Proposal (2002) Assessing the effect of Psilocybin, a serotonin 5-HT2 agonist, in OC-spectrum

disorders (e.g. obsessive-compulsive disorder, eating disorder, somatoform disorder) by Dr. S.

Ludewig
1) Summary
Obsessive-compulsive spectrum disorders are psychiatric disorders that show similarities in
symptomatology with obsessive-compulsive disorders. Into this unified syndromal category of
Obsessive-Compulsive Spectrum Disorders Somatoform disorders are subsumed. At Other Recent
Obsessive-compulsive disorders, Research speak eating disorders and in favor of that obsessive-
compulsive symptomatology, as a common core of these disorders, may be subject to a serotonin
deficit. This hypothesis is supported by the partial anti-obsessional efficacy of serotonin-releasing
substances. It is unclear which specific serotonin receptors contribute to this improvement.
contribute to this improvement. Pilot studies with the serotonergic 5-HT 2A agonist psilocybin,
suggest that stimulation of postsynaptic 5-HT 2A receptors may reduce obsessive-compulsive
symptoms. reduction of obsessive-compulsive symptoms (Delgado & Moreno, 1998). The purpose
of this project is to investigate the acute or possibly persistent symptom-reducing effects of the
mind-altering substance psilocybin in obsessive-compulsive spectrum disorders, particularly
obsessive-compulsive (obsessive thoughts, compulsive acts), eating disorders (bulimia nervosa,
anorexia nervosa), and Somatoform disorders (somatoform pain disorder) to be investigated. Key
symptoms of these disorders are a distorted perception of the body and diminished self-control,
which can be manifests itself in compulsive behavior and loss of impulse control. Further these
disorders are characterized by unstable or negative affectivity. Obsessive-compulsive behavior,
dysphoric mood, and loss of impulse control are associated with both serotonin deficiency and
associated with both serotonin deficiency and serotonin excess (Hollander, 1996, 1998).
In particular, case reports and initial pilot studies suggest that obsessive-compulsive disorder and
body dysmorphic disorders may be due to a lack of stimulation of 5-HT 2A receptors (Hanes, 1996;
Moreno & Delgado 1997; Delgado & Moreno, 1998). Specifically reported by Delgado and
coworkers (1998) that administration of the 5-HT 2A agonist psilocybin in obsessive-compulsive
disorder resulted in an acute decrease in obsessive-compulsive symptomatology and, in some cases,
even in a symptom reduction over months.
Psilocybin is a 5-HT 2A agonist and naturally occurring hallucinogen that, at moderate induces an
altered state of consciousness that is characterized by profound changes in sensory sensory
perception, affect, thought, and the ego and environmental boundary (Leuner, 1981; Vollenweider &
Geyer 2001). Numerous own studies on psychological, somatic, and physiological effects of
psilocybin in healthy subjects show that the mind-altering effects of psilocybin are transient and
dose-dependent, and is well tolerated at moderate doses without somatic and psychological
complications (Vollenweider 1998; Hasler 1997, 2002; Vollenweider & Geyer 2001). The fact that
psilocybin and and related substances can also be used in psychiatric patients in a controlled setting
without serious risks. risks, as shown by numerous earlier publications on this topic (Clark, 1968;
Duche, 1961; Gnirss, 1963; Grob, 1994; Leuner, 1981; Mascher, 1967; Strassman 1995).
Specific Purpose of the Study
The purpose of this study is to investigate the extent to which a single dose of psilocybin leads to
acute symptom reduction in obsessive-compulsive spectrum disorders. This is to determine the
importance of the 5-HT 2 receptor in the pathophysiology of this group of disorders. Furthermore it
will be whether this substance represents a possibility to reduce the therapy refractoriness of these
disorders. disorders. Furthermore, it will be investigated whether psilocybin, in addition to
modifying the positive influence on psychological variables, such as self-perception, body
perception and affectivity. body perception and affectivity. Finally, this study should also provide
insight into the 5-HT 2A agonist psilocybin in obsessive-compulsive spectrum disorders, to provide
a basis for the possible basis for a possible use of psilocybin in long-term treatment studies.
(2) Scientific background
Clinical aspects of obsessive-compulsive spectrum disorders Obsessive-compulsive disorder, eating
disorders, and somatoform disorders can be classified as compulsive-spectrum Disorders (McElroy
et al. 1994; Stein, 2000). The lifetime prevalence of Obsessive-Compulsive Disorder (OCD), for
example, is 2-3% worldwide, with some researchers suggesting 10%. The disorder usually begins
by age 25, with only 15% developing OCD after age 35, with average OCD, with an average
treatment duration of approximately 5-10 years (Goodman,1999). Symptomatology manifests as
obsessive thoughts and compulsive acts. Obsessive thoughts are recurrent or persistent ideas,
thoughts, or images that are experienced as unpleasant and meaningless and usually include fears of
harming others. Compulsive acts, meanwhile, are repetitive, purposeful, and intentional behaviors,
performed in response to a compulsive thought according to specific rules or in stereotyped form
such as frequent hand washing or checking rituals (APA, 1994).
Clinical manifestations of eating disorders such as anorexia nervosa (AN) include an increased fear
of gaining weight and obsessions with physical obesity, with concomitant cachexia. It is not
uncommon for compulsive rituals to occur when handling food. Characteristic of Bulimia Nervosa
(BN) are recurrent binge eating (consuming a large amount of food in a short period of time)
followed by self-induced vomiting to avoid weight gain. The loss of impulse control, compulsive
behaviors, and mood swings such as depressiveness are peculiarities of both disorders. In addition
to loss of impulse control, in eating disorders there is evidence of a distorted self-perception of
figure and weight, a disturbed body image, and a diminished self-esteem (Williamson et al. 1999).
Furthermore, in eating disorders there is evidence for a relationship between dysfunctional
behaviors such as eating attacks and dysphoric mood or negative affectivity (Kaye et al. 1986).
Frequently, the personality structure of individuals with obsessive-compulsive spectrum disorders
exhibits dispositional characteristics such as perfectionism, conformity, suppression of affect, and
emotional expressivity (Kaye4 et al. 2000; King, 1963; Bastiani et al. 1995). For the most part,
these personality traits exist prior to the the onset of a disorder and persist as the disorder
progresses.
Another obsessive-compulsive spectrum disorder is somatoform disorder. Somatoform disorders are
characterized by physical complaints that occur in the absence of identifiable physical\ pathology
and often present with a heterogeneous clinical picture with multiple such as hypochondriacal
manifestations (Fallon et al. 2000). Symptoms may refer to any body part or body system. Among
the most common are gastrointestinal discomfort, abnormal skin sensations, and persistent, severe,
and excruciating pain that may be cannot be fully explained by a physiological process or physical
disorder (APA, 1994). (APA, 1994). All three obsessive-compulsive spectrum disorders (OCD,
eating disorder, Somatoform disorder) represent psychiatric disorders with a chronic course
(Goodman, 1999; Fallon et al. 2000; Kruger & Kennedy, 2000).
Neurobiology of obsessive-compulsive spectrum disorder
Recent studies point to a central role of serotonin (5-HT) in the aetiology and pathogenesis of
obsessive-compulsive spectrum disorders (Arranz et al. 2001; King, 1990; Goodman, 1999; Kaye et
al. 1998; Stein, 2000). Evidence in support of this hypothesis emerged from the efficacy of
Selective 5HT reuptake inhibitors (SSRIs) in the treatment of obsessive-compulsive spectrum
Disorders (Hollander, 1998; Ravindran et al. 1999). In this context, it is postulated that the
reduction of symptoms in this group of disorders is due to a blockade of 5HT reuptake and an
increase in synaptic serotonin content, resulting in stimulation of postsynaptic 5-HT 1 and 5-HT 2
receptors. This cascade of events, it is hypothesized, is one of the initial steps in a neurobiological
process that results in symptom reduction. reduction. However, it is unclear why the described
clinical effects usually occur only after 6-8 weeks, although the 5 weeks, although 5HT reuptake
inhibition is immediate. It is possible that adaptive mechanisms adaptive mechanisms such as
modulation of sensitivity or modulation of different 5-HT receptor subtypes. receptor subtypes play
a central role in explaining this phenomenon, as has been shown in animal studies. been shown.
Which specific 5-HT subreceptors are involved in the partial improvement of the symptomatology
in obsessive-compulsive spectrum disorders is still to be further explored. Initial Evidence that 5-
HT 2 receptors play a central role in various obsessive-compulsive spectrum disorders such as
obsessive-compulsive disorders, has been reported in recent publications (Moreno and Delgado,
1997; Delgado & Moreno, 1998). The assumption that 5-HT is involved in the aetiology and
pathogenesis of obsessive-compulsive disorder is based, on the one hand, on the observation that
serotonergic anti-obsessional substances are effective in obsessive-compulsive disorder (Goodman,
1999) and, second, on the observation that administration of nonselective 5-HT antagonists leads to
an exacerbation of obsessive-compulsive symptoms (Greenberg et al. 1998). Moreover, various
scientific case reports have shown positive therapeutic effects of serotonergic hallucinogens such as
LSD and psilocybin in patients with obsessive-compulsive disorder (Brandrup and Vanggaard,
1977; Delgado & Moreno, 1998; Leonard & Rapoport, 1987; Moreno & Delgado,5 1997). The
specific decrease in symptomatology in obsessive-compulsive disorder began during the acute
period of action of the substance, and in some cases lasted until months after ingestion. The
stimulation of postsynaptic serotonergic receptors, probably 5-HT 2A/2C and/or 5-HT 1 receptors,
may ultimately increase the therapeutic efficacy of serotonergic hallucinogens used in clinical
populations such as obsessive-compulsive disorder and also body dysmorphic disorder have been
scientifically Have been described. Currently, a study is taking place on the efficacy and dose-.
effect relationship of psilocybin in obsessive-compulsive disorder at the University of Arizona,
USA. Further to be explored is the extent to which the profound effects of serotonergic
hallucinogens on self-perception and affectivity contribute to symptom reduction in clinical
populations. Involvement of serotonin in eating disorders arises from the use of psychotropic drugs
that intrasynaptically increase serotonin levels or directly activate serotonergic receptors, and tend
to Tend to produce satiety. Conversely, pharmacotherapeutic interventions that increase serotonergic
neurotransmissions or serotonergic receptor activities decrease the food intake and promote weight
gain (Blundell et al. 1984). In addition, the increase in fear of weight gain and binge eating in
patients with bulimia Nervosa during tryptophan depletion points to a central role of serotonin in
eating disorders such as bulimia nervosa (Kaye et al. 2000). Although the biological basis of eating
disorders has not yet been has not been adequately elucidated, recent PET (positron emission
tomography) Tomography) studies show a decrease in 5-HT 2A receptor density in mediotemporal
brain regions (Frank et al. 2002) and a reduction of serotonergic 5-HT 2A receptors in the medial
orbitofrontal cortex in patients with anorexia nervosa or bulimia nervosa who had already recovered
had recovered (Kaye et al. 2001). With respect to the present hypothesis that psilocybin might might
reduce symptoms of eating disorders, this is an interesting finding, firstly because psilocybin
predominantly stimulates 5-HT 2A receptors (Vollenweider et al. 1998) and second, because the
repeated administration of serotonergic hallucinogens (e.g., LSD, psilocybin) in animal studies
down-modulates 5- HT 2A receptors down-modulates (Buckholtz et al. 1990). Whether the
alteration of 5-HT 2A receptors is a cause or an effect of the pathophysiology of obsessive-
compulsive spectrum disorders remains to be further explored. Another obsessive-compulsive
spectrum disorder is somatoform disorder, which is a heterogeneous with multiple manifestations,
e.g. hypochondriacal, and also has a comorbidity to OCD. comorbidity to obsessive-compulsive
spectrum disorders (Fallon et al. 2000). The efficacy of psilocybin in somatoform disorder such as
body dysmorphic disorder has been described by Hanes (1996) been described and supports the
hypothesis of serotonergic dysfunction in this Disorder group. Moreover, the hypochondriacal fears
of some patients correspond qualitatively to the intrusive thoughts of patients with obsessive-
compulsive disorder, although hypothetically, as in somatoform pain disorders, there is no direct
relation between noradrenergic and serotonergic neurotransmission. role of serotonergic
neurotransmissions is assumed (Van Kempen et al. 1992).

Relationship between obsessive-compulsive, eating and somatoform disorders

Studies in the last decade have discussed the relationship between individual obsessive-compulsive
spectrum Disorders.The majority of these studies point at a common occurrence of obsessive-
compulsive symptoms in various spectrum disorders (Fahy, 1991; Hsu et al. 1993). Ranson et al.
(1999) showed that patients with bulimia nervosa and patients who had recovered from bulimia
nervosa recovered had equally high scores on a scale of obsessive-compulsive symptoms (Y-
BOCS). Furthermore, for example, obsessive-compulsive symptoms increased in patients who had
recovered from bulimia nervosa. had recovered. Similarly, eating disorder symptoms occur in
patients with obsessive-compulsive disorder. Thus studies reported that patients with obsessive-
compulsive disorder had high prevalences of bulimia nervosa and showed elevated scores on an
eating disorder scale (Rubenstein et al. 1992; Braun et al. 1994; Grabe et al. 2000). In somatoform
disorders, the hypochondriacal fears of some patients qualitatively to the intrusive thoughts of
patients with obsessive-compulsive disorder (Fallon et al. 2000).
Therapy resistance of the clinical disorder group to be explored. In addition to cognitive behavioral
therapy, selective serotonin reuptake inhibitors (SSRIs) were found to be effective in the treatment
of obsessive-compulsive spectrum disorders. However, compared with other psychiatric disorders
such as depression or anxiety disorders, the response to drug therapy is lower, and patients with
obsessive-compulsive spectrum disorders often show only a partial only a partial decrease in
symptoms and are highly likely to relapse (Goodman, 1999; Case (Goodman, 1999; Fallon et al.
2000; Kruger & Kennedy, 2000; Kaye et al. 2000). The probability of full remitting of obsessive-
compulsive disorder symptoms with SSRIs over a 2-year period is years is 12%, and the relapse rate
is very high at 48% (Goodman, 1999). For eating disorders such as bulimia nervosa, the average
decrease from baseline was of approximately 8-10 episodes of binge eating per week was
approximately 55%, with a high dispersion in different studies (Kaye et al. 2000). Only a minority
of patients treated with SSRIs achieved near normalization of eating behavior. Controlled clinical
trials indicate cognitive behavioral therapy is effective in approximately 60-70% of individuals with
bulimia nervosa. with a decrease in symptoms occurring in only 30-50% of cases (Kaye et al.
2000). Little research has been done on somatoform disorder. Due to this it seems interesting to
examine further therapeutic strategies for disorders from the obsessive-compulsive spectrum.
Pharmacology and spectrum of action of psilocybin
Psilocybin (PY, 4-phosphoryloxy-N,N-dimethyltryptamine) represents a substituted indole-
alkylamine and belongs to the hallucinogenic tryptamine derivatives. Mental functions are
modulated depending on the dose. In medium doses (12-20 mg), psilocybin induces an easily
controllable altered state of consciousness that lasts up to 3-6 hours and is characterized by
alterations in sensory perception, affectivity, thinking, and ego-environmental boundaries (Leuner
1981; Vollenweider et al. 1997, 1998, 1999). Changes in the perception of time and space, as well
as visual illusions, elementary and complex hallucinations, and synaesthesias were frequently
observed during the main effect of the substance is observed. Increased introspection ability is
likewise an interesting effect of the spectrum of action of psilocybin in the context of this study. The
acute toxic effects of psilocybin are minor, and somatic effects were first reported by Delay et al.
(1958) and Quentin (1960) in 150 subjects with a subacute dose of 10-25 mg psilocybin, showing
slight changes in heart rate and blood pressure were observed, as well as a slight tremor. were
observed. The results of Hasler et al. (1997, 2001) on the metabolism and pharmacokinetics of
Psilocybin indicate that psilocin is metabolized within 20-40 min after oral administration of
psilocybin can be measured in plasma, the psychological effects at a plasma concentration of 4-6 ng
PI/mL, and the maximum plasma level of psilocin 70-90 minutes after substance ingestion is
reached. After repeated ingestion of psilocybin and and other hallucinogenic tryptamine derivatives,
tolerance develops with rapid regression upon discontinuation. development of physical and
psychological dependence has not been described in any study been described (Abramson, 1956;
Balestrieri, 1967). Psychoses are generally associated with the administration and use of psilocybin,
but studies on this subject are scarce. Cohen (1960) estimated the likelihood that the use of
psilocybin, which is related to psilocybin in its psychoactive effect and highly potent serotonergic
hallucinogen d-lysergic acid-diethylamide (LSD), induces psychosis at approximately 0.8/1000
persons. McGlothlin & Arnold (1971) reported one case of psychotic decompensation in 247
persons taking LSD. ingested. During the extensive experimental human studies with psilocybin in
recent years at our institution, no physical or psychological side effects have occurred to date,
lasting longer than 24 hours (Vollenweider et al. 1997).

(3) Study design

Experimental procedure and methods
Inclusion criteria
ICD-10 / DSM-IV diagnosis for obsessive-compulsive disorder, eating disorder, somatoform
disorder. In each case 14-16 subjects will be recruited by physicians, psychiatrists, outpatient
services and psychiatric hospitals Or may self-enroll. 
Age: 18-47 years, gender: women and men, careful Diagnosis according to ICD-10 / DSM-IV
diagnosis based on a structured psychiatric Interview (DIA-X; Wittchen and Pfister, 1997), for
eating disorders according to SIAB, conducted by A trained and experienced psychologist or
psychiatrist. Performance of various psychological ratings for initial diagnosis (e.g.: EDI, Y-BOCS).
A comparison is made with healthy control subjects who have been tested by an experienced
internist for somatic (electrocardiogram, physical examination and standard clinical laboratory
tests) and for mental health (DIA-X screening).
 
Exclusion criteria
The following criteria are used as exclusion criteria from the study:
(a) DSM IV Axis I disorders
1) Lifetime DSM-IV diagnosis of substance dependence or substance abuse.
2) (nicotine abuse and dependence are not exclusion criteria), Manic episode or
Psychosis as per DIA-X interview.
3) Lifetime [or within the last 5 years] DSM-IV diagnosis (Axis I, obsessive-compulsive spectrum
Disorders are not excluded) As per DIA-X.
3) a) Persistent (2 months) DSM IV diagnosis of Major Affective or Anxiety Disorder; as per. DIA-
X.
b) DSM-IV Axis II disorders, lifetime DSM-IV diagnosis of a Personality Disorder according to
SCID-.
II screening
c) Family history     
Psychotic disorder in first-degree relatives.
d) Other conditions
Another additional significant medical disorder, neurological disorder (e.g., diabetes, nephropathy,
cardiomyopathy, hypertension) or genetic disorder will result in exclusion from the Study.
Pregnancy is an exclusion criterion.
e) Ongoing treatment with psychotropic medication.
Exclude patients without central nervous medication (antidepressants, antipsychotics, tranquilizers,
etc.) of a duration of two weeks will be admitted to the study. The use of fluoxetine for a duration of
5 weeks is an exclusion criterion.

Test procedure
a-Registration, contact
b-Information, clarification: inclusion and exclusion criteria, weight control, psychometric ratings
c-Pre-trial day interview, somatic examination (weight, height, internal check,
laboratory, pregnancy test, drug urine).
d-Two trial days, one week apart, with the same schedule: Administration of substance (placebo or
0.25 mg psilocybin/kg; range 15-24 mg abs. mg/kg). Supervision by investigator, completion of
psychometric ratings. After effects wore off, discharge home or overnight stay in clinic. 
e-On the day following the trial: follow-up interview, psychometric ratings.
f-Follow-up after 1 or 4 weeks.

Psychometric ratings
Implementation of psychometric ratings and standardized questionnaires for the assessment of the
symptomatology and other psychological variables, such as body image, eating behavior, altered
States of Consciousness, Obsessive-Compulsive Behavior, Dissociation, and Positive and Negative
Affects. These questionnaires do not represent a burden for the patient or the control person and are
standard instruments in clinical and scientific practice:
1.) DIA-X interview (DIA-X, Wittchen and Pfister 1997). The DIA-X interview is an objective,
valid and fully standardized interview that allows for a computerized diagnosis of psychiatric of
psychiatric disorders according to DSM-IV and ICD-10 criteria. The SCID-II (First et al. 1994) is a
semi-structured interview and allows for the diagnosis of personality disorders according to DSM-
IV criteria.
2.) SIAB (SIAB, Fichter et al. 1991). The Structured Inventory for Anorexic and Bulimic Eating
Disorders Eating Disorders is a reliable, valid, and structured interview for assessing the entire
spectrum of eating spectrum of eating disorder symptoms (anorexia nervosa, bulimia nervosa,
unspecified eating disorder including binge eating disorder according to DSM-IV, and anorexia
nervosa and bulimia nervosa according to ICD-10) and the comorbidity often associated with eating
disorders (depression, anxiety, alcohol and drug problems).
3.) Symptom Checklist-90 R (SCL-90 R, Derogatis, 1977). The scale is a 90 item consisting of,fully
standardized Procedure for self-assessment and enables a mutidimensional assessment of general
psychopathology.
4.) Trait Word List (EWL, Janke and Debus 1978). The scale is a multidimensional procedure for
the quantitative description of the current state of mind.
5.) State-Trait Anxiety Inventory (STAI) The State-Trait Anxiety Inventory consists of two scales
which anxiety as a relatively enduring personality trait and anxiety as a transient emotional state.
emotional state separately. The two scales each contain 20 items (STAI G Form X1 and STAI G
Form X).
6) Eating Disorders Inventory (EDI, Garner et al. 1983): The Eating Disorders Inventory is a 64-
item consisting of 64 items for the assessment of behavioral and personality traits in eating
disorders.
7.) Questionnaire of Extraordinary States of Consciousness (OAV, Dittrich 1998): The OAV-
questionnaire is an instrument for retrospective assessment of altered, unusual states of
consciousness. states of consciousness and consists of three dimensions: Oceanic Self-Exclusion
(OSE), Anxious Ego Dissolution (AIA) and Visionary Restructuring (VUS).
8) Visual Analogue Scale (VAS) of Body Awareness: The VAS is a 10 cm long Visual Analog Scale
for self-assessment of body perception (extreme points: 0 = absolutely satisfied, 10 = absolutely
dissatisfied).
Psychometric scales: Structured Inventory for Anorexic and Bulimic Eating Disorders (SIAB,
Fichter et al 1991), DIA-X interview (DIA-X, Wittchen and Pfister 1997), Structured Clinical
Interview for DSM-IV. (SCID, First et al 1994), State-Trait Anxiety Inventory (STAI, Spielberger et
al. 1970), trait word list (EWL, Janke and Debus 1978), Questionnaire of Extraordinary States of
Consciousness (OAV, Dittrich 1998), Complaints List (BL, von Zerssen 1976), Eating Disorders
Inventory (EDI, Garner et al. 1983), Symptom Checklist-90 (SCL-90, Derogatis 1976), Yale-Brown
Obsessive-Compulsive Scale (Y-BOCS, Goodman et al. 1989)
2) Implemented in evaluation.
3) 1 week and 4 weeks after PY.

Statistical Analyses
Two-way analyses of variance (ANOVAs) with Treatment (psilocybin vs placebo)
and psychometric scale scores as repeated measures will be conducted to examine the effect of of
psilocybin on the psychological dimensions studied. Post-hoc tests for the individual variables will
be conducted using planned comparisons ("planned comparisons"). In addition, effect sizes will be
calculated according to Cohen's method, and multiple regression analyses are performed to analyze
changes in symptomatology and other psychological psychological dimensions on the one hand and
to investigate the relationships between the psychometric scales.
(4) Risks and care
No physiological intolerance reactions have been described to date for the psychoactive substance
Psilocybin have been described. The physiological reactions caused are only discretely and are
classified as harmless in the literature (see section 3. "Pharmacology and spectrum of action of
psilocybin"). The development of a physical dependence is only the possibility of a slightly
pronounced psychological dependence in a marginal number of in a marginal number of
predisposed individuals is known, but can be ruled out by the selectivity of the indication in this
study. In the late 1960s, published Evidence of chromosomal damage by psilocybin was refuted
(Dishotsky et al. 1971; Leuner, 1981). Some of the nonspecific and specific complication
possibilities due to the administration of serotonergic hallucinogens have been retrospectively
studied in 9,300 patients have been made (Cohen, 1960; Malleson, 1971). It should be mentioned
that in Cohen and Malleson also treatments that date back to the earliest experimental beginnings of
the study of psychoactive substances. In addition, the vast majority of the treated patients consisted
of so-called therapy-refractory cases with severe psychopathological conditions or personality
disorders. Relevant possible complications included prolonged psychotic reactions, suicide
attempts, suicides, short-term psychotic experience and behavior, anxiety reactions, reverberation
effects, and depressive aftershocks have been described. With respect to psychotic reactions, Cohen
(1960) and Malleson (1971) emphasized that initially (pre-)psychotic and borderline patients were
also treated with psilocybin, and in the documented cases psychotic dispositions were described.
Regarding the suicides, it should be noted that these occurred weeks or months after the
administration of psilocybin, which makes the causality hypothesis highly questionable. Almost all
of these patients had a history of suicide attempts, suggesting that such patient populations in the
future by appropriate psychometric methods and to exclude them from an indication. This was also
recommended by Leuner (Leuner, 1996).
In summary, according to the available research, the incidence of psychotic reactions, suicide
attempts and suicides caused by the administration of psilocybin does not exceed that of a normal
population of, for example, psychotherapy patients. In addition to these nonspecific complications,
some specific complications may arise (cf. Cohen, 1960; Grof, 1967; Leuner, 1971): 1) Brief
psychotic experience and behavior: This may occur in connection with aggression and anxiety
effects. In moderate dosage and orderly setting, such reactions are very rare and remain
therapeutically controllable (Leuner, 1971; Grof, 1983). 2) Anxiety reactions: These are imprinted
by the occurrence of strong fears and panic reactions (e.g., of loss of control, assumed death or
"going crazy") and occur almost and occur almost exclusively with uncontrolled use. With adequate
dosage and these reactions can be almost completely avoided. If they occur once, they can be
overcome by special therapeutic care in the form of "talking down". In rare cases where this is not
possible, the administration of benzodiazepines (e.g. benzodiazepines (e.g. diazepam), the effects of
the substance can be brought to a rapid resolution. There is agreement in the literature on the good
tolerability of psilocybin in anxiety disorders (cf. reviews in Leuner 1971; Grof 1983). 3)
Reverberation effects (so-called "flash-backs"): These effects can be as a without substance effect
occurring altered state of consciousness, which revives certain experiences or contents ("state-
dependent remembering"). In the scientific literature, these effects are still as a phenomenon and as
a potential danger (cf. Diezi, 1980; Strassman, 1984). The Occasional occurrence of reverberation
effects may occur mainly in connection with specific key stimuli such as specific music or
situational contextual conditions and was harmless to patients (Leuner, 1981; Leuner, 1996).
Occasionally, however, anxiety may also be induced. Hazards due to behavioral changes resulting
from reverberation effects are not described in the literature (cf. Strassman, 1984). A disposition for
reverberation effects seems to be particularly in the case of intense and unprocessed experiences.
This has to be and to be taken into account in the specific aftercare of individual patients.to be taken
into account. 4) Depressive aftershocks: These may occur during intense experiences and self-
awareness characterized experiences occur and are depth psychological as stability fluctuations in
the reconsolidation of a more realistic self-perception. more realistic self-perception.
Neurobiologically, adaptive mechanisms as well as a trait-related modulation of the sensitivity of
certain to take into account the targeted follow-up care of individual patients.be taken into account.
4) Depressive aftershocks: These can occur with intensive and of great self-awareness experiences
occur and are depth psychological as stability fluctuations in the reconsolidation of a more realistic
self-perception. more realistic self-perception. Neurobiologically, adaptive mechanisms as well as a
trait-related modulation of the sensitivity of certain serotonergic subreceptor types can be assumed.
Complications can be avoided by the following procedure (patient remains under supervision for
under supervision for 24 h, availability of the investigator by phone also in the days after the
session) can be avoided. Basically, in the course of numerous controlled neuropsychological and
neuroendocrinological studies on a total of well over one hundred healthy subjects, no persistent
somatic or psychological complications occurred under psilocybin doses of 12-20 mg (Hasler et al.,
1997, 2001; Vollenweider et al., 1997; Ametamey et al, 1998; Gouzoulis-Mayfrank et al, 1998a,
1998b, 1998c; Schreckenberger et al., 1998; Vollenweider et al, 1998a, 1998b; Gouzoulis-Mayfrank
et al, 1999a, 1999b; Umbricht et al,1999; Vollenweider et al., 1999, 2001). Any side effects and
complications should be reported in the be recorded by the principal investigator on a
documentation form and documented with a patient questionnaire.

Duration of the study

approx. 3 years
Financing of the study
Informed Consent
Patients sign a declaration of consent that the data of the performed examinations for a scientific
work used can be used. This consent form will be kept separate from the examination protocols.
The Study Record will be registered anonymously by a numerical code. 
Data protection regulation
For the scientific processing of the data, anonymization by means of number coding is carried out
which is recorded within the scope of data archiving.
(6). Schedule
Purpose
Amount1
2002: Submission to the FOPH and to the local ethics committee, Completion of the final study
protocol
Jan-Dec 2003: Implementation of the study at the Heffter Research Center Königsfelden, Start of
the study in the clinical population (focus on OCD) and in healthy healthy control subjects
Jan-Dec 2004: Evaluation of initial results, continuation of the clinical study with a focus on eating
disorders
Jan-Dec 2005: Continuation of clinical study with focus on somatoform disorder, final data analysis
and publication, in case of clear indications for a therapeutic launch of a study with clinical
populations including psychotherapeutic populations with inclusion of psychotherapeutic measures
and repeated administration of the substance ("treatment" study)
(7) Significance of the study.
The investigation of the 5-HT 2A agonist psilocybin in obsessive-compulsive spectrum disorders
yields first insights into the therapeutic potential of this compound in clinical populations. This
further elucidates the importance of the 5-HT 2 receptor in the pathophysiology of this group of
disorders. elucidated. Furthermore, it will be explored for the first time whether psilocybin, in
addition to a possible acute symptom-modifying effect, psilocybin also has an influence on
psychological variables, such as self- and body perception and affectivity. Furthermore, this study
also yields insight into the tolerability of the 5-HT 2A agonist psilocybin in obsessive-compulsive
spectrum disorders. Overall with the inclusion of further research results the basis for a possible
pharmacotherapeutic use of the 5-HT pharmacotherapeutic use of the 5-HT 2A agonist psilocybin in
long-term treatment studies. can be established.
Literatur
Abramson, HA, Jarvik, ME, Gorin, MH, Hirsch, MW. 1956. Lysergic acid diethylamide (LSD 25):
XVII. Tolerance development and its relationship to a theory of psychosis. Journal of Psychology
41:81-86.
American Psychiatric Association. 2000. Diagnostic and Statistical Manual of Mental Disorders
DSM-IV-TR (Text Revision), 4th edition. American Psychiatric Press. 943 p.
Ametamey, S, Vollenweider, FX, Patt, J, Bourquin, D, Hasler, F, Beer, HF, Schubiger, PA. 1998.
11C-Radiolabeling of hallucinogenic psilocin, a potential radioligand for studying the role of
serotonin receptors in psychotic symptom formation. J Label Comp and Radiopharm 41:585-594.
Arranz, B, Rosel, P, Ramirez, N, San, L. 2001. Genetic dysfunction of the serotonin receptor 5-
HT2A in psychiatric disorders. Actas Esp Psiquiatr 29:131-138.1
Balestrieri, C. 1967. On the action mechanisms of LSD 25. In: Abramson HA, editor. The Use of
LSD in Psychotherapy and Alcoholism. Indianapolis, New York, Kansas City. p 653-660.
Bastiani, AM, Rao, R, Weltzin, T, Kaye, W. 1995. Perfectionism in anorexia nervosa. Int J Eat
Disord 17:147-152.
Blundell, JE. 1984. Serotonin and appetite. Neuropharmacology 23:1537-1551.
Brandrup E, Vanggaard T. 1977. LSD treatment in a severe case of compulsive neurosis. Acta
Psychiat Scand, 55:127-141.
Braun, DL, Sunday, SR, Halmi, KA. 1994. Psychiatric comorbidity in patients with eating
disorders. Psychol Med 24:859-867.
Buckholtz, NS, Zhou, DF, Freedman, DX, Potter, WZ. 1990. Lysergic acid diethylamide (LSD)
administration selectively downregulates serotonin 2 receptors in rat brain.
Neuropsychopharmacology 3: 137-148.
Clark, B. 1968. Some early observations on the use of psilocybin in psychiatric patients. Br J Social
Psychiatry 2:21-26.
Cohen, S 1960. Lysergic Acid Diethylamide: Side Effects and Complications. Journal of Nervous
and Mental Disease 130: 30-40.
Delay, J, Pichot, P, Nicolas-Charles, PJ. 1959. Premiers essais de la psilocybine en psychiatrie.
[First essays on psilocybine in psychiatry] In: Bradley P, Deniker P, Radouco-Thomas C, editors.
Neuro-Psychopharmacology. Amsterdam p 528-531.
Delgado, PL, Moreno, FA. 1998. Hallucinogens, Serotonin, and Obsessive Compulsive Disorder. J
Psychoactive Drugs 30(4): 359-366.
Derogatis, LR, Lipman, RS, Covi, L. 1976. SCL-90 (Symptom-Check-List). Self-report symptom
inventory. In: Guy W, editor. ECDEU assessment manual for psychopharmacology.
Rockville/Maryland: NIMH.
Diezie, P. 1980. Theorien über Flashback nach Halluzinogenkonsum. Zürich: Universität Zürich,
Abt. für klinische Psychologie. Unveröffentlichtes Manuskript.
Dishotsky, NI, Loughman, WB, Mogar, RE, Lipscomb, WR. 1971. LSD and Genetic Damage.
Science 172:431-440.
Dittrich, A. 1998. The standardized psychometric assessment of altered states of consciousness
(ASCs) in humans. Pharmacopsychiat 31:80-84 .
Duche, D. 1961. The effects of psilocybin in a case of hysteria. Semaine des Hospitaux de Paris
37:3061-3062.
Fahy, TA. 1991. Obsessive compulsive symptoms in eating disorders. Behav Res Ther 29:113-116.
Fallon, BA, Qureshi, AI, Laje, G, Klein, B. 2000. Hypochondriasis and its relationship to obsessive-
compulsive disorder. Psychiatr Clin North Am 23:605-616.
Frank, GK, Kaye, WH, Meltzer, CC, Price, JC, Greer, PJ, McConaha, CW, Skovira, K. 2002
Altered serotonin 2A receptor activity in woman who have recovered from anorexia nervosa. Biol
Psychiatry, abstract.1
Fichter, MM, Elton, M, Engel, K, Meyer, AE, Mall, H, Poustka, F. 1991. Structured Interview for
Anorexia and Bulimia nervosa (SIAB): Developement of a new instrument for the assessment of
eating disorders. Int J Eat Disorders 10: 571-592.
First, MB, Spitzer, R, Gibbon, M, Williams J. 1994. Structured clinical interview for Axis I DSM-
IV disorders. Patient Edition (SCID-I/P, vs 2.0).
Garner, DM, Olmsted, MP, Polivy, J. 1983. The eating disorders inventory: a measure of cognitive
behavioral dimensions of anorexia and bulimia. In: Darby DL, editor. Anorexia Nervosa. New York
p 21-40.
Gnirss, F. 1963. Therapie der Neurosen mit Phantastica. Schweizer Archiv für Neurologie,
Neurochirurgie und Psychiatrie 92:234-236.
Goodman, WK, Price, LH, Rasmussen, SA, Mazure, C, Fleischmann, RL, Hill, CL, Heninger, GR,
Charney, DS. 1989. The Yale-Brown Obsessive Compulsive Scale, I: development, use, and
reliability. Arch Gen Psychiatry 46:1006-1011.
Goodman, WK, Price, LH, Rasmussen, SA, Mazure, C, Delgado, P, Heninger, GR, Charney, DS.
1989. The Yale-Brown Obsessive Compulsive Scale, I: validity. Arch Gen Psychiatry 46:1012-
1016.
Goodman, WK. 1999. Obsessive-compulsive disorder: diagnosis and treatment. J Clin Psychiatry
60 Suppl 18:27-32.
Gouzoulis-Mayfrank, E., Schneider, F., Friedrich, J., Spitzer, M., Thelen, B., Sass, H. 1998a.
Methodological issues of human experimental research with hallucinogens. Pharmacopsychiatry 31
Suppl 2:114-118.
Gouzoulis-Mayfrank, E, Thelen, B, Maier, S, Habermeyer, E, Spitzer, M, Sass, H. 1998b.
Modulation of semantic priming effects by psilocybin, MDE (ecstasy), and d-methamphetamine.
Neurology, Psychiatry and Brain Research 6:19-28.
Gouzoulis-Mayfrank, E, Heekeren, K, Thelen, B, Lindenblatt, H, Kovar, KA, Sass, H, Geyer, MA
1998c. Effects of the hallucinogen psilocybin on habituation and prepulse inhibition of the startle
reflex in humans. Behav.Pharmacol. 9:561-566.
Gouzoulis-Mayfrank, E, Schreckenberger, M, Sabri, O, Arning, C, Thelen, B, Spitzer, M, Kovar,
KA, Hermle, L, Buell, U, Sass, H. 1999a. Neurometabolic effects of psilocybin, 3,4-
methylenedioxy-ethylamphetamine (MDE) and d-methamphetamine in healthy volunteers.
Neuropsychopharmacology 20:565-581.
Gouzoulis-Mayfrank, E, Thelen, B, Habermeyer, E, Kunert, HJ, Kovar, KA, Lindenblatt, H,
Hermle, L, Spitzer, M, Sass, H. 1999b. Psychopathological, neuroendocrine and autonomic effects
of 3,4-\methylenedioxyethylamphetamine (MDE), psilocybin and d-methamphetamine in healthy
volunteers. Psychopharmacology 142:41-50.
Grabe, HJ, Thiel, A, Freyberger, HJ. 2000. Symptoms of eating disorders in obsessive-compulsive
disorder. Acta Psychiatr Scand 102:449-453.
Greenberg, BD, Benjamin, J, Martin, JD, Keuler, D, Huang, SJ, Altemus M, Murphy, DL. 1998.
Delayed obsessive-compulsive disorder symptom exacerbation after a single dose of a serotonin
antagonist in fluoxetine-treated but not untreated patients. Psychopharmacology 140:434-444.
Grob, C. 1994. Psychiatric research with hallucinogens: what have we learned? Yearbook for
Ethnomedicine and the study of consciousness 1994:91-112.1
Grof, S. 1967. The Use of LSD 25 in Personality Diagnostics and Therapy of Psychogenic
Disorders. In: Abramson, H.A. (ed.): The Use of LSD in Psychotherapy and Alcoholism.
Indianapolis/New York/ Kansas City 1967, pp. 154-190.
Grof, S. 1983. LSD-Psychotherapie. Stuttgart 1983.
Hanes, KR. 1996. Serotonin, psilocybin and body dysmorphic disorder: A case report. J Clin
Psychopharm 16:188-189.
Hasler, F, Bourqin, D, Brenneisen, R, Bär, T, Vollenweider, FX. 1997. Determination of psilocybin
and 4-hydroxyindole-3-acetic acid in plasma by hplc-ecd and pharmacokinetic proflies of oral and
intravenous psilocybin in man. Pharmaceutica Acta Helvetiae 72: 175-184.
Hasler, F, Bourquin, D, Brenneisen, R, Vollenweider, FX, 2001. Renal excretion profiles of psilocin
following oral administration of psilocybin in man. submitted
Hollander, E. 1996. Obsessive-compulsive related-disorders: the role of selective serotonergic
reuptake inhibitors. Int Clin Psychopharmacol Suppl 5:75-87.
Hollander, E. 1998. Treatment of obsessive-compulsive spectrum disorders with SSRIs. Br J
Psychiatry Suppl 35:7-12.
Hsu, LKG, Kaye, W, Weltzin, T. 1993. Are eating disorders related to obsessive compulsive
disorder? Int J Eat Disord 14:305-318.
Kaye, WH, Gwirtsmann, HE, George, DT, et al. 1986. Relationship of mood alterations to beinging
behavior in bulimia. Br J Psychiatry 149:479-485.
Kaye, W, Gendall, K, Strober, M. 1998. Serotonin neuronal function and selective reuptake
inhibitor treatment in anorexia and bulimia nervosa. Biol Psychiatry 44:825-838.
Kaye, WH, Klump, KL, Frank, GKW, Strober, M. 2000. Anorexia and bulimia nervosa. Annu Rev
Med 51:299-313.
Kaye, WH, Frank, GK, Meltzer, CC, Price, JC, McConaha, CW, Crossan, PJ, Klump, KL, Rhodes,
L. 2001. Altered serotonin 2A receptor activity in woman who have recovered from bulimia
nervosa. Am J Psychiatry 158:1152-1155.
King, A. 1963. Primary and secondary anorexia nervosa syndrome. Br J Psychiatry 109:470-475.
King, BH. 1990. Hypothesis: involvement of the serotonergic systems in the clinical expression of
monosymptomattic hypochondriasis. Pharmacopsychiatry 23:85-89.
Kruger, S, Kennedy, SH. 2000. Psychopharmacotherapy of anorexia nervosa, bulimia nervosa and
binge-eating disorder. J Psychiatry Neurosci 25:497-508.
Leonard, HL, Rapoport, JL. 1987. Relief of obsessive-compulsive symptoms by LSD and
psilocin.Am J Psychiatry 144:1239-40.
Leuner, H. 1971. Halluzinogene in der Psychotherapie. Pharmakopsychiatry/Neuropsycho-
pharmakologie 4: 333-351.
Leuner, H. 1981. Halluzinogene. Psychische Grenzzustände in Forschung und Psychotherapie.
Bern, Stuttgart, Wien: Huber
Malleson, N. 1971. Acute Adverse Reactions to LSD in Clinical and Experimental Use in the
United Kingdom. Br J Psychiatry 118: 229-230.
Mascher, E. 1967. Psycholytic therapy: Statistics and indications. In: Brill, H, Cole, JO, Hippius, H,
Bradley, PB (eds.): Neuro-Psychopharmacology. Excerpta Medica Foundation. Amsterdam 1967,
pp. 441-444.
McElroy, SL, Phillips, KA, Keck, PE Jr. 1994. Obsessive compulsive spectrum disorder. J Clin
Psychiatry Suppl 55:33-51.
Moreno, FA, Delgado, PL. 1997. Hallucinogen-induced relief of obsessions and compulsions. Am J
Psychiatry 154:1037-38.
Quetin, AM. 1960. La Psilocybine en psychiatrie clinique et experimentale. [Psilocybin in Clinical
and Experimental Psychiatry] Paris: Med. Diss.
von Ranson, KM, Kaye, WH, Weltzin, TE, Rao, R, Matsunaga, H. 1999. Obsessive-Compulsive
disorder symptoms before and after recovery from bulimia nervosa. Am J Psychiatry 156: 1703-
1708.
Ravindran, AV, Lapierre, YD, Anisman, H. 1999. Obsessive-compulsive spectrum disorders:
effective treatment with paroxetine. Can J Psychiatry 44:805-807.
Rubenstein, CS, Pigott, TA, L'Heureux, F, Hill, JL, Murphy, DL. 1992. A preliminary investigation
of the lifetime prevalence of anorexia and bulimia nervosa in patients with obsessive compulsive
disorder. J Clin Psychiatry 53:309-14.
Schreckenberger, M, Gouzoulis-Mayfrank, E, Sabri, O, Arning, C, Schulz, G, Zimny, M, Kaiser,
HJ, Wagenknecht, G, Tuttass, T, Sass, H, Buell, U. 1998. The psilocybin psychosis as a model
psychosis paradigma for acute schizophrenia: a PET study with 18-FDG. Eur J Nucl Med 877-877.
Stein, DJ. 2000. Neurobiology of the obsessive-compulsive spectrum disorders. Biol Psychiatry
47:296-304.
Strasssman, RJ. 1984. Adverse Reactions to Psychedelic Drugs. A Review of the Literature. Journal
of Nervous and Mental Diseases 172: 577-595.
Strassman, RJ, 1995. Hallucinogenic drugs in psychiatric research and treatment. Perspectives and
prospects. J Nerv Ment Dis 183:127:138.
Umbricht, D, Vollenweider, FX 1999. Effects of NMDA-antagonists and 5-HT2A-agonists on
generation of MMN in human volunteers. Biol Psychiatry 45, 51-52.
Van Kempen, GM, Zitman, FG, Linssen, AC, Edelbroek, PM. 1992. Biochemical measures in
patients with a somatoform pain disorder, before, during, and after treatment with amitriptyline with
or without flupentixol. Biol Psychiatry 31:670-680.
Vollenweider, F.X, Leenders, KL, Scharfetter, C, Maguire, P, Stadelmann, O, Angst, J. 1997.
Positron Emission Tomography and Fluorodeoxyglucose Studies of Metabolic Hyperfrontality and
Psychopathology in the Psilocybin Model of Psychosis. Neuropsychopharmacology 16:357-372.
Vollenweider, FX, Vollenweider-Scherpenhuyzen, MFI, Bäbler, A, Vogel, H, Hell, D. 1998a.
Psilocybin Induces Schizophrenia-Like Psychosis in Humans via Serotonin-2 Agonist Action.
Neuroreport 9:3897-3902.
Vollenweider, FX. 1998b. Advances and pathophysiological models of hallucinogen drug actions in
humans: a preamble to schizophrenia research. Pharmacopsychiatry 31: 92-103.1
Vollenweider, FX, Vontobel, P, Hell, D, Leenders, KL. 1999. 5-HT modulation of dopamine release
in basal ganglia in psilocybin-induced psychosis in man: A PET study with [11C]raclopride.
Neuropsychopharmacology 20: 424-433.
Vollenweider, FX, Geyer, MA. 2001. A systems model of altered consciousness: Integrating natural
and drug-induced psychoses. Brain Res Bull. 56:495-507.
Williamson, DA, Muller, SL, Reas, DL, Thaw, JM. 1999. Cognitive bias in eating disorders:
implications for theory and treatment. Behav Modif 23:556-477.
Wittchen, HU, Pfister, H. 1997. DIA-X-Interview. Frankfurt:Swets Test Services.201p.
 
Publication List:
Ludewig S , Ludewig K, Geyer MA, Hell D, Vollenweider FX (2002): Prepulse inhibition deficits
in patients with panic disorder. Depress Anxiety 15(2):55-60
Ludewig S , Paulus MP, Ludewig K, Vollenweider FX. Decision-making strategies by panic
disorder subjects are more sensitive to errors. J Affect Disord (in press)
Ludewig K, Ludewig S, Seitz A, Obrist M, Geyer MA, Vollenweider FX. The Acoustic Startle
Reflex and its Modulation: Effects of Age and Gender in Humans. Biol Psychology (in press)
Ludewig S , Ludewig K, Hell D, Vollenweider FX (2000): Panic disorder and deficits in
information-processing. Eur Arch Psychiatry Clin Neurosci 250, Suppl 1:I/18
Ludewig K, Ludewig S, Seitz A, Obrist M, Vollenweider FX (2001): Prepulse inhibition: Age-and
gender-effects in healthy comparisons. Eur Neuropsychopharmacology 11, Suppl 3:S 358-359
Ludewig S , Ludewig K, Geyer MA, Hell D, Vollenweider FX (2001): Deficient prepulse inhibition
of the acoustic startle reflex in panic disorder. Eur Neuropsychopharmacology 11, Suppl 3:S312
Ludewig K, Ludewig S, Vollenweider FX (2001): Decreased habituation of the acoustic startle
reflex in unmedicated first episode schizophrenia. Pharmacopsychiatry 34:187
Ludewig S , Ludewig K, Geyer MA, Hell D, Vollenweider FX (2001): PPI deficit in panic disorder
patients correlated with high trait anxiety. Pharmacopsychiatry 34:188
Ludewig K, Ludewig S, Geyer MA, Vollenweider FX (2002): Sensory gating and attention in
schizophrenia. Schiz Research 53, Supplement:216
Ludewig S , Hasler F, Studerus E, Lindner K, Vollenweider FX (2002): Effects of MDMA
(“Ecstasy”) on cognitive performance in healthy humans. BAG-Congress, Zürich (Poster)
Ludewig S, Vollenweider FX. No lasting effects of moderate doses of MDMA on memory
performance and mood states. submitted
Ludewig S, Ludewig K, Hasler F, Studerus E, Lindner K, Vollenweider FX. Acute effects of
MDMA (“Ecstasy”) on cognitive performance and psychology in healthy humans: a pretreatment
study with the 5-HT 1A antagonist pindolol. submitted