OPEN Foundation

Chemistry

LSD, my problem child

LSD, My Problem Child. Albert Hofmann. Oxford University Press. ISBN: 978-0198840206

In a highly candid and personal account, the father of LSD details the history of his “problem child” and his long and fruitful career as a research chemist. An essential read for anyone wanting to learn about how LSD originated and Hofmann’s view on its transition to recreational use.

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Breaking Open the Head: A Psychedelic Journey into the Heart of Contemporary Shamanism

Breaking Open the Head: A Psychedelic Journey into the Heart of Contemporary Shamanism. Daniel Pinchbeck. Broadway Books. ISBN: 978-0767907439

Daniel Pinchbeck tells the story of the encounters between the modern consciousness of the West and psychedelic substances, including thinkers like Allen Ginsberg, Antonin Artaud, Walter Benjamin, and Terence McKenna, and the new wave present-day ethnobotanists, chemists, psychonauts and philosophers.

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TIHKAL: The Continuation

TIHKAL: The Continuation. Alexander Shulgin, Ann Shulgin. Transform Press. ISBN: 978-0963009692

In a sequel to PiHKAL, the first part continues the story of the Shulgins’ relationship and the second part provided synthesis information about tryptamines. Shulgin has made the second part freely available on Erowid.org.

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PiHKAL: A Chemical Love Story

PiHKAL: A Chemical Love Story. Alexander Shulgin, Ann Shulgin. Transform Press. ISBN: 978-0963009609

One part fictionalized autobiography of the Shulgin’s relationship and one part chemistry cookbook for a variety of phenethylamines. This book is not easy to get your hands on and while it is considered a classic text, the second part of the part will not be easily accessible to those without knowledge of chemistry. The Shulgin’s were motivated to make the synthesis information of these compounds readily available to protect public access to this information.

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Chemoenzymatic Synthesis of 5-Methylpsilocybin: A Tryptamine with Potential Psychedelic Activity

Abstract

A novel analogue of psilocybin was produced by hybrid chemoenzymatic synthesis in sufficient quantity to enable bioassay. Utilizing purified 4-hydroxytryptamine kinase from Psilocybe cubensis, chemically synthesized 5-methylpsilocin (2) was enzymatically phosphorylated to provide 5-methylpsilocybin (1). The zwitterionic product was isolated from the enzymatic step with high purity utilizing a solvent-antisolvent precipitation approach. Subsequently, 1 was tested for psychedelic-like activity using the mouse head-twitch response assay, which indicated activity that was more potent than the psychedelic dimethyltryptamine, but less potent than that of psilocybin.

Fricke, J., Sherwood, A. M., Halberstadt, A. L., Kargbo, R. B., & Hoffmeister, D. (2021). Chemoenzymatic Synthesis of 5-Methylpsilocybin: A Tryptamine with Potential Psychedelic Activity. Journal of natural products, 84(4), 1403–1408. https://doi.org/10.1021/acs.jnatprod.1c00087

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A non-hallucinogenic psychedelic analogue with therapeutic potential

Abstract

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., Vargas, M. V., McCarroll, M. N., Taylor, J. C., Myers-Turnbull, D., Liu, T., Yaghoobi, B., Laskowski, L. J., Anderson, E. I., Zhang, G., Viswanathan, J., Brown, B. M., Tjia, M., Dunlap, L. E., Rabow, Z. T., … Olson, D. E. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474–479. https://doi.org/10.1038/s41586-020-3008-z

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Synthesis and Characterization of 5-MeO-DMT Succinate for Clinical Use

Abstract

To support clinical use, a multigram-scale process has been developed to provide 5-MeO-DMT, a psychedelic natural product found in the parotid gland secretions of the toad, Incilius alvarius. Several synthetic routes were initially explored, and the selected process featured an optimized Fischer indole reaction to 5-MeO-DMT freebase in high-yield, from which the 1:1 succinate salt was produced to provide 136 g of crystalline active pharmaceutical ingredient (API) with 99.86% peak area by high-performance liquid chromatography (HPLC) and a net yield of 49%. The report provides in-process monitoring, validated analytical methods, impurity formation and removal, and solid-state characterization of the API essential for subsequent clinical development.

Sherwood, A. M., Claveau, R., Lancelotta, R., Kaylo, K. W., & Lenoch, K. (2020). Synthesis and Characterization of 5-MeO-DMT Succinate for Clinical Use. ACS omega, 5(49), 32067–32075. https://doi.org/10.1021/acsomega.0c05099

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Quantum chemical (QM:MM) investigation of the mechanism of enzymatic reaction of tryptamine and N,N-dimethyltryptamine with monoamine oxidase A

Abstract

The endogenous psychedelic (mind-altering) N,N-dimethyltryptamine (DMT) molecule has an important role in tissue protection, regeneration, and immunity via sigma-1 receptor activation as its natural ligand. The immunologic properties of DMT suggest this biogenic compound should be investigated thoroughly in other aspects as well. In our in silico project, we examined the metabolism of DMT and its primary analogue, the tryptamine (T), by the monoamine oxidase (MAO) flavoenzyme. MAO has two isoforms, MAO-A and MAO-B. MAOs perform the oxidation of various monoamines by their flavin adenine dinucleotide (FAD) cofactor. Two-layer QM:MM calculations at the ONIOM(M06-2X/6-31++G(d,p):UFF=QEq) level were performed including the whole enzyme to explore the potential energy surface (PES) of the reactions. Our findings reinforced that a hybrid mechanism, a mixture of pure H+ and H transfer pathways, describes precisely the rate-determining step of amine oxidation as suggested by earlier works. Additionally, our results show that the oxidation of tertiary amine DMT requires a lower activation barrier than the primary amine T. This may reflect a general rule, thus we recommend further investigations. Furthermore, we demonstrated that at pH 7.4 the protonated form of these substrates enter the enzyme. As the deprotonation of substrates is crucial, we presumed protonated cofactor, FADH+, may form. Surprisingly, the activation barriers are much lower compared to FAD with both substrates. Therefore, we suggest further investigations in this direction.

Kubicskó, K., , & Farkas, Ö., (2020). Quantum chemical (QM:MM) investigation of the mechanism of enzymatic reaction of tryptamine and N,N-dimethyltryptamine with monoamine oxidase A. Organic & biomolecular chemistry, 18(47), 9660–9674. https://doi.org/10.1039/d0ob01118e

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DARK Classics in Chemical Neuroscience: Salvinorin A

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

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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