907
is thus considered by some to be a "hallucinogen receptor
antagonist," and has been shown to improve sensory motor gating.
Reflections
Again, you can see the focus of the conference was using these powerful
substances as tools to study behavior, cognition, emotion, and to build
treatments, but not exactly how every MAPS member would hope for. The
general theme of this conference was that these psychedelic-induced states
were models of unwanted behavior to be quantified and analyzed in order to
provide understanding of and ideally treatment for those people suffering
from psychiatric illnesses. The catch words for the weekend were definit
ely "model psychosis." I know this idea offends some MAPS
members. You know these drugs have more to offer. I am just happy anyone
anywhere is allowed to do these studies at all. I think they are crucial,
they must be done, any work involving human consumption of psychedelics
is inherently good work and anywhere to start is a good place. After the
talks had ended, the conference slowly shifted into the usual casual
formation of small groups, where there was some talk of who has tried what
drugs and what's the best way to take what. On the side, some of these
researchers will acknowledge the benefits these drugs can give the
average normal healthy volunteer, and some will even privately allow that
these drugs have helped the scientists themselves to achieve desired
states. The bravest ones will be doing both, publically. Amen.
Julie Holland, M.D.
E-mail: jholland@inch.com
Comments by Sylvia Thyssen, MAPS Networks Coordinator
The purpose of my attending this small gathering was two-fold: to gain a
better understanding of the type of research that is currently underway
with psychedelic drugs in Germany, Switzerland and the United States, and
to seek out new opportunities to stimulate psychedelic psychotherapy
research.Traditions of research and approaches differ between Europe and
America. This workshop's topics were very specifically focused on the use
of psychedelic drugs in schizophrenia, or model psychosis, research. Th e
40 or so people attending were primarily psychiatrists and psychiatry
researchers. The forum's small size offered the opportunity for
researchers to bring up yet-unpublished preliminary data and discuss more
deeply aspects of their research. Many of the presenters utilized brain
imaging technologies illustrated by slides. To tease out what relevance
this has for MAPS' agenda was no small task.
American audience members' questions were focused on MDMA and the
psychotherapy agenda. One mention of Prof. Hanscarl Leuner and his work
with psycholytic psychotherapy was made during the introductory period of
the workshop. When I talked with Prof. Sass , one of the organizers of the
workshop, he suggested that Dr. Gouzoulis-Mayfrank's work may stimulate
therapy research somewhat in Germany, since if a researcher there studies
other aspects of psychedelics first, they may have a better chance of
eventually gaining permission to do therapy research.
Manfred Spitzer wrapped up the workshop. He mentioned several times the
psychotherapeutic applications of psychedelics and how they can enhance
the psychotherapeutic process. This raised the eyebrows of some of the
presenters who focus on model psychosis or related research and have
little knowledge of this aspect of psychedelics.
MAPS as Metaphor
Surprisingly, Spitzer mentioned MAPS from the podium, noting that there
were "representatives of MAPS" (just myself) at the workshop. He
brought this up in the context of the metaphor of the map. He went on to
elaborate considerably on this metaphor, mentioning neural-network models
and the example of phantom pain. He explained how psychedelics are tools
that can be used to describe the maps of networks and brain regions and
their interaction.
When we want to introduce changes into these maps, we want to learn more
about which neuromodulators do what. Psychedelics can be useful for that.
But mapping is one thing, changing and adapting the (brain) maps is
another. Commenting on the next step, the possible therapeutic use of
these agents, Spitzer went into detail. Change involves activating and
forming new associations, which requires broad activation, an idea
reminiscent of Grof's "non-specific amplifiers." Put another
way, "noise " is good for learning and reorganization. The
concept of signal to noise ratio is an often used analogy in
neurophysiology. As an example, anxious people have a narrow range of
activation. To change anxiousness, an agent that introduces a state of
broad activation - like a psychedelic drug - may be involved in the process
of change.
This was a surprising and encouraging end to a workshop that wasn't
designed to discuss the use of psychedelics outside of schizophrenia
research.
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