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Shannon entropy of brain functional complex networks under the influence of the psychedelic Ayahuasca

/ Ayahuasca, Neuroscience, Papers, Psychology, Publications / / , , , ,

Abstract

The entropic brain hypothesis holds that the key facts concerning psychedelics are partially explained in terms of increased entropy of the brain’s functional connectivity. Ayahuasca is a psychedelic beverage of Amazonian indigenous origin with legal status in Brazil in religious and scientific settings. In this context, we use tools and concepts from the theory of complex networks to analyze resting state fMRI data of the brains of human subjects under two distinct conditions: (i) under ordinary waking state and (ii) in an altered state of consciousness induced by ingestion of Ayahuasca. We report an increase in the Shannon entropy of the degree distribution of the networks subsequent to Ayahuasca ingestion. We also find increased local and decreased global network integration. Our results are broadly consistent with the entropic brain hypothesis. Finally, we discuss our findings in the context of descriptions of “mind-expansion” frequently seen in self-reports of users of psychedelic drugs.
Viol, A., Palhano-Fontes, F., Onias, H., de Araujo, D. B., & Viswanathan, G. M. (2016). Shannon entropy of brain functional complex networks under the influence of the psychedelic Ayahuasca. arXiv preprint arXiv:1611.00358. 10.1038/s41598-017-06854-0
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Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy prolong the therapeutic effects of single ketamine infusion on post-traumatic stress disorder and comorbid depression: a pilot randomized, placebo-controlled, crossover clinical trial

/ Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Papers, Psychology / / , , , , , ,

Abstract

Background and objectives: Trauma memories lay at the core in etiopathogenesis of post-traumatic stress disorder (PTSD). Using pharmacological and cognitive behavioral treatments that specifically target trauma memories can improve the outcome. Ketamine has been shown to rapidly improve symptoms in PTSD and comorbid depression, but unfortunately these effects are short-lived. Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy is a type of mindfulness based cognitive behavioral therapy that targets the trauma memories. TIMBER psychotherapy in combination with (R,S)-ketamine are increasingly used to treat PTSD and comorbid depression. This study aims to determine if the combination of (R,S)-ketamine chemotherapy and TIMBER psychotherapy would produce a positive synergistic response in patients with PTSD.
Design: This is a randomized, placebo-controlled, cross-over clinical study.
Methods: Because response to ketamine alone is short-lived, this study combined TIMBER with a single infusion of 0.5 mg/kg (R,S)-ketamine to sustain its therapeutic effects. Ten patients with chronic and refractory PTSD were randomly assigned to two groups (n = 5 each): TIMBER-K group patients received ketamine infusion in combination with 12 TIMBER sessions (3 sessions in the first week followed by 9 sessions conducted on a weekly basis) and TIMBER-P group patients received placebo (normal saline infusion) in combination with 12 TIMBER sessions. The patients in the TIMBER-P group were switched to those in the TIMBER-K group after they experienced a sustained relapse.
Outcome measures: PTSD Checklist (PCL), Clinician Administered PTSD Scale for DSM-IV (CAPS), the 17-item Hamilton Rating Scale for Depression (Ham-D-17, clinician rated), Beck Anxiety Inventory (BAI), and Montreal Cognitive Assessment (MoCA) at baseline and 8 hours after infusion were used to investigate if ketamine selectively affected trauma memories leaving the general memory intact. The mindfulness interventions in TIMBER were personalized based on subject’s scores on Assessment Scale for Mindfulness Interventions which was administered at baseline, and after 5 sessions and 9 sessions (completion) of TIMBER. In this study, scores on CAPS and PCL scales were the primary outcome measures.
Results: In the acute phase trial ( first 3 months after infusion), nine out of 10 subjects showed robust response in primary outcome measures (PCL and CAPS scores for PTSD) and in the secondary outcome measures (Ham-D-17 and Beck Anxiety Inventory for depression and anxiety respectively) with a sustained response of 31.78 ± 18.29 days. The TIMBER-K group had a more sustained response (33 ± 22.98 days) compared to the TIMBER-P group (25 ± 16.8 days, P = 0.545). After switch from TIMBER-P group to TIMBER-K, patients experienced significantly prolonged response (49 vs. 25 days, P = 0.028). There were no intolerable side effects or dropouts during the 18-month follow-up period.
Conclusion: TIMBER psychotherapy augmented with low dose (R,S)-ketamine prolongs the therapeutic effects of the later and may be a valuable treatment option for PTSD.
Pradhan, B. K., Wainer, I. W., Moaddel, R., Torjman, M. C., Goldberg, M., Sabia, M., … & Pumariega, A. J. (2017). Trauma Interventions using Mindfulness Based Extinction and Reconsolidation (TIMBER) psychotherapy prolong the therapeutic effects of single ketamine infusion on post-traumatic stress disorder and comorbid depression: a pilot randomized, placebo-controlled, crossover clinical trial. Asia Pacific Journal of Clinical Trials: Nervous System Diseases, 2(3), 80. 10.4103/2542-3932.211589
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Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges

/ Anxiety Disorders / PTSD, Depressive Disorders, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Substance Use Disorder / / , , , , ,

Abstract

Background Recently, scientific interest in the therapeutic potential of serotonergic and psilocybin hallucinogens (psychedelics) such as lysergic acid diethylamide (LSD) and entactogens like 3,4-methylendioxymethamphetamine (MDMA) within the framework of psychotherapy has resumed. The present article provides an overview on the current evidence on substance-assisted psychotherapy with these substances.
Method A selective search was carried out in the PubMed and Cochrane Library including studies investigating the clinical use of serotonergic psychoactive substances since 2000.
Results Studies were found investigating the following indications: alcohol (LSD and psilocybin) and tobacco addiction (psilocybin), anxiety and depression in patients suffering from life-threatening somatic illness (LSD and psilocybin), obsessive-compulsive disorder (OCD) (psilocybin), treatment-resistant major depression (psilocybin), and posttraumatic stress disorder (PTSD) (MDMA).
Discussion Substance use disorders, PTSD and anxiety and depression in patients suffering from life-threatening somatic illness belong to the indications with the best evidence for substance-assisted psychotherapy with serotonergic psychoactive agents. To date, studies indicate efficacy and relatively good tolerability. Further studies are needed to determine whether these substances may represent suitable and effective treatment options for some treatment-resistant psychiatric disorders in the future.
Majić, T., Jungaberle, H., Schmidt, T. T., Zeuch, A., Hermle, L., & Gallinat, J. (2017). Psychotherapy with Adjuvant use of Serotonergic Psychoactive Substances: Possibilities and Challenges. Fortschritte der Neurologie-Psychiatrie, 85(7), 383. 10.1055/s-0043-103085
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Oral Ketamine in Treatment-Resistant Depression: A Clinical Effectiveness Case Series

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / , , , ,

Abstract

PURPOSE:
The aim of the study was to assess the effectiveness, tolerability, and safety of oral ketamine as an antidepressant treatment in adults with treatment-resistant depression.
METHODS:
We reviewed retrospective data on 22 patients with treatment-resistant depression, who failed at least 3 adequate antidepressant treatment trials and 1 adequate trial of repetitive transcranial magnetic stimulation; subsequently, they received open-label treatment with oral ketamine, commenced at a dose of 50 mg every 3 days, titrated up by 25 mg every 3 days, according to response and tolerability. The primary outcome measure was the Beck Depression Inventory II, which was used to rate subjective mood improvement at baseline and then at each follow-up visit. Data about adverse effects related to ketamine and a self-harm risk assessment were also obtained.
FINDINGS:
Over the course of treatment, 18% of the patients showed greater than 50% reduction in the Beck Depression Inventory II scores, 14% reported partial improvement in mood symptoms, while 45% had no response to ketamine and 23% showed a mild worsening in their depressive symptoms. The most frequent adverse effects were acute dissociation, dizziness, blurred vision, numbness and sedation. Neither serious adverse effects, nor any cases of abuse or dependence were observed.
CONCLUSIONS:
Although this case series found oral ketamine to be safe and well tolerated, the findings also showed rather modest effectiveness of oral ketamine in treatment-resistant depression, with only approximately 30% reporting some benefit and approximately 70% reporting no change or worsening of mood. However, bearing in mind the limitations of this small, open-label case series, further exploration of the effectiveness of oral ketamine is warranted.
Al Shirawi, M. I., Kennedy, S. H., Ho, K. T., Byrne, R., & Downar, J. (2017). Oral Ketamine in Treatment-Resistant Depression: A Clinical Effectiveness Case Series. Journal of Clinical Psychopharmacology, 37(4), 464. 10.1097/JCP.0000000000000717
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A Systematic Review Of Research On N,N-Dimethyltryptamine

/ DMT, Neuroscience, Papers, Psychology / / ,

Abstract

Introduction: The effects of the endogenous hallucinogen N,N-dimethyltryptamine are poorly understood and its medical significance is widely unknown. A small number of  studies regarding its biochemical, pharmaceutical and physiological role have been conducted and the efficacy of its therapeutic potential is presently disregarded. How can scientists proceed in gaining insight into DMT and discovering possible medical uses of this substance?
Materials and Methods: Published articles from  1964 to the present year have been reviewed and the outcome of the studies summarized. The results of drug action,  therapeutic use and potential were investigated . Studies that appeared to have little medical purpose or those, which focus on the use of  Ayahuasca, a South American ritual drink containing N,N-dimethyltryptamine and a monoamine oxidase (MAO)  inhibitor of plant origin, have been excluded.
Results: The research conducted between 1964 and 1987 seems to be an approach to understanding general chemical and biochemical properties of the substance (e.g. metabolites, tolerance, distribution, toxicity, etc.). Rick Strassman, who conducted a broad study from 1990 till 1994 has initiated a recurring interest in the field of psychopharmacology towards DMT. Thus, in the following years, the research was focused on the therapeutic gain of N,N-dimethyltryptamine but resulted mostly inconclusively leading to suggestions of further research. The findings have shown contradictions of already established knowledge, especially for receptors like the sigma-1 receptor, the only direct agonist of which is found to be N,N-dimethyltryptamie.
Conclusion: The studies that now need to be conducted should analyze the correlations between psychiatric diseases (e.g. schizophrenia), purpose of the normal endogenous production and exact action, and the already suggested in various studies therapeutic importance. The low amount of knowledge about the drug action (in case of pharmaceutical use), its targets and drug effect should motivate researchers to gain more insight.
Hristova, D., & Zhelyazkova-Savova, M. (2017). A SYSTEMATIC REVIEW OF RESEARCH ON N, N-DIMETHYLTRYPTAMINE. Scripta Scientifica Vox Studentium, 1(1).
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Oral Ketamine in Treatment-Resistant Depression: A Clinical Effectiveness Case Series

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / , , , ,

Abstract

Purpose The aim of the study was to assess the effectiveness, tolerability, and safety of oral ketamine as an antidepressant treatment in adults with treatment-resistant depression.
Methods We reviewed retrospective data on 22 patients with treatment-resistant depression, who failed at least 3 adequate antidepressant treatment trials and 1 adequate trial of repetitive transcranial magnetic stimulation; subsequently, they received open-label treatment with oral ketamine, commenced at a dose of 50 mg every 3 days, titrated up by 25 mg every 3 days, according to response and tolerability. The primary outcome measure was the Beck Depression Inventory II, which was used to rate subjective mood improvement at baseline and then at each follow-up visit. Data about adverse effects related to ketamine and a self-harm risk assessment were also obtained.
Findings Over the course of treatment, 18% of the patients showed greater than 50% reduction in the Beck Depression Inventory II scores, 14% reported partial improvement in mood symptoms, while 45% had no response to ketamine and 23% showed a mild worsening in their depressive symptoms. The most frequent adverse effects were acute dissociation, dizziness, blurred vision, numbness and sedation. Neither serious adverse effects, nor any cases of abuse or dependence were observed.
Conclusions Although this case series found oral ketamine to be safe and well tolerated, the findings also showed rather modest effectiveness of oral ketamine in treatment-resistant depression, with only approximately 30% reporting some benefit and approximately 70% reporting no change or worsening of mood. However, bearing in mind the limitations of this small, open-label case series, further exploration of the effectiveness of oral ketamine is warranted.
Al Shirawi, M. I., Kennedy, S. H., Ho, K. T., Byrne, R., & Downar, J. (2017). Oral Ketamine in Treatment-Resistant Depression: A Clinical Effectiveness Case Series. Journal of clinical psychopharmacology, 37(4), 464. 10.1097/JCP.0000000000000717
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Harmine is an inflammatory inhibitor through the suppression of NF-κB signaling

/ Ayahuasca, Papers, Psychiatry & Medicine / / , , , , ,

Abstract

Harmine is a major constituent in a hallucinogenic botanical mixture ayahuasca and medical plant Peganum harmala L. The plant is used for various illnesses and exhibits anti-inflammatory activity. However, the active constituents remain unclear. Here, we screened the seven alkaloids in P. harmala for their anti-inflammatory activity using an nuclear factor-κB (NF-κB) reporter assay. We found that harmine and harmol could inhibit NF-κB transactivity. As the most abundant compound, harmine inhibited tumor necrosis factor-α (TNF-α)- and lipopolysaccharides (LPS)-induced NF-κB transactivity and nuclear translocation in mouse macrophage RAW 264.7 cells. The mRNA and protein levels of NF-κB downstream inflammatory cytokines also reduced. In an LPS-challenged mouse model, harmine markedly averted inflammatory damage of the lung, and decreased serum TNF-α, interleukin-1β (IL-1β) and IL-6 levels. Our data indicate that harmine may exert the anti-inflammatory effect by inhibition of the NF-κB signaling pathway and harmine is probably responsible for the anti-inflammatory effects of P. harmala.

Liu, X., Li, M., Tan, S., Wang, C., Fan, S., & Huang, C. (2017). Harmine is an inflammatory inhibitor through the suppression of NF-κB signaling. Biochemical and Biophysical Research Communications. 10.1016/j.bbrc.2017.05.126
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Behavioral Changes Over Time Following Ayahuasca Exposure in Zebrafish

/ Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, Papers, Psychology / / , , , , , ,

Abstract

The combined infusion of Banisteriopsis caapi stem and Psychotria viridis leaves, known as ayahuasca, has been used for centuries by indigenous tribes. The infusion is rich in N, N-dimethyltryptamine (DMT) and monoamine oxidase inhibitors, with properties similar to those of serotonin. Despite substantial progress in the development of new drugs to treat anxiety and depression, current treatments have several limitations. Alternative drugs, such as ayahuasca, may shed light on these disorders. Here, we present time-course behavioral changes induced by ayahuasca in zebrafish, as first step toward establishing an ideal concentration for pre-clinical evaluations. We exposed adult zebrafish to five concentrations of the ayahuasca infusion: 0 (control), 0.1, 0.5, 1, and 3 ml/L (n = 14 each group), and behavior was recorded for 60 min. We evaluated swimming speed, distance traveled, freezing and bottom dwelling every min for 60 min. Swimming speed and distance traveled decreased with an increase in ayahuasca concentration while freezing increased with 1 and 3 ml/L. Bottom dwelling increased with 1 and 3 ml/L, but declined with 0.1 ml/L. Our data suggest that small amounts of ayahuasca do not affect locomotion and reduce anxiety-like behavior in zebrafish, while increased doses of the drug lead to crescent anxiogenic effects. We conclude that the temporal analysis of zebrafish behavior is a sensitive method for the study of ayahuasca-induced functional changes in the vertebrate brain.
Savoldi, R., Polari, D., Pinheiro-da-Silva, J., Silva, P. F., Lobao-Soares, B., Yonamine, M., … & Luchiari, A. C. (2017). Behavioral changes over time following ayahuasca exposure in zebrafish. Frontiers in behavioral neuroscience, 11. 10.3389/fnbeh.2017.00139
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Side-effects associated with ketamine use in depression: a systematic review

/ Depressive Disorders, Ketamine, Papers, Psychology / / , , , ,

Abstract

This is the first systematic review of the safety of ketamine in the treatment of depression after single and repeated doses. We searched MEDLINE, PubMed, PsycINFO, and Cochrane Databases and identified 288 articles, 60 of which met the inclusion criteria. After acute dosing, psychiatric, psychotomimetic, cardiovascular, neurological, and other side-effects were more frequently reported after ketamine treatment than after placebo in patients with depression. Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users. We recommend large-scale clinical trials that include multiple doses of ketamine and long-term follow up to assess the safety of long-term regular use.
Short, B., Fong, J., Galvez, V., Shelker, W., & Loo, C. K. (2017). Side-effects associated with ketamine use in depression: a systematic review. The Lancet Psychiatry. 10.1016/S2215-0366(17)30272-9
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The 2017 Ayahuasca Technical Report

/ Anthropology & Sociology, Anxiety Disorders / PTSD, Ayahuasca, Biology & Ethnobotany, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Publications, Substance Use Disorder /

ICEERS has just released the 2017 edition of the Ayahuasca Technical Report. Signed by ten of the world’s leading ayahuasca researchers, this report is an important document that summarizes the most relevant scientific findings from the past few decades, as well as key information about the history, legality, pharmacology, and potential therapeutic or adverse effects of ayahuasca. Our intention with this report is to provide objective and up-to-date information to policy makers, judges, lawyers and other officials in charge of developing policies, programs, legislation or involved in legal cases relating to ayahuasca.
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Journal Club #22: Applying the EU Regulatory Framework to Determine the Benefit–Risk Profile of Psychedelics - March 3

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