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Single-Dose ketamine followed by daily D-Cycloserine in treatment-resistant bipolar depression

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

Abstract

Bipolar depression is a leading cause of disability in the United States. Recently, N-methyl-D-asparate glutamate-receptor (NMDAR) antagonists, such as ketamine, have been shown to induce remission in bipolar depression. Nevertheless, ketamine use is limited by transient effects and psychogenic potential during repeated administration.

Kantrowitz, J. T., Halberstam, B., & Gangwisch, J. (2015). Single-Dose ketamine followed by daily D-Cycloserine in treatment-resistant bipolar depression. The Journal of clinical psychiatry, 76(6), 737-738. https://dx.doi.org/10.4088/JCP.14l09527
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Hunting and hallucinogens: The use psychoactive and other plants to improve the hunting ability of dogs.

/ Biology & Ethnobotany, Papers, Publications / / ,

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE:
Cultures throughout the world give plants to their dogs in order to improve hunting success. These practices are best developed in lowland Ecuador and Peru. There is no experimental evidence for the efficacy of these practices nor critical reviews that consider possible pharmacological effects on dogs based on the chemistry of the ethnoverterinary plants.

AIM:
This review has three specific aims: (1) determine what plants the Ecuadorian Shuar and Quichua give to dogs to improve their hunting abilities, (2) determine what plants other cultures give to dogs for the same purpose, and (3) assess the possible pharmacological basis for the use of these plants, particularly the psychoactive ones?

METHODS:
We gathered Shuar (Province of Morona-Santaigo) and Quichua (Napo and Orellano Provinces) data from our previous publications and field notes. All specimens were vouchered and deposited in QCNE with duplicates sent to NY and MO. Data presented from other cultures derived from published studies on ethnoveterinary medicine. Species names were updated, when necessary, and family assignments follow APG III (Angiosperm Phylogeny Group, 2009. An update of the Angiosperm Phylogeny Group classification for the orders and families of flowering plants: APG III. Bot. J. Linn. Soc. 161, 105-121). Chemical data were found using PubMed and SciFinder.

RESULTS:
The Shuar and Quichua of Ecuador use at least 22 species for ethnoveterinary purposes, including all but one of their principal hallucinogens. Literature surveys identified 43 species used in other cultures to improve hunting ability. No published studies have examined the pharmacological active of these plant species in dogs. We, thus, combined phytochemical data with the ethnobotanical reports of each plant and then classified each species into a likely pharmacological category: depuratives/deodorant, olfactory sensitizer, ophthalmic, or psychoactive.

CONCLUSIONS:
The use of psychoactive substances to improve a dog׳s hunting ability seems counterintuitive, yet its prevalence suggests that it is both adaptive and that it has an underlying pharmacological explanation. We hypothesize that hallucinogenic plants alter perception in hunting dogs by diminishing extraneous signals and by enhancing sensory perception (most likely olfaction) that is directly involved in the detection and capture of game. If this is true, plant substances also might enhance the ability of dogs to detect explosives, drugs, human remains, or other targets for which they are valued.

Bennett, B. C., & Alarcón, R. (2015). Hunting and Hallucinogens: The use psychoactive and other Plants to improve the Hunting ability of dogs. Journal of Ethnopharmacology. http://dx.doi.org/10.1016/j.jep.2015.05.035
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The positive effect on ketamine as a priming adjuvant in antidepressant treatment.

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

Abstract

Ketamine is an anesthetic with antidepressant properties. The rapid and lasting effect of ketamine observed in preclinical and clinical research makes it a promising therapeutic to improve current major depression (MD) treatment. Our work intended to evaluate whether the combined use of classic antidepressants (imipramine or fluoxetine) and ketamine would improve the antidepressant response. Using an animal model of depressive-like behavior, we show that the addition of ketamine to antidepressants anticipates the behavioral response and accelerates the neuroplastic events when compared with the use of antidepressants alone. In conclusion, our results suggest the need for a reappraisal of the current pharmacological treatment of MD.

Melo, A., Kokras, N., Dalla, C., Ferreira, C., Ventura-Silva, A. P., Sousa, N., & Pêgo, J. M. (2015). The positive effect on ketamine as a priming adjuvant in antidepressant treatment. Translational Psychiatry, 5(5), e573. https://dx.doi.org/10.1038/tp.2015.66
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Psychedelic drugs should be legally reclassified so that researchers can investigate their therapeutic potential

/ Humanities & Art, LSD, Mushrooms / Psilocybin, Papers, Publications / /

Abstract

Trials of physiologically safe and non-addictive drugs such as LSD are almost impossible, writes James J H Rucker, calling on the authorities to downgrade their unnecessarily restrictive class A, schedule 1 classification.

Rucker, J. J. (2015). Psychedelic drugs should be legally reclassified so that researchers can investigate their therapeutic potential. BMJ, 350, h2902. http://dx.doi.org/10.1136/bmj.h2902
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Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin

/ Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / / , , , , ,

Abstract

Ego-disturbances have been a topic in schizophrenia research since the earliest clinical descriptions of the disorder. Manifesting as a feeling that one’s “self,” “ego,” or “I” is disintegrating or that the border between one’s self and the external world is dissolving, “ego-disintegration” or “dissolution” is also an important feature of the psychedelic experience, such as is produced by psilocybin (a compound found in “magic mushrooms”). Fifteen healthy subjects took part in this placebo-controlled study. Twelve-minute functional MRI scans were acquired on two occasions: subjects received an intravenous infusion of saline on one occasion (placebo) and 2 mg psilocybin on the other. Twenty-two visual analogue scale ratings were completed soon after scanning and the first principal component of these, dominated by items referring to “ego-dissolution”, was used as a primary measure of interest in subsequent analyses. Employing methods of connectivity analysis and graph theory, an association was found between psilocybin-induced ego-dissolution and decreased functional connectivity between the medial temporal lobe and high-level cortical regions. Ego-dissolution was also associated with a “disintegration” of the salience network and reduced interhemispheric communication. Addressing baseline brain dynamics as a predictor of drug-response, individuals with lower diversity of executive network nodes were more likely to experience ego-dissolution under psilocybin. These results implicate MTL-cortical decoupling, decreased salience network integrity, and reduced inter-hemispheric communication in psilocybin-induced ego disturbance and suggest that the maintenance of “self”or “ego,” as a perceptual phenomenon, may rest on the normal functioning of these systems.

Lebedev, A. V., Lövdén, M., Rosenthal, G., Feilding, A., Nutt, D. J., & Carhart‐Harris, R. L. (2015). Finding the self by losing the self: Neural correlates of ego‐dissolution under psilocybin. Human brain mapping. https://dx.doi.org/10.1002/hbm.22833
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Noribogaine reduces nicotine self-administration in rats

/ Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / / , , ,

Abstract

Noribogaine, a polypharmacological drug with activities at opioid receptors, ionotropic nicotinic receptors, and serotonin reuptake transporters, has been investigated for treatment of substance abuse-related disorders. Smoking cessation has major benefits for both individuals and society, therefore the aim of this study was to evaluate the potential of noribogaine for use as a treatment for nicotine dependence. Adult male Sprague-Dawley rats were trained to self-administer nicotine intravenous. After initial food pellet training, followed by 26 sessions of nicotine self-administration training, the rats were administered noribogaine (12.5, 25 or 50 mg/kg orally), noribogaine vehicle, varenicline or saline using a within-subject design with a Latin square test schedule. Noribogaine dose-dependently decreased nicotine self-administration by up to 64% of saline-treated rats’ levels and was equi-effective to 1.7 mg/kg intraperitoneal varenicline. Noribogaine was less efficient at reducing food pellets self-administration than at nicotine self-administration, inhibiting the nondrug reinforcing effects of palatable pellets by 23% at the highest dose. These results suggest that noribogaine dose-dependently attenuates drug-taking behavior for nicotine, attenuates the reinforcing effects of nicotine and is comparable to varenicline power in that regard. The findings from the present study hold promise for a new therapy to aid smoking cessation.

Chang, Q., Hanania, T., Mash, D. C., & Maillet, E. L. (2015). Noribogaine reduces nicotine self-administration in rats. Journal of Psychopharmacology, 29(6), 704-711. http://dx.doi.org/10.1177/0269881115584461
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Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile

/ Ketamine, Neuroscience, Papers, Publications / / , , , , , ,

Abstract

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has been studied in relation to the glutamate hypothesis of schizophrenia and increases dissociation, positive and negative symptom ratings. Ketamine effects brain function through changes in brain activity; these activity patterns can be modulated by pre-treatment of compounds known to attenuate the effects of ketamine on glutamate release. Ketamine also has marked effects on brain connectivity; we predicted that these changes would also be modulated by compounds known to attenuate glutamate release. Here, we perform task-free pharmacological magnetic resonance imaging (phMRI) to investigate the functional connectivity effects of ketamine in the brain and the potential modulation of these effects by pre-treatment of the compounds lamotrigine and risperidone, compounds hypothesised to differentially modulate glutamate release. Connectivity patterns were assessed by combining windowing, graph theory and multivariate Gaussian process classification. We demonstrate that ketamine has a robust effect on the functional connectivity of the human brain compared to saline (87.5 % accuracy). Ketamine produced a shift from a cortically centred, to a subcortically centred pattern of connections. This effect is strongly modulated by pre-treatment with risperidone (81.25 %) but not lamotrigine (43.75 %). Based on the differential effect of these compounds on ketamine response, we suggest the observed connectivity effects are primarily due to NMDAR blockade rather than downstream glutamatergic effects. The connectivity changes contrast with amplitude of response for which no differential effect between pre-treatments was detected, highlighting the necessity of these techniques in forming an informed view of the mechanistic effects of pharmacological compounds in the human brain.

Joules, R., Doyle, O. M., Schwarz, A. J., O’Daly, O. G., Brammer, M., Williams, S. C., & Mehta, M. A. (2015). Ketamine induces a robust whole-brain connectivity pattern that can be differentially modulated by drugs of different mechanism and clinical profile. Psychopharmacology, 1-14. https://dx.doi.org/10.1007/s00213-015-3951-9

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Recreational 3,4-methylenedioxy-N-methylamphetamine (MDMA) or ‘ecstasy’ and self-focused compassion: Preliminary steps in the development of a therapeutic psychopharmacology of contemplative practices.

/ MDMA, Papers, Psychology, Publications / / , , , , , ,

Abstract

3,4-methylenedioxy-N-methylamphetamine (MDMA) produces diverse pro-social effects. Cognitive training methods rooted in Eastern contemplative practices also produce these effects through the development of a compassionate mindset. Given this similarity, we propose that one potential mechanism of action of MDMA in psychotherapy is through enhancing effects on intrapersonal attitudes (i.e. pro-social attitudes towards the self). We provide a preliminary test of this idea. Recreational MDMA (ecstasy) users were tested on two occasions, having consumed or not consumed ecstasy. Self-critical and self-compassionate responses to self-threatening scenarios were assessed before (T1) and after (T2) ecstasy use (or non-use), and then after compassionate imagery (T3). Moderating roles of dispositional self-criticism and avoidant attachment were examined. Separately, compassionate imagery and ecstasy produced similar sociotropic effects, as well as increases in self-compassion and reductions in self-criticism. Higher attachment-related avoidance was associated with additive effects of compassionate imagery and ecstasy on self-compassion. Findings were in line with MDMA’s neuropharmacological profile, its phenomenological effects and its proposed adjunctive use in psychotherapy. However, although conditions were balanced, the experiment was non-blind and MDMA dose/purity was not determined. Controlled studies with pharmaceutically pure MDMA are still needed to test these effects rigorously.

Kamboj, S. K., Kilford, E. J., Minchin, S., Moss, A., Lawn, W., Das, R. K., … & Freeman, T. P. (2015). Recreational 3, 4-methylenedioxy-N-methylamphetamine (MDMA) or ‘ecstasy’and self-focused compassion: Preliminary steps in the development of a therapeutic psychopharmacology of contemplative practices. Journal of Psychopharmacology, 0269881115587143.
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Immunomodulatory activity of ketamine in human astroglial A172 cells: Possible relevance to its rapid antidepressant activity.

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

Abstract

To determine if the immunomodulatory effect of ketamine is relevant to its rapid antidepressant activity, cultured human astroglial cells were incubated with ketamine, cytokine mix, or both. At 24h, ketamine dose-dependently (100-500 μM) decreased IL-6 and TNFα production and gene expression and, at clinically relevant concentration (100 μM), augmented IL-β release and gene expression in both unstimulated and cytokine-stimulated cells. In unstimulated cells, ketamine also increased IL-8 production and mRNA expression. The reduction in IL-6 mRNA was significant within 1h in unstimulated cells and at 4h after stimulation. Ketamine suppressed the production of the only established depression-relevant proinflammatory cytokines, IL-6 and TNFα.

Yuhas, Y., Ashkenazi, S., Berent, E., & Weizman, A. (2015). Immunomodulatory activity of ketamine in human astroglial A172 cells: Possible relevance to its rapid antidepressant activity. Journal of neuroimmunology, 282, 33-38. https://dx.doi.org/10.1016/j.jneuroim.2015.03.012
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Ketamine-induced state models schizophrenia

/ Ketamine, Psychology, Psychotic Disorders /

In the 1950’s, research on the psychoactive properties of lysergic acid diethylamide (LSD) led scientists to the serotonin hypothesis of schizophrenia, a theory still used to explain the neurochemical roots of schizophrenia. Today, Höflich et al. (2015) have used ketamine to explore the role of neurotransmitter glutamate in this mental disorder [3].

Since neuroimaging studies indicated dysfunctional glutamate pathways in schizophrenia, glutamate is thought to play a key role in its aetiology. These abnormalities are specifically apparent in the thalamus, a brain region regarded as the information integration system of the brain. By measuring brain activity in healthy volunteers after ketamine administration, Höflich et al. (2015) explored ketamine as a model for schizophrenia to further investigate the link between glutamate and schizophrenia. Ketamine is a glutamate antagonist, which means that it prevents neurotransmission by blocking the activity of glutamate on N-methyl-D-aspartate (NMDA) receptors. The effects of ketamine resemble some of the positive, negative, and cognitive symptoms of schizophrenia.

In the study of Höflich et al. (2015), thirty healthy volunteers completed a double-blind, placebo-controlled, randomized, crossover study in which each volunteer was scanned using fMRI on two separate days. Brain network activation under ketamine was compared to placebo. The brain images revealed higher functional connectivity in the thalamus hub network in the ketamine condition compared to placebo. Furthermore, ketamine induced higher connectivity between thalamic regions and somatosensory and temporal cortices. Connectivity between the thalamus and prefrontal, motor, posterior parietal, and occipital cortices did not differ significantly.

The authors conclude that ketamine temporarily triggers alterations in functional connectivity in healthy volunteers that resemble structural brain connectivity patterns in schizophrenic patients. They infer that the ketamine-induced state might function as a model of schizophrenia, especially relative to characteristic sensory filtering problems. However, their results did not reveal a decrease of prefrontal-thalamic connectivity typical for schizophrenic patients [4] suggesting that other neurotransmitters also account for the manifestation of schizophrenia. Using ketamine and other drug models [5] to investigate the relationship between neurotransmitter systems and the symptomatology of schizophrenia could yield valuable information about the neural underpinnings of this mental disorder.

[1] Gaddum, J. H., Hebb, C. O., Silver, A., & Swan, A. A. B. (1953). 5-Hydroxytryptamine. Pharmacological action and destruction in perfused lungs. Quart. J. Exper. Physiol., 38, 255.
[2] Woolley, D. W., & Shaw, E. (1954). a Biochemical and Pharmacological Suggestion About Certain Mental Disorders. Proceedings of the National Academy of Sciences of the United States of America, 40(4), 228–231. doi:10.1073/pnas.40.4.228
[3] Höflich, A., Hahn, A., Küblböck, M., Kranz, G. S., Vanicek, T., Windischberger, C., …Lanzenberger, R. (2015). Ketamine-Induced Modulation of the Thalamo- Cortical Network in Healthy Volunteers As a Model for Schizophrenia. International Journal of Neuropsychopharmacology, 1–11. doi:10.1093/ijnp/pyv040 [Abstract]
[4] Leitman DI, Sehatpour P, Higgins BA, Foxe JJ, Silipo G, Javitt DC (2010) Sensory deficits and distributed hierarchical dysfunction in schizophrenia. Am J Psychiatry 167:818–827
[5] Steeds, H., Carhart-Harris, R. L., & Stone, J. M. (2014). Drug models of schizophrenia. Therapeutic Advances in Psychopharmacology, 5(1), 43–58. doi:10.1177/2045125314557797 [Abstract][/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

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