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Action of Low Dose Naltrexone

The benefits and drawbacks of any drug development come from the fact that drugs are almost never 100% selective. Exogenous medications which alter human physiological processes often result in different effects when given at higher versus lower doses. The mechanisms of action that we will discuss today do not apply to naltrexone at conventional doses of 50mg to 300mg. These immunomodulary effects discussed here have been studied for LDN in doses between 0.1mg to 5mg.

LDN is very interesting because its pharmacological targets arise from its two different isomers: L-isomer (Levo-naltrexone) and R-isomer (Dextro-naltrexone).

Levo-naltrexone isomers bind to endorphin receptors and act as potent but transient reversible competitive antagonists. In this mechanism, LDN works to temporarily trick our immune system into thinking it is deficient in endorphin, and in response, will upregulate or stimulate our immune system to:

  1. Produce more endogenous endorphins and enkephalins
  2. Promote release of dopamine in the CNS, and
  3. Reduce pro-inflammatory cytokines

Dr. Bihari discovered that LDN was shown to increase endorphin production by 3 to 4 times and increase enkephalin levels by 12 to 15 times! Let’s break down the functions of these stimuli:

  • Support healing
  • Hinder cell growth
  • Slow down inflammation
  • Normalize immune response
  • Produce feeling of happiness, sense of well-being and contentment
  • Decrease pain sensation
  • Reduce stress
  • Modulate appetite

The other LDN isomer, Dextro-naltrexone, works by binding to several subtypes of immune cells called Toll Like Receptors (TLR4 and TLR9) and act as a potent antagonist or receptor blockers. These Toll-Like Receptors (TLRs) are found on macrophages (aka killer cells) called microglia cells in the central nervous system. When microglia cells are activated, they produce the pathways to inflammation and excitatory factors which can lead to neurotoxicity, neuropathic pain, opioid tolerance, downregulation of GABA receptors, and activation of oncogenes. Hence, by LDN blocking TLR4 and TLR9, the opposite effects are seen:

  • Neuroprotection
  • Controlled pain states
  • Downregulation of oncogenes by inhibiting growth and direct apoptosis (cancer cell death)
  • Increased sensitization to chemotherapy, thereby, enhancing cancer treatment
  • Promotion of DNA synthesis
  • Repair mucosal tissues