Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis

This early (1997) study looked at the effects of psylocybin/psilocin in the brain through a PET scan and found increases in metabolis (CMRglu) that correlated with the experienced ‘psychotic’ (psychedelic) effects.

Abstract

“The effects of the indolehallucinogen psilocybin, a mixed 5-HT₂ and 5-HT₁ agonist, on regional cerebral glucose metabolism were investigated in 10 healthy volunteers with PET and [F-18]-fluorodeoxyglucose (FDG) prior to and following a 15-or 20-mg dose of psilocybin. Psychotomimetic doses of psilocybin were found to produce a global increase in cerebral metabolic rate of glucose (CMRglu) with significant and most marked increases in the frontomedial and frontolateral cortex (24.3%), anterior ungulate (24.9%), and temporomedial cortex (25.3%). Somewhat smaller increases of CMRglu were found in the basal ganglia (18.5%), and the smallest increases were found in the sensorimotor (14.7%) and occipital cortex (14.4%). The increases of CMRglu in the prefrontal cortex anterior cingulate, temporomedial cortex, and putamen correlated positively with psychotic symptom formation, in particular with hallucinatory ego disintegration. The present data suggest that excessive 5-HT₂ receptor activation results in a hyperfrontal metabolic pattern that parallels comparable metabolic findings associated with acute psychotic episodes in schizophrenics and contrasts with the hypofrontality in chronic schizophrenic patients.”

Authors: Franz X. Vollenweider, Klaus L. Leenders, Christian Scharfetter, Philip Maguire, Otto Stadelmann, Jules Angst

Summary

Psilocybin, a mixed S-HT, and 5-HT, agonist, increased cerebral metabolic rate of glucose in 10 healthy volunteers, with the greatest increases found in the prefrontal cortex, anterior cingulate, temporomedial cortex, and putamen. This increase correlated positively with psychotic symptom formation.

Psilocybin and LSD are potent indolehallucinogens that can induce a psychosis-like syndrome in humans that resembles in various aspects the first manifestation of schizophrenia. The serotonergic system may play a critical role in the pathophysiology of schizophrenia.

In the present PET and FDG study, we take advantage of the psilocybin model of psychosis to examine the associations between serotonin receptor activation, acute psychotic symptom formation, and metabolic alterations in the living human brain. Several PET studies have found metabolic hypofrontality in chronic schizophrenic patients, but some studies could not confirm this finding. These studies investigated mainly subacute schizophrenics, and some studies demonstrated hypertemporality, a left-right asymmetry of metabolism, and increased or reduced metabolism in the basal ganglia.

In acute episodes, phrenic patients have a hyperfrontal metabolic pattern, and a frontostriatal dysfunction of sensory and cognitive information processing involving the thalamic filter theory has been advanced in schizophrenia. This model is consistent with the sensory flooding and cognitive fragmentation seen in naturally occurring psychosis.

The study was approved by the Ethics Committee of the Psychiatric University Hospital of Zurich and the Swiss Federal Health Office.

Fifteen healthy volunteers, aged 26 to 43 years, were recruited from university and hospital staff. They were screened for psychiatric disorders and had normal MRI scans.

In an open study, 15 subjects were tested in two phases: a preliminary drug tolerance test phase (I) followed by a PET phase (II). The subjects received a baseline PET scan and a second and third PET scan in combination with a stimulant or a hallucinogenic drug.

This report focuses on the relation between psilocybin-induced cerebral metabolic alterations and psychotomimetic reactions such as hallucinations and ego disorders. Psilocybin was given to healthy volunteers at doses of 15 mg PO for subjects weighing 50 kg and 20 mg PO for subjects weighing 51 kg.

An experienced psychiatrist assessed the scores in baseline and drug conditions using the Ego Pathology Inventory (EPI) and the Inventory of the Association for Methodology and Documentation in Psychiatry (AMDP). The EPI yields a global score and five subscale scores that measure ego pathology and related behavior. The Ego activity subscale and the Ego vitality subscale have been validated in schizophrenics and comparison patients by an extensive empirical study using confirmatory factor analysis.

A self-assessment inventory was applied to evaluate drug effects. The Altered States of Consciousness Questionnaire (APZ) consists of 72 items that yield a global score (APZglo) and three subscale scores (factors) measuring shifts in mood and changes in the experience of the self, ego, and environment in altered states of consciousness.

Subjects received a preliminary drug exposure in a recreational environment at the PUK, and were examined by an experienced psychiatrist before and at regular intervals after substance administration to evaluate the psychological peak effects.

Phase II: PET Studies Each subject underwent a baseline, two drug FDG-PET scans, and was examined using the AMDP and EPI rating scales. Psilocybin was administered 90 minutes before FDG injection.

Psilocybin FDG-PET scans were performed in 10 volunteers using a CT1 (Siemens 933/04-16) tomograph. The scans were performed in two positions, with increasing time durations, and with a mean administered FDG dose of 177.6 MBq (107.3-244.2).

Using planes from the last time point of the dynamic measurement and the static measurement, a volume of rCMRglu was analyzed. The volume was transformed into a stereotaxic space using a combination of linear and non-linear transformations.

After spatial standardization, regions of interest were placed symmetrically in cortical and subcortical regions in both hemispheres using the Talairach coordinate system. These regions included the frontomedial and frontolateral cortex, insula, anterior and posterior cingulate, parietal cortex, somatosensory cortex, motor cortex, and white matter.

The number of ROIs in the left and right hemispheres varied from 88 to 94, but the number of ROIs in the frontal, temporal, and occipital cortex was always equal in a series of PET scans.

Regional glucose utilization was expressed as glucose metabolic rate and as relative glucose metabolic rate. Changes in metabolic rate and metabolic ratios from baseline to psilocybin scan were assessed as percent difference from baseline.

Plasma psilocybin levels were measured using a high-performance liquid chromatography method. The samples were stored at -20°C until analysis.

Statistical analyses were performed on computer using SAS and STATISTICA/wTM, version 4.5 (StatSoftTM, 1993). The Wilcoxon matched pairs test and Spearman correlation coefficient were used to evaluate differences in metabolic rates and psychopathology scores.

Psilocybin administration resulted in a psychotoxic syndrome, including disturbances of emotion, sensory perception, thought processes, reality appraisal, and ego functioning. The syndrome evolved in three phases, with the peak period characterized by derealization and depersonalization phenomena.

During the peak period of PET scanning, subjects experienced visual disturbances, synesthesias, auditory distortions, and derealization phenomena. Some subjects reported recalling experiences of the recent and remote past associated with emotional disturbances and vivid scenery hallucinations.

Psilocybin subjects reported a feeling of unreality and emotional alterations, ranging from euphoria to grandiosity or exaltation. Some subjects reported heightened anxiety, suspiciousness, or paranoid ideation, while others reported mild dysphoria and anxiety.

Psilocybin increased whole-brain glucose metabolism in all subjects, but the highest increases were found bilaterally in the frontomedial, frontolateral, anterior cingulate, temporomedial cortex, and thalamus. These increases were significantly correlated with the amount of psilocybin administered per kilogram of body weight.

The frontomedial-occipitomedial ratio was increased significantly in both hemispheres, and the frontolatera1 and temporolateral cortex ratio was changed slightly, but significantly in both hemispheres. The cortico-subcortical metabolic ratios were increased significantly only in the right hemisphere.

Psilocybin-induced reactions were correlated with changes in absolute metabolic rates of glucose or metabolic ratios in the left temporolateral cortex, putamen, and hallucinatory-disintegration (Hall, VUS, and OSE) subscales.

The APZ scores for anxious ego dissolution correlated positively with increased absolute CMRglu in the anterior cingulate cortex in both hemispheres, and the EPIglobal scores for ego identity impairment correlated positively with increased absolute CMRglu in the right frontomedial cortex.

Psilocybin administration to healthy volunteers resulted in a psychosis-like syndrome that resembled acute schizophrenic experiences in many respects, but was different in other respects. This syndrome was characterized by changes in affect, altered sense of time and space, illusions and hallucinations, and impaired ego functioning.

Psilocybin subjects experienced derealization and depersonalization phenomena, but were able to recognize them as abnormal experiences and attribute them to the drug. They also showed less impairment of the dimensions of ego-consistency, ego-identity, and ego-activity than schizophrenic patients.

PET data show that psilocybin, a mixed serotonin 5-HT, and 5-HT1 receptor agonist, leads to a hyperfrontal metabolic pattern associated with acute psychotic symptom formation. This finding is in line with the observation that administration of mescaline, which more specifically acts on 5-HT, receptors, results in a predominant activation of the frontal cortex.

Psilocybin activates 5-HT, receptors in the brain, but other neurotransmitter systems also are involved in the metabolic changes.

The hyperfrontality finding can be explained by the thalamic filter theory of schizophrenia, which suggests that disruption of cortico-striato-thalamic feedback loops controls a thalamic filter function and leads to sensory overload of the frontal cortex and its limbic relay stations.

Ketamine is thought to block primarily N-methyl-D-aspartate (NMDA) receptors, which may be a major cause responsible for the global increase of cortical metabolism under ketamine, whereas inhibition of NMDA receptor mediated cortico-striatal neurotransmission may add to the marked frontocortical activation seen in the ketamine model of psychosis.

The global ego pathology score (EPIglo) and the anxious ego dissolution scale (APZ AIA) correlated positively with the increase of absolute CMRglu in the right frontomedial cortex. Moreover, the Ego-identity impairment and Ego-demarcation scores correlated strongly with the frontomedial-anterior cingulate ratio in the left hemisphere.

Recent findings indicate that hyperfrontality, rather than hypofrontality, is associated with acute psychotic symptom formation, particularly in acutely psychotic schizophrenics. This finding corroborates similar findings with ketamine and mescaline, and contrasts with the hypofrontality seen in chronic schizophrenic patients.

The frontal and anterior cingulate cortex are involved in several functional networks implicated in attention, motivation, memory, emotion, and movement. This suggests that the functional integrity of the frontal and anterior cingulate cortex might be a critical component in the pathophysiology of psychotic symptom formation.

The anterior cingulate cortex may be a primary site for directing attention, and direct electrical stimulation of the anterior cingulate cortex can lead to a spectrum of psychosensory and behavioral phenomena, including affective changes, fear, euphoria, confusion and hallucinations, involuntary vocalization, and changes in speech. In patients with affective and anxiety disorders, cingulotomy has been reported to have the best uniform outcome, and second best in obsessive-compulsive disorders and schizophrenia patients.

Fronto-temporal ratios are increased in the left hemisphere in patients with schizophrenia, suggesting that neuronal dysfunctions in remote areas of the frontal cortex are critically involved in the pathophysiology of ego disorders and hallucinations.

The Schizophrenic syndrome and the global El’1 score correlated also bilaterally with increased CMRglu in the putamen and in the left caudate nucleus in unmedicated chronic schizophrenic patients, and with increased CBF in the left globus pallidus and the right putamen in drug-free schizophrenic patients.

Psilocybin induces hyperfrontality, ego disintegration, and hallucinations. This hyperfrontality finding is consistent with the recent hyperfrontality finding in acutely ill schizophrenic patients, and contrasts with the hypofrontality finding in chronic schizophrenics.