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Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons

/ LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Publications / /

Abstract

Recordings made from layer V (L5) pyramidal cells of the prefrontal cortex (PFC) and neocortex in rodent slice preparations have shown that serotonin (5-hydroxytryptamine, 5-HT) and serotonergic hallucinogens induce an increase in the frequency of spontaneous excitatory postsynaptic currents (EPSCs) in the apical dendritic field by activating 5-HT2A receptors. Serotonergic hallucinogens induce late EPSCs and increase recurrent network activity when subcortical or mid-cortical regions are stimulated at low frequencies (e.g., 0.1 Hz). A range of agonists or positive allosteric modulators (PAMs) for mostly Gi/o-coupled receptors, including metabotropic glutamate2 (mGlu2), adenosine A1, or μ-opioid receptors, suppress these effects of 5-HT2A receptor stimulation. Furthermore, a range of mostly Gq/11-coupled receptors (including orexin2 [OX2]; α1-adrenergic, and mGlu5 receptors) similarly induce glutamate (Glu) release onto L5 pyramidal cells. Evidence implicates a number of brain regions in mediating these effects of serotonergic hallucinogens and Gq/11-coupled receptors including the midline and intralaminar thalamic nuclei, claustrum, and neurons in deep PFC. These effects on 5-HT2Areceptors and related GPCRs appear to play a major role in the behavioral effects of serotonergic hallucinogens, such as head twitches in rodents and higher order behaviors such as rodent lever pressing on the differential-reinforcement-of-low rate 72-s (DRL 72-s) schedule. This implies that the effects of 5-HT2A receptor activation on the activity of L5 pyramidal cells may be responsible for mediating a range of behaviors linked to limbic circuitry with connectivity between the PFC, striatum, thalamus, claustrum, striatum, amygdala, and the hippocampal formation.

Marek, G. J. (2017). Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons. 10.1007/7854_2017_480
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The 21st century psychedelic renaissance: heroic steps forward on the back of an elephant

/ LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology / /

Abstract

Given the plethora of new studies and published papers in the scientific press and the increasingly emerging presence of articles about positive psychedelic experiences appearing in the popular media, there is little doubt that we are in the midst of a Psychedelic Renaissance. The classical psychedelic drugs LSD and psilocybin and the entactogen MDMA are showing promise as tools to assist psychotherapy for a wide range of mental disorders, with multiple pilot studies demonstrating their safety and efficacy. In this article, the author describes how MDMA in particular has inherent characteristics that make it well suited for assisting trauma-focused psychotherapy in a population of patients who have experienced child abuse. But despite these advances, there remain many obstacles ahead of the widespread mainstream acceptance of psychedelic medicines. The author argues that the Misuse of Drugs Act 1971 is one such obstacle. Other impediments include a prevailing attitude of pseudoscience and rigidity from within the non-scientific psychedelic community itself. Resolution of these conflicts must be sought if medicine and society are to see psychedelics gaining a place in mainstream culture and science.
Sessa, B. (2017). The 21st century psychedelic renaissance: heroic steps forward on the back of an elephant. Psychopharmacology, 1-10. 10.1007/s00213-017-4713-7
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MDMA Impairs Both the Encoding and Retrieval of Emotional Recollections

/ MDMA, Papers, Psychology, Publications / / , , ,

Abstract

The psychoactive drug ±3,4-methylenedioxymethamphetamine (MDMA) is increasingly used for its perceived emotional effects (eg, prosociality, empathy, psychotherapy), but surprisingly little research has been aimed at identifying the effect of the drug on emotional episodic memory in humans. Here, we report the first double-blind placebo-controlled study to examine the effects of MDMA on emotional memory separately during encoding and retrieval in healthy participants. Participants viewed emotionally negative, neutral, and positive pictures and their labels. Forty-eight hours later, they were given cued recollection and recognition memory tests designed to assess recollection and familiarity for the studied pictures. Participants were randomly assigned to one of three groups who received MDMA (1 mg/kg) either during encoding (Encoding group; N=20), retrieval (Retrieval group; N=20), or neither (Placebo group; N=20). Although MDMA administered at either phase did not affect overall memory accuracy, it did alter the recollection of details associated specifically with emotional memories as estimated using a dual process signal detection analysis of confidence judgments and subjective ‘remember’ judgments. In the Encoding group, MDMA reduced recollection estimates for negative and positive pictures but had little to no effect on neutral items or familiarity estimates. There was evidence for similar trends in the Retrieval group. These findings indicate that MDMA attenuates the encoding and retrieval of salient details from emotional events, consistent with the idea that its potential therapeutic effects for treating posttraumatic stress disorder are related to altering emotional memory.
Doss, M. K., Weafer, J., Gallo, D. A., & de Wit, H. (2017). MDMA Impairs Both the Encoding and Retrieval of Emotional Recollections. Neuropsychopharmacology. 10.1038/npp.2017.171
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Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs

/ DMT, Ketamine, Papers, Publications / / , , , , , ,

Abstract

A feature of human culture is that we can learn to consume chemical compounds, derived from natural plants or synthetic fabrication, for their psychoactive effects. These drugs change the mental state and/or the behavioral performance of an individual and can be instrumentalized for various purposes. After the emergence of a novel psychoactive substance (NPS) and a period of experimental consumption, personal and medical benefits and harm potential of the NPS can be estimated on evidence base. This may lead to a legal classification of the NPS, which may range from limited medical use, controlled availability up to a complete ban of the drug form publically accepted use. With these measures, however, a drug does not disappear, but frequently continues to be used, which eventually allows an even better estimate of the drug’s properties. Thus, only in rare cases, there is a final verdict that is no more questioned. Instead, the view on a drug can change from tolerable to harmful but may also involve the new establishment of a desired medical application to a previously harmful drug. Here, we provide a summary review on a number of NPS for which the neuropharmacological evaluation has made important progress in recent years. They include mitragynine (“Kratom”), synthetic cannabinoids (e.g., “Spice”), dimethyltryptamine and novel serotonergic hallucinogens, the cathinones mephedrone and methylone, ketamine and novel dissociative drugs, γ-hydroxybutyrate, γ-butyrolactone, and 1,4-butanediol. This review shows not only emerging harm potentials but also some potential medical applications.
Hassan, Z., Bosch, O. G., Singh, D., Narayanan, S., Kasinather, B. V., Seifritz, E., … & Müller, C. P. (2017). Novel Psychoactive Substances—Recent Progress on Neuropharmacological Mechanisms of Action for Selected Drugs. Frontiers in psychiatry, 8, 152. 10.3389/fpsyt.2017.00152
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Horizontal gene cluster transfer increased hallucinogenic mushroom diversity

/ Mushrooms / Psilocybin, Papers, Publications / / , , , , ,

Abstract

Secondary metabolites are heterogeneous natural products that often mediate interactions between species. The tryptophan-derived secondary metabolite, psilocin, is a serotonin receptor agonist that induces altered states of consciousness. A phylogenetically disjunct group of mushroom-forming fungi in the Agaricales produce the psilocin prodrug, psilocybin. Spotty phylogenetic distributions of fungal compounds are sometimes explained by horizontal transfer of metabolic gene clusters among unrelated fungi with overlapping niches. We report the discovery of a psilocybin gene cluster in three hallucinogenic mushroom genomes, and evidence for its horizontal transfer between fungal lineages. Patterns of gene distribution and transmission suggest that psilocybin provides a fitness advantage in the dung and late wood-decay niches, which may be reservoirs of fungal indole-based metabolites that alter behavior of mycophagous and wood-eating invertebrates. These hallucinogenic mushroom genomes will serve as models in neurochemical ecology, advancing the prospecting and synthetic biology of novel neuropharmaceuticals.

Reynolds, H. T., Vijayakumar, V., Gluck-Thaler, E., Korotkin, H. B., Matheny, P. B., & Slot, J. C. (2017). Horizontal gene cluster transfer increased hallucinogenic mushroom diversity. bioRxiv, 176347. 10.1101/176347
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The Non-Peptide Arginine-Vasopressin v1a Selective Receptor Antagonist, SR49059, Blocks the Rewarding, Prosocial, and Anxiolytic Effects of 3,4-Methylenedioxymethamphetamine and Its Derivatives in Zebra Fish

/ MDMA, Neuroscience, Papers, Psychology, Publications / / , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) and its derivatives, 2,5-dimethoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA), are recreational drugs whose pharmacological effects have recently been attributed to serotonin 5HT2A/C receptors. However, there is growing evidence that the oxytocin (OT)/vasopressin system can modulate some the effects of MDMA. In this study, MDMA (2.5–10 mg/kg), DOB (0.5 mg/kg), or PMA (0.005, 0.1, or 0.25 mg/kg) were administered intramuscularly to adult zebra fish, alone or in combination with the V1a vasopressin antagonist, SR49059 (0.01–1 ng/kg), before carrying out conditioned place preference (CPP), social preference, novel tank diving, and light–dark tests in order to evaluate subsequent rewarding, social, and emotional-like behavior. The combination of SR49059 and each drug progressively blocked: (1) rewarding behavior as measured by CPP in terms of time spent in drug-paired compartment; (2) prosocial effects measured on the basis of the time spent in the proximity of a nacre fish picture; and (3) anxiolytic effects in terms of the time spent in the upper half of the novel tank and in the white compartment of the tank used for the light–dark test. Antagonism was obtained at SR49059 doses which, when given alone, did not change motor function. In comparison with a control group, receiving vehicle alone, there was a three to five times increase in the brain release of isotocin (the analog of OT in fish) after treatment with the most active doses of MDMA (10 mg/kg), DOB (0.5 mg/kg), and PMA (0.1 mg/kg) as evaluated by means of bioanalytical reversed-phase high-performance liquid chromatography. Taken together, these findings show that the OT/vasopressin system is involved in the rewarding, prosocial, and anxiolytic effects of MDMA, DOB, and PMA in zebra fish and underline the association between this system and the behavioral alterations associated with disorders related to substance abuse.
Ponzoni, L., Braida, D., Bondiolotti, G., & Sala, M. (2017). The Non-Peptide Arginine-Vasopressin v1a Selective Receptor Antagonist, SR49059, Blocks the Rewarding, Prosocial, and Anxiolytic Effects of 3, 4-Methylenedioxymethamphetamine and Its Derivatives in Zebra Fish. Frontiers in psychiatry, 8, 146. 10.3389/fpsyt.2017.00146
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The Non-Peptide Arginine-Vasopressin v1a Selective Receptor Antagonist, SR49059, Blocks the Rewarding, Prosocial, and Anxiolytic Effects of 3,4-Methylenedioxymethamphetamine and Its Derivatives in Zebra Fish Read More »

Psychedelics and connectedness

/ LSD, Mushrooms / Psilocybin, Papers, Psychology, Publications / / , , , ,

Abstract

Psychedelic drugs are creating ripples in psychiatry as evidence accumulates of their therapeutic potential. An important question remains unresolved however: how are psychedelics effective? We propose that a sense of connectedness is key, provide some preliminary evidence to support this, and suggest a roadmap for testing it further.
Carhart-Harris, R. L., Erritzoe, D., Haijen, E., Kaelen, M., & Watts, R. (2017). Psychedelics and connectedness. Psychopharmacology, 1-4. 10.1007/s00213-017-4701-y
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Entheogenesis: Toward an Expanded Worldview for Our Time

/ Papers, Philosophy & Religious Studies, Psychology / /

Abstract

Whereas the terminology of psychedelics has acquired spurious cultural associations of “tripping,” the historically primal concept of consciousness expansion has two advantages. One, it connects psychedelic drugs with other modes of consciousness expansion, such as meditation and creative visioning; and two, it suggests contrasting comparison with the consciousness contraction involved in concentration and focus. Both expansions and contractions can be observed at the level of an individual’s states of consciousness and also at the level of the shared worldview of society. Contemporary world culture is moving toward an expanded worldview that recognizes both the material and the spiritual dimensions of our existence.
Metzner, R. (2017). Entheogenesis: Toward an Expanded Worldview for Our Time. Journal of Humanistic Psychology, 57(5), 443-449. 10.1177/0022167817723405
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MDMA and brain activity during neurocognitive performance: An overview of neuroimaging studies with abstinent ‘Ecstasy’ users

/ MDMA, Papers, Psychology, Publications / / , , ,

Abstract

MDMA/Ecstasy has had a resurgence in popularity, with recent supplies comprising higher strength MDMA, potentially leading to increased drug-related harm. Neurocognitive problems have been widely reported in ecstasy users, equally some studies report null findings, and it remains unclear which factors underlie the development of neurocognitive impairments. This review covers the empirical research into brain activity during neurocognitive performance, using fMRI, fNIRS, and EEG. Our main conclusion is that chronic repeated use of recreational ecstasy can result in haemodynamic and electrophysiological changes that reflect recruitment of additional resources to perform cognitive tasks.

Findings are consistent with serotonergic system changes, although whether this reflects neurotoxicity or neuroadaptation, cannot be answered from these data. There is a degree of heterogeneity in the methodologies and findings, limiting the strengths of current conclusions. Future research with functional neuroimaging paired with molecular imaging, genetics or pharmacological challenges of the serotonin system may help to decipher the link between serotonergic and cognitive changes in ecstasy users.

Roberts, C. A., Quednow, B. B., Montgomery, C., & Parrott, A. C. (2017). MDMA and brain activity during neurocognitive performance: An overview of neuroimaging studies with abstinent ‘Ecstasy’users. Neuroscience & Biobehavioral Reviews. 10.1016/j.neubiorev.2017.07.015
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