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Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats

March 13, 2018 / Anxiety Disorders / PTSD, Ketamine, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , ,

Abstract

Short-term moderate doses of serotonergic and dissociative hallucinogens can be useful in the treatment of anxiety. Recently, a trend has developed for long-term intermittent ‘microdosing’ (usually one-tenth of a ‘full’ active dose), with reports of long-lasting relief from anxiety and related disorders; however, there is no scientific evidence for the efficacy of therapeutic microdosing nor to show its lasting effects. The objective of this study was to test for lasting effects on anxiety in rats after microdosing with ketamine or psilocin. Over 6 days, Wistar rats (N=40) were administered ketamine (0.5 or 3 mg/kg), psilocin (0.05 or 0.075 mg/kg), or saline on three occasions. A 5-min elevated plus-maze test was conducted 48 h after the final drug treatment (n=8). Dependent variables were entries (frequency), spent time (%), and distance traveled (cm) in each zone, as well as total frequency of rears, stretch-attend postures, and head dips. Statistical analyses of drug effects used separate independent one-way analysis of variance and pair-wise comparisons using independent t-tests. Statistical effects were modest or borderline and were most consistent with a mildly anxiogenic profile, which was significant at lower doses; however, this conclusion remains tentative. The lower doses of ketamine and psilocin produced comparable effects (to one another) across each variable, as did the higher doses. This pattern of effects may suggest a common (e.g. neurotransmitter/receptor) mechanism. We conclude that microdosing with hallucinogens for therapeutic purposes might be counter-productive; however, more research is needed to confirm our findings and to establish their translational relevance to clinical ‘psychedelic’ therapy.
Horsley, R. R., Páleníček, T., Kolin, J., & Valeš, K. (2018). Psilocin and ketamine microdosing: effects of subchronic intermittent microdoses in the elevated plus-maze in male Wistar rats. Behavioural pharmacology. 10.1097/FBP.0000000000000394
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Acute pharmacological effects of 2C-B in humans: An observational study

March 13, 2018 / Papers, Psychology, Publications / By / , , , , , ,

Abstract

2,5-dimethoxy-4-bromophenethylamine (2C-B) is a psychedelic phenylethylamine derivative, structurally similar to mescaline. It is a serotonin 5-hydroxytryptamine-2A (5-HT2A), 5-hydroxytryptamine-2B (5-HT2B), and 5-hydroxytryptamine-2C (5-HT2C) receptor partial agonist used recreationally as a new psychoactive substance. It has been reported that 2C-B induces mild psychedelic effects, although its acute pharmacological effects and pharmacokinetics have not yet been fully studied in humans. An observational study was conducted to assess the acute subjective and physiological effects, as well as pharmacokinetics of 2C-B. Sixteen healthy, experienced drug users self-administered an oral dose of 2C-B (10, 15, or 20 mg). Vital signs (blood pressure and heart rate) were measured at baseline 1, 2, 3, 4, and 6 hours (h). Each participant completed subjective effects using three rating scales: the visual analog scale (VAS), the Addiction Research Centre Inventory (ARCI), and the Evaluation of the Subjective Effects of Substances with Abuse Potential (VESSPA-SSE) at baseline, 2–3 and 6 h after self-administration (maximum effects along 6 h), and the Hallucinogenic Rating Scale (maximum effects along 6 h). Oral fluid (saliva) was collected to assess 2C-B and cortisol concentrations during 24 h. Acute administration of 2C-B increased blood pressure and heart rate. Scores of scales related to euphoria increased (high, liking, and stimulated), and changes in perceptions (distances, colors, shapes, and lights) and different body feelings/surrounding were produced. Mild hallucinating effects were described in five subjects. Maximum concentrations of 2C-B and cortisol were reached at 1 and 3 h after self-administration, respectively. Oral 2C-B at recreational doses induces a constellation of psychedelic/psychostimulant-like effects similar to those associated with serotonin-acting drugs.
Papaseit, E., Farré, M., Perez-Maña, C., Torrens, M., Ventura, M., Pujadas, M., … & González, D. (2018). Acute pharmacological effects of 2C-B in humans: An observational study. Frontiers in Pharmacology, 9, 206. 10.3389/fphar.2018.00206
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MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?

March 7, 2018 / Anxiety Disorders / PTSD, MDMA, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

MDMA-assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA-assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear- and anxiety-related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD.

Feduccia, A. A., & Mithoefer, M. C. (2018). MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?. Progress in neuro-psychopharmacology and biological psychiatry. 10.1016/j.pnpbp.2018.03.003
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Altered network hub connectivity after acute LSD administration

March 7, 2018 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

LSD is an ambiguous substance, said to mimic psychosis and to improve mental health in people suffering from anxiety and depression. Little is known about the neuronal correlates of altered states of consciousness induced by this substance. Limited previous studies indicated profound changes in functional connectivity of resting state networks after the administration of LSD. The current investigation attempts to replicate and extend those findings in an independent sample. In a double-blind, randomized, cross-over study, 100 μg LSD and placebo were orally administered to 20 healthy participants. Resting state brain activity was assessed by functional magnetic resonance imaging. Within-network and between-network connectivity measures of ten established resting state networks were compared between drug conditions. Complementary analysis were conducted using resting state networks as sources in seed-to-voxel analyses. Acute LSD administration significantly decreased functional connectivity within visual, sensorimotor and auditory networks and the default mode network. While between-network connectivity was widely increased and all investigated networks were affected to some extent, seed-to-voxel analyses consistently indicated increased connectivity between networks and subcortical (thalamus, striatum) and cortical (precuneus, anterior cingulate cortex) hub structures. These latter observations are consistent with findings on the importance of hubs in psychopathological states, especially in psychosis, and could underlay therapeutic effects of hallucinogens as proposed by a recent model.
Müller, F., Dolder, P. C., Schmidt, A., Liechti, M. E., & Borgwardt, S. (2018). Altered network hub connectivity after acute LSD administration. NeuroImage: Clinical. 10.1016/j.nicl.2018.03.005
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The Meaning-Enhancing Properties of Psychedelics and Their Mediator Role in Psychedelic Therapy, Spirituality, and Creativity

March 6, 2018 / Mushrooms / Psilocybin, Papers, Psychology, Publications / By /

Abstract

Past research has demonstrated to the ability of psychedelics to enhance suggestibility, and pointed to their ability to amplify perception of meaning. This paper examines the existing evidence for the meaning-enhancing properties of psychedelics, and argues that the tendency of these agents to enhance the perception of significance offers valuable clues to explaining their reported ability to stimulate a variety of therapeutic processes, enhance creativity, and instigate mystical-type experiences. Building upon previous research, which suggested the potential role of psychedelic meaning-enhancement in enhancing placebo response, the paper explores the mechanisms by which the meaning-amplifying properties of psychedelics might also play a role in enhancing creativity, as well as in effecting mystical-type experiences. The wider social and public-health implications of this hypothesis are discussed, and suggestions are made as to the various ways in which scientific understanding of the meaning-enhancing properties of psychedelics might be advanced and utilized.
Hartogsohn, I. (2018). The meaning-enhancing properties of psychedelics and their mediator role in psychedelic therapy, spirituality and creativity. Frontiers in neuroscience, 12, 129. 10.3389/fnins.2018.00129
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Unifying Theories of Psychedelic Drug Effects

March 2, 2018 / Papers, Psychology, Publications / By /

Abstract

How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories—model psychoses theory, filtration theory, and psychoanalytic theory—and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks—entropic brain theory, integrated information theory, and predictive processing—and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function.
Swanson, L. R. (2018). Unifying Theories of Psychedelic Drug Effects?. Frontiers in Pharmacology, 9, 172. 10.3389/fphar.2018.00172
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Sex differences in sub-anesthetic ketamine’s antidepressant effects and abuse liability.

March 2, 2018 / Depressive Disorders, Ketamine, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Sub-anesthetic ketamine produces rapid antidepressant effects in patients with bipolar and unipolar major depression where conventional monoaminergic-based antidepressant drugs have been ineffective or ridden with side effects. A single ketamine infusion can produce antidepressant effects lasting up to two weeks, and multiple ketamine infusions prolong this effect. Pre-clinical studies are underway to uncover ketamine’s mechanisms of action, but there are still many questions unanswered regarding the safety of its long-term use. Abuse liability is one area of concern, as recreational ketamine use is an ongoing issue in many parts of the world. Another understudied area is sex differences in responsivity to ketamine. Women are twice as likely as men to be diagnosed with depression, and they progress through stages of drug addiction more rapidly than their male counterparts. Despite this, preclinical studies in ketamine’s antidepressant and addictive-like behaviors in females are limited. These intersecting factors in recent clinical and pre-clinical studies are reviewed to characterize ketamine’s therapeutic potential, its limitations, and its potential mechanisms of action.
Wright, K. N., & Kabbaj, M. (2018). Sex differences in sub-anesthetic ketamine’s antidepressant effects and abuse liability. Current opinion in behavioral sciences, 23, 36-41., 10.1016/j.cobeha.2018.02.001
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Sex differences in sub-anesthetic ketamine's antidepressant effects and abuse liability.

March 2, 2018 / Depressive Disorders, Ketamine, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Sub-anesthetic ketamine produces rapid antidepressant effects in patients with bipolar and unipolar major depression where conventional monoaminergic-based antidepressant drugs have been ineffective or ridden with side effects. A single ketamine infusion can produce antidepressant effects lasting up to two weeks, and multiple ketamine infusions prolong this effect. Pre-clinical studies are underway to uncover ketamine’s mechanisms of action, but there are still many questions unanswered regarding the safety of its long-term use. Abuse liability is one area of concern, as recreational ketamine use is an ongoing issue in many parts of the world. Another understudied area is sex differences in responsivity to ketamine. Women are twice as likely as men to be diagnosed with depression, and they progress through stages of drug addiction more rapidly than their male counterparts. Despite this, preclinical studies in ketamine’s antidepressant and addictive-like behaviors in females are limited. These intersecting factors in recent clinical and pre-clinical studies are reviewed to characterize ketamine’s therapeutic potential, its limitations, and its potential mechanisms of action.
Wright, K. N., & Kabbaj, M. (2018). Sex differences in sub-anesthetic ketamine’s antidepressant effects and abuse liability. Current opinion in behavioral sciences, 23, 36-41., 10.1016/j.cobeha.2018.02.001
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Ergot Alkaloids and their Hallucinogenic Potential in Morning Glories

March 2, 2018 / Biology & Ethnobotany, Papers, Publications / By / ,

Abstract

Naturally occurring and semisynthetic ergot alkaloids play a role in health care or as recreational drugs in Western and indigenous Mexican societies. Evidence is summarized that ergot alkaloids present in Central American Convolvulaceae like Turbina corymbosa, Ipomoea violacea, and Ipomoea asarifolia are colonized by different species of a newly described clavicipitaceous fungal genus named Periglandula. The fungi are associated with peltate glandular trichomes on the adaxial leaf surface of its host plants. The Periglandula fungi are not yet culturable in vitro but were demonstrated to have the capacity to synthesize ergot alkaloids. The alkaloids do not remain in the fungal mycelium but are translocated via the glandular trichomes into their plant host. Both fungi and host benefit from a symbiotic lifestyle. In evolutionary terms the alkaloid biosynthetic gene cluster in the Periglandula/Ipomoea symbiosis is likely to have a conserved (basic) structure while biosynthetic ergot gene clusters within the genera Claviceps and Epichloe were under ecological selection for alkaloid diversification.

Steiner, U., & Leistner, E. (2018). Ergot Alkaloids and their Hallucinogenic Potential in Morning Glories. Planta medica.,  10.1055/a-0577-8049
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Convergent Mechanisms Underlying Rapid Antidepressant Action

March 1, 2018 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , ,

Abstract

Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone pre-clinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e., CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e., 4-chlorokynurenine, pro-drug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.
Zanos, P., Thompson, S. M., Duman, R. S., Zarate, C. A., & Gould, T. D. (2018). Convergent mechanisms underlying rapid antidepressant action. CNS drugs, 1-31. 10.1007/s40263-018-0492-x
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