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Pharmacology & Chemistry

DARK Classics in Chemical Neuroscience: Salvinorin A

January 3, 2022 / Neuroscience, Papers, Pharmacology & Chemistry, Salvia / Salvinorin A / Leave a Comment / By / , , ,

Abstract

Salvinorin A is the main bioactive compound in Salvia divinorum, an endemic plant with ancestral use by the inhabitants of the Mazateca mountain range (Sierra Mazateca) in Oaxaca, México. The main use of la pastora, as locally known, is in spiritual rites due to its extraordinary hallucinogenic effects. Being the first known nonalkaloidal opioid-mediated psychotropic molecule, salvinorin A set new research areas in neuroscience. The absence of a protonated amine group, common to all previously known opioids, results in a fast metabolism with the concomitant fast elimination and swift loss of activity. The worldwide spread and psychotropic effects of salvinorin A account for its misuse and classification as a drug of abuse. Consequently, salvinorin A and Salvia divinorum are now banned in many countries. Several synthetic efforts have been focused on the improvement of physicochemical and biological properties of salvinorin A: from total synthesis to hundreds of analogues. In this Review, we discuss the impact of salvinorin A in chemistry and neuroscience covering the historical relevance, isolation from natural sources, synthetic efforts, and pharmacological and safety profiles. Altogether, the chemistry behind and the taboo that encloses salvinorin A makes it one of the most exquisite naturally occurring drugs.

Hernández-Alvarado, R. B., Madariaga-Mazón, A., Ortega, A., & Martinez-Mayorga, K. (2020). DARK Classics in Chemical Neuroscience: Salvinorin A. ACS chemical neuroscience, 10.1021/acschemneuro.0c00608. Advance online publication. https://doi.org/10.1021/acschemneuro.0c00608

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Stability of psilocybin and its four analogs in the biomass of the psychotropic mushroom Psilocybe cubensis

November 30, 2021 / Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry / Leave a Comment / By / , , , , ,

Abstract

Psilocybin, psilocin, baeocystin, norbaeocystin, and aeruginascin are tryptamines structurally similar to the neurotransmitter serotonin. Psilocybin and its pharmacologically active metabolite psilocin in particular are known for their psychoactive effects. These substances typically occur in most species of the genus Psilocybe (Fungi, Strophariaceae). Even the sclerotia of some of these fungi known as “magic truffles” are of growing interest in microdosing due to them improving cognitive function studies. In addition to microdosing studies, psilocybin has also been applied in clinical studies, but only its pure form has been administrated so far. Moreover, the determination of tryptamine alkaloids is used in forensic analysis. In this study, freshly cultivated fruit bodies of Psilocybe cubensis were used for monitoring stability (including storage and processing conditions of fruiting bodies). Furthermore, mycelium and the individual parts of the fruiting bodies (caps, stipes, and basidiospores) were also examined. The concentration of tryptamines in final extracts was analyzed using ultra-high-performance liquid chromatography coupled with mass spectrometry. No tryptamines were detected in the basidiospores, and only psilocin was present at 0.47 wt.% in the mycelium. The stipes contained approximately half the amount of tryptamine alkaloids (0.52 wt.%) than the caps (1.03 wt.%); however, these results were not statistically significant, as the concentration of tryptamines in individual fruiting bodies is highly variable. The storage conditions showed that the highest degradation of tryptamines was seen in fresh mushrooms stored at -80°C, and the lowest decay was seen in dried biomass stored in the dark at room temperature.

Gotvaldová, K., Hájková, K., Borovička, J., Jurok, R., Cihlářová, P., & Kuchař, M. (2021). Stability of psilocybin and its four analogs in the biomass of the psychotropic mushroom Psilocybe cubensis. Drug testing and analysis, 13(2), 439–446. https://doi.org/10.1002/dta.2950

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Polypharmacology or “Pharmacological Promiscuity” In Psychedelic Research: What Are We Missing?

November 26, 2021 / Ayahuasca, Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry / Leave a Comment / By / , , ,

Abstract

Research with psychedelic drugs has mainly focused on isolated compounds. However, this approach is challenged by the “polypharmacology” paradigm. In this Viewpoint, we suggest that we may be missing something if we do not use the whole product in the case of ayahuasca or Psilocybe mushrooms. After describing how research on psychedelic drugs can be effectively combined with the polypharmacology paradigm, ethical issues are also briefly discussed.

Ona, G. S., Dos Santos, R. G., Hallak, J., & Bouso, J. C. (2020). Polypharmacology or “Pharmacological Promiscuity” In Psychedelic Research: What Are We Missing?. ACS chemical neuroscience, 11(20), 3191–3193. https://doi.org/10.1021/acschemneuro.0c00614

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Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids

February 21, 2022 / LSD, Papers, Pharmacology & Chemistry / Leave a Comment / By / ,

Abstract

While the use of ergot alkaloids in folk medicine has been practiced for millennia, systematic investigations on their therapeutic potential began about 100 years ago. Subsequently, Albert Hofmann’s discovery of lysergic acid diethylamide (LSD) and its intense psychedelic properties garnered worldwide attention and prompted further studies of this compound class. As a result, several natural ergot alkaloids were discovered and unnatural analogs were synthesized, and some were used to treat an array of maladies, including Alzheimer’s and Parkinson’s disease. While LSD was never commercially approved, recent clinical studies have found it can be an innovative and effective treatment option for several psychiatric disorders. Ongoing biosynthetic and total synthetic investigations aim to understand the natural origins of ergot alkaloids, help develop facile means to produce these natural products and enable their continued use as medicinal chemistry lead structures. This review recounts major developments over the past 20 years in biosynthetic, total synthetic, and pharmaceutical studies. Many ergot alkaloid biosynthetic pathways have been elucidated, with some of them subsequently applied toward “green” syntheses. New chemical methodologies have fostered a fast and efficient access to the ergoline scaffold, prompting some groups to investigate biological properties of natural product-like ergot alkaloids. Limited pharmaceutical applications have yet to completely bypass the undesirable side effects of ergotism, suggesting further studies of this drug class are likely needed and will potentially harness major therapeutic significance.

Tasker, N. R., & Wipf, P. (2021). Biosynthesis, total synthesis, and biological profiles of Ergot alkaloids. The Alkaloids. Chemistry and biology, 85, 1–112. https://doi.org/10.1016/bs.alkal.2020.08.001

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Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis

November 26, 2021 / Depressive Disorders, Ketamine, Papers, Pharmacology & Chemistry, Psychology / Leave a Comment / By / , ,

Abstract

Background: Ketamine appears to have a therapeutic role in certain mental disorders, most notably depression. However, the comparative performance of different formulations of ketamine is less clear.

Objectives: This study aimed to assess the comparative efficacy and tolerability of racemic and esketamine for the treatment of unipolar and bipolar major depression.

Design: Systematic review and meta-analysis.

Data sources: We searched PubMed, MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for relevant studies published since database inception and December 17, 2019.

Study eligibility criteria: We considered randomized controlled trials examining racemic or esketamine for the treatment of unipolar or bipolar major depression.

Outcomes: Primary outcomes were response and remission from depression, change in depression severity, suicidality, retention in treatment, drop-outs, and drop-outs due to adverse events.

Analysis: Evidence from randomized controlled trials was synthesized as rate ratios (RRs) for treatment response, disorder remission, adverse events, and withdrawals and as standardized mean differences (SMDs) for change in symptoms, via random-effects meta-analyses.

Findings: 24 trials representing 1877 participants were pooled. Racemic ketamine relative to esketamine demonstrated greater overall response (RR = 3.01 vs. RR = 1.38) and remission rates (RR = 3.70 vs. RR = 1.47), as well as lower dropouts (RR = 0.76 vs. RR = 1.37).

Conclusions: Intravenous ketamine appears to be more efficacious than intranasal esketamine for the treatment of depression.

Bahji, A., Vazquez, G. H., & Zarate, C. A., Jr (2021). Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of affective disorders, 278, 542–555. https://doi.org/10.1016/j.jad.2020.09.071

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Structure of a Hallucinogen-Activated Gq-Coupled 5-HT 2A Serotonin Receptor

November 18, 2021 / LSD, Neuroscience, Papers, Pharmacology & Chemistry / Leave a Comment / By / , , , , , , , , , , , ,

Abstract

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

Kim, K., Che, T., Panova, O., DiBerto, J. F., Lyu, J., Krumm, B. E., Wacker, D., Robertson, M. J., Seven, A. B., Nichols, D. E., Shoichet, B. K., Skiniotis, G., & Roth, B. L. (2020). Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell, 182(6), 1574–1588.e19. https://doi.org/10.1016/j.cell.2020.08.024

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Chemical Composition of Traditional and Analog Ayahuasca

November 18, 2021 / Anthropology & Sociology, Ayahuasca, Papers, Pharmacology & Chemistry / Leave a Comment / By / , , , ,

Abstract

Traditional ayahuasca can be defined as a brew made from Amazonian vine Banisteriopsis caapi and Amazonian admixture plants. Ayahuasca is used by indigenous groups in Amazonia, as a sacrament in syncretic Brazilian religions, and in healing and spiritual ceremonies internationally. The study aimed to determine concentrations of the main bio- and psychoactive components of ayahuasca used in different locations and traditions. We collected 102 samples of brews from ayahuasca-using communities. Concentrations of N,N-dimethyltryptamine (DMT), tetrahydroharmine, harmine, and harmaline were determined by ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). Qualitative analyses for non-traditional additives (moclobemide, psilocin, yuremamine) were performed by high resolution mass spectrometry. Higher and more variable concentrations of DMT in neoshamanic ayahuasca samples compared to indigenous samples may indicate use of higher and more variable proportions of DMT-containing admixture plants. From European samples, we found two related samples of analog ayahuasca containing moclobemide, psilocin, DMT, yuremamine, and very low concentrations of B. caapi alkaloids. Some analogs of ayahuasca (Peganum harmala, Mimosa tenuiflora) were used in Europe. No analogs were found from Brazil or Santo Daime ceremonies in Europe. We recommend awareness about the constituents of the brew and ethical self-regulation among practitioners of ayahuasca ceremonies.

Kaasik, H., Souza, R., Zandonadi, F. S., Tófoli, L. F., & Sussulini, A. (2021). Chemical Composition of Traditional and Analog Ayahuasca. Journal of psychoactive drugs, 53(1), 65–75. https://doi.org/10.1080/02791072.2020.1815911

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The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3,4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats

September 1, 2020 / MDMA, Neuroscience, Papers, Pharmacology & Chemistry, Publications / By / , , , , ,

Abstract

Rationale: The nonmedical use of new psychoactive substances (NPS) is a worldwide public health concern. The so-called “benzofury” compounds, 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (6-APB), are NPS with stimulant-like properties in human users. These substances are known to interact with monoamine transporters and 5-HT receptors in transfected cells, but less is known about their effects in animal models.

Methods: Here, we used in vitro monoamine transporter assays in rat brain synaptosomes to characterize the effects of 5-APB and 6-APB, together with their N-methyl derivatives 5-MAPB and 6-MAPB, in comparison with 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA). In vivo neurochemical and behavioral effects of 5-APB (0.3 and 1.0 mg/kg, i.v.) and 6-APB (0.3 and 1.0 mg/kg, i.v.) were assessed in comparison with MDA (1.0 and 3.0 mg/kg, i.v.) using microdialysis sampling in the nucleus accumbens of conscious male rats.

Results: All four benzofuran derivatives were substrate-type releasers at dopamine transporters (DAT), norepinephrine transporters (NET), and serotonin transporters (SERT) with nanomolar potencies, similar to the profile of effects produced by MDA and MDMA. However, the benzofurans were at least threefold more potent than MDA and MDMA at evoking transporter-mediated release. Like MDA, both benzofurans induced dose-related elevations in extracellular dopamine and serotonin in the brain, but benzofurans were more potent than MDA. The benzofuran derivatives also induced profound behavioral activation characterized by forward locomotion which lasted for at least 2 h post-injection.

Conclusions: Overall, benzofurans are more potent than MDA in vitro and in vivo, producing sustained stimulant-like effects in rats. These data suggest that benzofuran-type compounds may have abuse liability and could pose risks for adverse effects, especially if used in conjunction with abused drugs or medications which enhance monoamine transmission in the brain.

Brandt, S. D., Walters, H. M., Partilla, J. S., Blough, B. E., Kavanagh, P. V., & Baumann, M. H. (2020). The psychoactive aminoalkylbenzofuran derivatives, 5-APB and 6-APB, mimic the effects of 3, 4-methylenedioxyamphetamine (MDA) on monoamine transmission in male rats. Psychopharmacology, 237(12), 3703-3714; 10.1007/s00213-020-05648-z

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Phytochemical, Cytotoxicity, Antioxidant and Anti-Inflammatory Effects of Psilocybe Natalensis Magic Mushroom

August 31, 2020 / Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Publications / By / , , ,

Abstract

Psilocybin-containing mushrooms, commonly known as magic mushrooms, have been used since ancient and recent times for depression and to improve quality of life. However, their anti-inflammatory properties are not known. The study aims at investing cytotoxicity; antioxidant; and, for the first time, anti-inflammatory effects of Psilocybe natalensis, a psilocybin-containing mushroom that grows in South Africa, on lipopolysaccharide-induced RAW 264.7 macrophages. Macrophage cells were stimulated with lipopolysaccharide and treated with different concentrations of Psilocybe natalensis mushroom extracted with boiling hot water, cold water and ethanol over 24 h. Quercetin and N-nitro-L-arginine methyl ester were used as positive controls. Effects of extracts on the lipopolysaccharide-induced nitric oxide, prostaglandin E2, and cytokine activities were investigated. Phytochemical analysis, and the antioxidant and cytotoxicity of extracts, were determined. Results showed that the three extracts inhibited the lipopolysaccharide-induced nitric oxide, prostaglandin E2, and interleukin 1β cytokine production significantly in a dose-dependent manner close to that of the positive controls. A study proposed that ethanol and water extracts of Psilocybe natalensis mushroom were safe at concentrations used, and have antioxidant and anti-inflammatory effects. Phytochemical analysis confirmed the presence of natural antioxidant and anti-inflammatory compounds in the mushroom extracts.

Nkadimeng, S. M., Nabatanzi, A., Steinmann, C. M., & Eloff, J. N. (2020). Phytochemical, Cytotoxicity, Antioxidant and Anti-Inflammatory Effects of Psilocybe Natalensis Magic Mushroom. Plants, 9(9), 1127; https://doi.org/10.3390/plants9091127

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Plasma psilocin critically determines behavioral and neurobiological effects of psilocybin

August 25, 2020 / Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry, Psychiatry & Medicine, Publications / By / ,

Madsen, M. K., & Knudsen, G. M. (2021). Plasma psilocin critically determines behavioral and neurobiological effects of psilocybin. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 46(1), 257-258; 10.1038/s41386-020-00823-4
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