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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

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

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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Enhanced repertoire of brain dynamical states during the psychedelic experience

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

Abstract

The study of rapid changes in brain dynamics and functional connectivity (FC) is of increasing interest in neuroimaging. Brain states departing from normal waking consciousness are expected to be accompanied by alterations in the aforementioned dynamics. In particular, the psychedelic experience produced by psilocybin (a substance found in `magic mushrooms`) is characterized by unconstrained cognition and profound alterations in the perception of time, space and selfhood. Considering the spontaneous and subjective manifestation of these effects, we hypothesize that neural correlates of the psychedelic experience can be found in the dynamics and variability of spontaneous brain activity fluctuations and connectivity, measurable with functional Magnetic Resonance Imaging (fMRI). Fifteen healthy subjects were scanned before, during and after intravenous infusion of psilocybin and an inert placebo. Blood-Oxygen Level Dependent (BOLD) temporal variability was assessed computing the variance and total spectral power, resulting in increased signal variability bilaterally in the hippocampi and anterior cingulate cortex. Changes in BOLD signal spectral behavior (including spectral scaling exponents) affected exclusively higher brain systems such as the default mode, executive control and dorsal attention networks. A novel framework enabled us to track different connectivity states explored by the brain during rest. This approach revealed a wider repertoire of connectivity states post-psilocybin than during control conditions. Together, the present results provide a comprehensive account of the effects of psilocybin on dynamical behaviour in the human brain at a macroscopic level and may have implications for our understanding of the unconstrained, hyper-associative quality of consciousness in the psychedelic state.

Tagliazucchi, E., Carhart-Harris, R. L., Leech, R., Nutt, D., & Chialvo, D. R. (2014). Enhanced repertoire of brain dynamical states during the psychedelic experience. Human Brain Mapping, 35(11), 5442-5456. http://dx.doi.org/10.1002/hbm.22562
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(R,S)-Ketamine metabolites (R,S)-norketamine and (2S,6S)-hydroxynorketamine increase the mammalian target of rapamycin function

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

Abstract

BACKGROUND: Subanesthetic doses of (R,S)-ketamine are used in the treatment of neuropathic pain and depression. In the rat, the antidepressant effects of (R,S)-ketamine are associated with increased activity and function of mammalian target of rapamycin (mTOR); however, (R,S)-ketamine is extensively metabolized and the contribution of its metabolites to increased mTOR signaling is unknown.

METHODS: Rats (n = 3 per time point) were given (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine and their effect on the mTOR pathway determined after 20, 30, and 60 min. PC-12 pheochromocytoma cells (n = 3 per experiment) were treated with escalating concentrations of each compound and the impact on the mTOR pathway was determined.

RESULTS: The phosphorylation of mTOR and its downstream targets was significantly increased in rat prefrontal cortex tissue by more than ~2.5-, ~25-, and ~2-fold, respectively, in response to a 60-min postadministration of (R,S)-ketamine, (R,S)-norketamine, and (2S,6S)-hydroxynorketamine (P < 0.05, ANOVA analysis). In PC-12 pheochromocytoma cells, the test compounds activated the mTOR pathway in a concentration-dependent manner, which resulted in a significantly higher expression of serine racemase with ~2-fold increases at 0.05 nM (2S,6S)-hydroxynorketamine, 10 nM (R,S)-norketamine, and 1,000 nM (R,S)-ketamine. The potency of the effect reflected antagonistic activity of the test compounds at the α7-nicotinic acetylcholine receptor.

CONCLUSIONS: The data demonstrate that (R,S)-norketamine and (2S,6S)-hydroxynorketamine have potent pharmacological activity both in vitro and in vivo and contribute to the molecular effects produced by subanesthetic doses of (R,S)-ketamine. The results suggest that the determination of the mechanisms underlying the antidepressant and analgesic effects of (R,S)-ketamine requires a full study of the parent compound and its metabolites.

Paul, R. K., Singh, N. S., Khadeer, M., Moaddel, R., Sanghvi, M., Green, C. E., … & Wainer, I. W. (2014). (R, S)-Ketamine metabolites (R, S)-norketamine and (2S, 6S)-hydroxynorketamine increase the mammalian target of rapamycin function. The Journal of the American Society of Anesthesiologists, 121(1), 149-159. http://dx.doi.org/10.1097/ALN.0000000000000285
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Examining the psychological mechanisms of psilocybin-assisted smoking cessation treatment: A pilot study

/ Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / / , ,

Abstract

Anthropological evidence and early experimental studies suggest that structured administration of 5-HT2A agonist hallucinogens (e.g., LSD, psilocybin) may have potential in treating addictions, including alcoholism and opioid dependence. Psilocybin administration has been recently linked to persisting effects including personality change (i.e., increased NEO Openness), mood enhancement, and behavior change. The association between mood, personality, and addiction has been well documented, and suggests that psilocybin may be useful in the treatment of addiction.

Garcia-Romeu, A. P., Johnson, M. W., & Griffiths, R. R. (2014). Examining the psychological mechanisms of psilocybin-assisted smoking cessation treatment: A pilot study. Drug & Alcohol Dependence, 140, e66. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.200
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Harmine for catatonic schizophrenia. A forgotten experiment

/ Depressive Disorders, Humanities & Art, Papers, Psychiatry & Medicine, Psychology, Publications / / , ,

Abstract

The purpose of this letter is to present a lesser-known experiment suggesting a positive response of catatonic schizophrenia to Harmine, a monoamine oxidase A inhibitor(MAO-A), a study conducted by Petre Tomescu, in the late 1920’s.

 

Hostiuc, S., Buda, O., & Ion, D. A. (2014). Harmine for catatonic schizophrenia. A forgotten experiment. Schizophrenia research, 1(159), 249-250. http://dx.doi.org/10.1016/j.schres.2014.08.006

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Ayahuasca Shamanism in the Amazon and Beyond

/ Publications /

Ayahuasca_shamanism

Beatriz Caiuby Labate and Clancy Cavnar offer an in-depth exploration of how Amerindian epistemology and ontology concerning indigenous shamanic rituals of the Amazon have spread to Western societies, and of how indigenous, mestizo, and cosmopolitan cultures have engaged with and transformed these forest traditions. The volume focuses on the use of ayahuasca, a psychoactive drink essential in many indigenous shamanic rituals of the Amazon. Ayahuasca use has spread far beyond its Amazonian origin, spurring a variety of legal and cultural responses in the countries to which it has spread. The essays in this volume look at how these responses have influenced ritual design and performance in traditional and non-traditional contexts, how displaced indigenous people and rubber tappers are engaged in the creative reinvention of rituals, and how these rituals help build ethnic alliances and cultural and political strategies for their marginalized position. Some essays explore important classic and contemporary issues in anthropology, including the relationship between the expansion of ecotourism and ethnic tourism and recent indigenous cultural revival and the emergence of new ethnic identities. The volume also examines trends in the commodification of indigenous cultures in post-colonial contexts, the combination of shamanism with a network of health and spiritually related services, and identity hybridization in global societies. The rich ethnographies and extensive analysis of these essays will allow deeper understanding of the role of ritual in mediating the encounter between indigenous traditions and modern societies.

Ayahuasca Shamanism in the Amazon and Beyond, door Beatriz Caiuby Labate & Clancy Cavnar (Editors), Oxford Ritual Studies reeks, Oxford University Press, 320 pagina’s.

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The Consumption of Psychoactive Plants in Ancient Global and Anatolian Cultures During Religious Rituals: The Roots of the Eruption of Mythological Figures and Common Symbols in Religions and Myths

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

Abstract

Psychoactive plants which contain hallucinogenic molecules that induce a form of altered states of consciousness (H-ASC) have been widely used during the religious rituals of many cultures throughout the centuries, while the consumption of these plants for spiritual and religious purposes is as old as human history. Some of those cultures were shaman and pagan subcultures; African native religions; Bwiti Cult; South American native religions; Amazon Cultures; Central American Cultures; Mexican subcultures; Aztec, Maya and Inca; Wiccan and witch subcultures; Satanists; American Indians; Greek and Hellenistic cultures; Sufis; Hassan Sabbah’s Hashissins; Hindu, Indian and Tibetan cultures; some of the Nordic subcultures etc. Some of the psychoactive ingredients of the plants that were used during these religious rituals 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. The main purposes of the practice of these plants were: spiritual healing; to contact with spirits; to contact with the souls of ancestors; to reach enlightenment (Nirvana or Satori); to become a master shaman, pagan or witch; to reach so-called-other realities, etc. Such “psychedelic-philosophical plant rituals” changed participating persons’ psychology, philosophy and personality to a great degree. In these two successive articles, the consumption of psychedelic plants during religious rituals is reviewed and it is hypothesized that the images, Figures, illusions and hallucinations experienced during these “plant trips” had a great impact on the formation and creation of many Figures, characters, creatures, archetype images that exist not only in the mythology, but also in many religions, as well, such as angels, demons, Satan, mythological creatures, gods, goddesses etc. In the Middle East and Anatolia, within many hermetic and pagan religions, Greek and Hellenic cultures psychoactive plant use was a serious part of the religious rituals, such as Dionysian rituals or Witch’s’ Sabbaths. Although the impact of the “psychedelic experience and imagination” was enormous to the configuration of many religious and mythological characters, and archetypes, this fact has been underestimated and even unnoticed by many historians and anthropologists, because of the quasi-ethical trends of “anti-drug-brain-washed Western Societies”.
Sayin, H. U. (2014). The Consumption of Psychoactive Plants in Ancient Global and Anatolian Cultures During Religious Rituals: The Roots of the Eruption of Mythological Figures and Common Symbols in Religions and Myths. NeuroQuantology, 12(2), 276-296. https://dx.doi.org/10.14704/nq.2014.12.2.753
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Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder

/ Anxiety Disorders / PTSD, Ketamine, Papers, Psychology, Publications / / , , , , , ,

Abstract

Importance  Few pharmacotherapies have demonstrated sufficient efficacy in the treatment of posttraumatic stress disorder (PTSD), a chronic and disabling condition.

Objective  To test the efficacy and safety of a single intravenous subanesthetic dose of ketamine for the treatment of PTSD and associated depressive symptoms in patients with chronic PTSD.

Design, Setting, and Participants  Proof-of-concept, randomized, double-blind, crossover trial comparing ketamine with an active placebo control, midazolam, conducted at a single site (Icahn School of Medicine at Mount Sinai, New York, New York). Forty-one patients with chronic PTSD related to a range of trauma exposures were recruited via advertisements.

Interventions  Intravenous infusion of ketamine hydrochloride (0.5 mg/kg) and midazolam (0.045 mg/kg).

Main Outcomes and Measures  The primary outcome measure was change in PTSD symptom severity, measured using the Impact of Event Scale–Revised. Secondary outcome measures included the Montgomery-Asberg Depression Rating Scale, the Clinical Global Impression–Severity and –Improvement scales, and adverse effect measures, including the Clinician-Administered Dissociative States Scale, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale.

Results  Ketamine infusion was associated with significant and rapid reduction in PTSD symptom severity, compared with midazolam, when assessed 24 hours after infusion (mean difference in Impact of Event Scale–Revised score, 12.7 [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”][95% CI, 2.5-22.8]; P = .02). Greater reduction of PTSD symptoms following treatment with ketamine was evident in both crossover and first-period analyses, and remained significant after adjusting for baseline and 24-hour depressive symptom severity. Ketamine was also associated with reduction in comorbid depressive symptoms and with improvement in overall clinical presentation. Ketamine was generally well tolerated without clinically significant persistent dissociative symptoms.

Conclusions and Relevance  This study provides the first evidence for rapid reduction in symptom severity following ketamine infusion in patients with chronic PTSD. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with this disabling condition.

Feder, A., Parides, M. K., Murrough, J. W., Perez, A. M., Morgan, J. E., Saxena, S., … & Charney, D. S. (2014). Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA psychiatry, 71(6), 681-688. https://dx.doi.org/10.1001/jamapsychiatry.2014.62
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Psychoactive Plants: A Neglected Area of Ethnobotanical Research in Southern Africa (Review)

/ Biology & Ethnobotany, Papers, Publications / /

Abstract

Psychoactive plant research has been actively pursued over the last century around the world, particularly in the Americas. Yet, southern Africa has often been regarded to have relatively few psychoactive plant species of cultural importance with little research conducted on the region’s potential psychoactive flora. However, in the last decade, renewed interest has occurred in the study of psychoactive plants from southern Africa. Recent anthropological studies have demonstrated the significance of psychoactive plant medicines in the initiation process of southern African traditional healers and in treating mental illness, while numerous ethnopharmacological studies have screened southern African plants for psychotropic activity, with promising new findings and research directions resulting. Yet, despite this great progress, the indigenous cultural (ritual) uses of psychoactive plants by the indigenous people of southern Africa remains a neglected area of ethnobotanical research. Aspects identified as requiring further study include: the indigenous cultural understandings of mental illness and psychoactive plants, the role of psychoactive plants in the spiritual practices of southern African traditional healers, the influence of various psychoactive plant species used in traditional formulas and the folklore and mythology relating to indigenous psychoactive plants. Thus, much is still to be learnt and documented from the southern African traditional healers regarding their worldview and their botanical, diagnostic, methodological and healing knowledge that can provide insights into the treatment of mental illness and the actions of psychoactive plants.

Jean-Francois, S. (2014). Psychoactive Plants: A Neglected Area of Ethnobotanical Research in Southern Africa (Review). STUDIES ON ETHNO-MEDICINE, 8(2), 165-172.
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Hallucinogen persisting perception disorder and the serotonergic system: A comprehensive review including new MDMA-related clinical cases

/ Neuroscience, Papers, Psychology, Publications / / , , ,

Abstract

Hallucinogen persisting perception disorder (HPPD) is a drug-induced condition associated with inaccurate visual representations. Since the underlying mechanism(s) are largely unknown, this review aims to uncover aspects underlying its etiology. Available evidence on HPPD and drug-related altered visual processing was reviewed and the majority of HPPD cases were attributed to drugs with agonistic effects on serotonergic 5-HT2A receptors. Moreover, we present 31 new HPPD cases that link HPPD to the use of ecstasy (MDMA), which is known to reverse serotonin reuptake and acts as agonist on 5-HT2A receptors. The available evidence suggests that HPPD symptoms may be a result from a misbalance of inhibitory-excitatory activity in low-level visual processing and GABA-releasing inhibitory interneurons may be involved. However, high co-morbidities with anxiety, attention problems and derealization symptoms add complexity to the etiology of HPPD. Also, other perceptual disorders that show similarity to HPPD cannot be ruled out in presentations to clinical treatment. Taken together, evidence is still sparse, though low-level visual processing may play an important role. A novel finding of this review study, evidenced by our new cases, is that ecstasy (MDMA) use may also induce symptoms of HPPD.

Litjens, R. P., Brunt, T. M., Alderliefste, G. J., & Westerink, R. H. (2014). Hallucinogen persisting perception disorder and the serotonergic system: A comprehensive review including new MDMA-related clinical cases. European Neuropsychopharmacology, 24(8), 1309-1323. https://dx.doi.org/10.1016/j.euroneuro.2014.05.008

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Breath and Body: Scientific and Experiential Perspectives on Breathwork - September 23rd

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