Treatments that help attenuate opioid tolerance

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Opioids/opiates, specifically mu opioid agonists (occasionally delta) can be an important part of pain treatment and also help other me/cfs symptoms, such as insomnia or PEM. But they cause rapid tachyphylaxis (development of tolerance).

This thread will be a long one in which we discuss all of the medications that can lower tolerance or slow its development.

Anecdotal reports welcome, and i will provide science lirerature soon. But right now in a crash so going to start with a list of relevant chemicals without much citation:

Classes of drugs known or thought to help with this:
NMDA antagonists:
(Ketamine is one example)

Low dose opioid antagonists
(LDN is one example)

Kappa opioid agonists (low evidence)
(Ibogaine is one example)

Tlr4 antagonists/glial cell inhibitors
(Ibudilast is one example)


Heres the full list of specific substances:
Agmatine
Memantine
Ketamine
Dextromethorphan
Nitrous oxide (risk b12 deficiency)
High dose transdermal or iv magnesium

Xenon
Ibudilast
LDN
ULDN
Rhyncophylline (p sure this is opioid and nmda antagonist in cats claw and kratom, maybe spelled wrong)

Ibogaine
Salvia divinorum
Taurine
 
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Ibogaine is probably one of the weirdest on this list bc it supposedly resets the opioid receptors somehow, not just dealing with psychological aspects of withdrawal only but also physical aspects of tolerance and dependence, but i cant find any info on which parts of its pharmacology are responsible for this. Is it the Kappa opioid agonism, in which case the safer salvinorin a should work? Is it the nmda antagonism in which case the safer ketamine or memantine should work?
 
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Agmatine

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923207/
"Agmatine is an endogenous amine derived from arginine that potentiates morphine analgesia and blocks symptoms of naloxone-precipitated morphine withdrawal in rats. In this study, we sought to determine whether treatment with agmatine during the development of morphine dependence inhibits the withdrawal symptoms and that the effect is mediated by cAMP system. Exposure of rats to morphine for 7 days resulted in marked naloxone-induced withdrawal symptoms and agmatine treatment along with morphine significantly decreasing the withdrawal symptoms. The levels of cAMP were markedly increased in morphine-treated rat brain slices when incubated with naloxone and this increase was significantly reduced in rats treated with morphine and agmatine. The induction of tyrosine hydroxylase after morphine exposure was also reduced in locus coeruleus when agmatine was administered along with morphine. We conclude that agmatine reduces the development of dependence to morphine and that this effect is probably mediated by the inhibition of cAMP signaling pathway during chronic morphine exposure."

This makes me wonder what cAMP is and if there are other inhibitors of it that may be useful. The following article: https://www.frontiersin.org/articles/10.3389/fimmu.2016.00123/full
Explains that this pathway has to do with cellualr signalling and inflammation and immunity and is dysregulated in autoimmune disorders.
 
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LDN.
https://academic.oup.com/painmedicine/article/16/6/1239/2460766
This isnt about tolerance, but LDN is used in humans alongside morphine to prevent adverse effects, which is interesting, bc maybe it suggests something simialr to the literature on ibudilast, that the subtle antiinflammatory effect helps offset side effects without lowering analgesia.
As for tolerance: here we go, a rat study. https://pubmed.ncbi.nlm.nih.gov/16527399/
That said there are many more studies but i am going to try and stick with one for now, as im getting tired, others are free to fill in gaps. There are studies on LDN attenuating hyperalgesia, which is interesting as maybe attenuation of hyperalgesia is related to attenuation of tolerance
 

Hip

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but i cant find any info on which parts of its pharmacology are responsible for this.
It's possible that iboga's stimulating effects on the growth factor GDNF may underlie its anti-addition effects. Not sure if this also translates to anti-tolerance as well.

African herb yields its anti-addiction secret
22 January 2005
New Scientist
Bob Holmes

THE secret of an African herb that helps drug addicts and alcoholics kick the habit has been discovered. The finding could lead to safer and more effective medications for treating addiction.

Since the 1960s, many addicts have reported that even a single dose of ibogaine, a hallucinogenic alkaloid extracted from the root of an African shrub, helps them kick their habit by reducing their cravings for drugs. And there is hard evidence to back these claims, as well. However, troubling side effects - including heart problems and several deaths - have kept ibogaine from being widely accepted as a medical treatment. Instead, a few researchers have begun searching for ways to deliver ibogaine's benefits without its risks (New Scientist, 26 April 2003, p 34).

A few previous studies have suggested that becoming addicted to a substance lowers the production of a nerve growth factor called glial cell-line derived neurotrophic factor, or GDNF. So Dorit Ron's team at the University of California, San Francisco, decided to test whether ibogaine affects GDNF levels in the brain.

In rats injected with ibogaine, the researchers found that production of GDNF increased in a region of the brain called the ventral tegmental area. What's more, injecting either ibogaine or GDNF itself directly into this brain area decreased alcohol cravings in addicted rats, whereas injecting anti-GDNF antibodies eliminated any beneficial effect of ibogaine. The results appear in The Journal of Neuroscience.

"The paper looks very solid," says Stanley Glick, a neuropharmacologist at Albany Medical Center in New York, who has studied ibogaine for many years. "They may indeed be on to a major finding." However, both Glick and Ron point out that boosting GDNF may be only one of several mechanisms by which ibogaine acts to ease addiction.

A synthetic ibogaine compound, 18-methoxycoronaridine, which Glick has shown can help addicts with fewer harmful side effects than ibogaine, may also work by controlling GDNF levels. In preliminary studies with cultured nerve cells, Ron's team found that 18-MC also raises GDNF levels.

But the team is not pursuing the ibogaine approach. Instead, Ron thinks it is time to narrow her focus. "Our idea now is to move away from ibogaine and concentrate on GDNF," she says. Her team plans to look for ways to stimulate GDNF without side effects.
 

Hip

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Another interesting anti-tolerance substance is oxytocin, the "love hormone".

Oxytocin is one of Dr Jay Goldstein's ME/CFS treatments, and it does seem to make major improvements in a very small subset of ME/CFS patients (did not work for me though).

But oxytocin also inhibits tolerance to alcohol, opioids, and stimulants as well as withdrawal from alcohol and opioids. Ref: here.



Interestingly, oxytocin just on its own can provide pain relief:
Oxytocin also stimulates cannabinoid receptors and is known to relieve pain as well as induce a feeling of calm, and lower serum cortisol, stress, and anxiety.
Ref: here.

You can buy oxytocin from peptide suppliers, like Peptide Sciences. You can either inject it, or make it into a nasal spray. I tried both. I noticed some boosting of emotion with oxytocin (but mostly aggressive emotion, which I did not like). Unfortunately it did not help ME/CFS symptoms.

To inject, you need to reconstitute the dry oxytocin peptide with bacteriostatic water.

I used an oxytocin dose of 10 IU for subcutaneous injection, and 30 IU for a nasal spray application.

1 IU of oxytocin = 2 micrograms. So a dose of 10 IU would be 20 micrograms = 0.02 mg.



Dr Jay Goldstein used oxytocin doses of 5 to 10 IU by intramuscular injection. On pages 157-158 of his book Betrayal by the Brain, Goldstein says:
Approximately one-fifth of my patients have a good response to intramuscular oxytocin.

There may be an inverted U-shaped dose-response curve; some patients do well on 5 units, but become agitated and have some return of symptoms on 10 units.
 
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Another interesting anti-tolerance substance is oxytocin, the "love hormone".

Oxytocin is one of Dr Jay Goldstein's ME/CFS treatments, and it does seem to make major improvements in a very small subset of ME/CFS patients (did not work for me though).

But oxytocin also inhibits tolerance to alcohol, opioids, and stimulants as well as withdrawal from alcohol and opioids. Ref: here.



Interestingly, oxytocin just on its own can provide pain relief:

Ref: here.

You can buy oxytocin from peptide suppliers, like Peptide Sciences. You can either inject it, or make it into a nasal spray. I tried both. I noticed some boosting of emotion with oxytocin (but mostly aggressive emotion, which I did not like). Unfortunately it did not help ME/CFS symptoms.

To inject, you need to reconstitute the dry oxytocin peptide with bacteriostatic water.

I used an oxytocin dose of 10 IU for subcutaneous injection, and 30 IU for a nasal spray application.

1 IU of oxytocin = 2 micrograms. So a dose of 10 IU would be 20 micrograms = 0.02 mg.



Dr Jay Goldstein used oxytocin doses of 5 to 10 IU by intramuscular injection. On pages 157-158 of his book Betrayal by the Brain, Goldstein says:
I have been prescribed oxytocin. A doctor used it in troche form initially which had only mild effects. Intranasal was quite intense. It does help with pain but only for a short period , so not sure how practical it is. But intranasal is definitely centrally active, no doubt about it.
 

Hip

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It can be a good idea to use another search engine like duckduckgo.com when looking for medical info which may be alternative or unconventional. Google no longer places alternative or non-authoritative medical websites in its top search results.
 
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It can be a good idea to use another search engine like duckduckgo.com when looking for medical info which may be alternative or unconventional. Google no longer places alternative or non-authoritative medical websites in its top search results.
Interesting, and concerning,especially for mold related stuff. However, would this apply to thinfs within western medicine that are not "alternative ' or woo, but are merely experimental? Like basically every me/cfs treatment? That could be terrible
 

Hip

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However, would this apply to thinfs within western medicine that are not "alternative ' or woo, but are merely experimental?
If it is experimental but non-authoritative (non-authoritative means no medical credentials associated with the website it's posted on), then Google penalizes it, and it will not appear in the top Google search results.

Google now uses what it calls EAT criteria (expertise, authoritativeness, trustworthiness) for assessing websites, and it applies this particularly fastidiously to medical websites.

There was the "medic update" to Google's algorithm in August 2018 which applied EAT to all health and medical websites, and as a result of the medic update, Phoenix Rising threads are now rarely listed in the top Google results. This is the main reason that PR readership fell dramatically after August 2018, and PR is no longer as busy as it used to be.

PR would be considered non-authoritative (no medical credentials associated with the posts on PR), so Google now penalizes it. Whereas before August 2018, I remember my Google searches on ME/CFS matters would very often bring up PR threads.

SelfHacked (Joe Cohen) was particularly upset about the medic update, as his website was decimated by it. People like Mercola, longecity.org, GreenMedInfo were also decimated. In the weblink there's a list of health sites which were badly hit by the medic update, and PR was one of the worst hit.
 

Hip

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I thought things that act via growth factors generally take longer than a couple days to work
Yes, you would have thought so. From what I heard, a full iboga psychedelic session (which is an arduous undertaking lasting 12 hours) resets and eliminates drug addiction and tolerance in one go.

I don't think the anti-tolerance and anti-addiction mechanism of ibogaine is properly understood. This study from 1995 suggests it works on multiple mechanisms:
Ibogaine interacted with a wide variety of receptors at concentrations of 1-100 microM. These included the mu, delta, kappa, opiate, 5HT2, 5HT3, and muscarinic1 and 2 receptors, and the dopamine, norepinephrine, and serotonin uptake sites.

In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [3H]MK-801 and [3H]bactrachotoxin A 20-alpha-benzoate binding (BTX-B), respectively.

This broad spectrum of activity may in part be responsible for ibogaine's putative anti-addictive activity.

And this 2013 paper argues that the anti-addiction effect of ibogaine is not due to its mu-opioid receptor activation, and suggest there may be some undiscovered novel mechanism of action.



I tried some iboga microdosing a while ago (I took 50 to 200 mg of root bark daily), to see if it might improve my blunted emotions, since the iboga trip is know to induce strong emotions, but did not notice much.


Years ago I saw this Joe Rogan video, comparing the iboga trip to the ayahuasca trip, and found it fascinating. It's just the first 10 minutes of the video that are really interesting. At 4:18 it says things like:
The iboga sharmans and the way they talk about it is completely different than the ayahuasca shamans.

The ayahuasca shamans talk about going farther, everything is about exploring other dimensions, going beyond, and bringing back information from those dimensions.

And the Bwiti shamans, they talk about going deeper, like going farther inside yourself, because inside of you, is a soul that has access to infinite knowledge. So you can actually go inside yourself, and find out the truth to virtually anything, without having to go outside. So it's a whole kind of different paradigm.
I only wish I had a normal healthy mind, because I alway liked to explore these spiritual philosophies and landscapes of consciousness, but you don't seem to get access to even just ordinary everyday spiritual feelings once you have ME/CFS brain fog.
 

Hip

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By the way, have you ever tried electrical therapies for your neck pain?

I would suggest something like microcurrent therapy might be worth exploring. This is much gentler that TENS therapy devices, but often more effective. With TENS, you can feel the electrical current, but with microcurrent therapy the current is lower, and there is no sensation at all.

You can buy machines like this one which offer both microcurrent and TENS.
 
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Memantine seems to be helping w tolerance but I would really like to try higher doses. I'm pretty sure the person who totally reset their tolerance used doses 4 times what I use. I also really want to work on getting A custom synthesis of one of the glycine site specific nmda antagonists, the ones besides xenon, like glyx13 or the other ones ... Need to look on the diScord to see if anyone is interested. The glycine site specific nmda antagonists have such a High priority. Unless its the trek channel or other ion channel stuff, glycine site nmda antagonism is how xenon is able to work its magic without the harm that , for example, ketamine causes. And besides rat and maybe one or two human studies there's not much in the other ones besides xenon in that class. Nmda is involved in everything from upregulation in brain injury like the stretch injury in cci, to pain and opioid tolerance , to mood, to modulating glutamate which is released in excess in response to biotoxins. I believe people have underrated the importance of nmda antagonists in treating me/cfs bc the non glycine site ones come with so many side effects vs and aren't as incredibly Neuro protective