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J. Horáček

The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action

February 6, 2022 / Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / , , , , , , , , , , , , , , , ,

Abstract

Serotonergic agonist psilocybin is a psychedelic with antidepressant potential. Sleep may interact with psilocybin’s antidepressant properties like other antidepressant drugs via induction of neuroplasticity. The main aim of the study was to evaluate the effect of psilocybin on sleep architecture on the night after psilocybin administration. Regarding the potential antidepressant properties, we hypothesized that psilocybin, similar to other classical antidepressants, would reduce rapid eye movement (REM) sleep and prolong REM sleep latency. Moreover, we also hypothesized that psilocybin would promote slow-wave activity (SWA) expression in the first sleep cycle, a marker of sleep-related neuroplasticity. Twenty healthy volunteers (10 women, age 28-53) underwent two drug administration sessions, psilocybin or placebo, in a randomized, double-blinded design. Changes in sleep macrostructure, SWA during the first sleep cycle, whole night EEG spectral power across frequencies in non-rapid eye movement (NREM) and REM sleep, and changes in subjective sleep measures were analyzed. The results revealed prolonged REM sleep latency after psilocybin administration and a trend toward a decrease in overall REM sleep duration. No changes in NREM sleep were observed. Psilocybin did not affect EEG power spectra in NREM or REM sleep when examined across the whole night. However, psilocybin suppressed SWA in the first sleep cycle. No evidence was found for sleep-related neuroplasticity, however, a different dosage, timing, effect on homeostatic regulation of sleep, or other mechanisms related to antidepressant effects may play a role. Overall, this study suggests that potential antidepressant properties of psilocybin might be related to changes in sleep.

Dudysová, D., Janků, K., Šmotek, M., Saifutdinova, E., Kopřivová, J., Bušková, J., Mander, B. A., Brunovský, M., Zach, P., Korčák, J., Andrashko, V., Viktorinová, M., Tylš, F., Bravermanová, A., Froese, T., Páleníček, T., & Horáček, J. (2020). The Effects of Daytime Psilocybin Administration on Sleep: Implications for Antidepressant Action. Frontiers in pharmacology, 11, 602590. https://doi.org/10.3389/fphar.2020.602590

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The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication

November 26, 2021 / Depressive Disorders, Ketamine, Papers, Psychology / Leave a Comment / By / , , , , ,

Abstract

The rapid antidepressant effect of ketamine has become a breakthrough in the research and treatment of depression. Although predictive and modulating factors of the response to ketamine are broadly studied, little is known about optimal concurrent medication protocols. Concerning gamma-aminobutyric acid neurotransmission being a shared target for both ketamine and benzodiazepines (BZD), we evaluated the influence of BZD on the antidepressant effect of a single ketamine infusion in depressed patients. Data from 47 patients (27 females) with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) who participated in two previous studies (EudraCT Number: 2009-010625-39 and 2013-000952-17) entered the analysis. All of the subjects were given an infusion of a subanesthetic dose of racemic ketamine (0.54 mg per kg) as an add-on medication to ongoing antidepressant treatment. Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis. The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001). RM-ANOVA revealed a different time pattern of response to ketamine between the BZD+ (>8mg of DZ equivalent) and BZD- (≤8mg of DZ equivalent) groups, with a significantly worse outcome in BZD+ on day 3 (p=0.04) and day 7 (p=0.02). The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine’s antidepressant effect. The pathophysiological, clinical and methodological implications of this finding should be considered in future research and ketamine treatment.

Andrashko, V., Novak, T., Brunovsky, M., Klirova, M., Sos, P., & Horacek, J. (2020). The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication. Frontiers in psychiatry, 11, 844. https://doi.org/10.3389/fpsyt.2020.00844

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Sex differences and serotonergic mechanisms in the behavioural effects of psilocin

October 12, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Publications / By / , , , , ,

Abstract

Psilocybin has recently attracted a great deal of attention as a clinical research and therapeutic tool. The aim of this paper is to bridge two major knowledge gaps regarding its behavioural pharmacology – sex differences and the underlying receptor mechanisms. We used psilocin (0.25, 1 and 4 mg/kg), an active metabolite of psilocybin, in two behavioural paradigms – the open-field test and prepulse inhibition (PPI) of the acoustic startle reaction. Sex differences were evaluated with respect to the phase of the female cycle. The contribution of serotonin receptors in the behavioural action was tested in male rats with selective serotonin receptor antagonists: 5-HT1A receptor antagonist (WAY100635 1 mg/kg), 5-HT2A receptor antagonist (MDL100907 0.5 mg/kg), 5-HT2B receptor antagonist (SB215505 1 mg/kg) and 5-HT2C receptor antagonist (SB242084 1 mg/kg). Psilocin induced dose-dependent inhibition of locomotion and suppression of normal behaviour in rats (behavioural serotonin syndrome, impaired PPI). The effects were more pronounced in male rats than in females. The inhibition of locomotion was normalized by 5-HT1A and 5-HT2B/C antagonists; however, PPI was not affected significantly by these antagonists. Our findings highlight an important issue of sex-specific reactions to psilocin and that apart from 5-HT2A-mediated effects 5-HT1A and 5-HT2C/B receptors also play an important role. These findings have implications for recent clinical trials.

Tylš, F., Páleníček, T., Kadeřábek, L., Lipski, M., Kubešová, A., & Horáček, J. (2015). Sex differences and serotonergic mechanisms in the behavioural effects of psilocin. Behavioural pharmacology. https://dx.doi.org/10.1097/FBP.0000000000000198

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Psilocybin – Summary of knowledge and new perspectives

December 17, 2013 / Anxiety Disorders / PTSD, Depressive Disorders, Headache Pain and Neurological Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Pharmacology & Chemistry, Psychology, Psychotic Disorders, Publications, Substance Use Disorder / By / , ,

Abstract

Psilocybin, a psychoactive alkaloid contained in hallucinogenic mushrooms, is nowadays given a lot of attention in the scientific community as a research tool for modeling psychosis as well as due to its potential therapeutic effects. However, it is also a very popular and frequently abused natural hallucinogen. This review summarizes all the past and recent knowledge on psilocybin. It briefly deals with its history, discusses the pharmacokinetics and pharmacodynamics, and compares its action in humans and animals. It attempts to describe the mechanism of psychedelic effects and objectify its action using modern imaging and psychometric methods. Finally, it describes its therapeutic and abuse potential.

Tylš, F., Páleníček, T., & Horáček, J. (2014). Psilocybin – Summary of knowledge and new perspectives. European Neuropsychopharmacology, 24, 342-365. http://dx.doi.org/10.1016/j.euroneuro.2013.12.006

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Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression

June 25, 2013 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , ,

Abstract

OBJECTIVES:
Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder.
METHODS:
In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients.
RESULTS:
Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen´s d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point.
CONCLUSION:
The substantial relationship between ketamine’s antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine’s action, trough NMDA receptors, shared by both ketamine’s clinical effects.
Sos, P., Klirova, M., Novak, T., Kohutova, B., Horacek, J., & Palenicek, T. (2013). Relationship of ketamine’s antidepressant and psychotomimetic effects in unipolar depression. Neuroendocrinology Letters, 34(4), 287-293.
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