Can an Addiction Drug Treat Long Covid?

When pharmacist Jack Korbutov opened The Art of Medicine, a Philadelphia compounding pharmacy, in September 2012, low-dose naltrexone (LDN) was among the first prescriptions he filled. Before starting his own specialty pharmacy, Korbutov had worked exclusively in traditional establishments, and had only encountered naltrexone being prescribed in 50 mg doses to treat opioid addiction and alcohol use disorder.

“My initial thought was, ‘What the hell is this?,’” he recalls. “I wondered how we were going to treat someone with addiction with a 4.5 milligram capsule.” 

Digging into the research, Korbutov learned that while naltrexone only has approval from the U.S. Food and Drug Administration (FDA) for treating people recovering from addiction to heroin, morphine, oxycodone, and alcohol, some doctors prescribe it off-label in much smaller doses for chronic conditions like fibromyalgia, multiple sclerosis, and Crohn’s disease. 

“Once I looked into the science, I was kind of shocked that it wasn’t more mainstream medication,” Korbutov tells Rolling Stone. “It’s one of those things you have to discover yourself.” 

This is, in part, because unlike new-to-the-market blockbuster drugs, pharmaceutical companies don’t stand to profit much from one that’s been around for decades, and, as a result, aren’t spending money promoting it. LDN also has yet to go fully mainstream because the medical establishment has long ignored and dismissed the chronic and invisible conditions it has been used to treat — myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in particular.

Now, some doctors are prescribing LDN for patients with symptoms that develop or persist after a Covid-19 infection: also known as Long Covid. It’s estimated that millions of Americans are living with Long Covid, and without a viable treatment in place, the economic impact of their continued absence from the country’s workforce will be much harder to ignore.

Korbutov first started filling LDN prescriptions for this new off-label use in mid-to-late 2020. “It was definitely before ‘Long Covid’ had an official name,” he notes. “Since then, the demand has exploded.” 

Naltrexone, first developed in 1963, received the FDA’s stamp of approval for treating opioid addiction in 1984, and alcohol use disorder a decade later. The off-label use of low-dose naltrexone began in 1985 to regulate the immune systems of people living with HIV/AIDS, and has continued as an experimental treatment for a number of chronic conditions ever since.

“I almost think of low-dose naltrexone as a different drug,” says Linda Geng, MD, PhD, co-director of the Stanford Post-Acute COVID-19 Syndrome Clinic, and clinical assistant professor of medicine and population health at Stanford University. “We’re not targeting the opioid receptor, which is the purpose of naltrexone. Rather, low dose-naltrexone is considered an immunomodulator and has anti-inflammatory properties, especially in the neurological system.” 

Or, as Korbutov put it, taking less than one-tenth the usual dose of naltrexone “almost acts like a thermostat for the immune system, calming down inflammation.”

Though it’s not yet known why some people end up with new and lasting symptoms following a Covid-19 infection, Geng says that one of the leading hypotheses is that it’s the result of persistent inflammation and immune dysregulation. “If that’s the case, then having an immunomodulator might be helpful in dampening that response,” she tells Rolling Stone.

That said, Geng emphasizes that it’s improbable that LDN — or any other therapy — will be universally beneficial for everyone living with Long Covid. “Right now, ‘Long Covid’ is a huge umbrella term that encompasses more than 200 symptoms,” she explains. “It’s unlikely that everything currently labeled ‘Long Covid’ is all the same condition and would respond to the same treatment.” 

It’s been at least a year since doctors at the Stanford Post-Acute Covid-19 Syndrome Clinic began prescribing LDN for some of their patients. It’s one of several healthcare facilities around the world gathering data on the experimental use of LDN to treat Long Covid. “The anecdotal experience with clinical off-label use is that [the results] are mixed,” Geng says, noting that naltrexone has been prescribed for decades, and is known as a well-tolerated medication. “For some, it has really changed their lives. And even if that’s a few people, that’s an encouraging sign that needs to be investigated further.”

In addition to studying who has responded to LDN, learning more about those who don’t respond to LDN could help researchers distinguish the different subtypes of Long Covid and identify other potential treatments to test.

“When you put these reports [on clinical experience using LDN to treat Long Covid] together, it generates a hypothesis, and creates a rationale for a rigorously designed randomized control trial to determine whether it’s a safe and effective drug,” Geng explains. Until data from those studies are available, she sees the benefit of the off-label use of LDN. “All in all, considering the different types of medications that are out there, especially ones that are being considered for Long Covid, this one of the safer ones, for sure,” she says.

For now, research findings are limited to a small pilot study out of Ireland, published in October 2022, involving 36 people living with Long Covid who had been prescribed LDN. After two months on the medication, the participants reported at least some improvement in their energy levels, pain, sleep quality, and ability to concentrate, as well as a reduction in respiratory symptoms, and changes to their personality. Like Geng, the study’s authors make it clear that “larger more robust studies” must come next.

For now, Luis Nacul, MD, PhD, an associate professor at the University of British Columbia’s Faculty of Medicine and the principal investigator of a clinical trial investigating the use of LDN as a potential treatment for post-Covid fatigue, discourages LDN’s off-label use.

“Until this research is completed, we do not recommend the use of LDN for people with Long Covid-19 because it is essential to create the evidence before recommending its use,” Nacul told Rolling Stone in an email. 

The Canadian Institutes of Health Research-funded 160-participant double-blind randomized control trial will take place at B.C. Women’s Hospital in Vancouver, and is expected to wrap up in April 2024.

In the meantime, researchers will continue to learn from the experience of people living with Long Covid taking LDN, including Jennifer Dornan-Fish, a California-based professor and author. Following a mild initial Covid-19 infection in March 2020, Dornan-Fish’s health declined drastically over a period of several months, as they developed everything from rashes, vertigo, and a heart condition, to tremors, seizures, and severe brain fog.  

“My symptoms progressed to such an extent that I became bed-bound for over a year, and my partner had to feed and bathe me,” they tell Rolling Stone. “I had severe post-exertional malaise that would cause a severe crash after any attempt at activity.”

Dornan-Fish first tried LDN for their Long Covid symptoms more than a year ago, but the dose was too high, and resulted in side effects like night terrors. But in August 2022, their neurologist suggested that they try LDN again: this time, at a much lower dose.

“I felt an almost immediate boost in energy and clarity, followed by a more subtle but sustained shift in my overall energy levels,” Dornan-Fish says. “When I started LDN, I was functioning at about 30 percent [of] my pre-Long Covid capacity. I could barely walk down the stairs, had to sit in the shower, and couldn’t cook a meal or talk on the phone for more than two or three minutes. Since starting LDN, I’m at about 65 percent, which is a massive improvement.”

Still, they emphasize that LDN shouldn’t be considered a “cure” for Long Covid, noting that they still have lingering symptoms like tachycardia and occasional fatigue and vertigo. Plus, as Geng points out, LDN doesn’t work for everyone living with post-Covid symptoms and conditions.

Dornan-Fish has been one of the lucky ones. The medication has allowed them to provide a basic level of care for themself and their child, and begin working again. 

“LDN has changed my life in a dramatic way, and I’m thankful that I have decent insurance and access to the right medical care,” they say. “If I didn’t have a partner willing and able to support me while I was bedbound, I would be homeless and destitute. I worry about all the Americans that don’t have access to good healthcare and I know many people are suffering without treatment or support.”

While there has long been a consistent demand for LDN at Korbutov’s compounding pharmacy, it has grown significantly over the past two years, since he started filling prescriptions for the drug for people living with Long Covid. “Year-over-year, we’re probably seeing at least a 50 percent increase,” he says.

What’s perhaps even more telling, “at least eight out of ten” of his pharmacy’s customers who were initially prescribed one month of the drug come back for a refill. “This is one of our biggest indicators of whether a medication is working — especially one like low-dose naltrexone, which a lot of insurance companies don’t cover,” Korbutov explains. “It’s been pretty profound. LDN is definitely one of the most quote-unquote, ‘refillable’ prescriptions that we’ve seen in the pharmacy in a long time.”

According to Korbutov, anyone can ask their doctor to prescribe off-label LDN for Long Covid, or other chronic conditions, including chronic pain. “The worst they can do is say no,” he says. Because Long Covid affects many different areas of the body, prescriptions for LDN have been coming from general practitioners, psychiatrists, dermatologists, and other specialists, in addition to post-Covid clinics, he notes.

Though it depends on the dosage and pharmacy, a one-month prescription for LDN to treat Long Covid typically costs between $20 and $100. “The biggest risk [of taking LDN] in my opinion, is paying for it and it not working,” Korbutov says, noting that if people see an improvement in their symptoms, it typically happens after two and three months on LDN. “But in terms of side effects, some people may experience a little bit of GI upset or trouble sleeping initially, but that seems to go away after a week or two.” 

LDN hasn’t yet been studied extensively as a potential treatment for Long Covid, but thanks to anecdotal evidence from people experiencing symptom relief after taking it, and doctors at reputable institutions like the Stanford post-Covid clinic prescribing the drug, it’s on its way to becoming more mainstream. 

“More providers are finding out about it, and more patients are getting educated about it,” Korbutov explains. “TikTok is also making a difference.” In fact, he’s among those using the platform to raise awareness of LDN by posting explainer videos on the drug and its potential as a treatment option for Long Covid and other chronic conditions.

The research team in Vancouver has been inundated with queries from interested parties ever since their LDN study was posted on the NIH’s website ClinicalTrials.gov in June 2022.

“We frequently get emails from Long Covid-19 patients across North America inquiring about participating or learning more,” Nacul told Rolling Stone in an email. “We have also been contacted by a variety of companies, researchers, research hospitals, and public universities expressing interest in collaborating with us.” 

Since there’s little incentive for pharmaceutical companies to invest resources into LDN, some experts, including Geng, believe that the best chance of large-scale randomized control trials taking place in the United States is with federal dollars. 

“It would be great if the NIH could fund randomized controlled trials,” she says, “because that would really give [the drug] a boost in credibility and rigor and reputation behind a scientific study in this area.” 

This would be entirely possible through the $1.15 billion Congress provided to the National Institutes of Health’s (NIH) Researching COVID to Enhance Recovery (RECOVER) initiative in December 2020 to fund Long Covid research over a four-year period. At this point, $811 million has already been allocated; part of the remaining $339 million will be used to fund clinical trials to evaluate potential treatments for Long Covid symptoms.

According to an NIH statement emailed to Rolling Stone, these clinical trials “are expected to launch in the coming months,” and “will test more than a dozen potential treatments/interventions at once while learning the effects Long Covid has on every system in the body.” 

An October 2022 Reuters article reported that “advisers to the trial” told the news agency that LDN was “on the short list” of treatments to be studied as part of the NIH RECOVER initiative, but the NIH statement did not include responses to Rolling Stone’s request to confirm this, nor which other treatments were under consideration for funding. 

Separately, in November 2022, the Patient-Led Research Collaborative — a group of researchers living with Long Covid — announced funding for nine projects, including a clinical trial to determine the efficacy and safety of LDN in treating Long Covid and ME/CFS, and a study identifying other drugs that may have the potential to be similarly repurposed.

According to Geng, there’s an urgent need for randomized control trials testing LDN and other potential therapeutics, given that Long Covid has left millions of people with disruptive, long-lasting symptoms, and doctors struggling to treat them. “We have tools in our toolbox for acute Covid, but no established treatment for Long Covid,” she says. “Long Covid is a huge public health problem right now.”