Why do we not see MDxx Fenethylline analogues?

[Didgital]

I'm really not sure the best location to ask this question, but I figured I would get a better response here vs. the ED forum.

Fenethylline (trade name Captagon) is a drug that metabolizes into two separate prodrugs, amphetamine and theophylline (a caffeine analogue). Seeing how a good percentage of ecstasy pills have caffeine in them in addition to MDxx, I'm surprised that we've never see illicit chemists capitalizing on this. AFAIK it would be legal in most jurisdictions...

My main reason for thinking maybe it's not a great idea, is that MDxx are just too impotent dose wise related to the theophylline. So maybe for an active dose of MDxx, you'd be taking way too much theophylline and the experience would just not be fun. Theres plenty of other more potent phenethylamine compounds that more closely resemble amphetamine dosing levels, such as 2C-B.. although again, I try not to take caffeine with my 2C-B..

So yeah, just wondering if anyone has any thoughts or ideas why we don't see other Fenethylline type prodrugs?

Oh and in case you didn't know, Captagon is the ISIS stimulant that they use in battle and sell to finance their operations.

 

[unodelacosa]

Probably because there's no clear market for it. Fenethylline itself seems only to have a market in the Arab world. Besides, it could be challenging and/or low-yielding to synthesize. Apparently knock-off Fenethylline pills made with substituted, more readily available stimulants are fairly common, so that says something.

A novel synthetic route to "methylenedioxyphenethylline", if you will, would need to be developed with careful thought applied to starting precursors and their relative availability, cost, and risk of seizure at international borders. Plus it should be considered whether the 3,4-methylenedioxy ring could potentially break apart during some reaction not intended to target it. High-heat + caustic conditions will render a catecholamine (3,4-dihydroxy compound) in lieu of a 3,4-methylenedioxy-substituted prodrug amphetamine/xanthine combo.

Sometimes when clandestine chemists attempt to isomerize safrole to isosafrole for MDMA production, they reflux it in caustic conditions with too much heat, and this 3,4-methylenedioxy-ring-breaking occurs, usually only in part, not a full conversion. Then those 3,4-dihydroxy compounds follow the same route as the isosafrole (and unconverted safrole), leading to impurities and side product contamination in the form of speedy catecholamine stimulants that can dramatically alter MDMA's effects. I've heard this imbues a tan color to the end product but I wouldn't know as all the MDMA I ever made back in the early 2000s came out as a bright white crystalline salt because: purity, competence, and basic concern for the health of the end user. But I digress.

Read this wikipedia article: https://en.wikipedia.org/wiki/Fenethylline Notice the illegal trade section. Interesting read.

But I believe what the clandestine chemist would face here is manufacturing MDMA or MDA, and then separately obtaining theophylline (can be isolated from cocoa beans I think), and finally bonding them together through an intermediate of some sort. This seems like much more trouble than it could be worth, given that they couldn't charge any more than MDMA prices for it, and it wouldn't be a safe enough legal protection to feel any kind of confident about prosecutors catching wind of the operation.

For that matter, trans-4-methylaminorex is specifically not scheduled, unlike cis-4-methylminorex. And when the govt. tried applying the Analog Act to a 4-MAR case in 2004, United States of America v William Hahne, this attempt failed, and Hahne was sentenced to 48 months for only the portion of cis-4-methylaminorex he possessed. The bulk had been the technically-not-illegal enantiomer. So you've got precedent set in case law now, and proof that trans-4-MAR would stand-up well as a gray-market RC, yet no one makes it. The synthesis from refluxing PPA and KOCN is ridiculously easy, too. … I mean, it's a one-pot synthesis for chrissakes Chemistry doesn't get much easier than this.

I think “Serotoni” may have effed up the reputation of this drug, unfortunately, as it was known to cause serotonin syndrome, even multiple days after its use… Come to think of it, that too featured a 3,4-methylenedioxy ring… So who knows? It could prove to be hella neurotoxic, particular if it predominantly forms the primary amine (MDA) instead of the secondary (MDMA), the former known to be a more toxic agent, and plus caffeine is known to increase the neurotoxic effects of MDMA as well, quite significantly in fact. There's a journal paper floating around out there about it…

 

[Didgital]

I really appreciate this detailed response. There are many valid points that I simply did not consider. The main one in my eye is this:

But I believe what the clandestine chemist would face here is manufacturing MDMA or MDA, and then separately obtaining theophylline (can be isolated from cocoa beans I think), and finally bonding them together through an intermediate of some sort

I guess I should have looked up the synthetic routes for fenethylline but I didn't. And I'm really not enough of an organic chemist to know for sure, but it does look at first glance that the starting material would be MDMA or MDA which are illegal. Woops. Your other points regarding synthesis are also very possibly true. And I don't know how familiar you are with the "whats wrong with MDMA these days thread" but I'd honestly never heard about this catecholamine theory, which IMO seems like a likely culprit. That or different enantiomeric ratios.

Come to think of it, that too featured a 3,4-methylenedioxy ring

Both P-methylaminorex and 4,4-DMAR don't have the MD ring. Though I have wondered about MD or 2C aminorex hybrids in the past. I remember reading about that case, pretty sure that case is the reason the feds actually don't like to use the analogue act in trial. Usually the threat is enough to get a plea bargain...

 

[unodelacosa]

I really appreciate this detailed response.

To be clear, I appreciate your line of thought on this one. Given that caffeine potentiates MDMA—and I have a hunch nicotine does as well b/c it's one of the only times I crave a cigarette: when I'm on MDMA and/or MDA—what you're proposing makes a lot of sense from the user's perspective, but not so much for the chemists, I would imagine.

I guess I should have looked up the synthetic routes for fenethylline but I didn't.

I can't believe how popular this drug is on the Arabian Peninsula and through western Asia. Seems like Syria, Jordan, and Lebanon are the sources, no doubt being produced by Shia Islamists and politico-terrorist organizations adhering to fundamentalist views and publicly stating their goals of world domination w/eradication of all non-muslim people worldwide. Fenethylline production probably funds quite a good deal of arms procurement and acts of violence and terrorism from groups like ISIL, Hezbollah, the Houthi movement in Yemen, and others… (actually, Yemen is all about the Catha Edulis tree's leaves, which contains beta-ketone-amphetamine ("khat") with stimulant properties. It's in Yemen and the Ethiopian Highlands. In fact, PPA consists of norephedrine and norpseudoephedrine. We're just interested in the norephedrine. Trouble is: PPA is a List I precursor for meth as well…

And I'm really not enough of an organic chemist to know for sure, but it does look at first glance that the starting material would be MDMA or MDA which are illegal. Woops. Your other points regarding synthesis are also very possibly true. And I don't know how familiar you are with the "whats wrong with MDMA these days thread" but I'd honestly never heard about this catecholamine theory, which IMO seems like a likely culprit. That or different enantiomeric ratios.

Generally, yes, I hear this. However, I've secured multiple good sources still over the last decade or longer, so I think in some ways this is a product of consumer expectations being set too high… And while yes, DEA has confirmed the presence of this specific line of catecholamine impurities in samples of blackmarket MDMA, it's still unclear just how pervasive this is.

Another common reason for MDMA to be off-white is because the chemists actually drizzle just a teeny bit of pure sassafras oil into each batch of finished MDMA. The reason they do this is to prove that they actually had sassafras for synthesizing MDP-2-P, the most common MDMA intermediate precursor, analogous to racemic meth's P-2-P intermediate. Circa 2013 several big MDMA markets were flooded with bullshit beta ketone MDx knock-off drugs masquerading as actual MDMA. This stuff was most commonly bright white, too; and this in turn became something both dealers and their customers would avoid. The root beer, licorice smell of sassafras is placed back into the product to authenticate it to the user and middle-man dealer.

Both P-methylaminorex and 4,4-DMAR don't have the MD ring.

Yeah whoops, my bad; I misspoke there. Good catch. I was stoned earlier and forgot which compound was under discussion. Derp. I was thinking of some of the pyrovalerone compounds with the MD ring:

• 3,4-Methylenedioxy-α-pyrrolidinopropiophenone (MDPPP)
• 3',4'-Methylenedioxy-α-pyrrolidinobutiophenone (MDPBP)

And even MDPV of bath salt glory… then I just mashed that into the compound of current topic… I mean clearly, the drug is called 4-methylaminorex; there'd be no room on the 4-position for a 3,4 methylenedioxy bridge. What's more, 3',4'-Methylenedioxy-4-methylaminorex (3',4'-MD-4-MAR) does in fact exist. (Peep: https://en.wikipedia.org/wiki/List_of_aminorex_analogues)

Regardless, two (mostly unrelated) things seem clear to me: 1. I'm pretty certain if the synthesis were pulled off, the pharmacokinetic route of this prodrug would mirror that of Fenethylline most likely, and 2. Aminorex compounds have some profound effects if/when potentiated in certain ways… per usual, 4-substitution—or para-substitution if you prefer that nomenclature—tends to be the most dramatic point of potentiation.

Though I have wondered about MD or 2C aminorex hybrids in the past.

As mentioned, the MD version has at least been dreamt up if not already tasted, and 2C-B-aminorex (2C-B-AR) has also been made and tasted by the RC community, though it's far from being a commonplace drug.

I remember reading about that case, pretty sure that case is the reason the feds actually don't like to use the analogue act in trial. Usually the threat is enough to get a plea bargain...

They use it on certain cases involving drugs with established Analogue Act precedents favoring the U.S. district attorney's case. For example, don't let them catch you with certain GHB precursors/analogs. They've built numerous cases on that one. Also, many years ago I was locked up with a guy doing time for 5-MeO-DiPT, aka: Foxy Methoxy. There, it wasn't the connection to Foxy being seen as an analogue, but rather that the drug was being sold in a manner that was pretty clearly intended for human consumption, violating one of the Analogue Act's three-pronged tests for prosecutability.

EDIT: ”That or different enantiomeric ratios.” What would make you think this? It isn't like some pharma company is seeking a new “formulation of MDMA salts” to patent, and every well known clandestine chemistry path produces racemic results. While I'm certain enantiomerically pure syntheses can occur via enantiomeric shielding and other asymmetric reactions, either isomer on its own is generally less potent than the potentiating combination of optical isomers in the racemate. I.e.: MDMA racemate > R-MDMA > L-MDMA, and the R-isomer is responsible more for the serotonergic effects plus has a longer half-life to elimination whereas the S-isomer releases more dopamine and norepinephrine.

BTW: 3,4-dihydroxyamphetamine, the aforementioned catecholamine, is also known as the neurotoxin, alpha-methyldopamine. Serotonin that enters the dopamine clefts during MDMA's massive 5-HT brain-tsunami is converted by MAO into alpha-methyldopamine and in turn this causes atrophy of the dopaminergic, dendritic arms and possibly harms the axon terminals, too. You seem well informed though, so apologies if you already knew all of this.

 

[Didgital]

”That or different enantiomeric ratios.” What would make you think this? It isn't like some pharma company is seeking a new “formulation of MDMA salts” to patent, and every well known clandestine chemistry path produces racemic results

I could have swore I had read in the "what is wrong with mdma these days" that there was a decent amount of speculation regarding the synthesis of mdma from different and more modern day precursors such as PMK-glycidate and relatives that could potentially result in non racemic mixtures of the two enantiomers. I was always a little skeptical of this theory, but again I'm not "enough" of an organic chemist to really understand the mechanisms well enough to agree or refute that theory.

I've never had the luxury of tasting the isomers separately but I see it as feasible that one of them could have a speedier feeling than the other. I dont love the thread as it seems like the discussion participants just say the same damn things over and over to the point I havent actually read it in its entirety, but up until this point I had thought the asymmetrical enantiomeric mixture theory held the most weight.

The only reason I have any interest in the thread is I have 2 batches of MDMA HCL lab tested by energy control, one is 97% and the other 98%. Both positively identified MDMA and nothing else. Still, the qualitative effects of the two Crystals are noticeably different with the 97% definitely being speedier and edgier, while the 98% is so smooth I have fallen asleep in total bliss multiple times. Every single person I know who has tasted them would say the same thing and interestingly enough, the speedier material is generally preferred tho I like having the option for different situations.

IMO the catecholamine impurity theory makes more/as much sense to me, and would explain my experience of the 97% material having more of an off feeling/hangover the next day. The 98%, as long as I dont overdo it, I feel almost entirely fine.

You seem well informed though, so apologies if you already knew all of this.

No need to apologize. Everything you've said has been enlightening and as long as the info is accurate, it never hurts to brush up and learn more in the process.

As I said, your feedback is highly appreciated. I do not expect to see any MDxx xanthene hybrids anytime soon after this conversation.

If my comments arent as detailed its because I'm usually commenting with my phone and general laziness.

Much respect!

 

[Gaffy]

Capte un gone

 

[unodelacosa]

I could have swore […] there was a decent amount of speculation […]

And you would've been correct. There was a lot of speculation. Regarding PMK-glycidate and PMK-methylglycidate, these are just technical workarounds Chinese manufacturers use to skirt the law, as I'm sure you know. PMK is piperonyl methyl ketone, which is aka MDP-2-P, so it's really not much of a novel approach to MDMA synthesis as you might think. The glycidate moiety is attached solely to be easily removed later but works as a sort of chemical "decoy" if you will for international shipments. What's more, reductive amination of the ketone to MDMA is not stereospecific and will result in a racemic product, and this is preferable to all parties involved desiring a strong, effective drug as the two isomers potentiate one another.

Moreover, EDIT: oh yeah, duh, I just remembered that the ketone doesn't possess a chiral center, the racemic split occurs upon reductive amination, and then it's technically possible to separate the isomers probably with tartaric acid, but it cuts the yields in half instantly. Nothing adds up about this line of thinking. I'm inclined to believe that the drugs of years past always seem so much more potent in the memory thanks to several things. Firstly, our brains produce more MAO over the course of our lives as we grow older. Older heads usually can take much more of a substance than young noobies, and a part of this is experience (or "brain training") and a part of it is increased MAO presence, which oxidize and quickly remove a drug from the synaptic clefts. Secondly, I think there's a tendency to be more dazzled the first few times one experiences a new compound. Thirdly, I think there is a tendency to embellish our memories and this is totally natural but should be carefully considered.

Regarding pills claiming to have contained 100 mg back in the day and smacking harder than today's supposed 300 mg stacked pressie, I call bullshit on both sides on this all day long. Firstly, we need to have a scientific breakdown of the two products being compared. Unless someone can lend us a time machine, that's just not possible and an irrelevant point to attempt to make given that it can't be proven.

While we're on the topic, I get what you're saying about the 97% batch vs the 98% batch, but consider for a moment:

• The above argument outlining the unlikelihood of PMK affecting isomeric percentages of the end product MDMA
• The influence of placebo, which can be very persuasive; I mean it's not like you were doing double-blind studies
• The full credibility of Energy Control in Spain – I've seen them questioned enough times online that I would look into their credibility, personally. I guess they are trustworthy and reputed for following ISO standards and such?

And anyway there are incredibly simple lab techniques a trained chimp can do that will resolve any isomeric mixture back into the 50/50 racemate. Given the low input of work and time needed to make this simple adjustment, I can't really think of compelling argument why a clandestine chemist wouldn't simply follow this technique. I could throw outlandish ideas out there, but I just can't come up with anything that makes true sense, because I just don't think this speculation is correct, though I will concede I am no expert in stereospecific chemistry and enantiomeric shielding, &c.

Having said all of the above, I have a similar thing with LSD. I've handled a LOT of LSD over the years, and tasted so many different batches. But I swear on a Bible of Orange Sunshine that different batches of LSD have consistent qualitative effects and can be distinguished in a blind study. I've tried hard to back this claim up scientifically, you know, just SOMETHING beyond subjective experience, and the best I have is that perhaps the differences owe to a sort of entourage effect between LSD and its many known impurities that are formed during its synthesis and are usually removed via chromatography column. This chromatography column is the most credible story, btw, explaining the reason behind LSD names having at one point taken on the spectrum of light; e.g.: white-on-white, cream, silver, amber, green, blue, lavender, purple. The trouble is: Dr. David Nichols and his group separately tested many of these impurities like nor-LSD, lumi-LSD, and iso-LSD, and none of them exhibited any activity. So unless they are activated by LSD or something like this, I have no way of explaining why LSD has consistently different qualitative effects beyond placebo and my own expectations. Res ipsa loquitur.

 

[cdin]

Having said all of the above, I have a similar thing with LSD. I've handled a LOT of LSD over the years, and tasted so many different batches. But I swear on a Bible of Orange Sunshine that different batches of LSD have consistent qualitative effects and can be distinguished in a blind study. I've tried hard to back this claim up scientifically, you know, just SOMETHING beyond subjective experience, and the best I have is that perhaps the differences owe to a sort of entourage effect between LSD and its many known impurities that are formed during its synthesis and are usually removed via chromatography column. This chromatography column is the most credible story, btw, explaining the reason behind LSD names having at one point taken on the spectrum of light; e.g.: white-on-white, cream, silver, amber, green, blue, lavender, purple. The trouble is: Dr. David Nichols and his group separately tested many of these impurities like nor-LSD, lumi-LSD, and iso-LSD, and none of them exhibited any activity. So unless they are activated by LSD or something like this, I have no way of explaining why LSD has consistently different qualitative effects beyond placebo and my own expectations. Res ipsa loquitur.

100% my experience. I am also completely puzzled as to how this is the case. I also find it extremely interesting that sub 300mcg or so IV administration has such a delayed onset effect.

 

[fm3]

I don't think Fenethylline is as desirable/recreational as all of the use in the middle east would have you believe - those pills going around are a mix of amphetamine and theophylline instead of fenethylline itself.

 

[SKL]

Plus it should be considered whether the 3,4-methylenedioxy ring could potentially break apart during some reaction not intended to target it. High-heat + caustic conditions will render a catecholamine (3,4-dihydroxy compound) in lieu of a 3,4-methylenedioxy-substituted prodrug amphetamine/xanthine combo.

Tangentially, this once briefly circulated:

Which is to MDA as Vyvanse is to Dexedrine. I don't think it was that good. I never sampled it and I don't think it got made more than once or a handful of times. It's pharmacokinetics were, I think, probably as you might expect, but that would necessarily be speculatory.

I was reminded of this by a hypothetical methylenedioxyfenethylline due to the same situation of condensation, "jamming molecules together." Just putting it out there to say that stuff like this has been tried. The synthetic routes to lisdexamfetamine and fenethylline appear to be different, at least the ones that appear on cursory search, and I have no idea of what the route to lys-MDA was, but someone has done it. I would imagine it's similar to the one used to get to lys-AMP and I'm not sure if that's one that could suggest a route to fenethylline other than the one that's in the literature.

Not sure if this matters. It probably doesn't. As for hypothetical methylenedioxyfenethylline, agree it's way too much trouble for too little payoff. As ways lys-MDA, which was more someone's vanity project.

e2a: Captagon and Vyvanse inspired phenethylamines crop up with some regularity in the random molecules thread, e.g. around here, both before and after, and I'm sure quite a few times in the six years since I just remember talking about that stuff, particularly "captadrone"

 

[unodelacosa]

Which is to MDA as Vyvanse is to Dexedrine.

This is interesting, but I can't help but imagine this is an abject failure given that Vyvanse is intended to be metabolized more slowly, thus extending the half-life and effects of amphetamine. While this may be efficacious for amphetamine use, in the case of MDA and other serotonergic psychedelics/entactogens, I've found the strongest results come from ingesting a lump sum of powder rather than doing it little by little. This is true of mushrooms, acid, 2c-b, etc. Basically anything agonizing 5-HT2A. Extending its release contingent upon metabolism of the prodrug compound seems like it would hinder the proper onset conditions necessary to feel the full effects of MDA… At any rate, the use of a charged oxygen atom as biological/metabolic target doesn't surprise me, although I do wonder if this affects the drug's bioavailability via modulation of some specific enantiomeric shielding property…

Not sure if this matters. It probably doesn't.

FWIW, I found it worthy of note. Besides: nothing matters as much as everything matters. Don't sweat it; no one gets out of this world alive.

At any rate, considering the popularity of khat in places like Yemen and Ethiopia, I'm not totally surprised that other parts of the Arab world are fixated with some unique formulation of [stimulant].

 

[SKL]

This is interesting, but I can't help but imagine this is an abject failure given that Vyvanse is intended to be metabolized more slowly, thus extending the half-life and effects of amphetamine. While this may be efficacious for amphetamine use, in the case of MDA and other serotonergic psychedelics/entactogens, I've found the strongest results come from ingesting a lump sum of powder rather than doing it little by little. This is true of mushrooms, acid, 2c-b, etc. Basically anything agonizing 5-HT2A. Extending its release contingent upon metabolism of the prodrug compound seems like it would hinder the proper onset conditions necessary to feel the full effects of MDA… At any rate, the use of a charged oxygen atom as biological/metabolic target doesn't surprise me, although I do wonder if this affects the drug's bioavailability via modulation of some specific enantiomeric shielding property

Agree completely. I don't know what they were thinking. There are better ways to get to a prodrug. Heck, the lysine in Vyvanse is designed to be a time release mechanism.

 

[unodelacosa]

the lysine in Vyvanse is designed to be a time release mechanism.

That's my point. That action, by design, would be countering of the desired effects. What a waste.

 

[atara]

Theophylline is not OTC. It cannot be replaced by caffeine or synthesized from caffeine. Its concentration in cacao or tea is inutile. It's not very good as a drug anyway and the synthesis from small molecules is impractical.

Compared to caffeine, it has higher relative activity at A1 (increases heart rate) vs A2A (constricts pulmonary arteries) but neither activity is really good for combining with MDMA from a safety standpoint and I'm not sure whether this makes theophylline better or worse than caffeine for combining with ecstasy.

But in either case it's unlikely to happen.

 

[fm3]

Theophylline has a much lower theraputic index than caffeine, but it still seems to be preferred by medical professionals in adults with breathing problems (enough so that monitoring of serum levels of theophylline is commonplace). This would lead one to believe theophylline is clearly superior to caffeine citrate when it comes to increasing respiration.

 

[SKL]

Theophylline has a much lower theraputic index than caffeine, but it still seems to be preferred by medical professionals in adults with breathing problems

Another medical application is use (intravenously) it to decrease the seizure threshhold when doing ECT, which is in every other situation the opposite of what you want to be doing, but caffeine was better. Unfortunately, they stopped formulating caffeine for IV use, as it was a very rarely used medication and there was no money it. It was also used for respiratory issues but as you say theophylline is usually preferred. I think caffeine was mostly used in the NICU for some reason (don't ask me, my expertise is rather limited beyond psychiatry.) Use in ECT was of course strictly off label and in effect using the "negative side effects" of a medication as the intended effect, unusual situation. Sometimes you really needed it when people were on heavy anticonvulsants for psychiatric purposes (they'd be held before the procedure, but sometimes especially in high doses they'd linger.) People who got caffeine were extra jumpy coming out of the ECT. And hadn't gotten their AM psych meds to boot. Always a fun time. Other stuff like Thorazine would incidentally decrease the seizure threshhold, too.

 

[fm3]

Another medical application is use (intravenously) it to decrease the seizure threshhold when doing ECT, which is in every other situation the opposite of what you want to be doing, but caffeine was better. Unfortunately, they stopped formulating caffeine for IV use, as it was a very rarely used medication and there was no money it. It was also used for respiratory issues but as you say theophylline is usually preferred. I think caffeine was mostly used in the NICU for some reason (don't ask me, my expertise is rather limited beyond psychiatry.) Use in ECT was of course strictly off label and in effect using the "negative side effects" of a medication as the intended effect, unusual situation. Sometimes you really needed it when people were on heavy anticonvulsants for psychiatric purposes (they'd be held before the procedure, but sometimes especially in high doses they'd linger.) People who got caffeine were extra jumpy coming out of the ECT. And hadn't gotten their AM psych meds to boot. Always a fun time. Other stuff like Thorazine would incidentally decrease the seizure threshhold, too.

You're right on about use limited to the NICU, caffeine citrate (actually caffeine di-citrate, I believe) is widely used in premature births to increase respiratory volume and rate. I can attest to the effectiveness of citric acid in greatly increasing the sublingual/buccal absorption of caffeine, and I would assume it allows oral administration to take immediate effect.

Theophylline (and Theobromine, to fully include all of the naturally-occuring xanthine stimulants) are seen as having much lower dose thresholds for causing adverse effects and acute poisoning. Theophylline still has wide use in clinical settings despite this, while Theobromine seems only to have a reputation as a troublemaker (very possibly hurt by how poisonous chocolate is to man's best friend).