Image by Iván Tamás from Pixabay 

Full dose Naltrexone (at 50 mg) was developed as an opiate antagonist: in other words, it blocks opiate receptors so that they cannot be stimulated, and is prescribed for those suffering from opiate or alcohol dependence. Since opiates also stimulate endorphin release, side effects of regular dose naltrexone include blocking the feel-good effects of endorphins, potentially leading to depression, pain, and fatigue.

But during its trials, a curious and opposite effect was found at lower doses. It almost sounds like the mechanism of homeopathy: give the body a tiny push in the direction it’s already going, and its secondary, lasting response to that push will be to swing back in the opposite direction, like a pendulum.

An Effective Immune Modulator

While Low Dose Naltrexone (LDN) is still technically an opiate antagonist, the low doses cause the effects to last for only a short period of time. But because of the body’s inherent feedback mechanisms, the body compensates for this brief endorphin blockade by increasing endorphin production, even after LDN is no longer in the system.  Think of it this way: while the receptors are blocked, the body gets the signal, “we don’t have enough endorphins! Make more!” For the duration of the blockade, the body continues to overproduce… and then once LDN is gone, all those endorphins, in excess of what the body would ordinarily produce, are now available to stimulate the newly vacated receptors.

Why is this a good thing? Endorphins, or “endogenous morphine,” are compounds made from amino acids L-tyrosine and L-methionine. Your body naturally produces them from activities like exercise, eating chocolate, or as a response to pain (as a natural painkiller), to name a few.

But endorphins do more than just make you feel good.

When you’re stressed, the hypothalamus in the brain, your “master endocrine gland,” sets off a cascade of events that eventually leads to the production of endorphins. This sets up a feedback loop: high levels of endorphins, in turn, shut down the stress response, so that it doesn’t continue in excess of the need.

This feedback loop is proportional when endorphins are triggered by the stress response. But LDN appears to “trick” the body into producing more endorphins than it might otherwise, which is helpful when the stress response is chronic. In other words, it modulates, or helps to balance, the immune response, secondary to the stress response.

Autoimmunity and LDN

For this reason, LDN is probably best known as an alternative treatment for autoimmune conditions. Inflammation is not inherently a bad thing. It has an important purpose, to recruit the body’s efforts in order to fix a short-term or acute problem. But if the inflammation produced is insufficient to correct that problem, then the inflammation itself becomes the problem: a hallmark of autoimmunity. 

As part of its immunomodulatory effects, LDN has been shown to reduce inflammatory cytokines. This study shows that it specifically reduces many inflammatory cytokines in fibromyalgia. It has also been used for similar purposes for lupus, modulating the Th1/Th2 balance, as well as for Crohn’s disease, multiple sclerosis and complete regional pain syndrome, among many others.

Since these improvements really have to do with cytokine modulation, that makes me wonder whether it might be indicated for other inflammatory conditions, such as chronic infections or multiple chemical sensitivity. LDN is not immunosuppressive; it works with, rather than against the body to achieve its results.

Hypothyroidism and LDN

Probably because inflammation has a tendency to block conversion of T4 to T3 in cases of inflammation, known as euthyroid sick syndrome, LDN has also been shown to improve T4 to T3 conversion, and to reduce T4 to reverse T3 conversion.

Depression and LDN

When endorphins bind to their receptors, they release the neurotransmitter dopamine, associated with pleasure and reward. Probably for this reason, LDN increases release of dopamine, and thus has been used as an alternative treatment for depression.

Potential Side Effects

By far the most common side effect with LDN is insomnia, since it tends to boost endorphins and thus, dopamine (a stimulating neurotransmitter). I’ve found this side effect goes away for most if it is taken in the morning and not at night, and if dosing starts low and tapers up over a period of weeks.

A small handful of my more sensitive patients have developed abdominal pain from LDN. This is a side effect from the full dose naltrexone, and the low dose should have the opposite effect—but it is something I watch for.

For the most part, studies show and my clinical experience suggests that it is well tolerated.