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Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

March 14, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , , , , , , ,

Abstract

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.

Siegel, J. S., Palanca, B., Ances, B. M., Kharasch, E. D., Schweiger, J. A., Yingling, M. D., Snyder, A. Z., Nicol, G. E., Lenze, E. J., & Farber, N. B. (2021). Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacology, 238(4), 1157–1169. https://doi.org/10.1007/s00213-021-05762-6

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Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants

January 7, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , , , ,

Abstract

Background: The glutamatergic modulator ketamine has created a blueprint for studying novel pharmaceuticals in the field. Recent studies suggest that “classic” serotonergic psychedelics (SPs) may also have antidepressant efficacy. Both ketamine and SPs appear to produce rapid, sustained antidepressant effects after a transient psychoactive period.

Methods: This review summarizes areas of overlap between SP and ketamine research and considers the possibility of a common, downstream mechanism of action. The therapeutic relevance of the psychoactive state, overlapping cellular and molecular effects, and overlapping electrophysiological and neuroimaging observations are all reviewed.

Results: Taken together, the evidence suggests a potentially shared mechanism wherein both ketamine and SPs may engender rapid neuroplastic effects in a glutamatergic activity-dependent manner. It is postulated that, though distinct, both ketamine and SPs appear to produce acute alterations in cortical network activity that may initially produce psychoactive effects and later produce milder, sustained changes in network efficiency associated with therapeutic response. However, despite some commonalities between the psychoactive component of these pharmacologically distinct therapies-such as engagement of the downstream glutamatergic pathway-the connection between psychoactive impact and antidepressant efficacy remains unclear and requires more rigorous research.

Conclusions: Rapid-acting antidepressants currently under investigation may share some downstream pharmacological effects, suggesting that their antidepressant effects may come about via related mechanisms. Given the prototypic nature of ketamine research and recent progress in this area, this platform could be used to investigate entirely new classes of antidepressants with rapid and robust actions.

Kadriu, B., Greenwald, M., Henter, I. D., Gilbert, J. R., Kraus, C., Park, L. T., & Zarate, C. A. (2021). Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants. The international journal of neuropsychopharmacology, 24(1), 8–21. https://doi.org/10.1093/ijnp/pyaa087

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A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT 2A Receptor Density in the Pig Brain

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

Abstract

A single dose of psilocybin, a psychedelic and serotonin 2A receptor (5-HT2AR) agonist, may be associated with antidepressant effects. The mechanism behind its antidepressive action is unknown but could be linked to increased synaptogenesis and down-regulation of cerebral 5-HT2AR. Here, we investigate if a single psychedelic dose of psilocybin changes synaptic vesicle protein 2A (SV2A) and 5-HT2AR density in the pig brain. Twenty-four awake pigs received either 0.08 mg/kg psilocybin or saline intravenously. Twelve pigs (n = 6/intervention) were euthanized one day post-injection, while the remaining twelve pigs were euthanized seven days post-injection (n = 6/intervention). We performed autoradiography on hippocampus and prefrontal cortex (PFC) sections with [3H]UCB-J (SV2A), [3H]MDL100907 (5-HT2AR antagonist) and [3H]Cimbi-36 (5-HT2AR agonist). One day post psilocybin injection, we observed 4.42% higher hippocampal SV2A density and lowered hippocampal and PFC 5-HT2AR density (-15.21% to -50.19%). These differences were statistically significant in the hippocampus for all radioligands and in the PFC for [3H]Cimbi-36 only. Seven days post-intervention, there was still significantly higher SV2A density in the hippocampus (+9.24%) and the PFC (+6.10%), whereas there were no longer any differences in 5-HT2AR density. Our findings suggest that psilocybin causes increased persistent synaptogenesis and an acute decrease in 5-HT2AR density, which may play a role in psilocybin’s antidepressive effects.

Raval, N. R., Johansen, A., Donovan, L. L., Ros, N. F., Ozenne, B., Hansen, H. D., & Knudsen, G. M. (2021). A Single Dose of Psilocybin Increases Synaptic Density and Decreases 5-HT2A Receptor Density in the Pig Brain. International journal of molecular sciences, 22(2), 835. https://doi.org/10.3390/ijms22020835

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Development of the Psychological Insight Questionnaire among a sample of people who have consumed psilocybin or LSD

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

Abstract

Background: Several measures have been developed to examine acute psychedelic effects (e.g. mystical-type and challenging experiences), but no measure assesses acute psychologically insightful experiences that may occur during psychedelic experiences.

Aim: The purpose of this study was to develop and examine the psychometric properties of the Psychological Insight Questionnaire.

Method: A cross-sectional survey study among psilocybin and LSD users. Respondents (n=1661; Mage=22.9, standard deviation=8.5; Caucasian/White=83%; non-Hispanic=91%; men=72%; United States resident=66%) completed an Internet-based survey.

Results: The Psychological Insight Questionnaire consists of 23 items with two subscales: (a) Avoidance and Maladaptive Patterns Insights and (b) Goals and Adaptive Patterns Insights. Construct validity of the Psychological Insight Questionnaire was supported by strong correlations of the Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores with the insight subscale of the Session Impacts Scale, and weak-to-moderate correlations with the Mystical Experiences and Challenging Experiences Questionnaires. Furthermore, Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores were moderately-to-strongly correlated with retrospectively reported increases in psychological flexibility, and well-being/life satisfaction that were attributed to a memorable psychedelic experience. Lastly, incremental validity was established showing that the Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights subscale) scores predict unique variance in changes in psychological flexibility, and Psychological Insight Questionnaire (and Avoidance and Maladaptive Patterns Insights and Goals and Adaptive Patterns Insights subscales) scores predict changes in well-being and life satisfaction, beyond measures of acute mystical-type and challenging effects.

Conclusions: The Psychological Insight Questionnaire has the potential to extend the understanding of the acute and enduring effects of psychedelics. Further longitudinal research is necessary to determine the long-term predictive validity of the Psychological Insight Questionnaire and to examine the role of psychological insight in predicting therapeutic outcomes.

Davis, A. K., Barrett, F. S., So, S., Gukasyan, N., Swift, T. C., & Griffiths, R. R. (2021). Development of the Psychological Insight Questionnaire among a sample of people who have consumed psilocybin or LSD. Journal of psychopharmacology (Oxford, England), 35(4), 437–446. https://doi.org/10.1177/0269881120967878

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The acute effects of classic psychedelics on memory in humans

February 6, 2022 / Papers, Psychology / Leave a Comment / By /

Abstract

Rationale: Memory plays a central role in the psychedelic experience. The spontaneous recall and immersive reliving of autobiographical memories has frequently been noted by researchers and clinicians as a salient phenomenon in the profile of subjective effects of classic psychedelic drugs such as psilocybin, LSD, and ayahuasca. The ability for psychedelics to provoke vivid memories has been considered important to their clinical efficacy.

Objective: This review aims to examine and aggregate the findings from experimental, observational, and qualitative studies on the acute modulation of memory by classic psychedelics in humans.

Method: A literature search was conducted using PubMed and PsycInfo as well as manual review of references from eligible studies. Publications reporting quantitative and/or qualitative findings were included; animal studies and case reports were excluded.

Results: Classic psychedelics produce dose-dependently increasing impairments in memory task performance, such that low doses produce no impairment and higher doses produce increasing levels of impairment. This pattern has been observed in tasks assessing spatial and verbal working memory, semantic memory, and non-autobiographical episodic memory. Such impairments may be less pronounced among experienced psychedelic users. Classic psychedelics also increase the vividness of autobiographical memories and frequently stimulate the recall and/or re-experiencing of autobiographical memories, often memories that are affectively intense (positively or negatively valenced) and that had been avoided and/or forgotten prior to the experience.

Conclusions: Classic psychedelics dose-dependently impair memory task performance but may enhance autobiographical memory. These findings are relevant to the understanding of psychological mechanisms of action of psychedelic-assisted psychotherapy.

Healy C. J. (2021). The acute effects of classic psychedelics on memory in humans. Psychopharmacology, 238(3), 639–653. https://doi.org/10.1007/s00213-020-05756-w

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The acute effects of classic psychedelics on memory in humans

February 21, 2022 / Ayahuasca, LSD, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By /

Abstract

Rationale: Memory plays a central role in the psychedelic experience. The spontaneous recall and immersive reliving of autobiographical memories has frequently been noted by researchers and clinicians as a salient phenomenon in the profile of subjective effects of classic psychedelic drugs such as psilocybin, LSD, and ayahuasca. The ability for psychedelics to provoke vivid memories has been considered important to their clinical efficacy.

Objective: This review aims to examine and aggregate the findings from experimental, observational, and qualitative studies on the acute modulation of memory by classic psychedelics in humans.

Method: A literature search was conducted using PubMed and PsycInfo as well as manual review of references from eligible studies. Publications reporting quantitative and/or qualitative findings were included; animal studies and case reports were excluded.

Results: Classic psychedelics produce dose-dependently increasing impairments in memory task performance, such that low doses produce no impairment and higher doses produce increasing levels of impairment. This pattern has been observed in tasks assessing spatial and verbal working memory, semantic memory, and non-autobiographical episodic memory. Such impairments may be less pronounced among experienced psychedelic users. Classic psychedelics also increase the vividness of autobiographical memories and frequently stimulate the recall and/or re-experiencing of autobiographical memories, often memories that are affectively intense (positively or negatively valenced) and that had been avoided and/or forgotten prior to the experience.

Conclusions: Classic psychedelics dose-dependently impair memory task performance but may enhance autobiographical memory. These findings are relevant to the understanding of psychological mechanisms of action of psychedelic-assisted psychotherapy.

Healy C. J. (2021). The acute effects of classic psychedelics on memory in humans. Psychopharmacology, 238(3), 639–653. https://doi.org/10.1007/s00213-020-05756-w

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A Systematic Review of the MDMA Model to Address Social Impairment in Autism

February 6, 2022 / Autism Spectrum Disorder, MDMA, Papers, Psychology / Leave a Comment / By / , , , , ,

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by repetitive behaviours, cognitive rigidity/inflexibility, and social-affective impairment. Unfortunately, no gold-standard treatments exist to alleviate the core socio-behavioural impairments of ASD. Meanwhile, the prosocial empathogen/entactogen 3,4-methylene-dioxy-methamphetamine (MDMA) is known to enhance sociability and empathy in both humans and animal models of psychological disorders.

Objective: We review the evidence obtained from behavioural tests across the current literature, showing how MDMA can induce prosocial effects in animals and humans, where controlled experiments were able to be performed.

Methods: Six electronic databases were consulted. The search strategy was tailored to each database. Only English-language papers were reviewed. Behaviours not screened in this review may have affected the core ASD behaviours studied. Molecular analogues of MDMA have not been investigated.

Results: We find that the social impairments may potentially be alleviated by postnatal administration of MDMA producing prosocial behaviours in mostly the animal model.

Conclusion: MDMA and/or MDMA-like molecules appear to be an effective pharmacological treatment for the social impairments of autism, at least in animal models. Notably, clinical trials based on MDMA use are now in progress. Nevertheless, larger and more extended clinical studies are warranted to prove the assumption that MDMA and MDMA-like molecules have a role in the management of the social impairments of autism.

Chaliha, D., Mamo, J. C., Albrecht, M., Lam, V., Takechi, R., & Vaccarezza, M. (2021). A Systematic Review of the MDMA Model to Address Social Impairment in Autism. Current neuropharmacology, 19(7), 1101–1154. https://doi.org/10.2174/1570159X19666210101130258

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Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

January 27, 2022 / Neuroscience, Papers / Leave a Comment / By / , ,

Abstract

Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin-, brain-derived neurotrophic factor-, and early growth response-related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds. SIGNIFICANCE STATEMENT: Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.

Inserra, A., De Gregorio, D., & Gobbi, G. (2021). Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms. Pharmacological reviews, 73(1), 202–277. https://doi.org/10.1124/pharmrev.120.000056

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Investigating the role of 5-HT2A and 5-HT2C receptor activation in the effects of psilocybin, DOI, and citalopram on marble burying in mice

February 6, 2022 / Mushrooms / Psilocybin, Neuroscience, Papers / Leave a Comment / By / , ,

Abstract

Psychedelic drugs acting as 5-hydroxyptryptamine 2A receptor (5-HT2AR) agonists have shown promise as viable treatments of psychiatric disorders, including obsessive-compulsive disorder. The marble burying test is a test of compulsive-like behavior in mice, and psychedelics acting as 5-HT2AR agonists can reduce digging in this test. We assessed the 5-HT2R contribution to the mechanisms of two 5-HT2A agonists on digging behavior in female NMRI mice, using citalopram as a reference compound. While the 5-HT2AR antagonist M100907 blocked the effect of DOI and the 5-HT2CR antagonist SB242084 blocked the effect of citalopram, neither antagonist blocked the effect of psilocybin. This study confirms 5-HT2AR agonism as a mechanism for reduced compulsive-like digging in the MB test and suggests that 5-HT2A and 5-HT2CRs can work in parallel on this type of behavior. Our results with psilocybin suggest that a 5-HT2R-independent mechanism also contributes to the effect of psilocybin on repetitive digging behavior.

Odland, A. U., Kristensen, J. L., & Andreasen, J. T. (2021). Investigating the role of 5-HT2A and 5-HT2C receptor activation in the effects of psilocybin, DOI, and citalopram on marble burying in mice. Behavioural brain research, 401, 113093. https://doi.org/10.1016/j.bbr.2020.113093

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A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

February 6, 2022 / Ketamine, Neuroscience, Papers / Leave a Comment / By / , ,

Abstract

Pilot studies have hinted that serotonergic psychedelics such as psilocybin may relieve depression, and could possibly do so by promoting neural plasticity. Intriguingly, another psychotomimetic compound, ketamine, is a fast-acting antidepressant and induces synapse formation. The similarities in behavioral and neural effects have been puzzling because the compounds target distinct molecular receptors in the brain. In this opinion article, we develop a conceptual framework that suggests the actions of ketamine and serotonergic psychedelics may converge at the dendrites, to both enhance and suppress membrane excitability. We speculate that mismatches in the opposing actions on dendritic excitability may relate to these compounds’ cell-type and region selectivity, their moderate range of effects and toxicity, and their plasticity-promoting capacities.

Savalia, N. K., Shao, L. X., & Kwan, A. C. (2021). A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics. Trends in neurosciences, 44(4), 260–275. https://doi.org/10.1016/j.tins.2020.11.008

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