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Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

January 27, 2022 / Neuroscience, Other substances, Papers, Psychopharmacology / 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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Set and Setting: A Randomized Study of Different Musical Genres in Supporting Psychedelic Therapy

March 16, 2022 / Other disciplines, Papers, Psychotherapy, Substance Use Disorder / Leave a Comment / By / , ,

Abstract

Mounting evidence supports the serotonin 2A receptor agonist psilocybin as a psychiatric pharmacotherapy. Little research has experimentally examined how session “set and setting” impacts subjective and therapeutic effects. We analyzed the effects of the musical genre played during sessions of a psilocybin study for tobacco smoking cessation. Participants (N = 10) received psilocybin (20-30 mg/70 kg) in two sessions, each with a different musical genre (Western classical versus overtone-based), with the order counterbalanced. Participants chose one genre for a third session (30 mg/70 kg). Mystical experiences scores tended to be higher in overtone-based sessions than in Western classical sessions. Six of ten participants chose the overtone-based music for a third session. Biologically confirmed smoking abstinence was similar based on musical choice, with a slight benefit for participants choosing the overtone-based playlist (66.7% versus 50%). These data call into question whether Western classical music typically used in psychedelic therapy holds a unique benefit. Broadly, we call for experimentally examining session components toward optimizing psychedelic therapeutic protocols.

Strickland, J. C., Garcia-Romeu, A., & Johnson, M. W. (2020). Set and Setting: A Randomized Study of Different Musical Genres in Supporting Psychedelic Therapy. ACS pharmacology & translational science, 4(2), 472–478. https://doi.org/10.1021/acsptsci.0c00187

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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, Other subjects, Other substances, 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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How psychedelic researchers’ self-admitted substance use and their association with psychedelic culture affect people’s perceptions of their scientific integrity and the quality of their research

February 6, 2022 / Other disciplines, Other subjects, Other substances, Papers / Leave a Comment / By / ,

Abstract

Across three studies (total N = 952), we tested how self-admitted use of psychedelics and association with psychedelic culture affects the public’s evaluation of researchers’ scientific integrity and of the quality of their research. In Studies 1 and 2, we found that self-admitted substance use negatively affected people’s assessment of a fictitious researcher’s integrity (i.e. being unbiased, professional, and honest), but not of the quality of his research, or how much value and significance they ascribed to the findings. Study 3, however, found that an association with psychedelic culture (i.e. presenting work at a scientific conference that includes social activities stereotypically associated with psychedelic culture) negatively affected perceived research quality (e.g. less valid, true, unbiased). We further found that the latter effect was moderated by participants’ personal experience with psychedelic substances: only participants without such experience evaluated research quality more negatively when it was presented in a stereotyped context.

Forstmann, M., & Sagioglou, C. (2021). How psychedelic researchers’ self-admitted substance use and their association with psychedelic culture affect people’s perceptions of their scientific integrity and the quality of their research. Public understanding of science (Bristol, England), 30(3), 302–318. https://doi.org/10.1177/0963662520981728

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Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression

February 6, 2022 / Depression, Ketamine, Papers, Safety / Leave a Comment / By / , , ,

Abstract

Ketamine’s pharmacological profile makes it an interesting and useful drug to challenge treatment-resistant-depression (TRD). Emerging adverse events associated with single-slow-sub-anaesthetic doses for the treatment of depression are common, although generally transient and self-limited. Nevertheless, data on the safety of this practice are scarce. Thus, it seems timely before ketamine is used for clinical treatment of depression to recommend careful monitoring and reporting of all potential adverse events related to ketamine administration. Here, we describe a case of apnea during slow sub-anaesthetic infusion of intravenous ketamine for the treatment of resistant depression. As far as we are concerned, this is an uncommon, previously unreported, and potentially severe adverse event that clinicians should be aware of, and specific management measures should be implemented.

Gómez-Revuelta, M., Fernández-Rodríguez, M., Boada-Antón, L., & Vázquez-Bourgon, J. (2020). Apnea during slow sub-anaesthetic infusion of intravenous ketamine for treatment-resistant depression. Therapeutic advances in psychopharmacology, 10, 2045125320981498. https://doi.org/10.1177/2045125320981498

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

February 6, 2022 / Ketamine, Neuroscience, Other substances, 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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A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis

February 6, 2022 / Anxiety disorders / PTSD, MDMA, Papers, Psychiatry, Psychotherapy / Leave a Comment / By / , , , , , ,

Abstract

Rationale: Novel, evidence-based treatments are required for treatment-resistant post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine (MDMA) has beneficially augmented psychotherapy in several small clinical trials.

Objective: To review the use of MDMA-assisted psychotherapy in treatment-resistant PTSD.

Methods: Systematic searches of four databases were conducted from inception to February 2020. A meta-analysis was performed on trials which were double-blinded, randomised, and compared MDMA-assisted psychotherapy to psychotherapy and placebo. The primary outcomes were the differences in Clinician Administered PTSD Scale (CAPS-IV) score and Beck’s Depression Inventory (BDI). Secondary outcome measures included neurocognitive and physical adverse effects, at the time, and within 7 days of intervention.

Results: Four randomised controlled trials (RCTs) met inclusion criteria. When compared to active placebo, intervention groups taking 75 mg (MD -46.90; 95% (confidence intervals) CI -58.78, -35.02), 125 mg (MD -20.98; 95% CI -34.35, -7.61) but not 100 mg (MD -12.90; 95% CI -36.09, 10.29) of MDMA with psychotherapy, had significant decreases in CAPS-IV scores, as did the inactive placebo arm (MD -33.20; 95% CI -40.53, -25.87). A significant decrease in BDI when compared to active placebo (MD -10.80; 95% CI -20.39, -1.21) was only observed at 75 mg. Compared to placebo, participants reported significantly more episodes of low mood, nausea and jaw-clenching during sessions and lack of appetite after 7 days.

Conclusion: These results demonstrate potential therapeutic benefit with minimal physical and neurocognitive risk for the use of MDMA-assisted psychotherapy in TR-PTSD, despite little effect on Beck’s Depression Inventory. Better powered RCTs are required to investigate further.

Illingworth, B. J., Lewis, D. J., Lambarth, A. T., Stocking, K., Duffy, J. M., Jelen, L. A., & Rucker, J. J. (2021). A comparison of MDMA-assisted psychotherapy to non-assisted psychotherapy in treatment-resistant PTSD: A systematic review and meta-analysis. Journal of psychopharmacology (Oxford, England), 35(5), 501–511. https://doi.org/10.1177/0269881120965915

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Consciousness, Religion, and Gurus: Pitfalls of Psychedelic Medicine

March 14, 2022 / Other subjects, Papers, Psychotherapy / Leave a Comment / By /

Abstract

This viewpoint identifies pitfalls in the study of psychedelic compounds, including those that pose challenges for the potential use of psychedelics as medicines. They are as follows: (1) Sloppiness regarding use of the term “consciousness”. (2) Inappropriate introduction of religious/spiritual beliefs of investigators or clinicians. (3) Clinical boundaries and other ethical challenges associated with psychedelic treatments.

Johnson M. W. (2020). Consciousness, Religion, and Gurus: Pitfalls of Psychedelic Medicine. ACS pharmacology & translational science, 4(2), 578–581. https://doi.org/10.1021/acsptsci.0c00198

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Ketamine as an adjunctive therapy for major depression – a randomised controlled pragmatic pilot trial (Karma-Dep Trial)

January 27, 2022 / Depression, Ketamine, Papers, Psychiatry / Leave a Comment / By / , , , , ,

Abstract

Background: Depression is a common psychiatric disorder that has become the leading cause of disability worldwide. The standard medical care for depression over the past 50 years has focused on monoamine neurotransmitters. These treatments can take weeks to take effect, highlighting the need for novel treatment strategies. One such approach may be ketamine. Ketamine acts as an antagonist of the N-methyl-D-asparate receptor and thus targets the excitatory amino acid neurotransmitter glutamate. Interestingly, at sub-anaesthetic doses, a single infusion of ketamine can elicit a rapid, though transient, antidepressant response. Methods: The aim of this study was to conduct a pragmatic randomised controlled pilot trial of four once-weekly ketamine infusions as an adjunctive therapy for depression. The main objective was to assess trial procedures to inform a future definitive trial. The primary clinical outcome was the 24-item Hamilton Rating Scale for Depression (HRSD-24). Trial participants were patients admitted to St Patrick’s Mental Health Services for treatment of a depressive episode. They underwent usual inpatient care as prescribed by their treating team. Consented participants were randomly allocated to a four-week course of either once-weekly ketamine (0.5mg/kg) or midazolam (0.045mg/kg) infusions given over 40 minutes and with 12 weeks follow-up. Results: In total, 1581 admissions to St Patrick’s Hospital were assessed for eligibility over nine months, with 125 (8%) meeting criteria, with 25 (20%) providing consent. In total, 13 were randomly assigned to the ketamine arm and 12 to the midazolam arm. There were no major differences in HRSD-24 scores between the two groups. The infusions were generally safe and well tolerated. Conclusions: This is the first pragmatic pilot trial of adjunctive serial ketamine infusions for hospitalised depression, an important possible use of ketamine. This study suggests that a definitive trial of adjunctive ketamine is feasible. Trial registration: ClinicalTrials.gov NCT03256162 21/08/2017; EudraCT 2016-004764-18 30/11/2016.

Gallagher, B., Foley, M., Slattery, C. M., Gusciute, G., Shanahan, E., & McLoughlin, D. M. (2020). Ketamine as an adjunctive therapy for major depression – a randomised controlled pragmatic pilot trial (Karma-Dep Trial). HRB open research, 3, 90. https://doi.org/10.12688/hrbopenres.13182.1

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Neural network models for DMT-induced visual hallucinations

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

Abstract

The regulatory role of the serotonergic system on conscious perception can be investigated perturbatorily with psychedelic drugs such as N,N-Dimethyltryptamine. There is increasing evidence that the serotonergic system gates prior (endogenous) and sensory (exogenous) information in the construction of a conscious experience. Using two generative deep neural networks as examples, we discuss how such models have the potential to be, firstly, an important medium to illustrate phenomenological visual effects of psychedelics-besides paintings, verbal reports and psychometric testing-and, secondly, their utility to conceptualize biological mechanisms of gating the influence of exogenous and endogenous information on visual perception.

Schartner, M. M., & Timmermann, C. (2020). Neural network models for DMT-induced visual hallucinations. Neuroscience of consciousness, 2020(1), niaa024. https://doi.org/10.1093/nc/niaa024

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