OPEN Foundation

Psychosis

On the transmethylation hypothesis: stress, N,N-dimethyltryptamine, and positive symptoms of psychosis

November 2, 2014 / DMT, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / ,

Abstract

Past research suggests a relationship between stress and positive symptoms of psychosis. However, the biological substrate of this relationship remains unknown. According to the transmethylation hypothesis, schizophrenia could result from a biochemical disruption in the stress mechanism. This biochemical disruption would lead to the production of a substance that would account for the symptoms of psychosis. Moreover, some studies have tested endogenous N,N-dimethyltryptamine (DMT) in the context of the transmethylation hypothesis. Stress has been found to elevate DMT levels in rodents. Also, elevated DMT levels have been associated with positive features of psychosis in psychiatric patients. Additionally, healthy participants treated with exogenous DMT experience predominantly positive symptoms of psychosis. The present paper examines endogenous DMT as a possible biological mediator of the relationship between stress and positive symptoms of psychosis.

Grammenos, D., & Barker, S. A. (2014). On the transmethylation hypothesis: stress, N, N-dimethyltryptamine, and positive symptoms of psychosis. Journal of Neural Transmission, 1-7. https://dx.doi.org/10.1007/s00702-014-1329-5
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Pharmacology of Hallucinations: Several Mechanisms for One Single Symptom?

June 4, 2014 / LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , , ,

Abstract

Hallucinations are complex misperceptions, that principally occur in schizophrenia or after intoxication induced by three main classes of drugs: psychostimulants, psychedelics, and dissociative anesthetics. There are at least three different pharmacological ways to induce hallucinations: (1) activation of dopamine D2 receptors (D2Rs) with psychostimulants, (2) activation of serotonin 5HT2A receptors (HT2ARs) with psychedelics, and (3) blockage of glutamate NMDA receptors (NMDARs) with dissociative anesthetics. In schizophrenia, the relative importance of NMDAR and D2R in the occurrence of hallucinations is still debated. Slight clinical differences are observed for each etiology. Thus, we investigated whether the concept of hallucination is homogenous, both clinically and neurobiologically. A narrative review of the literature is proposed to synthesize how the main contributors in the field have approached and tried to solve these outstanding questions. While some authors prefer one explanatory mechanism, others have proposed more integrated theories based on the different pharmacological psychosis models. In this review, such theories are discussed and faced with the clinical data. In addition, the nosological aspects of hallucinations and psychosis are addressed. We suggest that if there may be common neurobiological pathways between the different pharmacological systems that are responsible for the hallucinations, there may also be unique properties of each system, which explains the clinical differences observed.

Rolland, B., Jardri, R., Amad, A., Thomas, P., Cottencin, O., & Bordet, R. (2014). Pharmacology of Hallucinations: Several Mechanisms for One Single Symptom? Biomed Research International. http://dx.doi.org/10.1155/2014/307106
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Psilocybin – Summary of knowledge and new perspectives

December 17, 2013 / Addiction, Anxiety disorders / PTSD, Chemistry, Cluster headache, Depression, HPPD, Mushrooms / Psilocybin, Mystical experiences, Neuroscience, Papers, Personality, Phenomenology, Psychiatry, Psychology, Psychopharmacology, Psychosis, Psychotherapy, Publications, Safety, Spirituality, Toxicology / By / , ,

Abstract

Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its action using modern imaging and psychometric methods. Finally, it describes its therapeutic and abuse potential.

Tylš, F., Páleníček, T., & Horáček, J. (2014). Psilocybin – Summary of knowledge and new perspectives. European Neuropsychopharmacology, 24, 342-365. http://dx.doi.org/10.1016/j.euroneuro.2013.12.006

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Reviewing the ketamine model for schizophrenia

November 20, 2013 / Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / ,

Abstract

The observation that antagonists of the N-methyl-D-aspartate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory γ-aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal NMDAR aberrations might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity,and abnormal cortical oscillations observed in acute schizophrenia.

Frohlich, J., & van Horn, J. D. (2014). Reviewing the ketamine model for schizophrenia. Journal of Psychopharmacology, 28(4), 287-302. http://dx.doi.org/10.1177/0269881113512909
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Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

October 8, 2012 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychosis, Publications / By / , , , , , ,

Abstract

Psilocybin is a classic psychedelic and a candidate drug model of psychosis. This study measured the effects of psilocybin on resting-state network and thalamocortical functional connectivity (FC) using functional magnetic resonance imaging (fMRI). Fifteen healthy volunteers received intravenous infusions of psilocybin and placebo in 2 task-free resting-state scans. Primary analyses focused on changes in FC between the default-mode- (DMN) and task-positive network (TPN). Spontaneous activity in the DMN is orthogonal to spontaneous activity in the TPN, and it is well known that these networks support very differ -ent functions (ie, the DMN supports introspection, whereas the TPN supports externally focused attention). Here, inde -pendent components and seed-based FC analyses revealed increased DMN-TPN FC and so decreased DMN-TPN orthogonality after psilocybin. Increased DMN-TPN FC has been found in psychosis and meditatory states, which share some phenomenological similarities with the psy -chedelic state. Increased DMN-TPN FC has also been observed in sedation, as has decreased thalamocortical FC, but here we found preserved thalamocortical FC after psi -locybin. Thus, we propose that thalamocortical FC may be related to arousal, whereas DMN-TPN FC is related to the separateness of internally and externally focused states. We suggest that this orthogonality is compromised in early psychosis, explaining similarities between its phenomenol -ogy and that of the psychedelic state and supporting the utility of psilocybin as a model of early psychosis.

Carhart-Harris, R. L., Leech, R., Erritzoe, D., Williams, T. M.,  Stone, J. M.,  Evans, J., …. Nutt, D. J. (2012). Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis. Schizophrenia Bulletin, 39(6), 1343-1351. http://dx.doi.org/10.1093/schbul/sbs117
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Exploring the impact of ketamine on the experience of illusory body ownership

January 1, 2011 / Consciousness, Ketamine, Papers, Psychology, Psychosis, Publications / By / , , , , , ,

Abstract

Background: Our sense of body ownership is profound and familiar, yet it may be misleading. In the rubber-hand illusion, synchronous tactile and visual stimulation lead to the experience that a rubber hand is actually one’s own. This illusion is emer in schizophrenia. Given the evidence that ketamine, a noncompetitive N-methyl-D-aspartate antagonist reproduces symptoms of schizophrenia, we sought to determine whether the rubber-hand illusion is augmented by ketamine.

Methods: We studied 15 healthy volunteers in a within-subjects placebo-controlled study. All volunteers carried out two versions of the rubber-hand task, each under both placebo and ketamine infusions. In one task, they saw a rubber hand being stroked in synchrony with tactile stimulation of their real, hidden hand. In the other, stroking of the real and rubber hands was asynchronous. We recorded subjective changes in sense of ownership, as well as participants’ ability to localize their hidden hand.

Results: Ketamine was associated with significant increases in subjective measures of the illusion and in hand mislocalization. Although asynchronous visuotactile stimulation attenuates the strength of the illusion during both placebo and ketamine, there remained a significant illusory effect during asynchronous visuotactile stimulation under ketamine compared with placebo. The strength of the illusion during asynchronous visuotactile stimulation correlated with other subjective effects of the drug.

Conclusions: Ketamine mimics the perturbed sense of body ownership seen in schizophrenia, suggesting that it produces a comparable alteration in integration of information across sensory domains and in the subjective and behavioral consequences of such integration.

Morgan, H. L., Turner, D. C., Corlett, P. R., Absalom, A. R., Adapa, R., Arana, F. S., … Fletcher, P. C. (2011). Exploring the impact of ketamine on the experience of illusory body ownership. Biological Psychiatry, 69(1), 35-41. http://dx.doi.org/10.1016/j.biopsych.2010.07.032
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Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference

September 22, 2010 / Ketamine, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , ,

Abstract

Modulating glutamatergic neurotransmission induces alterations in conscious experience that mimic the symptoms of early psychotic illness. We review studies that use intravenous administration of ketamine, focusing on interindividual variability in the profundity of the ketamine experience. We will consider this individual variability within a hypothetical model of brain and cognitive function centered upon learning and inference. Within this model, the brains, neural systems, and even single neurons specify expectations about their inputs and responding to violations of those expectations with new learning that renders future inputs more predictable. We argue that ketamine temporarily deranges this ability by perturbing both the ways in which prior expectations are specified and the ways in which expectancy violations are signaled. We suggest that the former effect is predominantly mediated by NMDA blockade and the latter by augmented and inappropriate feedforward glutamatergic signaling. We suggest that the observed interindividual variability emerges from individual differences in neural circuits that normally underpin the learning and inference processes described. The exact source for that variability is uncertain, although it is likely to arise not only from genetic variation but also from subjects’ previous experiences and prior learning. Furthermore, we argue that chronic, unlike acute, NMDA blockade alters the specification of expectancies more profoundly and permanently. Scrutinizing individual differences in the effects of acute and chronic ketamine administration in the context of the Bayesian brain model may generate new insights about the symptoms of psychosis; their underlying cognitive processes and neurocircuitry.

Corlett, P. R., Honey, G. D., Krystal, J. H., & Fletcher, P. C. (2011). Glutamatergic Model Psychoses: Prediction Error, Learning, and Inference. Neuropsychopharmacology Reviews, 36, 294–315. http://dx.doi.org/10.1038/npp.2010.163
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Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies

September 20, 2010 / Mushrooms / Psilocybin, Papers, Psychology, Psychopharmacology, Psychosis, Publications, Safety / By / , , ,

Abstract

Psilocybin and related hallucinogenic compounds are increasingly used in human research. However, due to limited information about potential subjective side effects, the controlled medical use of these compounds has remained controversial. We therefore analysed acute, short- and longterm subjective effects of psilocybin in healthy humans by pooling raw data from eight double-blind placebo-controlled experimental studies conducted between 1999 and 2008. The analysis included 110 healthy subjects who had received 1–4 oral doses of psilocybin (45–315mg/kg body weight). Although psilocybin dose-dependently induced profound changes in mood, perception, thought and self-experience, most subjects described the experience as pleasurable, enriching and non-threatening. Acute adverse drug reactions, characterized by strong dysphoria and/or anxiety/panic, occurred only in the two highest dose conditions in a relatively small proportion of subjects. All acute adverse drug reactions were successfully managed by providing interpersonal support and did not need psychopharmacological intervention. Follow-up questionnaires indicated no subsequent drug abuse, persisting perception disorders, prolonged psychosis or other long-term impairment of functioning in any of our subjects. The results suggest that the administration of moderate doses of psilocybin to healthy, high-functioning and well-prepared subjects in the context of a carefully monitored research environment is associated with an acceptable level of risk.

Studerus, E., Kometer, M., Hasler, F., & Vollenweider, F. X. (2010). Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. Journal of Psychopharmacology, 25(11), 1434-1452. http://dx.doi.org/10.1177/0269881110382466
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Ayahuasca and Spiritual Crisis: Liminality as Space for Personal Growth

September 16, 2008 / Anthropology, Ayahuasca, Mystical experiences, Papers, Personal development, Psychology, Psychosis, Psychotherapy, Publications, Spirituality / By / ,

Abstract

There is an increased controversy surrounding Westerners’ use of ayahuasca. One issue of importance is psychological resiliency of users and lack of screening by ayahuasca tourism groups in the Amazon. Given the powerful effects of ayahuasca coupled with lack of cultural support, Western users are at increased risk for psychological distress. Many Westerners who experience psychological distress following ayahuasca ceremonies report concurrently profound spiritual experiences. Because of this, it may be helpful to consider these episodes “spiritual emergencies,” or crises resulting from intense and transformative spiritual experiences. Although the author warns readers to avoid romantic comparisons of Western ayahuasca users to shamans, ethnographic data on indigenous shamanic initiates along with theory on liminality may be of some use to understand difficult experiences that accompany ayahuasca use. Given that psychotherapy is culturally sanctioned, therapists trained in treating spiritual crises can help Western ayahuasca users make meaning of their distress. Three case studies are offered as examples of individuals working through various sorts of crises following ayahuasca ceremonies.

Lewis, S. E. (2008). Ayahuasca and spiritual crisis: Liminality as Space for Personal Growth. Anthropology of Consciousness, 19(2), 109-133. https://dx.doi.org/10.1111/j.1556-3537.2008.00006.x
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[Hallucinogen-induced psychological disorders]

June 1, 2008 / HPPD, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , ,

Abstract

OBJECTIVE:

The purpose of this article is to provide an overview of the current research on hallucinogen induced psychiatric disorders. In addition to LSD and psilocybin hallucinogens of biologic origin are increasingly used by adolescents and young adults.

METHODS:

Relevant literature and related articles were identified by means of a computerized MEDLINE search including the years 1997 – 2007. As keywords “hallucinogen induced psychosis”, “hallucinogen induced flashback”, “hallucinogen persisting perception disorder (HPPD)” were used. Finally, 64 journal articles and books out of 103 were included in the review.

RESULTS:

Acute psychotic syndromes in adolescents are rarely due to intoxications with hallucinogenic drugs. However, clinical relevance of flashback phenomena as post-hallucinogenic psychiatric disorder has to be disputed. Because of the high popularity of biogenic hallucinogens and LSD knowledge of intoxications and resulting psychiatric disorders as well as medical complications and therapeutical approaches are clinically important. Especially intoxications with drugs of herbal origin like tropanalcaloids play an important role in emergency situations.

Hermle, L., Kovar, K. A., Hewer, W., & Ruchsow, M. (2008). [Hallucinogen-induced psychological disorders]. Fortschritte der Neurologie-Psychiatrie, 76(6), 334-342. http://dx.doi.org/10.1055/s-2008-1038191
Link to full text [Article in German]

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