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Other substances

Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions.

October 1, 2011 / Other subjects, Other substances, Papers, Psychopharmacology, Publications / By / , , ,

Abstract

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.

Shen, H. W. , Jiang, X. L., Winter, J. C., Yu, A. M. (2013). Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions. Current Drug Metabolism, 11(8),659-66.
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Revisiting Wasson's Soma: Exploring the Effects of Preparation on the Chemistry of Amanita Muscaria

September 20, 2011 / Ethnobotany, History, Indigenous use, Mushrooms / Psilocybin, Other disciplines, Other subjects, Other substances, Papers, Publications / By /

Abstract

In 1968 R. Gordon Wasson first proposed his groundbreaking theory identifying Soma, the hallucinogenic sacrament of the Vedas, as the Amanita muscaria mushroom. While Wasson’s theory has garnered acclaim, it is not without its faults. One omission in Wasson’s theory is his failure to explain how pressing and filtering Soma, as described in the Rig Veda, supports his theory of Soma’s identity. Several critics have reasoned that such preparation should be unnecessary if equivalent results can be obtained by consuming the raw plant, as is done with other psychoactive mushrooms. In order to address these specific criticisms over 600 anecdotal accounts of Amanita muscaria inebriation were collected and analyzed to determine the impact of preparation on Amanita muscaria’s effects. The findings of this study demonstrated that the effects of Amanita muscaria were related to the type of preparation employed, and that its toxic effects were considerably reduced by preparations that paralleled those described for Soma in the Rig Veda. While unlikely to end debate over the identity of Soma, this study’s findings help to solidify the foundation of Wasson’s theory, and also to demonstrate the importance of preparation in understanding and uncovering the true identity of Soma.

Feeney, K. (2010). Revisiting Wasson’s Soma: Exploring the Effects of Preparation on the Chemistry of Amanita Muscaria. Journal of psychoactive drugs, 42(4), 499-506. https://dx.doi.org/ 10.1080/02791072.2010.10400712
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Reassessing the cultural and psychopharmacological significance of Banisteriopsis caapi: preparation, classification and use among the Piaroa of Southern Venezuela

September 8, 2011 / Anthropology, Ayahuasca, Ethnobotany, Indigenous use, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By

Abstract

Recent attention to the monoamine oxidase inhibiting properties of Banisteriopsis caapi‘s harmala alkaloids has precluded a balanced assessment of B. caapi‘s overall significance to indigenous South American societies. Relatively little attention has been paid to the cultural contexts, local meanings and patterns of use of B. caapi among snuff-using societies, such as the Piaroa, who do not prepare decoctions containing N,N-dimethyltryptamine (DMT) admixtures. This article reviews the psychopharmacological literature on B. caapi in light of recent ethnographic work conducted among the Piaroa of southern Venezuela. Piaroa shamans use only B. caapi’s cambium, identify at least five distinct varieties of B. caapi, and emphasise the plant’s importance for heightening empathy. Some Piaroa people also attribute a range of extra-shamanic uses to B. caapi, including as a stimulant and hunting aid. In light of the psychopharmacological complexity of harmala alkaloids, and ethnographic evidence for a wide range of B. caapi uses, future research should reconsider B. caapi‘s cultural heritage and psychopharmacological potential as a stimulant and antidepressant-like substance.

Rodd, R. (2008). Reassessing the cultural and psychopharmacological significance of Banisteriopsis caapi: preparation, classification and use among the Piaroa of Southern Venezuela. Journal of psychoactive drugs, 40(3), 301-307. 10.1080/02791072.2008.10400645
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Heaven and Hell—A Phenomenological Study of Recreational Use of 4-HO-MET in Sweden

August 29, 2011 / New substances, Other substances, Papers, Phenomenology, Psychology, Publications / By / ,

Abstract

The psychoactive substance 4-HO-MET (4-hydroxy-N-methyl-N-ethyltryptamine) with psychedelic qualities is one of many legal so-called Internet drugs. The aim of this qualitative study was to establish an understanding of what characterizes its recreational use. Very little is known about the effects of this substance. Twenty-five anonymous Swedish experience reports (from persons aged 18–30 years) from public Internet forums were analyzed using the Empirical Phenomenological Psychological Method. The analysis produced 37 categories that were compiled into nine general themes: (1) motivation, preparation and expectation; (2) initial effects; (3) change of perception; (4) unfiltered awareness and intensified flow of information; (5) lateral cognition; (6) border between subject and object is erased; (7) heaven; (8) hell; and (9) subsiding effects. An understanding of the chronological happenings, called The Process, appeared out of the general structure. Drastic changes in cognitive, emotional and bodily functions were described. The motivation for use seemed to be driven by a strong curiosity. The experiences shifted between “heaven” and “hell,” but participants appeared satisfied and ready to repeat the experience. The experiences described show great similarity with classic psychedelic substances as LSD or psilocybin. More research is needed about health hazards or possible therapeutic potentials.

Kjellgren, A., & Soussan, C. (2011). Heaven and Hell—A Phenomenological Study of Recreational Use of 4-HO-MET in Sweden. Journal of Psychoactive Drugs, 43(3), 211-219. http://dx.doi.org/10.1080/02791072.2011.605699
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β-Carboline Compounds, Including Harmine, Inhibit DYRK1A and Tau Phosphorylation at Multiple Alzheimer's Disease-Related Sites

May 6, 2011 / Ayahuasca, Medicine, Other subjects, Other substances, Papers, Publications / By / , , , , , ,

Abstract

Harmine, a β-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR) on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer’s disease (AD). Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional β-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope), and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the β-carboline compounds (1) potently reduce the expression of all three phosphorylated forms of tau protein, and (2) inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several β-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.

Frost, D., Meechoovet, B., Wang, T., Gately, S., Giorgetti, M., Shcherbakova, I., & Dunckley, T. (2011). β-carboline compounds, including harmine, inhibit DYRK1A and tau phosphorylation at multiple Alzheimer’s disease-related sites. PLoS One, 6(5). https://dx.doi.org/10.1371/journal.pone.0019264

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Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens

January 20, 2011 / Ayahuasca, Cacti / Mescaline, DMT, LSD, Mushrooms / Psilocybin, Neuroscience, Other subjects, Other substances, Papers, Psychiatry, Psychology, Publications / By / ,

Abstract

Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT(2) receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT(2A) receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5-HT(2) and non-5-HT(2) receptors.

Halberstadt, A. L., & Geyer, M.A. (2011). Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology, 61(3), 364-381. http://dx.doi.org/10.1016/j.neuropharm.2011.01.017
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Investigating the Mechanisms of Hallucinogen-Induced Visions Using 3,4-Methylenedioxyamphetamine (MDA): A Randomized Controlled Trial in Humans

December 2, 2010 / Other subjects, Other substances, Papers, Psychology, Publications / By / , , , , ,

Abstract

Background: The mechanisms of drug-induced visions are poorly understood. Very few serotonergic hallucinogens have been studied in humans in decades, despite widespread use of these drugs and potential relevance of their mechanisms to hallucinations occurring in psychiatric and neurological disorders.

Methodology/Principal Findings: We investigated the mechanisms of hallucinogen-induced visions by measuring the visual and perceptual effects of the hallucinogenic serotonin 5-HT2AR receptor agonist and monoamine releaser, 3,4-methylenedioxyamphetamine (MDA), in a double-blind placebo-controlled study. We found that MDA increased self-report measures of mystical-type experience and other hallucinogen-like effects, including reported visual alterations. MDA produced a significant increase in closed-eye visions (CEVs), with considerable individual variation. Magnitude of CEVs after MDA was associated with lower performance on measures of contour integration and object recognition.

Conclusions/Significance: Drug-induced visions may have greater intensity in people with poor sensory or perceptual processing, suggesting common mechanisms with other hallucinatory syndromes. MDA is a potential tool to investigate mystical experiences and visual perception.

Baggott, M. J., Siegrist, J. D., Galloway, G. P., Robertson, L. C., Coyle, J. R., & Mendelson, J. E. (2010). Investigating the Mechanisms of Hallucinogen-Induced Visions Using 3,4-Methylenedioxyamphetamine (MDA): A Randomized Controlled Trial in Humans. PLoS ONE, 5(12), 1-13. http://dx.doi.org/10.1371/journal.pone.0014074
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Serotonin, But Not N-Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo

October 6, 2010 / Other subjects, Other substances, Papers, Psychopharmacology, Publications / By / ,

Abstract

Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT2AR). Although serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT2AR and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactiveN-methyltryptamines by its ability to engage a β-arrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head-twitch response in wild-type (WT) mice that is a behavioral proxy for 5-HT2AR activation. The response in β-arrestin2 knock-out (βarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, βarr2-KO mice display a head-twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in βarr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in βarr2-KO mice, indicating that N-methyltryptamines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a β-arrestin2/phosphoinositide 3-kinase/Src/Akt cascade, whereas N-methyltryptamines do not. Furthermore, disruption of any of the components of this cascade prevents 5-HTP-induced, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT2AR signaling that is neurotransmitter and β-arrestin2 dependent. This demonstration of agonist-directed 5-HT2AR signaling in vivo may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression.

Schmid, C. L., & Bohn, L. M. (2010). Serotonin, But Not N-Methyltryptamines, Activates the Serotonin 2A Receptor Via a β-Arrestin2/Src/Akt Signaling Complex In Vivo. The Journal of Neuroscience, 30(40), 13513-13524. http://dx.doi.org/10.1523/JNEUROSCI.1665-10.2010

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Abnormal visual experiences in individuals with histories of hallucinogen use: A web-based questionnaire

September 21, 2010 / HPPD, LSD, Neuroscience, Other disciplines, Other subjects, Other substances, Papers, Publications / By / , , , ,

Abstract

Despite longstanding reports of prolonged or reoccurring perceptual changes in a subset of hallucinogen users, very little is known about Hallucinogen Persisting Perception Disorder and related visual abnormalities in hallucinogen users. We used an online questionnaire to document the symptoms and relationship to drug use of unusual visual phenomena in hallucinogen users. 16,192 individuals viewed the information sheet and 2679 were included in the study. Of these, 224 reported having unrelated diagnoses associated with unusual visual experiences and were excluded from main analyses. Most (60.6%) of the remaining 2455 participants reported having experienced drug-free visual experiences that resembled hallucinogen effects. Probability of experiencing constant or near-constant symptoms was predicted by greater past exposure to specific hallucinogens, including lysergic acid diethylamide (LSD). Although symptoms were common, few (104, or 4.2% of the sample) found them distressing or impairing enough to consider seeking treatment. Visual changes in hallucinogen users may be more common than previously suspected and are worthy of further study.

Baggott, M. J., Coyle, J. R., Erowid, E., Erowid, F., & Robertson, L. C. (2011). Abnormal visual experiences in individuals with histories of hallucinogen use: A web-based questionnaire. Drug and alcohol dependence, 114(1), 61-67. http://dx.doi.org/10.1016/j.drugalcdep.2010.09.006
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Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit

September 9, 2010 / LSD, Other subjects, Other substances, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Rationale: Parenteral injections of d-lysergic acid diethylamide (LSD), a serotonin 5-HT2A receptor agonist, enhance eyeblink conditioning. Another hallucinogen, (±)-1(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), was shown to elicit a 5-HT2A-mediated behavior (head bobs) after injection into the hippocampus, a structure known to mediate trace eyeblink conditioning.

Objective: This study aims to determine if parenteral injections of the hallucinogens LSD, d,l-2,5-dimethoxy-4-methylamphetamine, and 5-methoxy-dimethyltryptamine elicit the 5-HT2A-mediated behavior of head bobs and whether intrahippocampal injections of LSD would produce head bobs and enhance trace eyeblink conditioning.

Materials and methods: LSD was infused into the dorsal hippocampus just prior to each of eight conditioning sessions. One day after the last infusion of LSD, DOI was infused into the hippocampus to determine whether there had been a desensitization of the 5-HT2A receptor as measured by a decrease in DOI-elicited head bobs.

Results: Acute parenteral or intrahippocampal LSD elicited a 5-HT2A but not a 5-HT2C-mediated behavior, and chronic administration enhanced conditioned responding relative to vehicle controls. Rabbits that had been chronically infused with 3 or 10 nmol per side of LSD during Pavlovian conditioning and then infused with DOI demonstrated a smaller increase in head bobs relative to controls.

Conclusions: LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT2A receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT2A receptor within the hippocampus as a result of repeated administration of its agonist (LSD).

Romano, A. G., Quinn, J. L., Li, L., Dave, K. D., Schindler, E. A., Aloyo, V. J., & Harvey, J. A. (2010). Intrahippocampal LSD accelerates learning and desensitizes the 5-HT2A receptor in the rabbit. Psychopharmacology, 212(3), 441–448. http://dx.doi.org/10.1007/s00213-010-2004-7
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7 May - Psychedelics, Nature & Mental Health with Sam Gandy

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