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New Avenues in the Search for Biological Correlates of Altered States
of
Consciousness - From Model to Practice

Dr. med. F.X. Vollenweider

University of Zurich Psychiatric Hospital Research Department
(Director: Prof. Dr. med. J. Angst)
Box 68
CH-9029 Zurich
SCHWEIZ/SUISSE/SVIZZERA
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Note to readers: Dr. F.X. Vollenweider obtained his MD from the
University
of Zurich in 1986 and did a thesis in the field of experimental
neurotoxicology at the Institute of Toxicology of the Swiss Federal
Institute of Technology and the University of Zurich (1982-1986). From
1987-1989 he served as a Research Assistant in neurobiology at the
Brain
Research Institute, University of Zur ich, particularly in the field
of the
neurochemistry and neurophysiology of the NMDA receptor. Dr.
Vollenweider
has been engaged at the PUK, Zurich (Burgholzli), since April 1989 and
has
been trained in Psychiatry and undergone 6 years of Freudian
psychoanalysis. In addition to clinical work Dr. Vollenweider has also
been
actively concerned with basic research in the neurobiology of
schizophrenia. In particular, since 1990 he has been responsible for
the
initiation and performance of the ongoing PET projects at the PUK.
1991 Dr.
Vollenweider earned the "Twinning Grant 1991" (an achievement grant)
given
by the Swiss Society for Biological Psychiatry for his outstanding
PET-project on model-psychosis.

The Burgholzli-Tradition in Psychedelic-Research

For more than half a century, research work in the field of
hallucinogens
and related substances has been conducted at the Psychiatric
University
Hospital in Zurich. In 1926, Maier presented a monograph on cocainism
[1].
In 1932, Wertham and Bleuler studied Rorschach-tests of volunteers who
had
taken mescaline [9]. In the late 1940's, Stoll [13], together with
Condrau
[8] did some clinical trials to study the effect of LSD-25 on
schizophrenics.

More recently, as Professor J. Angst's directionship of the research
department was established, the very real problems experienced by
youngsters when they take hallucinogens and related drugs motivated us
to
continue the department's research in this field [2,11].

Dittrich initated and performed a series of studies to investigate
with
standarized methods (APZ) the psychic efffect of cannabinoids,
dimethyltryptamine (DMT), psilocybin, nitrosoxide (N2 0), and
nonpharmacological inducers of altered states of consciousness
(sensory
deprivation) in healthy volunteers. His work led to the publication in
1985
of a monograph on altered states of consciousness (ASC) demonstrating
by
dimensional analysis and algorithms of classical theory of mental
testing
that the main themes (content clusters) of ASC are three (oceanic
feeling
of merging with the cosmos, fearful ego-disintegration, perceptual
changes
of surroundings) and that they arise independent of the inducing
technique
[4,15]. Ego-disorders and perceptual changes are especially prominent
features of psychedelic states as well as of endogenous" psychotic
states.
Scharfetter developed an internationally accepted operationalization
of the
most important psychopathological terms [3]. He further developed and
studied empirically a new differentiated approach to the
psychopathology of
schizophrenia [5]. He published about the differential diagnosis of
hallucinations under various conditions [6] and presented a book
entitled
Observations and Reflexions on Delusions and Alltered States of
Consciousness" (1990, in print).

In 1990, I have been the motivating factor for the initiation of the
PET
project Brain energy metabolism in human experimental psychosis" as
described below [7,17].

"Chemical scalpels" for exploring the human mind

Hallucinogens and related drugs are remarkable "chemical scalpels" for
exploring the human mind. They are useful laboratory tools in the
study of
the neurochemical changes associated with altered states of
consciousness,
variously experienced as psychotomimetic, psychedelic or mystical
states.

Thus far, the analysis of psychedelic drug actions has been one of the
most
effective approaches to generate heuristic biochemical hypotheses
underlying experimentally induced psychopathological conditions
("model-psychosis"). However, little attention has been paid to
holistic
neurophysiological explanations of psychedelic experiences.

This failure has both conceptual and methodological bases. The
conceptual
basis relates to the foundation of a biological theory of
consciousness,
insofar as the foundation of such a theory is restricted to inherent
metaphysical issues, such as ontological and epistemiological
constraints.
However, the development of a physiological model of altered states of
consciousnesss which is based on correlations between mental and
neuronal
activity is not beyond scientific methodology.

In this respect, the recent development of functional neuroimaging
techniques such as the position emission tomography (PET) allows
scientists
to investigate neuronal activity throughout the brain by measuring
brain
energy metabolism in vivo in man . This approach brings together the
disparate lines of neurochemistry, neurophysiology and psychology.

Research strategies to investigate biological correlates of altered
states
of consicousness using hallucinogens and PET
(Positron-Emission-Tomography).

In 1990, the Psychiatric University Hospital (PUK), Research
Department and
the Paul Scherrer Institute (PSI), PET unit (Head: PD Dr. K.L.
Leenders),
have started a project to investigate the intra-individual effects of
amphetamine, ketamine, and psilocybin on cerebral energy metabolism in
a
group of selected healthy volunteers. The practise and theory of
"model-psychosis" as employed at the PUK is used as an experimental
paradigm of schizophrenia. Brain energy metabolism is measured using
PET
and the radioligand [18-F]-fluorodeoxyglucose, a technology used on a
routine basis at the PSI. The experimental protocols have been
approved by
the University Ethics Committee while the use of psychoative drugs has
been
approved by the Swiss Federal Health Office, Department for
Pharmacology
and Narcotics, in the Swiss capital city of Berne.

The psychoactive drugs used in this study are of paramound interest
because
they interfere with distinct neurotransmitter systems thought to be
disturbed in schizophrenic psychosis. Amphetamine interferes
predominantly
with the catecholaminergic, psilocybin with the serotonergic and
ketamine
with the glutamanergic neurotransmitter systems. Moreover, during
recent
years schizophrenia research using PET technique has emphasized
absolute or
relative decreased metabolic activity in the frontal cortex
(hypofrontality), while other PET-studies could not confirm this
so-called
hypofrontality but instead demonstrated bilateral hyperfrontality,
hypertemporality and lateral asymmetries of glucose utilization.
Hyperfrontality in acute and subacute schizophrenics seems to be
associated
with positive symptoms. However, whether these metabolic changes are a
consequence or a cause of schizophrenic symptoms is not clear.

Therefore it is crucial and fundamental to know to what extend mental
activity under psychotomimetic or psychedelic conditions contributes
to
cerebral metabolic changes.

Thus the first aim of the study was to investigate which brain regions
metabolically respond to specific pharmacological stimulation under
psychedelic conditions. A second aim will be to elucidate complex
interrelationships between cerebral metablic changes and
psychopathological
alterations. Moreover, it is important to compare the metabolic data (
patterns") obtained from these model psychoses" with the results of
metabolic PET studies of schizophrenic patients. And last but not
least, we
think that such investigations will be decisive in the foundation of
biological models of altered states of consciousness.

Outlook

A cortical-subcortical model of sensory information processing, the
"complex- loop" model (CSTC-loops), is advanced to interpret
psychedelic
drug actions (for details see [7,16]). According to this model,
psychotic
and psychedelic symptoms may be produced by blocking neuronal
information
flow within cortical-striato- thalamo-cortical feedback-loops
(CSTC-loops)
resulting in a cortical overload of information, especially of the
frontal
cortex.

Indeed, our PET-data analysed so far indicate that ketamine and
psilocybin
induce different metablic patterns," but that both drugs dramatically
stimulate glucose utlization in the frontal cortical regions (for
details
see [10,12,14]). This "hyperfrontality" corroborates the PET-findings
as
seen in acute hallucinating persons hospitalized for the first time
with
the diagnosis of schizophrenia, but stands in contrast to the observed
"hypofrontality" of chronic schizophrenics. Whether or not this
"hyperfrontality" is a common feature of psychedelic mental states and
acute hallucinaotry phenomenons as seen in schizophrenics remains open
for
further investigations.

The difference between ketmine and psilocybin is rather complex.
Psilocybin
significantly stimulates glucose uptake in the frontal and occipital
brain
regions only in the right brain hemisphere while ketamine does so in
both
hemispheres. Similarly, the insula, a part of the brain that is
involved in
language and hearing, is stimulated in both brain sides only under
ketamine. A common characteristic of both drugs may be the disruption
of
the frontal-to-ventral striatal metabolic gradient, and a right brain
side
hyper-frontality.

Under subanesthetic conditions, ketamine blocks the NMDA receptor
(glutaminergic neurotransmission) which seems to be involved in
psychotic
processes such as schizophrenia. And if there is a difference between
ketamine and psilocybin induced effects, it is important because
psychedelic experiences are not simply psychotic processes.

References:

1. Maier, H.W., Der Kokainismus, Thieme, Leipzig, 1926.

2. Woggon, B., Haschisch. Konsum und Wirkung, Springer, Berlin, 1974.

3. Scharfetter, C., General Psychopathology, Cambridge University
Press,
Cambridge, 1980, 1 pp.

4. Dittrich, A., Atiologie-unabhangige Strukturen veranderter
Wachbewusstseinszustande, Ferdinand Enke Verlag, Stuttgart, 1985, 1
pp.

5. Scharfetter, C., Schizophrene Menschen, 2nd edn., Psychologishe
Verlags
Union, Urban & Schwarzenberg, Munich, 1986, 1 pp.

6. Scharfetter, C., Paranoid-halluzinatorische Zustandsbilder bei
drogeninduzierten Psychosen. In H.M. Olbrich (Ed.), Halluzination und
Wahn,
Springer-Verlag, Berlin, 1987, pp. 42-51.

7. Vollenweider, F.X., Der Einsatz von PET
(Positronen-Emissions-Tomographie) zum Studium neuronaler Aktivitat
wahrend
veranderter Bewusstseinszustande. In H. Leuner and M. Schlichtin
(Eds.),
Jarbuch des Europaischen Collegiums fur Bewusstseinsstudien 1992,
VWB-Verlag fur Wissenschaft und Bildung, Berlin, 1991, pp. 33-52.

8. Condrau, G., Klinische Erfahrungen an Geisteskranken mit
Lysergsaure-
Diathylamid, Acta Psychiatrica et Neurologica 24 (1949) 9-32.

9. Wertham, F. and Bleuler, M., Inconstancy of the formal structure of
the
personality, experimental study of the influence of mescaline on the
Rorschach test, Arch. Neorol. Psychiatry 28 (1932) 52-70.

10. Vollenweider, F.X., Antonini, A., Angst, J. and Leenders, K.L.,
Cerebrale Aktivitat im PET bei Ketamin und Psilocybin induzierten
Modellpsychosen, DPGN (1992)(in press).

11. Binder, J., Bendel, H. and Angst, J., Wie hat sich der
Suchtmittelkonsum bei Jugendlichen zwischen 1971 und 1978 entwickelt
und
verandert? Drogalkohol 1 (1980) 3-18.

12. Vollenweider, F.X. Antonini, A., Scharfetter, C., Angst, J. and
Leenders, K.L., Zerebraler Energiemetabolismus wahrend akut
induzierter
Ketamin-Modell- Psychose bei gesunden Probanden, gemessen mittels PET
(Positronen- Emissions- Tomographie) und [18F]-Fluorodeoxyglukose,
Fortschr. Neurol. Psychiat. 60 (1992) 43-44.

13. Stoll, W.A., Lysergsaure-diathylamid, ein Phantastikum aus der
Mutterkorngruppe, Schweiz. Arch. Neurol. Psychiat. 60 (1947) 279-323.

14 Vollenweider, F.X., Antonini, A., Angst, J. and Leenders, K.L.,
Effekt
von Amphetamin und Ketamin auf den zerebralen Energiemetabolismus bei
gesunden Probanden, gemessen mittels PET und 18F-FDG, Schweiz. med.
Wschr.
122:Suppl. 45 (1992) 25.

15 Dittrich, A., von Arx, S. and Staub, S., International study on
altered
states of consicousness (ISASC), Schweiz. Z. Psychol. und Anw. 40
(1981)
189-200.

16 Vollenweider, F.X., Die Anwendung von Psychotomimetika in der
Schizophrenieforschung unter besonderer Brucksichtigung der
Ketamin/PCP-
Modelll-Psychose, Sucht (1992)(in press).

17 Vollenweider, F.X., Leenders, K.L. and Angst, J., Brain energy
metabolism in human experimental psychosis, Swiss National Science
Foundation No:32- 28746.90 (1990).