Antihistamines Offer Small, Temporary Relief for Long COVID Fatigue, Major Trial Finds
For people living with long COVID, fatigue can be far more severe than ordinary tiredness. It may affect concentration, mobility, employment, household tasks and even the ability to hold a conversation without becoming exhausted.
A major UK clinical trial has now found that two inexpensive, commonly used treatments may provide a small amount of temporary relief.
The phase 3 STIMULATE-ICP trial studied 778 non-hospitalized adults with long COVID and severe fatigue. Researchers found that participants receiving either a combination of famotidine and loratadine or the anti-inflammatory medicine colchicine experienced slightly greater improvement after 12 weeks than those receiving specialist long COVID care without an additional study drug.
However, the results are much more modest than some headlines suggest.
The extra improvement associated with the medicines was small, and it disappeared within 12 weeks of stopping treatment. The trial therefore does not establish antihistamines or colchicine as cures for long COVID, nor does it show that patients should begin taking them without medical supervision.
Instead, the findings provide an encouraging but limited signal that immune- and inflammation-related pathways may be worth investigating further.
What Did the STIMULATE-ICP Trial Study?
The trial was conducted across 12 specialist National Health Service long COVID clinics in the United Kingdom.
Researchers enrolled adults over 18 who had post-COVID-19 symptoms but had not been hospitalized during their original COVID-19 illness. All participants received specialist-led long COVID care and were randomly assigned to one of four groups.
For 12 weeks, participants received:
- Colchicine, 500 micrograms twice daily
- Famotidine, 40 milligrams, plus loratadine, 10 milligrams once daily
- Rivaroxaban, 10 milligrams once daily
- No additional study drug, alongside usual specialist care
Of the 778 participants, 192 received colchicine, 193 received famotidine–loratadine, 197 received rivaroxaban and 196 received no study drug. Recruitment took place between August 2022 and August 2024.
The mean age was approximately 46, 64% of participants were women and the group entered the study with severe fatigue.
What Are Famotidine and Loratadine?
Loratadine is a familiar allergy medicine. It blocks histamine activity and is commonly used for symptoms such as sneezing, itching, runny nose and watery eyes.
Famotidine is also connected to histamine, although most people know it as an acid-reducing medicine rather than an allergy treatment. It is an H2 receptor antagonist that reduces stomach-acid secretion.
The trial therefore combined medicines affecting two different histamine pathways:
- Loratadine targets H1-related histamine activity.
- Famotidine targets H2 receptors.
Researchers investigated the combination because immune dysregulation and inflammatory activity have been proposed as possible contributors to at least some forms of long COVID. The investigators emphasized, however, that the exact reason for the observed benefit remains uncertain.
How Much Did Fatigue Improve?
Fatigue was measured using the Fatigue Assessment Scale, or FAS.
Scores range from 10, representing little or no fatigue, to 50, representing extremely debilitating fatigue. The study considered a change of more than 10% clinically meaningful.
At the beginning of the trial, the average fatigue score was 36.8, indicating severe symptoms.
After 12 weeks, the average score across all four groups had fallen by approximately 4.3 points, reaching 32.5. This means that participants improved whether they received colchicine, antihistamines, rivaroxaban or no additional medicine.
Compared with the no-drug group:
- Colchicine produced an additional average reduction of 1.49 points.
- Famotidine–loratadine produced an additional average reduction of 1.48 points.
- Rivaroxaban produced an additional reduction of 1.06 points, but this difference was not statistically significant.
The colchicine and famotidine–loratadine results reached statistical significance, but the size of the additional benefit remained small.
In practical terms, specialist care and the passage of time were accompanied by a larger overall improvement than the extra difference attributable to either successful drug treatment.
Imrul
Why “Small Benefit” Is More Accurate Than “Breakthrough”
The results are encouraging because long COVID still lacks reliably effective drug treatments for persistent fatigue.
Nevertheless, describing the study as proof that common antihistamines “treat” or “reverse” long COVID would overstate the evidence.
The antihistamine combination produced only about 1.5 points of additional average improvement on a 40-point measurement range compared with specialist care alone. The same was true of colchicine.
That extra difference was statistically detectable, meaning it was unlikely to be explained entirely by random variation under the study’s analysis. Statistical significance, however, does not automatically mean that every patient experienced a noticeable change.
Some participants may have improved considerably, others may have experienced little change and some may have worsened. The reported result represents the average difference between groups.
The trial therefore identifies a possible treatment signal rather than a transformative therapy.
The Improvement Disappeared After Treatment Stopped
The most important limitation emerged during follow-up.
Participants stopped taking the study medicines after 12 weeks. Fatigue was assessed again at week 24—approximately 12 weeks after treatment ended.
At that point, there were no statistically significant differences between the colchicine, famotidine–loratadine, rivaroxaban and no-drug groups. The small advantages previously seen with colchicine and antihistamines had disappeared.
This suggests that the medicines did not produce a lasting change in the underlying condition during the treatment period.
They may have temporarily influenced symptoms or biological pathways while participants were taking them, but the trial provides no evidence that a 12-week course leads to sustained recovery.
Professor Amitava Banerjee, the study’s corresponding author, said that these medicines alone were unlikely to be the answer to long COVID fatigue because the benefits did not continue after treatment stopped.
Colchicine Produced a Similar Result
Colchicine is an anti-inflammatory medicine most commonly associated with conditions such as gout. It is not an ordinary painkiller and affects inflammatory processes in the body.
In the STIMULATE-ICP trial, colchicine produced almost exactly the same additional average improvement as famotidine–loratadine.
This strengthens the possibility that inflammation or immune activity may contribute to fatigue in certain long COVID patients. However, the trial did not establish a specific biological mechanism, and the effect also disappeared after colchicine was stopped.
Colchicine also requires particular caution. The difference between a therapeutic amount and a harmful amount can be important, and excessive exposure may cause serious or even fatal poisoning. It should not be used for long COVID without appropriate clinical assessment and supervision.
Imrul
The Blood Thinner Rivaroxaban Did Not Work
The third medicine tested was rivaroxaban, an anticoagulant that reduces blood clot formation.
It was included because abnormal clotting, blood-vessel dysfunction and microvascular problems have been investigated as possible contributors to long COVID symptoms.
In this trial, however, rivaroxaban did not produce a statistically significant improvement in fatigue compared with specialist care alone. The researchers concluded that their findings do not support anticoagulation treatment for long COVID fatigue.
This is an especially important negative result because rivaroxaban is not a harmless experimental supplement. Its expected effects include an increased tendency to bleed, bruise or experience heavier and longer-lasting bleeding.
Taking an anticoagulant without a recognized medical reason can expose a person to risk without offering a proven benefit.
Were the Treatments Safe?
The researchers described the study treatments as generally well tolerated.
Ten serious adverse events requiring hospitalization occurred among eight participants, representing approximately 1% of the 778-person trial population. Investigators judged these serious events unrelated to the trial medicines. Five of the events occurred among three people assigned to rivaroxaban.
Less severe adverse events were more common in the medication groups than in the no-drug group. Trial data presented before publication showed adverse events reported by approximately 26% of the famotidine–loratadine group, 30% of the colchicine group, 36% of the rivaroxaban group and 11% of the usual-care group. Bleeding events were particularly associated with rivaroxaban, while gastrointestinal complaints were more common with colchicine.
The absence of drug-related serious events in this trial is reassuring, but it does not mean the medicines are suitable for everyone.
Why Did Every Group Improve?
One of the study’s most interesting findings was that fatigue improved meaningfully across every treatment group—including the participants who received no additional drug.
The average 4.3-point improvement was larger than the approximately 1.5-point extra advantage associated with either colchicine or famotidine–loratadine.
The investigators considered this encouraging evidence for the value of specialist long COVID services. Participants received care involving clinical assessment, symptom management and access to multidisciplinary or community-based rehabilitation.
However, an important scientific distinction should be made.
Because everyone in the drug trial received specialist care, the medication comparison cannot determine precisely how much of the overall improvement was caused by that care. Other possible contributors include natural symptom fluctuation, regression toward the average, behavioral changes, study participation or expectations associated with receiving treatment.
The results are consistent with specialist care being beneficial, but the drug trial alone does not prove that specialist care caused the entire 4.3-point reduction.
The Trial Was Open-Label
Participants knew whether they were receiving medication, and there was no placebo tablet for the no-drug group.
This is known as an open-label design.
The researchers acknowledged that they could not completely exclude expectation or placebo effects, particularly because fatigue was measured through a self-reported questionnaire.
The team argued that expectations were unlikely to explain everything because rivaroxaban did not produce the same significant improvement as the other two medicines. Nevertheless, a blinded, placebo-controlled design would provide stronger protection against expectation bias.
Participants taking famotidine–loratadine or colchicine may have expected improvement because they knew they were receiving an active treatment. Those receiving no study drug may have had different expectations.
The open-label design does not make the findings meaningless, but it reduces the certainty with which the small differences can be attributed entirely to pharmacological effects.
What Does the Trial Tell Us About Long COVID Biology?
Long COVID is not necessarily a single biological condition.
People may experience different combinations of fatigue, cognitive problems, breathlessness, post-exertional symptom worsening, sleep disturbance, pain, autonomic symptoms and cardiovascular complaints.
The modest responses to antihistamines and colchicine suggest that immune or inflammatory pathways may influence fatigue in at least some patients. The study does not show that histamine or inflammation is the primary cause of every case.
It is possible that a subgroup of patients benefited more strongly while the average effect was diluted by participants whose symptoms arose from different mechanisms.
Future studies may need to identify biological markers or symptom patterns that predict who is most likely to respond. The investigators specifically recommended research into patient subgroups, combination treatments and alternative ways of delivering care.
Why Repurposed Medicines Are Attractive
Developing a completely new medicine can take years and require extensive safety testing.
Repurposing an existing drug means investigating whether a medicine already used for one condition could benefit another. Researchers already have substantial information about manufacturing, dosing, side effects and interactions.
Famotidine, loratadine and colchicine were therefore attractive candidates because they were familiar, relatively inexpensive and connected to biological theories about long COVID that were considered promising when the trial began in 2021.
Repurposing still requires rigorous trials.
A medicine being cheap, available or generally safe for its licensed purpose does not establish that it works for an entirely different condition.
The rivaroxaban result demonstrates why controlled studies matter. Biological theories about clotting provided a reason to test it, but the trial did not find meaningful fatigue relief.
Imrul
Should People With Long COVID Take Famotidine and Loratadine?
The study is not a recommendation for unsupervised self-treatment.
Although loratadine and famotidine may be available without prescription in some countries, availability varies, and neither is appropriate for every person.
The NHS advises people to consult a clinician or pharmacist before using antihistamines when they are pregnant, breastfeeding, taking other medicines or living with conditions involving the heart, liver, kidneys or epilepsy.
Famotidine can also affect the absorption or action of certain medicines because it reduces stomach acidity. Its dosing may require adjustment in some people, including those with impaired kidney function.
Most importantly, the trial tested a specific combination and dose for 12 weeks under research and specialist-clinic supervision. It did not investigate indefinite use, different doses or every possible long COVID patient.
Anyone considering the findings in relation to their own symptoms should discuss them with a qualified healthcare professional who can review existing medicines, medical history and potential risks.
What About Colchicine?
Colchicine should not be treated as an over-the-counter long COVID remedy.
It can interact dangerously with other medicines, and incorrect dosing can cause severe gastrointestinal illness, organ damage or fatal toxicity. Official guidance emphasizes following prescribed limits carefully.
The trial found only a small, temporary average benefit.
That finding may justify further controlled research, but it does not create a general reason for people with long COVID to obtain or take colchicine independently.
Why the Findings Still Matter
The results may sound disappointing because neither successful treatment produced lasting recovery.
Yet the trial remains important for several reasons.
First, it demonstrates that large, randomized long COVID drug studies can be conducted across multiple specialist clinics.
Second, it provides credible evidence that rivaroxaban should not be used routinely for fatigue based solely on theories about abnormal clotting.
Third, it identifies small treatment signals for famotidine–loratadine and colchicine that researchers can investigate in more precisely selected patient groups.
Finally, it provides a benchmark against which future therapies can be evaluated. New treatments will need to deliver greater and more durable benefits than the approximately 1.5-point temporary advantage observed here.
Not a Cure, but a Useful Step
The most balanced interpretation is that the trial offers cautious hope rather than a breakthrough.
For some patients, even a temporary reduction in fatigue may be valuable. A small improvement could help someone complete daily tasks, participate in rehabilitation or regain part of their routine.
At a population level, however, an average 1.5-point advantage that vanishes after treatment ends is not enough to solve the enormous burden of long COVID.
Researchers will need to determine whether longer treatment maintains benefit, whether symptoms return immediately after withdrawal, whether certain subgroups respond more strongly and whether combinations with other therapies produce more durable improvement.
Those questions remain unanswered.
A Note About the Study Citation
The paper was published online in The Lancet Infectious Diseases on July 8, 2026.
The full citation begins with Emma C. Wall and colleagues on behalf of the STIMULATE-ICP consortium. Professor Amitava Banerjee was the corresponding author, but referring to the paper simply as “Banerjee et al.” does not reflect the journal’s published author order.
The study’s DOI is 10.1016/S1473-3099(26)00242-2.
Final Thoughts
The STIMULATE-ICP trial provides some of the clearest randomized evidence yet on commonly discussed repurposed medicines for long COVID fatigue.
Famotidine combined with loratadine produced a statistically significant but modest improvement after 12 weeks. Colchicine produced an almost identical result. Rivaroxaban did not provide a significant benefit.
The encouraging signal must be balanced against three realities:
The additional improvement was small.
The trial was open-label and did not use placebo tablets.
The treatment advantage disappeared after the medicines were stopped.
These drugs therefore cannot currently be described as cures or durable solutions for long COVID. At most, famotidine–loratadine and colchicine may offer limited short-term symptom relief for some patients under appropriate clinical supervision.
The broader message is that long COVID remains complex. Its patients need careful assessment, individualized symptom management and better-targeted research—not exaggerated promises based on modest early findings.
Frequently Asked Questions
Did antihistamines cure long COVID fatigue?
No. Famotidine–loratadine produced a small additional improvement during 12 weeks of treatment, but the difference disappeared 12 weeks after treatment ended.
How many people participated in the trial?
The trial randomized 778 non-hospitalized adults with long COVID across 12 specialist NHS clinics.
Which antihistamines were tested?
Researchers tested famotidine, an H2 receptor antagonist, together with loratadine, a familiar allergy antihistamine.
How much additional improvement did they produce?
The famotidine–loratadine group had approximately 1.48 points more improvement on the Fatigue Assessment Scale than the no-drug group after 12 weeks.
Did colchicine work?
Colchicine produced a similarly small additional reduction of approximately 1.49 points at week 12. The advantage was no longer present at week 24.
Did rivaroxaban help?
No statistically significant fatigue benefit was found with rivaroxaban. The researchers said the findings do not support anticoagulant treatment for long COVID fatigue.
Can patients start taking famotidine and loratadine themselves?
The trial does not support unsupervised self-treatment. People should first discuss potential benefits, contraindications and interactions with a doctor or pharmacist.
Were the medicines safe?
Serious events were uncommon and were judged unrelated to the study medicines. Less serious adverse events occurred more frequently among participants receiving active drugs, particularly rivaroxaban and colchicine.
Why might antihistamines affect long COVID?
The researchers suggested that immune dysregulation could be relevant because famotidine, loratadine and colchicine affect immune or inflammatory pathways. The trial did not establish the precise mechanism.
What happens next?
Future research may test longer treatment periods, different medicine combinations and biologically defined long COVID subgroups to identify patients who might receive a greater or more durable benefit.
