It's been a long, winding road to get here.
We'll consider this a little side adventure from our usual destination of CBD effects across health.
With good reason.
The trip (from hell) began with a nearly debilitating perimenopause (that story is here).
Multiple doctors, dozens of medications (benzos and SSRI's included), 100's of labs, and in the end...we had to crawl our way out.
We have tried almost everything out there.
Two left-over symptoms...intense heel pain and jolts in the middle of the night.
- Dozens (maybe over 100??) of supplements, medications, balms, etc? Yes.
Fisher Wallace brain stimulators? Check
- Sensate Vagal nerve vibrator? Sure
- Rapid Release (that's actually not bad) for heel pain? You bet
- Nerve conductance tests (basically mini-cattle prods). Reluctantly but yes.
Acupuncture, chiro, PT, medications, all of it.
After all the nonsense from the past 2 years, there were two resulting issues.
- Jolting away in the middle of the night
- Screaming heel pain
Of all things, metformin helped with the first (see the full review here).
The second was far stickier.
Back to the drawing board.
Across studies on regional complex pain syndromes and chronic pain, I came across Naltrexone.
Low dose naltrexone specifically.
At higher doses, it is used for alcohol dependency but a brilliant researcher discovered that it had it quite different properties at much lower doses.
Fascinating properties really with a strong safety profile.
So deep dive we go!
Other sites will gloss over how things are working but we want to understand to make sure it's actually based on research and doesn't do more harm than good.
After all, just like the CBD that started it all, we're using it ourselves!
Here are the topics we'll cover:
- A quick introduction to low dose naltrexone
- How does low dose naltrexone work
- Low dose naltrexone and the immune system
- Low dose naltrexone and the opioid system
- Low dose naltrexone and pain
- Low dose naltrexone and autoimmune
- Low dose naltrexone and fibromyalgia
- Low dose naltrexone and anxiety or other mood issues
- Low dose naltrexone and weight
- Low dose naltrexone and the gut bacteria
- Low dose naltrexone and cancer
- Low dose naltrexone safety and side effects
- Low dose naltrexone for perimenopause
- Low dose naltrexone and CBD
Lots of cover...let's get started!
A quick introduction to low dose naltrexone
First, it's big brother...Naltrexone (basically, full dose).
Made in 1963, full-dose naltrexone has a fascinating history that you can read here.
It's a great explanation of what's wrong with our healthcare system where drugs can survive the marketplace based on their ability to profit almost solely.
It wasn't until 1980 that the use of low dose naltrexone was recognized for its different effects in the body.
- Full dose naltrexone for opioid and alcohol addiction is generally around 50 mg's.
- Low dose naltrexone usually runs around 1/10th that amount at around 5 mg's.
There's a great timeline of subsequent trials and discoveries here:
At full doses, naltrexone exerts most of its effect on the opioid system, our naturally occurring pain (and more!!) system.
It essentially blocks the "high" or "pleasure" feeling derived from alcohol or opioids.
THC has also been added to this list.
Naltrexone is neither habit-forming or does it present withdrawals.
First, the opioid system is so much more than just pain and pleasure. We'll get into that below.
More importantly, at the lower doses (5 mg's approximate), naltrexone has powerful effects on the immune system.
People...this is the root of most of our modern medical ills.
Just watch a daytime TV show and check out the commercials.
Most likely they're for autoimmune disease.
This is right in the wheelhouse of where low dose naltrexone operates and we'll look at that in-depth below.
Unfortunately, the autoimmune tent just keeps growing in breadth and numbers including issues you might not expect:
- Dementia and Alzheimer's
- Anxiety and Depression
We've covered the latter at our CBD and neuroinflammation for anxiety article but all new research is pointing to a new field of immunopsychiatry.
The immune system is incredibly powerful and maybe the linchpin to many different illnesses and even aging itself (which we'll touch on this below).
Most sites focus on the opioid piece since that's better established from the addiction prevention angle of full strength naltrexone.
What you'll see below is that the low dose naltrexone's effect on immune response (which the full strength doesn't exhibit) may be the real star of the show...especially in our modern world!
So...the big question that we're curious about...how does naltrexone really work?
How does low dose naltrexone work
Researchers are now teasing out multiple pathways but some are very visible and powerful.
- Low dose naltrexone boosts and rebalances opioid system functioning (different from just increasing opioid levels)
- Low dose naltrexone calms immune response, especially for a specific pathway call TLR4
The first is very different from the effects of high dose naltrexone (opposite really):
Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade.
That's a mouthful but we'll break it down below.
Basically, by blocking the opioid system temporarily, it allows it to reset and function better afterward.
As a result of these pathways, low dose actually operates differently from full strength levels:
At the low dosage level, naltrexone exhibits paradoxical properties, including analgesia and anti-inflammatory actions, which have not been reported at larger dosages.
Analgesia just means pain reduction.
Keep in mind that inflammation is under control of our immune system so that makes sense once we unravel its effect there.
Again, this is the most exciting aspect of LDN (as it's called) from our perspective.
Don't underestimate the participation of the immune system in pain sensitivity as well:
The focus is an examination of how activation of immune-like glial cells within the spinal cord can amplify pain by modulating the excitability of spinal neurons.
Ah...glia cells. Our nervous system's immune responders.
They're coming into focus across a range of mental health issues from schizophrenia to anxiety and depression.
We'll get into that as well.
Okay...periscope down...let's really get into it.
We'll start with the obvious and end up in the immune system (a briar patch of complexity but soooo cool).
Low dose naltrexone and the opioid system
This is our obvious starting point since it's where naltrexone itself started.
Low dose naltrexone is different.
We have to first introduce our crazy pain system pathway.
The opioid system.
You have 4 different opioid receptors plus one more wildcard which acts very differently:
- Delta opioid receptor (DOR)
- Kappa opioid receptor (KOR)
- Mu opioid receptor (MOR)
- Nociceptin receptor (NOR)
- Zeta opioid receptor (ZOR)
We think of the opioid system strictly in terms of pain/pleasure due to its sordid association with the drug and the carnage driven by its abuse.
That's just a small (albeit focused) effect of the system.
At the intersection of pain and pleasure, you have almost every human drive, behavior, and function!
There's a great run through how our brain (really evolution) uses pain and pleasure as constraints for almost everything we do.
We can get lost in the complexity of the opioid system but let's look at a few pathways directly tied to low dose naltrexone before we head to the main event...the immune system.
Low dose naltrexone temporarily blocks the mu and kappa opioid receptors primarily.
There are two net effects in terms of neurotransmitters from this action.
It frees up GABA, our brain's "brake" (see CBD and GABA for anxiety) and it blocks dopamine activity.
And you thought they were just for pain!
Dopamine is the "do it again" neurotransmitter which is part of our reward circuit and indeed...addiction.
Now we know that dopamine is involved in pain as well:
For example, the more a person rated the pain as causing emotional distress and fear, the more dopamine was released in the area known as the nucleus accumbens - the same region implicated in drug addiction.
Here's where it gets interesting.
Researchers used a pretty sophisticated study to show that the temporary block of the opioid receptors (from low dose naltrexone) actually leads to a rebound increase in natural opioid processing (both levels and receptor).
Their findings which we'll decipher after:
LDN causes a compensatory increase in an endogenous opioid, the opioid growth factor (OGF, [Met5]-enkephalin), and the OGF receptor (OGFr).
Don't be worried...natural endorphins work very differently than their external cousins:
But in the most intriguing twist, the research team discovered that morphine and synthetic opioids activate receptors in yet another internal location called the Golgi apparatus, where endogenous opioids are unable to produce any activation at all.
Back to OGF...
OGF is fascinating. It's that little known zeta receptor we talked about. We'll really look at it in the LDN and cancer section but there are some interesting clues.
The net result of this temporary block:
a general opioid receptor antagonist devoid of intrinsic activity results in an elevation in endogenous opioids and opioid receptors in response to the opioid receptor blockade.
A reset of our naturally occurring opioid processing system!
It's known that opioids (taken externally) can actually cause more pain sensitivity by skewing this entire system.
Basically, the body responds by creating more pain receptors to get the signal through again and afterward, makes less of our naturally occurring pain opioids called endorphins.
This is at the heart of normalization...our brain's opposite adjustment to a drug.
Low dose naltrexone was shown to blunt this effect from morphine:
Cotreatment with ultra-low-dose NTX (ca. 1-100 pg/kg) blocks this opioid-induced hyperalgesia and unmasks potent opioid analgesia.
Hyperalgesia just means heightened feelings of pain.
Again...resetting the natural opioid system by basically giving it a rest.
It's like a good 8 hours period of sleep for your opioid system.
Otherwise, how could blocking our pain-relieving system actually lead to more pain relief long term?
We see this in many health issues.
Type 2 Diabetes is really about reducing sensitivity in insulin receptors from being bombarded by sugar all the time.
Back to our opioid system.
Both the mu and kappa opioid systems have powerful effects on pain sensitivity.
Kappa then adds a layer of other intriguing pathways:
- anticonvulsant effects
- dissociative/hallucinogenic effects
Um...did you catch some of those? Nothing to do with pain.
Stress. Neuroprotection. Depression??
There's a reason that depression tends to walk side by side with chronic pain and the opioid system may be critical to this connection:
However, chronic pain patients with comorbid depression are more likely to develop opioid abuse than non-depressed patients, which is correlated with higher opioid doses and longer duration of use.
We're leading up to the powerful effects of the immune system, inflammation, and low dose naltrexone so let's look at the stress and neuroprotection effects in particular since those drive inflammation.
Yes, exhaustion of our opioid system can result from physical injury but chronic stress and trauma are processed about the same as physical pain.
Another interesting study looked at chronic pain and either stimulating or blocking KOR activity.
The results were fascinating and match what we've described below in terms of an oversubscribed opioid response:
The conditioned place preference was restored in rats with chronic pain when KORs were blocked by an antagonist, suggesting that KORs antagonists restore blunted reward-related processing in chronic pain.
This is a very sophisticated experiment with different setups to really pinpoint what was happening.
By the way, low dose naltrexone is a KOR antagonist (blocks activity).
The most interesting piece is that they specifically looked at the dopamine angle (the weird interaction with both pain and pleasure from above).
suggesting that chronic neuropathic pain causes a sex-dependent increase in KOR expression and function.
This specific effect only showed in males although the restoration of opioid function was for both sexes.
Remember that KOR activity is also key to stress response and neuroinflammation.
Inflammation….that may be the trigger for this overuse and powerful clues abound.
For example, remember the OGF pathways above?
Dysregulation of the OGF-OGFr pathway is apparent in a number of human disorders including diabetes, multiple sclerosis, and cancer, and thus opioid antagonist disruption of interaction prevails as a therapeutic intervention.
Wait a minute...MS is an inflammatory (autoimmune) disease and both diabetes and cancer have inflammatory pathways (to say the least).
Goodness...the opioid system is intimately linked with our immune system.
Both are ridiculously complicated and now we have to tease out how they interrelate?
We'll stick to the main points.
We'll really dive into KOR and dynorphin below for mental health and mood disorders.
Next stop...the star of the show for LDN...inflammation response and the immune system.
Low dose naltrexone and the immune system
We're going to focus on these main points:
- Lose dose naltrexone and microglia
- Low dose naltrexone and TLR4 (toll-like receptor 4)
- Low dose naltrexone and IL4, IL6, and cytokines
Before you give up and punch the screen, stay with us….we'll decipher along the way but there's a huge payoff.
First, some very top-level description of those three things.
Microglia are the immune system's cop on the beat in the brain.
They look for and respond to foreign entities in our brain and nervous system.
Hyperactivation is now tied to a range of issues from schizophrenia and autism to...chronic pain and autoimmune!
Inflammation in a cut of your skin is one thing. Inflammation in your nervous system is quite another issue.
Again, check our CBD and microglia article to really understand the impacts.
TLR4 is a specific flavor of immune agents that responds to bacteria. Gram-negative bacteria to be specified which makes up most of the bad bacteria our body is trying to protect us from.
TLR4 reacts to any sign of these bacteria with an inflammatory response including various cytokines.
Speaking of which.
IL4 and IL10.
IL4 is a pro-inflammation cytokine. IL10 is an anti-inflammatory cytokine.
There are many others but these two are integral to our study of LDN and the immune system.
So...now that we know some of the key players (of many), let's get into it.
What does LDN do with these closely-related pieces?
First, microglia (also called glia or glial cells).
In contrast to normal states, with chronic pain, microglia come into play:
While glia has little-to-no role in pain under basal conditions, pain is amplified when glia become activated, inducing the release of proinflammatory products, especially proinflammatory cytokines.
We could almost stop there….all the elements are at play.
It's fascinating to us why evolution has the immune system involved in pain pathways at all.
Perhaps 40,000 years ago, if you got a cut on the arm, the immune system would respond (for the infection) and pain is a "co-conspirator" to alert you to the issue.
Pain is not only one result from microglia activation:
Once activated, microglia produce inflammatory and excitatory factors that can cause sickness behaviors such as pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise
Read that back over...you'll looking at the immediate future of mental health.
Anyway...what does LDN do for microglia hyperactivation?
Both naloxone and naltrexone have been demonstrated to exert neuroprotective and analgesic effects . The neuroprotective action appears to result when microglia activation in the brain and spinal cord is inhibited
Interestingly, researchers used dextro-naltrexone to show that these anti-inflammatory and neuroprotective effects were not from the opioid system:
Therefore, the analgesic, anti-inflammatory, and neuroprotective effects of naltrexone do not appear to be dependent on opioid receptors we discussed above.
Pointing to the futility of using opioids for pain, it has been shown that they directly increase glia activity which sets up a nasty feedback and partially speaks to the increasing pain sensitivity following wear-off:
These downstream effects of glial activation amplify pain, suppress acute opioid analgesia, contribute to the apparent loss of opioid analgesia upon repeated opioid administration (tolerance), and contribute to the development of opioid dependence.
Basically, our immune system partially governs (but always well) or pain system.
This activation can also occur in the body as well as the central nervous system.
This speaks to complex regional pain syndromes and other chronic pain issues specific to bodily areas:
Here, immune- and trauma-induced alterations in peripheral nerve function lead to the release of substances within the spinal cord that triggers the activation of glia.
Think of a feedback loop where the pain system is stuck as if the injury is still there.
So what triggers the microglia to go on high alert?
Next up Toll-Like Receptor 4 and low dose naltrexone
You're about to be a rocket scientist...ahead of most of your doctors.
TLR4 is a fascinating member of our immune response.
It's primarily on the lookout for LPS which is a signature chemical trail for bacteria.
Upon detection, it triggers the microglia above to release a slew of inflammatory agents (our body's weaponry really).
We share this basic armory with house flies and even plants!
It's estimated at about 500,000 million years old so evolution clearly likes (needs) it.
It appears that TL4 may be a key piece that gets "stuck" in the pain loop.
The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI).
TL4 activation keeps the pain party going.
So what about low dose naltrexone...is it a TL4 "antagonist" (reduces activity)?
Additionally, (+)-naltrexone, (+)-naloxone, and (-)-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion.
The words to focus on there was "complete reversal". Sure, suppresses neuropathic pain is the end goal but it's nice to know how we're getting there.
That's maintaining the pain circuit...what about initiating it?
Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously but also for maintaining established neuropathic pain.
Then there's a study that showed LDN's effect on super-oxides...a very potent type of oxidative stress tied to inflammation and pain:
Strong evidence is provided indicating that NOX2 is a non-opioid novel binding site for naloxone, which is critical in mediating its inhibitory effect on microglia overactivation and superoxide production.
Naloxone is a related chemical to naltrexone (which is more bioavailable in humans).
This is an entirely different pathway than either the opioid or microglia one.
As for TL4, the net takeaway is this:
Procedures blocking TLR functionality have shown pronounced effects on pain behavior otherwise observed in models of chronic inflammation and nerve injury
We're going to see how TLR activity is key to LDN's effect on many pathways below.
Just a teaser:
LDN can act as an immunomodulator in multiple autoimmune diseases and malignant tumors as well as alleviate the symptoms of some mental disorders.
"Immunomodulator" may be the most important word in health these days.
Also, check out our review of metformin which has similar effects:
Metformin attenuates the TLR4 inflammatory pathway in skeletal muscle of diabetic rats.
The fascinating piece is how full strength naltrexone is completely opposite from low dose naltrexone (blocks TL4 activity):
In the same cells, the mu-opioid receptor (MOR) antagonist Naltrexone increases TLR4 levels, thus suggesting a role of the endogenous opioid system in TLR4 regulation.
The key takeaway is that our opioid system governs our immune response! And vice-versa!
Next up, cytokines such as IL4 and IL 6 with low dose naltrexone
If TL4 is the sentry and microglia is the headquarters of our immune system, cytokines are the actual weapons.
They're released to kill foreign entities. They also tend to kill anything else around (collateral damage) so there's a delicate balance that is needed.
Some are inflammatory (kill) while others are anti-inflammatory (call off the dogs).
What does LDN do in this cage match of trained killers/healers?
A great study on fibromyalgia went to great lengths to find out.
Get ready to have your eyes gloss over:
We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF).
It's a who's who of the cytokine world which can roughly be summarized as a "wet blanket" on the inflammatory pathway.
Think of it as a reduction in defcon alert level of our immune system.
This inflammatory response is directly tied to chronic pain and a host of issues.
Let's start to dig deeper into those specific effects now.
We'll start with our (lease) favorite….pain.
Low dose naltrexone and chronic or nerve pain
We went through some primary pathways affected by LDN above.
Needless to say, they all affect pain.
- Opioid system - direct control of pain
- Immune system - direct control of inflammatory pain
- Redox system - oxidation and pain
Let's focus on chronic and nerve pain with low dose naltrexone.
After all, that's what I personally needed it for (not to be selfish but chronic pain is the most prevalent health issues in the US).
The most intriguing aspect is the "reset" of the pain system when it's become desensitized to chronic pain signals which can last way past any original injury.
This is at the heart of complex regional pain syndromes and fibromyalgia.
First, let's look at the pain system directly and LDN.
It's the "temporary" block of the opioid system that LDN causes (as opposed to chronic) which has a positive resetting effect.
The results from this on our own powerful pain responders:
The upregulation of the endogenous opioid system is evident in experimental models by rising levels of endorphin and met-enkephalin, also known as an opioid growth factor, with concomitant respectively increased μ-opioid, δ-opioid, and ζ-opioid receptor expression, the latter also termed opioid growth factor receptor
Endogenous just mean our own internal system...not from outside.
Goodness...the entire complex gets a reboot!
Chronic pain may be just like chronic sugar.
One eventually decreases signaling and sensitivity for pain relievers (which see as a result of external opioid use) while the other decreases sensitivity for insulin.
This is very common across the body and brain.
For example, when a person smokes cannabis chronically, the brain responds by reducing CB1 signaling and even receptors.
That's bad since CB1 is where Anandamide (the bliss molecule) operates.
The key takeaway is that LDN appears to reset this reaction:
Cotreatment with ultra-low-dose NTX (ca. 1-100 pg/kg) blocks this opioid-induced hyperalgesia and unmasks potent opioid analgesia.
For LDN and nerve pain, we need to also look at the immune system.
Remember what happens when microglia are over-excited?
When chronically activated, the resulting proinflammatory cascade may become neurotoxic, causing several deleterious effects
Neurotoxic. Death to nerves!
The first step is to stop the onslaught which LDN has been shown to do:
A novel glial cell inhibitor, low dose naltrexone, reduces pain and depression and improves function in chronic pain: A CHOIR study
You saw the depression also included as a bonus.
Also, on the repair side, check out CBD and BDNF and neurotrophins.
It's critical to also repair and/or regrow nerves after we bring down the immune response.
Finally, inflammatory pain.
The microglia are culprits in this mix but oxidation and cytokines are doing the dirty work.
One study found that the greater the inflammatory markers in fibromyalgia, the more that LDN helped with pain:
In our study, individuals with greater ESR at baseline experienced a greater drop in pain when taking LDN, despite the fact that FM is not considered to be a classic inflammatory disorder, and ESR values were in the normal to the high-normal range.
Let's look at a pain-related subject.
Low dose Naltrexone and autoimmune
Turn on a TV (not Netflix….yet) and you'll likely see an ad for autoimmune diseases.
Watch the happy lady flying a kite while the voice in the background runs through a litany of horror-movie caliber potential side effects.
Autoimmune is THE disease of our modern world.
Some of these medications run $1000's of dollars per month and they're prescribed for psoriasis!!
Not kidding…$4-5K/month is not unheard of.
Really, until this is addressed, our healthcare system is cooked no matter how you pay for it.
What about LDN at about $50/month?
The primary study (outside of pain) has been on a host of autoimmune diseases.
Remember its role:
Within a specific dosage window, LDN can act as an immunomodulator in multiple autoimmune diseases and malignant tumors as well as alleviate the symptoms of some mental disorders.
"Immunomodulator" is worth billions of dollars in today's world.
Hence the silence?
A quick recap of autoimmune issues.
Essentially, it's when your body's immune system becomes overactive and starts to attack our own tissue.
Hmmmm….sound like the microglia hyperactivity above?
To dig deeper...it probably starts in the gut and the lining or barrier of the gut.
When bacteria can get through this barrier due to breaks in the lining from chemicals, pesticides, preservatives, chronic stress, age, etc….the immune system eventually finds them floating around the body and attacks!
It's called Serum LPS.
Wait a minute...LPS is the signal that sends TLR4 above into tizzy which sets the whole thing in motion!
So let's start in the gut...autoimmune diseases of the gut specifically.
What does LDN do for the gut barrier for people with IBS or Crohn's disease?:
Low dose Naltrexone induced clinical improvement in 74.5%, and remission in 25.5% of patients. Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers.
What about the mucous that makes up most of the barrier?
Inflamed mucosa from IBD patients showed high ER stress levels, which was reduced in patients treated with LDN.
Ummm….there goes a few billion.
In staying with the topic, for shits and giggles, go check out the side effects of Humira, a popular autoimmune medication here:
- Sunken eyes?
- Pink growth?
See how our healthcare system is cooked?
As we mentioned above, our immune system is incredibly complicated, interconnected, and widespread.
We'll look at the side effects of low dose naltrexone below (it will be brief).
Let's look at some of the most prevalent autoimmune diseases.
Low dose naltrexone and rheumatoid arthritis
First, we'll start with why the big pharma companies don't really want to research this:
Persistent LDN users had significantly reduced DDDs of NSAID and opioids, and a lower proportion of users of DMARDs
It's sad that we have to look at how LDN reduces the need for competing medications since the trials require lots of money and big Pharma clearly doesn't want to rock their profitable apple cart.
We'll have to focus on these clues across different studies.
That's for patients with rheumatoid arthritis.
- DDD is a daily dose of other meds
- DMARD is disease-modifying antirheumatic drugs
That's the billion-dollar part.
Keep in mind that 30% of IBD patients get no relief from the standard autoimmune medications.
Another study gave further detail by drug class:
Of the 256 patients who became persistent LDN users, there were reductions in the number of users for [i] all examined drugs [–12%], [ii] intestinal anti-inflammatory agents [–17%], [iii] other immunosuppressants [–29%], [iv] intestinal corticosteroids [–32%] and [v] aminosalicylates [–17%]. In subgroups of identified CD and UC patients, there were significant reductions in the number of users of intestinal corticosteroids [CD: –44%, UC: –53%] and systemic corticosteroids [UC: –24%].
God bless the Norwegians for providing these clues since Big Pharma can't afford to run trials!
Low dose naltrexone and Multiple Sclerosis
Some early, smaller studies on LDN and MS:
LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05).
If you want the abbreviated summary:
LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.
Remember how LDN suppressed TLR4 activity?
This plays a role in MS as well:
Baseline expression of the interleukin-1 receptor-associated kinase 3 (IRAK3), a negative regulator of TLR4 signaling primarily expressed in monocytes, was found to be significantly decreased in IFNβ responders compared with nonresponders.
Basically, there's a reduction in another chemical that keeps TLR4 in check.
You can think of those wandering bacteria getting to the nervous system. Add Dementia, Parkinson's and a host of mental health issues to that category.
Also, remember how LDN calms down the cytokine circus..the little assassins of our immune system?
That's important for MS:
These chemicals, called cytokines, drive the inflammation in the brain, attracting more immune cells, and causing the debilitating disease marked by loss of neurological function.
Autoimmune may have many different flavors (depending on what immune system attacks...islet cells (Diabetes), skin (psoriasis), joints (arthritis), nerve sheaths (MS), etc but the central process has similar ingredients:
- Overactive microglia
- Increased inflammatory state via cytokines
- Overactive TLR activity
All of these are in LDN's wheelhouse so we look forward to trials and studies.
We won't be surprised by the results...just how long it takes to get there while people suffer.
Check out CBD and autoimmune here.
Low dose naltrexone and fibromyalgia
This may be one of the most interesting uses of LDN since fibromyalgia is so intransigent with other treatments.
The disease has elements of inflammation (immune system) but other pathways as well.
That study above on the reduction across cytokines was actually for patients with fibromyalgia.
The net effect of this calming response:
We also found a 15% reduction in FM-associated pain and an 18% reduction in overall symptoms.
Research is starting to point general systemic inflammation of the nervous system.
In fact, many of the symptoms of fibromyalgia resemble cytokine sickness:
The hypothesis is indirectly and partially supported by the high degree of symptomatic overlap between fibromyalgia and cytokine-induced sickness behaviors.
You also see this in people undergoing cancer treatment.
Chemo and radiation's net effect is a tremendous increase in oxidation and inflammation to kill cells after all.
So...do we have studies on LDN and fibromyalgia?
Low-dose naltrexone reduced fibromyalgia symptoms in the entire cohort, with a greater than 30% reduction of symptoms over placebo. In addition, laboratory visits showed that mechanical and heat pain thresholds were improved by the drug.
The higher the initial inflammatory state, the more the relief.
Another double-blind study:
When contrasting the condition endpoints, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039)
We look forward to further studies. Also, see CBD and perimenopause pain since fibromyalgia primarily hits women and more so as they enter this period of hormone flux.
We wouldn't be surprised if the people who don't respond directly to LDN for fibromyalgia won't see results from hormone balancing. Really check out the estradiol review.
Low dose naltrexone for anxiety and mental health
We're not surprised.
After studying every aspect of CBD and anxiety, the effects of inflammation, microglia, gut bacteria, and more are the usual suspects.
This really is the future for many mental health issues.
People...this is crazy talk!!! SO exciting.
Don't get us started on hyperactive microglia!
So...let's look at LDN and common mental health issues.
We'll focus on:
- LDN and Anxiety
- LDN and Depression
- LDN and schizophrenia
- LDN and OCD
- LDN and Autism
Obviously, we're leaving plenty out but immune system response and inflammation have roles to play across almost every issue.
Low dose naltrexone and anxiety
We now know the pathways that LDN effects from above so let's start there as we wait for researchers to catch up.
We'll start with microglia and immune response.
Neuroinflammation is written all over anxiety in the brain:
The results show that 12 weeks of chronic mild stress-induced remarkable depressive- and anxiety-like behavior, simultaneously causing hippocampal microglial activation detected by PET, immunofluorescence staining, and western blotting
We've covered this in our CBD and neuroinflammation article.
We're fascinating with the response to stress.
Why does one person develop anxiety while another one doesn't from the same stress level?
Psychosocial stress is capable of causing immune dysregulation and increased neuroinflammatory signaling by repeated activation of the neuroendocrine and autonomic systems that may contribute to the development of anxiety and depression
Depression shares a similar pathway.
Let's drill down a bit to areas we know LDN affects.
Remember toll receptor 4 which LDN directly calms down:
Toll-like receptor-4 regulates anxiety-like behavior and DARPP-32 phosphorylation.
Hyper or hypoactivity there is not good.
Then there are the resulting cytokines which LDN moderates:
However, the production capacity of several cytokines was positively associated with the severity of depressive and in particular anxiety symptoms, even while taking lifestyle and health factors into account.
As for the opioid system and anxiety, is there a connection?
Remember that LDN primarily affects the Kappa Opioid Receptor which listed depression and anxiety directly as pathways above.
This is really fascinating and requires a full article since social stress and rejection can skew this whole pathway!
The effects of low dose naltrexone and social anxiety are probably what we're most curious about since that system is highly impacted by social rejection. See CBD and social anxiety here.
As for KOR and anxiety:
A cellular mechanism has been discovered by which kappa opioid receptors (KORs) drive anxiety. These proteins inhibit the release of the neurotransmitter glutamate in a part of the brain that regulates emotion.
Glutamate is the "gas pedal" in the brain and nervous system which opposes GABA.
GABA is the primary target of benzo's (see CBD versus benzo's) which immediately brings down anxiety (albeit with nasty side effects from dopamine interaction).
This is just a sampling...like we said, there's a full article lurking in that corner.
Notice how depression keeps trying to steal the limelight from anxiety in the studies above?
Low dose naltrexone and depression
Depression might even be more relevant for degradation at the hands of overactive immune response and opioid dysregulation.
Outside of serotonin function (see CBD for serotonin), you can think of depression as a brain retrenching.
Connections being destroyed or not repaired.
What's doing the damage?
- Hormone loss (see estradiol or pregnenolone)
- Lifestyle issues (see CBD, exercise, and mindful meditation for neurogenesis)
- Pesticides (see pregnenolone)
- Chronic stress (see CBD and inflammation)
- Trauma (see CBD and PTSD)
- Gut issues (see CBD and probiotics)
What's not doing the repair?
Like we said...we've covered the yin and yang of this for a while now.
LDN and microglia for depression
To put a point to it:
Although several hypotheses have been proposed for the microglial role in the onset of depression, it is clear that all molecular pathways to depression are linked through microglia-associated neuroinflammation and hippocampal degeneration.
That article then goes on to describe how brain repair (see CBD and neurotrophins) and gut bacteria have key roles in this inflammatory pathway.
Inflammatory cytokines have been written all over depression for quite some time now:
Episodes of depression have been characterized by an increase in levels of various markers of inflammation, centrally and peripherally
The TLR4 connection is really interesting:
Tlr4 upregulation in the brain accompanies depression- and anxiety-like behaviors induced by a high-cholesterol diet.
For example, SSRI's (the most common medication for depression) primarily boost serotonin.
Serotonin function during infection (or inflammation) is really fascinating.
Upon detection of infection (TLR4 response to bacteria), the brain starves itself and the body of tryptophan.
Serotonin is made from tryptophan!
That's why low energy and mood typically accompany the flu.
The brain does this to start bacteria and viruses of their primary building blocks...tryptophan.
Pretty cool, huh. Check out CBD and tryptophan for serotonin.
The problem is that the immune system is a one-trick pony (albeit with many different bells and whistles) and responds to chronic stress, trauma, and other social stresses much the same way as infection!
You just partially unraveled the connection between chronic stress and anxiety or depression.
Check out CBD versus SSRI for serotonin to learn more about that.
So...our immune system controls the master switch to our feel-good neurotransmitter.
Then, there's the KOR pathway in our opioid system which LDN helps to restore.
Its role is front and center with depression...even severe depression.
The development of KOR antagonists as potential antidepressants are mainly driven  by their antidepressant-like effects in vivo studies.
Antagonist just means that chemical blocks activity.
There are clinical trials right now for LDN and depression or anxiety.
We won't be surprised by the results.
LDN and schizophrenia
Newer research is pointing to immune hyperactivity and schizophrenia.
Researchers have known that early interaction with infection (in utero for example) is a risk for developing schizophrenia (and other mental health issues) later in life.
This work has already yielded several intriguing findings, including associations between schizophrenia and two in utero infections--rubella and respiratory infection.
The theory is that a heightened immune response to infection by the mother's system primes the baby's immune response which overacts during critical periods of brain development.
This has knock-on effects:
The current theory postulates microglial dysfunction initiated by early CNS viral exposure results in the abnormal neural development and neurotransmitter dysfunction seen in schizophrenia.
At the heart of this are the microglia of course.
Microglia not only control immune response but also govern synaptic pruning during critical periods of brain remodeling:
Recent work by Howes and colleagues found that in the earliest stages of schizophrenia, people experience a surge in the number and activity of immune cells in the brain. As well as fighting infection, these cells, called microglia, have a “gardening” role, pruning unwanted connections between neurons. But in schizophrenia patients, the pruning appears to become more aggressive, leading to vital connections being lost.
Schizophrenia commonly occurs later in puberty during such a period of remodeling.
Did you catch that…"More aggressive" microglia.
LDN calms microglia response.
As a side note, check out the ridiculous effects that CBD has on schizophrenia (once established).
It may be the first clue for us way back when we started studying CBD as to its potential.
Scientist are also finding the KOR pathway may be involved for symptoms of schizophrenia:
Yet another promising therapeutic application of KOR antagonism suggested by the preclinical research is the treatment of impairment in reward-related function as frequently occurs in patients with mood and anxiety spectrum disorders but may occur in those with other types of conditions such as schizophrenia.
Again...KOR antagonism. LDN does this.
Also, a common symptom for schizophrenia…
Low dose naltrexone and dissociation and hallucinations.
That's right in the wheelhouse of the KOR pathway.
In fact, those are side effects of drugs that boost KOR activity:
However, KOR agonists also produce side effects such as dysphoria, hallucinations, and dissociation, which has limited their clinical usefulness
LDN goes the other way! It's an antagonist in the terminology of researchers.
Just check out the side effects of other KOR boosters:
As an agonist of the KOR, levallorphan can produce severe mental reactions at sufficient doses including hallucinations, dissociation, and other psychotomimetic effects, dysphoria, anxiety, confusion, dizziness, disorientation, derealization, feelings of drunkenness, delusions, paranoia, and bizarre, unusual, or disturbing dreams.
Holy crap! That's a laundry list of schizophrenia symptoms.
We can't wait till they tease out the relationship between hyperactive microglia and KOR function.
A new study shows that schizophrenia, bipolar, and autism all share a similar trait in the immune system.
All three conditions show an activation of genes in star-shaped brain cells called astrocytes, and the suppression of genes that function at synapses, the junctions between neurons. The autism brains also show a unique increase in the expression of genes specific to immune cells called microglia.
And the effect of naloxone, a related opioid antagonist like LDN?
The cell functions of astrocytes in an inflammatory state were virtually restored to their normal non-inflammatory state and it could be of clinical significance and may be useful for the treatment of long-term pain.
Low dose naltrexone and OCD
First, let's introduce PANDA.
Not the cute animal on loan from China but the sudden onset of OCD in children as a result of strep throat infection.
Yes, that's a thing.
It's also a clue.
Immune system over-activity!
And you thought microglia were just immune responders. Shame on you!
Synaptic pruning by microglia is necessary for the formation of brain circuitry and normal connectivity. Disruption of neuron-microglia interactions, through disruption of the fractalkine/fractalkine receptor signaling pathway, results in a range of neural and behavioral abnormalities.
And one of those abnormalities?
For example, in animal studies, researchers knocked out a microglia gene called HOX8.
An early study reported that knockout of the Hoxb8 gene produces compulsive grooming, progressing to hair removal and ultimately to skin lesions.
Another range of research pinpointed a similar immune response in Tourette's syndrome in that article.
New research is pointing to a loss of neuroprotection rather than neuroinflammation.
Another study looked at the KOR pathway and OCD or compulsive behavior equivalents in animal studies.
Kappa-opioid receptor stimulation quickens pathogenesis of compulsive checking in the quinpirole sensitization model of obsessive-compulsive disorder (OCD)
It appears to be KOR's interaction with dopamine.
Check out CBD and OCD here to learn about that pathway.
LDN and Autism
We keep seeing "synaptic pruning" come up with mental health issues such as schizophrenia, OCD, Bipolar, and more above.
This is incredibly relevant for autism.
First, the causes of autism are varied and complicated but we'll focus on the pathways affected by LDN since they are very much in play.
Like schizophrenia, the maternal infection can increase the risk of autism for children.
This speaks to an overactive immune response and that leads to...microglia.
So...what does research show there?
Growing evidence for the presence of inflammation in the fetal brain includes microglial activation and proliferation in addition to the presence of increased pro-inflammatory cytokines.
This is in response to bacteria and viral signatures which researchers have shown can move from the mother to the fetus in animal studies.
Here's where microglia's role in "brain architecture" becomes critical:
Therefore, in addition to the inflammatory role of microglia implicated in dysfunctional microglial activation and pathogenesis of ASD,26) dysfunction in such microglia-mediated synaptic pruning process during the neural development in the offspring has been associated with neurodevelopmental disorders, such as ASD
Synaptic pruning...determining which neurons to keep and which ones to get rid of.
It's critical to a well-integrated and balanced brain function.
A side note...look at rapamycin to help with this pruning processed (called autophagy). More detail here:
The KOR pathway is also in play.
It's known that exposure to various chemicals, pesticides, and pollutants can increase risk.
New research is focusing on the role of resulting nitrous oxide NO and autism as a result.
Guess where it has this interaction?
Given the antagonistic actions of the MOR and KOR, dysregulation of MOR may leave the heightened dynorphin/KOR system unchecked, possibly inducing a negative emotional state that is characteristic of ASD.
What about trials for LDN and autism?
One double-blind experiment found that LDN would help a subset of children with autism:
The best clinical responders exhibited the clearest normalization of the elevated plasma chemistries, especially in C-terminal-beta-endorphin and serotonin.
Endorphins are actors in the opioid system and serotonin is a master neurotransmitter (see CBD and serotonin here).
We look forward to further research of course.
As we mentioned above...a crazy study just showed that one injection of allopregnanolone during pregnancy could offset autism (which was tied to lower levels). Hence the tie with preemies.
Low dose naltrexone and weight
We'll skip over the obvious effects of inflammation on appetite and weight.
Let's just summarize that inflammation = weight and appetite gain!
For various reasons.
Let's drill down into specific pathways that LDN uses which can affect weight.
As we saw in our review of metformin, insulin resistance is key to obesity and weight gain.
Basically, the mechanism in the brain that tells us we're full stops responding because it's stripped out.
Think of a screw where it's stripped. You can turn all you want but the screw won't budge.
Too much sugar chronically will eventually cause a resulting downregulation of insulin receptivity.
Treatment with naltrexone in hyperandrogenic patients resulted in a decrease in fasting insulin concentrations of 40% and C-peptide concentrations of 50%.
A 40% reduction in insulin!
They pointed to elevated opioid signaling as the cause of the initial insulin insensitivity.
Another study found that as insulin went down from naltrexone, growth hormone went up!
A negative correlation was found between basal insulin and GH peak values, both before (r = -0.641, P = 0.027) and after NTX (r = -0.714, P = 0.013).
This is the holy grail of the new longevity study with metformin and growth hormone which actually REVERSED epigenetic aging.
Metformin also reduces insulin.
The growth hormone decreases as we get older and this loss is directly tied to weight gain.
Then, there's an appetite.
Remember that naltrexone has its origin as an agent against addiction.
Addiction requires the opioid system!
Addiction to food may be our most prevalent one judging by obesity levels and it's only growing.
We would expect the opioid system to be at the heart of overeating.
What does naltrexone do there?
Subjects ate significantly less of both foods after 50 mg naltrexone than in either the placebo condition or on the initial (familiarisation) day.
When used for alcohol, THC, or opioid dependency, naltrexone reduces the craving and more importantly, the "pleasure" of the hit or drink.
Naltrexone also reduced the rated pleasantness of both foods and reduced overall eating rate.
This is very exciting as obesity drives almost every other issue above.
Check out CBD and perimenopause weight (search above).
You can't talk about weight without looking at the gut bacteria and LDN.
Low dose naltrexone and the gut bacteria
All-new research points to the microbiome, the sea of gut bacteria which direct a host of different pathways.
What about LDN and gut bacteria?
First, remember how effective LDN was for IBD, an autoimmune disease of the gut!
Almost 80% clinical improvement.
A big part of this:
Naltrexone improved wound healing and reduced ER stress induced by Tunicamycin, lipopolysaccharide or bacteria in epithelial barriers.
Did you catch that...damage from "bacteria".
That's a critical key to its effect on autoimmune diseases.
In fact, some of the really bad bacteria require opioid receptor activity to thrive:
Furthermore, morphine may be involved in the development of bacterial infections, induced by Streptococcus pneumonia, Toxoplasma gondii, Klebsiella pneumonia, Candida albicans, and other bacterial strains. Interestingly, these infections promoted by morphine were shown to be dependent on MOR
That's a who's who of bacteria you DO NOT want in your gut.
In fact, naltrexone was shown to block the process of sepsis (bacteria internal infection) from morphine which is so dangerous:
Moreover, the application of naltrexone blocked the effect of morphine, indicating that opioid receptors are involved in sepsis development.
The interaction of gut bacteria and LDN requires much more research but it's most powerful effects are on IBD (Irritable Bowel Disease) which literally operates in the gut.
Finally, maybe the most interesting aspect of LDN.
Low dose naltrexone and cancer
How on earth would low dose naltrexone affect cancer?
This unintended consequence of LDN quickly gained attention:
Researchers discovered that not only does LDN cause cancer cells to stop growing, it also alters their internal machinery, making them more likely to kill themselves.
How is it doing this?
Realize that we get "cancer" all the time.
Our body has an entire system to detect faulty genes/cells and destroy them before they get out of hand.
It's called autophagy.
Guess what system governs this process (with help from the endocannabinoid system).
The Immune and Opioid system in cahoots!!
Thus, it stimulates the hypothalamus to increase the production of endorphins . Evidence suggests that endorphins upon binding to the cancer cells trigger apoptosis along with stimulating natural killer cells and helper T cells (TH).
Let's break that down because it's too cool.
Endorphins are actors in our opioid system. When they attach to cancer cells, they tell it to kill itself while bringing in back-up from the immune system (T cells).
It's beautiful really!!
All that immunotherapy cancer treatment in the news is essentially trying to recreate this wheel.
Not to knock those advances but LDN directly boosts this process.
And remember the OGF effect above (we won't be angry if you don't...it's a few 1000 words ago).
Moreover, evidence suggests that OGF and OGFr play a significant role in regulating cell growth
Don't forget TL4!
Finally, LDN blocks toll-like receptor 4 (TLR-4) signaling to the glial cells thus decreasing their activation. In turn, inactive glial cells cannot activate pro-inflammatory cytokines resulting in decreased neuro-inflammation
The medical community is finally looking at LDN as an adjunct treatment due to its safety.
There's an argument for using both LDN and metformin prophylactically to reset cancer detection and destruction systems as we get older.
Speaking of safety…
Low dose naltrexone safety and side effects
LDN has been around for a long time.
From the studies above.
First, the study on MS:
The drug was well-tolerated, and a statistically significant decrease in spasticity was noticed (secondary outcome).
Long term studies also reflect this:
The mean duration of disease was 14 years, and the mean use of LDN as therapy was three years. Such a period without adverse effects or directly causing disease exacerbation corroborates the safety of LDN when applied for MS.
And the effect on other parameters in labs:
Additionally, as determined per available historical laboratory test, LDN use in relapsing-remitting MS does not alter any standard liver, kidney, or blood parameters.
Stanford Medical's take on it for fibromyalgia:
LDN is a widely available, inexpensive medication with few side effects that could prove to be a useful treatment for fibromyalgia.
It's hard to separate out LDN from full strength naltrexone which does have side-effects although moderate and well-tolerated.
Those are here:
As for LDN:
In the Stanford studies, side effects were reported as rare, mild, and transient.
Keep in mind that LDN would probably interfere with opioids since it's actually used to wean off of those.
We would expect it to counter the opioid's effect.
Work with your doctor on that one.
LDN is also interesting for THC, alcohol, food, and other addictions by the sheer nature of its effect in resetting the opioid system which would be blunted by such addictions.
The one side effect I had was a bit of insomnia which went away after a while.
One note...you can use CBD at night and take LDN in the morning.
The CBD should help with the sleep issue until it goes away.
Next up...my favorite territory.
Low dose naltrexone for perimenopause
First, perimenopause is a time of hormone flux and although these systems are all interconnected, we don't have research there yet.
That being said, the flux of hormones is incredibly stressful to your body and brain.
Stress, after all, just means anything that pushes systems one way or another.
Estradiol is pushing both ways during perimenopause!
We saw from the cancer section how endorphins are increased with LDN and endorphins are key stress responders in the body.
To put a point to it:
In the broadest sense, β-endorphin is primarily utilized in the body to reduce stress and maintain homeostasis.
The most important word there is "homeostasis" which means balance.
This is critical during perimenopause.
That's not all they do...
The secretion of endorphins also induces feelings of euphoria, controls appetite and plays a role in the careful balance of sex hormones as well as immunity.
Like we said...it's all inter-related!
Speaking of which.
Low dose naltrexone and CBD
After 1000's of hours studying the various effects of CBD in the body, this was bound to happen.
LDN and CBD, aside from too many letters, maybe partners in crime towards good health.
We'll leave some of the heavy lifting to our other articles but CBD has complementary effects across LDN's pathways:
This really speaks to the endocannabinoid system which is intimately involved in balancing other key systems:
- Immune system - cytokines, microglia, TL4, etc
- Endocrine system - hormones
- Nervous system - neurotransmitters like serotonin and endorphins
In fact, CBD was shown to increase LDN's effect of lessening pain:
Ultra-low dose naltrexone enhances cannabinoid-induced antinociception.
This section really requires a full article as the two affect many different pathways.
As we mentioned before, insomnia can be a side effect of LDN temporarily.
CBD is a great companion on this front (see CBD and sleep here).
LDN is best in the morning and CBD can be taken before bed.
Why on earth would we spend countless hours on LDN if our main focus is CBD?
Because our main focus is on reducing suffering.
Whatever works towards that end deserves equal time.
The same is true for our review of Siberian Rhubarb for perimenopause here.
We've suffered personally from a brutal perimenopause so we know how helpless that can be.
Be well. Be informed. Be empowered!
Always work with a doctor or naturopath with any supplement!
The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.