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Positional Isomers of Amphetamine

Hammilton

Hammilton

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As I understand, positional isomers of Schedule I and II drugs are automatically controlled in the US, meaning that beta-methyl-beta-phenethylamine and N-methyl-beta-phenethylamine are both controlled. I may misunderstand though, and these may actually be controlled if intended for personal use.

I like to stay current on what's being sold as weight loss supplements and I came across some pretty surprising stuff. I took a brief run through the local GNC and Walmart this week and read the ingredients in all of them.

Mostly they contain caffeine, and to a lesser extent, synephrine and yohimbine (and apparently some yohimbine analogues). Besides legitimate weight loss drugs, they also contain things like guggelsterones and other compounds that don't have well documented ability to reduce weight.

Four "OTHER" drugs have been found in these, though.

One is 1,3-dimethylamylamine (1,3-DMAA), a basic-ish compound which is described as being an okay stimulant. Some apparently experience a decent degree of euphoria as well.

Another is hordenine. It's an alkaloid found all over the place, but if it has any effect, I have no idea. Taking it with an MAOI would probably be a bad idea though.

The "OTHER" two are both positional isomers of amphetamine:

N-methyl-beta-phenethylamine
Beta-methyl-beta-phenethylamine

These are both obviously positional isomers of amphetamine. Everyone is aware that amphetamine the word is taken from alpha-methyl-phenethylamine. I suppose this would be beta-methyl-"phetamine" or betyphetamine (betaphetamine maybe?).

I don't doubt that it's fairly active (probably less potent than amphetamine) and probably euphoric and addictive, but who knows how much is actually in these tablets.

The latter is less interesting. Without a substitution on the carbon chain, I doubt it's going to get past MAO enzymes. If it does it might be a decent drug. Phenethylamine was an amazingly euphoric drug while I was on selegiline, but one overdose changed my mind about it pretty quickly (I still used it many times though).

I'd only bet on it's being active if the payout was better than two to one (3:2, 3:1, or better), meaning that I think there's worse than a 50% chance of it not being active.



So at least one compound is very likely active (I haven't searched yet, but I'll assume it is), and another is maybe active. However, they're both positional isomers of amphetamine. It's one thing for Igor from Ukraine or Brett and Jermaine from New Zealand to sell these online as research chems, but it's quite another to have them on the shelf at GNC and Walmart!

I kind of hope that Walmart and GNC are forced to pay big fines for this. If your or I had a shop downtown selling "weight loss supplements" that contained compounds that similar to amphetamine we'd go to jail. When it's found out that Walmart has been, they'll just be asked to take them off the shelf and turn them over to the DEA. They'll probably prosecute the manufacturer, but the distributor won't. This is the sort of stuff the DEA supposedly exists for- taking out major producers and dealers of illegal drugs- and it's hard to get bigger than Walmart.

I'd like to see these laws scrapped, ultimately, but in the mean time, it's an injustice that Walmart will be treated differently.

Basically three things and questions:

1. Are positional isomers automatically illegal, or only when meant for human consumption (which is obviously the point of a "supplement" sold in pills)?
2. How does betaphetamine compare to N-methylphenethylamine and to amphetamine itself?
3. Does it bother you that Walmart is getting away selling these drugs for human consumption (so they're definitely treated as Schedule I drugs by law), that they're not treated the same as you or I would be?

Ham
 
1. It depends on your local law. I'm no expert on scheduled substances in the U.S. but I guess no. If it were true, then isomethadone wouldn't be in the schedule along with methadone.

2. 2-phenylpropan-1-amine is what you're talking about (with amphetamine being 1-phenylpropan-2-amine). Actually, various Acacia species contain this, some other being N-methyl analog, N-methylphenethylamine, and also hordenine you mentioned.

How does it compare? I don't know. These drugs are at best either MAO inhibitors or centrally weak stimulants like ephedrine... Anyway, they don't seem to be valuable as recreational drugs.

3. I don't really care. And as I wrote it'd be strange if they could be treated as schedule I drugs because of analog act because of the example of 2 positional isomers listed I mentioned.
 
if you have to wonder whether or not it's even active, it doesn't fall under the analogue act. At least it shouldn't, by virtue of the "substantially similar to or greater than" language.

(depending on which functional groups you fix) there are at least 8 positional isomers of amphetamine and AFAIK they're all relatively worthless as stimulants. I'm just theorizing though.

adder said:
If it were true, then isomethadone wouldn't be in the schedule along with methadone.
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I don't know when isomethadone was listed but it's substantially easier to convict someone of possession of a controlled substance than possession of a controlled substance analogue.
 
Yeah, the effect of the compound has to be similar to the drug it is an analog of. Also it has to be possessed or sold with the intent of human use. For example, if you were a grad student synthesizing a compound, say 14-hydroxydesomorphine, a very potent positional isomer of dihydromorphine which is not explicitly scheduled but is a positional isomer of a controlled substance, and making the compound to study it's synthesis or pharmacology in non-humans, somehow avoiding any scheduled compound as a precursor or contaminant, that would be completely legal.

From what I've read adding an N-methyl to beta-pea still requires an MAOI to be a noticeable stimulant, and it's effects are less desirable when taken with an maoi.
 
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seep said:
if you have to wonder whether or not it's even active, it doesn't fall under the analogue act. At least it shouldn't, by virtue of the "substantially similar to or greater than" language.
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True but these aren't analogs, they are isomers. And isomers are specifically illegal, no "substanstially similar" language. I'd say let wal-marts lawyers worry about it, I would be very surprised if it has any recreactional value.
 
fs, I think you're remembering laws that don't exist. If we're talking about what the law means by "isomer", the CSA gives a definition:

(14) The term "isomer" means the optical isomer, except as used
in schedule I(c) and schedule II(a)(4). As used in schedule I(c),
the term "isomer" means any optical, positional, or geometric
isomer. As used in schedule II(a)(4), the term "isomer" means any
optical or geometric isomer.
Click to expand...

Schedule I(c) lists "hallucinogenic substances" like MDA, MDMA, LSD and etc.
Schedule II(a)(4) talks about cocaine.

Any other mention of isomer, then, refers to an optical isomer.


Just noticed that amphetamine is schedule III, so the analogue law doesn't apply to it.
 
seep said:
fs, I think you're remembering laws that don't exist. If we're talking about what the law means by "isomer", the CSA gives a definition:



Schedule I(c) lists "hallucinogenic substances" like MDA, MDMA, LSD and etc.
Schedule II(a)(4) talks about cocaine.

Any other mention of isomer, then, refers to an optical isomer.


Just noticed that amphetamine is schedule III, so the analogue law doesn't apply to it.
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Amphetamine is Schedule II d. Optical isomerism is explicitly illegal for amphetamine but isomerism is instead listed for methamphetamine, meaning that methamphetamine positional isomers are probably illegal while amphetamine positional isomers are not.

Ergo beta-methyl-beta-phenethylamine and N-methyl-beta-phenethylamine are not controlled... but if you include any N-methyl-beta-methylphenethylamine you would be in possession of a mixture containing a controlled substance (methamphetamine). I fear I'd been one of the ones propagating this myth, since I'd mentioned the illegality of a-ethylphenethylamine and N-methyl-beta-methylphenethylamine quite some time ago in a few places.

Since the analogue law can be interpreted as outlawing any substance with a similar effect to an illegal drug, the point is kind of unimportant anyway.

Edit: There seems to be a source of contradiction here; I'm guessing the alternative isomer definition is from:

1105 Methamphetamine, its salts, isomers, and salts of its isomers
Click to expand...
http://isomerdesign.com/Cdsa/scheduleUS.php?schedule=2&section=4&structure=C

However, the PDF scanning of the law from when it was passed lists optical isomers:
Methamphetamine, its salts, optical isomers, and salts of its optical isomers 1105
Click to expand...

So... what is the truth? Perhaps the isomer design listing is some sort of a mistake, or the law was amended at a later time. Someone with more knowledge will have to clarify.
http://isomerdesign.com/Cdsa/FR/36FR9563.pdf
 
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My bad, I didn't know that the CSA had an appendix that published updated schedules. Usually they just revise the original document, no? That's what the states are doing with the JWHs: revising the original documents.

so then section 1301 of the CFR 21 CFR 1300.01(b)(21) has this definition of isomer:

(21) (i)The term isomer means the optical isomer, except as used in Sec. 1308.11(d) and Sec. 1308.12(b)(4) of this chapter. As used in Sec. 1308.11(d) of this chapter, the term isomer means the optical, positional, or geometric isomer. As used in Sec. 1308.12(b)(4) of this chapter, the term isomer means the optical or geometric isomer.

(ii) As used in Sec. 1308.11(d) of this chapter, the term "positional isomer'' means any substance possessing the same molecular formula and core structure and having the same functional group(s) and/ or substituent(s) as those found in the respective schedule I hallucinogen, attached at any position(s) on the core structure, but in such manner that no new chemical functionalities are created and no existing chemical functionalities are destroyed relative to the respective schedule I hallucinogen. Rearrangements of alkyl moieties within or between functional group(s) or substituent(s), or divisions or combinations of alkyl moieties, that do not create new chemical functionalities or destroy existing chemical functionalities, are allowed i.e., result in compounds which are positional isomers. For purposes of this definition, the "core structure'' is the parent molecule that is the common basis for the class; for example, tryptamine, phenethylamine, or ergoline. Examples of rearrangements resulting in creation and/or destruction of chemical functionalities (and therefore resulting in compounds which are not positional isomers) include, but are not limited to: ethoxy to alpha-hydroxyethyl, hydroxy and methyl to methoxy, or the repositioning of a phenolic or alcoholic hydroxy group to create a hydroxyamine. Examples of rearrangements resulting in compounds which would be positional isomers include: tert- butyl to sec-butyl, methoxy and ethyl to isopropoxy, N,N-diethyl to N- methyl-N-propyl, or alpha-methylamino to N-methylamino.
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So then amphetamine is indeed schedule II, but its positional isomers aren't explicitly scheduled.



Turing Machine said:
Fwiw, the US Dept Of Justice website says..

(1) Amphetamine, its salts, optical isomers, and salts of its optical isomers 1100
(2) Methamphetamine, its salts, isomers, and salts of its isomers 1105
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Apparently "isomer" in (2) refers to optical isomers since it doesn't fall under any of the exceptions in the CFR definition of "isomer" I quoted. Unless there's yet another section of the Federal law which supercedes the supercessions of the original CSA.
 
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By the way, one of the more interesting articles to appear in the Microgram Journal is Synthesis of trans-4-Methylaminorex from Norephedrine and Potassium Cyanate. This is relevant here because the CSA back then (2004) only explicitly outlawed the cis diastereomers of 4-methylaminorex and their optical isomers. trans-4-methylaminorex (racemic) are not optical isomers of the cis, and the law doesn't explicitly outlaw the positional isomers of anything but the "hallucinogens" and the ecgonines (cocaine and friends). Therefore the analogue law had to be invoked. The author explains it in detail:

When 4-methylaminorex was first temporarily controlled [5] in the summer of 1987, very little was known regarding the individual optical isomers of both the cis and trans forms [6]. Since the clandestine procedure employed at the time resulted in the production of the racemic cis isomer, there was no evidence that the trans isomer had any abuse potential, much less if it even existed in the clandestine market. As a result, only the cis isomer was explicitly controlled [7]. This marked the first and to date the only time a specific diastereomer has been listed as a controlled substance.

The production of trans-4-methylaminorex therefore raised an interesting legal issue. Since cis-4-methyl-aminorex is a Schedule I controlled substance, it can be inferred that “...its salts, isomers, and salts of isomers...” would also be Schedule I controlled substances. However, the term isomer, as defined in 21 CFR 1300.01(b)(21) means “...the optical isomer except as used in... [Schedules I(d) and II(b)].” cis-4-Methylaminorex is specifically listed as a stimulant in Schedule I(f). Since trans-4-methylaminorex is not an optical isomer of cis-4-methylaminorex, the “isomer” provision does not apply and it is not formally controlled.

Therefore, the legal issue is whether trans-4-methylaminorex is a controlled substance analogue. Under the Controlled Substance Analogue provision of the Controlled Substances Act, it must first be demonstrated that trans-4-methylaminorex has a chemical structure that is substantially similar to the chemical structure of controlled substance in Schedule I or II. The controlled substance in this case is cis-4-methylaminorex. The diastereomeric relationship between these two compounds clearly satisfies the requirements of the first “prong” of the provision.

Secondly, trans-4-methylaminorex must exhibit a stimulant effect that is substantially similar to or greater than the stimulant effect of cis-4-methylaminorex -OR- must be represented or intended to have a stimulant effect that is substantially similar to or greater than the stimulant effect of cis-4-methylaminorex. The rank order of potencies of the four enantiomers of 4-methylaminorex has been shown to be:

trans-4S,5S > cis-4S,5R ~ cis-4R,5S > trans-4R,5R

in several pharmacological studies [6,8-11]. One group of researchers suggested that the trans-4S,5S isomer may have sufficient abuse potential to warrant its classification as a Schedule I controlled substance [10]. Thus, the second “prong” of the Controlled Substance Analogue provision is also met.

Finally, the trans-4-methylaminorex seized in this case was specifically stated by the clandestine chemist to be “Euphoria,” which is the generic street nomenclature for 4-methylaminorex without any stereochemical (cis or trans) designation [12,13]. Therefore, all three “prongs” of the Controlled Substance Analogue provision are satisfied, and it is virtually certain that Federal prosecution of trans-4-methylaminorex as a “controlled substance analogue” would be successful. In this case, the clandestine chemist was convicted of manufacture of a controlled substance.
Click to expand...
 
I suspect N-methylphenethylamine will be inactive without a MAO-B inhibitor. Taken with a MAO-B inhibitor, it'll probably be like meth.
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A datum:
phenethylamine requires activation via inhibition of maob (no....it REALLY does :P), but it is a great deal more selective for nor-epinephrine than d-amphetamine.

ebola
 
I don't believe that to be correct at all. With very careful dosing and checking, I found no effect on BP and HR until very high doses, what could reasonably be called overdosing.
 
From memory. :/
I'm not arguing the specific behavioral relevance of phenethylamine's larger ratio of NE to DA release. Because phenethylamine must be taken with some type of mao-inhibitor, its behavioral effects are tied to how NE and DA function changer under such conditions of enzymatic inhibition.

I can tell you that amphetamine was worlds smoother than phenethylamine when I took selegiline.

ebola
 
Just asking. If there is a paper, I'd really like to read it. PEA is probably my favorite stimulant drug... though the half life is a serious problem.
 
I didn't dig thoroughly enough through the links, but RockNRoll put it up a couple years ago, in some thread in this forum. Now I'm wishing that I saved it too.

I found phenethylamine to quickly lose its luster with tolerance to the drug.
 
I don't know when isomethadone was listed but it's substantially easier to convict someone of possession of a controlled substance than possession of a controlled substance analogue.
Click to expand...

I don't know either when as I'm far away from the U.S. and its law acts doesn't apply to me at all... Anyway, it is scheduled in II (c).
 
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