Ultra low dose naltrexone (ULDN)

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For a few months now I've been experimenting with microdoses of naltrexone, an opioid receptor antagonist

I'd like to unpack some of the benefits I've noticed and the most likely mechanisms through which it works
Naltrexone works through two primary mechanisms

1. antagonizing (inhibiting) the opioid receptors, most potently the mu opioid receptors which are responsible for the euphoria and pain relief from opiates and endorphins
2. inhibiting inflammation in the brain by blocking TLR4 receptors, TLR4 is involved in pain sensing and may play a role in mental issue like depression and brain fog, it's also upregulated during long term opiate addiction or chronic stress
Naltrexone has a secondary effect inhibiting the kappa opioid receptors, which mediate many aspects of trauma and negative conditions through their dysphoric effects when activated by dynorphin, which could be considered the "anti-endorphin" though it still produces analgesia
High doses of naltrexone either injected or taken orally are you super vent relapse in opiate and alcohol addiction because of their ability to inhibit the drugs' reward response

However, low doses, especially microdoses, have been found to produce very different effects
Most naltrexone pills on the market are dosed at 50mg, in comparison a microdose starts as low as 0.5 micrograms, aka 0.0005 milligrams

Doses are typically started as low as possible and titrated up over time
Everyone has an optimal dosage range, while lower or higher doses outside the range produce less beneficial effects

For individuals currently dependent on opiates, doses are typically limited to 20 micrograms max as anything higher may start to induce withdrawal
For individuals who haven't used opiates, dosages can stills start low but can range higher, often up to the 0.1-1 milligram range

Low dose naltrexone, as opposed to ULDN, is another dose protocol that uses the 1-4.5 milligram range, taken before bed to avoid side effects
The current theory as to how ULDN produces benefit is by causing a "rebound" effect, where endorphins are increased in response to a small % of the opioid receptors being blocked, ideally below the threshold of noticeable effect
TLR4 inhibition almost certainly plays a role as well by reducing inflammation

Pairing ULDN with opiates has also been shown to reduce changes in transcription associated with tolerance, likely by binding to a site called filamin A which regulates opioid receptor downregulation
An experimental opioid called PTI-609 is currently under development that also binds to filamin A, and in rodent studies so far it has been hailed as the first non-addictive opioid which does not produce tolerance, time will tell if this holds true in humans as well
Interestingly, microdoses of morphine were found to actually enhance pain signalling before the discovery of ULDN, suggesting that this paradoxical effect may be inherent to anything that activates or inhibits the opioid receptors
Now briefly I want to touch on my experience with ULDN:

I started using ULDN when I was still actively dependent on opiates and found something like a 10-20% increase in analgesia with reduced buildup of tolerance, it also noticeably relieved withdrawal making it easier to taper
I found that very low doses in the 1-5mcg per day range seemed to work best for me and produce the most noticeable effect without blocking the action of opioids

I've since been able to push the dose higher but I've still stayed below 20mcg as I still have sensitivity to it
The biggest benefit I've noticed personally has been the increase in endorphins and reducing in hypersensitivity to pain after long term opiate use

I find that I'm in a better mood waking up in the morning, and lifting weight feels more rewarding as well
ULDN and LDN have been suggested to treat IBS, multiple sclerosis, celiac disease, various autoimmune conditions, autism, chronic pain, and even HIV/AIDS

Obviously do your own research, as this is an off-label use and therefore not approved for any of these conditions explicitly
I hope you all found this thread interesting and insightful

Here's a link to a YouTube channel the shares a number of lectures about LDN for those interested:

I'll post a few of my favorite research papers on the subject below as well

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