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In order to understand how LDN works, it is crucial to briefly introduce the workings of the ‘natural opioid’ (endorphin) system.


Endorphins are opiate-like molecules produced naturally in the body. The term ‘endorphin’ comes from ‘endogenous morphine’, meaning that it is created within the body, and differentiating it from opioids that are administered from external sources.

Endorphins are produced in most cells in the body, and are important regulators of cell growth, and therefore the immune system. Disorders of the immune system can occur with unusually low levels of these endorphins. The particular endorphin that has been found to influence cell growth as well as immunity is called Opioid Growth Factor (OGF) or Met-Enkephalin.

For an endorphin such as OGF to exert its beneficial effects, it must interact with the body’s cells. It does this by binding to a receptor on the surface of the cells. The receptor to which OGF binds is the ‘Opioid Growth Factor Receptor’ (OGFr) – previously known as the Zeta (ζ) receptor.

Thus, for the endorphin system to be fully functional, two elements are required: opioid production and cell interaction.

Naltrexone Stimulates the OGF Receptors Producing Therapeutic Effect

Naltrexone is an externally administered drug that binds to opioid receptors. In doing so, it displaces the endorphins which were previously bound to the receptors. Specifically, by binding to the OGF receptors, it displaces the body’s naturally produced OGF.

As a consequence of this displacement, the affected cells become deficient in OGF and three things happen:

  1. Receptor production is increased, in order to try to capture more OGF.
  2. Receptor sensitivity is increased, also to try to capture more OGF.
  3. Production of OGF is increased, in order to compensate for the perceived shortage of OGF.

Since LDN blocks the OGF receptors only for a few hours before it is naturally excreted, what results is a rebound effect; in which both the production and utilization of OGF is greatly increased. Once the LDN has been metabolized, the elevated endorphins produced as a result of the rebound effect can now interact with the more-sensitive and more-plentiful receptors and assist in regulating cell growth and immunity.

Low Dose Naltrexone (LDN)

The duration of the rebound effect varies from individual to individual, but generally persists for about one day.

The benefits of the rebound effect can only be utilized by taking a low dose of regular Naltrexone. Taking a high dose of Naltrexone or using a timed-release formulation will result in continuous blockade of OGF receptors, and the rebound effect will not serve any useful purpose.

In scientific terminology, the use of regular-dose Naltrexone results in ‘continuous opioid receptor blockade’ whilst the use of LDN results in ‘intermittent opioid receptor blockade’. In order to benefit from the rebound effect and achieve the therapeutic benefit of LDN, it is essential to avoid timed-release (or slow-release) versions of Naltrexone.

Individuals vary in their metabolic speed and this will result in inter-patient variation in the speed at which LDN is eliminated from the body, as well as the length of the rebound effect. Whilst a single daily dose of between 3mg and 5mg will be suitable for most patients, individual modification of dosage or frequency is sometimes needed.

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