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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

August 29, 2014 / Ayahuasca, DMT, Papers, Psychiatry & Medicine, Publications / By / , , ,

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

August 27, 2014 / Ayahuasca, DMT, Papers, Psychiatry & Medicine, Publications / By / , , , , ,

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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Entheogens, Mysticism, and Neuroscience

August 26, 2014 / Ayahuasca, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By /

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.

August 18, 2014 / Biology & Ethnobotany, Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Publications / By / , , ,

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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Iboga-Type Alkaloids from Ervatamia officinalis

August 5, 2014 / Biology & Ethnobotany, Iboga / Ibogaine, Papers, Pharmacology & Chemistry, Publications / By / , , , , , ,

Abstract

Seven new iboga-type alkaloids, ervaoffines A–D (1–4), (7S)-3-oxoibogaine hydroxyindolenine (5), ibogaine-5,6-dione (6), and 19-epi-5-oxovoacristine (7), and 10 known alkaloids were isolated from Ervatamia officinalis. The absolute configurations of 1–7 were determined through X-ray diffraction and electronic circular dichroism (ECD) analyses. Ervaoffines A and B represent the first iboga-type pseudoindoxyl alkaloids in which the C-2 spiro carbon configuration is opposite to that of other members of this class, such as iboluteine (8). The relationship between the absolute configuration of the spiro carbons and the Cotton effect in the ECD spectrum is established for the first time for iboga-type pseudoindoxyl and oxindole alkaloids. Additionally, a plausible biogenetic pathway for these alkaloids is proposed.

Tang, B. Q., Wang, W. J., Huang, X. J., Li, G. Q., Wang, L., Jiang, R. W., … & Ye, W. C. (2014). Iboga-Type Alkaloids from Ervatamia officinalis. Journal of natural products, 77(8), 1839-1846. https://dx.doi.org/10.1021/np500240b
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Does the Nervous System Have an Intrinsic Archaic Language? Entoptic Images and Phosphenes

August 2, 2014 / Ayahuasca, Biology & Ethnobotany, DMT, Iboga / Ibogaine, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Publications, Salvia / Salvinorin A / By /

Abstract

Psychoactive plants have been consumed by many cultures, cults and groups during religious rituals and ceremonies for centuries and they have been influential on the eruption of the many images, secret and religious symbols, esoteric geometrical shapes, archetypes, religious figures, philosophy of religions since the dawn of Homo sapiens. Some of the psychoactive plants used for religious purposes were; narcotic analgesics (opium), THC (cannabis), psilocybin (magic mushrooms), mescaline (peyote), ibogaine (Tabernanthe iboga), DMT (Ayahuasca and phalaris species), peganum harmala, bufotenin, muscimol (Amanita muscaria), Thujone (Absinthe, Arthemisia absinthium), ephedra, mandragora, star lotus, salvia divinorum etc. An important property of these natural chemicals is to induce the human psyche to perceive some optical forms and shapes, which are existent in the subconscious and collective unconsciousness, and which emerge during some certain trance states and ASCs. Some of these simple geometric forms are called entoptic images and phosphenes. Entopic images and phosphenes have been found in various cultural art work and the drawings of cave walls, which were formed during the shamanic religious rituals since the Neolithic times. Also entoptic images exist in many folkloric, traditional and cultures geometrical shapes. Long before the creation of languages, visual perception and information was the only source for the mankind to perceive outer world, as it is the only one in the primate world. This article reviews the possibility of an ancient forgotten visual sign and symbol language, which is genetically existent in the human brain and that, emerges out during ASCs, trance states and the consciousness altered by the psychoactive plants. The basics of this geometrical sign and symbol language may have generated the formation of some archetypal symbols and concepts, which are yet to be discovered. Near to this, emerging of many attributes of the sub-or-un-consciousness, during those “psychedelic plant journeys” had had a prodigious impact on the formation and creation of many religious “figures, characters, creatures, archetype images” that today exist, not only in the mythology, but also in many religions, as well, such as angels, spirits, Jinns, demons, Satan, mythological creatures, supra-natural creatures, gods, and goddesses. Mystical and religious experiences during the rituals using psychoactive plants may have also helped the archaic ancestral information, coded in the limbic system, to come out onto the consciousness, which may also have helped the evolution of the hominoids and Homo sapiens.

Sayin, H. U. (2014). Does the Nervous System Have an Intrinsic Archaic Language? Entoptic Images and Phosphenes. Neuroquantology, 12(3), 427-445. https://dx.doi.org/10.14704/nq.2014.12.3.756
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Ketamine administration in depressive disorders: a systematic review and meta-analysis

July 20, 2014 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , , , , , , , ,

Abstract

Introduction
Ketamine’s efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine’s effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment.

Methods
Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic.

Results
We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD = −0.99; 95 % CI −1.23, −0.75; p < 0.01). Ketamine’s efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not) (SMD = −0.91; 95 % CI −1.19,−0.64; p < 0.01), in bipolar depression (SMD = −1.34; 95 % CI −1.94, −0.75), and in drug-free patients as well as patients under medication. Four ECT trials (118 patients) were included in our quantitative analysis. One hundred and three patients were diagnosed with major depressive disorder and 15 with bipolar depression. Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD = −0.56; 95 % CI −1.10, −0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine’s effects was assessed in only two non-ECT studies and seemed to persist for 2–3 days; this result needs to be confirmed. Three of four studies found significant decrease of suicidal thoughts and one found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine’s use should remain cautious in patients with a cardiovascular history.

Conclusion
The present meta-analysis confirms ketamine’s efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. The results of this first meta-analysis are encouraging, and further studies are warranted to detail efficacy in bipolar disorders and other specific depressed populations. Middle- and long-term efficacy and safety have yet to be explored. Extrapolation should be cautious: Patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy.

Fond, G., Loundou, A., Rabu, C., Macgregor, A., Lançon, C., Brittner, M. … Boyer, L. (2014). Ketamine administration in depressive disorders: a systematic review and meta-analysis. Psychopharmacology, 231, 3663-3676. http://dx.doi.org/10.1007/s00213-014-3664-5
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Recent advances in the neuropsychopharmacology of serotonergic hallucinogens

July 15, 2014 / DMT, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By /

Abstract

Serotonergic hallucinogens, such as (+)-lysergic acid diethylamide, psilocybin, and mescaline, are somewhat enigmatic substances. Although these drugs are derived from multiple chemical families, they all produce remarkably similar effects in animals and humans, and they show cross-tolerance. This article reviews the evidence demonstrating the serotonin 5-HT2A receptor is the primary site of hallucinogen action. The 5-HT2A receptor is responsible for mediating the effects of hallucinogens in human subjects, as well as in animal behavioral paradigms such as drug discrimination, head twitch response, prepulse inhibition of startle, exploratory behavior, and interval timing. Many recent clinical trials have yielded important new findings regarding the psychopharmacology of these substances. Furthermore, the use of modern imaging and electrophysiological techniques is beginning to help unravel how hallucinogens work in the brain. Evidence is also emerging that hallucinogens may possess therapeutic efficacy.

Halberstadt, A. L. (2014). Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behavioural Brain Research, 277, 99-120. http://dx.doi.org/10.1016/j.bbr.2014.07.016
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The Effects of Ayahuasca Ritual Participation on Gay and Lesbian Identity

July 14, 2014 / Ayahuasca, Papers, Psychology, Publications / By /

Abstract

The practice of drinking ayahuasca—a psychoactive brew indigenous to the Amazon—has been investigated in several studies and shown to have positive long-term effects on mental states, and a particularly strong positive effect on perceptions of identity. This article discusses if these previous findings can be found in the experience of gay people, who are often taught by their culture and religion that their lifestyles, values, and sexual orientation are unacceptable. The qualitative study examined the interview responses of 17 self-identified gay and lesbian participants who had drunk ayahuasca in a ceremonial context within the past three years, regarding their self-perceptions and integration of group beliefs. Participants drank either in shamanic or Santo Daime ceremonies or, in the case of one participant, with an Afro-Brazilian group that used ayahuasca. Participants reported affirmation of their sexual orientation, and no participants reported negative effects on perception of identity. Additional positive effects in other areas of their lives, which they attributed to ayahuasca sessions, contributed to the overall positive outcomes that were reported by this group as a result of their ritual participation.

Cavnar, C. (2014). The effects of ayahuasca ritual participation on gay and lesbian identity. Journal of psychoactive drugs, 46(3), 252-260. https://dx.doi.org/10.1080/02791072.2014.920117

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The role of 5-HT2A, 5-HT2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N,N-dimethyltryptamine and N,N-diisopropyltryptamine in rats and mice

July 3, 2014 / Neuroscience, Papers, Publications / By / , , , , ,

Abstract

Rationale

Serotonin 5-HT2A and 5-HT2C receptors are thought to be the primary pharmacological mechanisms for serotonin-mediated hallucinogenic drugs, but recently there has been interest in metabotropic glutamate (mGluR2) receptors as contributors to the mechanism of hallucinogens.

Objective

The present study assesses the role of these 5-HT and glutamate receptors as molecular targets for two tryptamine hallucinogens, N,N-dimethyltryptamine (DMT) and N,N-diisopropyltryptamine (DiPT).

Methods

Drug discrimination, head twitch, and radioligand binding assays were used. A 5-HT2AR inverse agonist (MDL100907), 5-HT2CR antagonist (SB242084), and mGluR2/3 agonist (LY379268) were tested for their ability to attenuate the discriminative stimulus effects of DMT and DiPT; an mGluR2/3 antagonist (LY341495) was tested for potentiation. MDL100907 was used to attenuate head twitches induced by DMT and DiPT. Radioligand binding studies and inosital-1-phosphate (IP-1) accumulation were performed at the 5-HT2CR for DiPT.

Results

MDL100907 fully blocked the discriminative stimulus effects of DMT, but only partially blocked DiPT. SB242084 partially attenuated the discriminative stimulus effects of DiPT, but produced minimal attenuation of DMT’s effects. LY379268 produced potent, but only partial blockade of the discriminative stimulus effects of DMT. LY341495 facilitated DMT- and DiPT-like effects. Both compounds elicited head twitches (DiPT>DMT) which were blocked by MDL1000907. DiPT was a low-potency full agonist at 5-HT2CR in vitro.

Conclusions

The 5-HT2AR likely plays a major role in mediating the effects of both compounds. 5-HT2C and mGluR2 receptors likely modulate the discriminative stimulus effects of both compounds to some degree.

Carbonaro, T. M., Eshleman, A. J., Forster, M. J., Cheng, K., Rice, K. C., & Gatch, M. B. (2014). The role of 5-HT2A, 5-HT2C and mGlu2 receptors in the behavioral effects of tryptamine hallucinogens N, N-dimethyltryptamine and N, N-diisopropyltryptamine in rats and mice. Psychopharmacology, 1-10. https://dx.doi.org/10.1007/s00213-014-3658-3

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