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Research & Innovation

Yale Researchers Discover Possible 'Brain Fog' Treatment for Long COVID


When Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine neuropsychiatrist, met his first patient experiencing lasting symptoms from COVID-19 (sometimes called long COVID) in June 2020, he had an idea.

His patient complained of “brain fog,” a colloquial term for significant, persistent cognitive problems, including impairments in executive functions, memory, attention regulation, and motivation. These cognitive abilities are generated by a part of the brain called the prefrontal cortex, and Dr. Fesharaki-Zadeh recognized the symptoms as being like those of his patients with a history of traumatic brain injury (TBI) suffering from post-concussive syndrome (PCS).

As he saw more patients experiencing these issues after a COVID-19 infection, Dr. Fesharaki-Zadeh wondered if N-acetylcysteine (NAC), an antioxidant that is being tested for TBI, could also help the cognitive deficits associated with long COVID. He saw some improvement in his patients’ energy and memory but decided to add a second medication, guanfacine, which is known to strengthen prefrontal cortical circuits.

Guanfacine is approved by the Food and Drug Administration (FDA) for the treatment of ADHD (a neurodevelopmental disorder associated with prefrontal cortex function), and is also being tested off-label for TBI and other brain disorders. It was developed by Amy Arnsten, PhD, a Yale School of Medicine neuroscientist who researches the molecular needs of prefrontal cortical circuits.

Dr. Fesharaki-Zadeh worked with Arnsten and treated 12 patients with a combination of guanfacine and NAC. Eight patients reported significant benefits, including improved memory, multitasking abilities, and organizational skills.

The Yale researchers, who were assisted in data gathering and organization by Naomi Lowe, a Yale physician assistant, published their case study in the Nov. 25 issue of Neuroimmunology Reports. They hope it will lead to funding placebo-controlled clinical trials involving a larger cohort of patients undergoing this treatment.

In the meantime, people suffering from long COVID—often referred to as “long-haulers”—might try asking their physicians for a prescription for guanfacine; NAC is available over the counter.

Below, the researchers share more from their findings.

What happened with patients in the case study?

For the study, patients took 1 mg of guanfacine before bed. If it was tolerated well, they increased it to 2 mg after one month. They also took 600 mg of NAC once a day.

As mentioned earlier, eight patients reported substantial benefits. For some, the brain fog completely resolved, and they were able to return to normal activities. Two patients weren’t available for follow-up, and two had to stop taking the medication because of side effects, including low blood pressure and dry mouth.

The researchers have since changed guanfacine to an extended-release form to reduce the risk of side effects.

One patient in the cohort was a nurse who had to significantly reduce her hours at work due to her long COVID symptoms. Although she found relief with the treatment, she had to stop briefly due to dizzy episodes, and her cognitive deficits returned. However, when she resumed treatment, her brain fog once again lifted. She has not experienced any dizziness since.

“This was not a placebo-controlled trial, but anecdotes like this make one more confident that the relief is really due to the drug and not the placebo effect,” says Arnsten.

“She needed to greatly reduce her working hours at a time when she was needed most,” says Dr. Fesharaki-Zadeh. “Treating her condition not only helps her; it helps all of us.”

What else could this treatment be used for?

Long COVID is not the only post-viral syndrome to cause brain fog—patients with conditions including post-Lyme disease and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), for example, can also experience debilitating cognitive deficits.

Dr. Fesharaki-Zadeh has already seen promising results while treating one post-Lyme patient with the regimen. He has also seen cognitive benefits in one of his multiple sclerosis (MS) patients who was struggling with cognitive and memory deficits.

“I feel so grateful for my collaboration with Amy Arnsten and that my understanding of traumatic brain injury could be helpful,” he says. “Our success was a combination of having the right knowledge at the right place and time while working with the right people.”