U. Schneider

Towards a Cannabinoid Hypothesis of Schizophrenia: Cognitive Impairments Due to Dysregulation of the Endogenous Cannabinoid System

Cognitive impairments during psychotic episodes are assumed to be caused not only by one single putative classical neurotransmitter dysfunction but also by an impaired equilibrium of the interaction between different neurobiological generators of cognitive processes. Herein, the perceptual abnormalities induced by psychotogenic agents play a major role as tools for the understanding of model psychoses. The recently discovered cannabinoid receptor system with its endogenous ligand anandamide can be regarded as an extremely relevant regulator system, a dysfunctionality of which may explain at least one subtype of endogenous psychoses. Neuropsychological results (three-dimensional inversion illusion) in delta 9-tetrahydrocannabinol-intoxicated normal volunteers exhibit strong similarities with data acquired from patients suffering from productive schizophrenic psychoses, regarding disturbances in internal regulation of perceptual processes. The relevance of this finding to a general cognitive dysfunction concept of schizophrenic psychosis is discussed.

Different Effects of Nabilone and Cannabidiol on Binocular Depth Inversion in Man

The physiological and pathophysiological roles of the central nervous endogenous cannabinoid system are not completely understood, but still represent a challenge in basic neurobiological, cognitive, and psychiatric research. The system has been implicated in the pathogenesis of schizophrenia. Binocular depth inversion, an illusion of visual perception, provides a model of impaired perception during psychotic states. Using this model the effects of nabilone, a psychoactive synthetic 9-trans-ketocannabinoid, and of cannabidiol, the main natural component of herbal cannabis, and a combined application of both substances on binocular depth inversion and behavioural states were investigated in nine healthy male volunteers. The time course of the effects of both substances on binocular depth inversion was analysed after oral administration using three different groups of natural stimuli. A significant impairment of binocular depth perception was found when nabilone was administered, but combined application with cannabidiol revealed somewhat reduced effects on binocular depth inversion. The influence of psychoactive cannabinoids on this perceptual model and the role of the endogenous cannabinoid system in visual information processing are discussed.

Reduced binocular depth inversion in schizophrenic patients

Binocular depth inversion represents an illusion of visual perception, serving to invert the perception of implausible hollow objects, e.g. a hollow face into a normal face. Such inversion occurs frequently, especially when objects with a high degree of familiarity (e.g. photographs of faces) are displayed. Under normal conditions, cognitive factors apparently override the binocular disparity cues of stereopsis. This internal mechanism--a kind of censorship of perception balancing top-down and bottom-up processes of perception--appears to be disturbed in psychotic states. The clinical and neuropsychological performance of schizophrenic patients was assessed using the Brief Psychiatric Rating Scale (BPRS), the Positive And Negative Symptoms Scale (PANSS), the Clinical Global Impression Scale (CGI), the Mehrfach-Wahlwortschatz Intelligence Test (MWT-B) and the binocular depth inversion test (BDIT) using pictures with a high degree of familiarity. In schizophrenic patients, the performance in the BDIT differed significantly from healthy controls and from patients with major depression. The schizophrenic patients were more veridical in their judgements in the BDIT. During antipsychotic treatment, BPRS and PANSS scores improved and the inversed faces were seen as more illusionary, driven by an increase in top-down processing. At the end of treatment, there was no significant difference between the patient group and the healthy controls in the score of binocular depth inversion. These findings suggest that testing of binocular depth inversion can detect specific dysfunctions in visual perception and might be useful as a state-marker for psychotic states.

Effects of synthetic Δ9-tetrahydrocannabinol on binocular depth inversion of natural and artificial objects in man

Abstract Binocular depth inversion represents an illusion of visual perception that is sensitive to various behavioural and psychiatric conditions. It is affected by cannabinoids, reflecting associated changes in perception. The present study investigated the differences in binocular depth inversion of different classes of natural and artificial objects and the effect of synthetic Δ9-tetrahydrocannabinol (Dronabinol) on these illusionary perceptions. Using this model, the effects of orally administered Dronabinol on binocular depth inversion were investigated in 17 healthy male volunteers. Pictures from natural and artificial objects were presented stereoscopically and the depth perception of the volunteers was scored in an operationalized way. The time-course of the effects of Dronabinol on binocular depth inversion was analyzed with regard to the stimulus classes (natural and synthetic objects). Significant differences in binocular depth inversion of the different groups of stimuli were revealed. Objects with a higher degree of everyday familiarity were generally seen as more illusionary than those with a lower degree of everyday familiarity. A strong impairment of binocular depth inversion due to Dronabinol was found in most classes of objects. Analysis of different stimulus classes provides further information on the underlying perceptual processing of binocular depth inversion. An impairment of top-down processing of visual sensory data by Dronabinol is suggested. The anandamidergic system seems to be involved in areas of visual information processing.

Disturbances of visual information processing in early states of psychosis and experimental delta-9-tetrahydrocannabinol altered states of consciousness

Recent data on alterations of the endogenous cannabinoid system in schizophrenia have raised the question of its functional role in this disease. The psychoactive compound of Cannabis sativa, delta-9-tetrahydrocannabinol (Delta9-THC), has been shown to induce psychotic symptoms, but it is unknown to what extend prodromal states of psychoses are reflected by these experimental approaches. This study compares four groups of subjects: antipsychotic-naïve patients suffering from acute paranoid schizophrenic or schizophreniform psychosis (SZ), patients in the prodromal state (IPS), healthy controls without any pharmacological intervention (HC) and a second group of healthy volunteers who were orally administered synthetic Delta9-THC (Dronabinol) (HC-THC). Neither SZ and IPS nor HC received the experimental drug. All subjects were assessed using the Brief Psychiatric Rating Scale (BPRS) and the Binocular Depth Inversion Illusion Test (BDII). The latter represents a sensitive measure of impaired visual information processing that manifests in various experimental and naturally occurring psychotic states. BDII values were well comparable in SZ, IPS and HC-THC, and all groups differed significantly to HC. The BPRS revealed no significant difference between HC-THC and IPS while both were significantly different from SZ and HC, respectively. Our results suggest that Delta9-THC-induced altered states of consciousness may serve as a useful tool for modeling psychotic disorders, particularly their prodromal states. Furthermore, they provide insight into the perceptual and psychopathological alterations induced by Delta9-THC, which is essential for the understanding of the pro-psychotic effects of herbal cannabis preparations with highly enriched Delta9-THC content.

Propsychotische Veränderung der binokulären Tiefeninversion durch Schlafentzug

ZusammenfassungBei der Tiefeninversion handelt es sich um eine optische Illusion, die in Abhängigkeit vom präsentierten Objekt auftritt. Dabei wird die räumliche Tiefeninformation durch kognitive Faktoren in einem kritischen Interaktionsprozeß„überarbeitet”. In dieser Studie wird untersucht, ob durch Schlafentzug das ZNS dahingehend beeinfluß werden kann, implausible visuelle Information insuffizient zu korrigieren. In einem Tiefeninversionsparadigma wurde die Wahrnehmung von 3-D-Objekten bei nachtschichtig arbeitendem medizinischem Personal und gesunden Kontrollprobanden untersucht. Der Tiefeninversionsscore war bei den Schlafentzügigen im Vergleich zu den Kontrollprobanden deutlich erhöht. Die Daten verdeutlichen eine Beeinträchtigung der binokulären Tiefeninversion im Schlafentzug, möglicherweise hervorgerufen durch eine Störung der Interaktion zwischen visueller Perzeption (Bottom-up-Komponente) und der Generierung von Wirklichkeitshypothesen (Top-down-Komponente).SummaryBinocular depth inversion represents an illusion of visual perception. Such inversion does not occur in all cases, especially when objects with a higher degree of familiarity (e.g. photographs of faces) are displayed. Cognitive factors are assumed to override the binocular disparity cues of stereopsis. Wexa0tested the hypothesis that during sleep deprivation the human CNS is unable to correct the implausible perceptual information. Measurements of binocular depth inversion in perception of 3D objects were taken in sleep-deprived medical staff and healthy volunteers. The binocular depth inversion scores were highly elevated in the sleep-deprived group in comparison to the healthy volunteers. The data demonstrate a strong impairment of binocular depth inversion after sleep deprivation and support the view that sleep deprivation may be accompanied by a disorganisation of the interaction between sensory input and generation of perceptual hypotheses.

[Hawaiian baby woodrose: (Psycho-) Pharmacological effects of the seeds of Argyreia nervosa. A case-orientated demonstration].

ZusammenfassungDie Samen der Hawaiianischen Holzrose (Argyreia nervosa) werden von Jugendlichen immer häufiger als vermeintlich halluzinogene Droge verwendet. Die Samen sind frei verkäuflich und werden breit vertrieben. Die wirksamen Inhaltsstoffe sind als Alkaloide mit Indolstruktur dem LSD ähnlich. Nach Einnahme zeigen sich jedoch keine eigentlich halluzinogenen Wirkungen, sondern eine durch unangenehme vegetative Störungen gekennzeichnete, vorwiegend sedierende Intoxikation, die sich am ehesten mit der Wirkung von Scopolamin vergleichen lässt. Das (psycho)pharmakologische Profil wird anhand der wirksamen Bestandteile der Samen Lysergsäureamid und Lysergsäureäthylamid (und deren Stereoisomere) dargestellt. Dabei zeigt sich, dass die Einzelsubstanzen wie auch das Alkaloidgemisch keine für LSD typischen Wahrnehmungsveränderungen hervorrufen können. Das Gefahrenpotenzial wird anhand der potenziellen Uterotoxizität durch das enthaltene Ergometrin und der kasuistischen Beschreibung des Falles einer klinisch behandlungsbedürftigen Intoxikation geschildert.SummaryThe seeds of the Hawaiian baby woodrose (Argyreia nervosa) are used by adolescents as a supposed hallucinogenic drug. These seeds are legally available and broadly sold. The active components are alkaloids structurally related to lysergic acid diethylamide (LSD). However, the psychic effects are very different from those of LSD and are dominated by rather sedative, uncomfortable autonomic disturbances similar to the effects of scopolamine. The (psycho)pharmacological profile is described on the basis of the active substances lysergacidamide and lysergacidethylamide (and their isomers). It is shown that neither the substances themselves nor the mixture are able to evoke LSD-like perceptual variances. The exposure of Argyreia nervosa is described focusing on potential fetal distress by contained ergometrine and the case history of an intoxication.

Hawaiianische Holzrose: (Psycho-)Pharmakologische Wirkungen der Samen der Argyreia nervosa Eine fallbezogene Darstellung

ZusammenfassungDie Samen der Hawaiianischen Holzrose (Argyreia nervosa) werden von Jugendlichen immer häufiger als vermeintlich halluzinogene Droge verwendet. Die Samen sind frei verkäuflich und werden breit vertrieben. Die wirksamen Inhaltsstoffe sind als Alkaloide mit Indolstruktur dem LSD ähnlich. Nach Einnahme zeigen sich jedoch keine eigentlich halluzinogenen Wirkungen, sondern eine durch unangenehme vegetative Störungen gekennzeichnete, vorwiegend sedierende Intoxikation, die sich am ehesten mit der Wirkung von Scopolamin vergleichen lässt. Das (psycho)pharmakologische Profil wird anhand der wirksamen Bestandteile der Samen Lysergsäureamid und Lysergsäureäthylamid (und deren Stereoisomere) dargestellt. Dabei zeigt sich, dass die Einzelsubstanzen wie auch das Alkaloidgemisch keine für LSD typischen Wahrnehmungsveränderungen hervorrufen können. Das Gefahrenpotenzial wird anhand der potenziellen Uterotoxizität durch das enthaltene Ergometrin und der kasuistischen Beschreibung des Falles einer klinisch behandlungsbedürftigen Intoxikation geschildert.SummaryThe seeds of the Hawaiian baby woodrose (Argyreia nervosa) are used by adolescents as a supposed hallucinogenic drug. These seeds are legally available and broadly sold. The active components are alkaloids structurally related to lysergic acid diethylamide (LSD). However, the psychic effects are very different from those of LSD and are dominated by rather sedative, uncomfortable autonomic disturbances similar to the effects of scopolamine. The (psycho)pharmacological profile is described on the basis of the active substances lysergacidamide and lysergacidethylamide (and their isomers). It is shown that neither the substances themselves nor the mixture are able to evoke LSD-like perceptual variances. The exposure of Argyreia nervosa is described focusing on potential fetal distress by contained ergometrine and the case history of an intoxication.

Detoxifikation polytoxikomaner Patienten mit Buprenorphin Auswirkungen auf Affektivität, Angst und Entzugssymptomaik

ZusammenfassungDie vorliegende prospektive offene kontrollierte Studie vergleicht die Effizienz einer 10-tägigen Buprenorphin-/19-tägigen Carbamazepin-Entgiftungsmedikation (BPN/CBZ) in der Prüfgruppe versus einer 14-tägigen Oxazepam-/19-tägigen Carbamazepin-Entgiftungsmedikation (OXA/CBZ) in der Kontrollgruppe bei 27 opioidabhängig-polytoxikomanen Patienten hinsichtlich der Behandlung akuter Entzugssymptome. Prüfgrößen waren die somatischen und psychischen Entzugssymptome, die mit den Skalen ASI, HAMD, SCL-90-R und SOWS erfasst wurden, sowie die Abbruchquote.Von den 15 Patienten der BPN/CBZ-Gruppe und 12 Patienten der OXA/CBZ-Gruppe, schlossen 18 (67%) die Studie am 21. Tag ab. Von den 9 Studienabbrechern bekamen 4 (27%) Buprenorphin/Carbamazepin und 5 (42%) Oxazepam/Carbamazepin. Der SOWS-Gesamt-Score zeigte einen signifikanten Gruppenunterschied über den Testzeitraum zugunsten der BPN/CBZ-Gruppe. Der HAMD-Score unterschied sich am Aufnahmetag nicht (BPN/CBZ 11,6; OXA/CBZ 11,0), am 14. Tag jedoch hochsignifikant (BPN/CBZ 3,0; OXA/CBZ 6,1). Bei 3 von 9 Faktoren des SCL-90-R zeigte sich ein Trend zugunsten des BPN/CBZ. Die ASI-Testung ergab für BPN/CBZ am 7. und 14. Behandlungstag einen hochsignifikant bzw. signifikant geringeren Score im Vergleich zu OXA/CBZ. In beiden Gruppen traten keine ernsten Nebenwirkungen auf.Das Behandlungsschema mit BPN/CBZ zeigt gegenüber dem Behandlungsschema OXA/CBZ eine signifikant bessere Wirkung auf Angst, Depressivität und Entzugssymptome während der Opioidentgiftung sowie einen Trend zu einer geringeren Abbruchquote. Die Eignung von Buprenoprphin zur Detoxifikation wird anhand seiner pharmakologischen Eigenschaften (κ-Antagonismus, partieller μ-Agonismus) diskutiert.AbstractWe used an open-labeled, 21-day inpatient detoxification treatment to compare the short-term effects of a 10-day buprenorphine plus 19-day carbamazepine regimen (n=15) to a 14-day oxazepam plus 19-day carbamazepine regimen (n=12) during rapid detoxification from opioids and other abused drugs. Somatic and psychopathological changes were assessed using the following rating scales: ASI, HAMD, SCL-90-R, and SOWS. Eighteen of 27 patients (67%) completed the study. Four dropouts (27%) were treated with buprenorphine/carbamazepine (BPN/CBZ) and the other five dropouts (42%) were treated with oxazepam/carbamazepine (OXA/CBZ). Repeated measures analysis of variance showed that SOWS scores were significantly less pronounced with BPN-CBZ than with OXA/CBZ. On the first day of admission, no significant difference in HAMD scores was detected (BPN/CBZ 11.6, BPN/CBZ 1.0). On day 14, HAMD was significantly less pronounced in BPN/CBZ (3.0) than in OXA/CBZ (6.1). BPN/CBZ showed a significant improvement in the ASI score on days 7 and 14 compared with OXA/CBZ. Three of nine items of the SCL-90-R showed a trend toward less pronounced outcome in BPN-CBZ. No severe side effects occurred during treatment in either group. The buprenorphine/carbamazepine regimen provided significantly more effective relief from affect disturbances and withdrawal syndromes than the oxazepam/carbamazepine regimen. The pharmacological basis of these effects of buprenorphine (κ-antagonism activity, μ-agonism activity) are discussed.

Das endogene Cannabinoidsystem

ZusammenfassungSeit ca. 5000 Jahren werden Medikamente auf Cannabisbasis genutzt. In den vergangenen Jahren ist ein starkes Interesse an der medizinischen Nutzung von Cannabinoiden entstanden. Grundlage dafür sind die Erkenntnisse, dass Cannabinoide über spezifische Rezeptoren (CB1 und CB2) wirken. Die CB1-Rezeptoren werden in spezifischen Hirnarealen (u. a. Zerebellum, Basalganglien und Hippokampus) und die CB2-Rezeptoren auf immunkompetenten Zellen exprimiert. Außerdem wurden körpereigene Liganden der Cannabinoidrezeptoren entdeckt (z.xa0B. Anandamid). Eine Vielzahl physiologischer Prozesse wird u. a. über die Cannabinoidrezeptoren moduliert (Steuerung der Motorik, Gedächtnisfunktionen, Appetit, Schmerzen etc.). Aufgrund dieser neurobiologischen/pharmakologischen Erkenntnisse ergeben sich eine Reihe von möglichen Bereichen für die Anwendung von natürlichen und synthetischen Cannabinoiden. Bereits heutzutage werden Cannabinoide bei verschiedenen Erkrankungen eingesetzt, wobei die Datenlage unterschiedlich ist. Gesicherte Erkenntnisse liegen für die Behandlung von therapierefraktärer Übelkeit und Erbrechen bei Chemotherapie sowie beim HIV-wasting-Syndrom vor. Für die Wirksamkeit bei anderen Störungen wie Multiple Sklerose, bestimmten Formen der Bewegungsstörungen (Gilles-de-la-Tourette-Syndrom), Schmerzen etc. gibt es Hinweise. Die neuen Erkenntnisse über das Cannabinoidsystem und seine endogenen Liganden erklären auch die möglichen unerwünschten Wirkungen von Cannabinoiden.SummaryFor about 5,000 years, cannabis has been used as a therapeutic agent. There has been growing interest in the medical use of cannabinoids. This is based on the discovery that cannabinoids act with specific receptors (CB1 and CB2). CB1 receptors are located in specific brain areas (e.g. cerebellum, basal ganglia, and hippocampus) and CB2 receptors on cells of the immune system. Endogenous ligands of the cannabinoid receptors were also discovered (e.g. anandamids). Many physiologic processes are modulated by the two subtypes of cannabinoid receptor: motor functions, memory, appetite, and pain. These innovative neurobiologic/pharmacologic findings could possibly lead to the use of synthetic and natural cannabinoids as therapeutic agents in various areas. Until now, cannabinoids were used as antiemetic agents in chemotherapy-induced emesis and in patients with HIV-wasting syndrome. Evidence suggests that cannabinoids may prove useful in some other diseases, e.g. movement disorders such as Gilles de la Tourette’s syndrome, multiple sclerosis, and pain. These new findings also explain the acute adverse effects following cannabis use.