Low-Dose Naltrexone: Benefits and Side Effects
Naltrexone is an FDA-approved medication for the treatment of opioid addiction and alcohol dependence  that was developed in 1961 . Naltrexone blocks the action of opioids at three key receptors that regulate a range of bodily functions, including immune function; cell growth and proliferation; and mood and cognition.
Naltrexone was customarily given in doses ranging from 50 to 150 milligrams per day, which is enough to continuously block these receptors. However, in the late 1980s, Dr. Bernard Bihari noted that his patients with AIDS had low endorphin levels. He knew that boosting natural endorphin levels might improve immune function and thought that transiently blocking opioid receptors might elevate endogenous opioids [3,4].
He began prescribing low dose naltrexone (LDN) to his AIDS patients and saw their endogenous opioids increase along with their immune function. Since then, LDN has been prescribed to treat immune system dysregulation, neurotransmitter depletion, and, in some cases, cancer.
AgelessRx, headed by Dr. Sajad Zalzala, is currently recruiting participants for a clinical study of LDN’s effects on the diseases of aging .
Mechanism of action and benefits of low-dose naltrexone
Low-dose naltrexone’s effects are caused by temporary blocking opioid growth factor receptor (OGFr) , Toll-like receptor 4 (TLR4) , and the Mu opioid receptor (MOR). The location of these receptors and their signaling effects explain the use of LDN and its potential as a longevity drug.
OGFr and opioid growth factor (OGF)
OGFr expression is highest in monocytes, microglia, and lymphocyte immune cells. Cells from the reproductive and urinary systems, accessory digestive organs, digestive tract, adrenaline glands, and breast tissue are also high in OGFr, although these tissues express about ten times less OGFr than immune cells do. Certain cells of the nervous system also express significant amounts of OGFr, such as the prefrontal and cerebral cortex, the spinal cord, and the retina .
OGF is normally engulfed by cells in a process called clathrin-mediated endocytosis . Once inside the cell, it attaches to OGFr located on the surface of the cellular nucleus, forming a complex. The OGF-OGFr complex is then guided into the nucleus, where it binds to DNA and stimulates the production of p16INK4a and p21 [10,11].
These two proteins, in turn, slow down cell division. In addition, p16INK4a inhibits the action of NFkB, a central player in initiating the inflammatory response .
When LDN is administered, the transient blockage of the OGFr receptor results in a compensatory upswing in the number of OGFr receptors and OGF. As LDN blockage wears off in the following hours, the effects of OGF and OGFr are amplified. Thus, there is a further decrease in cell growth and proliferation , and the inflammatory response is also decreased . This effect has been shown to improve the regulation of cell growth, promote healing [14, 15], reduce inflammation , modulate immune function , and stimulate autophagy .
LDN’s ability to slow cell growth and proliferation suggest a therapeutic application for the treatment of cancers in tissues where OGFr expression is high. This would include primary cancers of organs such as the bladder, testis, ovaries, breast, lung, lymph nodes, adrenaline glands, and bone . While this is one method by which LDN can affect the development of cancer through OGFr, this is not the only means by which LDN may prevent cancer.
The effect of LDN on cell growth and proliferation in immune cells may provide an explanation for how LDN affects patients with multiple sclerosis. LDN causes a reduction in the proliferation of CD4+ and CD8+ T cells along with B220+ lymphocytes, which are present in the spleens and lymph nodes of multiple sclerosis patients. This effect may also occur in other conditions in which the immune system is overactive . People with autoimmune diseases often have low levels of opioids .
Toll-like receptor 4 (TLR4)
TLR4 is activated by patterns of molecules found on the surface of pathogens. Thus, it is referred to as a pattern recognition receptor. When TLR4 is activated, NFkB, AP1, and IRK3 are also activated as part of the downstream signaling cascade. AP1 functions similarly to NFkB. IRK3 specifically triggers the production and release of interferon 1, which initiates the antiviral response.
In a healthy body, these three signaling molecules help manage the response to infection. Unfortunately, in autoimmune disease, this triad of signaling molecules can become hyperactive, resulting in chronic inflammation.
TLR4 expression is highest in immune cells, including monocytes, microglia, and peripheral blood mononuclear cells. Since TLR4 functions as a pathogen detector, it makes sense that it is most strongly concentrated in the areas of the body that are vulnerable to infectious pathogens. These include the reproductive and urinary system, the liver, and the heart.
The reproductive organs are vulnerable to sexually transmitted diseases. The liver is equally vulnerable, as it continually receives foreign debris from the digestive system and spleen via hepatic portal circulation. The heart cannot afford interference from myocardial injury or pathogen infection, which can occur with surprising ease in individuals with poor oral health and other conditions . Patients with heart failure frequently have elevated levels of TLR4 expression .
LDN transiently blocks TLR4 signaling and, therefore, has the potential to short-circuit the inflammatory and antiviral response in select tissues. However, It does not appear that transient blocking of TLR4 causes a compensatory increase in TLR4 receptors as it does in opioid receptors.
If there were a compensatory increase in TLR4, the effects of LDN on TLR4 signaling would increase inflammation and drive the antiviral response. Instead, it appears that blocking TLR4 reinforces the anti-inflammatory effects of blocking OGFr in the immune system by dampening cytokine production.
In addition, evidence suggests that low-dose naltrexone might improve the viral immune response in individuals with chronic IFN-1 activity . This suggests a role for LDN in the treatment of post-viral syndromes, including Epstein-Barr, chronic fatigue syndrome, and more recently, long COVID. In fact, Dr. Sajad Zalzala is also organizing a study to examine the efficacy of LDN in combination with NAD in the treatment of long COVID.
Taken together, these results suggest that transient blocking of TLR4’s signaling cascade can temporarily reduce the immune response. Therefore, LDN administration could be therapeutic against autoimmune disease, which would be further enhanced in some instances by its effect on OGFr activity.
Microglia, the nervous system’s version of macrophages, are activated when PAMPs bind to TLR4. Overactivation of microglia can lead to inflammation, pain sensitivity, fatigue , sleeplessness , mood disorders, and cognitive problems [25,27]. When microglia are chronically activated, as they are with fibromyalgia and other pain disorders, it results in neurotoxicity. Thus, LDN may improve outcomes in several neurodegenerative diseases.
Mu opioid receptor (MOR)
LDN has a very strong affinity for the Mu opioid receptor (MOR) . Like OGFr, transient MOR blockage results in increased production of opioid receptors and enhanced sensitivity to opioids . MOR receptors are distributed throughout the central and peripheral nervous systems as well as the skin [30-32]. Evidence indicates that the binding of LDN to MOR primarily affects pain perception and dopamine secretion .
LDN and pain management
Opioid receptor blockage causes a compensatory increase in opioid receptors . This increases opioid receptor sensitivity to any concentration of opioids. However, opioid binding to GABAergic brain cells prevents the release of GABA, which, in turn, stops pain signals. Some evidence suggests that LDN does not exert its reported effects on pain reduction in this manner, despite what would appear to be strong theoretical underpinnings .
LDN and dopamine
A similar mechanism would lead to an increase in dopamine secretion. In this case, the prevention of GABA release enhances the release of dopamine, which would logically provide multiple benefits, as the symptoms of low dopamine are well-known. These include chronic pain, anxiety, depression, attention difficulties, low motivation, constipation , weight gain , difficulty swallowing , sleep disorders , fatigue , low libido , and poor mood in general .
Most dopamine is produced in one of two places: the adrenal glands and the hypothalamus. Adrenal dopamine has numerous functions. It is released as part of the fight-or-flight reaction . It relaxes blood vessels at low doses and helps remove excess sodium and urine from the body . It reduces insulin production , protects the GI lining , and reduces lymphocyte activity in the immune system .
Dopamine originating in the hypothalamus is strongly associated with the brain’s reward system. When individuals engage in activities associated with survival, the brain releases dopamine, which induces a sense of pleasure. This provides the motivation to repeat the behavior. This also explains in part how exogenous opiates can lead to addiction .
Therefore, LDN, through its action on MOR, can theoretically reduce pain, anxiety, depression, and attention difficulties, improve motivation, and possibly contribute to better weight control, sleep, libido, and energy. In combination with LDN’s effects through OGFr, LDN may improve conditions like IBS, Crohn’s disease, and other gastrointestinal disorders.
LDN and weight loss
Contrave is an FDA-approved prescription drug that combines 8 milligrams of slowly released naltrexone with a 90-milligram extended-release dose of the antidepressant bupropion. The use of Contrave is limited to obese individuals with a BMI of 30 or greater or individuals with a BMI of 27 or greater who also have high cholesterol or controlled hypertension .
The proposed mechanism of weight loss induction by Contrave suggests that bupropion stimulates secretion of the appetite suppressing hormone called aMSH. However, bupropion also induces the secretion of endogenous opioid products that inhibit aMSH. It is believed that naltrexone circumvents this problem by blocking the inhibitory action of these opioid products on aMSH [49,50].
An 8-milligram extended-release dose of naltrexone would not be considered LDN. Evidence supporting LDN for weight loss is limited; however, there is reason to believe that LDN could support weight loss.
There is evidence that increasing endogenous endorphin levels can improve insulin control . Improvements in insulin control carry numerous benefits, including easier fat loss, decreased disease risk, fewer cravings, better brain health, and improved cognition .
Additionally, chronic inflammation is associated with metabolic syndrome and weight gain. Therefore, the anti-inflammatory effects of LDN could support weight loss . There is limited evidence to support this theory.
LDN may indirectly stimulate increases in fat-burning growth hormone, as insulin is a growth hormone antagonist. Naltrexone has been shown to reduce insulin output in some contexts [54,55]. Finally, LDN may improve sleep, and poor sleep is associated with weight gain .
Wilfrid Noel Raby, PhD, MD, and adjunct clinical professor at Albert Einstein College of Medicine, prescribes very low-dose naltrexone at night to treat insomnia. He explains that abolishing the cortisol surge in the evening reduces sympathetic activity, which contributes to the delay in falling asleep.
LDN is short-acting, causing a “rebound surge of cortisol in the morning that contributes to alertness during the daytime, but there is also improved sleep at night” . It should be noted, however, that LDN has been known to cause sleep disturbances at the onset of prescription; this effect is generally short-lived .
Can LDN increase longevity?
LDN is likely to influence several hallmarks of aging. Aging is known to drive chronic inflammation, a condition known as inflammaging. Rising numbers of senescent cells, the accumulation of advanced glycation end-products, and other age-related changes drive inflammaging. LDN has shown the potential to mitigate inflammaging through multiple routes.
The binding of LDN to OGFr suppresses NFkB, AP1, and IRK3, all of which are inflammatory compounds. Additionally, LDN’s binding to the TLR4 complex short-circuits inflammation and could also potentially block the binding of glycated LDL and other AGEs that drive the destruction of aging tissues through TLR4 .
LDN’s capacity to modestly increase endogenous opioids suggests that it has the potential to reduce stress through the promotion of a greater sense of well-being. Stress has been shown to drive telomere shortening , and it is likely there are other potential mechanisms through which LDN could affect the hallmarks of aging as well.
Low-dose naltrexone side effects
Evidence supports the safety and tolerability of LDN in the treatment of multiple sclerosis, fibromyalgia, and Crohn’s disease. Subjective reports indicate that patients experience reduced pain and improved quality of life. However, studies documenting the objective benefits of LDN in these diseases are limited .
The most reported side effects for LDN are transient sleep disturbance and mild headache . Sleep disturbance, usually in the form of vivid dreams, occurs in about 37% of patients. A small minority also experience nightmares .
Some physicians have anecdotally reported anxiety and tachycardia as adverse reactions to LDN. Reports of this nature are sprinkled across the internet. As anxiety is a known symptom of opioid withdrawal, it is possible that some individuals would experience anxiety due to blockade of endogenous opioids. Interestingly, naltrexone has also been reported as a treatment for orthostatic tachycardia, and endorphins, in general, reduce anxiety [3,63].
Graphical summary of LDN
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