The Potential of Low-Dose Naltrexone in Treating Depression

March 29, 2023


Naltrexone is an opiate antagonist used since 1984 in treating opiate addiction (preventing euphoric feelings) and alcoholism. During the last few years, Naltrexone used in low doses (Named  Low Dose Naltrexone) earned favor as a novel medication that may be used in depression treatment.

Major Depressive Disorder symptoms:

  1. Duration of two weeks or more.
  2. Depressed mood and lack of interest or pleasure, in addition to at least four of the following symptoms:
  • Significant weight change.
  • Sleeping disorder.
  • Slowed thinking or movement.
  • Feeling tired almost every day.
  • A feeling of worthlessness and guilt.
  • Loss of concentration.
  • Recurrent thoughts of suicide and death

LDN as a Psychiatric Medication:

LDN boosts the release of opioid peptides (endorphins, enkephalins, etc..) which act on mu, kappa, and delta opioid receptors in the body. This indeed makes it relevant to psychiatry as LDN can assist in reducing fatigue and further somatic symptoms, This alone may help the patients in improving their mental health and possibly be less depressed.

One of the main side effects of LDN is that it may cause vivid dreams, which implies that it can alter sleep architecture. Modifying sleep architecture can modify many psychiatric disorders. For illustration, REM sleep (Rapid eye movement sleep) deprivation is a notable strategy for the treatment of a major depressive disorder.

LDN as a Psychiatric Medication

LDN Mechanisms of action in depression:

mu receptors, activated by betaendorphins and enkephalins, are linked to pain modulation, euphoria, and also sedation experienced by opiate users. Activation of these receptors also leads to an elevation in GABA.

Also, kappa receptors are sensitive to dynorphins and endogenous opioids. Kappa receptors’ role is applied to stress-related depression and anxiety. Overactivation of kappa receptors as seen in opioid withdrawal will result in dysphoria, body aches, anxiety, and depression. Therefore Blocking kappa receptors may be beneficial for depression treatment. 

Naltrexone is an FDA-approved opioid (mu and kappa) receptor blocker, Blocking kappa receptors may have a beneficial role in the treatment of depression. Combining LDN with buprenorphine (potent kappa antagonist and partial mu agonist) is being studied as a novel antidepressant combination therapy

LDN stimulates the release of neurotransmitters, they activate delta receptors and activation of these receptors can reduce the symptoms of depression and anxiety. Activation of delta receptors may also increase the production of brain-derived neurotrophic factor (BDNF) its decrease is thought to be linked to depression, bipolar disorder, obsessive-compulsive disorder(OCD), schizophrenia, anorexia nervosa, bulimia, autism spectrum, dementia,  addiction. Various studies have linked depression with brain atrophy, BDNF can not only reduce the development of brain atrophy but also it may repair part of the structural changes occurred in the brain.

LDN has a role as a dopamine enhancer because it has a direct effect on opioid receptors, and beta-endorphins stimulate dopamine release directly. And also indirectly by inhibiting GABA production. Both of these processes will increase positive feelings. This is important as most of the disorders linked with dopamine deficiency are also linked with depression.

Does LDN Cause Depression?

No, LDN theoretically and practically doesn’t cause depression. A published study in 2006 suggests that depression shouldn’t be considered a common side effect of naltrexone treatment or a treatment contraindication and that naltrexone treatment may cause fewer depressive symptoms.

This is because opioid receptors are activated by LDN for a very short duration of time, not long enough for the effect of the blocked endorphin receptors to result in depression. Moreover, the brief duration of opioid-receptor blockage is followed by an increase in endorphins, which causes mood improvement. 

Depression Related to Inflammation

Prolonged Subacute or Chronic inflammation will impact the brain. thus,

Depression that is begun by an inflammatory process is also possible to respond to LDN.

LDN’s anti-inflammatory activity may be promoted by the addition of St. John’s wort, willow bark, omega-3, gingerturmeric, pomegranate, green tea, and pineapple. Modifications such as avoiding processed food and eating vegetables, fruit, and fish; and adhering to a Mediterranean diet can also help reduce inflammation.

Always consult your physician before combining any medication or herbal medicine with LDN. 

Adding LDN to Depression Treatment Regimen

Treating depression with LDN produces incredible results when combined with other antidepressants and the effect of the treatment is shown to be separated from the improvement in the medical conditions that depression frequently accompanies. Although in some cases depression can be treated by LDN alone, most of the cases which are “treatment resistant” needs LDN to be taken in the form of an add-on treatment. 

Even if depression is serotonin-related, LDN can be effective as it’s thought that receptors pretreated with serotonin are more sensitive to dopamine. Some patients who suffer from depression and did not respond to treatment with selective serotonin reuptake inhibitor (SSRI)  will undergo improvement in their condition when LDN is added.

LDN in depression treatment


  • The LDN Book: How a Little-Known Generic Drug — Low Dose Naltrexone — Could Revolutionize Treatment for Autoimmune Diseases, Cancer, Autism, Depression, and More. Book by Linda Elsegood.
  • The LDN Book 3: Low Dose Naltrexone: The Latest Research on: Viral Infections, Long COVID, Mold Toxicity, Longevity, Cancer, Depression, and More. Book by Linda Elsegood.