Minocycline: far beyond an antibiotic. N Garrido-Mesa, A Zarzuelo and J Gálvez. British Journal of Pharmacology (2013) 169 337–352 337 DOI:10.1111/bph.12139.
Tetracyclines and Neuromuscular Disorders. Daniele Orsucci1,*, Michelangelo Mancuso, Massimiliano Filosto and Gabriele Siciliano. Current Neuropharmacology, 2012, Vol. 10, No. 2 137
Drug repurposing – finding new uses for old drugs – is a hot industry right now. Antidepressants reduce pain (in people without depression) and antipsychotics can improve sleep. Low dose naltrexone (LDN) reduces pain in Fibromyalgia, while high (or typical) dose naltrexone is helpful in combating addiction. Most promisingly for Chronic Fatigue Syndrome, the Solve ME/CFS Initiative (formerly the CFIDS Association) has found two FDA-approved drugs (identity not yet revealed) their research indicates may be helpful. These have never before been combined in ME/CFS treatment. Dr. Klimas has made drug repurposing a focus of her work at Nova Southeastern University.
Tetracycline antibiotics are generally used to treat bacterial infections, but animal studies indicate that some tetracycline antibiotics are effective microglial inhibitors and have anti-inflammatory properties. The microglia protect the neurons by calling up powerful immune and neurotoxic factors in times of danger, but chronic microglial activation can contribute to pain sensitization and neuroinflammation. Some researchers believe chronic microglial activation is producing neuroinflammation in Chronic Fatigue Syndrome and Fibromyalgia.
The tetracycline antibiotics include tetracycline, minocycline, doxycycline, and others. Tetracycline antibiotic effectiveness is currently being evaluated in several neurological disorders including Parkinson’s and Huntington’s diseases and Fragile X Syndrome, and in inflammatory conditions such as sarcoidosis, rheumatoid arthritis, diabetes, scleroderma, and HIV.
Most of the research has been focused on minocycline – a tetracycline antibiotic able to easily penetrate the blood-brain barrier. Minocycline is FDA approved to treat some sexually transmitted diseases as well as rheumatoid arthritis.
Neuroprotectant and Immunomodulator
Animal studies suggest minocycline may be effective in a range of neurological conditions and disorders including ischemia, traumatic brain injury, neuropathic pain, Parkinson’s, Huntington’s, ALS, multiple sclerosis, and autism.
Animal studies suggest that Minocycline’s effects in Parkinson’s is to reduce microglial activation, pro-inflammatory cytokine production, and amyloid production, and that it also improves learning and reduces memory impairment. Several animal studies suggest minocycline may be able to halt or reduce Multiple Sclerosis progression, possibly by reducing macrophage penetration (and microglial activation) into the central nervous system, and by reducing free radicals (reactive oxygen species (ROS)).
Few good options exist for the treatment of nerve (neuropathic) pain. Minocycline, however, has been able to reverse the neuronal sensitization associated with nerve pain in several animal models. Its ability to reduce nerve pain in animals induced by a variety of factors suggests it may be affecting core factors in the production of nerve pain.
Minocycline significantly reduced the occurrence of allodynia and sensitivity to heat in a diabetic animal model by lowering pro-inflammatory cytokine levels and reducing oxidative stress in the spinal cord.
Mitochondrial Disorders and Exercise
Some evidence suggests reduced mitochondrial functioning may be hampering energy production in ME/CFS. Minocycline appears able to protect the mitochondria. Its ability, in one study, to reduce oxidative stress markers and lactate levels suggested it might be able to improve aerobic energy production as well.
In what could have implications for those bedridden with ME/CFS, tetracycline antibiotics have been shown to increase muscle recovery factors in mice that had been immobilized for long periods of time.
Some evidence suggests, though, that minocycline may, in some instances, have a negative effect on the mitochondria.
Minocycline’s ability to reduce the consequences of ischemia (low blood flow) is intriguing given the evidence of low blood flow in the brain in ME/CFS.
Chronic Fatigue Syndrome
Minocycline (1oo mgs/day) did not, in a very small study (four patients), improve symptoms. In an experimental rodent model of ME/CFS – produced by putting rats under continuous stress by filling the bottom of their cage with water (ouch!) – minocycline, however, wiped out the microglial activation and allodynia produced by the stress.
Pretreatment with minocycline in a rodent study that produced fatigued CFS-like mice by running them frequently was also successful. Minocycline reduced their fatigue, the oxidative damage produced by over exercising and it restored the mitochondrial enzyme complex activities.
Not Ready for Prime Time?
Animal studies suggest minocycline shows great promise in reducing microglial activation and neuroinflammation, reducing nerve pain and perhaps even assisting with energy production. However, the results from the few human clinical trials have been mixed. Minocycline significantly reduced relapse rates, brain lesions, and brain atrophy in multiple sclerosis, but a large ALS trial which found that patients on minocycline deteriorated more quickly demonstrated how difficult it can be to translate animal study results to humans.
How safe the drug is for long term use is not clear. Two reviews stated long-term treatment (with doses up to 200 mg/day) is ‘generally safe and well tolerated’, but the UK Health Service recommends tests for liver toxicity and Lupus as well as watching for irreversible changes in skin pigmentation after six months use. Doxycycline, another tetracycline antibiotic, has been preferred for use in acne because of its lesser potential side-effects.
We’ll know more about minocycline’s effectiveness over the next couple of years as human trials in peripheral neuropathy, Huntington’s disease and other disorder finish up.
- See Microglial Inhibiting Drugs – Providing Hope for Fibromyalgia and Chronic Fatigue Syndrome (ME/CFS)? – for information on other microglial inhibiting treatments
- Next up – Repurposing II, an abortion inducing drug that increases natural killer cell functioning
Share your pain, make friends, find new treatment options, check out recovery stories and more in the Health Rising ME/CFS, FM and Chronic Pain Forums here