How Low Dose Naltrexone (LDN) Works

How Low Dose Naltrexone (LDN) Works – Updated 2021 with the latest information

The History, Pharmacology and Mechanism of action of Low Dose Naltrexone (LDN)

Understanding how LDN works requires a grasp of three fundamental biological principles.

First, opiate receptors are present in multiple biological systems in the human body, as they regulate a great number of biological functions via the central release of natural opiates (endorphins/met-enkephalins). (1) (2)

Second, a class of proteins called toll-like receptors (TLRs) are part of the immune system, providing a first line of defense against microbial invasion and possessing the ability to recognize and be activated by not only pathogens but also endogenous signaling molecules. (3)

Lastly, naltrexone, when given at a low dose, has antagonistic activity in both of these areas, and is able to modify biological functions of these receptor groups by suppressing unwanted immune reactions, or by stimulating disease-suppressed immune activity. (4)

Naltrexone, taken at the full dose of 200mg daily, has been licensed for use for the treatment of addictions since 1984. (5) It is currently used for both opiate and alcohol addiction, as a full dose is able to completely block endogenous (endorphins released by the brain) and exogenous (recreational drugs such as heroin) opiates. In the licensed dose, it is used as an oral tablet, a long-acting injection, and as an additive in painkillers to prevent them from being abused. (5)

As have many drugs that have been widely used for an extended period, naltrexone has been found to have different actions when used in lower doses than originally intended. These in part are due to the chiral nature of the molecule and the different, dose-dependent effects of the Levo and Dextro isomers of naltrexone.

The concept of chirality is not new, (chiral chemistry was discovered by Louis Pasteur in 1848), like all drugs when synthesized are produced as a racemic mixture of 50:50 left- and right-handed molecules. (6)  Half of the mixture synthesized is a left-handed shape and the other half is a right-handed shape. Although consisting of the same components, and being chemically identical, they have different shapes (as with left and right hands), enabling the different isomers to interact with different groups of receptors in the body.

In general, most drugs only have biological activity in the human body in Levo (left) handed shape, as this is how most of the receptor groups in the human body are arranged. Common examples of these drugs—such as levothyroxine, levocetirizine, levobutanol—are manufactured as racemic mixtures of 50:50 Levo and Dextro isomers; however, the manufacturer discards the Dextro isomer and presents the medication in the Levo-only form, sometimes because the Dextro isomer carries unwanted side effects, or is not active on the intended target receptor. (7)

In the case of naltrexone, the Levo isomer interacts with the commonly understood opiate (endorphin) receptors group and the Dextro isomer interacts with the toll-like receptor group. (8) (9)

The basic effects of LDN can be summarized as follows:

DEXTRO-Naltrexone

• Blocks (antagonises) some TLR receptors
• Reduces production of pro-inflammatory cytokines
• Suppresses cascade inflammation
• Central and system effects as TLR receptors are present on microglial cells, mast cells, and macrophages

LEVO-Naltrexone

• Blocks opiate receptors for a brief period
• Increases natural production of anti-inflammatory endorphins
• Upregulates opiate receptors
• Has direct effect on some cell proliferation rates

Again, these mechanisms are fully elucidated in both volumes of The LDN Book, but the main point is that LDN is extremely useful in the treatment of many poorly managed autoimmune and oncological conditions.

1.Mørch H, Pedersen BK. Beta-endorphin and the immune system--possible role in autoimmune diseases. Autoimmunity. 1995;21(3):161-71. doi: 10.3109/08916939509008013. PMID: 8822274

2. Zagon IS, McLaughlin PJ. Endogenous Opioids in the Etiology and Treatment of Multiple Sclerosis. In: Zagon IS, McLaughlin PJ, editors. Multiple Sclerosis: Perspectives in Treatment and Pathogenesis [Internet]. Brisbane (AU): Codon Publications; 2017 Nov 27. Chapter 8.

3. El-Zayat, S.R., Sibaii, H. & Mannaa, F.A. Toll-like receptors activation, signaling, and targeting: an overview. Bull Natl Res Cent 43, 187 (2019). https://doi.org/10.1186/s42269-019-0227-2

4. The LDN Book 1. Chelsea Green Publishing.

5. Srivastava AB, Gold MS. Naltrexone: A History and Future Directions. Cerebrum. 2018;2018:cer-13-18. Published 2018 Sep 1.

6. Gal J, Cintas P. Early history of the recognition of molecular biochirality. Top Curr Chem. 2013;333:1-40. doi: 10.1007/128_2012_406. PMID: 23274573.

7. Nguyen LA, He H, Pham-Huy C. Chiral drugs: an overview. Int J Biomed Sci. 2006;2(2):85-100.

8. Cant R, Dalgleish AG, Allen RL. Naltrexone Inhibits IL-6 and TNFα Production in Human Immune Cell Subsets following Stimulation with Ligands for Intracellular Toll-Like Receptors. Front Immunol. 2017 Jul 11;8:809. doi: 10.3389/fimmu.2017.00809. PMID: 28744288; PMCID: PMC5504148.

9. Hutchinson MR, Zhang Y, Brown K, et al. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci. 2008;28(1):20-29. doi:10.1111/j.1460-9568.2008.06321.

 

Stephen Dickson, BSC (hons) MRPharmS - Mechanism of Action of Low Dose Naltrexone (2019 Conference) (LDN, low dose naltrexone)

 

Jill Cottel, MD - Pain Seminar in VA 2019 (LDN 2019 Pain Seminar) (LDN, low dose naltrexone)

 

John Kim, MD - Ultralow Dose Naltrexone: Exploring microgram doses of LDN (LDN, low dose naltrexone)

 

Stephen Dickson, BSC (hons) MRPharmS - Using an Old Drug to Trick the Immune System into Healing Itself (2018 Conference) (LDN, low dose naltrexone)

 

Leonard Weinstock, MD - Low Dose Naltrexone: Mechanism of Action and Clinical Applications (LDN, low dose naltrexone)

 

Stephen Dickson, BSC (hons) MRPharmS - Pharmacokinetics, Pharmacodynamics, Interactions, and Cautions in Common Practice (LDN, low dose naltrexone)

 

Pradeep Chopra, MD - Mechanism of action of low dose naltrexone (2016 Conference) (LDN, low dose naltrexone)

 

Stephen Dickson BSC (hons) MRPharmS - The Pharmacology of LDN (LDN, low dose naltrexone)

 

Dr Sato-Re Presentations: How and why I prescribe LDN in my integrative and general practice. Sponsored by Innovative Compounding Pharmacy https://icpfolsom.com/