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Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial

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

Abstract

Major Depressive Disorder affects about 350 million people worldwide, and about one-third of the patients are considered treatment-resistant. Furthermore, available antidepressants take usually two weeks for the onset of their antidepressant effect. Recent open label trials show that psychedelics, such as ayahuasca and psilocybin, hold promise as fast-onset antidepressants. Although promising, these studies were not controlled for the placebo effect. To address this issue, and to further test the antidepressant effects of ayahuasca, we conducted a parallel arm, double blind randomised placebo-controlled trial, in patients with treatment-resistant major depression. Thirty-five patients with treatment-resistant major depression received a single dose of ayahuasca or placebo. We measured as primary outcome the change in the Hamilton Depression Rating scale (HAM-D) seven days after the dosing session, and as secondary outcomes the changes in Montgomery-Asberg Depression Rating Scale (MADRS), and response rates at one day (D1), two days (D2) and seven days (D7) after dosing, and remission rates at D7. This study is registered with http://clinicaltrials.gov (NCT02914769). We observed robust evidence of rapid antidepressant effects of a single dosing session with ayahuasca when compared to placebo. HAM-D scores at D7 were significantly lower in patients treated with ayahuasca than in those treated with placebo (p=0.019; Cohen’s d=0.98). MADRS scores were significantly reduced in the ayahuasca group compared to the placebo group at all endpoints (at D1 and D2, p=0.04; at D7, p<0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen’s d=0.84; D2: Cohen’s d=0.84; D7: Cohen’s d=1.49). Response rates were high for both groups at D1 and D2, and were significantly higher in the ayahuasca group only at D7 (64% vs. 27%; OR = 4.95; p = 0.04; NNT = 2.66). Remission rate was not significantly different between groups. Our study provides new evidence of rapid antidepressant effects of ayahuasca for treatment-resistant major depression.

Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M., Pessoa, J., … & Tofoli, L. (2017). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomised placebo-controlled trial. bioRxiv, 103531. 10.1101/103531
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A Receptor on Acid

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

Abstract

Wacker et al. report the crystal structure of LSD in complex with one of its major targets in the brain, the 5-HT2B receptor, the first such structure for any psychedelic drug. The results shed light on the molecular mechanisms underlying its ability to induce hallucinations with greater duration and potency than closely related compounds.
Chen, Q., & Tesmer, J. J. (2017). A receptor on acid. Cell, 168(3), 339-341. 10.1016/j.cell.2017.01.012
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Crystal Structure of an LSD-Bound Human Serotonin Receptor

/ LSD, Neuroscience, Papers, Publications / / , , , , , ,

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 Bouso et al., 2016

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

Barrett, F. S., & Griffiths, R. R. (2017). The factor structure of the Mystical Experience Questionnaire (MEQ): Reply to Bouso et al., 2016. Human Psychopharmacology: Clinical and Experimental, 32(1). 10.1002/hup.2564
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The factor structure of the Mystical Experience Questionnaire (MEQ): Reply to Barrett & Griffiths (2016)

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

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)

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

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

/ Depressive Disorders, Ketamine, Papers, Psychology, Psychotic Disorders, Publications / / , ,

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

/ Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / / , , , , ,

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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Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects

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

Abstract

In vitro studies showed that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to 3,4-methylenedioxyamphetamine (MDA). However, the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans is unknown. The effects of genetic variants in these CYP enzymes on the pharmacokinetics and pharmacodynamics of MDMA were characterized in 139 healthy subjects (69 male, 70 female) in a pooled analysis of eight double-blind, placebo-controlled studies. MDMA-MDA conversion was positively associated with genotypes known to convey higher CYP2C19 or CYP2B6 activities. Additionally, CYP2C19 poor metabolizers showed greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes. Furthermore, the maximum concentration of MDA was higher in tobacco smokers that harbored the inducible CYP1A2 rs762551 A/A genotype compared with the non-inducible C-allele carriers. The findings indicate that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may moderate the cardiovascular toxicity of MDMA.

Vizeli, P., Schmid, Y., Prestin, K., zu Schwabedissen, H. E. M., & Liechti, M. E. (2017). Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects. European Neuropsychopharmacology, 27(3), 232-238. 10.1016/j.euroneuro.2017.01.008
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Determination of Tryptamines and β-Carbolines in Ayahuasca Beverage Consumed During Brazilian Religious Ceremonies

/ Ayahuasca, Biology & Ethnobotany, Papers, Pharmacology & Chemistry, Publications / / , ,

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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Women and Psychedelics: Cycles, Care, and Conditions - October 23rd

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