The Use of Compounded Low-Dose Naltrexone (LDN)

 

Abstract 1, 2, 3

 

Naltrexone is an opioid non-selective antagonist, possessing both stimulating and inhibiting properties, commonly indicated to treat patients who has an opioid addiction or alcohol use disorder. However, low-dose naltrexone (LDN) has been found to alleviate symptoms severity in various autoimmune conditions, mental disorder, and malignant tumors acting as an immunomodulator. There has been an increasing number of physicians prescribing LDN to treat long COVID conditions (also known as post-COVID) and Hashimoto’s, a thyroid disease. When naltrexone is given at a low dose it modifies the biological functions of these immune system proteins called toll-like receptors (TLR) to suppress unwanted immune reaction or stimulates disease-suppressed immune activity. Toll-like receptors are important mediators of inflammatory pathways in the innate immune system that plays a major role in the responses towards pathogen-derived ligands.

 

Background 4, 5

 

Low-dose naltrexone (LDN) was first introduced by Dr. Bernard Bihari, who discovered the clinical effects of LDN as an adjunct therapy for acquired immune deficiency syndrome (AIDS) in the 1980s. Dr. Bihari noticed that there was a low level of endorphins in patients with weakened immune system. From his research, Dr. Bihari experimented the use LDN at bedtime which increased the production of -endorphins, promoting healing and boosting the body’s immune system as the patient sleeps.

 

A placebo-controlled trial was conducted in patients infected with HIV for roughly 9 months. Resulting in fewer deaths and opportunistic infection in the controlled-group when compared to the placebo-group. Unfortunately, HIV treatment effectiveness was measured to increase CD4+ cells whereas low-dose naltrexone had an opposite effect ultimately ceasing the potential use of LDN in HIV treatment at the time.

 

From Dr. Bihari’s revelation, physicians and patients are recognizing the benefits that arises from low-dose naltrexone. Current clinical studies have found LDN favorable in numerous autoimmune disease such as multiple sclerosis, fibromyalgia, and Crohn’s disease. Due to the absence of large-scale clinical trials and standardized experiments focused on determining appropriate uses for LDN, it continues to be considered as an off-label choice.

 

Introduction  6, 7

 

Naltrexone HCl, an opioid receptor antagonist, typically given orally at minimum daily dosage of 50 mg, requires patients to detox from any opioid drug to combat low adherence and occurrence of relapse. Opioid receptors are widely distributed in nerve cells found throughout the body. The main opioid receptor that naltrexone target is the opioid growth factor receptor (OGFr), which is also expressed on the immune cells indicating possible immunoregulatory roles. Opioid growth factor is an opioid peptide also known as met-enkephalin that acts as an agonist at opioid receptor. OGF-OGFr axis dysregulation is associated with many diseases and malignant tumors. 

 

The pharmacodynamics in low-dose naltrexone (LDN), dose ranging from 1 to 5 mg, have shown to be a therapeutic glial cell modulator. In a clinical trial conducted by Penn State investigators Ian Zagon and his colleagues, LDN strongly blocks OGFr which inhibits the growth of neuroblastoma found in tumors of mice. Studies show evidence that OGF and low-dose naltrexone can promote tumor-cell proliferation and would healing. However, normal dosage of naltrexone has an opposite effect on the tumor, accelerating the growth and somatic cell development. This is where compounded low-dose naltrexone becomes beneficial for treatment and prophylaxis of various disorders.

 

Mechanism of Action of Low-Dose Naltrexone 6, 7, 8, 9

 

LDN Research Trust acknowledges the publication by Dr. Jill Smith, informing readers about the existence of naltrexone’s 50:50 racemic mixture of isomers. That dextro- and levo-naltrexone isomers possess different biological activities observed with LDN. Dextro-naltrexone binds toll-like receptor-4 providing the antagonist effect that leads to the cascade of decreased proinflammation. Whereas levo-naltrexone also provides an antagonistic effect that upregulates of endogenous opioid production and its receptors that precedes a rise in favorable endorphins in the immune system

Mechanism of low-dose naltrexone is still unclear. Dr. Timothy Schwaiger, ND published an article stating that there are several mechanisms of action of LDN that have been reported. Three of which he pointed out as most prominent: 1) increasing -endorphines release from opioid receptors; 2) reduction of pro-inflammatory cytokines and increase anti-inflammatory cytokines; 3) regulation of OGF-OGFr axis. 

 

1. Production of endorphin

 

As discovered by Dr. Bihari, -endorphines binds to opioid receptors that is responsible for the analgesic effects that occurs in the body. Low-dose naltrexone interacts with -endorphin receptors, triggering the body’s production and release of endorphins even after there is no longer LDN found in the system. LDN may induce a temporary blockade of opioid receptors in the brain, potentially resulting in the heightened production of naturally occurring pain-relieving compounds like endorphins and enkephalins. These endogenous opioids have the dual capability to alleviate pain and influence immune system regulation. The increase of endorphins modulates the immune response to reduce the speed of unwanted cell growth.

 

2. Anti-inflammatory activity

 

Glia, commonly referred to a neuroglia cells, are non-neuronal cells found in the central nervous system and peripheral nervous system, where they help support, protect, and modulate the activity of neurons. A role that glia is responsible for is to create and maintain enhanced pain such as neuropathic pain. Proinflammatory cytokines are released when pain is amplified when glia is activated, becoming neurotoxic and causing several deleterious effects. Low-dose naltrexone acts as a glial modulator that binds to toll-like receptor 4 where an antagonist property takes place exerting an attenuated pro-inflammatory response. Reducing inflammation within the body can be favorable in managing autoimmune disease and chronic pain conditions.

 

3. Opioid growth factor regulation 

 

The opioid growth factor receptor axis is biologically expressed in the pathway of regulating cell proliferation of cancerous cells. OGF-OGFr axis dysregulation is associated with a wide range of physical illnesses such as multiple sclerosis, Crohn's disease, diabetes, and cancer, along with various mental disorders. Low-dose naltrexone blocks OGF-OGFr axis creating an upregulation of OGF and OGFr leading to a possible decrease growth in tumors.

 

 

Indications 2, 3, 4,  6, 8

 

As briefly mentioned low-dose naltrexone is currently being used for the treatment in various cancers, autoimmune disease, chronic pain, and mental health issues. LDN is continuously being studied in other possible conditions due to central involvement of neuroimmune axis. 

 

Off-label treatment of LDN has been use :

 

• Autoimmune thyroid disorders

• Cancer

• Chronic fatigue syndrome

• Crohn’s disease

• Fibromyalgia

• Multiple sclerosis

• Myalgia encephalomyelitis

• Long COVID symptoms

 

Safety and Side Effects 2, 6

 

Low-dose naltrexone is generally well-tolerated in most patients. Reported side effects from LDN treatment are mild. If side effects become unbearable, physicians should consider reducing the dose or titrating the dose at the start of LDN treatment.

 

Common side effects:

 

• Sleep disturbances, vivid dreams

• Headache

• Agitation

• Nausea/ GI effects

• Hyperthyroidism in patients diagnosed with Hashimoto’s

 

Uncommon

 

• Flu-like symptoms

• Dizziness

• Increased fatigue or spasticity 

 

Precaution

 

LDN generally complements a wide range of other treatment approaches, as it does not have direct interactions with steroids. However, it's important to note that it may counteract the effectiveness of pain relievers that are opioid based. Therefore, patients should provide their healthcare provider with a comprehensive list of their medication history before beginning LDN therapy. 

 

For individuals who are concurrently using multiple medications or herbal remedies, particularly those dealing with cancer or advanced illnesses, it is advisable to seek guidance from a qualified physician or pharmacist before incorporating LDN into their treatment plan.

 

Conclusion

 

The entirety of both basic and clinical research conducted thus far indicates that low-dose naltrexone holds promise as a treatment method for chronic pain conditions believed to be associated with inflammatory mechanisms. Due to its affordability and minimal risk of side effects, compounded LDN holds promise as a valuable option in the management of diverse conditions. Possibly enhancing the quality of life with the usage of LDN. However, it's important to note that the clinical evidence supporting its application is currently in its early stages, necessitating further investigation before this treatment approach can be confidently endorsed on a broader scale.

​

- Thao Aparicio

 

References:

 

1. Li Z, You Y, Griffin N, Feng J, Shan F. Low-dose naltrexone (LDN): A promising treatment in immune-related diseases and cancer therapy. Int Immunopharmacol. 2018;61:178-184. doi:10.1016/j.intimp.2018.05.020

2. How low dose naltrexone (LDN) works. LDN Research Trust. Accessed September 29, 2023. https://ldnresearchtrust.org/how-low-dose-naltrexone-works. 

3. O'Kelly B, Vidal L, McHugh T, Woo J, Avramovic G, Lambert JS. Safety and efficacy of low dose naltrexone in a long covid cohort; an interventional pre-post study. Brain Behav Immun Health. 2022;24:100485. doi:10.1016/j.bbih.2022.100485

4. Brief discovery of low dose naltrexone. Harbor compounding pharmacy. Accessed September 29, 2023. https://www.harborcompounding.com/brief-discovery-of-low-dose-naltrexone

5. Toljan K, Vrooman B. Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization. Med Sci (Basel). 2018;6(4):82. Published 2018 Sep 21. doi:10.3390/medsci6040082

6. Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014;33(4):451-459. doi:10.1007/s10067-014-2517-2

7. Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses. 2009;72(3):333-337. doi:10.1016/j.mehy.2008.06.048

8. Schwaiger T. The uses of low-dose naltrexone in clinical practice. Natural Medicine Journal. April 20, 2022. Accessed October 2, 2023. https://www.naturalmedicinejournal.com/journal/uses-low-dose-naltrexone-clinical-practice. 

9. Zagon IS, Donahue RN, McLaughlin PJ. Opioid growth factor-opioid growth factor receptor axis is a physiological determinant of cell proliferation in diverse human cancers. Am J Physiol Regul Integr Comp Physiol. 2009;297(4):R1154-R1161. doi:10.1152/ajpregu.00414.2009