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Monoamine biosynthesis via a noncanonical calcium-activatable aromatic amino acid decarboxylase in psilocybin mushroom

/ Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Publications / / , , , ,

Abstract

Aromatic l-amino acid decarboxylases (AAADs) are a phylogenetically diverse group of enzymes responsible for the decarboxylation of aromatic amino acid substrates into their corresponding aromatic arylalkylamines. AAADs have been extensively studied in mammals and plants as they catalyze the first step in the production of neurotransmitters and bioactive phytochemicals, respectively. Unlike mammals and plants, the hallucinogenic psilocybin mushroom Psilocybe cubensis reportedly employs an unrelated phosphatidylserine-decarboxylase-like enzyme to catalyze l-tryptophan decarboxylation, the first step in psilocybin biosynthesis. To explore the origin of this chemistry in psilocybin mushroom, we generated the first de novo transcriptomes of P. cubensis and investigated several putative l-tryptophan-decarboxylase-like enzymes. We report the biochemical characterization of a noncanonical AAAD from P. cubensis (PcncAAAD) that exhibits substrate permissiveness toward l-phenylalanine, l-tyrosine, and l-tryptophan, as well as chloro-tryptophan derivatives. The crystal structure of PcncAAAD revealed the presence of a unique C-terminal appendage domain featuring a novel double-β-barrel fold. This domain is required for PcncAAAD activity and regulates catalytic rate and thermal stability through calcium binding. PcncAAAD likely plays a role in psilocybin production in P. cubensis and offers a new tool for metabolic engineering of aromatic-amino-acid-derived natural products.

Torrens-Spence, M. P., Liu, C. T., Pluskal, T., Chung, Y. K., & Weng, J. K. (2018). Monoamine Biosynthesis via a Noncanonical Calcium-Activatable Aromatic Amino Acid Decarboxylase in Psilocybin Mushroom. ACS chemical biology, 13(12), 3343-3353., 10.1021/acschembio.8b00821
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Self-Experiments with Psychoactive Substances: A Historical Perspective

/ Humanities & Art, Papers, Publications / / ,

Abstract

The purpose of this chapter is to highlight the rich tradition of self-experiments (SEs) with psychoactive substances carried out by scientists and therapists for more than a century. Scientifically inspired controlled SEs dominated until the end of the twentieth century, when ethical requirements minimized controlled SEs and “wild” SEs expanded particularly with the emergence of new psychoactive substances. The review focuses on laughing gas (nitrous oxide), cannabis, cocaine, hallucinogens, entactogens, and dissociative hallucinogens. This is due to the fact that substances that induce “complex” effects such as alteration of space/time experience, ego dissolution, and increased feelings and insights (e.g., hallucinogens, entactogens) represent by far the majority of SEs, whereas SEs with substances inducing “simple” effects such as euphoria, anxiolysis, dissociation, or emotional blunting (e.g., cocaine, opioids) are much rarer or even absent (e.g., benzodiazepines). Complex drug effects are much harder to describe, thus allowing SEs to fulfill a more important function.

SEs with psychoactive drugs appeared to emerge in the mid-eighteenth century, which triggered a long-standing tradition throughout the nineteenth and early twentieth century. SEs have been de facto performed for a variety of reasons, ranging from establishing scientific knowledge and gaining philosophical insights to compensating for personal deficits. Self-experimenters can be divided into two general types. Besides their scientific intentions, “exploratory” self-experimenters intend to expand awareness and insight, whereas “compensatory” self-experimenters might aim for coping with psychiatric symptoms or personality deficits. Scientific limitations of SEs are obvious when compared to double-blind, randomized, placebo-controlled trials. Whereas the former might lead to more “realistic” detailed description of subjective effects, the latter lead to more solid results in respect to objectively measurable “average” effects. Possible adverse effects of SEs were identified that resulted in loss of scientific objectivity and decreased control over substance use and addiction, development of isolation, problematic group dynamics, and “social autism.”

Passie, T., & Brandt, S. D. (2018). Self-Experiments with Psychoactive Substances: A Historical Perspective., 10.1007/164_2018_177
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The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial.

/ LSD, Papers, Psychology, Publications / / , , , , ,

Abstract

RATIONALE:
Previous research demonstrating that lysergic acid diethylamide (LSD) produces alterations in time perception has implications for its impact on conscious states and a range of psychological functions that necessitate precise interval timing. However, interpretation of this research is hindered by methodological limitations and an inability to dissociate direct neurochemical effects on interval timing from indirect effects attributable to altered states of consciousness.
METHODS:
We conducted a randomised, double-blind, placebo-controlled study contrasting oral administration of placebo with three microdoses of LSD (5, 10, and 20 μg) in older adults. Subjective drug effects were regularly recorded and interval timing was assessed using a temporal reproduction task spanning subsecond and suprasecond intervals.
RESULTS:
LSD conditions were not associated with any robust changes in self-report indices of perception, mentation, or concentration. LSD reliably produced over-reproduction of temporal intervals of 2000 ms and longer with these effects most pronounced in the 10 μg dose condition. Hierarchical regression analyses indicated that LSD-mediated over-reproduction was independent of marginal differences in self-reported drug effects across conditions.
Yanakieva, S., Polychroni, N., Family, N., Williams, L. T., Luke, D. P., & Terhune, D. B. (2018). The effects of microdose LSD on time perception: a randomised, double-blind, placebo-controlled trial. Psychopharmacology, 1-12., 10.1007/s00213-018-5119-x
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An exploratory study of experiences with conventional eating disorder treatment and ceremonial ayahuasca for the healing of eating disorders

/ Anxiety Disorders / PTSD, Ayahuasca, Papers, Psychology, Publications, Scientific Discipline / / , , , , ,

Abstract

Purpose

Ayahuasca is a traditional Amazonian medicine that is currently being researched for its potential in treating a variety of mental disorders. This article reports on exploratory qualitative research relating to participant experiences with ceremonial ayahuasca drinking and conventional treatment for eating disorders (EDs). It also explores the potential for ayahuasca as an adjunctive ED treatment.

Methods

Thirteen individuals previously diagnosed with an ED participated in a semi-structured interview contrasting their experiences with conventional ED treatment with experiences from ceremonial ayahuasca. The interviews were analyzed using thematic analysis.

Results

Participant reports were organized with key themes including that ayahuasca: led to rapid reductions in ED thoughts and symptoms; allowed for the healing of the perceived root of the ED; helped to process painful feelings and memories; supported the internalization of greater self-love and self-acceptance; and catalyzed spiritual elements of healing.

Conclusions

The results suggest that ayahuasca may have potential as a valuable therapeutic tool, and further research—including carefully controlled clinical trials—is warranted.

Renelli, M., Fletcher, J., Tupper, K. W., Files, N., Loizaga-Velder, A., & Lafrance, A. (2018). An exploratory study of experiences with conventional eating disorder treatment and ceremonial ayahuasca for the healing of eating disorders. Eating and Weight Disorders-Studies on Anorexia, Bulimia and Obesity, 1-8., 10.1007/s40519-018-0619-6
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Neuroimaging of chronic MDMA (“ecstasy”) effects: A meta-analysis

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

Abstract

In this meta-analysis, we aimed to assess the evidence from neuroimaging studies for chronic alterations in the brains of MDMA users. The databases PubMed, Embase, and Web of Science were searched for studies published from inception to August 24, 2018, without any language restriction. Sixteen independent studies comprising 356 MDMA users and 311 controls were included. Of these, five studies investigated frontal and occipital N-acetylaspartate/creatine and myo-inositol/creatine ratios, three studies assessed basal ganglia blood flow and ten studies investigated serotonin transporter (SERT) density in various regions. We found significantly decreased SERT density in eight of 13 investigated regions. Meta-regression indicated a positive association with abstinence, but none with lifetime episodes of use. Therefore, other variables (such as doses taken per occasion) might be more important determinants. Positive associations between time of abstinence and SERT density might indicate that these alterations are reversible to some extent. Furthermore, there were no significant differences between user and control groups in terms of neurochemical ratios in the frontal and occipital lobes and blood flow in the basal ganglia. Overall, MDMA user groups showed heavy use patterns and study quality was poor.

Müller, F., Brändle, R., Liechti, M. E., & Borgwardt, S. (2018). Neuroimaging of chronic MDMA (“ecstasy”) effects: A meta-analysis of the literature. Neuroscience & Biobehavioral Reviews., 10.1016/j.neubiorev.2018.11.004
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Lecture: Michael Pollan on psychedelics

/ Publications /

On Monday December 10th, OPEN is hosting an event with best-selling author Michael Pollan. On this evening, he will discuss his own research into psychedelics, and the implications of the latest scientific findings for therapy, consciousness and personal transformation.
In his newest book ‘How to change your mind‘, best-selling author and journalist Michael Pollan investigates the science of psychedelics, and their relation to consciousness, therapy and transformation. Pollan is best known for his award-winning writing on food, such as ‘The Omnivore’s Dilemma’ and ‘Food Rules’. His style of ‘immersive journalism’ is ideally suited to explore the world of psychedelics, and he reluctantly experiments with LSD, psilocybin mushrooms and 5-MeO-DMT to find out what psychedelics are all about. In addition he interviews many neuroscientists and therapists.
The result is a fascinating journey through the history of psychedelics, moving from promising psychedelic treatment for alcoholism and death anxiety in the fifties to present-day neuroscience research, and the renewed interest in therapy for depression, addiction and trauma. Can psychedelics help us to improve our relationship towards ourselves and our surroundings? Come and find out on December 10th.
Doors open at 19:30, and the program starts at 20:00. Address: Tivoli/Vredenburg, Vredenburgkade 11, Utrecht.
Tickets are in limited supply and can be bought here.
After the lecture, you will be able to purchase the recent Dutch translation of ‘How to change your mind’. Michael Pollan will be available to sign your books.

 

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Acute effects of ayahuasca in a juvenile non-human primate model of depression

/ Ayahuasca, Depressive Disorders, Papers, Psychology, Publications / / , , , , , ,

Abstract

OBJECTIVE:
The incidence rate of major depression in adolescents reaches approximately 14%. This disorder is usually recurrent, without remission of symptoms even after pharmacological treatment, and persists throughout adult life. Since the effects of antidepressants take approximately 2 weeks to begin, new pharmacological therapies are under continuous exploration. Recent evidence suggests that psychedelics could produce rapid antidepressant effects. In this study, we evaluated the potential antidepressant effects of ayahuasca in a juvenile non-human primate model of depression.
METHODS:
While living with their families, juvenile marmosets (8 males; 7 females) were observed on alternate days for four weeks during a baseline phase. This was followed by 8 weeks of an induced depressive state protocol, the social isolated context (IC), in which the animals were monitored in the first and last weeks. Subsequently, five males and four females were randomly selected for treatment, first with a single administration of saline vehicle (1.67 mL/300 g of body weight, via gavage), followed by a single dose of ayahuasca (1.67 mL/300 g of body weight, via gavage). Both phases lasted 1 week and the animals were monitored daily. A third week of sampling was called the tardive-pharmacological effects phase. In all phases the marmosets were assessed for behavior, fecal cortisol levels, and body weight.
RESULTS:
After IC, the animals presented typical hypocortisolemia, but cortisol recovered to baseline levels 24 h after an acute dose of ayahuasca; this recovery was not observed in vehicle-treated animals. Additionally, in males, ayahuasca, but not the vehicle, reduced scratching, a stereotypic behavior, and increased feeding. Ayahuasca treatment also improved body weight to baseline levels in both sexes. The ayahuasca-induced behavioral response had long-term effects (14 days). Thus, in this translational juvenile animal model of depression, ayahuasca presented beneficial effects.
CONCLUSIONS:
These results can contribute to the validation of ayahuasca as an antidepressant drug and encourage new studies on psychedelic drugs as a tool for treating mood disorders, including for adolescents with early-onset depression.
da Silva, F. S., Silva, E. A., Sousa Jr, G. M. D., Maia-de-Oliveira, J. P., Soares-Rachetti, V. D. P., de Araujo, D. B., … & Galvão-Coelho, N. L. (2018). Acute effects of ayahuasca in a juvenile non-human primate model of depression. Brazilian Journal of Psychiatry, (AHEAD), 0-0. 10.1590/1516-4446-2018-0140
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The Varieties of the Psychedelic Experience: A Preliminary Study of the Association Between the Reported Subjective Effects and the Binding Affinity Profiles of Substituted Phenethylamines and Tryptamines

/ Neuroscience, Papers, Pharmacology & Chemistry, Publications / / , , , , ,

Abstract

Classic psychedelics are substances of paramount cultural and neuroscientific importance. A distinctive feature of psychedelic drugs is the wide range of potential subjective effects they can elicit, known to be deeply influenced by the internal state of the user (“set”) and the surroundings (“setting”). The observation of cross-tolerance and a series of empirical studies in humans and animal models support agonism at the serotonin (5-HT)2A receptor as a common mechanism for the action of psychedelics. The diversity of subjective effects elicited by different compounds has been attributed to the variables of “set” and “setting,” to the binding affinities for other 5-HT receptor subtypes, and to the heterogeneity of transduction pathways initiated by conformational receptor states as they interact with different ligands (“functional selectivity”). Here we investigate the complementary (i.e., not mutually exclusive) possibility that such variety is also related to the binding affinity for a range of neurotransmitters and monoamine transporters including (but not limited to) 5-HT receptors. Building on two independent binding affinity datasets (compared to “in silico” estimates) in combination with natural language processing tools applied to a large repository of reports of psychedelic experiences (Erowid’s Experience Vaults), we obtained preliminary evidence supporting that the similarity between the binding affinity profiles of psychoactive substituted phenethylamines and tryptamines is correlated with the semantic similarity of the associated reports. We also showed that the highest correlation was achieved by considering the combined binding affinity for the 5-HT, dopamine (DA), glutamate, muscarinic and opioid receptors and for the Ca+ channel. Applying dimensionality reduction techniques to the reports, we linked the compounds, receptors, transporters and the Ca+ channel to distinct fingerprints of the reported subjective effects. To the extent that the existing binding affinity data is based on a low number of displacement curves that requires further replication, our analysis produced preliminary evidence consistent with the involvement of different binding sites in the reported subjective effects elicited by psychedelics. Beyond the study of this particular class of drugs, we provide a methodological framework to explore the relationship between the binding affinity profiles and the reported subjective effects of other psychoactive compounds.

Zamberlan, F., Sanz, C., Martinez Vivot, R., Pallavicini, C., Erowid, E., & Tagliazucchi, E. (2018). The varieties of the psychedelic experience: a preliminary study of the association between the reported subjective effects and the binding affinity profiles of substituted phenethylamines and tryptamines. Frontiers in integrative neuroscience, 12, 54., 10.3389/fnint.2018.00054.
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Ayahuasca improves emotion dysregulation in a community sample and in individuals with borderline-like traits

/ Ayahuasca, Neuroscience, Papers, Publications / / , , , , , ,

Abstract

Background

Research suggests that mindfulness-based interventions may improve mindfulness-related capacities (e.g., decentering, non-judging, and non-reacting) and emotion regulation. Previously, our group reported that ayahuasca could be a potential analogue of mindfulness practice. The main aim of the current study was to examine the effects of ayahuasca on emotional regulation and mindfulness-related capacities. Secondarily, we sought to explore the effects of ayahuasca on individuals with borderline personality disorder (BPD) traits.

Method

This is an observational study of 45 volunteers who participated in an ayahuasca session. The volunteers completed various self-report instruments designed to measure emotional dysregulation (Difficulties in Emotion Regulation Scale (DERS)) and mindfulness traits (Five Facet Mindfulness Questionnaire (FFMQ)–Short Form and Experiences Questionnaire (EQ)) prior to and 24 h after the ayahuasca session. The volunteers were divided into two subgroups based on their score on the McLean Screening Instrument for BPD (MSI-BPD). Twelve participants were grouped into the BPD-like traits subgroup while the rest of them were included in the non-BPD-like subgroup. We performed within-subjects and between-group analyses.

Results

Overall, the participants showed significant improvements on the FFMQ subscales observing, acting with awareness, non-judging, and non-reacting and also significantly improved on decentering (EQ scale) and on the DERS subscales emotional non-acceptance, emotional interference, and lack of control. The BPD-like subgroup also showed significant improvements on the DERS subscales emotional interference and lack of control but not in mindfulness capacities.

Conclusions

These findings suggest a potential therapeutic effect for ayahuasca in emotion regulation and mindfulness capacities (including decentering, acceptance, awareness, and sensitivity to meditation practice). Based on these results, we believe that ayahuasca therapy could be of value in clinical populations, such as individuals with BPD, affected by emotion dysregulation.

Domínguez-Clavé, E., Soler, J., Pascual, J. C., Elices, M., Franquesa, A., Valle, M., … & Riba, J. (2018). Ayahuasca improves emotion dysregulation in a community sample and in individuals with borderline-like traits. Psychopharmacology, 1-8., 10.1007/s00213-018-5085-3
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