~ Low dose naltrexone is effective for some people with autoimmune diseases, pain syndromes, and chronic fatigue syndrome.
~ LDN modulates the immune response in a couple of different ways, including blocking TLR4 activation and impacting ion channels on natural killer cells.
~ Genetics plays a role in response to naltrexone by the mu opioid receptor, and genetic polymorphisms also impact the metabolism of naltrexone.
Low Dose Naltrexone:
Low dose naltrexone (LDN) is an off-label use of the opioid antagonist naltrexone.
Naltrexone is a competitive antagonist at the μ-opioid receptor (MOR). This means that it binds to the opioid receptor, blocks other opioids from the receptor, but also doesn’t activate the receptor. Naltrexone in higher doses (e.g., 50mg) treats alcohol and opioid drug addiction.
Low dose naltrexone is now used for several types of autoimmune diseases (MS, Crohn’s disease) and pain syndromes such as fibromyalgia.
Initially, in the 1980s, low dose naltrexone was prescribed in the 1.5-3mg range for AIDS patients. Currently, LDN doses can be 1-5mg or even lower – in the 1 mcg range.[ref]
LDN works in a different way compared to higher doses of naltrexone. The levels at which higher doses block the opioid receptor are different than the LDN levels, which act on differen
|Dose Range||Dose Specific Mechanism of Action||Clinical Use|
|Opioid receptor antagonism||Alcohol and opioid drug addiction|
|Toll-like receptor 4 (TLR4) antagonism, opioid growth factor antagonism||Fibromyalgia, multiple sclerosis, Crohn’s disease, cancer, Hailey-Hailey disease, complex-regional pain syndrome|
|Very low-dose (1mcg–1 mg)||Possibly same as low dose||Add-on to methadone detoxification taper|
How does LDN impact Inflammation?
One way that LDN is thought to work is by inhibiting TLR4 (toll-like receptor 4). It is also thought to inhibit the proliferation of T and B cells.[ref]
TLR4 is a receptor that recognizes lipopolysaccharide (LPS) on the surface of gram-negative bacteria. In addition, TLR4 binds to certain molecules produced as a result of tissue injury. TLR4 is expressed on the cell surface of endothelial cells (lining of blood vessels), cardiac myocytes (heart muscle), and cells in the central nervous system. When TLR4 is activated by bacterial LPS or by molecules from injured cells, it triggers a cascade of events that causes the cell to produce inflammatory cytokines.[ref]
LDN is thought to block the activation of TLR4, thus reducing the release of inflammatory cytokines such as TNF-alpha, IL-6, and IL-12.[ref]
LDN is one of the few TLR4 antagonists that can cross the blood-brain barrier.[ref] An animal study of multiple sclerosis found that naltrexone prevents the learning and memory issues associated with neuroinflammation. This study also found that in rats, naltrexone also blocks TLR2 activation in addition to blocking TLR4 activation.[ref]
Mechanism of action of LDN in ME/CFS:
A recent study looked at one way that low dose naltrexone may work for people with chronic fatigue syndrome. Calcium ions are essential in intracellular signaling, including for immune cells such as natural killer cells.
A 2016 study identified variants in the TRPM3 gene as impacting the relative risk of ME/CFS. The TRPM3 gene encodes a calcium channel on natural killer (NK) cells, and in people with ME/CFS, there was a loss of the TRPM3 channel in NK cells. One hypothesis now is that ME/CFS is caused, or partly caused, by impaired TRPM3 ion channels.[ref]
Naltrexone acts on the mu opioid receptors. Researchers have found that TRPM3 channels are strongly inhibited by peripheral mu opioid receptor activation.[ref] This may be the connection as to why LDN helps some people with ME/CFS.[ref –open access, worth reading]
LDN for MS:
Clinical trials of LDN in relapsing-remitting multiple sclerosis show conflicting results.
- One placebo-controlled trial of 4.5 mg LDN nightly showed statistically significant improvements in mental health and pain scales.[ref]
- However, another placebo-controlled trial, though, showed no statistical difference between LDN and placebo in MS patients.[ref]
In a review of six trials of LDN in MS, four out of six had positive results.[ref]
LDN for pain:
At low doses, naltrexone has a pain-relieving effect. (At high doses, naltrexone blocks the opioid receptor and doesn’t stop pain.)
Several clinical trials have evaluated low dose naltrexone for pain management in complex regional pain syndrome and fibromyalgia. Many trials showed positive results. For example, a study using 4.5 mg LDN for fibromyalgia showed a 30% reduction in symptoms compared to baseline.[ref]
LDN for chronic fatigue syndrome (ME/CFS):
A number of case studies of LDN for ME/CFS show that it can bring recovery to some people. The case studies show that finding the right dose takes time and experimentation. The optimal dose and schedule was different for everyone. The cases presented all started with very low doses, and they worked with a doctor to slowly increase the dose and then choose the right amount.[ref]
LDN and Long Covid:
An initial safety study in Long Covid patients showed that LDN improved energy levels, sleep, concentration, and daily living.[ref]
LDN interacts with and blocks TLR-4, thereby modulating the inflammatory response. Thus, researchers have theorized it may help with COVID-19 and Long Covid symptoms.[ref] This may be especially true for persistent, low-level SARS-CoV-2 infections.
A recent study also showed that the same TRMP3 ion channel impairment was also found in patients with Long Covid. Similar to ME/CFS patients, the TRPM3 dysfunction in natural killer cells also existed in Long Covid patients but not in healthy controls.[ref]
Safety and Side Effects:
Full doses of naltrexone (50-100mg) are considered safe. However, some report behavioral changes as side effects. There is no increased risk of serious adverse events with naltrexone compared with a placebo, according to a Cochrane analysis.[ref]
Clinical trials of LDN also show that it is safe, but side effects such as vivid dreams and insomnia have been noted when people start taking LDN at bedtime.[ref]
Of course, talk to your doctor before starting LDN or any medication. There may be individual cases where it is not well tolerated.
The rate at which a drug is broken down (metabolized) affects how long it stays in your system.
Naltrexone is primarily metabolized by AKR1C4 (ald0-keto reductase 1C4). Genetic variants in AKR1C4 can cause a 5-fold reduction in enzyme activity. Recent research shows that these variants affect the metabolism of naltrexone.[ref]
In addition, AKR1C4 is also involved in the biotransformation of testosterone. At certain levels, testosterone has been shown to inhibit the metabolism of naltrexone.[ref] This may be something to keep in mind for women or men on testosterone therapy, as well as a difference in naltrexone dosing between men and women.
Naltrexone Genotype Report:
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Note: Genetic studies directly looking at low dose naltrexone are lacking. The variants below have been studied in response to naltrexone at higher doses.
Talk with your doctor if you have questions on whether LDN is right for you.
OPRM1 gene: encodes the mu-opioid receptor, linked to alcohol cravings and substance abuse
Check your genetic data for rs1799971 Asn40Asp A118G (23andMe v4, v5; AncestryDNA):
- A/A: typical
- A/G: more responsive to naltrexone for reducing drinking; reduced opioid receptors; increased pain
- G/G: more responsive to naltrexone for reducing drinking[ref][ref][ref][ref]; reduced opioid receptors; Increased pain or fear of pain[ref]; On average, a higher opioid dose is needed for pain[ref][ref]; Less likely to have a response to placebo for pain[ref]
Members: Your genotype for rs1799971 is —.
TRPM3 gene: calcium ion channel that impacts function in natural killer cells, implicated in ME/CFS
Check your genetic data from rs6560200 (23andMe v4):
- C/C: (common genotype) higher risk of CFS/ME[ref][ref]; Naltrexone may act to restore impaired TRPM3 ion channel activity[ref]
- C/T: typical risk
- T/T: typical risk
Members: Your genotype for rs6560200 is —.
Check your genetic data for rs1891301 (AncestryDNA):
- T/T: higher risk of CFS/ME[ref][ref]; Naltrexone may act to restore impaired TRPM3 ion channel activity[ref]
- C/T: typical risk
- C/C: typical risk
Members: Your genotype for rs1891301 is —.
AKR1C4 gene: encodes the enzyme that metabolizes naltrexone
Check your genetic data for rs3829125 (23andMe v4):
- C/C: typical
- C/G: reduced function, reduced breakdown of naltrexone
- G/G: reduced function, reduced breakdown of naltrexone[ref][ref]
Members: Your genotype for rs3829125 is —.
Lifehacks: LDN metabolism, sources, and natural alternatives
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