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Salvinorin Cyclodextrin Complexation for Sublingual Administration Options
 
physics envy
#81 Posted : 7/24/2018 8:08:53 PM

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Zebbie wrote:
Have you ever wondered why extract has a patchy record when quidded? ...

On the other hand, if someone is lazy and does not purify the salvinorin solution, they would have a better fortified leaf for quidding. ...


That's all beyond my knowledge but makes sense.

In my particular trials above, I just used the straight up extract (which was probably 2:1 chlorophyll/leaf:salvinorin) and not a re-fortified leaf. So maybe that's why it worked. I haven't actually tried quidding any of my enhanced leaf...perhaps that experiment would fail.
Salvia quid enthusiast
 

Good quality Syrian rue (Peganum harmala) for an incredible price!
 
Zebbie
#82 Posted : 7/25/2018 10:23:02 AM

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I have read through this entire thread half a dozen times, because it is so interesting, and corresponds well with what I am trying to achieve.

Your straight up extract intrigues me. It is chemically active, but does not disperse well in saliva. It appears to be sticky, because it became embedded in your molars.

Perhaps it can be deposited onto an inert, non-porous substrate, like unscented talcum powder. Maybe corn starch is suitable. Under an electron microscope, corn starch granules appear smooth and round, without cracks or fissures. Cellulose fibres would probably work as well, because they are not porous. You need to avoid things like dried leaf, which behaves like a sponge. It is important to get the salvinorin to reside on the outside of the substrate, not the inside.

physics envy wrote:

I recently completed an extraction from 2oz of leaf. (I used long pulls, which resulted in black tar....)


I would like to repeat your extraction, and try depositing onto various substrates. I think the choice of solvent is important. Did you use 75% ethanol or 99% ethanol as a solvent? 99% ethanol may be an excellent solvent for salvinorin A, but a poor solvent for the gums and saponins you need. The 75% ethanol is a worse solvent for salvinorin A, but may be better for the other components.

I could also try a sequential extraction, e.g. acetone, followed by something that would dissolve the more water-soluble components in salvia leaf. I would combine the extracts, and deposit that onto my non-porous substrate.
 
physics envy
#83 Posted : 7/25/2018 6:09:54 PM

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Zebbie wrote:
Did you use 75% ethanol or 99% ethanol as a solvent? 99% ethanol may be an excellent solvent for salvinorin A, but a poor solvent for the gums and saponins you need. The 75% ethanol is a worse solvent for salvinorin A, but may be better for the other components.


Just to clarify, I only used the 75% Everclear during the complexation process...not during the salvinorin extraction process.

I used cold-to-luke warm acetone for the pulls (started at 20F), then naphtha several times to clean. I did not use additional cleaning steps with IPA to get a pure extract...I just left it at that somewhat crude phase which I eventually bioassayed.

For the extraction process, I basically followed the first half of Gibran's method from his pinned thread here.

I'm guessing you've extracted salvinorin previously, but if not, you can avoid the black tar mess I created on my most recent extraction if you use colder acetone and/or shorter pulls. It will save you a few days of extra cleaning that I had to go through. When I did my last one, I realized AFTER that I could have set my freezer much colder Confused .

Obviously, I'm interested in what you come up with!



Salvia quid enthusiast
 
Zebbie
#84 Posted : 7/25/2018 6:49:58 PM

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Black tar mess is good! It contains the magic molecules needed to make the extract orally active. You just need to spread it over a bigger surface area. So I will be buying some acetone this weekend, and do a warm extraction.
 
physics envy
#85 Posted : 7/25/2018 7:09:42 PM

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Zebbie wrote:
Black tar mess is good! It contains the magic molecules needed to make the extract orally active. You just need to spread it over a bigger surface area. So I will be buying some acetone this weekend, and do a warm extraction.


Maybe I'm misunderstanding...is your plan is to leave it as a black tar, without cleaning it and getting it into a (seemingly more usable) powder form? Then disperse the tar over various substrates?
Salvia quid enthusiast
 
Zebbie
#86 Posted : 7/26/2018 3:59:46 PM

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Yes, exactly! This is the low tech alternative to cyclodextrin complexation.

Thomas Munro wrote a PhD thesis entitled "The chemistry of Salvia Divinorum" links here and here.

On page 49 he says that amorphous solids (as in crude extracts) have better solubility than crystalline material. In the text, 1a refers to salvinorin A

On page 50 he says, "Many instances have been reported of enhanced absorption of active compounds from a crude extract relative to the pure compound. For instance, some terpenoids are known to act as permeation enhancers, increasing trans-dermal absorption of co-administered drugs up to 90x". I think both you and Loveall have found the same thing.

Are you familiar with the expression "throw the baby out with the bath water"? There are substances naturally present in the leaf that disperse and transports the salvinorin A across the mucous membrane. These substances are removed and discarded during purification. Purification is good if you want to smoke salvia, but bad if you want to absorb it sublingually.

I did not mean to derail the cyclodextrin thread. But it seemed to have reached an impasse. My reason for posting was to stimulate creative thinking in this area.
Zebbie attached the following image(s):
Munro page 49.jpg (70kb) downloaded 110 time(s).
Munro page 50.jpg (83kb) downloaded 111 time(s).
 
Loveall
#87 Posted : 7/26/2018 5:45:11 PM

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Thanks Zebbie, that is interesting Thumbs up

I want to do more work on cyclodextrin complexation, which seems reversible if heated. Want to thank all of you for being paitient.

It looks like complexed salvia does work, but it needs to be evaporated at low temperatures to achieve good complexation. It is a simple procedure, mix the extract with everclear and cyclodextrin powder and evap at room temp over a fan.

There a lot of questions such as how much has completed? Should the mix/dry process be repeated a few times to complex completely? Do we need a certain salvinorin/HPBCD ratio to maximize complexation? Does salvinorin need to be pure to complex properly without other stuff getting in the way?

I found good results: complexed salvinorin was active when drinking it. I think that was marvelous. physics envy had some promising results, but at the end of the day the crude uncompled extract and the complexed extract seemed similar in activity (for me the uncomplexed extract was not active). This may be due to different sensitivity and/or different amount of terpentines on our extracts.

I've promised physics envy a follup-up and that is coming. Salvia plants are happy growing outside. I also got thymeleaf sandwort to test too, see if we can make an effective complexed salviauasca.

Also, there are glaucoma drugs delivered with HPBCD as eye drops. Not telling anyone to try this but that would be a new ROI complexation may open up one day.
“... (a) psychedelic substance occasionally causes psychotic behaviour in people who have not taken it.”
Excerpt from a McKenna talk transcript / audio.
 
physics envy
#88 Posted : 7/26/2018 6:11:38 PM

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Zebbie wrote:
Yes, exactly! This is the low tech alternative to cyclodextrin complexation.

I did not mean to derail the cyclodextrin thread. But it seemed to have reached an impasse. My reason for posting was to stimulate creative thinking in this area.


Well - I'm curious as to how easy it will be to disperse the black tar, and then what it's like to use it. In my experience, it was just a sticky clump which was a PITA to break down...at least with my low-tech home-lab equipment Razz (I have only very rudimentary kitchen/lab equipment and skills...part of the reason this thread has been on pause.)

Loveall has some ideas on increasing the comlpexation efficiency (using more HPBCD, dissolving and drying several times, drying with a fan, etc.) that he is planning on trying after growing some more leaf this summer.

Also, he will be able to test via TLC, so we will then have a better idea of how much is actually being complexed. We had planned on having me test his batch next round, so perhaps that will happen this fall.



Zebbie wrote:

Are you familiar with the expression "throw the baby out with the bath water"? There are substances naturally present in the leaf that disperse and transports the salvinorin A across the mucous membrane. These substances are removed and discarded during purification. Purification is good if you want to smoke salvia, but bad if you want to absorb it sublingually.


I haven't re-read this thread in a while, and I probably mentioned this, but in my complexation bioassays it always felt like something was missing (although I realize that doesn't really make sense). But it was very hard for me to get all the way to that point that I shoot for when using my complexed material. It gets me most of the way, but not quite all the way. And I tried using much more material a few times which as I recall only resulted in longer trips, not deeper ones. This was another reason I paused working on this - to wait for a potentially stronger batch from Loveall.
Salvia quid enthusiast
 
Zebbie
#89 Posted : 7/26/2018 7:43:10 PM

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Loveall wrote:

Also, there are glaucoma drugs delivered with HPBCD as eye drops. Not telling anyone to try this but that would be a new ROI complexation may open up one day.


Far out! I love crazy ideas!

I managed to buy a small bottle of acetone this afternoon. So I am about to re-create physics envy's black tar mess.

Ready, Zebbie, go!
Zebbie attached the following image(s):
14. Acetone extraction.jpg (257kb) downloaded 92 time(s).
 
Loveall
#90 Posted : 8/6/2018 8:29:38 PM

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Attaching a new 2018 paper that used HPBCD to improve a the bioavailability of a drug.

The paper uses TLC to check complexation. Also measures a spectra, which we may be close to doing with home Raman. It then uses NMR to propose how the complexed drug looks (and some nexians have shown NMR results for DMT).

To form the drug complex they mix it and evaporate it (they do it in acetonitrile under alkaline conditions before going back to ph7). Anyone know why they used alkali conditions? Do they simply need the drug to be lipophilic so it slides into the cyclodextrin cavity? Makes me want to add ammonia to the everclear/salvinorin mix as a test.

It's a very nice paper for anyone interested in the subject.
“... (a) psychedelic substance occasionally causes psychotic behaviour in people who have not taken it.”
Excerpt from a McKenna talk transcript / audio.
 
Zebbie
#91 Posted : 8/10/2018 8:28:26 AM

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I think the reason for using alkali is to maintain stability. Toltrazuril has a triazone trione moiety in its structure. Many years ago I made triazone urea fertilizers. These were stable under alkaline conditions but hydrolyzed under acid conditions.

I believe adding ammonia will be detrimental to your process. The ester and lactone bonds in Salvinorin A will be targeted by ammonia.

Esters hydrolyze in water. Ester + water carboxylic acid + alcohol. Any alkali will react with the carboxylic acid to form the salt. This effectively removes one of the products, and shifts the reaction towards the right (Le Chatelier's principle).

 
Zebbie
#92 Posted : 8/10/2018 8:41:30 AM

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I think salvinorin A is stable while it is inside trichomes, or deep within a leaf as an extract, or as salvinorin A crystals. But once it is in molecular form, it is easily degraded by light (tinctures, for example) or maybe oxygen and substances like alkalis and esterase enzymes in solution or thin films.

How stable is your complexed salvinorin, Loveall? Have you done any stability tests?

 
Loveall
#93 Posted : 8/10/2018 3:20:15 PM

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It seemed pretty stable over a couple of weeks. I have a tiny bit of 1 year old complexed salvinorin in the pantry I need to test again by drinking. Since HPBCD can stabilize some drugs for long term storage maybe it protects salvinorin too.

The one thing that made it innactive was redisolving it in hot water. One possibility considered was that the heat kicked out the salivnorin from the complexed structure. That is why physicsenvy was saying that we are going to try again, this time evaporatating the alcohol/water/HPBCD/salvinorin dispersion at room temp with a fan.

Regarding the pH during complexation, I think we will want to target/test a pH where the molecule is neutral. Being neutral may help it get into the HPBCD lipophilic ring center. Will run the chemichalize demo to see what that pH is in water (I can't find a pka for salvinorin A). Will need to be careful since as you say some functional goups can break down at certain pH though. Not sure how it will work though since as we evaporate the pH can change. Hopefully simple neutral distilled water works.
“... (a) psychedelic substance occasionally causes psychotic behaviour in people who have not taken it.”
Excerpt from a McKenna talk transcript / audio.
 
Zebbie
#94 Posted : 8/10/2018 5:49:42 PM

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Thanks for the response, Loveall. It is quite possible that the instability I observe in my experiments is not due to any degradation of salvinorin A, but due to degradation of the "carriers" present in the crude extract. If the carriers get destroyed, then they are unable to transport salvinorin into the mucous membrane.

The article you attached is very interesting! I hope you and physics envy succeed in your quest.

There is no pKa for salvinorin A, because it does not have any ionizable acidic or basic groups, see attached image. But your refined salvinorin extract may still contain impurities that affect the pH of the alcohol/water mixture.

If you want to conduct your complexation at a neutral pH, you could buffer the alcohol/water mixture with a pH 7.00 buffer. These are sodium or potassium phosphate buffers made up for calibrating pH meters. The commercial buffers probably contain a biocide, so you would have to prepare your own from scratch.

Zebbie attached the following image(s):
Clipboard01.jpg (46kb) downloaded 36 time(s).
 
Loveall
#95 Posted : 8/10/2018 6:16:51 PM

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Thanks, that saves me from running the chemicalize(Marvin) program. Thumbs up

Since salvinorin is non ionazible I won't mess around with the pH, salvinorin should simply be in a lipophilic state. If on the other hand I one day try to complex DMT I'd try in a basic solution for starters, psilocybin at it's isoelectric point (pH~4 if I recall correctly), etc.

If you are interested is easy to get HPBCD for complexation tests. It can be seen as a fiber supplement I think. The most interesting part about complexation is that it seemed active orally (drinking it). However, we need to repeat and standardize the process. HPBCD boost to drug bioavailability opens interesting ROI possibilites like nebulizers and eyedroppers.

Edit: this particular passage in the previous attachment sounds interesting:

Quote:
Administering orally the aqueous suspension of a CD-complexed highly lipophylic
drug, e.g., to a fasting rat, the blood level reaches its-very high-peak within 5-15
min. By some exaggeration one could speak about an intravenous effect through oral
administration
“... (a) psychedelic substance occasionally causes psychotic behaviour in people who have not taken it.”
Excerpt from a McKenna talk transcript / audio.
 
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