does a drug need to be water soluble to snort??

ive seen a few different opinions on this subject.... some people say a substance wont be absorbed via the nasal membrane unless its water soluble.... ive been told otherwise by a couple people including a moderator on this site whos name will not be mentioned.... this leaves me confused on the subject, and google isnt providing me with much info.... if anyone can help clear this subject up, it will be appreciated.... if this is in the wrong forum, i apologize, feel free to move.... this forum seemed appropriate due to the lack of info i found on it.... thanx again....

I too have found it hard to find a reference to back this statement up. This is not because it is unknown or dubious in anyway, it is because it is so obvious to researchers that the don't need to feel to state it. However I will quote some abstracts from scientific journals, and underline pertinent sections.

You should know that octanol-water partion coefficents are a measure of lipid solubility, higher ratios mean higher lipid solubility. In this study, the show that esters of Tyrosine which are more fat soluble are absrobed faster than tyrosine through the nasal passage. It should be noted that one of the esters however, was more fat soluble but was absorbed at the same rate (but not slower)

Mechanism of nasal absorption of drugs. II: Absorption of L-tyrosine and the effect of structural modification on its absorption.
Huang CH, Kimura R, Bawarshi-Nassar R, Hussain A.
J Pharm Sci. 1985 Dec;74(12):1298-301.

The nasal absorption of L-tyrosine and the effect of structural modification on that absorption have been studied using an in-situ experimental technique. The extent of nasal absorption of the amino acid was found to be the same at pH values of 4.0 and 7.4 but dependent on concentration in the range of 2.8 X 10(-4)-2.2 X 10(-3) M. O-Acyl-L-tyrosine esters, although possessing higher octanol-water (pH 7.4) partition coefficients, have the same rate of nasal absorption as the parent amino acid. N-Acetyl-L-tyrosine, on the other hand, was found to have both partition coefficient and nasal absorption rate similar to those of L-tyrosine. Esterification of the carboxyl moiety of L-tyrosine results in derivatives that hydrolyze in the in-situ perfusion medium generating the original amino acid. The rate of nasal absorption of these derivatives was, therefore, determined from an overall disappearance rate which accounted for the rate of hydrolysis to L-tyrosine. These carboxylic esters were absorbed 4 to 10 times faster than L-tyrosine. Although the carboxylic esters of L-tyrosine possess higher octanol-water partition coefficients than the parent amino acid, the differences in the rates of nasal absorption could not be attributed solely to partition coefficient. The enhancement in the rate of absorption observed for these esters was attributed instead to the absenc
e of the negative charge on the carboxylate moiety. It is a result of this negative charge that the rates of nasal absorption of L-tyrosine, O-acyl-L-tyrosine esters and N-acetyl-L-tyrosine are similar, despite significant differences in their partition coefficients.

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In this study the show that Benzoic Acid, is absorbed 4 times faster in acidic environments. Benzoic acid is like the opposite of your classical alkaloid, in regards to the fact that it becomes water INSOLUBLE (hence fat soluble) in acidic environments. It also showed that the fattier certain barbiturates are the quciker they are absrobed (though you need to full article to view that result)

Mechanism of nasal absorption of drugs I: Physicochemical parameters influencing the rate of in situ nasal absorption of drugs in rats.
Huang CH, Kimura R, Nassar RB, Hussain A.
J Pharm Sci. 1985 Jun;74(6):608-11.

The effect of rate of perfusion, volume, pH of the perfusate, and partition coefficient of the drug on the rate of in situ nasal absorption in rats was examined. The studies showed that the rate constant for the nasal absorption of phenobarbital was independent of the rate of perfusion above a value of 2 mL/min. The nasal absorption of benzoic acid was found to depend on the pH of the perfusate with the benzoate anion being absorbed at a rate one-fourth of that of benzoic acid. The effect of lipid solubility on the extent of nasal absorption was studied using a series of barbiturates. The rate and extent of absorption was found to be dependent on the chloroform-water partition coefficient of the barbiturate. The effect of the volume of the perfusate on the absorption rate constant of phenobarbital, phenol red, tyrosine, and propranolol was studied. The data obtained showed that a linear relationship existed between the rate constants of absorption and the reciprocal of the volume of the perfusate. Using this in situ relationship it was possible to predict in vivo absorption rate constants for propranolol and L-tyrosine when volumes of 0.1 mL were administered. The calculated values for these compounds were found to be close to those determined in in vivo experiments. This indicates that the in situ technique can be used to predict in vivo absorption rate constants.

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And finally, [here is a condensed version of table 1 and 2 from:
The physicochemical properties, plasma enzymatic hydrolysis, and nasal absorption of acyclovir and its 2'-ester prodrugs.
Shao Z, Park GB, Krishnamoorthy R, Mitra AK.
Pharm Res. 1994 Feb;11(2):237-42.

It shows an increasing absorption of the drug (%uptake in 90 minutes) as the fat solubility increases (PC, partition coefficent) and the water solubility decreases.



That should thouroughly shut up your detractors, and finally, if they still don't believe you (at which point you can assume they are idiots), just look up reports from people who have snorted Benzodiazepines, especailly xanax or diazepam (very fat soluble, and water soluble)

BilZ0r said:

In this study the show that Benzoic Acid, is absorbed 4 times faster in basic invironments. Benzoic acid is like your classical alkaloid, in regards to the fact that it becomes water INSOLUBLE (hence fat soluble) as basic invironments.

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I think you got that backwards.

Also this site should help clarify a few things, though as they say log p values aren't the end all and be all for determining absorption, especially in vivo.

^^ Yep, benzoic acid is pretty insoluble in water, but in basic enviroments it forms the benzoate ion (eg sodium benzoate), which although not massively soluble, is moreso than benzoic acid.

Benzoic acid is like your classical alkaloid, in regards to the fact that it becomes water INSOLUBLE (hence fat soluble) as basic invironments

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Benzoic acid is like your classical alkaloid in regard to the fact that it becomes more water soluble when it is in salt form (ionized in solution)

I think that's more along the lines of what you meant


PS

The effect of lipid solubility on the extent of nasal absorption was studied using a series of barbiturates

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OUCH! (exorcist voice: "it burns master, it burns!")

Yes, I did get that backwards... but it still supports the fact that the ionoic, water soluble form is slowly absorbed....

I've read DMT freebase is snortable, but its much better absorbed when people have mixed a little sodium bicarbonate with it. Then there's 5-MeO-DMT fb which is also snortable.

This fits here, thought I'd paste a link in case anyone is looking for mroe information on the subject.
http://www.bluelight.ru/vb/showthread.php?p=9063153

no definitely not. Pretty much anything will get through your mucus membranes with enough time. The question is whether it gets through at a rate fast enough to make it a better route than oral.

I have snorted synthetic DMT freebase, it requires at least around 65mg and is horrendously painful. I have heard that the fumerate salt is the least painful form to snort - but I'm not sure if pain and absorption are interrelated ie if pain increases proportionally with absorption than increased absorption becomes a poor reason to administer a drug nasally!

yaesutom said:

I've read DMT freebase is snortable, but its much better absorbed when people have mixed a little sodium bicarbonate with it. Then there's 5-MeO-DMT fb which is also snortable.

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I've never considered snorting my freebase N,N-DMT but have not taken my freebase 5-MeO-DMT via any other route than that.
The one single reason for that is that 5-MeO-DMT is about 5 times as potent making a dose just bearable, although just like with 2C-B I must admit there were those times with 5-MeO that I thought: that's it!! that's the last time I snort this corrosive material!

Speaking of 2C-B, it is said not all salts are equally water soluble making some painful to snort and others significantly less. IIRC it was the HBr that was more soluble and less painful, while at the same time more acutely active (but it also could have been the HCl). I am fairly sure I have had both, taken from my direct sources.
So, water solubility is also a factor for how painful it is.
Other properties might influence if the pain is a fast sting or a lingering type of nagging sustained little burn.

But if I understand this thread correctly the pKa of a compound is also important to take into account? Or is it not, because we are thinking of water in every condition, at physiological (nose) pH ?
The factors probably depend on each other: if a base is less likely to be protonated to its ionized much more water-soluble form then the pKa/pKb is of direct influence on the solubility right? And therefore of influence on the snortability.

Amphetamine has poor water solubility but those adderall time release pill nublets can easily be ground up on a hard surface and the resulting material snorted.

Rule number one for me is to always make sure the nose is clear.

If you think something might be particularly nasty to try, have some sort of a medicinal nasal spray on hand to help. This can be to help get material that is stuck through the membrane if you think it didn't get all the way through or to clear up a stuffed nose, if you get that type of reaction after you insufflate the substance.

I've always snorted a little warmish water afterwards. Not enough to make it drip down the back (or front!) but enough to feel it in there. I believe I can tell the difference, but it's hard to say for certain.

so i have yet to gather an answer... yes or no?

From the information in this thread I would conclude a no.
Though I think it's commonly believed to be so because many snorted drugs are salts and not free bases.

I also always thought that pretty much none of the benzo's should be snorted because they have perfectly good oral bioavailability. Which is also what hammilton seems to say: it's pointless to snort a good number of drugs.
If nasal bioavailability is lower than oral why do it? For the rush? Then absorption should be fast enough to trump the enteral route. This here seems true regardless of water solubility.

So there seems to be a bias to me because many compounds are just most effective taken orally, and drugs typical to snort are their salts rather than their freebases.

For one single compound or drug the water-soluble salt definitely seems to be preferred over the fat or oil soluble freebase.
But how do you compare between different drugs? I welcome someone else to answer that.

If someone could find a trend by looking at opiates for example, their snortability and water solubility that would also be nice.

Hammilton said:

no definitely not. Pretty much anything will get through your mucus membranes with enough time. The question is whether it gets through at a rate fast enough to make it a better route than oral.

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I would back this oppinion up.

One way or another most substances seem to get thru the mucus membranes quicker than just swallowing. This reminds me of the loperamide debate, in which some people swear it has a euphoric effect or at least can keep withdrawals at bay for opiate addicts. I believe them.

BilZ0r said:

That should thouroughly shut up your detractors, and finally, if they still don't believe you (at which point you can assume they are idiots), just look up reports from people who have snorted Benzodiazepines, especailly xanax or diazepam (very fat soluble, and water soluble)

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Either I am not getting your post correctly after reading it 10 times or you're assuming that snorting xanax works because it is absorbed by your nose. Instead, something else apparently happens that I coincedentally stumbled about somewhere just now - quoting wiki's alprazolam page:

"For recreational effects, alprazolam is generally administered orally. Nasal insufflation (often called "snorting") sometimes occurs, but due to the drug's chemical structure, it is not absorbed through the mucous membranes. Instead, the powdered tablets and mucous drip down the back of the throat into the stomach, where they are absorbed as they would have been if taken orally. Therefore, insufflation of the drug is no more potent than when taken orally, and it often severely irritates the nasal passages. Furthermore, nasal insufflation may be significantly less potent than other means of administrations on a dosage-per-time basis, because the mucous drip enters the stomach at a slower rate than traditional ingestion."

Solipsis said:

"For recreational effects, alprazolam is generally administered orally. Nasal insufflation (often called "snorting") sometimes occurs, but due to the drug's chemical structure, it is not absorbed through the mucous membranes. Instead, the powdered tablets and mucous drip down the back of the throat into the stomach, where they are absorbed as they would have been if taken orally. Therefore, insufflation of the drug is no more potent than when taken orally, and it often severely irritates the nasal passages. Furthermore, nasal insufflation may be significantly less potent than other means of administrations on a dosage-per-time basis, because the mucous drip enters the stomach at a slower rate than traditional ingestion."

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I tell someone in BDD about once a day not to snort xanax, but back in my young and foolish days I snorted them many times and they certainly do work that way. I find it hard to believe this is entirely due to drip into the stomach as little drip was noted (they are tiny pills after all), and the onset seemed if anything faster than oral. Not suggesting this ROA by any means, but my personal experience is at odds with the wiki article.

and the onset seemed if anything faster than oral. Not suggesting this ROA by any means, but my personal experience is at odds with the wiki article.

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It's probably because the pill is crushed and thus dissolves quicker.