The Most Promising Treatments for Long COVID

Long COVID is a symptom-driven disease, meaning that with no cure, physicians primarily treat the symptoms their patients are experiencing. Effective treatments for long COVID remain elusive because what works for one patient may be entirely ineffective for another. But as 2024 winds down, researchers have begun to pinpoint a number of treatments that are bringing relief to the 17 million Americans diagnosed with long COVID.

Here’s a current look at what research has identified as some of the most promising treatments.

Low-Dose Naltrexone

Some research suggests that low-dose naltrexone may be helpful for patients suffering from brain fog, pain, sleep issues, and fatigue, said Ziyad Al-Aly, MD, a global expert on long COVID and chief of research and development at the Veterans Affairs St Louis Health Care System.

Low-dose naltrexone is an anti-inflammatory agent currently approved by the US Food and Drug Administration for the treatment of alcohol and opioid dependence.

“We don’t know the mechanism for how the medication works, and for that matter, we don’t really understand what causes brain fog. But perhaps its anti-inflammatory properties seem to help, and for some patients, low-dose naltrexone has been helpful,” said Al-Aly.

A March 2024 study found that both fatigue and pain were improved in patients taking low-dose naltrexone. In another study, published in the June 2024 issue of Frontiers in Medicine, researchers found that low-dose naltrexone was associated with improvement of several clinical symptoms related to long COVID such as fatigue, poor sleep quality, brain fog, post-exertional malaise, and headache.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Antidepressants

Last year, University of Pennsylvania, Philadelphia, researchers uncovered a link between long COVID and lower levels of serotonin in the body. This helped point to the potential treatment of using SSRIs to treat the condition.

For patients who have overlapping psychiatric issues that go along with brain fog, SSRIs prescribed to treat depression and other mental health conditions, as well as the antidepressant Wellbutrin, have been shown effective at dealing with concentration issues, brain fog, and depression, said Nisha Viswanathan, MD, director of the University of California, Los Angeles (UCLA) Long COVID Program at UCLA Health.

A study published in the November 2023 issue of the journal Scientific Reports found that SSRIs led to a “considerable reduction of symptoms,” especially brain fog, fatigue, sensory overload, and overall improved functioning. Low-dose Abilify, which contains aripiprazole, an antipsychotic medication, has also been found to be effective for cognitive issues caused by long COVID.

“Abilify is traditionally used for the treatment of schizophrenia or other psychotic disorders, but in a low-dose format, there is some data to suggest that it can also be anti-inflammatory and helpful for cognitive issues like brain fog,” said Viswanathan.

Modafinil

Modafinil, a medication previously used for managing narcolepsy, has also been shown effective for the treatment of fatigue and neurocognitive deficits caused by long COVID, said Viswanathan. She said that it’s another medication that she’s found useful for a number of her patients.

It’s thought that these cognitive symptoms are caused by an inflammatory cytokine release that leads to excessive stimulation of neurotransmitters in the body. According to a June 2024 article in the American Journal of Psychiatry, “Modafinil can therapeutically act on these pathways, which possibly contributed to the symptomatic improvement.” But the medication has not been studied widely in patients with long COVID and has been shown to have interactions with other medications.

Metformin

Some research has shown that metformin, a well-known diabetes medication, reduces instances of long COVID when taken during the illness’s acute phase. It seems to boost metabolic function in patients.

“It makes sense that it would work because it seems to have anti-inflammatory effects on the body,” said Grace McComsey, MD, who leads one of the 15 nationwide long COVID centers funded by the federal RECOVER (Researching COVID to Enhance Recovery) Initiative in Cleveland. McComsey adds that it may reduce the viral persistence that causes some forms of long COVID.

A study published in the October 2023 issue of the journal Lancet Infectious Diseases found that metformin seemed to reduce instances of long COVID in patients who took it after being diagnosed with acute COVID. It seems less effective in patients who already have long COVID.

Antihistamines

Other data suggest that some patients with long COVID showed improvement after taking antihistamines. Research has shown that long COVID symptoms improved in 29% of patients with long COVID.

While researchers aren’t sure why antihistamines work to quell long COVID, the thought is that when mast cells, a white blood cell that’s part of the immune system, shed granules and cause an inflammatory reaction, they release a lot of histamines. Antihistamine medications like famotidine block histamine receptors in the body, improving symptoms like brain fog, difficulty breathing, and elevated heart rate in patients.

“For some patients, these can be a lifesaver,” said David Putrino, the Nash Family Director of the Cohen Center for Recovery from Complex Chronic Illness and a national leader in the treatment of long COVID.

Putrino cautions patients toward taking these and other medications haphazardly without fully understanding that all treatments have risks, especially if you’re taking a number of them.

“Often patients are told that there’s no risk to trying something, but physicians should be counseling their patients and reminding them that there is a risk that includes medication sensitivities and medication interactions,” said Putrino.

The good news is that doctors have begun to identify some treatments that seem to be working in their patients, but we still don’t have the large-scale clinical trials to identify which treatments will work for certain patients and why.

There’s still so much we don’t know, and for physicians on the front lines of treating long COVID, it’s still largely a guessing game. “This is a constellation of symptoms; it’s not just one thing,” said Al-Aly. And while a treatment might be wildly effective for one patient, it might be ineffective or worse, problematic, for another.