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In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept

June 6, 2015 / Anxiety Disorders / PTSD, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , , , , ,

Abstract

We previously reported the rapid and robust clinical effects of ketamine versus saline infusions in a proof-of-concept crossover trial in unmedicated adults with obsessive-compulsive disorder (OCD). This study examined the concurrent neurochemical effects of ketamine versus saline infusions using proton magnetic resonance spectroscopy (H MRS) during the clinical proof-of-concept crossover trial. Levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurochemicals glutamate+glutamine (Glx) were acquired in the medial prefrontal cortex (MPFC), a region implicated in OCD pathology. Seventeen unmedicated OCD adults received two intravenous infusions at least 1 week apart, one of saline and one of ketamine, while lying supine in a 3.0 T GE MR scanner. The order of each infusion pair was randomized. Levels of GABA and Glx were measured in the MPFC before, during, and after each infusion and normalized to water (W). A mixed effects model found that MPFC GABA/W significantly increased over time in the ketamine compared with the saline infusion. In contrast, there were no significant differences in Glx/W between the ketamine and saline infusions. Together with earlier evidence of low cortical GABA in OCD, our findings suggest that models of OCD pathology should consider the role of GABAergic abnormalities in OCD symptomatology.

Rodriguez, C. I., Kegeles, L. S., Levinson, A., Ogden, R. T., Mao, X., Milak, M. S., … & Simpson, H. B. (2015). In vivo effects of ketamine on glutamate-glutamine and gamma-aminobutyric acid in obsessive-compulsive disorder: Proof of concept. Psychiatry Research: Neuroimaging. http://dx.doi.org/10.1016/j.pscychresns.2015.06.001
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Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans

June 5, 2015 / Neuroscience, Papers, Psychology, Publications, Salvia / Salvinorin A / By / , , , , , ,

Abstract

Background: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profile of subjective effects of increasing doses of salvinorin-A in healthy volunteers with special emphasis on interoception.

Methods: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1 mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included among others: the Hallucinogen Rating Scale (HRS), the Altered States of Consciousness (APZ), and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness (MAIA).

Results: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the high dose led to a sense of a complete loss of contact with the body.

Conclusions: Salvinorin-A induced intense psychotropic effects characterized by a dose-dependent gating of external audio-visual information and an inverted-U dose-response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception and the sense of body ownership in humans.

Maqueda, A. E., Valle, M., Addy, P. H., Antonijoan, R. M., Puntes, M., Coimbra, J., … & Riba, J. (2015). Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans. International Journal of Neuropsychopharmacology, pyv065. http://dx.doi.org/10.1093/ijnp/pyv065
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The use of ketamine for the treatment of depression in the context of psychotic symptoms

June 4, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, Psychotic Disorders, Publications / By / , , ,

Abstract

Mounting evidence from a series of small clinical trials and case series suggests ketamine can have rapid and robust antidepressant(1), and possibly anti-suicidal effects(2) in patients who had not responded to standard treatment options. However, due to ketamine’s variable psychotomimetic effects in healthy volunteers and exacerbation of previously experienced positive symptoms in schizophrenic volunteers(3,4), patients previously experiencing psychotic features have been excluded from the reported studies and trials.

da Frota Ribeiro, C. M., Sanacora, G., Hoffman, R., & Ostroff, R. (2015). The use of ketamine for the treatment of depression in the context of psychotic symptoms. Biological Psychiatry. http://dx.doi.org/10.1016/j.biopsych.2015.05.016
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MDMA for the treatment of mood disorder: all talk no substance?

June 1, 2015 / Depressive Disorders, MDMA, Papers, Psychology, Publications / By / ,

Abstract

BACKGROUND:

Unipolar depression is the third highest contributor to the global burden of disease, yet current pharmacotherapies typically take about 6 weeks to have an effect. A rapid-onset agent is an attractive prospect, not only to alleviate symptoms before first-line antidepressants display therapeutic action, but as a further treatment option in nonresponsive cases. It has been suggested that 3,4-methylene-dioxymethamphetamine (MDMA) could play a part in the treatment of depression, either as a rapid-onset pharmacological agent or as an adjunct to psychotherapy. Whilst these hypotheses are in keeping with the monoamine theory of depression and the principles surrounding psychotherapy, explicit experimental evidence of an antidepressant effect of MDMA has rarely been established.

AIMS:

To address the hypothesis surrounding MDMA as a rapid-onset antidepressant by examining pharmacological, psychological and behavioural studies. We consider whether this therapy could be safe by looking at the translation of neurotoxicity data from animals to humans.

METHOD:

A literature review of the evidence supporting this hypothesis was performed.

CONCLUSIONS:

The pharmacology of MDMA offers a promising target as a rapid-onset agent and MDMA is currently being investigated for use in psychotherapy in anxiety disorders; translation from these studies for use in depression may be possible. However, experimental evidence and safety analysis are insufficient to confirm or reject this theory at present.

Patel, R., & Titheradge, D. (2015). MDMA for the treatment of mood disorder: all talk no substance?. Therapeutic Advances in Psychopharmacology, 2045125315583786. https://dx.doi.org/10.1177/2045125315583786
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Single-Dose ketamine followed by daily D-Cycloserine in treatment-resistant bipolar depression

June 1, 2015 / Depressive Disorders, Ketamine, Neuroscience, Papers, Psychology, Publications / By / , ,

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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The positive effect on ketamine as a priming adjuvant in antidepressant treatment.

May 26, 2015 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

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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Finding the self by losing the self: Neural correlates of ego-dissolution under psilocybin

May 22, 2015 / Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Psychotic Disorders, Publications / By / , , , , ,

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

May 20, 2015 / Iboga / Ibogaine, Papers, Psychology, Publications, Substance Use Disorder / By / , , ,

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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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.

May 18, 2015 / MDMA, Papers, Psychology, Publications / By / , , , , , ,

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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Ketamine-induced state models schizophrenia

February 7, 2022 / Ketamine, Psychology, Psychotic Disorders / By

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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