N&PD Moderators: Skorpio
ULDN - The magic weapon to reduce and keep tolerance to Opioids low
Dastromar
Greenlighter
Thanks to all of those who answered to my questions. I'm glad that some things becoming more clear for me. So I'll try to use naloxone intranasally while trying to get some naltrexone tablets, it shouldn't be hard with a help of some fake recipes..
I'll report back if I'll get any noticeable results
I was actually just trying to help 'Dastromar' understand why naloxone isn't a great candidate for getting the same results as naltrexone at low doses. The potency and half-life of their different metabolites is the main reason, from what I've gathered. But I'm no expert at all, so I might be getting things mixed up.
Allylbenzene
Bluelighter
Enzymatic leverage strategies
• Re glucuronidation of naloxone:
Hepatic metabolism primarily occurs via glucuronidation to form naloxone-3-glucuronide, a pharmacologically inactive metabolite....Glucuronosyltransferase (UGT) is a glycosyltransferase that catalyzes the addition of a glycosyl group from a UTP-sugar to a small hydrophobic molecule. Although the majority of UGT enzymes are expressed in the liver...Some UGT enzyme inhibitors:
Glucuronosyltransferase (UGT) - HerbPedia
herbpedia.wikidot.com
• Re sulfation of opioid drugs:
Buprenorphine, pentazocine, and naloxone are opioid drugs used for the treatment of pain and opioid dependence or overdose. Sulfation [...] is involved in the metabolism of a variety of xenobiotics including drug compounds. Sulfation of opioid drugs has not been well investigated. Collectively, these results imply that sulfation may play a role in the metabolism of buprenorphine, pentazocine, and naloxone in vivo.Sulfotransferase (SULT) are transferase enzymes that catalyze the transfer of a sulfate group from a donor molecule to an acceptor alcohol (C-OH) or amine.
Some SULT enzyme inhibitors:
Sulfotransferase (SULT) - HerbPedia
herbpedia.wikidot.com
• Re glutathione conjugation of opioid drugs:
Glutathione binds not only morphine but also naloxone, methadone, and methionine enkephalin.Glutathione S-transferase (GST) enzymes catalyze the conjugation of reduced glutathione (GSH) (using a sulfhydryl group) to electrophilic centers on a wide variety of substrates.
Some GST enzyme inhibitors:
Glutathione S-Transferase (GST) - HerbPedia
herbpedia.wikidot.com
• P450 metabolism of morphine:
More than 90% of morphine N-demethylation could be accounted for via the action of both CYP3A4 and CYP2C8. The in vitro findings suggest that hepatic CYP3A4, and to a lesser extent CYP2C8, play an important role in the metabolism of morphine into normorphine.
CYP3A4 inhibitors
CYP2C8 inhibitors
CYP3A4 - HerbPedia
herbpedia.wikidot.com
CYP2C8 - HerbPedia
herbpedia.wikidot.com
Last edited:
UPDATE 2
I decided to stop the experiment. My willpower broke.
I failed again.
At least I confirmed that things like constipation and other methadone side effects can be fixed with VLDN, starting with ULDN and going up really slowly, though. I'll update if anything changes or if I decide to give it another try. It's terribly disappointing. None of my attempts to quit methadone ever work out.
Thanks to everyone who's been reading, and I hope you're all doing well
Allylbenzene
Bluelighter
Hang in there, you have many strategies left to explore.
Smyth2
Bluelighter
E-52862
S1RA is being developed by Esteve for the treatment of neuropathic pain and the potentiation of opioid analgesia and has successfully completed Phase I clinical trials showing good safety and tolerability, and a pharmacokinetic profile compatible with once a day oral administration.<a href="https://en.wikipedia.org/wiki/E-52862#cite_note-Abadias_2013-6"><span>[</span>6<span>]</span></a> Phase II clinical trials are currently underway, making S1RA the first selective sigma-1 receptor antagonist evaluated in humans for these conditions.
Hexenstahl
Bluelighter
I can't tell you how often life has proven to me how true this statement is. It has reached a point where I voluntarily refrain from discussions with people when I feel that those people are not at least a little bit open to other points of view. I just nod and pretend to agree with them to avoid verbal fights. Didn't Confucius say "whoever tells the truth needs a fast horse"? He was right. I don't like quoting from the bible but it got one thing right: never throw pearls before the swine...
@nosti
Your experiment was very fascinating. I was aware of the possibility of using naltrexone to avoid wd since I have done it myself using the method of the Biochemist Jonathan Ott as described in his bioassay, but I was not aware that you can get used to increasing doses and use that to obliterate wd.
4DQSAR
Bluelighter
@Hexenstahl - It isn't that people are purposefully ignoring information. It's simply the case that people feel threatened if something they believe is called into question. I read a psychology paper on how people end up joining cults or believing in various unlikely conspiracy theories. It's simply the case that they become emotionally invested in a given case to the point that alrering their position causes cognative dissonance. I mean to the point that you can lead them down a path and they argee every time and then when you demonstrate that last logical step, they irrationally refuse to accept the case in spite of agreeing the logical propositions from which the case is infered.
It's quite amazing how irrational we all are.
Allylbenzene
Bluelighter
When we consider all relevant substances [to this opioid/tlr4 scenario] that are readily available, naltrexone becomes one of several essential tools which together can accomplish much more than naltrexone alone. Interestingly, many of these items proactively ameliorate one's physiological coherence which can only be advantageous.
Actually, Jonathan Ott was one of my role models. I’ve read most of his articles and watched some of his talks and interviews on YouTube. I was really sad when he passed away last year.
Hexenstahl
Bluelighter
Me too. I even own a signed book he co-authored with the german Ethnopharmacologist Dr. Christian Rätsch (who also sadly passed away) in which they wrote extensively about Coca and Cocaine. The book is called "Koka und Kokain: Ethnobotanik, Kunst und Chemie" (Coca and Cocaine: ethnobotany, art and chemistry). It's a travelogue, drug experience report, history lesson, chemistry book, poetry and art presentation all at once. I'll never understand why this incredibly entertaining book that has such a unique writing style was never translated into english. Thankfully though, other books of Dr. Rätsch, such as his massive encyclopedia of psychoactive substances have been translated for non-german speakers to read.
Two geniuses that have died way too early. I know the world is unfair when someone like David Rockefeller becomes 101 yo, and people like Dr. Rätsch die at 65.
Hexenstahl
Bluelighter
Meh, that's only a very short-term "solution" and on top of it unreliable too. I never heard of anyone who was able to continuously keep tolerance low with DXM. I was initially positively surprised, but a) tolerance eventually catches up for some reason and b) its results pale in comparison to Naltrexone in my experience.
4DQSAR
Bluelighter
DXM was trialled in a fixed-dose combination with morphine with the tacit brand-name MorphiDex™ which failed stage 2 trials as having 'no clinical benefit'. Since then a few small-scale human trials seem to suggest that DXM MAY reduce AWS symptoms.
I capitalized and used bold-type for the word 'may' because every paper I've seen uses that qualifier term in it's conclusions.
On a related note I witnessed a chain (franchise?) of in-patient opiate detoxification clinics called 'Detox 5' appear in the UK and which charge anywhere from £1300 to £2,300 per day. Journalists uncovered the fact that patients were heavily sedated with powerful medicines such as ketamine, pumped full of naltrexone and after five days, would be 'cured'. The relapse rate was no better than the placebo group who detoxified without help.
Not a surprise because anyone who has worked in HR knows that most clients who truly wish to stop can successfuly do so but because opioids are at least partly used (both medically and otherwise) to produce emotional detachment, former users tend to relapse when something bad happens in their lives. It's just self-medication, not a sign of weakness. Our subconscious will push us to use whatever worked best in the past.
Last edited:
Hexenstahl
Bluelighter
I have always told people that detox clinics are nothing but business enterprises. They have a vested interest in NOT curing people because this is how they make money. Even if you start as a completely naive founder of a detox clinic with the genuine intention to help people quit for good, you're gonna realize that a) revenue will quickly plummet which results in you being unable to stay current with your debt repayment schedule and b) business is just too good to actually help people. This is the problem. The system doesn't actually incentivize permanent cures, addiction or otherwise. It is based on recurring customers. Why should a detox clinic be any different than other industries. Just type in the name of any detox clinic into Dun & Bradstreet's database and you'll see they are registered as business corporations. It's a BUSINESS guys, not an eleemosynary foundation.
THIS THIS THIS!!! I 100% subscribe to this! Why can't we go back to the way the drug market worked in the 19th century? People managed to have normal lives, have careers and lead a family despite their addiction. We didn't even have drug laws. Prices were low too, because the market was so incredibly decentralized back then. People just had a different attitude towards drugs. The word drug alone has been incredibly propagandized and emotionalized. According to Dr. Rätsch the word "drug" was actually used for dried plant material that was used for the manufacture of phytotherapeutics or pharmaceuticals. So people didn't even have a word for the modern concept of a "drug". It was just all medicine!
I sometimes wonder if addiction even exists. Let me explain what I mean to prevent misunderstandings: let's say there is a person named Paul and he has Type 1 Diabetes. We all know that T1D is a disease, right? We also know that these people have an endogenous lack of insulin in their body. This creates a need for insulin in Paul's body. If nobody told him directly that it is insulin he needs, he would trial & error with various substances until he has found the substance that relieves his symptoms. Thankfully, diabetes patients do not need to go on a drug odyssey to find the medicine that "fits". The health care system immediately helps them out by providing them with what they need. This means Paul can now compensate for his endogenous shortage of insulin, simply by taking exogenous insulin.
Let us now translate this example to that of an opioid "addict". Let's say there is someone called Max and unfortunately his body doesn't produce enough endorphins (endogenous morphine) due to genetic misexpression. This causes Max to have physiological and psychological symptoms (such as depression). Since the cause of his disease is biological in nature, all psychotherapeutical attempts have failed. Max starts to experiment with various substances, some legal, some illegal. He feels intuitively drawn to a specific class of drugs however, which he considers to be mere curiosity. It turns out that it is actually his body's desire to compensate his lack of endorphins. This compensation by the intake of exogenous opioids results in him feeling well. He realizes that this is exactly what he needs to function like a normal person.
The problem that I see now is this -> WHY the hell is Max' use of opioids pathologized and seen as a disease, while Paul's use of insulin is seen as legitimate medication?!?! How can we refer to Max' use of opioids as self-medication while at the same time labeling it as a disease?! It makes no sense. If my use of opioids is pathological, then it cannot be an act of medication at the same time, since medication is used to rid one of disease. We admit Paul's underlying condition but do not do so with Max. I believe the actual disease that we have is NOT the "addiction", since that is just an attempt of our body to compensate for the chronic lack of neurotransmitters, but instead the underlying condition that has TRIGGERED the self-medication. This is why I don't believe in addiction anymore and very likely also why our ancestors didn't have such a concept. It's because they had an intuitive understanding that people gravitate towards whatever they lack. Modern society however has managed to actually pathologize this type of completely natural behaviour. I think it's incredible how this is being completely ignored in the entire addiction discourse in both academia as well as outside of it. I think it would be very eye opening if scientists conducted a study in which they compared endogenous neurotransmitter levels of the non-addicted population with the addicted one. I would stake my life on it that the addict population has a pathological gene expression in regards to certain neurotransmitters and that this is the cause for their "addiction". This would be the actual disease.
Allylbenzene
Bluelighter
This imo applies to modern medicine which seems to fundamentally be a corporate healthcare system. The corporate element acutely undermines the quality of care available to a patient, specifically the types & integrity of ligands being designed (and approved), but also the actual research & progress in understanding (and naming) health conditions. The shambles of ADHD, BPD, MDD, PMDD, endometriosis, PCOS/PMOS, cancer, Alzheimer’s, hypercholesterolemia and diabetes is proof of this.
The issue with limited selection of drugs & their relatively poor quality (vis-a-vis sustainability) is encountered by everyone with a prescription. For example, someone on a long-term Rx for opiates becomes damaged (and usually dependant) by merely following the prescription guidelines. We see endocrine disruption, hyperalgesia and cognitive degeneration which occurs often without the person realising, this discreetly affects their behaviour, attitude and perceptions in diverse ways. This is partly due to opioid-induced demyelination (see here) which causes sutle impairment.
This deleterious effect applies to methadone also which has wide-spread use in modern medicine. Imo opiates are powerfully crude medications which whilst undeniably effective, lack sustainability (from a pharmacological and endocrine basis).
Diabetes is more than just insulin. Infact the modern (corporate) medicine "solution" for diabetes is short-sighted and inadequate, it's far from a solution as it exacerbates the issue. This is all due to various misconceptions about insulin/diabetes which have apparently become engrained and accepted as absolute truth.
The genetic context is attractive but it seems more reasonable to consider that people will habitually self-medicate with anything relevant, available and convenient to address unacknowledged health issues. The word "addiction" is imo misleading and has accrued connotations which makes it incompatible with recovery.
Some people on this forum have claimed that resolving habitual drug use doesn't justify "using more drugs" which seems rather idealistic, unreasonable and impractical. One of those things which is easier said than done.
Last edited:
Hexenstahl
Bluelighter
A corporation is simply a legal fiction in which entries in a court of record are treated as human beings (so called "legal persons") in order for actual human beings (so called "natural persons") to act through those entities for reasons of achieving limited liability since nobody would engage in significant risks if they were personally liable as is the case with direct joint ownership. It seems to be popular these days for people to blame "the corporate system" but corporations are very useful fictions, unless you like the thought of being liable for $ 200 million debt. The real problem is the underlying philosophical basis that drives human society, which is postmodernism, reductive materialism and the religion of exponential growth of revenue. Corporations don't do a damn thing. Humans on the other hand do.
Fun fact: your town is organized as a municipal corporation but behaves in a totally different way from a merchant corporation such as The City of London Corp. (not to be confused with the city London) with an exterritorial status. Both are corporations but they act in totally different ways.
I know this article and I have several issues with it. One of the problems already starts with their "insightful" realization that "polydrug use is particularly prevalent among patients with opioid use disorder. In the Netherlands, half of methadone users reported cocaine as their secondary drug. In a study in the United States, 60% of patients in a methadone maintenance program used crack cocaine and alcohol [7]. In Barcelona, more than one-third of heroin-addicted patients were found to be polydrug users when they BEGAN methadone maintenance treatment".
Hmmm...maybe...just maybe it has something to do with that maintenance treatment and less with the opioid dependence itself??? Maybe it has something to do with the fact that once you are in maintenance you cannot practice opioid rotation anymore (because the physician of today is more concerned with power plays rather than adhering to the hypocratic oath), which is proven, both in actual practice as well as in theory, to actually maintain the effects that drug users and pain patients alike perceive as positive when it comes to opioids.
Is it really ANY surprise then, that if I am taking one damn agonist for years and years, that I eventually won't be feeling anything at all anymore, which makes me crave other drugs to compensate for that loss???
It has nothing to do with eventual brain alterations that are being projected as being "pathological", but by the simple fact that those who are deemed as "recreational" users such as I, are taking the drug SPECIFICALLY and INTENTIONALLY to experience that so called "side effect" known as euphoria. Now take that feeling away and you'll end up with someone who is desperately seeking something that resembles that euphoria, no matter how remote that resemblance might be. This is why I don't take these "muh brain alterations" studies serious anymore, because it is the PERFECT example of why correlation isn't causation. These studies have become a marker to me, of who is merely an armchair, ivory tower theorist who is already starting his "scientific" research with a loaded question. Brain alterations don't prove anything because any chronic stimuli you experience alters the plasticity and even the (entire) rewiring of your neuronal pathways.
That's what makes epigenetics such a drastic influence when it comes to intergenerational trauma. If I subject you to operant conditioning, SOMETHING in your brain has changed. What does that actually prove? Well, nothing except the fact that your brain has changed which happens all the time for all sorts of reasons. What modern academia however does, is to point at those alterations and tell us "oh look, those changes happened WHILE and/or AFTER chronic intake of [insert "addictive" drug]. This can ONLY mean that trouble is afoot."
What they are NOT telling you however, not out of malice but out of psychological blind spots, is that the pathology is merely ascribed to those changes. I still don't have any proof that clearly shows the difference between a pathological brain change and a "normal" brain change. It is immediately assumed from the get-go that because self-medication is "bad", the associated changes within that brain must be "bad" too. How can we rule out that those changes are perhaps necessary adaptations of the brain to a playing field that has changed (and perhaps rapidly so)? Well, we don't because academia doesn't even ask those questions anymore. It is taking the ideas on which it operates for laws of nature which cannot be questioned.
Just to prevent any misunderstandings: I am NOT saying that these studies are worthless. All I am trying to say is that we can't even begin to classify biological changes as a reaction to something as normal or abnormal, healthy or unhealthy, good or bad, if that something is heavily colored by completely outdated puritanical beliefs, which is something that is not scientific to begin with, which in turn begs the question of how scientific the conclusions drawn actually are. Nobody in the scientific "community" seems to ask this question for some reason, which displays a concerning lack of critical thinking...
Any medicinal substance is going to lack sustainability if altered only with other cross-tolerant substances of the same class. The substance isn't to blame, the shitty protocol is.
Look, you're missing the point I was trying to convey there. It's not about the insulin, it's about the fact that at the end of the day, the T1D patient needs his fix just as much to function as the heroin "junky" needs his fix. The fact is this -> both need the fix, so why is the other guy who is dependent on the "wrong" substance being criminalized and turned into a pariah, while the other one is treated as a poor patient who desperately needs the help of society? The insulin thing was just my rhetorical vehicle to get my point across...
Last edited:
Allylbenzene
Bluelighter
Sure; semantics aside it's a structure nonetheless.
This seems like a valid but prevaricative rationalisation.
So in rhetorical summary, long-term use of opioids is quite safe and has no tangible harmful effects.
I would have to consider the disruptive biological implications of this, implying endocrine disruption amongst other things. This would most likely have a deleterious effect on cognitive function & one's perceptual, logic & reasoning abilities.
I'd consider all the opioid drugs as having rather "poor value" (except naloxone, naltrexone). They have an undeniable real purpose as short-term exposure, but long-term use is imo a very foolish endeavour, one that’s legitimised by modern medicine.
I'd theorise that the current set of opioid ligands (except naloxone, naltrexone) are flawed by virtue of their very pharmacological ideals. There are, I think, more intelligent, sustainable and efficient ways to achieve the desired result.
Last edited:
Hexenstahl
Bluelighter
You know, allylbenzene, something funny but very enlightening happened (call it synchronicity) after I posted my answer to you: a helpful and kind forum member who seems to have a lot of experience in partaking in forum discourse, sent me a PM warning me against arguing further with you because, to put it shortly, they considered you to be someone who argues in bad faith and one of those individuals who is too emotionally invested in their opinion to consider other ones, and recommended me to stop wasting my time talking to someone who isn't the slightest bit open about different points of view. 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.
So judging by the passive-aggressive and condescending tone of your answer, I now realize that he was 100% correct about you, which is why I will refrain from further discourse with you, simply to not waste precious time that is better invested in people who are somewhat open to change. Call it evasive, cowardly, or whatever makes you feel like you have "won", I don't really care about it.
- Mundus vult décípí, ergó décipiatur -
