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Chemistry

The hallucinogenic world of tryptamines: an updated review

April 16, 2015 / Chemistry, DMT, LSD, Mushrooms / Psilocybin, New substances, Other substances, Papers, Psychology, Publications, Safety, Toxicology / By / , , , ,

Abstract

In the area of psychotropic drugs, tryptamines are known to be a broad class of classical or serotonergic hallucinogens. These drugs are capable of producing profound changes in sensory perception, mood and thought in humans and act primarily as agonists of the 5-HT2A receptor. Well-known tryptamines such as psilocybin contained in Aztec sacred mushrooms and N,N-dimethyltryptamine (DMT), present in South American psychoactive beverage ayahuasca, have been restrictedly used since ancient times in sociocultural and ritual contexts. However, with the discovery of hallucinogenic properties of lysergic acid diethylamide (LSD) in mid-1900s, tryptamines began to be used recreationally among young people. More recently, new synthetically produced tryptamine hallucinogens, such as alpha-methyltryptamine (AMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT), emerged in the recreational drug market, which have been claimed as the next-generation designer drugs to replace LSD (‘legal’ alternatives to LSD). Tryptamine derivatives are widely accessible over the Internet through companies selling them as ‘research chemicals’, but can also be sold in ‘headshops’ and street dealers. Reports of intoxication and deaths related to the use of new tryptamines have been described over the last years, raising international concern over tryptamines. However, the lack of literature pertaining to pharmacological and toxicological properties of new tryptamine hallucinogens hampers the assessment of their actual potential harm to general public health. This review provides a comprehensive update on tryptamine hallucinogens, concerning their historical background, prevalence, patterns of use and legal status, chemistry, toxicokinetics, toxicodynamics and their physiological and toxicological effects on animals and humans.

Araújo, A. M., Carvalho, F., de Lourdes Bastos, M., de Pinho, P. G., & Carvalho, M. (2015). The hallucinogenic world of tryptamines: an updated review. Archives of toxicology, 1-23. https://dx.doi.org/10.1007/s00204-015-1513-x
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Concise synthesis of N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine starting with bufotenine from Brazilian Anadenanthera ssp..

April 10, 2015 / Chemistry, DMT, Ethnobotany, Other subjects, Papers, Publications / By / , , , ,

Abstract

Bufotenine (1, 5-hydroxy-N,N-dimethyltryptamine) was isolated from seeds of Anadenanthera spp., a tree widespread in the Brazilian cerrado, using an efficient acid-base shakeout protocol. The conversion of bufotenine into N,N-dimethyltryptamine (4) and 5-methoxy-N,N-dimethyltryptamine (5) was accomplished through an innovative and short approach featuring the use of novel bufotenine-aminoborane complex (7). Furthermore, an easy methodology for conversion of bufotenine into 5-hydroxy-N,N,N-trimethyltryptamine (6) was well-established. This is the first study that highlights bufotenine as a resource for the production of N,N-dimethyltryptamines for either pharmacological and toxicological investigations or for synthetic purposes.

Moreira, L. A., Murta, M. M., Gatto, C. C., Fagg, C. W., & dos Santos, M. L. (2015). Concise synthesis of N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine starting with bufotenine from Brazilian Anadenanthera ssp.. Natural product communications, 10(4), 581-584.
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Ex vivo effects of ibogaine on the activity of antioxidative enzymes in human erythrocytes

February 7, 2015 / Chemistry, Iboga / Ibogaine, Neuroscience, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Ethnopharmacological relevance

Ibogaine is a naturally occurring alkaloid with psychotropic and metabotropic effects, derived from the bark of the root of the West African Tabernanthe iboga plant. The tribes of Kongo basin have been using iboga as a stimulant, for medicinal purposes, and in rite of passage ceremonies, for centuries. Besides, it has been found that this drug has anti-addictive effects.

Aim of the study

Previous studies have demonstrated that ibogaine changed the quantity of ATP and energy related enzymes as well as the activity of antioxidant enzymes in cells thus altering redox equilibrium in a time manner. In this work, the mechanism of its action was further studied by measuring the effects of ibogaine in human erythrocytes in vitro on ATP liberation, membrane fluidity and antioxidant enzymes activity.

Materials and methods

Heparinized human blood samples were incubated with ibogaine (10 and 20 μM) at 37°C for 1 h. Blood plasma was separated by centrifugation and the levels of ATP and uric acid were measured 10 min after the addition of ibogaine using standard kits. The activity of copper–zinc superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were measured in erythrocytes after incubation period. The stability of SOD1 activity was further tested through in vitro incubation with H2O2 and scanning of its electrophoretic profiles. Membrane fluidity was determined using an electron paramagnetic resonance spin-labelling method.

Results

Results showed that ibogaine treatment of erythrocytes in vitro increased ATP concentration in the blood plasma without changes in neither erythrocytes membrane fluidity nor uric acid concentration. Ibogaine also increased SOD1 activity in erythrocytes at both doses applied here. Treatment with 20 μM also elevated GR activity after in vitro incubation at 37 °C. Electrophoretic profiles revealed that incubation with ibogaine mitigates H2O2 mediated suppression of SOD1 activity.

Conclusion

Some of the effects of ibogaine seem to be mediated through its influence on energy metabolism, redox active processes and the effects of discrete fluctuations of individual reactive oxygen species on different levels of enzyme activities. Overall, ibogaine acts as a pro-antioxidant by increasing activity of antioxidative enzymes and as an adaptagene in oxidative distress.

Nikolić-Kokić, A., Oreščanin-Dušić, Z., Spasojević, I., Slavić, M., Mijušković, A., Paškulin, R., … & Blagojević, D. P. (2015). Ex vivo effects of ibogaine on the activity of antioxidative enzymes in human erythrocytes. Journal of ethnopharmacology, 164, 64-70. http://dx.doi.org/10.1016/j.jep.2015.01.037
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Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues

December 26, 2014 / Addiction, Chemistry, Other subjects, Other substances, Papers, Psychopharmacology, Publications, Salvia / Salvinorin A / By / , , , , ,

Abstract

The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.

Riley, A. P., Groer, C. E., Young, D., Ewald, A. W., Kivell, B. M., & Prisinzano, T. E. (2014). Synthesis and Kappa Opioid Receptor Activity of Furan-Substituted Salvinorin A Analogues. Journal of medicinal chemistry. https://dx.doi.org/10.1021/jm501521d
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Conformational, spectroscopic and nonlinear optical properties of biologically active N,N-dimethyltryptamine molecule: A theoretical study

December 10, 2014 / Chemistry, DMT, Other subjects, Papers, Publications / By / , , ,

Abstract

The effective psychoactive properties of N,N-dimethyltryptamine (DMT) known as the near-death molecule have encouraged the imagination of many research disciplines for several decades. Although there is no theoretical study, a number of paper composed by experimental techniques have been reported for DMT molecule. In this study, the molecular modeling of DMT was carried out using B3LYP and HSEh1PBE levels of density functional theory (DFT). Our calculations showed that the energy gap between HOMO and LUMO is low, demonstrating that DMT is a biologically active molecule. Large hyperconjugation interaction energies imply that molecular charge transfer occurs in DMT. Moreover, NLO analysis indicates that DMT can be used an effective NLO material.

Öner, N., Tamer, Ö., Avcı, D., & Atalay, Y. (2014). Conformational, spectroscopic and nonlinear optical properties of biologically active N, N-dimethyltryptamine molecule: A theoretical study. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 133, 542-549. https://dx.doi.org/10.1016/j.saa.2014.06.037

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Dictyonema huaorani (Agaricales: Hygrophoraceae), a new lichenized basidiomycete from Amazonian Ecuador with presumed hallucinogenic properties

November 7, 2014 / Chemistry, Ethnobotany, New substances, Other subjects, Other substances, Papers, Publications / By / , , , , ,

Abstract

Dictyonema huaorani, a new species represented by a well-developed specimen found in the Ecuadorian Amazon region, is described in this paper. The material was collected during a Harvard ethnobotanical expedition in 1981 and originally determined by Mason E. Hale Jr. as belonging in the genus Dictyonema (D. sericeum s.lat.) and possibly representing an undescribed species. The species is morphologically distinctive in forming densely woven, semicircular thalli, closely resembling those of the paleotropical D. ligulatum but lacking clamps and with hyphal sheath around the photobiont filaments that resembles those of Cyphellostereum species. The species was reported to have hallucinogenic properties and chemical analyses suggest certain substances present that are shared with the hallucinogenic mushroom Psilocybe cubensis. Due to our inability to use pure reference compounds and scarce amount of sample for compound identification, however, our analyses were not able to determine conclusively the presence of hallucinogenic substances.

Schmull, M., Dal-Forno, M., Lücking, R., Cao, S., Clardy, J., & Lawrey, J. D. (2014). Dictyonema huaorani (Agaricales: Hygrophoraceae), a new lichenized basidiomycete from Amazonian Ecuador with presumed hallucinogenic properties. The Bryologist, 117(4), 386-394. http://dx.doi.org/10.1639/0007-2745-117.4.386

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A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2

October 8, 2014 / Chemistry, Other subjects, Papers, Psychopharmacology, Publications / By / , , , ,

Abstract

With recent progress in determination of G protein-coupled receptor (GPCR) structure with crystallography, a variety of other experimental approaches (e.g., NMR spectroscopy, fluorescent-based assays, mass spectrometry techniques) are also being used to characterize state-specific and ligand-specific conformational states. MD simulations offer a powerful complementary approach to elucidate the dynamic features associated with ligand-specific GPCR conformations. To shed light on the conformational elements and dynamics of the important aspect of GPCR functional selectivity, we carried out unbiased microsecond-length MD simulations of the human serotonin 2A receptor (5-HT2AR) in the absence of ligand and bound to four distinct serotonergic agonists. The 5-HT2AR is a suitable system to study the structural features involved in the ligand-dependent conformational heterogeneity of GPCRs because it is well-characterized experimentally and exhibits a strong agonist-specific phenotype in that some 5-HT2AR agonists induce LSD-like hallucinations, while others lack this psychoactive property entirely. Here we report evidence for structural and dynamic differences in 5-HT2AR interacting with such pharmacologically distinct ligands, hallucinogens, and nonhallucinogens obtained from all-atom MD simulations. Differential ligand binding contacts were identified for structurally similar hallucinogens and nonhallucinogens and found to correspond to different conformations in the intracellular loop 2 (ICL2). From the different ICL2 conformations, functional selective phenotypes are suggested through effects on dimerization and/or distinct direct interaction with effector proteins. The findings are presented in the context of currently proposed hallucinogenesis mechanisms, and ICL2 is proposed as a fine-tuning selective switch that can differentiates modes of 5-HT2AR activation.

Perez-Aguilar, J. M., Shan, J., LeVine, M. V., Khelashvili, G., & Weinstein, H. (2014). A functional selectivity mechanism at the serotonin-2A GPCR involves ligand-dependent conformations of intracellular loop 2. Journal of the American Chemical Society, 136(45), 16044-16054. https://dx.doi.org/10.1021/ja508394x
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Michael acceptor approach to the design of new salvinorin A-based high affinity ligands for the kappa-opioid receptor

October 6, 2014 / Chemistry, New substances, Other substances, Papers, Psychopharmacology, Publications, Salvia / Salvinorin A / By / , , , , ,

Abstract

The neoclerodane diterpenoid salvinorin A is a major secondary metabolite isolated from the psychoactive plant Salvia divinorum. Salvinorin A has been shown to have high affinity and selectivity for the κ-opioid receptor (KOR). To study the ligand–receptor interactions that occur between salvinorin A and the KOR, a new series of salvinorin A derivatives bearing potentially reactive Michael acceptor functional groups at C-2 was synthesized and used to probe the salvinorin A binding site. The κ-, δ-, and μ-opioid receptor (KOR, DOR and MOR, respectively) binding affinities and KOR efficacies were measured for the new compounds. Although none showed wash-resistant irreversible binding, most of them showed high affinity for the KOR, and some exhibited dual affinity to KOR and MOR. Molecular modeling techniques based on the recently-determined crystal structure of the KOR combined with results from mutagenesis studies, competitive binding, functional assays and structure–activity relationships, and previous salvinorin A–KOR interaction models were used to identify putative interaction modes of the new compounds with the KOR and MOR.

Polepally, P. R., Setola, V., Vardy, E., Roth, B. L., Mosier, P. D., & Zjawiony, J. (2014). Michael Acceptor Approach to the Design of New Salvinorin A-Based High Affinity Ligands to the Kappa-Opioid Receptor. Planta Medica, 78(5), 818-829. https://dx.doi.org/10.1016/j.ejmech.2014.07.077
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Determination of muscimol and ibotenic acid in mushrooms of Amanitaceae by capillary electrophoresis.

August 18, 2014 / Chemistry, Ethnobotany, Mushrooms / Psilocybin, Papers, 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 / Chemistry, Ethnobotany, Iboga / Ibogaine, New substances, Other subjects, Other substances, Papers, 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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7 May - Psychedelics, Nature & Mental Health with Sam Gandy

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