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Consciousness, Religion, and Gurus: Pitfalls of Psychedelic Medicine

March 14, 2022 / Papers / 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 / Depressive Disorders, Ketamine, Papers / 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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Subanesthetic dose of ketamine for the antidepressant effects and the associated cognitive impairments of electroconvulsive therapy in elderly patients-A randomized, double-blind, controlled clinical study

January 21, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , ,

Abstract

Objectives: We previously confirmed that low-dose ketamine, as an adjunctive anesthetic for electroconvulsive therapy (ECT) in adult patients with depression, accelerates the effects of ECT and reduces the ECT-induced learning and memory deficits. This study explored the efficacy and safety of low-dose ketamine in elderly patients with depression.

Methods: Elderly patients with depression (N = 157) were randomly divided into two groups: propofol anesthesia group (group P) and propofol combined with ketamine anesthesia group (group KP). Patients in group KP were given low-dose ketamine (0.3 mg/kg) for each ECT treatment; patients in group P were given the same amount of normal saline. Depressive symptoms and global cognitive functions were assessed using the 24-item Hamilton Depression Rating Scale and Mini-Mental State Examination, respectively, at baseline, 1 day after the 1st, 2nd, 4th, and 6th ECT sessions, and 1 day after the end of the ECT course. ECT effects of and complications were recorded.

Results: In total, 67 patients in group KP and 70 in group P completed the study. After the ECT, the response and remission rates were 82.09% and 73.13%, respectively, in group KP, and 81.43% and 68.57%, respectively, in group P; there was no statistical difference between groups. However, the incidence of cognitive function impairment was lower in group KP (10.4%) than in group P (25.7%), while different electrical dose and seizure duration were required during the course of treatment between the two groups. There was no difference in the complications of ECT between groups.

Conclusions: Low-dose ketamine is safe as an adjunct anesthetic for elderly patients subjected to ECT. It has a protective effect on cognitive function and may accelerate the antidepressant effects of ECT.

Zou, L., Min, S., Chen, Q., Li, X., & Ren, L. (2021). Subanesthetic dose of ketamine for the antidepressant effects and the associated cognitive impairments of electroconvulsive therapy in elderly patients-A randomized, double-blind, controlled clinical study. Brain and behavior, 11(1), e01775. https://doi.org/10.1002/brb3.1775

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Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression

January 27, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , ,

Abstract

Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.

Słupski, J., Cubała, W. J., Górska, N., Słupska, A., & Gałuszko-Węgielnik, M. (2020). Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression. Brain sciences, 10(12), 971. https://doi.org/10.3390/brainsci10120971

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The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects

March 14, 2022 / Papers / Leave a Comment / By /

Abstract

Psychedelics represent one of the most promising classes of experimental medicines for the treatment of neuropsychiatric disorders due to their ability to promote neural plasticity and produce both rapid and sustained therapeutic effects following a single administration. Conventional wisdom holds that peak mystical experiences induced by psychedelics are a critical component of their therapeutic mechanisms of action, though evidence supporting that claim is largely correlational. Here, I present data suggesting that the subjective effects induced by psychedelics may not be necessary to produce long-lasting changes in mood and behavior. Understanding the role of subjective effects in the therapeutic mechanisms of psychedelics will have important implications for both basic neuroscience and for increasing patient access to the next generation of medicines developed as a result of psychedelic research.

Olson D. E. (2020). The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects. ACS pharmacology & translational science, 4(2), 563–567. https://doi.org/10.1021/acsptsci.0c00192

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Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder

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

Abstract

Alcohol use disorder (AUD) is the most prevalent substance use disorder and causes a significant global burden. Relapse rates remain incredibly high after decades of attempting to develop novel treatment options that have failed to produce increased rates of sobriety. Ketamine has emerged as a potential treatment for AUD following its success as a therapeutic agent for depression, demonstrated by several preclinical studies showing that acute administration reduced alcohol intake in rodents. As such, ketamine’s therapeutic effects for AUD are now being investigated in clinical trials with the hope of it being efficacious in prolonging sobriety from alcohol in humans (ClinicalTrials.gov, Identifier: NCT01558063). Importantly, ketamine’s antidepressant effects only last for about 1-week and because AUD is a lifelong disorder, repeated treatment regimens would be necessary to maintain sobriety. This raises questions regarding its safety for AUD treatment since ketamine itself has the potential for addiction. Therefore, this review aims to summarize the neuroadaptations related to alcohol’s addictive properties as well as ketamine’s therapeutic and addictive properties. To do this, the focus will be on reward-related brain regions such as the nucleus accumbens (NAc), dorsal striatum, prefrontal cortex (PFC), hippocampus, and ventral tegmental area (VTA) to understand how acute vs. chronic exposure will alter reward signaling over time. Additionally, evidence from these studies will be summarized in both male and female subjects. Accordingly, this review aims to address the safety of repeated ketamine infusions for the treatment of AUD. Although more work about the safety of ketamine to treat AUD is warranted, we hope this review sheds light on some answers about the safety of repeated ketamine infusions.

Strong, C. E., & Kabbaj, M. (2020). Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder. Frontiers in behavioral neuroscience, 14, 593860. https://doi.org/10.3389/fnbeh.2020.593860

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Effectiveness of intravenous ketamine in mood disorder patients with a history of neurostimulation

January 21, 2022 / Depressive Disorders, Ketamine, Papers / Leave a Comment / By / , , , , , , , , , , , , , , ,

Abstract

Background: Patients unsuccessfully treated by neurostimulation may represent a highly intractable subgroup of depression. While the efficacy of intravenous (IV) ketamine has been established in patients with treatment-resistant depression (TRD), there is an interest to evaluate its effectiveness in a subpopulation with a history of neurostimulation.

Methods: This retrospective, posthoc analysis compared the effects of four infusions of IV ketamine in 135 (x̄ = 44 ± 15.4 years of age) neurostimulation-naïve patients to 103 (x̄ = 47 ± 13.9 years of age) patients with a history of neurostimulation. The primary outcome evaluated changes in depression severity, measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16). Secondary outcomes evaluated suicidal ideation (SI), anxiety severity, measured by the Generalized Anxiety Disorder 7-Item (GAD-7), and consummatory anhedonia, measured by the Snaith-Hamilton Pleasure Scale (SHAPS).

Results: Following four infusions, both cohorts reported a significant reduction in QIDS-SR16 Total Score (F (4, 648) = 73.4, P < .001), SI (F (4, 642) = 28.6, P < .001), GAD-7 (F (2, 265) = 53.8, P < .001), and SHAPS (F (2, 302) = 45.9, P < .001). No between-group differences emerged. Overall, the neurostimulation-naïve group had a mean reduction in QIDS-SR16 Total Score of 6.4 (standard deviation [SD] = 5.3), whereas the history of neurostimulation patients reported a 4.3 (SD = 5.3) point reduction.

Conclusion: IV ketamine was effective in reducing symptoms of depression, SI, anxiety, and anhedonia in both cohorts in this large, well-characterized community-based sample of adults with TRD.

Rodrigues, N. B., Siegel, A., Lipsitz, O., Cha, D. S., Gill, H., Nasri, F., Simonson, K., Shekotikhina, M., Lee, Y., Subramaniapillai, M., Kratiuk, K., Lin, K., Ho, R., Mansur, R. B., McIntyre, R. S., & Rosenblat, J. D. (2020). Effectiveness of intravenous ketamine in mood disorder patients with a history of neurostimulation. CNS spectrums, 1–7. Advance online publication. https://doi.org/10.1017/S1092852920002187

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Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine

January 21, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , ,

Abstract

Acute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine’s effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.

Tarrés-Gatius, M., Miquel-Rio, L., Campa, L., Artigas, F., & Castañé, A. (2020). Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine. Translational psychiatry, 10(1), 427. https://doi.org/10.1038/s41398-020-01110-y

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Psilocybin-Assisted Group Therapy and Attachment: Observed Reduction in Attachment Anxiety and Influences of Attachment Insecurity on the Psilocybin Experience

March 16, 2022 / Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / , , ,

Abstract

Attachment insecurity is determined early in life, is a risk factor for psychopathology, and can be measured on two separate continuous dimensions: attachment anxiety and attachment avoidance. Therapeutic changes toward more secure attachment correlate with reduction in psychiatric symptoms. Psilocybin-assisted psychotherapy has demonstrated promise in the treatment of psychopathology, such as treatment-resistant depression and substance use disorders. We hypothesized that psilocybin-assisted psychotherapy would reduce attachment anxiety and attachment avoidance, thus increasing attachment security. We also hypothesized that baseline measures of attachment insecurity, which can reflect a diminished capacity for trust and exploration, would inform the quality of the psilocybin session. Participants were male long-term AIDS survivors with moderate-severe demoralization (n = 18). Using the Experiences in Close Relationships scale, we measured attachment insecurity at baseline as well as immediately, and 3 months, after completion of a brief group therapy course, which included a single midtreatment open-label psilocybin session conducted individually. Clinically important aspects of the psilocybin session were assessed using the revised Mystical Experience Questionnaire and the Challenging Experience Questionnaire the day following psilocybin administration. Self-reported ratings of attachment anxiety decreased significantly from baseline to 3-months post-intervention, t(16) = -2.2; p = 0.045; d rm = 0.45; 95% CI 0.01, 0.87. Attachment avoidance did not change significantly. Baseline attachment anxiety was strongly correlated with psilocybin-occasioned mystical-type experiences, r(15) = 0.53, p = 0.029, and baseline attachment avoidance was strongly correlated with psilocybin-related challenging experiences, r(16) = 0.62, p = 0.006. These findings have important implications for the general treatment of psychopathology as well as optimizing psilocybin-assisted psychotherapy as a broadly applicable treatment modality.

Stauffer, C. S., Anderson, B. T., Ortigo, K. M., & Woolley, J. (2020). Psilocybin-Assisted Group Therapy and Attachment: Observed Reduction in Attachment Anxiety and Influences of Attachment Insecurity on the Psilocybin Experience. ACS pharmacology & translational science, 4(2), 526–532. https://doi.org/10.1021/acsptsci.0c00169

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