The microglia surround and protect the neurons in our brains and spinal cord. As the main immune defenders in the brain, they spew out an array of inflammatory and neurotoxic substances when activated. When we have a cold these substances cause the symptoms associated with ‘sickness behavior’ such as fatigue, pain, and mental fogginess.

alarm clocks

It’s all speculation at this point, but cellular stress factors called alarmins could be tweaking hypersensitive microglia in FM and ME/CFS

Some researchers speculate that stress, infections, repeated insults and/or  genetic factors can prime the microglia to over-respond to substances called alarmins generated by cellular stress. They believe that this microglial hypersensitivity is causing neuroinflammation in many diseases.

A small 2014 study using a PET scan to measure microglial activation suggested the microglia were indeed activated in large parts of the brains of people with ME/CFS. Dr. Jarred Younger’s small study at Stanford suggests microglial sensitization to leptin could be causing the fatigue in ME/CFS. He believes low dose naltrexone’s (LDN’s) success in small Fibromyalgia trials derives from LDN’s ability to reduce microglial activation.

While microglial activation clearly plays a role in neuropathic pain, direct evidence of microglial activation in ME/CFS or FM is still scanty. The potential microglial inhibitors listed below are not intended as a treatment prescription for ME/CFS or FM, but to illustrate treatment possibilities that future research may indicate are helpful.

The drugs in the list below have microglial inhibiting factors.  Although no specific microglial inhibiting drugs are known, some drugs that selectively suppress microglial activation are under development. The list is mostly taken from Jarred Younger’s presentation at the Stanford Symposium for Chronic Fatigue Syndrome – March, 2014.


No drugs have been developed to specifically inhibit the microglia, but a range of drugs appear to have microglial inhibiting factors

Possible Microglial Regulating Drugs

Low Dose Naltrexone (LDN)

LDN’s microglial inhibiting properties have not received a great deal of study. Studies suggest, though, that LDN is able to suppress microglia activation by suppressing receptors (TLR4) which play key role in the production of nerve pain. (Interestingly these same receptors may be responsible for opioid induced pain sensitivity and reduced opioid effectiveness).

A 2010 study found evidence of reduced microglial activation in morphine addicted rats. Dextro-naltrexone is a form of LDN which does not block opioid receptors. It’s ability to reduce neuropathic pain suggests LDN’s positive effects in Fibromyalgia are probably due to its microglial blocking characteristics.

Medical Marijuana  and Cannabidiol 

Cannabidiol makes up about forty percent of the marijuana plants extract. It, not THC, is probably responsible for marijuana's immune modulating effects

Cannabidiol makes up about forty percent of the marijuana plants extract. It, not THC, is probably responsible for marijuana’s immune modulating effects

Dr. Younger did not include medical marijuana in his list of microglial inhibitors, but it’s clear that a marijuana derivative called cannabidiol has strong microglial inhibiting factors.  Cannabidiol (CBD) – which does not have psychoactive affects – reduced inflammation and microglial activation in two viral models of multiple sclerosis  and in a laboratory study. CBD also inhibited microglial density and the creation of a neuropathic pain state in a diabetic mouse model. CBD is a much more effective immune regulator than the psychoactive tetrahydrocannabinol (THC).  Chronic THC exposure has been linked, in fact, to microglial activation in a mouse model.


There is no other compound available that is safer and displays specificity better than Minocycline in inhibiting microglial activation. Thus, the potential therapeutic benefits of this inexpensive, well tolerated, already FDA-approved drug that has minimal side effects would be enormous”

  • minocycline

    Minocycline is probably the best studied microglial inhibitor.

    Minocycline – an antibiotic, minocycline’s microglial inhibiting properties have probably received the most research of any of these drugs.  In combination with tramadol, minocycline was effective in reducing neuropathic pain and IL-1B activity in a rodent model. A current minocycline trial for treatment resistant hypertension is attempting to reduce sympathetic nervous system activation and enhance parasympathetic  nervous system activity. A similar pattern of SNS/PNS activity is found in ME/CFS and FM patients. Check out Drug Repurposing I: Antibiotics to Reduce Microglial Activation in ME/CFS and Fibromyalgia?

  • Rifampin – a bactericidal antibiotic, Rifampin inhibited a variety of inflammatory mediators from microglia including TNF-a, IL-1B, nitric oxide, and prostaglandin E2 in  a laboratory study. Few other studies have been done.
  •  Ceftriaxone – another antibiotic, Ceftriaxone has been shown to reduce neuronal hyperexcitability, regulate glutamate transport in the prefrontal cortex, reduce ischemic brain injury and reduce neuropathic pain in rodents.


  • Dextromethorphan –  Mostly used as the active ingredient in cough-suppressant formulations, dextromethorphan has also shown in animal models to protect neurons from glutamate excitotoxicity, hypoxia, and ischemia, and inhibits microglial activation. As with LDN, low doses were more effective and higher doses were not effective in reducing neuroinflammation in one study using a mouse model. Five to ten studies have examined dextromethorphan’s effects on central nervous system activation.
  •  Propentofylline – many studies have assessed the effects of propentofylline, a xanthine derivative, which is also being examined for its effectiveness in Alzheimer’s and ischemic stroke.  A recent study found propentofylline blocked allodynia in a mouse model
  • Glatiramer acetate – Glatiramer acetate (aka Copaxone) is an immunomodulatory drug which has been shown to reduce microglial cell activation in M.S., modulates TNF-1 and IL-10 expression in microglial cells, and is believed to have other neuroprotective properties.
  • Ibidulast  – the fact that ALL Ibidulast studies (except one) in the Clinicaltrials.gov database are recruiting (i.e., none have been completed yet) indicates how new the drug is to the Western medical establishment. Of the nine studies underway, two focus on  multiple sclerosis and one on the microglial inhibition in migraine.
  • Ganciclovir – of which valcyte is a prodrug – is a potent microglia inhibitor.
  • Palmitoylethanolamide (PEA)  – is a medical food which goes under the name of Normast. It was not mentioned by Dr. Younger.  Check out “Palmitoylethanolamide (PEA) – A Medical Food for Fibromyalgia and (ME/CFS)” 
drug development

Several drugs under development could be helpful

Drugs Under Development

  • 3-hydroxmorphinan – prodrug is in clinical trials for Parkinson’s disease
  • Dilmapimod – called a ‘cytokine-suppressive anti-inflammatory drug, Dilmapimod is being  trialed  for its effectiveness in  treating neuropathic pain in  several disorder.
  • ATL313
  • BAY 60-6583 – an adenosine receptor agonist, BAY 60-6583 protests  against damage due to low blood levels.
  • FP-1
  • Resolvin D-1
  • Resolvin E-1

 Nutrients and Supplements (from Younger’s presentation)

Luteolin, panax ginseng, tumeric, resveratrol, gastodia elata, obovatol, inflexin, piper gadsura, ganogerma lucidum, berberine, epimedium brevicornum, isodon japonicas, stephania tetrandra, stinging nettle, fisetin, pyncogenol, boswellia, kratom.

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