Nikita Obidin

Semi-professional swirler of test tubes. MIT graduate student building better tools for studying the brain.

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Further explorations into naturally-occurring isoquinolines: the aporphines

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This week’s post will be a shorter one than usual but I wanted to do another medium-intensity dive into the mysterious ‘third’ or ‘fourth’ family of hallucinogenic substances, depending on your taxonomic preference. Like I mentioned in a previous post, isoquinolines are a relatively unexplored group of naturally-occurring molecules which are somewhat ubiquitous in many plant species. They’re understudied partially due to their relative abundance and partially due to a lack of interest in elucidating activity in humans. I specifically wanted to focus on a subfamily of isoquinolines, known as aporphine derivatives. I’ve already talked about one of them, namely glaucine! Glaucine is a 5-HT2A selective agonist with a number of other properties, including bronchodilating and anti-inflammatory effects. Okay everything makes sense so far. Selective 5-HT2A agonism is the bread-and-butter of...

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Phenethylamines I have feared and loathed

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In the course of a burgeoning interest in atypical pharmacology as a tool for studying the brain, one comes across a number of similarly interested characters. You will find that some are neurotically obsessed with rigor and refuse to even discuss what these things do on a subjective level while others will insist you sit down and listen to their story of aligning a colleague’s moon chakra using an herbal intoxicant. While the two sides seem to disagree on pretty much everything, there does seem to be a common distaste for anything that’s not a ‘typical’ psychedelic like psilocybin or ayahuasca. Wait, no, you can’t move that hydroxy group from the 4 to the 5 position! Once the conversation drifts in that direction, they seem to conjure up images of underground drug labs in Ohio run by people named ‘toad pRofit$’ being raided by the DEA. If a tryptamine therapy is run with a shaman using...

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Isoquinolines: structural analogues of the mysterious third family

Isoquinolines are a rather large naturally-occurring family of benzopyridines which find medical applications in everything from antihypertensives to anti-retrovirals to anesthetics. But they have an interesting hidden side which is to date pretty unexplored.

Those familiar with Alex Shulgin’s work will no doubt remember making their way through PIHKAL, first through the autobiographical chapters and then the synthesis portion where phenethylamines (a family which includes 2C-B, 2C-C, MDMA, and mescaline) are described in impressive detail. Some have also picked up TIHKAL, the continuation of the journey through the space of hallucinogenic compounds, this time covering tryptamines (psilocin, bufotenine, DMT, and LSD) with the same basic book structure.

Not including the various compiled studies and reports that Shulgin wrote over the course of his career, there is a third major...

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The neurobiological activity of hallucinogenic tryptamines

the full preprint containing a tryptamine index is available at https://www.dropbox.com/s/orchzuivtsoos1y/Tryptamines%20of%20Interest.pdf?dl=0

TLDR

  • Hallucinogenic tryptamines appear highly effective against a variety of neuropsychiatric conditions

  • Central activity, including hallucinogenic properties, depends on functional selectivity at the 5-HT2A receptor

  • Neural correlates of psychedelic activity includes glutamatergic transmission in the cerebral cortex, inhibition of slow oscillations, increases in extracellular GABA, and an increase in spontaneous signal diversity

  • Central activity in humans is highly dependent on specific chemical functional group substitutions at the 4 and 5 positions on the benzene indole ring

Longer Abstract Summary

Tryptamine-derived compounds, many of them hallucinogenic, have been found to be potent pharmaceutical agents1. In particular, psilocin...

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Enantiomeric MDMA and Neurotoxicity

Some exciting research came out of Emory University a few years ago, though it was not widely reported at the time. Leonard Howell (who has since retired) and his group discovered that while racemic MDMA (a mixture of the R(-) and S(+) enantiomers) produced neurotoxic effects in mice, administering just the R(-)-enantiomer did no such thing.1,2

To give some background, the neurotoxicity of MDMA has been suspected for quite some time, going back a few decades. While the mechanism has not been fully uncovered, MDMA appears to produce damage to the serotonergic axon terminals in the striatum, hippocampus, and prefrontal cortex.3 As a result, we seem to find lower expression levels of tryptophan hydroxylase (the rate limiting enzyme involved in serotonin synthesis) and 5HT (serotonin itself) in rodents after a series of heavy doses of MDMA, as well as lower levels of DAT and SERT...

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On Lucretius

If you were to assemble a tea with the great Classical poets and philosophers from the ancient world, you would certainly leave a chair open for Cicero, for Homer, for Virgil, Sophocles, Plato, and Livy. Leaving an entire row empty for the Stoics and the Cynics would be indisputable. However, not many would choose to include Lucretius, that great Epicurean poet of the Roman Republic, on such a guest list, and if so, somewhere near the bottom of the invitation order. His great epic De Rerum Natura (The Nature of Things), has no great battles, no gods, or epic heroes or magic. It is devoid of all of the typical elements of a contemporary ‘Great’ work. Instead, it is a sprawling 7000 line tribute to science and philosophy, which manages to lay out a self-contained coherent axiomatic framework many millennia ahead of its time. In this strictly materialist world there are no deities, nothing...

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The Geographical Eden in Southern Iraq

The Garden of Eden is one of the most well known allegories in Western Christendom. While most would consider Eden to be primarily an Abrahamic myth, there is a reasonable amount of evidence to suggest that it has a historical basis. Notably, Genesis actually gives a detailed description of it from a geographical perspective:

And a river went out of Eden to water the garden; and from thence it was parted, and became into four heads. The name of the first is Pison: that is it which compasseth the whole land of Havilah, where there is gold; And the gold of that land is good: there is bdellium and the onyx stone. And the name of the second river is Gihon: the same is it that compasseth the whole land of Ethiopia. And the name of the third river is Hiddekel [Tigris]: that is it which goeth toward the east of Assyria. And the fourth river is Euphrates

(Genesis 2:10-14).

While two of those...

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2019 Bookshelf

Still Reading/In Progress

Reinforcement Learning - Richard Sutton and Andrew Barto

The Nature of Things by Lucretius

A Separate Reality by Carlos Castaneda

Finished

Generation “∏” by Victor Pelevin
(5/7)

A Scanner Darkly by Philip K. Dick
(4/7)

Autobiography of Red by Anne Carson
(5/7)

The Teachings of Don Juan: A Yaqui Way of Knowledge by Carlos Castaneda
(7/7)

The Hidden Life of Trees by Peter Wohlleben
(6/7)

Stranger in the Woods by Michael Finkel
(5/7)

Will read by the end of the year

High Output Management by Andrew Grove

Letter to Menoeceus by Epicurus

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The interplay of ‘pravda’ and ‘istina’ in the Russian language

Though it is not widely known, the Russian language contains two separate and distinct words which coarsely translate to ‘truth’, at least when put through Google Translate. I would argue that most native Russian speakers would consider the notion of any equivalence between the two to be entirely absurd, as pravda and istina represent not only two different conceptualizations of truth but also come at the question from two entirely different and distinct perspectives.

Pravda, also the name of the famous Soviet daily newspaper, is a fixed and factual truth. It is mathematical, rational, and debatable. You could imagine it at the end of a long two column proof. I think this is probably closer to the notion of truth or fact that most English speakers would relate to. But pravda is also limited by a certain subjectivity; specifically that it is something which requires definition and can...

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Favorite Books at the Moment

In no particular order:

1.) The Beginning of Infinity by David Deutsch

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2.) Homage to Catalonia by George Orwell

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3.) The World As Will And Representation by Arthur Schopenhauer

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4.) Groundwork of the Metaphysic of Morals by Immanuel Kant

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5.) Fear and Trembling by Søren Kierkegaard

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6.) An Introduction to Systems Biology by Uri Alon

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7.) The Origins and Ideals of the Modern School by Francisco Ferrer

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8.) Being and Event by Alain Badiou

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9.) Advanced Transport Phenomena by L. Gary Leal

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10.) Master and Margarita by Mikhail Bulgakov

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