red22
Bluelighter
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Although the subject of natural ergoamides is usually ignored, I just read some of the findings of the most in-depth study of synthetic LSA, after finally getting it translated, and it conveys something odd: the effects of iso-LSA sound decent, while the effects of LSA sound bad. Of course, it's kind of vague and seemingly written by researchers with the "psychotomimetic" attitude, so no conclusions can be drawn from it, but what's interesting is that even David Nichols distinguishes iso-LSA from LSA by suggesting that unlike other ergoamides, it may be active and may serve as a prodrug for LSA, and may even be the superior choice. So, because of that, I thought this was worth posting in here. You can read selections of the LSA study here and below is, I believe, an email of David Nichols'.
Also, one might speculate that their samples had an ergot toxin or a toxic ergot reactant in them. What are the chances of that?
[The title of the study, for reference: Die psychische Wirkung der mexikanischen Droge „Ololiuqui“ am Menschen. Heim, E., Heimann, H. & Lukács, G. Psychopharmacologia 13, 35–48 (1968). DOI: 10.1007/BF00401617]
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.
Source: https://mycotopia.net/topic/10352-lucid-and-visual-morning-glory-lsa-extracts/#entry190606
*Ergoline derivatives—VIII: Configuration and conformation of lysergamides and dihydrolysergamides. L. Bernardi, W. Barbieri. 1965. Tetrahedron, volume 21, issue 9, pages 2539-2551. DOI: 10.1016/S0040-4020(01)93909-2
This email was in reply to Peter Webster's comments about LSA's pharmacology in his lecture at the 2006 LSD symposium, wherein he claimed that Ipomoea tricolor seed extract "produced one of the most powerful psychedelic experiences I had known" (1:09:08 in the below video).
Carl P. Ruck, Peter Webster - The Mythology and Chemistry of the Eleusinian Mysteries (2006). @gaiamedia, Oct 25, 2013
The video is set to start at the pharmacology info (57:28).
If iso-LSA really is better than LSA, people will obviously want to do it at home. I think both the above study and the lecture explain how to do it, and I also found this...
Epimerization Studies of LSD Using 1H Nuclear Magnetic Resonance (NMR) Spectroscopy. S.J. Salamone, Z. Li, A.J. McNally, S. Vitone, R.S. Wu. 1997. Journal of Analytical Toxicology, volume 21, issue 6, pages 492–497. DOI: 10.1093/jat/21.6.492
Also, one might speculate that their samples had an ergot toxin or a toxic ergot reactant in them. What are the chances of that?
[The title of the study, for reference: Die psychische Wirkung der mexikanischen Droge „Ololiuqui“ am Menschen. Heim, E., Heimann, H. & Lukács, G. Psychopharmacologia 13, 35–48 (1968). DOI: 10.1007/BF00401617]
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.
Source: https://mycotopia.net/topic/10352-lucid-and-visual-morning-glory-lsa-extracts/#entry190606
*Ergoline derivatives—VIII: Configuration and conformation of lysergamides and dihydrolysergamides. L. Bernardi, W. Barbieri. 1965. Tetrahedron, volume 21, issue 9, pages 2539-2551. DOI: 10.1016/S0040-4020(01)93909-2
This email was in reply to Peter Webster's comments about LSA's pharmacology in his lecture at the 2006 LSD symposium, wherein he claimed that Ipomoea tricolor seed extract "produced one of the most powerful psychedelic experiences I had known" (1:09:08 in the below video).
Carl P. Ruck, Peter Webster - The Mythology and Chemistry of the Eleusinian Mysteries (2006). @gaiamedia, Oct 25, 2013
The video is set to start at the pharmacology info (57:28).
If iso-LSA really is better than LSA, people will obviously want to do it at home. I think both the above study and the lecture explain how to do it, and I also found this...
Epimerization Studies of LSD Using 1H Nuclear Magnetic Resonance (NMR) Spectroscopy. S.J. Salamone, Z. Li, A.J. McNally, S. Vitone, R.S. Wu. 1997. Journal of Analytical Toxicology, volume 21, issue 6, pages 492–497. DOI: 10.1093/jat/21.6.492
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