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Author: Subject: Transdermal lysergamides?
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[*] posted on 2-5-2018 at 01:16
Transdermal lysergamides?


Though this question involves controlled substances, its an issue of pharmacology, not synthesis, so I figured it would be ok. If it is not appropriate please have a moderator remove it.

Lysergic acid diethylamide has been rumoured to be able to enter the system via transdermal means.

I will hear stories where people tell me they have had this drug take effect by transdermal means.

Yet, I don't buy it.

Nick sand claims that even when mixed with DMSO transdermal absorption failed.


Quote:

Another fact: I've made LSD in my lab on many occasions for research purposes, possibly in not so meticulous a manner as Albert Hofmann. Nothing ever happened. I had several graduate students who made LSD as an intermediate for projects. No accidental ingestion of LSD ever occurred. A technician in my lab makes it routinely because we use it as a drug to train our rats. He's learned by experience that he never gets high, nothing ever happens. And yesterday I was talking to Nick Sand, and Nick said, "I made a solution of LSD in DMSO…" -- DMSO (dimethyl sulfoxide) is a chemical that greatly enhances absorption of other chemicals through the skin -- he says, "…I painted it on my skin. Nothing happened." A concentrated solution and nothing happened!

https://erowid.org/general/conferences/conference_mindstates...



When looking at online I had recieved mixed opinions.

I am of the opinion that LSD is not transdermally active.

Can anybody clear this up?
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[*] posted on 2-5-2018 at 02:39


Protonation?

N6 is pretty alkaline, and the skin is pretty acidic.
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[*] posted on 2-5-2018 at 04:41



The Albert Hoffman story about a small drop of solution on his hand possibly leading to his first experience of the effects? I also recall Hoffman's account specifically mentioning the hoods used in his lab used natural draft instead of a fan and were not very effective. Why would Hoffman call this detail out if he didn't think it was pertinent.

The Owsley story about running his chemists in shifts due to intoxication from their merely being in the vicinity of the process? (Didn't Owsley care to invest in a decent fume hood?!)

Perhaps handling solutions without an efficiently working hood exposed them to aerosols, chemists who breathed these could easily receive a sufficient dose.

Also, the skin application test might be repeated with the LSD dissolved in the solvents these chemists actually USED for the process instead of DMSO.




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[*] posted on 2-5-2018 at 04:41


Apparently Hofmann accidentally absorbed it through his fingertips on one of the occasions he first synthesised it as a research pharmaceutical, but it’s also equally as likely that he unconsciously touched near his eyes or mouth and it was absorbed that way, an unnoticeably small amount in any case. Seems like that would be the actual route of ingestion, people may say that it can be absorbed through the skin but in actuality it’s probably because they didn’t wash their hands properly enough after handling it then going on about their daily routine.

[Edited on 2-5-2018 by LearnedAmateur]




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[*] posted on 2-5-2018 at 07:24


Quote: Originally posted by LearnedAmateur  
Apparently Hofmann accidentally absorbed it through his fingertips on one of the occasions he first synthesised it as a research pharmaceutical, but it’s also equally as likely that he unconsciously touched near his eyes or mouth and it was absorbed that way, an unnoticeably small amount in any case. Seems like that would be the actual route of ingestion, people may say that it can be absorbed through the skin but in actuality it’s probably because they didn’t wash their hands properly enough after handling it then going on about their daily routine.

[Edited on 2-5-2018 by LearnedAmateur]


The story about how Hoffman got the LSD into his system is somewhat disputed, ill explain my view on it:

Hoffmann was told by sandoz that LSD was uninteresting, and was asked to move on. Then several years down the road, for some reason Hofmann decides to re-synthesize the compound, and claims that some had "accidentally" got into his system.

Hofmann was a respected Swiss chemist, and I feel he must have thought that sandoz was wrong about his compound, I believe Hofmann got the idea for condensation of diethylamine with lysergic acid from a similar process involving nicotinic acid being condensed with diethylamine to form "nicotinic acid diethylamide", I also feel that Hofmann would have figured this to be a useful compound, so my theory is that he might have intentionally consumed his new product, but being a meticulous and respected chemist admitting to synthesizing and testing an unknown compound on yourself would destroy your reputation, so he claimed it got into his system by unknown means.

Or, David E. Nichols had the right idea:


Quote:

About this Document



     

GENERAL

   

conferences

Modern humans must learn how to relate to psychoactives
responsibly, treating them with respect and awareness,
working to minimize harms and maximize benefits, and
integrating use into a healthy, enjoyable, and productive life.

MindStates IV LSD Panel:

Hypothesis on Albert Hofmann's Famous 1943 "Bicycle Day"

with brief overview of current research

BY DAVID NICHOLS

May 24, 2003

Transcription & Editing by Erowid.
Adapted from transcript of presentation given at Mindstates IV, Berkeley, CA

Citation:   Nichols, David. "Hypothesis on Albert Hofmann's Famous 1943 'Bicycle Day'" Adapted from a presentation given at Mindstates IV.Erowid.org/general/conferences/conference_mindstates4_nichols.shtml. May 24 2002.

Editor's Introduction

At Mindstates IV, Dr David Nichols, chemist and pharmacologist, professor of medicinal chemistry and molecular pharmacology at Purdue University, proposed a novel alternate reading of Albert Hofmann's famous 1943 "Bicycle Day" and a brief overview of his research.


Presentation

I'm here to give you a report from the institutional research division of your community. If you pay taxes to the IRS, you support my research to understand how psychedelics affect brain chemistry; thank you. 

Since we're just a slight bit past the 60th anniversary of the discovery of LSD, I thought I would have a little audience participation fun, and give you a little insight into how the scientific process works. Because, often times in this community, "scientist" has somewhat of a pejorative connotation. I want to show you how we're not so different, and do a little experiment. 

You know the way science works. We make observations, we develop or formulate a hypothesis that is consistent with those observations, and then we attempt to carry out experiments to test the hypothesis. I don't think we'll be able to carry out the experiments to test the hypothesis, but what I want to do is develop a hypothesis today that I think you'll find very interesting. But the first thing we need to know is what kind of a database we're working with. What I'd like you to do is raise your hand if you have read Albert Hofmann's account of the discovery of LSD.

[nearly everyone in the conference hall raises their hand]

"The only hypothesis I can come up with that's consistent with all of these facts is that on April 16, 1943, Albert Hofmann did not get LSD in his body at all. He had a spontaneous mystical experience!"

Ah, just as I suspected. So we have a good database, and probably an educated database.

What I want to do now is another experiment. I want you to raise your hand and hold it in the air as long as I am stating things that you hold to be true, and when I say something you believe not to be true, then put your hand down. 

So, the first thing I'm going to say, if you believe it to be true, raise your hand, and keep it up there until I say something you disagree with.

On April 16, 1943, when Albert Hofmann accidentally ingested LSD, he ingested at least 25 micrograms. Now keep your hand up until I say something you disagree with. 

[most people in the audience raise their hands]

On that same date in 1943, Albert Hofmann ingested at least 50 micrograms of LSD. 

[a few people put their hands down]

On that same date in 1943, Albert Hofmann ingested at least 75 micrograms. 

[several more people put their hands down]

And then again, on that date in 1943, Albert Hofmann ingested at least 100 micrograms.

[more people put their hands down]

On that same date, Albert Hofmann ingested 150 micrograms.

[only a few people still have their hands still up]

Well I think I've already proved the point. I think there's a consensus that Albert Hofmann must have ingested at least 50 to 75 micrograms, and there are people in here who believe he must have ingested 100 or 150 micrograms. Now we've estimated, with this educated database, approximately how much LSD he must have accidentally gotten inside himself.

Now, we'll do the same thing again. In April 1943, after his accidental ingestion, how many people believe that Albert Hofmann would have experienced the effects of LSD for at least 10 hours, based on that dose? 

[Several people put their hands up]

Now if we believe he took LSD, and if we believe he took 50 to 75 micrograms -- that's the context -- how many people believe the effects should have lasted at least 8 hours. [many more hands go up] How many believe the effects would have lasted at least 6 hours? [more hands go up] How believe the effects would have lasted at least four hours? [nearly all hands are up at this point]

Now, how many people believe that the effects of a 50-75 microgram dose of LSD would only have lasted two hours? [nearly all hands go down]

We read from his account: 
"I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours(emphasis added) this condition faded away." (Hofmann, 1983). 

Well now, that was a conundrum for me. I read that and I thought, "gee I'm a scientist, and this doesn't make sense with what I know." And for most of you, I think, that doesn't make sense either. So, the question: how can we formulate a hypothesis consistent with this observation? We need to consider a few things. 

We know that Albert originally synthesized LSD in 1938 as part of an ambitious program to make a number of lysergamides. LSD-25 was only the 25th in the series. I actually don't know how many of those compounds he made, but let's assume he only made 30. So we had up to 30 in the series. He may have made many more actually, but at least say 30. And they were all tested; he sent the pharmacology department LSD-25, 24, 23... and so forth. They then say, "LSD-25: not interesting." The assays of that day really didn't provide much information; they were very unsophisticated. But five years later, Albert has a hunch that the pharmacology department missed something on this 25th in the series. 

Now that's kind of peculiar. I'm familiar with the drug industry, and I've actually started a small company myself. Imagine you're a musician, and you've created this musical piece. It's really wonderful; it's one of the best pieces you've ever written; you play it for people, they think it's great. And this one artist comes down. He's very creative but he has no musical talent at all, really tone deaf, he listens to your music and he says, "Man that sucks. You missed something. There's something missing." Now you as a musician are probably going to have some sort of a gut reaction to that. And even though the pharmacologist at Sandoz was probably a friend of Albert's, can you imagine this chemist coming down the hall and saying, "You know, I made this compound five years ago, out of this whole series, and there's this one compound, LSD-25, that you said was uninteresting... but you must have missed something. I just have this 'peculiar presentiment,' this strange hunch that you missed something." You're going to look at Albert and say, "You know, really, I'm an expert in pharmacology Albert. We tested it very well."

The Germans and the Swiss are very precise chemists, and pharmacologists, and scientists. There wouldn't have been any question about this being somehow mis-analyzed the first time.

This is another interesting point. Why the 25th? We know that only the 25th in the series was active. Any other compound that he made -- and I've made many of them, we've tested many of them -- none of the others approach LSD, either in its sophistication or in its potency. Only the 25th. And this is unusual. In pharmacology often you have a regular series. If we think of things like DOB, and DOI, there's a kind of regular progression. They all fit into a kind of subgenus. And LSD doesn't. We don't call the other members of the series Albert made as LSD something or other, but if we had LSD-23, 24 and 26, they would all be one-tenth the activity of LSD-25. Peculiar presentiment indeed! 

As I've said, Swiss and German chemists have a reputation -- today and back then -- for being absolutely meticulous. If we had gone into Albert's lab at Sandoz in 1943, we would probably have found everything in its place, organized in an obsessively neat manner. No dirty glassware, no trash on the floor, meticulous. How in the world did a meticulous Swiss chemist get 50 to 75 micrograms or more of LSD into his body? We don't know. 

Another fact: I've made LSD in my lab on many occasions for research purposes, possibly in not so meticulous a manner as Albert Hofmann. Nothing ever happened. I had several graduate students who made LSD as an intermediate for projects. No accidental ingestion of LSD ever occurred. A technician in my lab makes it routinely because we use it as a drug to train our rats. He's learned by experience that he never gets high, nothing ever happens. And yesterday I was talking to Nick Sand, and Nick said, "I made a solution of LSD in DMSO…" -- DMSO (dimethyl sulfoxide) is a chemical that greatly enhances absorption of other chemicals through the skin -- he says, "…I painted it on my skin. Nothing happened." A concentrated solution and nothing happened! How did this very meticulous Swiss chemist get the LSD into his body? I don't know. 

The other fact we need to think about is when Albert was a child, he had a spontaneous mystical experience. Now depending on whether you're a psychologist or a psychiatrist or whatever, we could say that Albert had a predisposition to altered states of consciousness. 

So what facts do we know? I'm going to formulate a hypothesis. He took a dose that by your consensus should have lasted certainly more than two hours, but it only lasted two hours. He was a meticulous chemist -- a Swiss chemist. Anyone I know who's worked with LSD -- and Nick Sand painted a solution of it on his arm -- didn't get high. This doesn't make sense. And what is this peculiar presentiment? Why the 25th in the series? Inexplicable! And, he was predisposed to altered states of consciousness.

The only hypothesis I can come up with that's consistent with all of these facts is that on April 16, 1943, Albert Hofmann did not get LSD in his body at all. He had a spontaneous mystical experience! 

Now if I were working in the lab with a new chemical, and I started having kaleidoscopic visions of wonderful colors and patterns, my first thought wouldn't be that I was having a spontaneous experience. My first thought would be, "What was that new chemical I was working with? I need to tell Sasha about it." [laughter] 

I think that's what happened, that's the hypothesis. We can't test that hypothesis, but when I saw Albert in Basel a couple years ago, I presented that particular hypothesis to him and said, "What do you think?" He said, "It's entirely possible." So, that's our little experiment, and I think most of you really didn't think seriously about the discovery of LSD, but it puts a different light on it.

Now one aside to that we could then bring up is this. If the force that caused him to have this peculiar presentiment -- and very peculiar it is -- is the same force that induced him to have this mystical experience, which caused him to focus on this chemical, we can hope it might happen again. 


https://erowid.org/general/conferences/conference_mindstates...






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[*] posted on 2-5-2018 at 07:32


Quote: Originally posted by LearnedAmateur  
Apparently Hofmann accidentally absorbed it through his fingertips on one of the occasions he first synthesised it as a research pharmaceutical, but it’s also equally as likely that he unconsciously touched near his eyes or mouth and it was absorbed that way, an unnoticeably small amount in any case. Seems like that would be the actual route of ingestion, people may say that it can be absorbed through the skin but in actuality it’s probably because they didn’t wash their hands properly enough after handling it then going on about their daily routine.

[Edited on 2-5-2018 by LearnedAmateur]


Agreed. I feel individuals must have rubbed their mouth or eyes or whatever with the LSD on their skin.

David E. Nichols, alexander shulgin, and nick sand have all claimed that LSD will not properly absorb through the skin, and when it comes to LSD these are three of the names that I particularly trust.

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[*] posted on 2-5-2018 at 07:51


Quote: Originally posted by Bert  

The Albert Hoffman story about a small drop of solution on his hand possibly leading to his first experience of the effects? I also recall Hoffman's account specifically mentioning the hoods used in his lab used natural draft instead of a fan and were not very effective. Why would Hoffman call this detail out if he didn't think it was pertinent.

The Owsley story about running his chemists in shifts due to intoxication from their merely being in the vicinity of the process? (Didn't Owsley care to invest in a decent fume hood?!)

Perhaps handling solutions without an efficiently working hood exposed them to aerosols, chemists who breathed these could easily receive a sufficient dose.

Also, the skin application test might be repeated with the LSD dissolved in the solvents these chemists actually USED for the process instead of DMSO.


As far as aerosol application of LSD is concerned, the CIA experimented with this through their MKULTRA program and it was reported to have failed miserably, but who knows, I imagine inhaling actual LSD dust might actually do the trick. (The CIA through MKULTRA even made LSD "swizzle sticks" to spike enemy martinis, though it is also reported that this failed.

Ok, as far as why DMSO was used, this has to do with abbie Hoffman:

Quote:

[1967] When Washington authorities threatened to use Mace to control the demonstrators at the Capitol, Abbie claimed that hippies had come up with a new chemical aphrodisiac called Lace, consisting of LSD and a secret skin- penetrating agent.
https://books.google.ca/books?id=ECYjlcF6QIcC&pg=PA116&a...



...The agent used was reported to have been DMSO.

...there are also other cultural references such as this popular dead kennedys song:
Quote:

D. M. S. O.
Crypto Wonder Drug
In vogue
Some people say
It cures arthritis
Maybe that's why
It keeps getting banned
It's absorbed
Directly through the skin
Mix it with lemon juice
Touch your fingertips
You'll taste the lemon
The police
Started a riot
Down at the courthouse
Again
Running amok
Spilling blood
Bashing heads
I do my part
Behind the lines
Swabbing door handles of cop cars
With D.M.S.O.
Mixed with L.S.D

Dead kennedys


DMSO is also used to absorb medications transdermally fairly regularly.

So when choosing a solvent for transdermal LSD DMSO always seems to come up.

It doesn't work according to nick sand, but possibly another solvent could, who knows, personally I am somewhat happy is does not work.

As far as the owsley story, I have also heard this, I respect owsley and his opinion, but don't know what to make of the claim. Nick sand would talk about becoming intoxicated while working as well, though Nick sand would talk about spilling things on a hot plate, then burning his finger cleaning it up, and accidentally placing his finger in his mouth after, things like that.

...its difficult to get a clear answer here as the opinions seem fairly variable and mixed.
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[*] posted on 2-5-2018 at 07:59



Quote:

So what facts do we know? I'm going to formulate a hypothesis. He took a dose that by your consensus should have lasted certainly more than two hours, but it only lasted two hours. He was a meticulous chemist -- a Swiss chemist. Anyone I know who's worked with LSD -- and Nick Sand painted a solution of it on his arm -- didn't get high.

The only hypothesis I can come up with that's consistent with all of these facts is that on April 16, 1943, Albert Hofmann did not get LSD in his body at all. He had a spontaneous mystical experience!

-david E. Nichols

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[*] posted on 2-5-2018 at 14:50


TBH if this were actually a purely pharmacological inquiry, it would be better posted on a different website. However, in this particular case, the chemical question of what can carry a certain molecule through the skin is pretty interesting.
Not that I, personally, have any problem talking about drugs. I used to do that all the time.
Quote:
the CIA experimented with this through their MKULTRA program and it was reported to have failed miserably, but who knows, I imagine inhaling actual LSD dust might actually do the trick. (The CIA through MKULTRA even made LSD "swizzle sticks" to spike enemy martinis, though it is also reported that this failed.
In what sense "failed"? The CIA wanted LSD to make people vulnerable to manipulation, but LSD tends to defocus your attention and encourage you to follow meandering trains of thought, which is not generally amenable to interrogation. How do we know that "failed" to the CIA means people didn't get high?





[Edited on 04-20-1969 by clearly_not_atara]
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[*] posted on 2-5-2018 at 17:12


Per the first question, not highly credible IMO. Transdermal absorption/transport of drugs is a tricky business; the outer layer of dead skin is relatively impermeable and of course lacks active transport mechanisms (hence the need for solvents like DMSO to at least get the target molecule through the outer layers and to living tissues.)

And yet...even if absorption efficiency was extremely low, given the very high per-mg potency of substances like LSD *and* the sorts of exceptional concentrations of those drugs that might be present in a lab actively manufacturing them, perhaps a modest spill (say, a ml of concentrated solution splashed onto skin) might conceivably get enough into the bloodstream to be psychoactive.

I find the 'mystical experience' explanation ridiculous. I tend to agree with PEAM's theory of deliberate ingestion from the start. No cautious, reasonable, and sober researcher would have decided to follow up a mild accidental exposure to a clearly wildly powerful drug by deliberately ingesting more, which we know for certain he did. I think it most likely was indeed a deliberate experiment from the start, more in the vein of Shulgin's work, just more modestly garbed in the telling (while Shulgin was always an unrepentant fan of looking for the next novel high.)

[Edited on 3-5-2018 by Reboot]
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[*] posted on 3-5-2018 at 05:29


Quote: Originally posted by clearly_not_atara  
TBH if this were actually a purely pharmacological inquiry, it would be better posted on a different website. However, in this particular case, the chemical question of what can carry a certain molecule through the skin is pretty interesting.
Not that I, personally, have any problem talking about drugs. I used to do that all the time.
Quote:
the CIA experimented with this through their MKULTRA program and it was reported to have failed miserably, but who knows, I imagine inhaling actual LSD dust might actually do the trick. (The CIA through MKULTRA even made LSD "swizzle sticks" to spike enemy martinis, though it is also reported that this failed.
In what sense "failed"? The CIA wanted LSD to make people vulnerable to manipulation, but LSD tends to defocus your attention and encourage you to follow meandering trains of thought, which is not generally amenable to interrogation. How do we know that "failed" to the CIA means people didn't get high?



I don't use drugs any more, but had some very particular experiences with psychedelics which transformed my life, so I still love to research their chemistry, pharmacology, social impact, and so on.

I apologize that the topic is only semi-appropriate on this forum, the initial pharmacological interest has many side subjects which perhaps would be better discussed other places. I Will try to stay on topic and try to keep my comments in line with this venue.

Ok, as for how the MKULTRA attempts "failed", it was because a large part of the program was surreptitious administration of psychoactive substances to political targets, as well as creating a "manchurian candidate", the reports state these goals were never achieved, I believe even Fidel castro had some LSD or poison laced cigars prepared by the CIA, which he never got.


Quote:

Code-named MKULTRA (and pronounced m-k-ultra), the project Mr. Vance uncovered was the brainchild of CIA Director Allen Dulles, who was intrigued by reports of mind-control techniques allegedly conducted by Soviet, Chinese and North Korean agents on U.S. prisoners of war during the Korean War. The CIA wanted to use similar techniques on its own POWs and perhaps use LSD or other mind-bending substances on foreign leaders, including Cuba's Fidel Castro a few years after the project got underway in 1953.

http://www.washingtonpost.com/wp-dyn/content/article/2005/06...



Again, the reports all state that none of the substances lived up to their expectations, and that none of them were of value in espionage.

(Though just because the CIA claim they failed does not mean that this was actually the case)

The book "acid dreams" discusses a good deal of this material.

As for transdermal solvents used to carry pharmacological agents into the human system, this topic is particularly fascinating, and can be discussed without the mention of LSD, though this compound has a good deal of rumour and mythology surrounding it that needs to be cleared up.
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[*] posted on 3-5-2018 at 05:50


Quote: Originally posted by Reboot  
Per the first question, not highly credible IMO. Transdermal absorption/transport of drugs is a tricky business; the outer layer of dead skin is relatively impermeable and of course lacks active transport mechanisms (hence the need for solvents like DMSO to at least get the target molecule through the outer layers and to living tissues.)

And yet...even if absorption efficiency was extremely low, given the very high per-mg potency of substances like LSD *and* the sorts of exceptional concentrations of those drugs that might be present in a lab actively manufacturing them, perhaps a modest spill (say, a ml of concentrated solution splashed onto skin) might conceivably get enough into the bloodstream to be psychoactive.

I find the 'mystical experience' explanation ridiculous. I tend to agree with PEAM's theory of deliberate ingestion from the start. No cautious, reasonable, and sober researcher would have decided to follow up a mild accidental exposure to a clearly wildly powerful drug by deliberately ingesting more, which we know for certain he did. I think it most likely was indeed a deliberate experiment from the start, more in the vein of Shulgin's work, just more modestly garbed in the telling (while Shulgin was always an unrepentant fan of looking for the next novel high.)

[Edited on 3-5-2018 by Reboot]


Wow, great response! Not only did you help clear up part of my understanding of how molecules absorb through skin, but you offered thoughtful and clear insight into the matter.

Personally, I want to believe that Nichols was correct, I mean, how cool would it be if a chemist had a mystical experience in the lab, attributed it to a substance he was working with, and then having things later turn out that the substance was actually active in a mystical way? I think it has a certain quality to it that makes you want it to be the case, even if it is quite unlikely.

...but, yes, ultimately I feel he intentionally consumed the compound that first time, and to spare his reputation, and perhaps as to not encourage this type of experimentation, he decided to claim it "accidentally" entered his system.

...also, Hofmann knew that egrot and compounds derived from it carried certain potential exposure risks, such as ergotism, and being a very skilled and meticulous chemist you assume he would have taken extreme caution to limit unintentional exposure.

...it is a mystery, I don't think we will ever know for sure what happened during those days of April 16th to the 19th of 1943.

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[*] posted on 3-5-2018 at 05:58


Anyone know why fentanyl is readily capable of transdermal uptake but LSD is not?
Their dose is comparable. Their MW is comparable. Both are tertiary amines so I don't believe the 'your skin is acidic' theory. Both are metabolized in the liver so I don't believe in a large dermal first pass effect.
I did notice that their lipopholicity is different LogP = 4.05 VS 2.95 for fentanyl VS lsd. Is it just this 10 fold difference in lipopholicity that causes the difference in transdermal rates of absprbtion? And finally fentanyl has many more rotatable bonds, but IIRC more rotatable bonds means that a compound is less membrane permeable which diametrically opposes what we observe.

Edit: this makes me wonder how ALD-52 and 1P-LSD fare.

[Edited on 3-5-2018 by Sigmatropic]
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[*] posted on 3-5-2018 at 06:59


Quote: Originally posted by Sigmatropic  
Anyone know why fentanyl is readily capable of transdermal uptake but LSD is not?
Their dose is comparable. Their MW is comparable. Both are tertiary amines so I don't believe the 'your skin is acidic' theory. Both are metabolized in the liver so I don't believe in a large dermal first pass effect.
I did notice that their lipopholicity is different LogP = 4.05 VS 2.95 for fentanyl VS lsd. Is it just this 10 fold difference in lipopholicity that causes the difference in transdermal rates of absprbtion? And finally fentanyl has many more rotatable bonds, but IIRC more rotatable bonds means that a compound is less membrane permeable which diametrically opposes what we observe.

Edit: this makes me wonder how ALD-52 and 1P-LSD fare.

[Edited on 3-5-2018 by Sigmatropic]


Are you talking about those transdermal patches?

I think transporting chemicals through the skin is facilitated in those patches by something that makes the skin more permeable (not DMSO).

However I may be thinking of those estrogen/progesterone patches.






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[*] posted on 3-5-2018 at 08:05


Quote: Originally posted by SWIM  
Quote: Originally posted by Sigmatropic  
Anyone know why fentanyl is readily capable of transdermal uptake but LSD is not?
Their dose is comparable. Their MW is comparable. Both are tertiary amines so I don't believe the 'your skin is acidic' theory. Both are metabolized in the liver so I don't believe in a large dermal first pass effect.
I did notice that their lipopholicity is different LogP = 4.05 VS 2.95 for fentanyl VS lsd. Is it just this 10 fold difference in lipopholicity that causes the difference in transdermal rates of absprbtion? And finally fentanyl has many more rotatable bonds, but IIRC more rotatable bonds means that a compound is less membrane permeable which diametrically opposes what we observe.

Edit: this makes me wonder how ALD-52 and 1P-LSD fare.

[Edited on 3-5-2018 by Sigmatropic]


Are you talking about those transdermal patches?

I think transporting chemicals through the skin is facilitated in those patches by something that makes the skin more permeable (not DMSO).

However I may be thinking of those estrogen/progesterone patches.



...not a fan of the whole "swim" thing.

Moving on.

There are many means of making a compound amenable to transdermal absorbtion.

DMSO is a very common and effective means of doing this:


Quote:

Abstract

Dimethyl sulfoxide (DMSO) is a molecule with a long history in pharmaceutics and is now well established as a penetration enhancer in topical pharmaceutical formulations. It is currently used for this purpose in diclofenac sodium topical solution (approved in the United States to treat signs and symptoms of osteoarthritis) and idoxuridine topical solution (approved in Europe for the treatment of herpes zoster). This article reviews the mechanism of action of DMSO as a pharmaceutical penetration enhancer, the characteristics of the molecule that facilitate transdermal drug delivery, and studies of efficacy and safety. The clinical use of pharmaceutical-grade DMSO as a penetration enhancer is supported by the robust data that have accumulated over the past 3 decades demonstrating the favorable safety and tolerability profile. Dimethyl sulfoxide is a safe and effective mechanism for facilitating the transdermal delivery of both hydrophilic and lipophilic medications to provide localized drug delivery.

https://www.ncbi.nlm.nih.gov/pubmed/22030943
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[*] posted on 3-5-2018 at 08:18


Quote: Originally posted by Sigmatropic  
Anyone know why fentanyl is readily capable of transdermal uptake but LSD is not?
Their dose is comparable. Their MW is comparable. Both are tertiary amines so I don't believe the 'your skin is acidic' theory. Both are metabolized in the liver so I don't believe in a large dermal first pass effect.
I did notice that their lipopholicity is different LogP = 4.05 VS 2.95 for fentanyl VS lsd. Is it just this 10 fold difference in lipopholicity that causes the difference in transdermal rates of absprbtion? And finally fentanyl has many more rotatable bonds, but IIRC more rotatable bonds means that a compound is less membrane permeable which diametrically opposes what we observe.

Edit: this makes me wonder how ALD-52 and 1P-LSD fare.

[Edited on 3-5-2018 by Sigmatropic]


I really can not comment on fentanyl, my general focus is on tryptamine, phenethylamine, and lysergamide compounds. I'm sure I could have the answer for you after about 5 minutes of research, but I do not have enough interest fentanyl to do so.

As for ALD-52 and 1P-LSD, I'm not sure what you mean.

They should be pro-drugs of LSD.

Quote:

The compound [1P-LSD] would not be active as the N-propionyl however. The way that LSD docks into the 5-HT2A receptor, the indole NH hydrogen bonds to serine 5.46. With the propionyl, it won't fit into the receptor.”— David E. Nichols


So, We know these compounds must dock with the 5HT2a receptor, and we know that the NH hydrogen of the pyrrole ring moiety in the LSD molecule needs to be free for these compounds to properly dock with this receptor site, therefore the substitutions to the NH grouping at position 1 must be removed in vivo.

Not sure how it applies here though.
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[*] posted on 3-5-2018 at 08:28


Yeah I know about DMSO as a penetration enhancer, and ethanol too for that matter. Oh and if you look up the composition of those transdermal fentanyl patches you find there is only soybean oil, hydrogenated colophony resin and a ethylhecyl acrylate-vinyl acetate copolymer none of which strike me as penetration enhancers.

But if you read several posts up... It was mentioned someone painted his arm with a solution of LSD in DMSO and had no effects.

So in the absence (?) of penetration enhancers fentanyl does work but for LSD it fails in the presence of penetration enhancers? I don't buy it.

@phenethylamine machine
Those N1 acylated compounds would have a higher logP, and one less H bond donor and would thus be expected to be more membrane (and skin) permeable. That is what I meant when I said how will they fare.

[Edited on 3-5-2018 by Sigmatropic]
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[*] posted on 3-5-2018 at 09:02


Quote: Originally posted by PhenethylamineMachine  
Quote: Originally posted by SWIM  
Quote: Originally posted by Sigmatropic  
Anyone know why fentanyl is readily capable of transdermal uptake but LSD is not?
Their dose is comparable. Their MW is comparable. Both are tertiary amines so I don't believe the 'your skin is acidic' theory. Both are metabolized in the liver so I don't believe in a large dermal first pass effect.
I did notice that their lipopholicity is different LogP = 4.05 VS 2.95 for fentanyl VS lsd. Is it just this 10 fold difference in lipopholicity that causes the difference in transdermal rates of absprbtion? And finally fentanyl has many more rotatable bonds, but IIRC more rotatable bonds means that a compound is less membrane permeable which diametrically opposes what we observe.

Edit: this makes me wonder how ALD-52 and 1P-LSD fare.

[Edited on 3-5-2018 by Sigmatropic]


Are you talking about those transdermal patches?

I think transporting chemicals through the skin is facilitated in those patches by something that makes the skin more permeable (not DMSO).

However I may be thinking of those estrogen/progesterone patches.



...not a fan of the whole "swim" thing.

Moving on.

There are many means of making a compound amenable to transdermal absorbtion.

DMSO is a very common and effective means of doing this.


Not a fan of your whole rudeness thing.
Or your ignorant assumptions about me or my posts.

'moving on'

That DMSO is commonly (in your opinion, but not quite so much in real world medicine) used to promote transdermal absorbtion is in no way germane to the fact that it's not used in the patches being discussed.

Oils, and other non-polar compounds, such as those listed in that patch, do in fact promote transdermal absorbtion, and are the 'common' materials used for this.

DMSO gets papers written about it, but ordinary oils of various kinds are far more ubiquitous in actual pharmaceutical preparations.





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[*] posted on 4-5-2018 at 06:03


Quote: Originally posted by Sigmatropic  
Yeah I know about DMSO as a penetration enhancer, and ethanol too for that matter. Oh and if you look up the composition of those transdermal fentanyl patches you find there is only soybean oil, hydrogenated colophony resin and a ethylhecyl acrylate-vinyl acetate copolymer none of which strike me as penetration enhancers.

But if you read several posts up... It was mentioned someone painted his arm with a solution of LSD in DMSO and had no effects.

So in the absence (?) of penetration enhancers fentanyl does work but for LSD it fails in the presence of penetration enhancers? I don't buy it.

@phenethylamine machine
Those N1 acylated compounds would have a higher logP, and one less H bond donor and would thus be expected to be more membrane (and skin) permeable. That is what I meant when I said how will they fare.

[Edited on 3-5-2018 by Sigmatropic]


Hmm...

I can't believe you were able to get me to research fentanyl...

"Fentanyl is apparently small enough to slip through the skin and into the blood stream fairly effectively, therefore a transdermal absorption agent is not needed.

Quote:

Abstract

The rate and regional differences for the penetration of fentanyl through equine skin was investigated in vitro using a commercial transdermal therapeutic system (TTS) or ‘patch’. 

With an area of about two square meters, the skin is the largest organ in the human body, and it is also where around one third of all our blood circulates. The primary function of the skin is to protect the body from foreign objects and microorganisms. It also helps the body to retain moisture, yet it is not completely impermeable. Relatively small drug molecules can penetrate the skin, and this is how transdermal patches work.

https://www.sciencedirect.com/science/article/pii/S003452880...

https://ltslohmann.de/en/patients/transdermal-therapeutic-sy...



Moving on.

Its puzzling, I agree, but if I had to take some wild guesses:

LSD is an incredibly fragile molecule, Perhaps it can not pass through the skin with out epimerization or inversion at the 8-position carbon to form d-iso-LSD, or perhaps the double bond that lies between that 8-position and the aromatic ring is an issue, giving lumi-LSD before the compound can enter the system...

LSD is also larger than fentanyl, so while still not very large, perhaps it is just over the size limit for effective transdermal absorbtion.

Moving on.

That someone who painted LSD/DMSO on his arm was Nick Sand. Nick was a clandestine chemist who was most famous for the production of several kilograms of LSD which he named "orange sunshine". Nick also worked with a man named tim scully, a very smart and talented individual, and was also guided by owsley Stanley.

The person talking about nick in that quote was Dr. David E. Nichols, who was the distinguished Chair of Pharmacology at Purdue University and who co-founded the Heffter Research Institute with Denis McKenna. David Nichols is considered the to be one of the worlds foremost LSD experts.

So while I personally can not verify their claims, I value and respect their thoughts and opinions on the matter.

If anybody knows about LSD in an academic and scientific manner it is David E. Nichols, and if anybody knows about clandestine production of LSD its Nick sand...


Review:
Quote:

Another fact: I've made LSD in my lab on many occasions for research purposes, possibly in not so meticulous a manner as Albert Hofmann. Nothing ever happened. I had several graduate students who made LSD as an intermediate for projects. No accidental ingestion of LSD ever occurred. A technician in my lab makes it routinely because we use it as a drug to train our rats. He's learned by experience that he never gets high, nothing ever happens. And yesterday I was talking to Nick Sand, and Nick said, "I made a solution of LSD in DMSO…" -- DMSO (dimethyl sulfoxide) is a chemical that greatly enhances absorption of other chemicals through the skin -- he says, "…I painted it on my skin. Nothing happened." A concentrated solution and nothing happened! 

...

Anyone I know who's worked with LSD -- and Nick Sand painted a solution of it on his arm -- didn't get high.

https://erowid.org/general/conferences/conference_mindstates...


Personally, I have had LSD gel-tabs dissolve in my hand, and no psychological effect occurred.

Moving on.

As for ALD-52 and 1P-LSD, you would have to explain to me exactly how one less h bond donor would make the compound more amenable to transdermal absorption. I know the chemistry of these molecules, yet I know very little about transdermal application of pharmaceutical or psychoactive agents, so pardon my ignorance on the matter.
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[*] posted on 4-5-2018 at 06:36


Quote: Originally posted by SWIM  
Quote: Originally posted by PhenethylamineMachine  
Quote: Originally posted by SWIM  
Quote: Originally posted by Sigmatropic  
Anyone know why fentanyl is readily capable of transdermal uptake but LSD is not?
Their dose is comparable. Their MW is comparable. Both are tertiary amines so I don't believe the 'your skin is acidic' theory. Both are metabolized in the liver so I don't believe in a large dermal first pass effect.
I did notice that their lipopholicity is different LogP = 4.05 VS 2.95 for fentanyl VS lsd. Is it just this 10 fold difference in lipopholicity that causes the difference in transdermal rates of absprbtion? And finally fentanyl has many more rotatable bonds, but IIRC more rotatable bonds means that a compound is less membrane permeable which diametrically opposes what we observe.

Edit: this makes me wonder how ALD-52 and 1P-LSD fare.

[Edited on 3-5-2018 by Sigmatropic]


Are you talking about those transdermal patches?

I think transporting chemicals through the skin is facilitated in those patches by something that makes the skin more permeable (not DMSO).

However I may be thinking of those estrogen/progesterone patches.



...not a fan of the whole "swim" thing.

Moving on.

There are many means of making a compound amenable to transdermal absorbtion.

DMSO is a very common and effective means of doing this.


Not a fan of your whole rudeness thing.
Or your ignorant assumptions about me or my posts.

'moving on'

That DMSO is commonly (in your opinion, but not quite so much in real world medicine) used to promote transdermal absorbtion is in no way germane to the fact that it's not used in the patches being discussed.

Oils, and other non-polar compounds, such as those listed in that patch, do in fact promote transdermal absorbtion, and are the 'common' materials used for this.

DMSO gets papers written about it, but ordinary oils of various kinds are far more ubiquitous in actual pharmaceutical preparations.


Sorry if you feel I was being rude, I am sure that many people have mentioned the negative connotations associated with those who use "swim", I personally discourage the practice, but I also apologize for brining it up, I shouldn't have said anything.

DMSO is still very commonly used in modern medicine, and the fact that it is not used in fentanyl patches is irrelevant, this is a thread centered on transdermal lysergamides. The fentanyl patches were a side topic. DMSO or other agents are not used in fentanyl patches because fentanyl is small enough to slip through the skin without them.

Also, DMSO has a good safety record, which is another reason why it is used in medicine.


Quote:

The clinical use of pharmaceutical-grade DMSO as a penetration enhancer is supported by the robust data that have accumulated over the past 3 decades demonstrating the favorable safety and tolerability profile
https://www.ncbi.nlm.nih.gov/pubmed/22030943


When you say:
Quote:
"Oils, and other non-polar compounds, such as those listed in that patch, do in fact promote transdermal absorbtion, and are the 'common' materials used for this"


This is not correct, those oils are only used with compounds that are already amenable to transdermal absorption, Dimethyl sulfoxide is a mechanism for facilitating the transdermal absorbtion of both hydrophilic and lipophilic medications for which transdermal absorption would otherwise not be a viable route.

transdermal absorption ultimately comes down to the properties of the molecule itself.
Quote:

With an area of about two square meters, the skin is the largest organ in the human body, and it is also where around one third of all our blood circulates. The primary function of the skin is to protect the body from foreign objects and microorganisms. It also helps the body to retain moisture, yet it is not completely impermeable.  Relatively small drug molecules can penetrate the skin, and this is how transdermal patches work. [b/]
https://ltslohmann.de/en/patients/transdermal-therapeutic-sy...
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[*] posted on 4-5-2018 at 07:12


Oils and other non-polar compounds, such as those listed in that patch, do in fact promote transdermal absorbtion, and are the 'common' materials used for this.

You statement that this is not correct is followed directly by your admission that it is correct.:D


That DMSO is not used in the patches is entirely relevant to the question that I was replying to.

I must point out at this juncture that a more careful reading of posts would be much to your benefit.






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[*] posted on 4-5-2018 at 08:26


@PhenetylamineMachine; I really don't understand how you can say you won't research fentanyl just because "your interests are somewhere else". How do you expect to be able to explain things when you don't know the whole picture, but just your small window of interest?

You are at least missing some really important things here; LSD is a highly charged compound at pH<6, in that form it will never penetrate the skin. Fentanyl; not so much. Compounds passing the skin entering the blood have to pass at least one cellulair membrane, if it can do that, there is not too much more in the way except for mechanical barriers or active secretion.

In order to pass a membrane (ignoring actively transported compounds) it has to be not too hydrophilic, not too hydrophobic but something in between. As we know, LSD passes mucous membranes, the blood-brain barrier and probably some more. So we know LSD is not too hydrophilic, nor is it too hydrophobic. That leaves us with charge, one charge on a molecule and it will never ever pass a membrane passively.

What is the % charged at the pH of the skin? The pKa of the strongest basic N is about 8 (1), the pH of the skin is more acidic than pH 6, probably 5 (2), with those number, most of the molecules will be charged.

Now couldn't it be all people reporting no psychological effects after exposure too the skin where using a neutral solution of LSD, which is charged, and charged even further on contact with the skin. And couldn't it be Hoffman's solution was basic, and basic enough to buffer the acid from the skin?

You could use a liter of DMSO, but that will not help a charged molecule pass the skin.

1: https://www.drugbank.ca/drugs/DB04829
2: https://www.ncbi.nlm.nih.gov/pubmed/

Edit: your reasoning about molecules being big or small being relevant to transdermal action is bogus. You can pass molecules a lot bigger as long as they exhibit the right properties. Mechanically seen the skin is as porous as a kitchen sieve trying to catch water.

[Edited on 4-5-2018 by Tsjerk]

[Edited on 4-5-2018 by Tsjerk]
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[*] posted on 5-5-2018 at 07:37


Quote: Originally posted by Reboot  


I find the 'mystical experience' explanation ridiculous. I tend to agree with PEAM's theory of deliberate ingestion from the start. No cautious, reasonable, and sober researcher would have decided to follow up a mild accidental exposure to a clearly wildly powerful drug by deliberately ingesting more, which we know for certain he did. I think it most likely was indeed a deliberate experiment from the start, more in the vein of Shulgin's work, just more modestly garbed in the telling (while Shulgin was always an unrepentant fan of looking for the next novel high.)

[Edited on 3-5-2018 by Reboot]


I have my own hypothesis regarding this situation, in which Hofmann intentionally consumed the compound on that first occasion, however, I have been thinking about this lately, and Nichols does put forward some fairly confounding conjecture relating to the circumstances surrounding Hofmann's first ingestion.

Such as the duration of the experience:
Quote:

"I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors. After some two hours this condition faded away." -Hofmann, 1983


Pharmacologically speaking, if LSD had in fact entered Hofmann's system, even if it had done so at the most miniscule of doses, the duration would have to be far more than two hours...

Another puzzling aspect of the story involves the re-synthesis of the compound several years down the road, and that he picked the compound out of a series.

Hofmann was working with a large series of lysergamide compounds, Nichols estimates around 30 compounds of which LSD was the 25th. Now, NONE of these compounds produce as powerful or as profound of an experience as LSD, most were more or less inactive, or active in a manner which for the most part does not resemble LSD, yet somehow Hofmann picked the single "magic" molecule of his series. (Which again plays into Nichols "cosmic conspiracy theory).

Quote:

We know that Albert originally synthesized LSD in 1938 as part of an ambitious program to make a number of lysergamides. LSD-25 was only the 25th in the series. I actually don't know how many of those compounds he made, but let's assume he only made 30. So we had up to 30 in the series. He may have made many more actually, but at least say 30. And they were all tested; he sent the pharmacology department LSD-25, 24, 23... and so forth. They then say, "LSD-25: not interesting." The assays of that day really didn't provide much information; they were very unsophisticated. But five years later, Albert has a hunch that the pharmacology department missed something on this 25th in the series
https://erowid.org/general/conferences/conference_mindstates...



So, is it really that unlikely that a chemist with a propensity for altered state experiences could have been working in his lab, at which point he enters a natural mystical state, which he then logically attributes to the substance he was working with? The only truly hard to believe aspect of the hypothesis was that the compound actually turned out to generate intense mystical experiences.

...Well, that, and the fact that Hofmann chose this compound out of a large series of mostly inactive compounds, and re-synthesized it, for no apparent reason.

Quote:

The other fact we need to think about is when Albert was a child, he had a spontaneous mystical experience. Now depending on whether you're a psychologist or a psychiatrist or whatever, we could say that Albert had a predisposition to altered states of consciousness. 

So what facts do we know? I'm going to formulate a hypothesis. He took a dose that by your consensus should have lasted certainly more than two hours, but it only lasted two hours. He was a meticulous chemist -- a Swiss chemist. Anyone I know who's worked with LSD -- and Nick Sand painted a solution of it on his arm -- didn't get high. This doesn't make sense. And what is this peculiar presentiment? Why the 25th in the series? Inexplicable! And, he was predisposed to altered states of consciousness.

The only hypothesis I can come up with that's consistent with all of these facts is that on April 16, 1943, Albert Hofmann did not get LSD in his body at all. He had a spontaneous mystical experience! 

Now if I were working in the lab with a new chemical, and I started having kaleidoscopic visions of wonderful colors and patterns, my first thought wouldn't be that I was having a spontaneous experience. My first thought would be, "What was that new chemical I was working with? I need to tell Sasha about it." [laughter] 

I think that's what happened, that's the hypothesis. We can't test that hypothesis, but when I saw Albert in Basel a couple years ago, I presented that particular hypothesis to him and said, "What do you think?" He said, "It's entirely possible." So, that's our little experiment, and I think most of you really didn't think seriously about the discovery of LSD, but it puts a different light on it.

https://erowid.org/general/conferences/conference_mindstates...


I think it is also important to understand who david Nichols is, as Nichols is a highly accomplished and accredited figure in medicinal chemistry, pharmacology, and psychedelic research.
Quote:

David Earl Nichols (born December 23, 1944, Covington, Kentucky) is an American pharmacologist and medicinal chemist.[1] Previously the Robert C. and Charlotte P. Anderson Distinguished Chair in Pharmacology at Purdue University, Nichols has worked in the field of psychoactive drugs since 1969. While still a graduate student, he patented the method that is used to make the optical isomers of hallucinogenic amphetamines. His contributions include the synthesis and reporting of escaline, LSZ, 6-APB, 2C-I-NBOMe and other NBOMe variants (NBOMe-2C-B, NBOMe-2C-C, NBOMe-2C-D), and several others, as well as the coining of the term "entactogen".

He is the founding president of the Heffter Research Institute, named after German chemist and pharmacologist Arthur Heffter, who first discovered that mescaline was the active component in the peyote cactus. In 2004 he was named the Irwin H. Page Lecturer by the International Serotonin Club, and delivered an address in Portugal titled, "35 years studying psychedelics: what a long strange trip it's been." Among pharmacologists, he is considered to be one of the world's top experts on psychedelics. Nichols's other professional activities include teaching medicinal chemistry and molecular pharmacology at Purdue University in West Lafayette, IN, and teaching medical students at the Indiana University School of Medicine.

-Wikipedia

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[*] posted on 5-5-2018 at 08:59


Quote: Originally posted by Tsjerk  
@PhenetylamineMachine; I really don't understand how you can say you won't research fentanyl just because "your interests are somewhere else". How do you expect to be able to explain things when you don't know the whole picture, but just your small window of interest?

You are at least missing some really important things here; LSD is a highly charged compound at pH<6, in that form it will never penetrate the skin. Fentanyl; not so much. Compounds passing the skin entering the blood have to pass at least one cellulair membrane, if it can do that, there is not too much more in the way except for mechanical barriers or active secretion.

In order to pass a membrane (ignoring actively transported compounds) it has to be not too hydrophilic, not too hydrophobic but something in between. As we know, LSD passes mucous membranes, the blood-brain barrier and probably some more. So we know LSD is not too hydrophilic, nor is it too hydrophobic. That leaves us with charge, one charge on a molecule and it will never ever pass a membrane passively.

What is the % charged at the pH of the skin? The pKa of the strongest basic N is about 8 (1), the pH of the skin is more acidic than pH 6, probably 5 (2), with those number, most of the molecules will be charged.

Now couldn't it be all people reporting no psychological effects after exposure too the skin where using a neutral solution of LSD, which is charged, and charged even further on contact with the skin. And couldn't it be Hoffman's solution was basic, and basic enough to buffer the acid from the skin?

You could use a liter of DMSO, but that will not help a charged molecule pass the skin.

1: https://www.drugbank.ca/drugs/DB04829
2: https://www.ncbi.nlm.nih.gov/pubmed/

Edit: your reasoning about molecules being big or small being relevant to transdermal action is bogus. You can pass molecules a lot bigger as long as they exhibit the right properties. Mechanically seen the skin is as porous as a kitchen sieve trying to catch water.

[Edited on 4-5-2018 by Tsjerk]

[Edited on 4-5-2018 by Tsjerk]


You understand why most scientists, hobbyists, and researchers focus on a specific field, right?

My focus is the organic chemistry of tryptamine, phenethylamine, and lysergamide compounds.

Trust me, my decision to focus on a specific field does not limit me from seeing "the whole picture" in any way, you have to know the whole picture before you can decide to focus on a specific field any way.

I know the whole of my field well enough to where I can simply read the available material on fentanyl and understand it

When you know your field you do not have to have every detail regarding every compound memorized, and seeing as how fentanyl is not even structurally related to the molecules which are my focus, it should be understandable that I am not very enthusiastic to look into it. ...and when it comes to compounds which are highly abused, highly addictive, highly dangerous, and which are responsible for such a large number of deaths, it's hard to be enthusiastic in regards to them.

Ok, you are saying
Quote:

You are at least missing some really important things here; LSD is a highly charged compound at pH<6, in that form it will never penetrate the skin. Fentanyl; not so much. Compounds passing the skin entering the blood have to pass at least one cellulair membrane, if it can do that, there is not too much more in the way except for mechanical barriers or active secretion.



What are your sources here?

And If you could please elaborate on how charge and PH are essential to a molecule being amenable to transdermal adsorption I would appreciate it.

LSD has a PH of 6? Please elaborate.

I understand the chemistry of LSD, however, as would have been obvious from my prior posts in this thread, I do not fully understand the mechanisms by which a compound becomes amenable to transdermal absorption.

My understanding is that it is determined by the properties of the molecule itself, which is correct, and the size of the molecule does appear to be a factor here.

When you say:
Quote:
your reasoning about molecules being big or small being relevant to transdermal action is bogus. You can pass molecules a lot bigger as long as they exhibit the right properties. Mechanically seen the skin is as porous as a kitchen sieve trying to catch water.
you call it my reasoning, when in fact it was the information which I was provided*. If this information is incorrect could you please cite credible source confirming it?

*
Quote:

With an area of about two square meters, the skin is the largest organ in the human body, and it is also where around one third of all our blood circulates. The primary function of the skin is to protect the body from foreign objects and microorganisms. It also helps the body to retain moisture, yet it is not completely impermeable.  Relatively small drug molecules can penetrate the skin, and this is how transdermal patches work.
https://ltslohmann.de/en/patients/transdermal-therapeutic-sy...


Could you cite a source which states that the size of a molecule is not relevant to it's ability to pass the membrane of the skin?

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[*] posted on 5-5-2018 at 09:09


Quote: Originally posted by SWIM  
Oils and other non-polar compounds, such as those listed in that patch, do in fact promote transdermal absorbtion, and are the 'common' materials used for this.

You statement that this is not correct is followed directly by your admission that it is correct.:D


That DMSO is not used in the patches is entirely relevant to the question that I was replying to.

I must point out at this juncture that a more careful reading of posts would be much to your benefit.



That is not the part that I was saying was irrelevant, perhaps a closer read could benefit all parties here.

Those oils and so on listed do aide in transdermal absorption, but in these cases the molecule is already amenable to transdermal absorption to begin with.

When the molecule is NOT already amenable to transdermal absorption a skin penetrating agent, such as DMSO is required.

... though as the research paper below elucidates, various solvents can be employed for this purpose.


Quote:

As a possible approach to determining whether DMSO would enhance drug absorption through a biological membrane, we employed a simple test of immersing the tails of mice and rats into solutions of drugs dissolved in DMSO. We employed primarily psychoactive drugs since it would be possible to observe grossly any change in behavior, if, in fact, such did occur. This paper deals with the results of such a study and of a comparison of the ability of different solvents to permit passage of drugs across the skin barrier.
https://www.sciencedirect.com/science/article/pii/0024320564...
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