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Psychosis

Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist

October 24, 2007 / Other substances, Papers, Psychopharmacology, Psychosis, Publications / By / , ,

Abstract

Recent clinical studies in schizophrenic patients show that a selective agonist of group II metabotropic glutamate (mGlu) receptors has robust efficacy in treating positive and negative symptoms. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs, reducing the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. The use of mouse models provides an opportunity to investigate the dynamic action that mGlu2/3 receptors play in regulating the behavioral effects of hallucinogen-induced glutamatergic neurotransmission using genetic as well as pharmacological strategies. The current study sought to characterize the use of the two-lever drug discrimination paradigm in ICR (CD-1) mice, using the hallucinogenic 5-HT2A/2C receptor agonist (−)-2,5-dimethoxy-4-bromoamphetamine [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][(−)-DOB)] as a stimulus-producing drug. The (−)-DOB discriminative stimulus was dose-dependent, generalized to the hallucinogen lysergic acid diethylamide, and was potently blocked by the 5-HT2A receptor antagonist M100907. However, contrary to our prediction, the hallucinogen-induced discriminative stimulus was not regulated by mGlu2/3 receptors. In a series of follow-up studies using hallucinogen-induced head twitch response and phencyclidine-induced hyperlocomotion, it was additionally discovered that the repeated dosing regimen required for discrimination training attenuated the behavioral effects of the mGlu2/3 receptor agonist LY379268. Furthermore chronic studies, using a 14 day (−)-DOB treatment, confirmed that repeated hallucinogen treatment causes a loss of behavioral activity of mGlu2/3 receptors, likely resulting from persistent activation of mGlu2/3 receptors by a hallucinogen-induced hyperglutamatergic state.

Benneyworth, M. A., Smith, R. L., & Sanders-Bush, E. (2008). Chronic Phenethylamine Hallucinogen Treatment Alters Behavioral Sensitivity to a Metabotropic Glutamate 2/3 Receptor Agonist. Neuropsychopharmacology, 33, 2206–2216. http://dx.doi.org/10.1038/sj.npp.1301600
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The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval

February 14, 2007 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychosis, Publications / By / , , , ,

Abstract

Schizophrenia patients exhibit impairments in prepulse inhibition (PPI) of the startle response. Hallucinogenic 5-HT2A receptor agonists are used for animal models of schizophrenia because they mimic some symptoms of schizophrenia in humans and induce PPI deficits in animals. Nevertheless, one report indicates that the 5-HT2A receptor agonist psilocybin increases PPI in healthy humans. Hence, we investigated these inconsistent results by assessing the dose-dependent effects of psilocybin on PPI in healthy humans. Sixteen subjects each received placebo or 115, 215, and 315 mug/kg of psilocybin at 4-week intervals in a randomized and counterbalanced order. PPI at 30-, 60-, 120-, 240-, and 2000-ms interstimulus intervals (ISIs) was measured 90 and 165 min after drug intake, coinciding with the peak and post-peak effects of psilocybin. The effects of psilocybin on psychopathological core dimensions and sustained attention were assessed by the Altered States of Consciousness Rating Scale (5D-ASC) and the Frankfurt Attention Inventory (FAIR). Psilocybin dose-dependently reduced PPI at short (30 ms), had no effect at medium (60 ms), and increased PPI at long (120–2000 ms) ISIs, without affecting startle reactivity or habituation. Psilocybin dose-dependently impaired sustained attention and increased all 5D-ASC scores with exception of Auditory Alterations. Moreover, psilocybin-induced impairments in sustained attention performance were positively correlated with reduced PPI at the 30 ms ISI and not with the concomitant increases in PPI observed at long ISIs. These results confirm the psilocybin-induced increase in PPI at long ISIs and reveal that psilocybin also produces a decrease in PPI at short ISIs that is correlated with impaired attention and consistent with deficient PPI in schizophrenia.

Vollenweider, F. X, Csomor, P. A., Knappe, B., Geyer, M. A., & Quednow, B. B. (2007). The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval. Neuropsychopharmacology, 32(9), 1876-1887. http://dx.doi.org/10.1038/sj.npp.1301324
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Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers

October 1, 2005 / DMT, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , , , ,

Abstract

INTRODUCTION:
Pharmacological challenges with hallucinogens are used as models for psychosis in experimental research. The state induced by glutamate antagonists such as phencyclidine (PCP) is often considered as a more appropriate model of psychosis than the state induced by serotonergic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and N,N-dimethyltryptamine (DMT). However, so far, the psychological profiles of the two types of hallucinogenic drugs have never been studied directly in an experimental within-subject design.

METHODS:
Fifteen healthy volunteers were included in a double-blind, cross-over study with two doses of the serotonin 5-HT2A agonist DMT and the glutamate N-methyl-D-aspartate (NMDA) antagonist (S)-ketamine.

RESULTS:
Data are reported for nine subjects who completed both experimental days with both doses of the two drugs. The intensity of global psychological effects was similar for DMT and (S)-ketamine. However, phenomena resembling positive symptoms of schizophrenia, particularly positive formal thought disorder and inappropriate affect, were stronger after DMT. Phenomena resembling negative symptoms of schizophrenia, attention deficits, body perception disturbances and catatonia-like motor phenomena were stronger after (S)-ketamine.

DISCUSSION:
The present study suggests that the NMDA antagonist model of psychosis is not overall superior to the serotonin 5-HT2A agonist model. Rather, the two classes of drugs tend to model different aspects or types of schizophrenia. The NMDA antagonist state may be an appropriate model for psychoses with prominent negative and possibly also catatonic features, while the 5-HT2A agonist state may be a better model for psychoses of the paranoid type.

Gouzoulis-Mayfrank, E., Heekeren, K., Neukirch, A., Stoll, M., Stock, C., Obradovic, M., & Kovar, K .A. (2005). Psychological effects of (S)-ketamine and N,N-dimethyltryptamine (DMT): a double-blind, cross-over study in healthy volunteers. Pharmacopsychiatry, 38(6), 301-311. http://dx.doi.org/10.1055/s-2005-916185
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Hallucinogens

January 28, 2004 / Addiction, History, LSD, Medicine, Neuroscience, Other subjects, Other substances, Papers, Psychiatry, Psychopharmacology, Psychosis, Publications, Safety / By /

Abstract

Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT2A receptors, especially those expressed on neocortical pyramidal cells. Activation of 5-HT2A receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][18F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the ASC produced by hallucinogens. The 5-HT2A receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addition, it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.

Nichols, D. E. (2004). Hallucinogens. Pharmacology & therapeutics, 101(2), 131-181. https://dx.doi.org/10.1016/j.pharmthera.2003.11.002

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Effects of the 5-HT2A Agonist Psilocybin on Mismatch Negativity Generation and AX-Continuous Performance Task: Implications for the Neuropharmacology of Cognitive Deficits in Schizophrenia

February 1, 2003 / Ketamine, Mushrooms / Psilocybin, Neuroscience, Other subjects, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , , , ,

Abstract

Previously the NMDA (N-methyl-D-aspartate) receptor (NMDAR) antagonist ketamine was shown to disrupt generation of the auditory event-related potential (ERP) mismatch negativity (MMN) and the performance of an ‘AX’-type continuous performance test (AX-CPT)–measures of auditory and visual context-dependent information processing–in a similar manner as observed in schizophrenia. This placebo-controlled study investigated effects of the 5-HT(2A) receptor agonist psilocybin on the same measures in 18 healthy volunteers. Psilocybin administration induced significant performance deficits in the AX-CPT, but failed to reduce MMN generation significantly. These results indirectly support evidence that deficient MMN generation in schizophrenia may be a relatively distinct manifestation of deficient NMDAR functioning. In contrast, secondary pharmacological effects shared by NMDAR antagonists and the 5-HT(2A) agonist (ie disruption of glutamatergic neurotransmission) may be the mechanism underlying impairments in AX-CPT performance observed during both psilocybin and ketamine administration. Comparable deficits in schizophrenia may result from independent dysfunctions of 5-HT(2A) and NMDAR-related neurotransmission.

Umbricht, D., Vollenweider, F. X., Schmid, L., Gruebel, C., Skrabo, A., Huber, T., & Koller, R. (2003). Effects of the 5-HT2A agonist psilocybin on mismatch negativity generation and AX-continuous performance task: implications for the neuropharmacology of cognitive deficits in schizophrenia. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 28(1), 170-181. http://dx.doi.org/10.1038/sj.npp.1300005
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Effects of different subanaesthetic doses of (S)-ketamine on psychopathology and binocular depth inversion in man

January 1, 2003 / Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , , ,

Abstract

The role of the N-methyl-D-aspartate (NMDA) neurotransmitter system in relation to psychoses is not completely understood, but represent a challenge in neurobiological research. The psychotic states induced by NMDA antagonists such as phencyclidine and ketamine have been described as being most similar to schizophrenia and the NMDA system has been implicated in the pathogenesis of schizophrenia. Binocular depth inversion, an illusion of visual perception, has been shown to be impaired in psychotic and psychotomimetic states in healthy and schizophrenic subjects. In this study, pictures of natural and artificial objects were presented stereoscopically to 12 healthy male volunteers and depth perception assessed using an operationalized method. The effects of the psychotomimetic S-enantiomer of the anaesthetic ketamine in two different subanaesthetic doses were compared with those of a placebo. In spite of dose dependence and grave subjective and significant objective psychopathology, no significant impairment of binocular depth perception was found with (S)-ketamine. Implications related to memory function, perceptogenesis and ‘bottom-up’ processing in ketamine model psychosis and schizophrenia are discussed.

Passie, T., Karst, M., Borsutzky, M., Wiese, B., Emrich, H. M., & Schneider, U. (2003). Effects of different subanaesthetic doses of (S)-ketamine on psychopathology and binocular depth inversion in man. Journal of Psychopharmacology, 17(1), 51-56. http://dx.doi.org/10.1177/0269881103017001698
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Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action

December 1, 1998 / Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychopharmacology, Psychosis, Publications / By / , , , ,

Abstract

Psilocybin, an indoleamine hallucinogen, produces a psychosis-like syndrome in humans that resembles first episodes of schizophrenia. In healthy human volunteers, the psychotomimetic effects of psilocybin were blocked dose-dependently by the serotonin-2A antagonist ketanserin or the atypical antipsychotic risperidone, but were increased by the dopamine antagonist and typical antipsychotic haloperidol. These data are consistent with animal studies and provide the first evidence in humans that psilocybin-induced psychosis is due to serotonin-2A receptor activation, independently of dopamine stimulation. Thus, serotonin-2A overactivity may be involved in the pathophysiology of schizophrenia and serotonin-2A antagonism may contribute to therapeutic effects of antipsychotics.

Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F., Bäbler, A., Vogel, H., & Hell, D. (1998). Psilocybin induces schizophrenia‐like psychosis in humans via a serotonin‐2 agonist action. Neuroreport, 9(17), 3897-3902. https://dx.doi.org/doi:10.1097/00001756-199812010-00024
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Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity

July 2, 1997 / Ketamine, Other subjects, Other substances, Papers, Psychopharmacology, Psychosis, Publications / By / , , , ,

Abstract

Phencyclidine, ketamine, and other agents that block NMDA glutamate receptors trigger a schizophrenia-like psychosis in humans and induce pathomorphological changes in cerebrocortical neurons in rat brain. Accumulating evidence suggests that a complex network disturbance involving multiple transmitter receptor systems is responsible for the neuronal injury, and it is proposed that a similar network disturbance is responsible for the psychotomimetic effects of NMDA antagonists, and might also be involved in the pathophysiology of schizophrenia. In the present study we present evidence that serotonergic agents possessing 5HT2A agonist activity prevent NMDA antagonist neurotoxicity in rat brain. It isproposed that 5HT2A agonists may also prevent the psychotomimetic effects of NMDA antagonists. Among the 5HT2A agonists examined and found to be neuroprotective are LSD and related hallucinogens. The apparent contradiction in proposing that these agents might have antipsychotic properties is resolved by evidence linking their hallucinogenic activity to agonist action at 5HT2C receptors, whereas antipsychotic activity would be attributable to agonist action at 5HT2A receptors.

Farber, N. B., Hanslick, J., Kirby, C., McWilliams, L., & Olney, J. W. (1998). Serotonergic Agents That Activate 5HT2A Receptors Prevent NMDA Antagonist Neurotoxicity. Neuropsychopharmacology, 18(1), 57-62. http://dx.doi.org/doi:10.1016/S0893-133X(97)00127-9

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

October 14, 1996 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry, Psychology, Psychosis, Publications / By / , , , , ,

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 [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][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 cingulate (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.

Vollenweider, F. X., Leenders, K. L., Scharfetter, C., Maguire, P., Stadelmann, O., & Angst, J. (1997). Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology, 16(5), 357-372. http://dx.doi.org/10.1016/S0893-133X(96)00246-1
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The psychopharmacology of hallucinogens.

April 1, 1996 / History, LSD, Papers, Psychiatry, Psychology, Psychosis, Publications, Safety, Toxicology / By / , ,

Abstract

Hallucinogenic drugs have been inhaled, ingested, worshipped, and reviled since prehistory. With the purification and synthesis of bontanical preparations and the ensuing discovery of chemically unique agents, hope was raised regarding their therapeutic potential, but this hope has been clouded by an epidemic of abuse and an inventory of adverse effects. This review examines aspects of that controversy, including the history of hallucinogens, epidemiology of current hallucinogen abuse, the association of LSD use with prolonged psychoses and hallucinogen persisting perception disorder, and the efforts to demonstrate the drug’s therapeutic efficacy. Human subject ramifications in hallucinogen experimentation are discussed. Future lines of research are suggested in human, animal, and tissue culture paradigms.

Abraham, H. D., Aldridge, A. M., & Gogia, P. (1996). The psychopharmacology of hallucinogens. Neuropsychopharmacology, 14(4), 285-298. https://dx.doi.org/10.1016/0893-133X(95)00136-2
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7 May - Psychedelics, Nature & Mental Health with Sam Gandy

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