The National Institutes of Health's flagship long COVID research program has announced its second round of clinical trials, marking a shift toward testing biological interventions after facing criticism for its initial focus on behavioral treatments.
The RECOVER-TLC (Treating Long COVID) initiative revealed plans during a two-day workshop in Bethesda, Maryland, to launch trials testing glucagon-like peptide-1 (GLP-1) drugs like tirzepatide, stellate ganglion blocks, low-dose naltrexone, and provide additional funding for an ongoing baricitinib trial. The announcement comes nearly a year after RECOVER-TLC's launch as an offshoot of the broader $1.8 billion RECOVER program.
Community Input Drives Treatment Selection
The treatment selections emerged from an extensive community engagement process. Between September 30, 2024, and September 2, 2025, RECOVER-TLC's online portal received 572 submissions for potential clinical trial candidates. Notably, 72% of submissions came from patients themselves, with another 11% from universities, 7% from caregivers, 6% from companies, and 4% from research institutes.
"Seventy-three percent of the submissions suggested drugs, reflecting a desire for pharmacological interventions, which people with long COVID often can't access unless they join a clinical trial or have a doctor who's willing to prescribe medications off-label," according to the program's analysis.
Mixed Community Response
The trial announcements have generated divided reactions within the long COVID community. In an unofficial Twitter poll by advocate Billy Hanlon, 68.6% of 328 respondents expressed dissatisfaction with the treatment selections, with 38.4% selecting "strongly dissatisfied" and 30.2% "somewhat dissatisfied." Only 5.2% selected "strongly satisfied."
"Overall if [the first] round of trials was D grade, I'd put this in B- territory," wrote Long COVID advocate Charlie McCone, a member of the Patient-Led Research Collaborative.
David Putrino, director of the Cohen Center for Recovery from Complex Chronic Illnesses at Mount Sinai, noted concerns about duplication: "In my opinion, there are a lot of promising targets that have not been explored yet and we need to be casting a wide net with available resources and gathering as much data as possible, not duplicating efforts."
Clinical Evidence Supporting Selected Treatments
The selected interventions have varying levels of existing evidence. David Kaufman, a physician at the Center for Complex Diseases, reported treating more than 350 long COVID patients with tirzepatide "microdosing" at one-tenth to one-fifth of the standard 2.5 mg dose. He observed that 60%-90% of patients responded with decreases in fatigue, brain fog, pain, and symptoms of mast cell activation syndrome.
Low-dose naltrexone has the most established track record, having been used for decades to treat myalgic encephalomyelitis, chronic pain, and other inflammatory conditions. RECOVER-TLC's trial will be the first to study LDN specifically in children with long COVID, addressing a gap identified by pediatricians seeking safe treatment options.
Stellate ganglion blocks, involving anesthetic injection into stellate ganglion nerves to improve circulation, have shown promise in small observational studies for symptoms including cognitive issues, changes to smell and taste, and post-exertional malaise.
Addressing Previous Criticisms
The new trials represent a significant departure from RECOVER's initial clinical studies, which tested primarily behavioral interventions including exercise therapy and videogames. These earlier trials drew sharp criticism from patient advocates, particularly regarding exercise studies that could potentially worsen post-exertional malaise (PEM).
"This is not just a form of exercise intolerance. It's a serious adverse reaction to exertion. It's very serious," said Victoria Copeland, founder of Empowerment Through Community, during the workshop.
Joseph Breen, who co-chairs RECOVER-TLC, acknowledged the community's impatience: "This work is 'never fast enough' for the patient community." He noted that the initiative "had a few hiccups" during the transition to the Trump administration but emphasized continued commitment to patient feedback.
Accessibility and Design Challenges
Patient advocates continue to raise concerns about trial accessibility, particularly for people with severe long COVID who cannot leave their homes or beds. Victoria C., a social worker with long COVID serving as a RECOVER representative, emphasized that accessibility considerations must be "baked into the design" of studies.
"As someone who is bedbound I have given up on participating in any RECOVER trial," Victoria said, noting that excluding this patient group could mean trials don't capture "the full picture" of long COVID.
To address some accessibility concerns, Julia Moore Vogel at Scripps Research is planning a completely remote long COVID trial using tirzepatide, incorporating self-draw devices for at-home blood collection, wearables for activity and sleep tracking, and scales to monitor weight loss.
Budget and Timeline Considerations
RECOVER-TLC has allocated $300 million of RECOVER's total $1.8 billion funding specifically for clinical trials. While exact budgets for individual studies remain undetermined, Breen indicated the LDN study will be a "pivotal" trial, while GLP-1 and stellate ganglion block studies will be smaller "mechanistic" studies.
The baricitinib trial, REVERSE-LC, will receive additional funding to expand from four to 15 sites nationwide. Principal investigator Wes Ely noted the expansion will help "get across the finish line faster" by enabling broader patient participation without requiring long-distance travel.
Ongoing Concerns About Viral Persistence
Some advocates remain disappointed that the selected trials don't directly address viral persistence theories of long COVID. Amy Mitchell from the Long COVID Action Project submitted 49 treatment suggestions focused on viral persistence, but only baricitinib was selected for trials.
"Patients needed NIH to trial the tests and treatments their doctors can't prescribe, or at minimum to test the effectiveness of off-label antivirals," Mitchell said.
Responding to criticism about the lack of antiviral trials, Breen acknowledged the science behind viral persistence but noted that "the ability to measure it consistently has been a struggle."
Looking Forward
RECOVER-TLC's treatment submission portal remains open for new entries, and the initiative plans to announce additional trials in coming months. Patient advocate Mike Zissis captured the community's sentiment during the workshop: "We need commitment. We need candor. Patience is growing thin... Urgency, focus, and relentlessness."
The program continues to operate under scrutiny as one of the few federally funded long COVID research efforts to survive recent research cuts, with Health Secretary Robert F. Kennedy Jr. indicating continued support for long COVID research during recent Senate hearings.
