ULDN - The magic weapon to reduce and keep tolerance to Opioids low

[Allylbenzene]

...after I posted my answer to you: a helpful and kind forum member...sent me a PM warning me against arguing further

This was foreseen. He's a very knowledgeable person whom I learned a lot from over multiple DM discussions...but he made a misguided assumption about something trivial which led to strange behaviour and subsequent disparition (french word). He likely knew who I was talking about. I specifically used him as the 'case study' in my post regarding the deleterious cognitive & perceptual impact of long-term prescription opioid use; particularly without proper harm reduction measures. This is after all a forum dedicated to harm reduction, and this very thread is a good example of this. As I wrote previously, Naltrexone and Naloxone are excellent tools but more can be done to render long-term opioid use genuinely sustainable.

The fact you removed the central parts of my arguments and replaced them with dots, while calling it "semantics" is really just an outward manifestation of your close mindedness.

Not at all, that's just me saving space with the quote block. I don't see the value in these kinds of assumptions (about how the text was formatted) as the results are off-base.

Anyway, while you perceive an argument I actually agree with much of your core tenets.

 

[Larsetec]

Keep doses low, keep frequency low.

 

[4DQSAR]

Ultra-Low-Dose Naloxone or Naltrexone to Improve Opioid Analgesia: The History, the Mystery and a Novel Approace​

https://journals.sagepub.com/doi/full/10.4137/CMT.S4870

Just to be clear, a fixed-dose combination of oxycodone and naltrexone was given the tacit brand-name Oxytrex began to be evaluated but failed Stage 3 trials because of the dropout rate (48% in phase 1, 60% in phase 2) which was far higher than the dropout rate for the placebo (37%). BUT did notably reduce dependence rates.

The dropout rate appeared to be age-dependent with those over 50 being notable for NOT dropping out.

I think I have mentioned this before but fixed-dose combinations are a simply TERRIBLE idea. There sole benefit is that they can be patented.

I would be extremely surprised if one fixed ratio was optimal for more than one patent. I suppose the problem is that we have a LOT of evidence suggesting poor complience with prescribed medications so that the idea of a single pill will have the advantage of better complience.

It's a sad truth that in the UK 46% of prescribed medications are not adminstered as prescribed.

But there are a lot of papers that all seem to suggest ULDN works and that it's patient expectation that is the REAL issue i.e. they think if something will 'spoil their buzz' then they will avoid it. IF you are over 50, chances are you have lived with severe chronic pain for DECADES so a pill that actually INCREASES the analgesic activity as the mixture has been demonstrated to do in dozens of studies, likely you ARE going to prefer it. Buzz is NOT what you seek - the ability to just carry on living is the sole metric.

I was asked about it once and reflected 'death is easy, pain is hard'.

 

[vima]

damn, this has been fascinating to read! can't believe i haven't heard of this approach before (ULDN).

i've got an exam later today, so i sadly have to stop obsessively skimming this thread and relevant papers until later/tomorrow, but wow....

so, i'm taking methadone 150mg/day for chronic pain (several months now)... switched over from buprenorphine (16-24mg/day) b/c it was not great for pain--just easy to get without a hassle.

sounds to me like, if i want to approach tolerance reduction----naltrexone is preferable, and the starting dose should be around 1 mcg?

(based on the literature, and/or folks' direct experience)

... does that sound correct? how about timing of naltrexone dosing, as well as methadone dosing?

--- many thanks to anyone who may take the time to respond!

 

[vima]

Better yet: offer L-Methadone. That is what I am taking since 3 years now, I'm on 15mg, no side effects and I couldn't be happier.

ugh, i tried talking to the medical professionals at my clinic about levo MTD, including the medical director and all the pharmacists.... none of them even knew what it was, let alone any of the relevant pharmacological differences. it is always baffling to me how TF so few doctors understand what they are prescribing...

edit: sorry, new poster here, and I don't know how to merge this post with my last!

 

[4DQSAR]

Don't be too hard on clinicians. If a medication isn't used where you are based, it's unlikely a clinician would spend the time learning about it. After all, they have to know THOUSANDS of medications that are in use and not many of them enjoy the process of learning. Truth is, clinicians are ALWAYS learning and in my experience, while older clinicians have usually forgotten the fine detail, if they have prescribed a given medication thousands of times, they have experience and book-learning is of less value than experience.

I think the reason L-Polamidon isn't common in spite of it's clinical advanages is a mixture of clinicians being experienced in prescribing plain (raecemic) methadone and the fact that the synthesis of laevomethadone is a lot more demanding (thus costly) with research teams all over the world obtaining patents for more and more efficient syntheses. This is common.

The fact that optimization continues long after any patent has expired strongly suggests that the makers see the market continuing to expand.

While at bench-scale it's practical to resolve the two isomers of raecemic methadone using nothing more complex than tartaric acid, at scale it would mean the entire synthesis would undertaken then at least half of it being discarded. Not forgetting that the UNODC list and every nation on the planet still classifying that 'waste' as a schedule 2 controlled drug so it's disposal would be costly.

A US-based research company obtained 1Kg of laevomethadone (L-Polamidon) back in 2019. I strongly suspect it was Lyndra Therapeutics whose once-a-week oral formulation of laevomethadone (LYN-014) is currently listed as in-development by the FDA. But that's strictly aimed at patients with opiate use disorder.

That has ALWAYS been a serious problem with methadone. Almost every nation has one or more formulation that can ONLY be prescribed for the symptomatic treatment of long-term severe pain and one or more formulation that can ONLY be prescribed to treat opiate use disorder - and never the twain shall meet. In the UK we ended up with patients prescribed Physeptone tablets for pain running out because the law does not allow methadone linctus to be prescribed in the treatment of pain.

I suggest the primary reason that ULDN isn't an official stratergy is because the precise dose required varies between individuals hence the fixed-dose combination failing. With methadone expecially, the extreme range of onset, peak and duration as well as total bioavailability would make it extremely difficult to research and even if that research is a success, I don't see exactly how a patent would work.

 

[Hexenstahl]

still classifying that 'waste' as a schedule 2 controlled drug so it's disposal would be costly.

This is something I have never understood, so please help me understand this: WHY the hell do they not just get rid of that "waste" via pyrolysis? I mean, just decompose it thermally and the problem is solved, right? It can't be that expensive. And if the director of the board is acting like Ebenezer Scrooge, well then just go buy some fire wood and burn the chems outside.

I suggest the primary reason that ULDN isn't an official stratergy is because the precise dose required varies between individuals hence the fixed-dose combination failing. With methadone expecially, the extreme range of onset, peak and duration as well as total bioavailability would make it extremely difficult to research and even if that research is a success, I don't see exactly how a patent would work.

I think that is only a secondary reason. The primary reason is simply because patients on opioids with no or close to no tolerance would severely cut into the profits of the pharmaceutical companies. The reason opioids are so incredibly profitable is because as you keep taking opioids, not only does your required minimum dosage to maintain the necessary effects rise to an astronomical level, but the duration of action shortens as well. I remember when I was still bloody opioid naive, one 10 mg tab of IR morphine had me going for 12h and a few more hours of afterglow. Fast forward 3 years when I was deep into my heroin habit I had to use 1.5 g a day (IV) and only felt something for like 2h or so, with the rest of the time just being happy to not be in wd. Such a playing field is extremely favorable for the opioid market. Why would they wanna change this? Even though I hate how they are profiteering from our dependence and tolerance, I can understand, from an economic point of view, why things are the way they are. If I was leading a pharmaceutical company and someone came up with the idea of selling something that obliterates opioid tolerance, I would send them to an "economic thinking 101" class...unless ofc they could prove with hard data that a non-tolerant opioid market is a more profitable one.

naltrexone is preferable, and the starting dose should be around 1 mcg?

Start with 1 µg and slowly go up to 100 µg in daily 1 µg steps. If that leads to no results, you very likely belong to a minority whose sweet spot is probably somewhere in the picogram range. In that case you should start with 50 pg and up the dose in 25 pg increments until you have reached your ideal dose. The important thing to keep in mind is to not stop when you start to notice positive effects, but to keep increasing the dosage until you notice a decline. As soon as you notice that decline in intensity, you just go back to your previous dose because THAT is you sweet spot. That is the peak you should maintain. It is your personal ULDN dose.

And please don't forget to post your experiences with ULDN here. We need data, data, data. The more people report, the more empirical the information in this thread becomes...

 

[kimmermanz]

Ultra-Low-Dose Naloxone or Naltrexone to Improve Opioid Analgesia: The History, the Mystery and a Novel Approace​

https://journals.sagepub.com/doi/full/10.4137/CMT.S4870

Just to be clear, a fixed-dose combination of oxycodone and naltrexone was given the tacit brand-name Oxytrex began to be evaluated but failed Stage 3 trials because of the dropout rate (48% in phase 1, 60% in phase 2) which was far higher than the dropout rate for the placebo (37%). BUT did notably reduce dependence rates.

The dropout rate appeared to be age-dependent with those over 50 being notable for NOT dropping out.

I think I have mentioned this before but fixed-dose combinations are a simply TERRIBLE idea. There sole benefit is that they can be patented.

I would be extremely surprised if one fixed ratio was optimal for more than one patent. I suppose the problem is that we have a LOT of evidence suggesting poor complience with prescribed medications so that the idea of a single pill will have the advantage of better complience.

It's a sad truth that in the UK 46% of prescribed medications are not adminstered as prescribed.

But there are a lot of papers that all seem to suggest ULDN works and that it's patient expectation that is the REAL issue i.e. they think if something will 'spoil their buzz' then they will avoid it. IF you are over 50, chances are you have lived with severe chronic pain for DECADES so a pill that actually INCREASES the analgesic activity as the mixture has been demonstrated to do in dozens of studies, likely you ARE going to prefer it. Buzz is NOT what you seek - the ability to just carry on living is the sole metric.

I was asked about it once and reflected 'death is easy, pain is hard'.

This!

 

[4DQSAR]

This is something I have never understood, so please help me understand this: WHY the hell do they not just get rid of that "waste" via pyrolysis? I mean, just decompose it thermally and the problem is solved, right? It can't be that expensive. And if the director of the board is acting like Ebenezer Scrooge, well then just go buy some fire wood and burn the chems outside.

I would ASSUME that the unwanted isomer would be incinerated because it's the only univerally accepted method of destruction.

It's just that a production-line built specifically to produce methadone won't have an incinerater on-site, or certainly not one designed for such scales of waste. So a medical waste incinerator (not just any incinerator) has to be located and that 'waste' still has to have the same chain-of-custody as the isomer that ends up being used medically. At every step both the quantity and quality of the material has to be checked.

Why? Well if a producer could just burn the unwanter isomer with no oversight, that's a loophole begging to be abused by workers.

I also pointed out that AT LEAST half of the product would have to be sent to the medical waste incinerator because it's hard to avoid at least a little bit of the isomer that is wanted ending up in the waste. Now just how much that is I couldn't tell you but suddenly you added an extra step to the synthesis and that means extra time, extra space, extra solvents, extra reagents and extra energy.

As I said, all the time newer and newer optimizations for the production of laevomethadone are being patented and the fact they all go for a chiral synthesis does rather suggest that whoever compared the costs of chiral synthesis vs resolution of product seems to have come down firmly on the side of chiral synthesis.

I should add that another inherent problem is that production sites that synthesize schedule 2 drugs are like prisons. I went to the McFarlan-Smith factory in Edinburgh (long ago) and it was at least as secure as a prison. Three sets of turnstiles, ID checked before each turnstile, razor-wire at the top of the (very high fences) and security staff and cameras everywhere. In short, they couldn't have made the workspace any larger - they would have had to knock the entire thing down and rebuild - all while NOT producing an income.

 

[Hexenstahl]

@4DQSAR
Thank you for that explanation. I wasn't aware that quality control protocols are applied to such a pedantic degree to pyrolized material. Ofc having absolutely no oversight over that process would be asking for someone to steal stuff, but that is not what I had in mind.

Oh I am aware of controlled substances factories being set up like prisons. A friend of mine used to work for ALIUD Pharma, who has a near monopoly on the manufacture of Tilidine, and I was astonished to see how much it looked like a high-tech prison ward when he showed me the photos of the lab. They had 24/7 security personnel in front of each of the armoured glas doors (the walls themselves were actually made out of transparent glas so security could observe you) who had to check you EACH time you walked in/out of every room where any chemicals or intermediate/final products where stored. And the checking wasn't done the old fashioned way by searching your clothing, but was conducted via terahertz based full-body scanners. The lab workplace was intentionally set up in a way so each employee could see what the other employee in front of him was doing. The automatic doors could only be opened via biometric facial ID, which means the company knows exactly who went in/out of which room and at what time.
Remember, this is a company that produces a weak opioid-naloxone mixture which isn't the slightest bit interesting for fullblown junkies, so if they already have such tight security protocols for something like Tilidine, just imagine what they have to do in facilities that synthesize oxycodone, fentanyl, hydromorphone, etc.

For those who are wondering why he left: it was precisely because of those prison-like security routines, which is very stressful for employees. Feeling constantly watched, not just by cameras, but by everyone around you as well, isn't exactly something that is psychologically healthy. The company knows that and the figures show it too. The churn rate (labor turnover rate) is incredibly high, people are constantly coming and going. Even the salary reflects that. They have to constantly attract new chemists with ridiculously above average salaries because there is absolutely nothing else that would keep someone in such an environment. Here in Germany the average annual gross salary of a medicinal chemist with a masters degree is 78.000,00 €, with an average cost of living of 25.000,00 € p.a. for a single household in the suburbs. My friend earned 105.000,00 € p.a., which is 34.6 % more than his peers earned for producing harmless APIs like Ibuprofen or Aspirin.
He didn't manage to stay for more than 2 years which really says a lot...

 

[scimittarr11]

"if they already have such tight security protocols for something like Tilidine, just imagine what they have to do in facilities that synthesize oxycodone, fentanyl, hydromorphone, etc"

haha, lol *imagine what they have to do in facilities that synthesize narcotics* ,

 

[4DQSAR]

@4DQSAR
Thank you for that explanation. I wasn't aware that quality control protocols are applied to such a pedantic degree to pyrolized material. Ofc having absolutely no oversight over that process would be asking for someone to steal stuff, but that is not what I had in mind

Well, that just shows you don't have a criminal mind ;-)

I am constantly amazed at the risks some people will take when compared to the profits involved.

I do think Eric Berne is at least partially right when he describes 'cops an robbers' as a game. That most criminals get a thrill out of getting away with something. I've met people who were perfectly able to make as much money in a totally legal manner - but they LIKED the risk!

So I suspect the rules are so strict because if there is even a small profit but a large risk - someone will still do it.

I just checked and just as radical initiators are used to raecemize unwanted laevomethamphetamine, they can also be used to raecemize dextromethadone. BUT the problem is that N-demethylation is a major-side reaction so it seems finding uses for the waste were explored and discarded.

I can see why chemical engineers get paid more to work in those high-security facilities. They must feel like being prisoners. Always an assumption that they are up to something... it just hasn't been found out... YET.

I'm too risk adverse. I don't want to end up with anyone even thinking I'm stealing or conning. I'm prepared to work hard on legal projects and while loopholes interest me, I've ALWAYS noted them with the proviso 'I would not rely in this in a court of law'.

 

[vima]

Start with 1 µg and slowly go up to 100 µg in daily 1 µg steps. If that leads to no results, you very likely belong to a minority whose sweet spot is probably somewhere in the picogram range. In that case you should start with 50 pg and up the dose in 25 pg increments until you have reached your ideal dose. The important thing to keep in mind is to not stop when you start to notice positive effects, but to keep increasing the dosage until you notice a decline. As soon as you notice that decline in intensity, you just go back to your previous dose because THAT is you sweet spot. That is the peak you should maintain. It is your personal ULDN dose.

And please don't forget to post your experiences with ULDN here. We need data, data, data. The more people report, the more empirical the information in this thread becomes...

@Hexenstahl:

Wow--thank you so very much, sincerely--for writing such thoughtful, helpful, detailed messages. I really do appreciate it!

(oops, just hit the post button by mistake---finishing my post now as an edit)

First: totally with you, re: the importance of data collection here. Happy to be a data point, lol.

So, I took my first naltrexone dose last night around 8pm.

(FYI, I take my methadone ("MTD" from here forward) once per day in the morning. I have to do it on camera, and it can only be between 5am-12pm daily. Just got bumped up to 160mg, and have been on it since February, so I'm now totally physiologically dependent. And I'm scared, as many have expressed here, of precipitated w/d--especially because, given the timing of when I must dose the MTD, and since I don't have other opioids on deck, I don't have a way of correcting/ending precipitated w/d for the whole night (if that were to happen) until I can re-dose MTD in the morning.)

I dissolved 100mg of naltrexone, via legit scripted tablets, powdered, into 1000mL of water. I figure that's 0.1mg per mL. Assuming 20-30 drops/mL (I don't have a good measuring dropper at home), if my math is right that's between 3.3 and 5 micrograms per drop. I took one drop last night, which apparently was too much.

I felt fine for at least an hour or two, but then at some point started sweating intensely and started to have weirdly intense muscle cramping in a lot of my body and general discomfort... the kind of brutal inescapable cramping / spasming that I have felt in strong opioid withdrawals. Not all the symptoms, but that one to a high degree of discomfort. As an aside / data piece, I had prescribed amphetamine on board as well, the later dose taken later than usual since I was studing (taken daily... used to be dex for years but had to switch to adderall generic recently b/c my health insurance decided to stop covering dex, and it went from $0 to $400 a month; addy is $40/mo for #90.) I also had 0.5mg alprazolam on board. When those spasms started, though, I felt a strong need to stop them and started drinking tequila to ease it, plus 1mg more alpraz. It settled enough for me to sleep (and then I slept in and missed the start of my class; oyé...).

This morning, then, I took 120mg methadone, in case it was way stronger. Definitely don't feel like it hit stronger, or even the same, as 160mg (the full dose).
I have the 40mg extra still for later.

Maybe I will try 1mcg tonight, and have the 40mg methadone available in case the naltrexone does something funky again....

Must admit, I am somewhat apprehensive about it... it sucked last night to feel that w/d stuff. I remember it well: having to stay in a hot shower because it was the only thing that would touch the seething feeling under my skin, everywhere.... barely sleeping for the first three weeks straight.... everything feeling horrible and hopeless... writhing every night wracked with full body spasms.... uggghhhhh **shudders** ... fuck. that.

I really thought I was in the clear at first, but yeah, a few hours later it was definitely not fun. And I don't notice a change in tolerance.
(I was hoping for that magical one-day immediate decrease in tolerance, to a significant degree... maybe that's too naiive.)

Anyway, so: 3-5mcg was apparently too much. Sounds like I should try 1mcg, and if that's okay, slowly move up in 1mcg increments per day... right?

What do you think about timing? Like, does it make sense to take it at night and the MTD in the morning? or is a different timing better?
And for the naltrexone--once per day, or twice?

 

[Hexenstahl]

@vima
It is impossible to have any wd symptoms, especially such prominent ones, after taking between 3.3 - 5 µg of Naltrexone. Even if you have a very sensitive neurobiology it still is virtually impossible to end up with what you had to go through. Wd symptoms start at around 100 µg for most people, some can go even higher according to what I have read on various reddit self-reports, but going through wd after just 5 µg?!?! That would only be possible if your receptors have 20x the sensitivity of an average human which is absurdly high! I'm pretty certain that you must have somehow ended up dissolving way more solute into the solvent than you think. Can you tell me who the manufacturer of those tabs is? Can you post a photo of the blister here if possible? Did you get a legit script from your doc or did you order them via the net (indiamart, darknet, etc.)? Have you followed my instructions on the first page regarding volumetric dosing?

I have read and calculated those numbers multiple times to make sure that it isn't ME who is mistaken here, but I really do end up with 5 µg per drop if assuming 20 drops per mL. Whatever the case may be, please do NOT take the same or a similar dose until we have cleared this up. These precipitated wds put an enormous amount of stress on your mind and body. The naltrexone doesn't run away, so pls just be patient until we have cleared this up. If however you really feel like you MUST take NTX again, then pls reduce your dose by a factor of at least 15. Assuming you really took 5 µg, you would need to reduce that dose down to 5 µg / 15 = 0.33 µg or 330 pg (picogram). Let's just say 350 pg to make the math easier. Here is how you do it: take 1 mL of your current solution and dissolve that into a SEPARATE amount of 100 mL of pure water. You'll end up with 50 pg NTX per mL, which means that you need to take 7 mL in order to have 350 pg in your system. I would actually recommend to just start with those 1 mL (50 pg) simply to be on the safe side and increase the dose by another 1 mL daily if you didn't feel anything. Btw, it would be better if you took your ULDN right before you take your methadone. That gap is too big. 6ß-naltrexol has a half-life of about 10h, which means that after that time, half of your dose has been already eliminated from your blood serum. Take your pipette into the restroom of the clinic or doctor's office and take your dose there before you go and down your methadone. ULDN works best if taken simultaneously or 10 - 15 min. before you take your opioid.

@4DQSAR
What do you think about this whole thing? Did he mess up the solution making process, or is he really that sensitive? I really can't explain this any other way...

Well, that just shows you don't have a criminal mind ;-)

Uuh yeah exactly...why would anyone think anything else about me? *laughs nervously*

I'm too risk adverse. I don't want to end up with anyone even thinking I'm stealing or conning. I'm prepared to work hard on legal projects and while loopholes interest me, I've ALWAYS noted them with the proviso 'I would not rely in this in a court of law'.

What's funny is that I am actually pretty much a law abiding citizen, not because I'm an angel but simply because I don't want to be bothered. However, if I had access to kilos upon kilos of potent opioids and nobody was looking, you can bet your life that I would steal absolutely everything that's there. The idea of being completely independent of dealers, other junkies (no offense other junkies lol), maintenance docs and their arbitrary rules, where to get money, how to get it, etc., is just way too attractive for me not to steal a lifetime supply of my medicine. And let's not forget that there is no certainty that maintenance will continue to exist ad infinitum as it is very dependent on the political climate. One shouldn't rely on these things.
So all in all, the potential pros outweigh the cons for me. I would probably bury all of it somewhere and let it stay there for a year, just to make sure that I'm out of the picture if police ever ends up raiding me as a suspect. I wouldn't feel bad about it because the only one who got "hurt" in this process is a multibillion dollar corporation and its even richer investors who would have incurred, what, a couple hundred thousand dollars in inventory losses and millions of dollars in opportunity costs?

Btw, it's interesting what you mentioned about many criminals doing the act for the thrill. It reminds me of an interview I watched a while ago where a spec ops guy was asked what he earned. He replied with 50K p.a. which surprised the interviewer because he couldn't understand why someone would risk his life over that little bit of money. His answer to that was "I'm not doing it for the money. None of us does. We do it for the adrenaline."
Both of these groups' professions revolve around getting away with something. It's hard for me to understand because I'm someone who likes to be as safe and secure as possible. I suppose it's a certain type of character that feels drawn to these types of things?

 

[4DQSAR]

-I dissolved 100mg of naltrexone, via legit scripted tablets, powdered, into 1000mL of water. I figure that's 0.1mg per mL. CORRECT
-Assuming 20-30 drops/mL - The metric most often cited for general purpose droppers rather than ones for a specific medicine is 20 drops/mL. CORRECT
-100ug/20 = 5ug. CORRECT.

I think I already suggested the reason why the fixed-combination of naltrexone/opiate agonist failed was that the amount of naltrexone approprate just varied too widely.

If you look at the paper I linked to, the range was in the pg/Kg of bodyweight upto ng/Kg of bodyweight.

They seem to suggest that the term 'ultra-low dose' may span several orders of magnitude and that a large shift seems to occur when a subject crosses the ultra-low to the low dose range.

I truly think this is an example where there IS medical utility but it requires what is increasingly being called 'personalised medicine' i.e. the most appropriate dose for you may differ hugely to what is most appropriate for another other. I mean orders of magnitude difference in dosage. That could be genetics or could be that more or less of the drug crossed the BBB. I don't think anyone knows exactly why the range is so large.

If the methadone really did work far better next day, you might infer that the naltrexone is indeed modifying the receptors in a way that results in lower tolerance. But by which mechanism? Low dose or ultra low dose? Because sepearate mechanisms are proposed for the seperate protocols.

The researchers seem to suggest that their own way of defining what is an 'ultra low dose' and what is a 'low dose' is not based on a fixed amount of the antagonist. It seems to be defined as the point where even in rodent models, side-effects were evident. Below that dose, the same reduction of tolerance was shown but how it actually worked was still uncertain.

I guess if if worked, I would try moving down an order of magnitude and trying again. In fact, play it safe and go down by two orders then increase dose by 50% each day until you find a dose that produces no side-effects but does reduce tolerance.

I'm almost certain this is why there isn't as much research as would seem appropriate.

But I think it's important to note that they were always basing results on how ULDN improved the analgesia chronic administration of opioids provided for. They didn't really focus on the generally higher doses associated with substitution therapy. For that, the appropriate dose may be different again.

Sorry for sounding so vague but the paper is quite vague. ALL of the papers are quite vague. All agree it works, none can suggest how this discovery could be turned into a commerical product and sadly, if research doesn't eventually lead to profit, it gets ditched. This isn't the first example in which a medication that worked never ended up being turned into a medicine simply because the economics didn't work out.

 

[4DQSAR]

@Hexenstahl - Yes, I can see that IF a single transaction followed by retirement in a nation with no extradition treaty is possible, the odds favour the seller.

Got something in mind ;-)

 

[Hexenstahl]

Oh damn, I just realized that I mistakenly wrote pg (PICOgram) when it should have been ng (NANOgram). I forgot that nano comes before pico LOL.
@vima please mentally replace all the instances where I mentioned pg with ng.

On a more general note, I'm going to update my initial post on the first page to reflect the fact that the line between LDN and ULDN cannot be so easily drawn. If people can be put into wd by a meagre 3 - 5 µg, then that's something that I must point out. I'm getting PTSD flashbacks just thinking about what vima had to go through. I find the mental agony of cold turkey already horrible, but at least that is something that gradually builds up over time. You can handle that in some way. Precipitated wds however cram all of those symptoms together into a "small" window of time at the highest possible intensity. Imagine cold turkey at peak intensity x10 for at least 24h. It's a psychologically traumatic experience. I wouldn't want my worst enemy to go through that. I know many people say this casually, but I really mean it. This is something nobody should experience.

EDIT:
I read vima's post again and it appears he was on the verge of having a precipitated wd. It was bad but not an actual, full blown precipitated wd because if you are in that state of body and mind, you are most definitely NOT able to drink some tequila or take a shower LOL. You're screaming and writhing in pain on the ground, covered in your own puke and shit, you experience anxiety on a level you never thought was even humanly possible to experience and some people even hallucinate a little bit (delirium kind of hallucinations). I'm glad vima didn't actually go through this level of torture because I felt guilty for recommending doses up to 100 µg as totally safe. I'm still going to update my post on the first page to inform readers that they need to be careful and ideally start with single-digit nanogram dosages just to be on the safe side. I'll do that tomorrow though since I need to catch a good amount of sleep now.

Stay safe everyone

 

[vima]

hey, following up---so, a few points---

1. Yeah, I re-ran the math myself too several times and I get the same numbers each time... also, these are prescription tablets, from a friend's legal US script. I can double check the brand.

2. It's interesting and definitely very relevant that the proper dose may indeed be so individually varied that it spans multiple orders of magnitude... and a good point that this could be a place where genetic-based personalized medicine will make huge contributions. @4DQSAR I really appreciate your contributions and nuanced reading.

3. @Hexenstahl, lol I did pick up on the pico- vs nanogram mixup and I figured what you meant. No worries. Agree that the line between LDN and ULDN seems more flexible than I realized.

4. Yes, it's true that what I described was not 100% peak intensity precip w/d. Certainly not nearly as intense as the worst of what I've experienced in the past. But still super unpleasant; like a 'partial' precip w/d. Seems like precipitated w/d is not a black/white hard line, but a spectrum of intensity---to more knowledgeable folks, does the pharmacology science support that?

5. There's another really weird data point. The day following the experience I described before, I tried 1/3 the dose (approx 1 mcg) of naltrex and was okay. Then, two nights following that, I experienced something similar but even more intense---without dosing the naltrexone again. Full blown pouring sweat, freezing, shitting, writhing around with spasms, weirdly borderline visuals happening... I have no idea what happened or how I could have accidentally ingested another dose. Since that night I have been okay. And taking the same 160mg dose of MTD daily.

 

[Hexenstahl]

Now I'm even more confused. Your body is reacting in such an erratic way to NTX. Withdrawals while having no NTX in your system?! I think at this point the scientists over at the LDN research trust might be immensely interested in you as a test subject lol. They have the knowledge and the means to actually conduct research on you. A frankenstein neurobiology such as yours could give us tremendous insight into how (U)LDN and opioids interact with one another.

P.S.: if they end up asking you to sign a waiver, pls turn around by 180° and LEAVE. If they end up asking you to sign a waiver and don't even offer you compensation for potential damages, pls turn around by 180° and leave even faster. The medical industry only ever asks you to sign waivers if the responsible parties have knowledge of the odds being stacked against you to an overwhelming degree. Even if they do not end up asking you to sign a waiver, you can very easily test how honest the responsible parties really are with you when they say that it's "totally safe", simply by giving them a notice of liability. If they still wanna do "business" with you, then that's a sign that they are actually certain about the safety of their procedures. If however they end up rescinding their offer...well, I don't think I need to explain why they would do that.

If you ever end up being asked to partake in a study, send me a PM and I'll write you a notice of liability (free of charge ofc).

 

[4DQSAR]

Sci-Net: Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia

OK, I posted this a while back.

There is a novel ligand that has a two very interesting properties. If consumed alone, the ligand has no psychoactivity whatsoever but if co-comminent naltrexone and/or naloxone consumption (morphinan antagonists) is added to the mix, it seems the novel ligand turns those antagonists into into agonists.

As always, I assume if I can find this paper, so can anyone else.

Be aware that rodents tend to metabolise things faster and that slow and safe research is the ONLY way one could ethically research this novel class of compound.

I just find it interesting because it's highly likely that other allosteric modulators with the same action likely exist but simply have not been tested in this way. We could suddenly find that there are dozens of chemically unrelated compounds that do the same. Allosteric modulators of the MOR receptor have been around for at least a decade.

How does one legally control a ligand that if administered alone has no activity?

It does make me wonder if at a very low dose, naltrexone acts on the receptors in an allosteric manner as well as directly.