In 2011 the CFIDS Association (now the Solve ME/CFS Initiative) engaged a “drug repositioning” company called Biovista to search through thousands of drugs to find a new approach to ME/CFS.
(Clarification: I got the $250,000 number cited in the email blast and Facebook post regarding Laura Hillenbrand’s donation for this study from a Wall Street Journal article. It turns out the article was inaccurate; the CAA didn’t spend nearly that much money on this study. )
Biovista’s algorithm identified “every known gene, pathway, disease, anatomical location, cell structure and other component of potential drugs, including why and how they succeeded or failed, as well as potential side effects and drug/drug interactions”. They threw that, along with every bit of information on ME/CFS symptoms, pathophysiology and treatment into one pot.
Biovista’s searches had previously identified two possible new drugs for progressive multiple sclerosis as well as drugs for brain cancer, thyroid cancer and melanoma. In 2012 the firm boasted a 70 percent success rate in finding drugs that turned out to be efficacious in diseases.
It was exciting stuff and a good gamble.
Surely as Biovista ploughed through thousands of drugs something interesting would pop up. The list, after all, of drugs that had been repurposed for radically different uses was impressive. Antidepressants were helping with pain, Viagra – originally produced to reduce hypertension – was producing uplifting results in men, and thalidomide which caused horrible birth defects was helping people with multiple myeloma bone cancer.
In 2012 the Solve ME/CFS Initiative announced that a new drug combination had been found, and that Biovista would attempt to find partners to finance drug trials. Three years later, (no drug trials in sight) and the Solve ME/CFS Initiative’s contractual obligations of secrecy over, the SMCI announced the results.
Biovista’s Drug Combo for Chronic Fatigue Syndrome (ME/CFS)
Biovista stated its platform enabled it to find “non-obvious correlations between drugs, molecular targets, pathways, adverse events and diseases.” Unfortunately the two drugs it came up with – low dose naltrexone and trazodone – ended up looking pretty obvious. That wasn’t necessarily the case in 2011, however, when Biovista’s search started.
Only one small study on low dose naltrexone in FM had been done by then and LDN was probably not used much in ME/CFS. Trazodone was probably used more but only one study – involving a mouse model of ME/CFS – had been done on it.
Still, Biovista didn’t provide the out of box drug combination that made us think of ME/CFS in new ways. Nor did we get a drug trial.
The result was a not a total loss, though. For one thing, it focused on low dose naltrexone, a much understudied drug with a lot of promise but not a lot of funding. (This finding is good for LDN.) Plus, both drugs may be targeting a part of the body that could, if the research underway is successful, become very prominent in this disease over the next couple of years.
Low Dose Naltrexone – Glial Cell Inhibitor #1
Naltrexone is an opioid receptor antagonist that’s used in opioid withdrawal. Besides blocking opioid receptors it has the nice side-effect of increasing levels of the feel-good chemical endorphin.
The low dose form of naltrexone (LDN), on the other hand, is believed to reduce inflammation by blocking TLR4 receptors on the microglia. It’s important to note that LDN has been proposed to be useful in many diseases but most reports are anecdotal and few studies have been done. Much remains to be learned about this intriguing compound.
The fact that LDN popped out of Biovista’s search suggests, however, that Jarred Younger may be on the right track with his focus on microglial inhibitors for ME/CFS. (Younger is currently testing dozens of potential microglial inhibitors, including LDN, in his University of Alabama at Birmingham lab . Go here if you’re interested in participating in a study.)
Trazodone – Glial Cell Inhibitor #2
Trazodone is not your average antidepressant. Structurally very different from other antidepressants, this triazolopyridine derivative has complex effects on serotonin not seen in other antidepressants. It also reduces sympathetic nervous system activity and has some anti-histamine effects.
Trazodone is probably also used more as a sleep aid than as an antidepressant in chronic fatigue syndrome. (As with LDN, lower doses than usual are used to improve sleep.) It’s one of the few drugs (Zyrem is another) able to reduce the activity of the alpha waves known to hamper sleep in fibromyalgia.
A 2011 open-label FM study found that Trazodone significantly improved sleep quality, duration and efficiency. The authors called the increase in sleep quality ‘striking’. Another 2011 fibromyalgia trial study found that Trazodone in combination with Lyrica (pregbalin) improved pain, anxiety and morning stiffness.
The IACFS/ME Treatment Primer reported that Trazodone might be able to maintain its effects over time better than any other sleep drug. Dr. Bell and Dr. Lapp both promoted Trazodone use, with Dr. Bell stated Trazodone was one his favorite sleep medications for sleep.
A 2015 study suggested that Trazodone may be producing its effects in depression by reducing neuroinflammation. Neuroinflammation is common not just in neurodegenerative diseases like Parkinson’s, Alzheimer’s and multiple sclerosis but in depression as well.
In a mouse study Trazodone upregulated levels of BDNF – a brain growth factor. BDNF appears to play a critical role in pain sensitization and neuroplasticity. BDNF levels appear to be high in FM but low in ME/CFS.
Trazodone prevented glial cells called astrocytes, from spewing out pro-inflammatory cytokines when confronted with an inflammatory stressor. If Younger and Miller are right about microglial cells over-reacting to small amounts of inflammation, a drug like Trazodone could be beneficial.
- Breaking the BDNF Blues: Dr. Courtney Craig D.C. on Natural Ways to Raise BDNF Levels in Chronic Fatigue Syndrome
Trazodone also appears to effect astrocyte metabolism as well. The glia cells in the brains of mice respond to inflammatory triggers by pumping out lactate – a substance found elevated in the brains of ME/CFS patients. When given 72 hours prior to an inflammatory insult Trazodone enhanced lactate release. (Lactate may be produced in response to stress/pathogens, but the substance itself is believed to have neuroprotective effects.)
One of drug repurposing’s lessons is the different effects drugs can have in the body. Antidepressants aren’t just antidepressants anymore. The same drugs that relieve depression can relieve pain in people who are not depressed.
Nor is depression a purely psychological disorder either. A significant subset of people with depression are believed to have inflammation driven depression. Given the possible immune involvement in ME/CFS and FM, it’s possible that much of the depression is, in fact, immune based. If that’s true then perhaps two treatments targeting the microglial could be effective both in depressed and non-depressed ME/CFS patients.
Unfortunately we don’t know why Biovista’s results plucked out these two possible glial cell inhibiting treatment. (Biovista did not return queries.) They may synergize in ways we can’t imagine.
These kinds of exploratory studies are always risky. In this case the results did not fulfill the promise of the study. Even the President of the Solve ME/CFS Initiative, Carol Head, called the results of the Biovista experiment underwhelming.
(The Biovista study was also supposed to help identify biomarkers. If it did, that information has not been released.)
The study wasn’t entirely unsuccessful, though. The results teamed together two drugs that may target a hot topic in ME/CFS – glia cells in the central nervous system.
Although Biovista failed to get a clinical trial going, if imaging studies over the next year or two find evidence of neuroinflammation, we may have a drug combo backed by solid evidence that the NIH could use to get a study underway. A successful LDN/trazodone study demonstrating improvement which was correlated with reductions in neuroinflammation wouldn’t be the answer to ME/CFS, but it could be a good first step.