CCK inhibitor?
- Thread starter yelis300
- Start date
Simon Keller
New member
Ginger??? As a CCK antagonist???
yelis300
Member
yes cholecystokinin. I want to reverse or try to lower my tolerance to kratom. apparently cck is what causes a tolerance to build after taking certain types of drugs, like opioids.
Ape McGrapes
Well-known member
I'd take a break, and then from there dose your kratom with agmatine. Agmatine is supposed to reduce/prevent tollerance and potentiate opiates.
I don't have the research to support this, but a Google search should provide it pretty easily.
bigdavid
Well-known member
Yeah I think I remember reading that one somewhere also. There are a few meds being studied now for lowering tolerance to opioids specifically. I’ll have to go looking for those studies again.
OP the one that you mentioned is also an agonist at opioid receptors and it’s some what of a dirty drug its not very specific.
Ape McGrapes
Well-known member
Time off is your best option. Just suck it up. Taper down if you have to.
bigdavid
Well-known member
I think your best bet besides the obvious of taking time off is to use high doses of chelated magnesium daily. Also chelated zinc. Both can serve as nmda antagonists. Zinc also helps through its own specific pathway. Also memantine may be worth a try, though that may be hard to acquire.
cheftepesh1
Well-known member
The best option is to taper off and take some time away. The fact that you have such an issue should be a clue that you have been using to much or too long.
Ape McGrapes
Well-known member
Please explain the use of these chelated vitamins a little more in depth.
bigdavid
Well-known member
The chelated aspect is purely to increase bioavailability and decreases GI side effects. You could take non chelated magnesium and zinc but it’s suboptimal in comparison. But besides bioavailability some chelated products can more readily cross the blood brain barrier (more on that below). Magnesium acts as an nmda antagonist in the CNS, zinc does this as well but to a lesser degree, and usually only when cns magnesium levels are low. As far as the mechanism by which nmda antagonism is beneficial to tolerance of opiates and amphetamines, the long answer can be found by searching “nmda antagonism tolerance opiates amphetamines” (or something along those lines).. the short answer is that antagonizing these receptors causes an acute decrease in signaling, which subsequently leads to an up-regulation of these receptors (likely through both transcription and induction from storage vesicles intracellularly). The increase number of nmda receptors lead to increased signaling over what was present before the antagonism (antagonism does not always do this, sometimes it simply down-regulates the receptor like is the case with SSRIs and 5ht-2a, so we need in vitro experiments to figure out how the receptors respond). Chronic pain and opiate use is linked to downregulation and sensitization of these receptors (the antagonism not only increases the number of receptors but also allows for less chronic and more
Acute activation...chronic opiate use causes sensitization meaning they are constantly being activated and this leads to less down stream effects in the long run) and this is thought to be part of the reason for tolerance to opiate and other analgesics. By maintaining this pathway through compounds that antagonize this receptor we can both attenuate low dose opioids and possibly prevent tolerance for long term use. It gets somewhat complicated determining exactly how this prevents tolerance since many downstream events happen with nmda receptor activation (some neural pathways are stimulated releasing serotonin, acetylcholine and other neurotransmitters and others are repressed and this can be different for separate brain regions (meaning serotonin can go up in one area and down in another, etc).
Below are two articles showing superficial plausibility for efficacy. There are more detailed animal models out there. The assumption is that the same mechanism happens in us humans to explain the clinical effects. Take home point is that most people have suboptimal zinc levels and supplementing ameliorates that issue. But also higher doses of zinc (say 50 mg zinc picolonate) can act as nmda antagonists even if magnesium levels are ok. Magnesium levels in the brain can be increased above baseline by being chelated to amino acids that readily cross the BBB, such as glycine or aspartate (magnesium glycinate and magnesium aspartate respectively).
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This is far from a cure to tolerance, but it does plausibly play a role in its development...and even if it helps with tolerance it may also affect other neural pathways as magnesium can antagonize other receptors to small degrees and also serves as a cofactors for many enzymatic reactions both peripherally and centrally.
But that about sums up why I made the suggestion above.
Ape McGrapes
Well-known member
Wow, that was way more helpful, and an in-depth answer than I could ask for. Thanks man. Definitely interesting.
bigdavid
Well-known member
No problem man. I get carried away sometimes lol. But in all seriousness whenever someone tries to grill you and ask for explicit evidence for something beyond just musing and surmising, the go to answer (and one I use a lot) is “hmm... well...more research is needed!” Lol
yelis300
Member
I never said I have an issue and need to taper off. my dose has been very low thus far. just want to make the use of it more enjoyable. there are several potentiates to do this but I've not seen anything that will reduce or reverse tolerance such as proglumide is supposed to, hence my search for a natty cck inhibitor.
bigdavid
Well-known member
I have no personal experience with dosing the compound. But from what I’ve read lower doses are more stimulant like whereas higher doses have more opiate properties. Maybe your dose is not high enough? Just a thought.
bigdavid
Well-known member
And also I’m sorry to tell you what you probably already realize... the medications we have that target the CCK pathway are extremely limited. And even the ones that we do have are somewhat dirty meaning they don’t just do what you want them to do. Maybe in 20 years... It takes at least 10 years for a drug from development to even make it to approval. And if we don’t have big pharm companies doing the biochemical studies to see if the drug can actually influence that pathway (and then the human data to show that it can even make it to the brain and do all that), we are really just shooting randomly in the night, at best, trying to find something that fits the bill. But if you end up getting and trying the one drug you mentioned please let us know if it helps.
yelis300
Member
thanks for your responses, wasn't sure what you meant by "dirty" but it makes sense now. yeah my dose is very low, probably need to increase it or just back off for a while. I have had trouble in the past with using too much kratom and had some pretty severe withdrawals so I learned my lesson back then and now I pay close attention to how much I use and when to back off. never knew zinc affected nmda receptors, interesting stuff.