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Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder

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

Abstract

The glutamate N-methyl-D-aspartate receptor antagonist ketamine has demonstrated antidepressant effects in individuals with treatment-resistant major depressive disorder (TRD) within 24 h of a single dose. The current study utilized functional magnetic resonance imaging (fMRI) and two separate emotion perception tasks to examine the neural effects of ketamine in patients with TRD. One task used happy and neutral facial expressions; the other used sad and neutral facial expressions. Twenty patients with TRD free of concomitant antidepressant medication underwent fMRI at baseline and 24 h following administration of a single intravenous dose of ketamine (0.5 mg kg−1). Adequate data were available for 18 patients for each task. Twenty age- and sex-matched healthy volunteers were scanned at one time point for baseline comparison. Whole-brain, voxel-wise analyses were conducted controlling for a family-wise error rate (FWE) of P<0.05. Compared with healthy volunteers, TRD patients showed reduced neural responses to positive faces within the right caudate. Following ketamine, neural responses to positive faces were selectively increased within a similar region of right caudate. Connectivity analyses showed that greater connectivity of the right caudate during positive emotion perception was associated with improvement in depression severity following ketamine. No main effect of group was observed for the sad faces task. Our results indicate that ketamine specifically enhances neural responses to positive emotion within the right caudate in depressed individuals in a pattern that appears to reverse baseline deficits and that connectivity of this region may be important for the antidepressant effects of ketamine.

Murrough, J. W., Collins, K. A., Fields, J., DeWilde, K. E., Phillips, M. L., Mathew, S. J., … & Iosifescu, D. V. (2015). Regulation of neural responses to emotion perception by ketamine in individuals with treatment-resistant major depressive disorder. Translational psychiatry, 5(2). https://dx.doi.org/10.1038/tp.2015.10
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Neural correlates of change in major depressive disorder anhedonia following open-label ketamine

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

Abstract

Anhedonia is a cardinal symptom of major depression and is often refractory to standard treatment, yet no approved medication for this specific symptom exists. In this exploratory re-analysis, we assessed whether administration of rapid-acting antidepressant ketamine was associated specifically with reduced anhedonia in medication-free treatment-refractory patients with major depressive disorder in an open-label investigation. Additionally, participants received either oral riluzole or placebo daily beginning 4 hours post-infusion. A subgroup of patients underwent fluorodeoxyglucose positron emission tomography scans at baseline (1–3 days pre-infusion) and 2 hours post-ketamine infusion. Anhedonia rapidly decreased following a single ketamine infusion; this was sustained for up to three days, but was not altered by riluzole. Reduced anhedonia correlated with increased glucose metabolism in the hippocampus and dorsal anterior cingulate cortex (dACC) and decreased metabolism in the inferior frontal gyrus and orbitofrontal cortex (OFC). The tentative relationship between change in anhedonia and glucose metabolism remained significant in dACC and OFC, and at trend level in the hippocampus, a result not anticipated, when controlling for change in total depression score. Results, however, remain tenuous due to the lack of a placebo control for ketamine. In addition to alleviating overall depressive symptoms, ketamine could possess anti-anhedonic potential in major depressive disorder, which speculatively, may be mediated by alterations in metabolic activity in the hippocampus, dACC and OFC.

Lally, N., Nugent, A. C., Luckenbaugh, D. A., Niciu, M. J., Roiser, J. P., & Zarate, C. A. (2015). Neural correlates of change in major depressive disorder anhedonia following open-label ketamine. Journal of Psychopharmacology. https://dx.doi.org/10.1177/0269881114568041
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Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences?

/ Anxiety Disorders / PTSD, Depressive Disorders, Headache Pain and Neurological Disorders, Ketamine, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications, Substance Use Disorder / / , ,

Abstract

Interest in the therapeutic potential of psychedelic substances has recently resumed. During an early phase of human psychedelic research, their therapeutic application in different pathologies had been suggested, and the first evidence for efficacy was provided. The range of recent clinical applications of psychedelics spans from cluster headaches and obsessive-compulsive disorder to addiction and the treatment of fear and anxiety in patients suffering from terminal illness, indicating potentially different therapeutic mechanisms. A variety of approaches in psychotherapy emphasize subjective experiences, such as so-called peak experiences or afterglow phenomena, as differentially mediating therapeutic action. This review aims to re-evaluate earlier and recent concepts of how psychedelic substances may exert beneficial effects. After a short outline of neurophenomenological aspects, we discuss different approaches to how psychedelics are used in psychotherapy. Finally, we summarize evidence for the relationship between subjective experiences and therapeutic success. While the distinction between pharmacological and psychological action obviously cannot be clear-cut, they do appear to contribute differently from each other when their effects are compared with regard to pathologies.

Majić, T., Schmidt, T. T., & Gallinat, J. (2015). Peak experiences and the afterglow phenomenon: When and how do therapeutic effects of hallucinogens depend on psychedelic experiences? Journal of Psychopharmacology. https://dx.doi.org/10.1177/0269881114568040
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Ex vivo effects of ibogaine on the activity of antioxidative enzymes in human erythrocytes

/ Iboga / Ibogaine, Neuroscience, Papers, Pharmacology & Chemistry, Publications / / , , , , , ,

Abstract

Ethnopharmacological relevance

Ibogaine is a naturally occurring alkaloid with psychotropic and metabotropic effects, derived from the bark of the root of the West African Tabernanthe iboga plant. The tribes of Kongo basin have been using iboga as a stimulant, for medicinal purposes, and in rite of passage ceremonies, for centuries. Besides, it has been found that this drug has anti-addictive effects.

Aim of the study

Previous studies have demonstrated that ibogaine changed the quantity of ATP and energy related enzymes as well as the activity of antioxidant enzymes in cells thus altering redox equilibrium in a time manner. In this work, the mechanism of its action was further studied by measuring the effects of ibogaine in human erythrocytes in vitro on ATP liberation, membrane fluidity and antioxidant enzymes activity.

Materials and methods

Heparinized human blood samples were incubated with ibogaine (10 and 20 μM) at 37°C for 1 h. Blood plasma was separated by centrifugation and the levels of ATP and uric acid were measured 10 min after the addition of ibogaine using standard kits. The activity of copper–zinc superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were measured in erythrocytes after incubation period. The stability of SOD1 activity was further tested through in vitro incubation with H2O2 and scanning of its electrophoretic profiles. Membrane fluidity was determined using an electron paramagnetic resonance spin-labelling method.

Results

Results showed that ibogaine treatment of erythrocytes in vitro increased ATP concentration in the blood plasma without changes in neither erythrocytes membrane fluidity nor uric acid concentration. Ibogaine also increased SOD1 activity in erythrocytes at both doses applied here. Treatment with 20 μM also elevated GR activity after in vitro incubation at 37 °C. Electrophoretic profiles revealed that incubation with ibogaine mitigates H2O2 mediated suppression of SOD1 activity.

Conclusion

Some of the effects of ibogaine seem to be mediated through its influence on energy metabolism, redox active processes and the effects of discrete fluctuations of individual reactive oxygen species on different levels of enzyme activities. Overall, ibogaine acts as a pro-antioxidant by increasing activity of antioxidative enzymes and as an adaptagene in oxidative distress.

Nikolić-Kokić, A., Oreščanin-Dušić, Z., Spasojević, I., Slavić, M., Mijušković, A., Paškulin, R., … & Blagojević, D. P. (2015). Ex vivo effects of ibogaine on the activity of antioxidative enzymes in human erythrocytes. Journal of ethnopharmacology, 164, 64-70. http://dx.doi.org/10.1016/j.jep.2015.01.037
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Ex vivo effects of ibogaine on the activity of antioxidative enzymes in human erythrocytes

/ Biology & Ethnobotany, Iboga / Ibogaine, Papers, Psychiatry & Medicine, Publications / / , , , , , ,

Abstract

Ethnopharmacological relevance

Ibogaine is a naturally occurring alkaloid with psychotropic and metabotropic effects, derived from the bark of the root of the West African Tabernanthe iboga plant. The tribes of Kongo basin have been using iboga as a stimulant, for medicinal purposes, and in rite of passage ceremonies, for centuries. Besides, it has been found that this drug has anti-addictive effects.

Aim of the study

Previous studies have demonstrated that ibogaine changed the quantity of ATP and energy related enzymes as well as the activity of antioxidant enzymes in cells thus altering redox equilibrium in a time manner. In this work, the mechanism of its action was further studied by measuring the effects of ibogaine in human erythrocytes in vitro on ATP liberation, membrane fluidity and antioxidant enzymes activity.

Materials and methods

Heparinized human blood samples were incubated with ibogaine (10 and 20 μM) at 37°C for 1 h. Blood plasma was separated by centrifugation and the levels of ATP and uric acid were measured 10 min after the addition of ibogaine using standard kits. The activity of copper–zinc superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were measured in erythrocytes after incubation period. The stability of SOD1 activity was further tested through in vitro incubation with H2O2 and scanning of its electrophoretic profiles. Membrane fluidity was determined using an electron paramagnetic resonance spin-labelling method.

Results

Results showed that ibogaine treatment of erythrocytes in vitro increased ATP concentration in the blood plasma without changes in neither erythrocytes membrane fluidity nor uric acid concentration. Ibogaine also increased SOD1 activity in erythrocytes at both doses applied here. Treatment with 20 μM also elevated GR activity after in vitro incubation at 37 °C. Electrophoretic profiles revealed that incubation with ibogaine mitigates H2O2 mediated suppression of SOD1 activity.

Conclusion

Some of the effects of ibogaine seem to be mediated through its influence on energy metabolism, redox active processes and the effects of discrete fluctuations of individual reactive oxygen species on different levels of enzyme activities. Overall, ibogaine acts as a pro-antioxidant by increasing activity of antioxidative enzymes and as an adaptagene in oxidative distress.

Nikolić-Kokić, A., Oreščanin-Dušić, Z., Spasojević, I., Slavić, M., Mijušković, A., Paškulin, R., … & Blagojević, D. P. (2015). Ex vivo effects of ibogaine on the activity of antioxidative enzymes in Human erythrocytes. Journal of ethnopharmacology. http://dx.doi.org/10.1016/j.jep.2015.01.037
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The Effect of Repeated Ketamine Infusion Over Facial Emotion Recognition in Treatment-Resistant Depression: A Preliminary Report

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

Abstract

In contrast to improvement in emotion recognition bias by traditional antidepressants, the authors report preliminary findings that changes in facial emotion recognition are not associated with response of depressive symptoms after repeated ketamine infusions or relapse during follow-up in treatment-resistant depression.

Shiroma, P. R., Albott, C. S., Johns, B., Thuras, P., Wels, J., & Lim, K. O. (2015). The Effect of Repeated Ketamine Infusion Over Facial Emotion Recognition in Treatment-Resistant Depression: A Preliminary Report. The Journal of Neuropsychiatry and Clinical Neurosciences. http://dx.doi.org/10.1176/appi.neuropsych.14100243
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New World Tryptamine Hallucinogens and the Neuroscience of Ayahuasca

/ Ayahuasca, Biology & Ethnobotany, DMT, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / / ,

Abstract

New World indigenous peoples are noted for their sophisticated use of psychedelic plants in shamanic and ethnomedical practices. The use of psychedelic plant preparations among New World tribes is far more prevalent than in the Old World. Yet, although these preparations are botanically diverse, almost all are chemically similar in that their active principles are tryptamine derivatives, either DMT or related constituents. Part 1 of this paper provides an ethnopharmacological overview of the major tryptamine-containing New World hallucinogens.

McKenna, D., & Riba, J. (2015). New World Tryptamine Hallucinogens and the Neuroscience of Ayahuasca. Current Topics in Behavioral Neuroscience. https://dx.doi.org/10.1007/7854_2015_368

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Drug models of schizophrenia

/ Ketamine, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications, Salvia / Salvinorin A / / , ,

Abstract

Schizophrenia is a complex mental health disorder with positive, negative and cognitive symptom domains. Approximately one third of patients are resistant to currently available medication. New therapeutic targets and a better understanding of the basic biological processes that drive pathogenesis are needed in order to develop therapies that will improve quality of life for these patients. Several drugs that act on neurotransmitter systems in the brain have been suggested to model aspects of schizophrenia in animals and in man. In this paper, we selectively review findings from dopaminergic, glutamatergic, serotonergic, cannabinoid, GABA, cholinergic and kappa opioid pharmacological drug models to evaluate their similarity to schizophrenia. Understanding the interactions between these different neurotransmitter systems and their relationship with symptoms will be an important step towards building a coherent hypothesis for the pathogenesis of schizophrenia.

Steeds, H., Carhart-Harris, R. L., & Stone, J. M. (2014). Drug models of schizophrenia. Therapeutic Advances in Psychopharmacology. https://dx.doi.org/10.1177/2045125314557797
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Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers

/ Iboga / Ibogaine, Papers, Publications / / , , , , , ,

Abstract

Conversion of ibogaine to its active metabolite noribogaine appears to be mediated primarily by CYP2D6. We compared 168 h pharmacokinetic profiles of both analytes after a single oral 20 mg dose of ibogaine in 21 healthy subjects who had been pretreated for 6 days with placebo or the CYP2D6 inhibitor paroxetine. In placebo-pretreated subjects, ibogaine was rapidly converted to noribogaine. Median peak noribogaine concentrations occurred at 4 h. Compared with placebo-pretreated subjects, paroxetine-pretreated subjects had rapid (Tmax = 1.5 h) and substantial absorption of ibogaine, with detectable levels out to 72 h, and an elimination half-life of 10.2 h. In this group, ibogaine was also rapidly converted to noribogaine with a median Tmax of 3 h. Extent of noribogaine exposure was similar in both groups. CYP2D6 phenotype was robustly correlated with ibogaine AUC0-t (r = 0.82) and Cmax (r = 0.77). Active moiety (ibogaine plus noribogaine) exposure was ∼2-fold higher in paroxetine-pretreated subjects. Single 20 mg ibogaine doses were safe and well tolerated in all subjects. The doubling of exposure to active moiety in subjects with reduced CYP2D6 activity suggests it may be prudent to genotype patients awaiting ibogaine treatment, and to at least halve the intended dose of ibogaine in CYP2D6 poor metabolizers.

Glue, P., Winter, H., Garbe, K., Jakobi, H., Lyudin, A., Lenagh‐Glue, Z., & Hung, C. T. (2015). Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers. The Journal of Clinical Pharmacology. https://dx.doi.org/10.1002/jcph.471
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Forbidden therapies: Santo Daime, ayahuasca, and the prohibition of entheogens in Western society

/ Anthropology & Sociology, Ayahuasca, Biology & Ethnobotany, Papers, Publications / /

Abstract

Santo Daime, a Brazilian religion organized around a potent psychoactive beverage called ayahuasca, is now being practiced across Europe and North America. Deeming ayahuasca a dangerous “hallucinogen,” most Western governments prosecute people who participate in Santo Daime. On the contrary, members of Santo Daime (called “daimistas”) consider ayahuasca a medicinal sacrament (or “entheogen”). Empirical studies corroborate daimistas’ claim that entheogens are benign and can be beneficial when employed in controlled contexts. Following from anthropology’s goal of rendering different cultural logics as mutually explicable, this article intercedes in a misunderstanding between policies of prohibition and an emergent subculture of entheogenic therapy.

Blainey, M. G. (2015). Forbidden therapies: Santo Daime, ayahuasca, and the prohibition of entheogens in western society. Journal of religion and health, 54(1), 287-302. 10.1007/s10943-014-9826-2
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Psychedelics and Acceptance and Commitment Therapy (ACT): A Process-Based Approach - September 15th

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