The 20 minute habit

[clubcard]

Over the decades, I've run into a few people who made fentanyl just to try. Due to mechanical losses, they tended to make ≈ 20g. Now, has anyone else noted that all of the high potency opioids are short-acting? I'm presuming the MAOs attack them on the receptor or receptors are being internalized very quickly.

Now, out of all of the people who made a sample, 100% of them ended up with the infamous '20 minute habit'. Tachyphylaxis does it's thing and 20g goes a LONG way - long enough to get them into very deep water. Looking back, does anyone else remember the original articles in Desert News? Well, luckily for Tom, etonitazene is only x60 M in mammals (Staub test & ratatonia give highly misleading activity). Well, I don't know HOW much he made but he was busted when a co-worker noticed that he always had a 12ox nasal inhaler that he was taking hits from every 20 minutes. Complaint led to law led to probation before going to court. He never made it to court. The depth of his addiction was such that the amount of methadone that would be required would kill him quite dead due to other toxic actions (when given in BIG doses). It got so bad, I believe he hung himself.

I've been studying Europe and from Estonia (inside the Schengen Area and no visa required from Russia). Since 2001, the drug has been moving to the next country in line, it taking 3-4 years to become established (i.e. sold AS fentanyl).

Estonia->Finland->Norway->Sweden->Denmark.

It's always in 4 stages.

1-People chewing USED patches (Canadians cleverly insist that used patches are returned)
2-Low-quality heroin is cut with fentanyl. I mean, Finland? Not known for it's reliable sources but known for the prices!
3-Sold cut with caffeine so it could be smoked (the citrate smokes) under the name 'China White' or 'Number 4'
4-Openly sold as fentanyl.

North America has been thoroughly researched by my partner. The EU piece will be along in a few weeks.

Now, it just happens to be fentanyl but it seems that across the board, potent, synthetic, short-duration opioids with serious tachyphylaxis. No replacement therapy available and from those early experimenters, withdrawal that lasts 6 months at least. Now think about that. The 1 UK case killed 3 but our police got them fast. They found 19 wraps with 5mg in each and 8 wraps with 10mg in each and 3 dead people. This was Aberdeen so I expect that the stuff up their is cut to the bone. In short, we need a potent agent with slow onset & long duration to treat victims of this new danger. I also note that sufentanil (typically the hardest one to synthesize) has a truly massive therapeutic index (>25000) according to De Castro J. 'Practical applications and limitations of analgesic anesthesia: a review.' Acta Anaesthesiol Belg. 1976;27:107-128. But I cannot see the 'cooks' going to the trouble of adding a 4-methoxymethyl ether, even if it does increase potency - they lack the skills.

Having looked for a long time, I've noted that R-4066, while itself having a short duration typical of strong opiates. T1/2 3 hours. Like ORLAAM (but without the dangers of long-QT), reducing the ketone to an alcohol an acetylating it produces a drug with an analgesic duration of 20.4 hours. If, as one would hope, the (R) isomer is isolated, the potency is around 100x morphine. See Frincke, J. M.; Henderson, G. L.; Janssen, P. A. J.; Van Der Eycken, C. A. M. (1978). "Synthesis and analgesic activity of some long-acting piperidinospiro derivatives of methadone". Journal of Medicinal Chemistry 21 (5): 474–6.

Now, methadone is N-demethylated with normethadone being an important metabolite & when that second N-methyl is removed, it forms a cyclic imine that the body can remove. ORLAAM couldn't do this and dinorLAAM and the product was cardiotoxic. Now, given for pain, methadone is given every 8 hours, but this compound produced analgesia close to 24 hours. I'm guessing that the ester bond is broken and the alcohols aren't very active... although the body is an oxidative instrument so maybe those last 3 hours were due to R-4066 actually being formed in the body. Just a guess.

My point is, we are going to NEED substitution therapy and even though the patent on the chemical has run out, dose-formats and such may allow for an SR format producing analgesia lasting 2 days? With ORLAAM, the protocol was to dose on monday, wednesday & friday, a larger dose being given on the friday. I don't know if it's possible (maybe a prodrug?) but if this format could be produced for this new medicine for replacement therapy, fentanyl doesn't have to end up as a 1 way trip. I know 1 thing - the competition will bring down prices. With all of the analogues, plain fentanyl forms almost all of the market. It's my belief that this is because someone with a reasonable set of scales can make up bags of the uncut material. Carfentanil has turned up but the action was so brief that it wasn't accepted by the market.

Sorry for ramble. Just a synopsis of what I've found in the media, from drug workers & charities in Scandinavia and court reports detailing the purity of the material (generally pure). It's happening and I just want to bring people up to speed and on an eminently practical substitution therapy. Even if it's costly to make, how much will be prescribed? I've heard of people on >500mg/day of methadone but I can't see this getting much over 25mg on alternate days. Thoughts?

 

[adder]

Not all super-potent opioids are short-acting. Etorphine and dihydroetorphine are super-potent opioids with the half-lives akin to buprenorphine I imagine, I read anecdotal info that dihydroetorphine is used as a maintenance drug in China. I suppose we could have dihydroetorphine or etorphine as a maintenance drug not only for high-dose fentanyl addicts but also for those heroin/morphine/etc. addicts who don't want to take methadone but their tolerance is just too big for buprenorphine. Etorphine and dihydroetorphine seem to be much like buprenorphine binding with high affinity and slowly dissociating from receptors, so even though they're full agonists, they don't seem to be capable of producing heroin-like rush when injected. For a few years there has been another buprenorphine-like partial agonist opioid researched called thienorphine, supposedly it has a longer half-life and a bit higher intrinsic acitivity than buprenorphine which means perhaps it could be dosed every two or three days without levels drastically increasing and dropping. So really no need to revert to levomethadyl acetate which after all wouldn't be much different from methadone in terms of potency.

Now, methadone is N-demethylated with normethadone being an important metabolite & when that second N-methyl is removed, it forms a cyclic imine that the body can remove. ORLAAM couldn't do this and dinorLAAM and the product was cardiotoxic. Now, given for pain, methadone is given every 8 hours, but this compound produced analgesia close to 24 hours. I'm guessing that the ester bond is broken and the alcohols aren't very active... although the body is an oxidative instrument so maybe those last 3 hours were due to R-4066 actually being formed in the body. Just a guess

There is no way R-4066 could be produced within human body from LAAM or methadone (from what substrates?). Not sure why its half-life is so long as the ester bond shouldn't be hard to hydrolyze, I suppose it's due to its high lipophilicity.

 

[AlphaMethylPhenyl]

Monoamine oxidase works in tandem with g-protein coupled receptors. It doesn't break down chemicals at their receptors, as happens with ligand-gated ion channels (example: acetylchollinesterase). Monaomine oxidase breaks down pre-synaptic neurotransmitters in the cytoplasm.

It furthermore breaks down monoamine neurotransmitters (dopamine, serotonin, nor/epinephrine, and not sure if histamine is a monoamine or not) and similar exogenous chemicals. So it wouldn't have an effect directly on the metabolism of opiates (they tend to be long strings of chemicals, whereas monoamines are much smaller compounds). But monoamine oxidase a could break down the indirect dopamine and serotonin action triggered by opiates. A lot of dopaminergic neurotransmission is well-associated with mu opiate agonism (ethanol, amphetamine, nicotine, caffeine, cocaine, I would guess marijuana).

 

[serotonin2A]

There is no way R-4066 could be produced within human body from LAAM or methadone (from what substrates?). Not sure why its half-life is so long as the ester bond shouldn't be hard to hydrolyze, I suppose it's due to its high lipophilicity.

That is definitely true. There is no way that R-4066 is a metabolite of methadone.

 

[clubcard]

Sorry if I wasn't clear, NO, obviously R-4066 cannot metabolize to methadone but it can be esterified to an alcohol which MAY be oxidised making the original, short-acting analogue. It appears people spend more time finding faults than giving input to the growing fentanyl problem.

I realize that nobody here is interested in the lot of others and will remember not to post anything that constitutes 'help for others'. Never before have I seen such a mean-spirited group.

 

[Tryptamite]

what do you mean when you say the "growing fentanyl problem"? it seems me that you have a serious issue with fentanyl and fent analouges but I'm not really sure what the issue is.

Sure it is very addictive and dangerously hard to dose properly, lacks the "warmth" of other opiates and causes an incredible amount of overdoses and accidental deaths when used as pure powder, as a cut in heroin or other drugs, available on the street as a "china white" style drug mixed with an inactive bulking agent.

As a person who is currently dependent on opioids I would prefer morphine/heroin type drugs, but generally maintain on methadone and would gladly take fentanyl or similar if there was no heroin available. there was a terrible drought in parts of europe around 2011 or 2012 which took a long time (6 months - 1 year) for the market to recover to something like it was perviously.
Unfortunately it happened just at the time when I started to use heroin and cocaine IV, and the lack of opioid to combine with the coke led me stupidly to injecting all sorts of tablets and substances, which did a lot of vein damage.
Had fentanyl been available to me then or had I known that fent analouges were possibly available to me I would have saved myself an awful amount of money and hardship chasing something which I couldn't physically find!

I am interested in continuing discussion regarding fentanyl regardless of your stance on the matter. I find it fascinating that practically overnight in Tallin, Estonia heroin dissappeared and was repaced with 3-methylfentanyl. Likewise (as I did not know previosuly) I find it interesting that the drug has spread west, to Finland, Sweeden and Norway (& Denmark as well?). I know that heroin was not very available in many parts of Scandanavia as evidenced by the abuse of Subutex in said countries.

There is little heroin available in France as well, and what heroin is to be found is of terrible quality. The most widesly abused opiate is subutex, but morphine is available cheaply too, and subutex and methadone are offfered in ORT. Are we likely to see a 3MF product appearing in France in the near future?

I think all the 3MF we are discussing about in this instance originates in Russia, probably St. Petersburg. There is a BLer from Estonia who seems to be very knowledgeable about the subject. tyler5 i think is his name,

 

[Solipsis]

Definitely keep posting 'synopses' and other reports etc, please. They are really interesting and insightful, even if they are sadly often a response to tragic developments and trends. I think it's amazing that you are e.g. alerting the CAS people and initiating analysis of problems that - I'd agree - have potential to become epidemics.

It's a shame if we have to sit and wait until a big surge of suffering and death become so hard to ignore that people who can make shit happen do something about it.

Maintenance therapy that actually works would be a first stage I guess, but if withdrawing takes 6 months then how long is tapering a replacement? Still seems like a life sentence, but that is a good start instead of a death sentence.
Would developing high affinity / potency mixed agonist-antagonists even make sense or is that a crazy challenge?

Does creating the ester of R-4066 much longer to make it a time-release drug make sense - though not quite as long as palmitoyl probably?

I'm also curious about possible treatments of high affinity agonists with antagonists, which are for example with NBOMe type drugs apparently also a problem. Would it just require making even higher affinity antagonists than currently known?

--

Whether or not the 'growing fentanyl problem' is a personal quest or not, I think what is especially alarming about it has been explained well already ^ : It doesn't have much to do with medical use of fent type drugs whatsoever I think, so its value there doesn't have to be argued, but abuse is a different thing.
Buying it or making it for whatever reason and underestimating the dangers apparently and not that surprising leads to dangerous situations way too quickly / way too easily, same with U-47700. I think that if you don't really medically need fent type drugs, it's hardly worth the risks, even compared to heroin. But sure everyone's free to do what they want... still if the truth is that drugs with such risk potential are on a rise, the argument IMO is to whatever is possible to find treatments and solutions to the problems people with such dangerous habits face. Since, if developing tolerance is so quick and likely and habituation probable, you can't be stuck in a situation with options that all jeopardize finances and health so heavily - you're faced with the impossible then.

Not bad at all to at least talk about what makes surviving them alright more 'possible'...

 

[serotonin2A]

Sorry if I wasn't clear, NO, obviously R-4066 cannot metabolize to methadone but it can be esterified to an alcohol which MAY be oxidised making the original, short-acting analogue. It appears people spend more time finding faults than giving input to the growing fentanyl problem.

I realize that nobody here is interested in the lot of others and will remember not to post anything that constitutes 'help for others'. Never before have I seen such a mean-spirited group.

In the field I work in, we face constant criticism in the form of manuscipt reviews and grant reviews. That is the price of exposing your work to others. It is certainly frustrating, but it often makes the final product much much better and it weeds out bad ideas, which are often difficult to see first-hand. Earlier in the thread you speculated about something that is incorrect. Two other people (myself included) pointed out your mistake. That is how critical discussions work. If that part of your post was so meaningless that it doesn't matter if it was right or wrong, then why include it in the post? The upside is that this discussion has helped to fine tune your idea -- you have now corrected a mistake in your post, which makes it better. If intellectually all you want to do is start discussions where everyone pats you on the back and no one ever challenges you then you are never going to get any useful feedback.

CC, as frustrating as it must be for you to get critical feedback on your ideas, it is equally annoying to take the time to read your posts and ask you a question, only to be completely ignored, or criticized for asking a question. That has happened more times then I can remember. As an example, you just posted something about CAS numbers. I didn't understand your arguments, and so I posted a response asking you to justify why you think this is important. You still haven't responded. You may think I am being mean, but I really don't understand why you think what you proposed would be helpful. If you really believe in your idea then at least you can take take the time to try to explain it.

 

[Solipsis]

That's certainly fair ser2a - but just fwiw, I know that when someone takes the time to write up some significant stuff it can be strange though a common phenomenon on a forum that however many people find it interesting to read but have nothing much to add about the real content that is important to you, it's always much easier for people to correct things even if not necessarily critical to the big picture. Regardless of corrections being constructive.
Not picking sides here, just hoping that if there are sides, you guys understand both of them. If just speaking for myself it can be disappointing when replies seem unrepresentative of the appreciation people have, for me it's not about being able to deal with criticism in those cases.
So my point is: its a shame appreciation is not always expressed, but dont let it skew your perception about all considerations from readers on the board.

At least that part of his frustration I think I understand. Don't know about the rest..

Wasn't the CAS numbers thing about it being a start for regulating quite a large number of certain precursors for pretty novel analgesics? I could be wrong...

 

[clubcard]

I've just spent a decade doing HR work - In the UK, their are news stories every DAY on fantanyl. If you haven't had an organic chemistry friend who developed a '20 minute habit' i.e. day & night, withdrawal returned every 20 minutes, you aren't in a position to comment. So bring something useful to the table, something that can be used for drug-replacement therapy for fentantyl addiction. Or is it 'their own damned fault and I don't give a shit' as would appear to be the overarching theme. Remember Thomas K Highsmith and his 20-minute habit on etonitazene. Arrest, bail, no replacement therapy, suicide.

 

[serotonin2A]

Cc, I'm sorry for your friend. That is certainly a tragedy. But that doesn't mean that the ideas you have proposed are good ones. Anecdotes aren't evidence. Do you actually have any evidence that methadone is failing to hold people who were using fentanyl? Data is what drives harm reduction practices, as in clinical studies. There are plenty of anesthesiologists who have had problems with fentanyl or sulfentanil and then been placed on methadone. Have you actually researched what happened to Highsmith by talking to primary sources like his family? Reports that you see on the internet are notoriously unreliable. He was facing federal charges and it is possible that he committed suicide over that. I've never heard of anyone actually looking at the autopsy report. Did he leave a note? Those are all things that would be interesting to see and that would be reliable sources of info.

Just because you have personal experiences doesn't mean yout ideas are perfect. This is a site for discussion of neuroscience, not an organizing site. You have no right to say that other people are not in a position to comment on your posts. You are calling others mean, but you are the one who is basically saying for others to shut up. If you really think your ideas are great ones then you should have no problem justifying them to others. You cant be bothered to do that?

I know you are going to think my questions are mean. But this is even a harm reduction site. What reception do you think you will get from non-harm reduction people?

 

[adder]

I'm sorry if my post sounded mean, but I thought all I did was giving some input. LAAM isn't the first opioid to start maintenance on for reasons that you mentioned (cardiotoxicity), so it felt natural for me to mention oripavines, not as a critic, but as an idea which isn't really mine after all. I myself am not a first-hand witness of addiction to fentanyl and its analogues with ultra-high tolerance, but I know it definitely happens due to their availability as RC's, such fentanyl addicts are indeed maintained on methadone here and it seems to work fine, I suppose one would have to hit 5-10mg of fentanyl a day or more for methadone to become completely useless for them due to side effects.

 

[Solipsis]

sir 2a
I like skepticism at least as much as the next person, but do we have to wait for hundreds of official reports or metastudies on case reports proving that maintenance therapy doesn't seem to work? Is it enough to just do the math on it and find that normal replacement therapies face things like problems with the toxicity / therapeutic index?

Some of this seems so self-evident to be an unusually big challenge to get out of dependency on such a heavy drug, that it becomes a little uncalled for to try and find all the other reasons that may have been making those victims desperate.

You're not obliged to come up with a breakthrough idea for a new replacement therapy meant for superpotent short acting opioid dependency, but it's borderline insensitive to just start question less relevant things instead.. What are the relevant doubts here? You think that current replacement therapies are actually an option, and there were other reasons while these people failed to successfully use those therapies?

Oh sorry though: I only now see that apparently fent addicts have been (successfully I assume) placed on methadone therapy - that is actually a valid and relevant point. So adder, the difference is how extreme the tolerance is?

Which would mean that it's not necessarily directly being dependent on fent analogues, but fent analogues having the properties to make a tolerance possible so high that it wouldn't be realistically possible with normal potency opioids?

So that brings nuance but still raises the question of what to do in those cases, as the properties of superhigh potency agonists inherently make such ultra tolerances more likely and steadily more prevalent as feared.

 

[adder]

I'm not sure if it's a characteristic of fentanyl and its analogues that it can make tolerance to opioids higher than regular morphinans such as heroin or morphine, or oxycodone, perhaps it is, I have no idea from the point of view of pharmacodynamics, but I suppose it has an ability to increase tolerance super-fast given its short action and that at some point with every dose with any opioid you have to increase it so it still works as strong (or perhaps so it only kills your withdrawal). I don't know the details about methadone maintenance in people addicted to fentanyl analogues or how many of them there are in my program right now, I only know for some time an increasing number of fentanyl addicts was quite a problem due to read availability of them online, and that such patients were detoxed and maintained on methadone if necessary. On the other hand Suboxone program is so small here that if you have 1 person on bupe per 20-30 people on methadone (for reasons other than medical), chances are low anyone addicted to a fentanyl analogue would be first subjected to buprenorphine treatment. I guess we can at least agree it is very easy to lose control over your fentanyl analogue use if you can have large quantities of it cheap relative to its strength per weight. On the other hand I know from my own experience that people take much more opioids or any drug they use and are addicted to when they run short of them and have problems with acquiring as much as they need.

 

[serotonin2A]

sir 2a
I like skepticism at least as much as the next person, but do we have to wait for hundreds of official reports or metastudies on case reports proving that maintenance therapy doesn't seem to work? Is it enough to just do the math on it and find that normal replacement therapies face things like problems with the toxicity / therapeutic index?

Some of this seems so self-evident to be an unusually big challenge to get out of dependency on such a heavy drug, that it becomes a little uncalled for to try and find all the other reasons that may have been making those victims desperate.

You're not obliged to come up with a breakthrough idea for a new replacement therapy meant for superpotent short acting opioid dependency, but it's borderline insensitive to just start question less relevant things instead.. What are the relevant doubts here? You think that current replacement therapies are actually an option, and there were other reasons while these people failed to successfully use those therapies?

Oh sorry though: I only now see that apparently fent addicts have been (successfully I assume) placed on methadone therapy - that is actually a valid and relevant point. So adder, the difference is how extreme the tolerance is?

Which would mean that it's not necessarily directly being dependent on fent analogues, but fent analogues having the properties to make a tolerance possible so high that it wouldn't be realistically possible with normal potency opioids?

So that brings nuance but still raises the question of what to do in those cases, as the properties of superhigh potency agonists inherently make such ultra tolerances more likely and steadily more prevalent as feared.

I don't think we need to see actual studies -- just a few case reports from methadone clinics. If there is actually a problem then that is what it would take to alert regulators and to pressure them to find a solution (in many countries there are regulatory constraints on what drugs can be used for maintenance).

This isn't skepticism so much as wanting medical and regulatory decisions to be driven by actual evidence. If there really is a problem then it should be easy to document it.

adders post above indicates that he is aware of fentanyl addicts who are maintained on methadone, which is consistent with my understanding. But if there are people falling through the cracks then I would love to hear about them!

It is also worth noting that if this is a problem that folks here actually want to solve then the most useful thing we can do is compile evidence that the problem actually exists. Collecting evidence might actually influence someone to apply for funding to study the problem or to run a trial with fentanyl addicts. In terms of thinking about a solution, that would almost certainly be accomplished by a committee of MDs and experts.

 

[clubcard]

Mexican superlabs, busts of US & Canadian labs.... it's in the news and seen the patterns in Estonia - maybe someone should look at THEIR news and how it's spreading. Estonia->Finland->Norway->Sweden->Denmark. You see, I did some actual research on the subject..... await's bitching from the people who apparently don't give a shit about lives, just their own. Look at the death toll in Russia! No, don't bother. Some minor detail will be pounced upon, avoiding actual WORK. Russians can visit Latvia without a visa and Latvia is in the Schengen Area. I presume you will ALL have to look that word up; yep, little respect sinking to NO respect for a talking shop!

Adder is the only person with any practical information and since I started in Chemistry (1995) I've seen 6 chemists make an oz or 2 of material (smaller and mechanical losses are a problem, and does anyone have a microscale set?) and all 6 of them went to the wall. No replacement therapy, HUGE dependency issues with no substitution - methadone is far too toxic to use in the doses required.

I spent 2 weeks, so who is better informed? Adder and nobody else.

 

[bingey]

I've had an IV 3-methyl fentanyl habit on 2 separate occasions, I went through approximately 5-6 and 10 grams. Still alive , maybe cause my connect a chem student vanished after making (tens) thousands of euros off me.

Any questions?

 

[Limpet_Chicken]

I cannot help but wonder WHY your connect suddenly vanished bingey....


Especially if he was making it himself.

Microscale set? sure, down to 5ml. Its a royal bugger working at that scale though. Mechanical losses mean an awful lot more working in hundreds of mg than in the or multi-gram scale.

Its spread to england, pretty damn sure of it. Theres been some stuff going round my part of the NW, and its strong enough to drop an ox. I did some basic dose-response testing, factoring tolerance into the equation, in an activity-guided bioassay, IV route bugger of a syringe, or multiple rigs. Don't do that much every time due to concerns about fluid overload. Took a bit of this street heroin, and yes, I am fairly sure there was H in it, could taste it when smoked.
and had to stop at moderate effect level as frankly, the stuff was too damn hot to handle. Now my tolerance, using pharmaceutical morphine sulfate as benchmark is 1.25-1.5g/dose/IV. Needs a fair belter of a dose of H to get me nervous. So, I'd tested a spot maybe 1/3rd the size of a split lentil, the merest crumb, and it was of moderate activity, typical opioid warmth, little rush, although I've had fentanyl itself IV, as well as alfentanil, lofentanil, and others, and only alfentanil gave any rush of any sort, it was comparably short acting, tachyphylaxis present upon repetitive use. The quantity used could just as well have been pharmaceutical purity equivalent heroin or dipropionylmorphine (far more used to it than I am to H~) andit would have had no effect at all. So there must have been another opioid, a stronger one by far, present.

Had to stop any IV testing as it became rapidly clear that it was just WAY too potent. Smoked the rest of what I had, and damned if one bag didn't last over a week! and with a heavy tolerance like that...makes one think, no?

I think whoever made this GROSSLY underestimated how potent it is, or else improper mixing/settling out. Your average user who'd just shoot a bag, is going to die if they do it with this stuff. I reckon the only reason I was able to do IV testing at all was my tolerance level. Never been thankful for it before.