Activity of Ergolines in Ergot

[red22]

UPDATE Anybody who's interested in the topic of morning glory seeds and ergot should read the following post in this thread (#95); and I've made many of my reference on this topic available here: http://www.bluelight.org/vb/entries/7141-morning-glory-seed-information-archive

My latest contributions to this topic can be found in my Shroomery journal: http://www.shroomery.org/forums/postlist.php/Journal/240779


Originally I created this thread to ask about the hypothetical equilibrium of three different forms of ergine that Peter Webster talks about here:

The equilibrium reaction takes some time to occur, perhaps an hour or more, and is brought about most effectively by basic conditions

Peter Webster, "Secret Recipes - Hofmann Symposium," The Invisible College Magazine, issue no. 2, page 30 http://www.earthrites.org/invisible-college.htm

Webster's hypothesis is based on the following paper:

Full paper: http://rapidgator.net/file/64513007/Tetrahedron.pdf.html

 

[sekio]

If you cannot figure out how to basify water safely; you should not attempt to do ergoloid chemistry.

That epimerization is with sodium methoxide, which is a much stronger base than sodium hydroxide. The epimerization doesn't look like it would work in water solution because as you say, the alkaloid would become a free base and become insoluble. I bet in the presence of water the LSD would be hydrated to lumi-LSD, or outright hydrolysed to lysergic acid and ammonia. (That epimerization is done in dry benzene and methanol, not water).

According to my research, iso-ergine is essentially inactive at the doses ergine is active at. HBWR seeds are about a 40:60 mix of ergine:isoergine, I belive morning glory seeds may be a little higher.

Don't even attempt this process with crude seed extract, you should purify the LSA by chromatography first if you want to (ab)use it that way.

(FYI lysergamide is the axial amide, isolysergamide is the equatiorial amide)

The human oral tract is not really accustomed to strong alkali. So long as the pH of the sol'n does not exceed about 8 to 8.5, it should be safe to drink. Higher pH would cause irritation as you turn the cells in your mouth/esophagus into soap.

ref:food ph list

 

[Solipsis]

Considering this is obviously a little out of your league, why not try the peppermint oil / (was formaldehyde in it the agent?) conversion? Supposedly what is made is LSH but that seems untrue. Anyway whatever the mechanism, people say it is a worthwhile experiment some steps in the direction of LSD and it can be done at home...

 

[sekio]

see this post, & the rest of the thread too.

 

[red22]

Webster seems to be saying that the equilibrium can be achieved by casual processes.


ergine spontaneously changes to isoergine when in solution, over a period of an hour or more...any process to partially hydrolyze the alkaloids of ergot, such as our proposed recipe - or even the Aztec shamans' procedure for extracting ololiuhqui - should result in an equilibrium mixture of the three forms.

So, we have the possibility that a molecule of ergine can be in one of three different states: It can be ergine in the chair or boat conformation, or it can be isoergine in the chair conformation. And in many chemical and physical situations, the three forms are constantly converting from one form to the others, and achieving a typical equilibrium distribution.

We therefore must consider that in an ergot preparation made according to our suggested method - and in morning glory seeds as prepared by Mesoamerican shamans - we are not dealing with pure ergine or pure isoergine.

Source: PDF located at earthrites link in first post (pages 28 to 31)


Even if equilibration cannot be achieved when using water, David Nichols, in his response to Webster, seems to be saying that the benefit of the equilibrium is the increased amount of isoergine (contrary to Webster's idea that all three chemicals in the equilibrium are important). So, even a half way equilibrium may be better than a straight extraction.


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: LSD Symposium transcripts? Posted here.

 

[skillet]

According to my research, iso-ergine is essentially inactive at the doses ergine is active at. HBWR seeds are about a 40:60 mix of ergine:isoergine, I belive morning glory seeds may be a little higher.

What did you find? If that's true it rules out Nichols theory that they'll isomerise in vivo, so it would be better to try to drive the equilibrium towards ergine.

(Methoxide is about as basic as hydroxide, there's not much difference. I wouldn't worry about hydration - look at the conditions lysergic acid stands up to in the hydrolysis of ergotamine. Or hydrolysis - the article in the OP uses only 0.05M methoxide at room temp. for around an hour. And lysergamide seems to have the amide equatorial, isolysergamide axial)

 

[red22]

He probably wasn't aware of Nichols' hypothesis. As Nichols says, "the iso epimers are generally inactive, at least when compared to the normal amides."

I wouldn't go by Hofmann's self trials in the Harvard Botannical Museaum leaflet series, either. Hofmann used intramuscular injection for ergine; and he may have used intramuscular injection for isoergine (it's not clear). Muscles are acidic. As the literature presented indicates, lysergic acid amides are highly reactive. Additionally, a dose of lysergamides in a typical seed extraction may be significantly greater than Hofmann's trials with the isolated chemicals.

Note: The H. Solms study - which Hofmann stated confirmed his self trial - states that "injection" was used (intramuscular injection?): https://www.erowid.org/references/refs_view.php?ID=4195 ("Full Text - Multiple (169 K)") There are two citations above because one publication is in English, and one is in German ( http://www.erowid.org/references/refs_view.php?ID=4089 )

Hofmann, A.: The active principles of the seeds of Rivea Corymbosa and Ipomoea violacea. Botanical Museum Leaflets (Harvard Univ.) 20, 6, 194–211 (1963). http://www.botanicus.org/item/31753003541189# (Must select v. 20 1962-1964 from the drop down menu)

 

[skillet]

Nichols was probably talking about in vitro assays, I read it as, "isoergine is inactive in in vitro assays because it can't effectively bind the receptor, but it's likely to be better absorbed than ergine. If they equilibrate in vivo it could be possible to get higher ergine concentrations at the receptors by ingesting isoergine than if ergine was ingested."

If isoergine is much less active in vivo it rules out that theory. I was just wondering what the evidence for the lower activity was, since ergolines have complex pharmacology it could be hard to tell if a reduced behavioural effect, for example, actually indicated reduced hallucinogenic potency or something else.

I think IM is fine, they're not that unstable. I'm sure plenty of LSD has been administered IM.

 

[red22]

I think IM is fine, they're not that unstable. I'm sure plenty of LSD has been administered IM.

Even Nichols believes the pH may play an integral role: "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?"

I don't think LSD can be compared in this context.

 

[C6541]

Does that say Hofmann used 0.5 mg of ergine? That seems a lowball dose to me, I would think ergine would be a bit less potent than that.

 

[B1tO'RoughJack]

If you cannot figure out how to basify water safely; you should not attempt to do ergoloid chemistry.

agreed. Study please.

 

[red22]

Considering this is obviously a little out of your league, why not try the peppermint oil / (was formaldehyde in it the agent?) conversion? Supposedly what is made is LSH but that seems untrue. Anyway whatever the mechanism, people say it is a worthwhile experiment some steps in the direction of LSD and it can be done at home...

Lysergic acid α-hydroxyethylamide has been identified in analyses of convolvulaceae seeds and ergot since research began on these things. I'm open to the hypothesis that one can increase "LAH" content in a preparation via simple mixing. dmthead420 on The Shroomery is someone who's obtained good experiences from seeds using extraction methods. When he tried the "LAH" procedure, he stated he would never do it any other way again: http://www.shroomery.org/forums/showflat.php/Number/6776759#6776759

Can somebody please provide the following research paper, which states that "LAH" was identified in blood and/or urine samples in two individuals who ingested Hawaiin Baby Woodrose seeds. This is interesting because Peter Webster alleges that LAH will immediately decompose when in the body (Source; Edit -> Find -> hydroxyethylamide (first result)). This paper indicates that that's not true.

Klinke HB, Müller IB, Steffenrud S and Dahl-Sørensen R, Two cases of lysergamide intoxication by ingestion of seeds from Hawaiin Baby Woodrose, Forensic Sci Int, 2010, 197(1-3), e1-5 | http://www.sciencedirect.com/science/article/pii/S0379073809004745

You can upload it to a public file host, such as the one I used (bottom of my first post in this thread).

 

[sekio]

Two cases of lysergamide intoxication by ingestion of seeds from Hawaiian Baby Woodrose
Totally useless IMO. They claim there was LSH detected but do not quantify that any further. (Guy died by flinging himself out a window.)

Identification of ergoline alkaloids in the genus Argyreia and related genera and their chemotaxonomic implications in the convolvulaceae
Demonstrates the highly variable nature of HBWR seeds in terms of subjective effects.

Ergoline alkaloidal constituents of hawaiian baby wood rose, argyreia nervosa (Burm. f.) bojer
Gives % concentrations of alkaloids in HBWR seeds. There is apparently significant LSH to begin with in seeds, but ergine predominates.

 

[King Kong]

dmthead420 on The Shroomery is someone who's obtained good experiences from seeds using extraction methods. When he tried the "LAH" procedure, he stated he would never do it any other way again: http://www.shroomery.org/forums/showflat.php/Number/6776759#6776759

Seems this does do alot more, its alot more refined, clean, less body high all mind high.. i extracted 700 riveas into 100 ml of lemon juice , 50ml water .. that sat 9hrs in the fridge(water stayed the color of lemon juice but smelled like alkaloids) i filtered and added 100ml of sherry wine and that sat 6hours..

How could this protocol leads to LAH?
How ergine, in an acidic and aqueous conditions, could reacts with acetaldehyde (when also many other constituents are present in solution)!
It's not an entropically favored reaction and I doubt it's enthalpically favored too.

Also, what is the smell of an alkaloid in its salt form?!

And "human bioassays" are the worst "analytical" method. It leads to myths such "tan mdpv" or "strychnine in my acid!"

Edit: a little example to show that coupling between aldehyde and amide are possible, but quite complex: http://www.sciencedirect.com/science/article/pii/S0040403907016838

 

[red22]

Thank you for posting those papers, sekio. I greatly appreciate it. Effective message board discussion.

@King Kong

Thank you for your post. I really appreciate your knowledgeable input. Soeone should post the full version of that paper. I can't comment on your statement, but I can point out that the reputable Bluelighter, fastandbulbous, states that simplistic mixture may be sufficient:


Apparently N-(1-hydroxyethyl)lysergamide is an adduct compound formed from lysergamide (lysergic acid amide, LSA/LAA, LA-111) and acetaldehyde. This hints towards the idea that isn't the most stable of compounds, but would be pretty easily formed by the combination of lysergamide & acetaldehyde under physiological conditions (ie a way to get much more & better psychedelic activity from any lysergamide extracted from seed sources)

http://www.bluelight.ru/vb/threads/...xyethylamide?p=3983423&viewfull=1#post3983423

Does that say Hofmann used 0.5 mg of ergine? That seems a lowball dose to me, I would think ergine would be a bit less potent than that.

Grof: Have you actually tried the ololiuqui yourself?

Hofmann: Yes, I did. But, of course, it is about ten times less active; to get a good effect, you need one to two milligrams.

Grof: And what was that experience like?

Hofmann: The experience had some strong narcotic effect, but at the same time there was a very strange sense of voidness. In this Void, everything loses its meaning. It is a very mystical experience.

Stanislav Grof Interviews Dr. Albert Hofmann. MAPS Bulletin 9.2 (Fall 2001): 22–35.


One additional note: According to Owsley Stanley, Albert Hofmann told Owsley that he determined that LAH was experientially the most LSD-like compound of the naturally-occuring lysergic acid amides.


B: Well, people could say the same thing about LSD, they could say there’s sassafras and there’s nutmeg in nature, and there is morning glories and ergot in nature, but you have to do the chemistry in order to make something that’s effective.

O: No, that’s not true. Ergot contains many natural, highly psychedelic alkaloids. Iso-ergine is one of them, hydroxy-methyl-lysergamide* is another one, and in fact, is considered nearly identical to LSD in effect. Albert Hoffman told me so himself. They believe that it was this derivative contained in extracts of c.paspalum that was used in the Eleusian Mysteries.

Eisner, Bruce. "Interview with an Alchemist: Bear Owsley Interview." Bruce Eisner's Writings


*Synonyms:

lysergic acid alpha-hydroxyethylamide
lysergic acid methyl carbinolamide
N-(alpha-Hydroxyethyl)lysergamide
(S)-9,10-Didehydro-N-(1-hydroxyethyl)-6-methylergoline-8beta-carboxamide
Ergoline-8-carboxamide, 9,10-didehydro-N-(1-hydroxyethyl)-6-methyl-, (8-beta)-
Lysergamide, N-(1-hydroxyethyl)- (7CI)
(8beta)-N-(1-hydroxyethyl)-6-methyl-9,10-didehydroergoline-8-carboxamide

http://www.guidechem.com/reference/dic-628998.html

 

[sekio]

I think the real dead end is that acetaldehyde is reactive (likes to trimerize/aldol) and considered toxic, hence levels in food and drink are controlled to the point where you will only ever have trifling quantities of acetaldehyde. Not enough to drive the equilibrium reaction towards LSH. if anytrhing, the natural LSH in the seed would hydrolise first, unless there was acetaldehyde in the liquid you extracted it with.

The equilibrium in question is acetaldehyde + (iso)ergine <--> (iso)LSH. Yes, it goes both ways. Therein lies the rub - an excess of reactants on one side is needed to 'drive' it to the other (or continuous removal of one of the products via Le Chatelier's priniple).

It may be best to stick with a quick alkaloid extraction into lemon juice, and hope for the best, rather than attempting home synthesis of acetaldehyde. Aliphatic aldehydes are... horrible compounds, to say the least. They will burn your skin, the vapours will burn your eyes and mucous membranes, and the smell is unbearable. Not something you want to consume.

The claims that spearmint oil, or brandy/aged spirits contain "appreciable amounts" of acetaldehyde are total hogwash - if they did contain acetaldehyde at appreciable levels they would be unconsumable. Acetaldehyde is toxic and probably a mutagen. (And in alcoholic solution acetaldehyde forms a compound called acetal, but that's something else). Acetaldehyde is also the compound responsible for hangovers.

 

[red22]

What do you guys think of this discussion: http://herbs.maxforum.org/2012/10/17/we-were-wrong-about-lsh/

 

[sekio]

It would produce LST [Lysergic Acid Tetraethylamide]:

Someone does not know how amides and aldehydes form carbinolamides, I see!
this is very, very wrong. Nobody would make the tetraethylamide w/o other reagents involved.

Also, nobody there has actually confirmed anything - it's just chemical masturbation.

 

[red22]

Many people express enthusiasm for synthesizing LSD and ask for details on how the process works. However, they're dissillusioned when they find out that the process of making LSD requires serious connections for chemical precursors and specialized equipment. How does feasibility of producing* LAH compare to the process for LSD? Would it be significantly less specialized?

*Or isolating from a natural source.

 

[sekio]

There's a few big prolems with making LSD and derivatives:
1. LSA, ergotamine, and lysergic acid (precursors) are all controlled substances, so you need to either rob a pharmacy distribution truck full of Cafergot, or set up a fermentation/HBWR grow-op.
2. Lysergic acid derivatives are not very stable, and seperating it from e.g. iso-lysergic acid can be difficult (involves chromatography, which is a bastard of a seperation technique even for experienced chemists). FWIW I think some steps of LSD synthesis need to be done under red light to avoid damage from light.
3. The synthesis of LSx is by no means "mix parts A and B and bake at 450F for an hour". It requires patience and care.


LSH is pretty much the same deal. If you were making LSH from acetaldehyde and LSA, you would first need to have a source of purified LSA, a fume cabinet to do the reaction in, and also a method to handle acetaldehyde (which is corrosive, easily evaporates, and an irritant). The product would probably be sensitive to light and moisture as well.
Given the difficulty of even seperating LSA from the other ergot alkaloids for the lay-man, I doubt people could make LSH in a home lab. The "syntheses" I have seen that involve mixing grain alcohol, hydrogen peroxide, and HBWR seed extract are not "real" syntheses at all, they are kitchen chemistry masturbation at its finest.