Recent Advances and Concepts in the Search for Biological Correlates of Hallucinogen-Induced Altered States of Consciousness Franz X

The Heffter Review of Psychedelic Research, Volume 1, 1998 3. Recent Advances and Concepts in the Search for Biological Correlates of hallucinogen-induced Altered States of Consciousness Franz X. Vollenweider, M.D. Introduction intrusive mental activity. Specifically, the CSTC loop model suggests that a deficient thalamic “filter” Hallucinogens and related substances constitute function leads to sensory overload of the cortex a powerful experimental basis to investigate which in turn results in cognitive fragmentation and biological correlates of altered states of sensory flooding as seen in hallucinogen-induced consciousness (ASC) (Hermle et al. 1988; Javitt and states and naturally occurring psychoses Zukin 1991; Vollenweider, 1994). In combination (Vollenweider, 1994). with functional brain imaging techniques and The theoretical conception of the “thalamic pharmacological methodologies, they are remarkable filter” theory is comparable to animal models of molecular probes to study the functional sensory gating deficits such as the prepulse organization of the brain and to generate chemical inhibition paradigm (PPI), although the PPI hypotheses of ASC. The study of hallucinogens in paradigm does not explicitly refer to the thalamus as humans is important because these substances affect an anatomical structure responsible for filtering a number of brain functions that typically deficits. However, both the CSTC model and the characterize the human mind, including cognition, PPI paradigm suggest that perturbations in cortico- volition, ego, and self-consciousness. They can elicit striato-thalamic pathways are critical for the loss of a clinical syndrome that resembles in various aspects inhibition processes and the pathogenesis of the first manifestation of schizophrenic disorders, psychotic symptoms. This assumption is supported but is different in other respects (Fischman, 1983; by increasing preclinical evidence demonstrating Gouzoulis et al. 1994; Vollenweider et al. 1997d). that hallucinogens specifically interfere with The various forms of ego-disorders are especially neurotransmitter systems within the limbic cortico- prominent features of psychedelic and naturally striatal-thalamic circuitry and produce PPI-deficits occurring psychoses. For example, they can produce comparable to those seen in several neuropsychiatric a form of ego-dissolution that is experienced with disorders characterized by failure to inhibit heightened awareness, en-hanced introspection, irrelevant cognitive, motor or sensory information. sublime happiness, as well as a form that is Positron emission tomography (PET) was used experienced with anxiety and fragmentation. Hence, to test the hypothesis that hallucinogens may lead to studies of the neuronal mechanisms of action of a disruption of “filter” functions and produce a hallucinogens should provide not only novel insights sensory overload of the frontal cortex. Moreover, a into the pathophysiology of psychiatric disorders and correlational analysis between hallucinogen-induced their treatments, but in a more wider sense into the changes in neuronal activity and specific dimensions biology of consciousness as a whole, e.g. into the of ASC was carried out to elucidate the neuronal biology of ego structuring processes. substrates of psychedelic states. Psychometric In the present discussion, I wish to summarize measures and PET investigations with specific some of the recent advances in hallucinogen research receptor ligands were and are performed to that have resulted from human studies conducted in investigate the effects of hallucinogens on brain our group. In the first part, a human model of functions before and after pretreatment with specific sensory gating deficits, the cortico-striato-thalamo- neuroreceptor antagonists. These studies provide a cortical (CSTC) loop model of psychosensory paradigm shift where interactions of different processing, is introduced to provide a perspective on neurotransmitter systems are seen as the basis for the how current scientific knowledge about hallucinogen psychological effects of hallucinogens. The PPI drug action could be visualized within a synthetic paradigm is used as a second measure to characterize framework to explain their subjective effects in the putative effects of hallucinogens on inhibition humans. The CSTC model is based on the processes in humans and functional interactions of assumption that psychedelic and psychotic symptoms neurotransmitter systems in ASC. Clearly, among can be conceptualized by failure to inhibit or “gate” the many topics that could be considered in this 21 Vollenweider, Hallucinogen-induced altered states context, I have to make some selection, and some of the subjects unavoidably will remain sketchy. 1400 1200 OSE 1000 VUS 800 AIA 600 400 APZ scores (mean) 200 0 psilocybin ketamine amphetamine MDMA placebo Figure 1. APZ Profiles in healthy volunteers (n = 20). Measurement of psychological dimensions of ASC second dimension “dread of ego-dissolution”(AIA) In the context of the present theme -relating measures thought disorder, ego-disintegration, loss psychological and biological effects of of autonomy and self-control variously associated hallucinogens- the assessment and characterization with arousal, anxiety, and paranoid feelings of being of altered states of consciousness (ASC) is of endangered. The third subscale “visionary restructur- fundamental importance. Among several rating alization”(VUS), refers to auditory and visual scales, the APZ questionnaire, which has become illusions, hallucinations, synaesthetic phenomena, as the standard in Europe for measuring specific states well as to changes in the meaning of various of consciousness and which has been used on a precepts. routine basis by our group, is to be described. In The intercultural consistency of the APZ short, the APZ questionnaire was developed based on dimensions OSE, AIA and VUS has been rigorously a large prospective study done with 393 subjects tested in a subsequent study, the International Study tested with cannabinoids, dimethyltryptamine, on Altered States of Consciousness (ISASC), and the psilocybin, mescaline, harmaline, nitrosoxide, dimensions have been shown to be altered con- hypnosis, autogenic training, and meditation sistently in a manner that is independent of the techniques (Dittrich, 1994). It measures three particular treatment, disorder, or condition that led primary and one secondary etiology-independent to the ASC (Dittrich et al. 1985; Dittrich, 1994). The dimensions of ASC. The first dimension, designated APZ rating scale is now available in an English as “oceanic boundlessness” (OSE), measures version and it is important to emphasize the need for derealization phenomena and ego-dissolution which a quantitative instrument such as the APZ to are associated with enhanced sensory awareness and exchange and integrate further research into the a positive basic mood ranging from heightened effects of hallucinogens on an international level. feelings to sublime happiness and exaltation. Ego- So far, the APZ questionnaire has been used to dissolution can include or start with a mere characterize the psychological effects of hallucino- loosening of ego-boundaries, but may end up in a gens, dissociative anesthetics, stimulants, and feeling of merging with the cosmos, where the entactogens. For example, using the APZ experience of the sense of time is changed or questionnaire, we recently demonstrated in a double- completely vanished. This state might be comparable blind placebo-controlled study that the psychological to a mystical experience, if fully developed. The effects of MDMA in normals can be clearly differ- 22 The Heffter Review of Psychedelic Research, Volume 1, 1998 entiated from those seen in comparable studies with Cortico-striato-thalamo-cortical feedback loops (CSTC) sensory assoc. cortex 1st proj. area frontal temporal Cx GABA cortex hippocampus Glu sensory Ach input Glu Glu ventr.pall. GABA ventr.str. DA VTA thalamus SNc 5-HT DR ketamine blocks NMDA receptors psilocybin activates 5-HT2 receptors Figure 2. Cortico-striato-thalamo-cortical feedback loops. ketamine, psilocybin, and amphetamine what was typically described was an intensification (Vollenweider et al. 1997e) (Figure 1). of sensory perception (“colors were more intense,” As seen in figure 1, MDMA (1.7 mg/kg p.o.) “objects appeared more detailed,” sound was more produced a unique pattern of APZ scores. Although clear, etc.), and visual illusions (“3D-vision of flat the OSE scores in MDMA subjects were approx- objects,” micropsia and macropsia, etc.). Finally, imately similar (80%) to those seen after psilocybin with regard to psychostimulants, euphorigenic doses and ketamine, the VUS and AIA scores were only of d-amphetamine produced similar AIA scores, but about 30-50% of the values seen in psilocybin and lower OSE and VUS scores than those seen in the ketamine subjects (Vollenweider et al. 1997b; study with MDMA (Vollenweider et al. 1997a). Vollenweider et al. 1997b). In contrast to psilocybin Although additional studies using multiple doses are and ketamine subjects, loosening of ego-boundaries needed to confirm these conclusions, the present and perceptual changes produced by MDMA were findings are suggestive of appreciable differences in generally not experienced as problematic or the psychological profiles produced by MDMA psychotic fusion, but instead as a positive or relative to psilocybin, ketamine, or d-amphetamine. pleasurable state in which

Load more