Dr. Nichols (chemical scientist at Purdue University who studies LSD) is so impressed with the effects that he is even synthesizing LSI, and writing a journal paper on this ground breaking discovery, citing my book of course he told me.
Can you post your email exchanges with him or highlights/summaries of them?
And can you answer the question I asked you about him in a private message?
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Do you know the source of these statements from David Nichols and Peter Webster:
tregar posted these on other forums.
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Although the pharmacology of isoergine (and even ergine itself) is not well studied, in other lysergic acid amides the iso epimers are generally inactive, at least when compared to the normal amides. Therefore, I still believe that ergine must be the species active at the receptor, but if the ergine/isoergine equilibration can occur at body pH and temp, then ergine could be generated in the brain from isoergine. This may be a key point, and you should go back and look at the Tetrahedron paper[ ✱ ] where they apparently did some kinetics on the process.
Thus, I think that isoergine would lack pharmacological effects. But… there is another factor to consider. Absorption and partitioning through the body and into the brain only occurs with the unprotonated forms of alkaloids. That is, ergine is an alkaloid that will be protonated, or charged, at body pH. As such, before it can be absorbed from the gut or cross into the brain, it must lose its charge, or give up its proton. In the uncharged form it will readily cross into the brain, but this fraction is relatively small, perhaps only a few percent of the total.
Because of the ability of the amide of the D-ring of isoergine to form a stabilizing hydrogen bond to the amine nitrogen, it can deprotonate very easily at body pH, giving a neutral species that will have a very high lipid solubility. The intramolecular hydrogen compensates for the energy cost of deprotonation and desolvation. Using semiempirical methods, I calculated the length of this hydrogen bond to be about 2.65 Angstroms. Somewhat long, but reasonable. The work you cite in Tetrahedron could be used for parallel discussion, but I don't have the paper here. The consequence of the hydrogen bond is that isoergine will be absorbed much more readily than ergine, and will penetrate the brain to a greater extent than ergine. Once inside the brain, however, facile epimerization of isoergine will lead back to an equilibrium that contains ergine, which is most likely the form of the molecule that I believe is active at the receptor. Importantly, however, I think the concentration of ergine could be much higher than if ergine itself was taken, IF epimerization of isoergine back to ergine can occur at physiological conditions. Thus, at the brain receptor where ergine acts, a much higher concentration will be achieved than if ergine had been administered originally. If isoergine did have significant pharmacological activity, something which I doubt, but without evidence, it could be there in pretty high concentration, compared to what would be there after pure ergine administration. So, the question is: if isoergine is placed in pH 7.4 at 37 degrees C, will a significant amount of ergine arise by epimerization in a reasonable amount of time?
This process is completely analogous to the proposal by G.P. Migliaccio, T.-L.N. Shieh, S.R. Byrn, B.A. Hathaway and D.E. Nichols, "Comparison of Solution Conformational Preferences for the Hallucinogens Bufotenin and Psilocin using 360 MHz Proton NMR Spectroscopy", J. Med. Chem. 24, 206-209 (1981) to explain the high lipid solubility of psilocin, compared to bufotenin. In that paper, the authors proposed that an intramolecular hydrogen bond forms between the 4-hydroxy group of psilocin and the side chain amino group, providing enhanced penetration into the brain. Similarly, in isoergine, the hydrogen bond between the amide hydrogen and the unprotonated basic amine provides a very lipid-soluble, neutral substance that can easily be absorbed and penetrate into the brain. In pharmaceutical terms, we could consider that the bioavailability of isoergine would be much higher than that of ergine, following oral administration.
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https://mycotopia.net/topic/10352-lucid-and-visual-morning-glory-lsa-extracts/#entry190606
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L. Bernardi, W. Barbieri, Ergoline derivatives—VIII: Configuration and conformation of lysergamides and dihydrolysergamides, Tetrahedron, Volume 21, Issue 9, 1965, Pages 2539-2551, ISSN 0040-4020, 10.1016/S0040-4020(01)93909-2.
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Also a comment about the graphs: The question here is what conditions is the extract subjected to (and for how long) before (and maybe even during) the HPLC? For instance, some researchers believe that perhaps all the content of MG seeds exists as the d-hydroxyethylamide, and it is the extraction/purification/testing procedures which then produce the APPARENT result that the alkaloids are ergine, isoergine, and maybe still some hydroxyethylamide. Thus your testing procedure might also be subject to this problem. A test that would fill us in on some important data would be to have the rate of epimerisation of ergine to isoergine in basic, neutral, and acidic media (and yes, the equilibrium is not far from 50/50). For this, you'd need to separate one epimer with chromatography, and then measure optical rotation over time. A little tricky to get it right unless ypu've done similar testing before. LSD takes a week to equilibrate even in basic conditions (to 88:12), whereas lysergic acid itself is almost instant in strong base (to 85:15). Prof Nichols believes the ergine-isoergine equilibration is rapid even in body fluids, I suspect it is not, and that this is one reason for the uncertainties we deal with in the book. But no one's got the hard data!
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Peter Webster,
https://www.shroomery.org/forums/showflat.php/Number/6054828#6054828
