Jabberwocky
Frumious Bandersnatch
Kratom has been shown not to downregulate opioid receptors with long term use like other opioids do. In another study, kratom was shown to reduce both tolerance and withdrawal from morphine in rats when administered together.
www.researchsquare.com
Due to some recent experimentation with NAC, I am forming a hypothesis about kratom tolerance and a method to rapidly reduce it by using NAC within specific time periods after kratom.
Kratom alkaloids contain both mu opioid agonists as well as antagonists. My hypothesis is that kratom tolerance develops due to accumulation of the opioid antagonists, or that chronic dosing somehow leads the mu opioid antagonists to take more action in the brain than usual. Maybe they have a longer half life attached as antagonists vs agonists. I think NAC may reduce tolerance by "washing out" these antagonists or somehow deactivating or removing them from the receptors.
NAC significantly dampens the euphoria from kratom if taken before or at the same time as kratom. It dampens all dopaminergic drugs, such as amphetamines and cocaine.
However, from my experiments this last week or two, I have noticed that if NAC is taken around 3-5 hours AFTER dosing kratom, I notice a VERY SIGNIFICANT drop in tolerance upon my next dose (as long as I wait for the NAC to leave my system). A couple of weeks ago I quickly went through 3g of 75% mit extract (on top of some regular powder), this caused a huge spike in my tolerance levels. After dosing NAC just once or twice, I noticed that 4-6g of kratom was enough to provide a huge effect to the point where I felt my tolerance to the opioid effects had reset almost completely. I was honestly a bit shocked and this was unexpected. I have found a few anecdotal reports on reddit who also have noticed this effect, whereas the majority of the anecdotal posts are in regards to how it dampens kratom if dosed beforehand.
The one drawback to this method is that dosing NAC after kratom will indeed dampen the remainder of the high. This is why I take it about 3-4 hours after dosing kratom, because by the time it takes for the dampening effect (~60 min onset), the kratom high is mostly gone anyways so it's not an issue. Then, you have to wait an amount of time, dependent on NAC dose, before you can take kratom again or else it will be muted.
Taking NAC after dosing kratom also, for me, seemed to induce withdrawal more quickly than without it. It's not like naloxone where it immediately precipitates withdrawal, it simply seems to speed up the time when withdrawal starts to hits you (by about ~25-35% or so). However, for me it is definitely worth feeling mild withdrawal for an hour or two in exchange for a much stronger buzz. Taking one dose of NAC and then waiting 8-10 hours to dose kratom seemed to reduce my tolerance more than if I had taken a full 24-36 hours off kratom without the NAC.
I am still experimenting, but this is what I have noticed so far:
(These dosage/time suggestions are what worked for me. You may need to adjust based on metabolism rates or other facts.
300mg NAC - wait a minimum of 5-6 hours before dosing kratom (optimally 7hr +)
600mg NAC - wait a minimum of 8-9 hours before dosing kratom (optimally 10-12hr +)
1200mg NAC - I'm less sure about this, as it seems to block kratom for minimum of 16-18+ hours, and it becomes less practical for me personally since I have a difficult time waiting that long between doses.
300mg NAC and 600mg NAC seem to produce similar effect as to tolerance reduction, but definitely more noticeable at 600mg. 1200mg is less practical, as seems to dampen for much longer without a noticeable tolerance reduction greater than 600mg
Unfortunately it seems like there is a tolerance itself to this tolerance reduction mechanism. After doing this for ~10 days (taking 300-600mg a few hours after kratom) I am not getting as much of a tolerance reduction as when I first started. This may be due to my body adjusting to it and creating less glutathione. Obviously glutathione production tolerance is just my uneducated hypothesis, and it may be due to different processes.
*Update/Warning* : NAC should be cycled!! This morning I randomly had a paradoxical effect from it. In the morning when withdrawal hit, instead of taking kratom I took 120mg of L-Dopa, because I've heard it can nearly eliminate the RLS from kratom withdrawal, and also can enhance kratom itself. I just wanted to check it out, was curious. When I took the L-Dopa, it did indeed stop my leg RLS and other withdrawal symptoms, however I immediately gained RLS in my arms which was not present before. I am familiar with RLS in arms from kratom withdrawal but it generally occurs later on day 2 or 3 of cold turkey. I took kratom, but it did NOT fix the arm restlessness! It continued for 14+ hours, regardless of taking any kratom. I was not in withdrawal, but had arm RLS.... it wasn't until the NAC dose completely left my system did the RLS stop.
I found this unusual because both NAC and L-Dopa are prescribed for RLS in people. However, it seems that NAC can paradoxically actually induce RLS if taken for long periods or in high doses, which I had been. It wasn't any issue at all for about 12 days, then hit out of nowhere.
I will be updating this thread/experiment, but for now I advise not to take NAC for more than a week for this purpose, and not to dose more than 600-1000mg per day while attempting to attenuate kratom tolerance.
Back to my theory, I believe NAC works like this because it may be "washing out" the antagonists out of your system, so the next dose hits you harder. Whether this is due to glutathione or something else, I do not know.
Anyways, I would be very curious if anyone wants to attempt this themselves and see if there's something to this. Maybe it's just unique to my body. It's definitely NOT placebo, though.
I have also read an anecdotal report that regular cysteine also has this effect.
and a bit about NAC itself:
Some people may find NAC useful with kratom in other ways, because although it does dampen the euphoria, it also eliminates the anxiety from stimulating kratom batches. While it does dampen the opioid head high, it might not dampen the analgesia. I haven't been able to assess this because I am not usually in pain.
NAC (n-acetyl cysteine) is an amazing drug in it's own right. It acts as a precursor to produce glutathione, which is an extremely powerful antioxidant and vital in all areas and processes in your body. NAC protects and heals the liver, kidney, and other organs. It also protects and repairs dopaminergic pathways in the brain, and is very useful in tapering or withdrawal from dopaminergic drugs (and others).
NAC is mildly psychoactive on it's own. It's mildly stimulating at higher doses (1200mg can keep me up at night, but 600mg doesn't), can reduce anxiety (particularly social anxiety), repetitive thoughts, and compulsive behavior. It has shown remarkable efficacy in treating various mental conditions such as OCD, bipolar and even schizophrenia. I highly suspect it may even be able to treat stimulant psychosis (although I probably wouldn't rely on this if you have better options, or a reason not to go seek medical care).
Unlike Morphine, Long-Term Exposure to Analgesic Mitragynine, 7-Hydroxymitragynine, Paynantheine, and Speciociliatine Alkaloids Does Not Contribute to Antinociceptive Tolerance of μ-Opioid Receptors
Background: Opioids are the most well known antinociceptive alkaloids all over the world, but tolerance and physical dependence are their dominant concerns in clinical applications. In contrast, monoterpene alkaloids are newly considered for their roles in pain management....

Due to some recent experimentation with NAC, I am forming a hypothesis about kratom tolerance and a method to rapidly reduce it by using NAC within specific time periods after kratom.
Kratom alkaloids contain both mu opioid agonists as well as antagonists. My hypothesis is that kratom tolerance develops due to accumulation of the opioid antagonists, or that chronic dosing somehow leads the mu opioid antagonists to take more action in the brain than usual. Maybe they have a longer half life attached as antagonists vs agonists. I think NAC may reduce tolerance by "washing out" these antagonists or somehow deactivating or removing them from the receptors.
NAC significantly dampens the euphoria from kratom if taken before or at the same time as kratom. It dampens all dopaminergic drugs, such as amphetamines and cocaine.
However, from my experiments this last week or two, I have noticed that if NAC is taken around 3-5 hours AFTER dosing kratom, I notice a VERY SIGNIFICANT drop in tolerance upon my next dose (as long as I wait for the NAC to leave my system). A couple of weeks ago I quickly went through 3g of 75% mit extract (on top of some regular powder), this caused a huge spike in my tolerance levels. After dosing NAC just once or twice, I noticed that 4-6g of kratom was enough to provide a huge effect to the point where I felt my tolerance to the opioid effects had reset almost completely. I was honestly a bit shocked and this was unexpected. I have found a few anecdotal reports on reddit who also have noticed this effect, whereas the majority of the anecdotal posts are in regards to how it dampens kratom if dosed beforehand.
The one drawback to this method is that dosing NAC after kratom will indeed dampen the remainder of the high. This is why I take it about 3-4 hours after dosing kratom, because by the time it takes for the dampening effect (~60 min onset), the kratom high is mostly gone anyways so it's not an issue. Then, you have to wait an amount of time, dependent on NAC dose, before you can take kratom again or else it will be muted.
Taking NAC after dosing kratom also, for me, seemed to induce withdrawal more quickly than without it. It's not like naloxone where it immediately precipitates withdrawal, it simply seems to speed up the time when withdrawal starts to hits you (by about ~25-35% or so). However, for me it is definitely worth feeling mild withdrawal for an hour or two in exchange for a much stronger buzz. Taking one dose of NAC and then waiting 8-10 hours to dose kratom seemed to reduce my tolerance more than if I had taken a full 24-36 hours off kratom without the NAC.
I am still experimenting, but this is what I have noticed so far:
(These dosage/time suggestions are what worked for me. You may need to adjust based on metabolism rates or other facts.
300mg NAC - wait a minimum of 5-6 hours before dosing kratom (optimally 7hr +)
600mg NAC - wait a minimum of 8-9 hours before dosing kratom (optimally 10-12hr +)
1200mg NAC - I'm less sure about this, as it seems to block kratom for minimum of 16-18+ hours, and it becomes less practical for me personally since I have a difficult time waiting that long between doses.
300mg NAC and 600mg NAC seem to produce similar effect as to tolerance reduction, but definitely more noticeable at 600mg. 1200mg is less practical, as seems to dampen for much longer without a noticeable tolerance reduction greater than 600mg
Unfortunately it seems like there is a tolerance itself to this tolerance reduction mechanism. After doing this for ~10 days (taking 300-600mg a few hours after kratom) I am not getting as much of a tolerance reduction as when I first started. This may be due to my body adjusting to it and creating less glutathione. Obviously glutathione production tolerance is just my uneducated hypothesis, and it may be due to different processes.
*Update/Warning* : NAC should be cycled!! This morning I randomly had a paradoxical effect from it. In the morning when withdrawal hit, instead of taking kratom I took 120mg of L-Dopa, because I've heard it can nearly eliminate the RLS from kratom withdrawal, and also can enhance kratom itself. I just wanted to check it out, was curious. When I took the L-Dopa, it did indeed stop my leg RLS and other withdrawal symptoms, however I immediately gained RLS in my arms which was not present before. I am familiar with RLS in arms from kratom withdrawal but it generally occurs later on day 2 or 3 of cold turkey. I took kratom, but it did NOT fix the arm restlessness! It continued for 14+ hours, regardless of taking any kratom. I was not in withdrawal, but had arm RLS.... it wasn't until the NAC dose completely left my system did the RLS stop.
I found this unusual because both NAC and L-Dopa are prescribed for RLS in people. However, it seems that NAC can paradoxically actually induce RLS if taken for long periods or in high doses, which I had been. It wasn't any issue at all for about 12 days, then hit out of nowhere.
I will be updating this thread/experiment, but for now I advise not to take NAC for more than a week for this purpose, and not to dose more than 600-1000mg per day while attempting to attenuate kratom tolerance.
Back to my theory, I believe NAC works like this because it may be "washing out" the antagonists out of your system, so the next dose hits you harder. Whether this is due to glutathione or something else, I do not know.
Anyways, I would be very curious if anyone wants to attempt this themselves and see if there's something to this. Maybe it's just unique to my body. It's definitely NOT placebo, though.
I have also read an anecdotal report that regular cysteine also has this effect.
and a bit about NAC itself:
Some people may find NAC useful with kratom in other ways, because although it does dampen the euphoria, it also eliminates the anxiety from stimulating kratom batches. While it does dampen the opioid head high, it might not dampen the analgesia. I haven't been able to assess this because I am not usually in pain.
NAC (n-acetyl cysteine) is an amazing drug in it's own right. It acts as a precursor to produce glutathione, which is an extremely powerful antioxidant and vital in all areas and processes in your body. NAC protects and heals the liver, kidney, and other organs. It also protects and repairs dopaminergic pathways in the brain, and is very useful in tapering or withdrawal from dopaminergic drugs (and others).
NAC is mildly psychoactive on it's own. It's mildly stimulating at higher doses (1200mg can keep me up at night, but 600mg doesn't), can reduce anxiety (particularly social anxiety), repetitive thoughts, and compulsive behavior. It has shown remarkable efficacy in treating various mental conditions such as OCD, bipolar and even schizophrenia. I highly suspect it may even be able to treat stimulant psychosis (although I probably wouldn't rely on this if you have better options, or a reason not to go seek medical care).
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