Could a cheap, generic drug used in ADHD help with long COVID, ME/CFS, and FM?
What an interesting idea! See if a drug that was designed to improve prefrontal cortex and executive functioning could help combat brain fog in long COVID. It makes sense. The bigger question is why this drug was not tried in either chronic fatigue syndrome (ME/CFS) or fibromyalgia (FM) a decade ago.
We’ve known, after all, about poor executive and prefrontal cortex functioning in them for a long time. We know that exercise reduces the flow of oxygenated blood to the prefrontal cortex in ME/CFS, thus impairing executive functioning and cognition. We know that children with ME/CFS have to engage more regions of their prefrontal cortex than normal to carry out tasks. We know that reduced gray matter has been found. Enough interest in the prefrontal cortex (PFC) in ME/CFS has shown up that a repetitive transcranial magnetic resonance (rTMS) trial that seeks to increase PFC functioning is underway.
Literally, dozens of studies have assessed the prefrontal cortex in fibromyalgia. A hyper prefrontal-motor connection has been associated with increased pain. Boosting prefrontal cortex functioning with rTMS has produced good results in several studies. Strange electrical oscillations have been found in the prefrontal cortices of FM patients.
The Guanfacine Gambit
In its short time with us, long COVID has once again produced something that neither fibromyalgia nor ME/CFS was able to do – but made sense to do: publish a treatment study of a prefrontal cortex-enhancing drug called guanfacine. Guanfacine is an anti-inflammatory drug that’s able to turn down the microglia and protect the prefrontal cortex from low oxygen states (which are apparently found after exercise in ME/CFS), and has been shown to enhance cognitive functioning in encephalomyelitis to boot.
Guanfacine (not to be confused with Guaifenesin) is sold under the brand name Tenex. It was created by the senior author of the study, Amy Arnsten, Ph.D., an Albert E. Kent Professor of Neuroscience and professor of psychology at Yale. Guanfacine, or Tenex, was FDA-approved for use in ADHD in 2009 but according to a Yale Magazine piece, has been used “extensively” off-label in PTSD and traumatic brain injury. It’s now available as a generic.
According to Wikipedia, Guanfacine is often used to reduce anxiety and to treat post-traumatic stress disorder. If you’re having nightmares, it may also help with them. It’s also FDA approved to be used in conjunction with stimulants.
NAC is Back
Guanfacine is being given with 600 mg of N-acetylcysteine or (NAC) daily. NAC has an unusual history in ME/CFS. One of the very rare NIH-funded treatment studies for ME/CFS is assessing the effects of different levels of NAC supplementation. NAC provides a nice complement to guanfacine as it is anti-inflammatory, inhibits an enzyme associated with kynurenine, and protects against calcium overload in the mitochondria.
- It made perfect sense. Given the evidence of poor executive and prefrontal cortex functioning in long COVID, why not try a cheap generic drug that was designed to improve cognition and prefrontal cortex functioning in long COVID?
- A bigger question might be – given the similar problems found in ME/CFS and FM why this drug wasn’t trialed in these diseases years ago. That’s long COVID for you, though: it keeps surfacing things that make sense in ME/CFS/FM but never saw the light of day.
- Guanfacine is an alpha-2aa adrenergic receptor agonist that was approved in 2009 to treat ADHD. Its also used off-label extensively in anxiety and PTSD. An anti-inflammatory drug it’s able to turn microglial activity (neuroinflammation), protect the prefrontal cortex and enhance cognitive functioning.
- This case report study simply followed 12 long-COVID patients given a 1 mg tablet PO (by mouth) at night for the first month, which was increased to 2 mg if patients could tolerate it, as well as 600 mg of NAC daily.
- Four patients quit – two due to low blood pressure and/or dizziness and two for unspecified reasons. The eight who remained all reported benefits with working memory, concentration, and multitasking, and some reported their brain fog went away completely.
- Guanfacine strengthens the ability of the prefrontal cortex to tame the fear center of the brain – the amygdala. One ME/CFS hypothesis proposes that damage to the prefrontal cortex has removed an inhibitory brake on the limbic system in ME/CFS. The resulting hyperarousal and hypervigilance causes their autonomic nervous systems to react to the slightest stimuli, leaving them tired and wired.
- The authors believe that problems with tryptophan and calcium metabolism – which have been highlighted recently in ME/CFS/FM and long COVID – play a key role in brain fog in long COVID.
- Guanfacine also enhances the activity of a receptor that may be associated with orthostatic intolerance in ME/CFS and that exercise decreases in about 30% of people with ME/CFS.
- While the rates of ADHD haven’t been assessed in long COVID yet, they appear to be high in both ME/CFS and fibromyalgia – making Guanfacine, which has been approved for ADHD, an interesting possibility for these diseases.
- The study was small – just 12 patients – but the authors were confident enough in their results to publicly call for doctors to read the paper – and try the combination therapy on their patients stating “You don’t need to wait to be part of a research trial. You can ask your physician – these drugs are affordable and widely available.”
Four patients quit – two due to low blood pressure and/or dizziness and two for unspecified reasons. The eight who remained all reported benefits with working memory, concentration, and multitasking, and some reported their brain fog went away completely.
The authors reported Guanfacine was generally well tolerated. (Typical side effects such as fatigue, irritability, and stomach upset reportedly usually subside within a week or two.)
Mode of Action
It appears that Guanfacine and other drugs of its ilk strengthen the ability of the prefrontal cortex to tame the fear center of the brain – the amygdala. One hypothesis proposes that damage to the prefrontal cortex has removed an inhibitory brake on the limbic system in ME/CFS. The resulting hyperarousal and hypervigilance causes their autonomic nervous systems to react to the slightest stimuli, leaving them tired and wired.
The authors also believe, interestingly enough, that increased kynurenine levels in long COVID block the NMDA receptors from turning the prefrontal cortex on. That’s an intriguing idea given the recent ME/CFS/FM and long-COVID studies that have connected impaired tryptophan metabolism in the gut with the production of toxic metabolites such as kynurenine that affect the brain.
Guanfacine also stimulates the adrenergic α-2A receptor. Because exercise decreased adrenergic α-2A receptor gene expression in about 30% of ME/CFS patients, many of whom also had trouble with orthostatic intolerance (problems standing), perhaps guanfacine is a possibility for them.
At the molecular level, the authors believe it all comes down to calcium signaling – which provides yet another possible ME/CFS connection (blog coming up).
The ADHD Connection in ME/CFS, Fibromyalgia… and Long COVID?
The fact that Guanfacine has been approved for ADHD and for use with stimulants is more than intriguing. Thus far, the ADHD connection appears to have been missed in long COVID, but if the past is prologue regarding this suite of disorders, it should be showing up soon.
According to the National Institute of Mental Health (NIMH), ADHD is characterized by difficulty staying on task and sustaining focus, feeling the need to move constantly, and increased impulsive behaviors. People with ADHD tend to miss details, have problems organizing activities, lose things, and are easily distracted. (That pretty much fits me to a tee…)
- Check out the WHO’s self-test for ADHD in Health Rising’s Cognitive Resource section.
Given common complaints of “racing minds”, difficulty concentrating, difficulty following conversations, reduced information processing speed, and the wired and tired state, ADHD seems like a natural fit for both FM and ME/CFS. In fact, several past studies have suggested that ADHD is increased in FM, and one found that 30% of children with ME/CFS met the criteria for ADHD.
And so long COVID opens up another potential treatment option for ME/CFS, FM, and similar diseases. It was nice to see quite a few potential overlaps between these diseases, including a weakened prefrontal cortex, problems with tryptophan and calcium metabolism and possibly ADHD. The authors noted that a similar type of brain fog was found in ME/CFS and post-treatment Lyme disease syndrome.
The study was small – just 12 patients – and the drug clearly needs a placebo-controlled trial, but the authors were confident enough in their results to publicly call for doctors to read the paper – and try the combination therapy on their patients stating
“You don’t need to wait to be part of a research trial. You can ask your physician – these drugs are affordable and widely available.”
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