Can Low-Dose Naltrexone Help Patients with Depression?

May 5, 2020

As we learn more about the immune system and its involvement in psychiatric conditions, including depression, LDN is an intriguing tool to keep in mind and for future exploration.

Patients with depressive disorders are constantly seeking information regarding various treatment modalities that might help ameliorate symptomatology and improve their mood. I have heard from my colleagues that one such popular clinical inquiry is the use of low-dose naltrexone (LDN), as based on the plausible hypothesis that depression is associated with central nervous system (CNS) inflammation1 while LDN can decrease inflammatory responses.2,3

As both an addictionologist well familiar with this compound and someone with an immunology background, I have taken a special interest to learn more about LDN and how it applies to the pathophysiology of depressive disorders. I am summarizing my findings here.

Proposed mechanism of action

LDN, as referenced by naltrexone doses between 1 mg and 5 mg daily, binds non-selectively to all opioid receptors antagonistically but extremely transiently.6 Short duration of this receptor-ligand interaction leads to a paradoxical downstream increase in endogenous endorphins and enkephalins. These in turn exert regulatory control on a subset of opioid receptors-the zeta, or opioid growth factor receptors-which are mainly expressed on immune cells. When intermittently activated, they inhibit cell proliferation.4-6

Additionally, LDN was found to block toll-like receptor-4 expressed on immune cells in the CNS which are responsible for triggering inflammatory responses. Blockade leads to a shift from production of pro-inflammatory cytokines to anti-inflammatory cytokines.4,6

What the literature says

There is only one randomized-controlled trial that examined augmentative treatment of depression with LDN. A total of 12 patients with depression who had relapsed despite receiving treatment with dopaminergic antidepressants were included. They received add-on 1 mg LDN for three weeks.7 Researchers found improvements in HAMD scores from the severe to the moderate range. The thought process here was not directly related to reduction in inflammation, but rather to an indirect increase in dopamine through the increase in endorphins.

The bottom line

LDN is an intriguing tool to keep in mind and for future exploration as we are learning more and more about the immune system and its involvement in psychiatric conditions, including depression. More robust studies are needed however, and based on existing data, there is not enough for a conclusion to be drawn. There are no studies exploring the use of LDN as monotherapy for depression, let alone in place of currently approved, evidence-based, modalities. LDN does appear to have some benefit in patients who have inflammatory conditions and fibromyalgia, and it is fairly well tolerated. It is imperative for us clinicians to be able to discuss the state of this literature with our patients who may inquire about LDN.


Dr Stanciu is Addiction Section Editor for Psychiatric Times. He is Assistant Professor of Psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH.