Neurometabolic Effects of Psilocybin, 3,4-Methylenedioxyethylamphetamine (MDE) and d-Meth-amphetamine in Healthy Volunteers. A Double-Blind, Placebo-Controlled PET Study with [18 F] FDG
Euphrosyne Gouzoulis-Mayfrank, Mathias Schreckenberger, Osama Sabri, Christoph Arning, Bernhard Thelen, Manfred Spitzer, Ph.D., Karl-Artur Kovar, Leopold Hermle, Udalrich Büll, and Henning Sass.
NEUROPSYCHOPHARMACOLOGY, 1999–VOL 20, NO 6, 565-581.
The neurometabolic effects of the hallucinogen psilocybin (PSI; 0.2 mg/kg), the entactogen 3,4- methylenedioxyethylamphetamine (MDE; 2 mg/kg) and the stimulant d-methamphetamine (METH; 0.2–0.4 mg/kg) and the drugs’ interactions with a prefrontal activation task were investigated in a double-blind, placebo-controlled human [F-18]fluorodeoxyglucoseFDG-positron emission tomographicPET study (each group: n 5 8). Subjects underwent two scans (control: word repetition; activation: word association) within 2–4 weeks. Psilocybin increased rMRGlu in distinct right hemispheric frontotemporal cortical regions, particularly in the anterior cingulate and decreased rMRGlu in the thalamus. Both MDE and METH induced cortical hypometabolism and cerebellar hypermetabolism. In the MDE group, cortical hypometabolism was more pronounced in frontal regions, with the exception of the right anterior cingulate, which tended to be hyperactive. Cognitive activation-related increases in left frontocortical regions were attenuated under all three psychoactive substances, but less so under MDE. Taking into account performance data and subjective reports on task difficulty, these effects may result from different mechanisms across the three groups. Our PSI data are in line with studies on acute schizophrenic patients suggesting frontal overactivity at rest, but diminished capacity to activate prefrontal regions upon cognitive demand. The MDE data support the hypothesis that entactogens constitute a distinct psychoactive substance class, which takes an intermediate position between stimulants and hallucinogens.
KEY WORDS : Psilocybin; MDE; Ecstasy; Methamphetamine; Model psychosis; FDG-PET; Activation study
Experimental studies of cerebral blood flow and metabolism with psychoactive drugs in humans aim to explore the interaction of these drugs with human brain function. Recent studies with hallucinogenic, “mind-expanding” drugs in healthy subjects provided evidence in favor of an altered functional interhemispheric balance with right hemispheric dominance and an increased activity in frontocortical regions after acute administration of mescaline, psilocybin, or ketamine (Hermle et al. 1992; Vollenweider et al. 1997a, b). The most profound increase in metabolism was found in the anterior cingulate (Vollenweider et al. 1997a, 1997b), which is linked to both emotional and attentional functions (Vogt et al. 1992; Devinsky et al. 1995; Murtha et al. 1996). These functions are, in turn, tightly connected to both the effects of hallucinogens and the symptoms of schizophrenic and schizophrenia-spectrum psychoses.
Hallucinogenic drug-induced states can be used as models for acute endogenous psychotic states in psychiatric research (Hermle et al. 1992; Vollenweider et al. 1997a, b; Gouzoulis-Mayfrank et al. 1998). Within the framework of this model psychosis paradigm neurometabolic data from the above-mentioned studies can be interpreted in the sense that acute psychotic states with prominent positive symptoms are linked to increased activity in frontal neocortical, and limbic areas. This is in contrast to the majority of functional neuroimaging studies with schizophrenic patients, which demostrate hypofrontality both in resting states (Buchsbaum et al. 1982; Farkas et al. 1984; Wolkin et al. 1988; Siegel et al. 1993) and under cognitive tasks believed to employ frontal brain areas (Cohen et al. 1987; Weinberger et al. 1988; Buchsbaum et al. 1990; Andreasen et al. 1992). However, most of these studies were performed with chronically ill patients on various neuroleptic medications, and evidence has accumulated in favor of an association between hypofrontality and negative symptoms (Volkow et al. 1987; Wolkin et al. 1992). Some few studies with acutely ill patients presenting with positive symptoms failed to demonstrate hypofrontality and did, in part, demonstrate hyperfrontal metabolic patterns (Sheppard et al. 1983; Wiesel et al. 1987; Cleghorn et al. 1989; Ebmeier et al. 1993; Parellada et al. 1994). Thus, a general link between acute, pharmacologically induced or naturally occurring psychotic states and hyperfrontal metabolic patterns may be hypothesized.
An important question is, whether the changes in cerebral activity demonstrated under hallucinogens are restricted to these substances. Several studies with other psychotropic substances with both stimulant and sedative properties (cocaine, morphine, benzodiazepines, barbiturates) reported decreased cortical activity (London et al. 1990a,b; Mathew and Wilson 1991). Studies on the effects of stimulant amphetamines are inconsistent with reports of decreases, no effects, or increases of glucose metabolism or cerebral blood flow (Wolkin et al. 1987; Kahn et al. 1989; Metz et al. 1991; Devous et al. 1995; Ernst et al. 1997). A recent study with intravenous d-amphetamine administration reported no global change, but frontal, limbic, subcortical, and cerebellar increases of regional glucose metabolic rates (Ernst et al. 1997). The discrepancies in functional neuroimaging studies with amphetamines may reflect the well-recognized variability of clinical amphetamine effects (Gunne 1977; Angrist 1994) and/or methodological differences among studies including samples (psychiatric patients, healthy controls), cognitive states (resting state, different cognitive tasks), imaging methods and indices of brain activity, as well as drugs, doses, and routes of administration. At present, no clear picture of stimulant amphetamine effects on cerebral activity can be drawn. Preliminary data from an ongoing study with an entactogenic amphetamine derivative (methylenedioxymethylamphetamine = MDMA) indicate that MDMA increases regional cerebral blood flow in prefrontal neocortical regions of the left hemisphere, while reducing it in the posterior cingulate, the right anterior cingulate, and the left caudate nucleus (Gamma et al. 1997). To our knowledge, this is the only experimental neuroimaging study on the acute effects of ecstasy in healthy nonuser subjects.
Recent studies with hallucinogens, entactogens, and stimulants were either open pilot studies or used placebo controls (Hermle et al. 1992; Lahti et al. 1995; Vollenweider et al. 1997a,b; Gamma et al. 1997). However, hallucinogens and entactogens exert very powerful effects in humans; thus, the nature of the administered agent mostly becomes apparent both for the subject and the researcher in the course of placebo-controlled experiments. Furthermore, hallucinogens exert very complex effects in humans, including alterations of perception, cognition, mood, and drive. Therefore, it is difficult to link distinct biological with psychological effects in subjects of placebo-controlled studies. To meet these methodological problems, designs with different psychoactive substances may be helpful.
The design of the present double-blind experimental study includes placebo and three psychoactive substances: the hallucinogen psilocybin, the stimulant d-methamphetamine, and the entactogen MDE (3,4-methylenedioxyethylamphetamine). Effects of entactogens (methylenedioxy- amphetamines = ecstasy group; e.g., MDMA, MDE, MBDB) are mainly emotional in nature, but they have additional significant perceptional and stimulant properties (Gouzoulis-Mayfrank et al. 1996; Pechnick and Ungerleider 1997). Several lines of evidence support the view of a distinct psychoactive substance class, which takes an intermediate position between stimulants and hallucinogens (Nichols 1986; Solowji et al. 1992; Hermle et al. 1993a, 1993b; Gouzoulis-Mayfrank et al. 1996). From a methodological point of view, the overlapping psychological effects of the three drug groups can help to realize a true double-blind design and may help to distinguish between mechanisms specifically related to hallucinogenic effects and mechanisms that pertain to other factors such as increased drive and energy (stimulant effects) and enhanced emotional responses (entactogenic effects).
The objectives of the study were the following :
1. to assess the effects of common recreational doses of psilocybin, MDE, and d-methamphetamine on regional cerebral glucose metabolism and to examine whether there are overlapping neurometabolic effects that correspond to the overlapping psychopathological effects of the drugs;
2. to detect correlations between neurometabolic and psychopathological effects of the drugs; and
3. to study the influence of the drugs on a cognitive activation.
The cognitive challenge was a word association task, compared to a word repetition task. We chose the word association task, because of the following considerations.
1. It is known from functional imaging studies that lateral prefrontal and frontal limbic cortical regions are employed in this task (Petersen et al. 1988). These regions have been shown to be involved in and to display metabolic alterations in both hallucinogenic states and endogenous psychoses (Benes and Bird 1987; Benes et al. 1987; Cleghorn et al. 1992; Liddle et al. 1992; Tamminga et al. 1992; Catafau et al. 1994; Lahti et al. 1995; Vollenweider et al. 1997a,b).
2. Hallucinogens induce formal thought disturbances with loosening of associations. Indirect semantic priming, an index of spreading activation in semantic networks, was reported to be increased in healthy volunteers after ingestion of psilocybin (Spitzer et al. 1996).
3. Disturbances of associations are considered a primary symptom of schizophrenia in the classical psychopathological literature (Bleuler 1911). Direct and indirect semantic priming were reported to be increased in thought-disordered schizophrenic patients (Manschreck et al. 1988; Kwapil et al. 1990; Spitzer et al. 1993).
For these reasons, the study of associative performance under hallucinogenic drugs is highly relevant within the frame of the model psychosis paradigm.