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Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin

January 3, 2022 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychopharmacology / Leave a Comment / By / , , ,

Abstract

Background: Psilocybin is a serotonergic psychedelic found in “magic mushrooms” with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and addiction. In rodents, psilocybin acutely induces plasticity-related immediate early genes in cortical tissue; however, studies into the effects on subcortical regions, of different doses, and the subsequent translation of corresponding proteins are lacking.

Methods: We examined the acute effects of a single administration of psilocybin (0.5-20 mg/kg) on the expression of selected genes in the prefrontal cortex and hippocampus. In total, 46 target genes and eight reference genes were assessed using real-time quantitative polymerase chain reaction. Corresponding protein levels of the three most commonly regulated genes were assessed using Western blotting.

Results: In the prefrontal cortex, psilocybin increased the expression of Cebpb, c-Fos, Dups1, Fosb, Junb, Iκβ-α, Nr4a1, P11, Psd95, and Sgk1, and decreased the expression of Clk1. In the hippocampus, psilocybin strongly increased the expression of Arrdc2, Dusp1, Iκβ-α, and Sgk1 in a dose-dependent manner, and decreased the expression of Arc, Clk1, Egr2, and Ptgs2. Protein levels of Sgk1, Dusp1, and Iκβ-α showed only partial agreement with transcriptional patterns, stressing the importance of assessing downstream translation when investigating rapid gene responses.

Conclusion: The present study demonstrates that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus. Our findings provide further evidence for the rapid plasticity-promoting effects of psilocybin.

Jefsen, O. H., Elfving, B., Wegener, G., & Müller, H. K. (2021). Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin. Journal of psychopharmacology (Oxford, England), 35(4), 483–493. https://doi.org/10.1177/0269881120959614O.

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Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context

November 30, 2021 / Ayahuasca, DMT, Papers, Psychopharmacology, Toxicology / Leave a Comment / By / , , , , , , , ,

Ayahuasca is a beverage obtained from Banisteriopsis caapi plus Psychotria viridis. B. caapi contains the β-carbolines harmine, harmaline, and tetrahydroharmine that are monoamine oxidase inhibitors and P. viridis contains N,N-dimethyltryptamine (DMT) that is responsible for the visionary effects of the beverage. Ayahuasca use is becoming a global phenomenon, and the recreational use of DMT and similar alkaloids has also increased in recent years; such uncontrolled use can lead to severe intoxications. In this investigation, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to study the kinetics of alkaloids over a 24 h period in saliva and serum of 14 volunteers who consumed ayahuasca twice a month in a religious context. We compared the area under the curve (AUC), maximum concentration (Cmax ), time to reach Cmax (Tmax ), mean residence time (MRT), and half-life (t1/2 ), as well as the serum/saliva ratios of these parameters. DMT and β-carboline concentrations (Cmax ) and AUC were higher in saliva than in serum and the MRT was 1.5-3.0 times higher in serum. A generalized estimation equations (GEEs) model suggested that serum concentrations could be predicted by saliva concentrations, despite large individual variability in the saliva and serum alkaloid concentrations. The possibility of using saliva as a biological matrix to detect DMT, β-carbolines, and their derivatives is very interesting because it allows fast noninvasive sample collection and could be useful for detecting similar alkaloids used recreationally that have considerable potential for intoxication.

Lanaro, R., Mello, S. M., da Cunha, K. F., Silveira, G., Corrêa-Neto, N. F., Hyslop, S., Cabrices, O. G., Costa, J. L., & Linardi, A. (2021). Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context. Drug testing and analysis, 13(3), 664–678. https://doi.org/10.1002/dta.2955

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Effect of Ketamine on Rumination in Treatment-Resistant Depressive Patients

November 26, 2021 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology / Leave a Comment / By / , , , ,

Abstract

Background: A rapid antidepressant effect of ketamine has repeatedly been documented in the literature, and identifying clinical features associated with a better response to this treatment is currently an essential question. Considering the relationship between rumination and depression and the need to identify potential predictors of response to ketamine, we analyzed the effect of a single injection of ketamine 0.5 mg/kg on rumination in treatment-resistant depressive (TRD) patients and explored whether baseline ruminative style and early improvements of rumination would predict a greater antidepressant effect of ketamine.

Methods: Ten TRD outpatients who participated in a 4-week open study on the antidepressant effect of ketamine also completed the Ruminative Response Scale the day before, the day after, and a week after ketamine administration.

Results: We found that in our patients, a single rapid 1-minute intravenous injection of ketamine 0.5 mg/kg was efficacious in reducing rumination, but neither severity of rumination at baseline nor early improvements of rumination after ketamine injection predicted antidepressant response.

Conclusions: Our preliminary data suggest that a single injection of ketamine 0.5 mg/kg can be efficacious in reducing rumination in TRD patients but rumination does not seem to be a useful clinical predictor of response to ketamine. Larger studies are necessary to confirm these results.

Vidal, S., Jermann, F., Aubry, J. M., Richard-Lepouriel, H., & Kosel, M. (2020). Effect of Ketamine on Rumination in Treatment-Resistant Depressive Patients. Journal of clinical psychopharmacology, 40(6), 607–610. https://doi.org/10.1097/JCP.0000000000001305

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Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies – PubMed

November 1, 2020 / Depression, Ketamine, Papers, Psychiatry, Psychology, Psychopharmacology, Publications / By / , , , ,

Abstract

Background: Most recent evidence support a rapid and sustained antidepressant effect of subanesthetic dose of intravenous ketamine in patients with major depressive disorder (MDD). However, clinical and animal studies investigating the effects of intravenous ketamine on specific functional domains disrupted by depression reported conflicting results. Therefore, the aim of this review is to provide an overview of the recent findings exploring the cognitive effects of ketamine in depression.
Methods: After a bibliographic search on PubMed, Medline and PsycInfo, we retrieved 11 original studies meeting our research criteria, 7 in humans with MDD or Treatment Resistant Disorder and 4 using rats models for depression.
Results: Overall the results showed that a) ketamine reduced activation and normalized connectivity measures of several brain regions related to depressive behaviors and reversed deficits in cognitive flexibility and coping response strategy in rats with depressive features, and b) ketamine leads to a no significant impairment on neurocognitive functions in most of the studies, with only three studies observing improvements in speed of processing, verbal learning, sustained attention and response control, verbal and working memory.
Limitations: The methodological heterogeneity, in terms of neuropsychological tests used and cognitive domain explored, of the studies included.
Conclusions: Most of the studies included showed no significant cognitive impairments in MDD patients after ketamine treatment. Furthermore, the results of the fMRI studies considered suggest that ketamine may have a normalizing effect on brain functions during attentional and emotional processing in MDD patients. However, further studies are needed to confirm these preliminary evidences.
Crisanti, C., Enrico, P., Fiorentini, A., Delvecchio, G., & Brambilla, P. (2020). Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies. Journal of Affective Disorders., 10.1016/j.jad.2020.07.119
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Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression

November 30, 2021 / Depression, Ketamine, Papers, Psychopharmacology / Leave a Comment / By / , , , , , ,

Abstract

Background: Esketamine nasal spray is approved for treatment-resistant depression.

Objective: The objective of this study was to characterize the pharmacokinetics of esketamine and noresketamine in healthy subjects and patients with treatment-resistant depression.

Methods: Esketamine and noresketamine were measured in > 9000 plasma samples collected from 820 individuals who received esketamine by the intranasal, intravenous, and oral routes. An open linear model for esketamine (three compartments) and noresketamine (two compartments) that included a hepato-portal compartment was developed using NONMEM® VII. The effects of covariates on esketamine pharmacokinetics and a model evaluation were performed using conventional methods.

Results: The fraction of a 28-mg intranasal dose absorbed through the nasal cavity (FRn) is 54% (100% of this fraction is completely absorbed); the remaining 46% is swallowed and undergoes intestinal and first-pass metabolism and 18.6% of the swallowed dose reaches the systemic circulation. The absolute bioavailability of 56 and 84 mg of intranasal esketamine is 54 and 51%, respectively. Esketamine volume at steady state and clearance were 752 L and 114 L/h, respectively. Noresketamine volume at steady state and apparent clearance were 185 L and 38 L/h, respectively. Relative to non-Asian subjects, Asian subjects showed a 64.0 and 19.4% decrease in the esketamine elimination rate constant and noresketamine apparent clearance, respectively. Japanese subjects exhibited a 34% increase in FRn vs other races. Hepatic blood flow decreased by 21.9 L/h for each decade in age in subjects aged > 60 years. These changes resulted in esketamine and noresketamine maximum concentration and area under the concentration-time curve after 24 h post-dose values that were up to 36% higher than those observed in other races or in younger adult subjects.

Conclusions: Esketamine and noresketamine pharmacokinetics was successfully characterized in healthy subjects and patients with treatment-resistant depression. The model quantified esketamine absolute nasal and oral bioavailability, its hepatic flow-limited clearance and biotransformation to the major metabolite noresketamine, and the influence of intrinsic and extrinsic factors on esketamine pharmacokinetics. Clinical trials registration numbers of the studies included in the analysis: ESKETINTRD1001 (NCT01780259), ESKETINTRD1002 (NCT01980303), ESKETINTRD1003 (NCT02129088), ESKETINTRD1008 (NCT02846519), ESKETINTRD1009 (NCT02343289), ESKETINTRD1010 (NCT02568176), ESKETINTRD1012 (NCT02345148), 54135419TRD1015 (NCT02682225), ESKETINTRD2003 (NCT01998958), ESKETINSUI2001 (NCT02133001), ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), and ESKETINTRD3005 (NCT02422186).

Perez-Ruixo, C., Rossenu, S., Zannikos, P., Nandy, P., Singh, J., Drevets, W. C., & Perez-Ruixo, J. J. (2021). Population Pharmacokinetics of Esketamine Nasal Spray and its Metabolite Noresketamine in Healthy Subjects and Patients with Treatment-Resistant Depression. Clinical pharmacokinetics, 60(4), 501–516. https://doi.org/10.1007/s40262-020-00953-4

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Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression

December 2, 2021 / Depression, Ketamine, Papers, Psychiatry, Safety / Leave a Comment / By / , , ,

Abstract

Introduction: Ketamine exhibits antidepressant properties in treatment-resistant depression (TRD) with some concern over its cardiovascular safety and tolerability issues. This paper reports on the cardiovascular safety in short-term intravenous ketamine treatment in TRD inpatients with major depressive disorder (MDD) and bipolar disorder (BP).

Materials and methods: The observational study population comprises 35 MDD and 14 BP subjects treated with intravenous ketamine.

Results: Blood pressure (RR) and heart rate (HR) values returned to baseline within 1.5-hours post infusion with no sequelae for all study subjects. Six time points were analyzed for each infusion: 0′, 15′, 30′, 45′, 60′ and 90′ for RR and HR. After the infusion significant peaks in systolic (p = 0.004) and diastolic (p = 0.038) RR were seen. In concomitant medication with selective serotonin reuptake inhibitors (SSRIs), higher RR peaks (p = 0.020; p = 0.048) were seen as compared to other subjects. The decrease in HR was greater (p = 0.02) in the absence of concomitant medication with mood stabilizers as compared to subjects receiving mood stabilizing medication accompanied by the observation of a greater decrease in diastolic RR among those taking mood stabilizers (p = 0.009).

Limitations: The study may be underpowered due to the small sample size. The observations apply to an inhomogeneous TRD population in a single-site, pilot study, with no blinding and are limited to the acute administration.

Conclusion: The study demonstrates good safety and tolerability profile of intravenous ketamine as add-on intervention to current psychotropic medication in TRD, regardless of the MDD or BP type of mood disorders. The abatement of elevated RR and BP scores was observed in time with no sequelae nor harm. Still, cardiovascular risks appear to be more pronounced in subjects with comorbid arterial hypertension and diabetes mellitus.

Szarmach, J., Cubała, W. J., Włodarczyk, A., & Gałuszko-Węgielnik, M. (2020). Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression. Neuropsychiatric disease and treatment, 16, 2539–2551. https://doi.org/10.2147/NDT.S273287

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Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial

December 2, 2021 / Ayahuasca, Depression, DMT, Papers, Psychiatry, Psychology / Leave a Comment / By / , , , , , ,

Abstract

Rationale: Suicidality is a major public health concern with limited treatment options. Accordingly, there is a need for innovative interventions for suicidality. Preliminary evidence indicates that treatment with the psychedelic ayahuasca may lead to decreases in depressive symptoms among individuals with major depressive disorder (MDD). However, there remains limited understanding of whether ayahuasca also leads to reductions in suicidality.

Objective: To examine the acute and post-acute effect of ayahuasca on suicidality among individuals with MDD.

Methods: We conducted a secondary analysis of an open-label trial in which individuals with recurrent MDD received a single dose of ayahuasca (N = 17). Suicidality was assessed at baseline; during the intervention; and 1, 7, 14, and 21 days after the intervention.

Results: Among individuals with suicidality at baseline (n = 15), there were significant acute (i.e., 40, 80, 140, and 180 min after administration) and post-acute (1, 7, 14, and 21 days after administration) decreases in suicidality following administration of ayahuasca. Post-acute effect sizes for decreases in suicidality were large (Hedges’ g = 1.31-1.75), with the largest effect size 21 days after the intervention (g = 1.75).

Conclusions: When administered in the appropriate context, ayahuasca may lead to rapid and sustained reductions in suicidality among individuals with MDD. Randomized, double-blind studies with larger sample sizes are needed to confirm this early finding.

Zeifman, R. J., Singhal, N., Dos Santos, R. G., Sanches, R. F., de Lima Osório, F., Hallak, J., & Weissman, C. R. (2021). Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial. Psychopharmacology, 238(2), 453–459. https://doi.org/10.1007/s00213-020-05692-9

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Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support

November 30, 2021 / Depression, Ketamine, Papers, Psychiatry / Leave a Comment / By / , , , , , , , , , ,

Abstract

Background: The glutamatergic modulator ketamine has been shown to result in rapid reductions in both suicidal ideation (SI) and depressive symptoms in clinical trials. There is a practical need for identification of pre-treatment predictors of ketamine response. Previous studies indicate links between treatment response and body mass index (BMI), depression symptoms and previous suicide attempts. Our aim was to explore the use of clinical and demographic factors to predict response to serial doses of oral ketamine for chronic suicidal ideation.

Methods: Thirty-two participants completed the Oral Ketamine Trial on Suicidality (OKTOS). Data for the current study were drawn from pre-treatment and follow-up time-points of OKTOS. Only clinical and sociodemographic variables were included in this analysis. Data were used to create a proof of concept Bayesian network (BN) model of variables predicting prolonged response to oral ketamine, as defined by the Beck Scale for Suicide Ideation (BSS).

Results: The network of potential predictors of response was evaluated using receiver operating characteristic (ROC) curve analyses. A combination of nine demographic and clinical variables predicted prolonged ketamine response, with strong contributions from BMI, Social and Occupational Functioning Assessment Scale (SOFAS), Montgomery-Asberg Depression Rating Scale (MADRS), number of suicide attempts, employment status and age. We evaluated and optimised the proposed network to increase the area under the ROC curve (AUC). The performance evaluation demonstrated that the BN predicted prolonged ketamine response with 97% accuracy, and AUC = 0.87.

Conclusions: At present, validated tools to facilitate risk assessment are infrequently used in psychiatric practice. Pre-treatment assessment of individuals’ likelihood of response to oral ketamine for chronic suicidal ideation could be beneficial in making more informed decisions about likelihood of success for this treatment course. Clinical trials registration number ACTRN12618001412224, retrospectively registered 23/8/2018.

Beaudequin, D., Can, A. T., Dutton, M., Jones, M., Gallay, C., Schwenn, P., Yang, C., Forsyth, G., Simcock, G., Hermens, D. F., & Lagopoulos, J. (2020). Predicting therapeutic response to oral ketamine for chronic suicidal ideation: a Bayesian network for clinical decision support. BMC psychiatry, 20(1), 519. https://doi.org/10.1186/s12888-020-02925-1

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Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N, N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact

November 30, 2021 / Ayahuasca, DMT, Papers, Psychiatry, Psychology, Psychopharmacology, Toxicology / Leave a Comment / By / , , , ,

Abstract

Ayahuasca is a hallucinogenic botanical beverage originally used by indigenous Amazonian tribes in religious ceremonies and therapeutic practices. While ethnobotanical surveys still indicate its spiritual and medicinal uses, consumption of ayahuasca has been progressively related with a recreational purpose, particularly in Western societies. The ayahuasca aqueous concoction is typically prepared from the leaves of the N,N-dimethyltryptamine (DMT)-containing Psychotria viridis, and the stem and bark of Banisteriopsis caapi, the plant source of harmala alkaloids. Herein, the toxicokinetics and toxicodynamics of the psychoactive DMT and harmala alkaloids harmine, harmaline and tetrahydroharmine, are comprehensively covered, particularly emphasizing the psychological, physiological, and toxic effects deriving from their concomitant intake. Potential therapeutic utility, particularly in mental and psychiatric disorders, and forensic aspects of DMT and ayahuasca are also reviewed and discussed. Following administration of ayahuasca, DMT is rapidly absorbed and distributed. Harmala alkaloids act as potent inhibitors of monoamine oxidase A (MAO-A), preventing extensive first-pass degradation of DMT into 3-indole-acetic acid (3-IAA), and enabling sufficient amounts of DMT to reach the brain. DMT has affinity for a variety of serotonergic and non-serotonergic receptors, though its psychotropic effects are mainly related with the activation of serotonin receptors type 2A (5-HT2A). Mildly to rarely severe psychedelic adverse effects are reported for ayahuasca or its alkaloids individually, but abuse does not lead to dependence or tolerance. For a long time, the evidence has pointed to potential psychotherapeutic benefits in the treatment of depression, anxiety, and substance abuse disorders; and although misuse of ayahuasca has been diverting attention away from such clinical potential, research onto its therapeutic effects has now strongly resurged.

Brito-da-Costa, A. M., Dias-da-Silva, D., Gomes, N., Dinis-Oliveira, R. J., & Madureira-Carvalho, Á. (2020). Toxicokinetics and Toxicodynamics of Ayahuasca Alkaloids N,N-Dimethyltryptamine (DMT), Harmine, Harmaline and Tetrahydroharmine: Clinical and Forensic Impact. Pharmaceuticals (Basel, Switzerland), 13(11), 334. https://doi.org/10.3390/ph13110334

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A mechanistic model of the neural entropy increase elicited by psychedelic drugs

November 26, 2021 / Neuroscience, Papers, Psychopharmacology / Leave a Comment / By / , , , , , ,

Abstract

Psychedelic drugs, including lysergic acid diethylamide and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, mediating both acute alterations in consciousness and long-term effects. However, no clear mechanistic explanation for this entropy increase has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in some regions and decreased in others, suggesting a topographical reconfiguration mediated by 5HT2A-R activation. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain’s anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.

Herzog, R., Mediano, P., Rosas, F. E., Carhart-Harris, R., Perl, Y. S., Tagliazucchi, E., & Cofre, R. (2020). A mechanistic model of the neural entropy increase elicited by psychedelic drugs. Scientific reports, 10(1), 17725. https://doi.org/10.1038/s41598-020-74060-6

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