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Crystal Structure of an LSD-Bound Human Serotonin Receptor

January 26, 2017 / LSD, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

The prototypical hallucinogen LSD acts via serotonin receptors, and here we describe the crystal structure of LSD in complex with the human serotonin receptor 5-HT2B. The complex reveals conformational rearrangements to accommodate LSD, providing a structural explanation for the conformational selectivity of LSD’s key diethylamide moiety. LSD dissociates exceptionally slow from both 5-HT2BR and 5-HT2AR—a major target for its psychoactivity. Molecular dynamics (MD) simulations suggest that LSD’s slow binding kinetics may be due to a “lid” formed by extracellular loop 2 (EL2) at the entrance to the binding pocket. A mutation predicted to increase the mobility of this lid greatly accelerates LSD’s binding kinetics and selectively dampens LSD-mediated β-arrestin2 recruitment. This study thus reveals an unexpected binding mode of LSD; illuminates key features of its kinetics, stereochemistry, and signaling; and provides a molecular explanation for LSD’s actions at human serotonin receptors.

Wacker, D., Wang, S., McCorvy, J. D., Betz, R. M., Venkatakrishnan, A. J., Levit, A., … & Shoichet, B. K. (2017). Crystal Structure of an LSD-Bound Human Serotonin Receptor. Cell, 168(3), 377-389. 10.1016/j.cell.2016.12.033
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The factor structure of the Mystical Experience Questionnaire (MEQ): Reply to Barrett & Griffiths (2016)

January 25, 2017 / Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , ,

Bouso, J. C., Pedrero‐Pérez, E. J., Gandy, S., & Alcázar‐Córcoles, M. Á. (2017). The factor structure of the Mystical Experience Questionnaire (MEQ): Reply to Barrett & Griffiths (2016). Human Psychopharmacology: Clinical and Experimental, 32(1). 10.1002/hup.2570
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The factor structure of the Mystical Experience Questionnaire (MEQ): Reply to Barrett & Griffiths (2016)

January 25, 2017 / Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , ,

Bouso, J. C., Pedrero‐Pérez, E. J., Gandy, S., & Alcázar‐Córcoles, M. Á. (2017). The factor structure of the Mystical Experience Questionnaire (MEQ): Reply to Barrett & Griffiths (2016). Human Psychopharmacology: Clinical and Experimental, 32(1). 10.1002/hup.2570
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Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion

January 23, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Psychotic Disorders, Publications / By / , ,

Abstract

New and encouraging findings regarding the use of ketamine for depression in the context of psychotic symptoms have been published by Pennybaker et al. (1). In their analysis, patients with bipolar disorder without a history of psychosis had a more robust response to ketamine, and patients with a history of psychosis had a significant response compared with placebo as well. Concerning dissociative symptoms, even though patients with a history of psychosis endorsed more symptoms, these were not maintained after a 40-minute period, and no full psychosis was induced in their sample.

da Frota Ribeiro, C. M., Sanacora, G., & Ostroff, R. (2017). Reply to: Ketamine and Psychosis History: Antidepressant Efficacy and Psychotomimetic Effects Postinfusion. Biological Psychiatry. 10.1016/j.biopsych.2017.01.012
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The fibrinolytic system: A new target for treatment of depression with psychedelics

January 23, 2017 / Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

Current understanding of the neurobiology of depression has grown over the past few years beyond the traditional monoamine theory of depression to include chronic stress, inflammation and disrupted synaptic plasticity. Tissue plasminogen activator (tPA) is a key factor that not only promotes fibrinolysis via the activation of plasminogen, but also contributes to regulation of synaptic plasticity and neurogenesis through plasmin-mediated activation of a probrain derived neurotrophic factor (BDNF) to mature BDNF. ProBDNF activation could potentially be supressed by competition with fibrin for plasmin and tPA. High affinity binding of plasmin and tPA to fibrin could result in a decrease of proBDNF activation during brain inflammation leading to fibrosis further perpetuating depressed mood. There is a paucity of data explaining the possible role of the fibrinolytic system or aberrant extravascular fibrin deposition in depression. We propose that within the brain, an imbalance between tPA and urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) and neuroserpin favors the inhibitors, resulting in changes in neurogenesis, synaptic plasticity, and neuroinflammation that result in depressive behavior. Our hypothesis is that peripheral inflammation mediates neuroinflammation, and that cytokines such as tumor necrosis factor alpha (TNF-α) can inhibit the fibrinolytic system by up- regulating PAI-1 and potentially neuroserpin. We propose that the decrement of the activity of tPA and uPA occurs with downregulation of uPA in part involving the binding and clearance from the surface of neural cells of uPA/PAI-1 complexes by the urokinase receptor uPAR. We infer that current antidepressants and ketamine mitigate depressive symptoms by restoring the balance of the fibrinolytic system with increased activity of tPA and uPA with down-regulated intracerebral expression of their inhibitors. We lastly hypothesize that psychedelic 5-ht2a receptor agonists, such as psilocybin, can improve mood through anti- inflammatory and pro-fibrinolytic effects that include blockade of TNF-α activity leading to decreased PAI-1 activity and increased clearance. The process involves disinhibition of tPA and uPA with subsequent increased cleavage of proBDNF which promotes neurogenesis, decreased neuroinflammation, decreased fibrin deposition, normalized glial-neuronal cross-talk, and optimally functioning neuro-circuits involved in mood. We propose that psilocybin can alleviate deleterious changes in the brain caused by chronic stress leading to restoration of homeostatic brain fibrinolytic capacity leading to euthymia.

Idell, R. D., Florova, G., Komissarov, A. A., Shetty, S., Girard, R. B. S., & Idell, S. (2017). The fibrinolytic system: A new target for treatment of depression with psychedelics. Medical Hypotheses, 100, 46-53. 10.1016/j.mehy.2017.01.013
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Determination of Tryptamines and β-Carbolines in Ayahuasca Beverage Consumed During Brazilian Religious Ceremonies

January 19, 2017 / Ayahuasca, Biology & Ethnobotany, Papers, Pharmacology & Chemistry, Publications / By / , ,

Abstract:

Ayahuasca is a potent hallucinogenic beverage prepared from Banisteriopsis caapi in combination with other psychoactive plants. N,N-dimethyltryptamine, tryptamine, harmine, harmaline, harmalol, and tetrahydroharmine were quantified in ayahuasca samples using a simple and low-cost method based on SPE and LC with UV diode-array detection. The experimental variables that affect the SPE method, such as type of solid phase and nature of solvent, were optimized. The method showed good linearity (r > 0.9902) and repeatability (RSD < 0.8%) for alkaloid compounds, with an LOD of 0.12 mg/L. The proposed method was used to analyze 20 samples from an ayahuasca cooking process from a religious group located in the municipality of Fortaleza, state of Ceará, Brazil. The results showed that concentrations of the target compounds ranged from 0.3 to 36.7 g/L for these samples.

Santos, M. C., Navickiene, S., & Gaujac, A. (2017). Determination of Tryptamines and β-Carbolines in Ayahuasca Beverage Consumed During Brazilian Religious Ceremonies. Journal of AOAC International. 10.5740/jaoacint.16-0337
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Administration of ketamine for unipolar and bipolar depression

January 18, 2017 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

OBJECTIVE: Clinical trials demonstrated that ketamine exhibits rapid antidepressant efficacy when administered in subanaesthetic dosages. We reviewed currently available literature investigating efficacy, response rates and safety profile.

METHODS: Twelve studies investigating unipolar, seven on bipolar depression were included after search in medline, scopus and web of science.

RESULTS: Randomized, placebo-controlled or open-label trials reported antidepressant response rates after 24 h on primary outcome measures at 61%. The average reduction of Hamilton Depression Rating Scale (HAM-D) was 10.9 points, Beck Depression Inventory (BDI) 15.7 points and Montgomery-Asberg Depression Rating Scale (MADRS) 20.8 points. Ketamine was always superior to placebo. Most common side effects were dizziness, blurred vision, restlessness, nausea/vomiting and headache, which were all reversible. Relapse rates ranged between 60% and 92%. To provide best practice-based information to patients, a consent-form for application and modification in local language is included.

CONCLUSIONS: Ketamine constitutes a novel, rapid and efficacious treatment option for patients suffering from treatment resistant depression and exhibits rapid and significant anti-suicidal effects. New administration routes might serve as alternative to intravenous regimes for potential usage in outpatient settings. However, long-term side effects are not known and short duration of antidepressant response need ways to prolong ketamine’s efficacy.

Kraus, C., Rabl, U., Vanicek, T., Carlberg, L., Popovic, A., Spies, M., … & Willeit, M. (2017). Administration of ketamine for unipolar and bipolar depression. International Journal of Psychiatry in Clinical Practice, 21(1), 2-12. 10.1080/13651501.2016.1254802
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Pharmacology and Toxicology of N-Benzylphenethylamine (“NBOMe”) Hallucinogens

January 18, 2017 / Neuroscience, Papers, Publications / By /

Abstract

Serotonergic hallucinogens induce profound changes in perception and cognition. The characteristic effects of hallucinogens are mediated by 5-HT2A receptor activation. One class of hallucinogens are 2,5-dimethoxy-substituted phenethylamines, such as the so-called 2C-X compounds 2,5-dimethoxy-4-bromophenethylamine (2C-B) and 2,5-dimethoxy-4-iodophenethylamine (2C-I). Addition of an N-benzyl group to phenethylamine hallucinogens produces a marked increase in 5-HT2A-binding affinity and hallucinogenic potency. N-benzylphenethylamines (“NBOMes”) such as N-(2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (25I-NBOMe) show subnanomolar affinity for the 5-HT2A receptor and are reportedly highly potent in humans. Several NBOMEs have been available from online vendors since 2010, resulting in numerous cases of toxicity and multiple fatalities. This chapter reviews the structure–activity relationships, behavioral pharmacology, metabolism, and toxicity of members of the NBOMe hallucinogen class. Based on a review of 51 cases of NBOMe toxicity reported in the literature, it appears that rhabdomyolysis is a relatively common complication of severe NBOMe toxicity, an effect that may be linked to NBOMe-induced seizures, hyperthermia, and vasoconstriction.

Halberstadt, A. L. (2016). Pharmacology and Toxicology of N-Benzylphenethylamine (“NBOMe”) Hallucinogens. 10.1007/7854_2016_64

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Harmine, a Novel DNA Methyltransferase 1 Inhibitor in the Leukemia Cell Line

January 17, 2017 / Ayahuasca, Papers, Psychiatry & Medicine, Publications / By / , , , ,

Abstract

DNA methylation followed by tumor suppressor gene repression plays a critical role in the leukemia development. So, DNA methyl transferase inhibitors have great importance in treatment of theses malignancies. Harmine, A beta carboline alkaloid derivative of Peganum harmala, had shown anti- proliferative effects on leukemic cell line. This study aimed to evaluate the effect of Harmine on DNMT1 (DNA methyl transferase 1) expression in a leukemic cell line. Cell proliferation and cell cycle analysis were studied in NB4 cell line after treatment with Harmine for 72 h. DNMT1 expression in treated cells was analyzed by real time PCR. Tumor suppressor gene hypometylation and reactivation was evaluated via MSP analysis and also real time PCR. Harmine reduced cell proliferation in NB4 cell line in a time and dose-dependent manner. 102 µg/ml of Harmine was increased amount of cells in G1 Phase of cell cycle (p < 0.05). Anti proliferative doses of Harmine, has suppressed DNMT1 gene in NB4 cell line. Down-regulated DNMT1 induced p15 tumor suppressor promoter hypomethylation and reactivation. Our data indicate that Harmine can be considered as a potential treatment for AML (Acute Myeloid Leukemia), and future studies are required to test the clinical efficacy of Harmine—whether used as a single agent or as an adjuvant—for AML treatment.

Oodi, A., Norouzi, H., Amirizadeh, N., Nikougoftar, M., & Vafaie, Z. Harmine, a Novel DNA Methyltransferase 1 Inhibitor in the Leukemia Cell Line. Indian Journal of Hematology and Blood Transfusion, 1-7. 10.1007/s12288-016-0770-z

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