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Blood d-serine levels as a predictive biomarker for the rapid antidepressant effects of the NMDA receptor antagonist ketamine

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

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The N-methyl-d-aspartate (NMDA) receptor antagonist ketamine is the most effective antidepressant drug for patients with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD) (Krystal et al. 2013). A single subanesthetic dose (0.5 mg/kg) of ketamine produces rapid antidepressant effects in up to two-thirds of patients with MDD and BD, and this effect can last for 7 days or more (Krystal et al. 2013; Zarate et al. 2012). However, the biochemical pathways defining the differences between patients who respond to ketamine and those who do not are currently unknown.

We read with great interest the article entitled “d-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression,” by Moaddel et al. (2014). d-Serine acts as an endogenous, obligatory co-agonist at the NMDA receptor, and in their study, the authors reported that plasma levels of d-serine in the ketamine responder group (3.02 ± …

Hashimoto, K. (2014). Blood d-serine levels as a predictive biomarker for the rapid antidepressant effects of the NMDA receptor antagonist ketamine. Psychopharmacology, 231(20), 4081-4082. https://dx.doi.org/10.1007/s00213-014-3735-7

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Ketamine safety and tolerability in clinical trials for treatment-resistant depression

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

Abstract

OBJECTIVE: Ketamine has demonstrated rapid antidepressant effects in patients with treatment-resistant depression (TRD); however, the safety and tolerability of ketamine in this population have not been fully described. Herein we report the largest study to date of the safety, tolerability, and acceptability of ketamine in TRD.

METHOD: Data from 205 intravenous (IV) ketamine infusions (0.5 mg/kg over 40 minutes) in 97 participants with DSM-IV-defined major depressive disorder (MDD) were pooled from 3 clinical trials conducted between 2006 and 2012 at 2 academic medical centers. Safety and tolerability measures included attrition, adverse events (AEs), hemodynamic changes, and assessments of psychosis and dissociation.

RESULTS: The overall antidepressant response rate, defined as a ≥ 50% improvement in Montgomery-Asberg Depression Rating Scale score, was 67% (65 of 97 participants). Four of 205 infusions (1.95%) were discontinued due to AEs. The overall attrition rate was 3.1% (3 of 97). In the first 4 hours after the infusion, the most common general AEs were drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. Approximately one third of individuals experienced protocol-defined hemodynamic changes. Ketamine resulted in small but significant increases in psychotomimetic and dissociative symptoms (all P <.05). There were no cases of persistent psychotomimetic effects, adverse medical effects, or increased substance use in a subgroup of patients with available long-term follow-up information.

CONCLUSIONS: In this relatively large group of patients with TRD, ketamine was safe and well tolerated. Further research investigating the safety of ketamine in severe and refractory depression is warranted.

Wan, L. B., Levitch, C. F., Perez, A. M., Brallier, J. W., Iosifescu, D. V., Chang, L. C., … & Murrough, J. W. (2014). Ketamine safety and tolerability in clinical trials for treatment-resistant depression. The Journal of clinical psychiatry. https://dx.doi.org/10.4088/JCP.13m08852

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PTSD and MDMA in the ‘picture’

/ Anxiety Disorders / PTSD, MDMA, Publications /

a5_ptsd_508With an upcoming fMRI study in the United Kingdom, an attempt is being made to outline the neurobiological mechanisms that are hypothesized to underlie the favorable outcome of MDMA-assisted psychotherapy in posttraumatic stress disorder (PTSD).

Earlier studies found that after just a few treatment sessions with MDMA in addition to psychotherapy, there was a significant short [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][1] and long [2] term improvement of PTSD symptomatology in patients that were resistant to regular psycho- and/or pharmacotherapy [3]. Up to today, not much is known about the factors that contribute to the success of this form of treatment. Several researchers suggest that MDMA, o.a. by temporarily reducing fear and by easing interpersonal contact, facilitate the therapy on a psychological level [4], but about the neurobiological foundations remains to be speculated.

By using fMRI, dr. Ben Sessa and his research team at Cardiff University will try to image the manifestation of MDMA in PTSD patients. To capture the effects of the compound in isolation, the patients will not receive any psychotherapy during this study.

The research proposal is currently waiting for approval of the Committee of Ethics.

 
[1] Mithoefer, Wagner, Mithoefer, Jerome, & Doblin (2011)
[2] Mithoefer et al. (2012)
[3] A similar study from Oehen, Traber, Widmer, & Schnyder (2013) did not reach significance on the primary measurement (p = .066), a diagnostic tool to assess PTSD symptomatology, though at a subjective level the patients indicated to have some relief from their former complaints. Bouso et al. (2008) couldn’t draw any firm conclusions on their data of the first MDMA-assisted psychotherapy study in PTSD, due to a sudden unexpected cancellation of the study and the consequencing small study sample.
[4] Bouso, Doblin, Farré, Alcázar, & Gómez-Jarabo (2008), Mithoefer et al. (2011), Oehen et al. (2013)
 
References
Bouso, J. C., Doblin, R., Farré, M., Alcázar, M. A., & Gómez-Jarabo, G. (2008). MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. Journal of Psychoactive Drugs, 40(3), 225–36. doi:10.1080/02791072.2008.10400637
Mithoefer, M. C. M., Wagner, M. M. T., Mithoefer, A. A. T., Jerome, L., Martin, S. F., Yazar-Klosinski, B., … Doblin, R. (2012). Durability of improvement in posttraumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Journal of Psychopharmacology (Oxford, England), 27, 28–39. doi:10.1177/0269881112456611
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology (Oxford, England) (Vol. 25, pp. 439–452). doi:10.1177/0269881110378371
Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2013). A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology (Oxford, England), 27(1), 40–52. doi:10.1177/0269881112464827[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

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PTSS en MDMA in ‘beeld’

/ Uncategorized /

a5_ptsd_508Met een aankomende fMRI studie in het Verenigd Koninkrijk wordt er een poging gedaan om de neurobiologische mechanismen achter het gunstige effect dat MDMA (3,4-methyleendioxymethamfetamine) lijkt te hebben bij de behandeling van posttraumatische stressstoornis (PTSS) bloot te leggen.

Eerdere studies toonden aan dat enkele behandelsessies met MDMA ter aanvulling op een psychotherapeutische behandeling op korte [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][1] en op lange [2] termijn tot een reductie van de symptomen van PTSS kunnen leiden bij patiënten die niet reageren op een reguliere psycho- en/of farmacologische therapie [3]. Het is tot nog toe onduidelijk aan welke factoren de therapeutische werking van deze behandelmethode toe te schrijven valt. Diverse onderzoekers suggereren dat MDMA de behandeling, o.a. door de gereduceerde staat van angst en het vergemakkelijken van interpersoonlijk contact, op psychologisch niveau faciliteert [4], maar over de achterliggende neurobiologische mechanismen is nog weinig bekend.

Middels fMRI zullen dr. Ben Sessa en zijn onderzoeksteam aan Cardiff University de farmacologische invloed van MDMA op het brein van PTSS-patiënten in beeld proberen te brengen. Om de effecten van het middel te isoleren zullen de deelnemers tijdens deze studie geen psychotherapie ondergaan.

Het onderzoeksvoorstel ligt nog ter goedkeuring bij de ethische commissie.

 
[1] Mithoefer, Wagner, Mithoefer, Jerome, & Doblin (2011)
[2] Mithoefer et al. (2012)
[3] Oehen et al. (2013) behaalden met een gelijksoortige studie geen significantie (p=.066) op het diagnostisch instrument waarmee de symptomen van PTSS werden gemeten, hoewel op subjectief niveau de symptomen wel waren verminderd na de behandeling. Bouso et al. (2008) waren met het hun data van het eerste gecontroleerde onderzoek naar psychotherapie met behulp van MDMA niet in staat conclusies te trekken over het therapeutisch potentieel van deze behandeling, omdat de studie onverwachts vroegtijdig werd afgebroken en het beperkte aantal geïncludeerde patiënten geen mogelijkheden bood tot het uitvoeren van statistische analyses.
[4] Bouso, Doblin, Farré, Alcázar, & Gómez-Jarabo (2008), Mithoefer et al. (2011), Oehen et al. (2013)
 
Referenties
Bouso, J. C., Doblin, R., Farré, M., Alcázar, M. A., & Gómez-Jarabo, G. (2008). MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. Journal of Psychoactive Drugs, 40(3), 225–36. doi:10.1080/02791072.2008.10400637
Mithoefer, M. C. M., Wagner, M. M. T., Mithoefer, A. A. T., Jerome, L., Martin, S. F., Yazar-Klosinski, B., … Doblin, R. (2012). Durability of improvement in posttraumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. Journal of Psychopharmacology (Oxford, England), 27, 28–39. doi:10.1177/0269881112456611
Mithoefer, M. C., Wagner, M. T., Mithoefer, A. T., Jerome, L., & Doblin, R. (2011). The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. Journal of psychopharmacology (Oxford, England) (Vol. 25, pp. 439–452). doi:10.1177/0269881110378371
Oehen, P., Traber, R., Widmer, V., & Schnyder, U. (2013). A randomized, controlled pilot study of MDMA (± 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). Journal of Psychopharmacology (Oxford, England), 27(1), 40–52. doi:10.1177/0269881112464827[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]

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Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells

/ Ayahuasca, DMT, Papers, Psychiatry & Medicine, Publications / / , , ,

Abstract

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Szabo, A., Kovacs, A., Frecska, E., & Rajnavolgyi, E. (2014). Psychedelic N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PloS one, 9(8). https://dx.doi.org/10.1371/journal.pone.0106533
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Potential applications for sigma receptor ligands in cancer diagnosis and therapy

/ Ayahuasca, DMT, Papers, Psychiatry & Medicine, Publications / / , , , , ,

Abstract

Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor subpopulations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for human lung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][18F]fluspidine and [18F]FTC-146 for sigma-1 receptors and [11C]RHM-1 and [18F]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported.

van Waarde, A., Rybczynska, A. A., Ramakrishnan, N. K., Ishiwata, K., Elsinga, P. H., & Dierckx, R. A. (2014). Potential applications for sigma receptor ligands in cancer diagnosis and therapy. Biochimica et Biophysica Acta (BBA)-Biomembranes. https://dx.doi.org/10.1016/j.bbamem.2014.08.022

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By its fruits? Mystical and visionary states of consciousness occasioned by entheogens

/ Mushrooms / Psilocybin, Papers, Publications / /

Abstract

A new era has emerged in research on entheogens largely due to clinical trials conducted at Johns Hopkins University and similar studies sponsored by the Council for Spiritual Practices. In these notes and queries, I reflect on implications of these developments for psychological studies of religion and on what this research may mean for Christian churches in the United States. I conclude that the aims and methods of this research fit well within Jamesian efforts of contemporary psychology of religion to assess religious practices by their fruits for life. Furthermore, some communitarian religious concerns that religious experiences occasioned by entheogens pose risks to the integrity of religious community are shown to be largely unfounded. However, it is suggested that certain risks for religious life posed by all investigations/interventions by knowledge experts—in particular, the colonization of the religious life world and the commodification of its practices—also attend these developments for Christian churches. Additionally, risks of individual harm in the use of entheogens appear to be significant and, therefore, warrant earnest ethical study.

Hummel, L. (2014). By its fruits? Mystical and visionary states of consciousness occasioned by entheogens. Zygon: Journal of Religion and Science, 49(3), 685-695. http://dx.doi.org/10.1111/zygo.12112
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Entheogens in a religious context: The case of the Santo Daime religious tradition

/ Ayahuasca, Papers, Publications / /

Abstract

This essay first draws upon the work of William James and others to propose a nonphysicalistic understanding of the relationship between the brain and consciousness in order to articulate a philosophical perspective that can understand entheogenic visionary/mystical experiences as something other than hallucinations. It then focuses on the Santo Daime tradition, a religious movement that began in Brazil in the early part of the twentieth century, to provide an example of the personal and social ramifications of taking an entheogen (ayahuasca) within a disciplined religious context. The essay claims that the Santo Daime is one example of a contemporary mystery school; gives a brief history of the development of this religion; discusses the key theological assumptions of this movement; investigates the important role played by visionary/mystical experiences within this religion; underscores the centrality of healing and spiritual transformation for members of this tradition; and ends with an examination of the crucial significance of spiritual discipline within this entheogenically based religion.

Barnard, G. W. (2014). Entheogens in a religious context: The case of the Santo Daime religious tradition. Zygon: Journal of Religion and Science, 49(3), 666-684. http://dx.doi.org/10.1111/zygo.12109
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Entheogens, Mysticism, and Neuroscience

/ Ayahuasca, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / /

Abstract

Entheogens or psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin are associated with mystical states of experience. Drug laws currently limit research, but important new work is under way at major biomedical research facilities showing that entheogens reliably occasion mystical experiences and thereby allow research into brain states during these experiences. Are drug-occasioned mystical experiences neurologically the same as more traditional mystical states? Are there phenomenological and theological differences? As this research goes forward and the public becomes more widely aware of its achievements, religious scholars and experts in science and religion will be called upon to interpret the philosophical and theological presuppositions that underpin this research and the significance of the findings that flow from it.

Cole-Turner, R. (2014). Entheogens, Mysticism, and Neuroscience. Zygon: Journal of Religion and Science, 49(3), 642-651. http://dx.doi.org/10.1111/zygo.12110
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Determination of muscimol and ibotenic acid in mushrooms of Amanitaceae by capillary electrophoresis.

/ Biology & Ethnobotany, Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Publications / / , , ,

Abstract

In this study, the CZE method for rapid quantitative and qualitative determination of ibotenic acid and muscimol in Amanita mushrooms naturally grown in Poland was developed. The investigations included the species of A. muscaria, A. pantherina, and A. citrina, collected in southern region of Poland. The studied hallucinogenic compounds were effectively extracted with a mixture of methanol and 1 mM sodium phosphate buffer at pH 3 (1:1 v/v) using ultrasound-assisted procedure. The obtained extracts were separated and determined by CZE utilizing a 25 mM sodium phosphate running buffer adjusted to pH 3 with 5% content of acetonitrile v/v. The calibration curves for both analytes were linear in the range of 2.5-7000 μg/mL. The intraday and interday variations of quantitative data were 1.0 and 2.5% RSD, respectively. The recovery values of analyzed compounds were over 87%. The identities of ibotenic acid and muscimol were confirmed by UV spectra, migration time, and measurements after addition of external standard.

Poliwoda, A., Zielińska, K., Halama, M., & Wieczorek, P. P. (2014). Determination of muscimol and ibotenic acid in mushrooms of Amanitaceae by capillary electrophoresis. Electrophoresis, 35(18), 2593-2599. https://dx.doi.org/10.1002/elps.201400104

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