Losing your sense of smell after a virus is one of the few conditions where palmitoylethanolamide has been tested repeatedly, by different research groups, in randomized trials, with a meta-analysis on top. That is more repeat testing than many other uses, but a Cochrane review rated the certainty of the evidence for PEA plus luteolin as very low [5].
It also comes with a constraint that gets dropped from almost every summary. In every one of those trials, PEA was combined with luteolin and given on top of olfactory training. Nobody has tested it alone. The honest claim ceiling is therefore that it may add something to training, not that it treats smell loss.
The trials also disagree with each other about how much it adds, and the most recent one exists specifically to raise that question.
Key Takeaways
- A multicentre double-blinded randomized placebo-controlled trial in 185 patients found that ultramicronized PEA plus luteolin added to olfactory training produced significantly greater improvement in smell threshold, discrimination and identification than training with placebo [1].
- In that trial 92% of the supplement group improved versus 42% of controls, with a mean recovery magnitude of 12.8 points versus 3.2 [1].
- A later randomized trial in 50 patients found the supplement group improved significantly while controls did not, but when the analysis asked whether the improvement was clinically meaningful, there was no significant difference between groups [2].
- A systematic review and meta-analysis of five studies covering 441 patients concluded the combination showed significant efficacy in overall olfactory recovery when added to training [3].
- Olfactory training remains the evidence-based backbone of treatment [1]. PEA and luteolin has never been tested as a replacement for it.
Why Anyone Tried PEA for Smell Loss at All
Olfactory training is the only evidence-based treatment for post-viral olfactory dysfunction [1]. It involves deliberately sniffing a fixed set of strong odours twice a day for months. It works for some people, slowly, and there has never been much else to offer.
Smell disorders after SARS-CoV-2 infection have been attributed to neuroinflammatory events within the olfactory bulb and the central nervous system, which makes targeting neuroinflammation a rational strategy for promoting recovery [1]. PEA and luteolin were picked as candidate anti-inflammatory and neuroprotective agents on exactly that reasoning [1]. PEA is thought to act largely through PPAR-alpha, with TRPV1 and GPR55 proposed as additional targets [4], [6][7] and luteolin is a flavonoid antioxidant paired with it in a fixed co-ultramicronized formulation.
The condition also became, briefly, one of the most common persistent complaints in the world, which is why a compound with a thin trial record in most areas suddenly accumulated several trials here.
The Largest Trial: A Clear Positive
The main study was a multicentre, double-blinded, randomized, placebo-controlled clinical trial [1]. Eligible participants had prior COVID-19 and persistent olfactory impairment more than six months after a follow-up negative test, with no prior history of smell dysfunction or other sinonasal disorders [1].
With olfactory training in both groups, smell scores rose with PEA plus luteolin and barely moved with placebo
In this double-blind trial the PEA-luteolin group improved clearly, but the result belongs to the combination.
Double-blind placebo-controlled trial in 185 adults with smell loss persisting after COVID. TDI is the Sniffin Sticks smell score. Source: Di Stadio et al., Current Neuropharmacology 2022.
Data table
| Item | Value |
|---|---|
| PEA-luteolin, start (T0) | 20.6TDI score |
| PEA-luteolin, end (T3) | 29.8TDI score |
| Placebo, start (T0) | 18.2TDI score |
| Placebo, end (T3) | 19.5TDI score |
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Research note: The smell-loss trial gave ultramicronized PEA combined with luteolin as a single daily oral supplement alongside olfactory training; the combined product dose was 770 mg [1].
185 patients were enrolled, 130 in the intervention group and 55 in the control group [1]. The intervention was daily oral ultramicronized PEA plus luteolin at 770 mg together with olfactory training. Controls did olfactory training with placebo [1]. Smell was assessed with Sniffin Sticks at baseline and at 90 days [1].
The intervention group showed significantly greater improvement in olfactory threshold, discrimination and identification scores than controls [1]. 92% of the intervention group improved versus 42% of controls, and the magnitude of recovery was 12.8 points against 3.2 [1]. There was more than a tenfold higher prevalence of anosmia in the control group at the 90-day endpoint [1].
Those are large numbers. One structural detail is worth noticing: the groups were not balanced in size, 130 against 55, which is an unusual allocation for a randomized trial and slightly complicates direct comparison.
The Trial That Asked a Harder Question
A 2024 randomized study took the same intervention into an outpatient clinic and asked something the first trial did not: is the improvement large enough for a patient to notice [2].
Fifty patients with persistent olfactory dysfunction following upper respiratory tract infection, mainly COVID-19, were randomized either to olfactory training plus PEA and luteolin or to training alone [2]. The study group showed significant improvements in odour discrimination and overall olfactory function after treatment, while the control group did not [2].
Then comes the sentence that defines the article: when clinically meaningful improvements were considered, there was no significant difference between the groups [2]. The authors conclude that while the combination may have potential in post-viral dysfunction, the additional benefit over training alone may be limited, and note that these results contrast with some previous studies [2].
This is a genuinely important distinction and it applies well beyond smell. A statistically significant change on a test score is not the same as a change a person can use. Trials can detect the first while patients only care about the second.
What the Meta-Analysis Concluded
A systematic review and meta-analysis screened Pubmed, Embase and Web of Science from inception to 31 May 2023, recovering 407 articles of which five studies covering 441 patients across treatment and control groups met inclusion criteria [3]. The combination demonstrated significant efficacy in overall recovery of olfactory function compared with conventional therapy, and the authors suggest it could represent a possible future adjuvant treatment [3].
Note the framing the reviewers themselves use. Adjuvant. Possible. Future. That is the appropriate register for a five-study evidence base where the interventions are not identical and the largest study dominates the pooled estimate.
The pooled result also depends on the statistical model. A meta-analysis of PEA plus luteolin added to olfactory training reported an odds ratio of 3.07 under a fixed-effect model, but under a random-effects model heterogeneity stayed at 89% and the confidence interval crossed zero (p = 0.05) [3].
Broader reviews of interventions for persistent post-COVID-19 olfactory dysfunction place all of this in context: the field as a whole has been searching for anything that reliably outperforms training [5].
A Cochrane review found only one randomised trial of PEA plus luteolin for persistent smell loss after COVID, with 12 participants, compared against no treatment, and rated the certainty of that evidence as very low [5].
The Constraint Nobody Should Skip
In every trial described above, PEA was given with luteolin, and the pair was given on top of olfactory training [1][2][3]. There is no arm anywhere in this literature in which someone took PEA alone for smell loss and did nothing else.
Two consequences follow, and both are easy to state.
First, the evidence cannot tell you what PEA does by itself for this condition. It is entirely possible that luteolin carries part or all of the effect, or that the two only work together. This site covers the PEA and luteolin combination in a dedicated article for the same reason: combination products cannot be read as evidence for a single ingredient.
Second, buying the supplement and skipping the training inverts the evidence. Training is the part with the established record. The supplement is the addition being tested against it.
Practical Reading
If you have lost smell after a virus, the sequence supported by the literature is to do olfactory training properly and consistently, and to treat a PEA and luteolin supplement as a possible addition to it rather than a substitute. Expect the honest range of outcomes to sit somewhere between the large trial’s striking recovery figures [1] and the later trial’s finding that the added benefit may not be clinically meaningful [2].
Persistent smell loss also deserves a proper ear, nose and throat assessment rather than self-management, particularly if it followed something other than a clear viral illness, or if it came on suddenly with other neurological symptoms. The trials above deliberately excluded people with other sinonasal disorders [1], which means their results say nothing about smell loss from those causes.
Frequently Asked Questions
Does PEA restore smell after COVID?
Trials tested PEA combined with luteolin and added to olfactory training, and results range from a large significant benefit [1] to a benefit that was not clinically meaningful compared with training alone [2]. No trial tested PEA on its own.
What dose was used?
The multicentre trial used daily oral ultramicronized PEA plus luteolin at 770 mg, alongside olfactory training, assessed at 90 days [1].
Can I skip olfactory training and just take the supplement?
Nothing in this literature supports that. Olfactory training is described as the only evidence-based treatment for post-viral olfactory dysfunction, and every trial gave the supplement on top of it [1].
How long before any effect would show?
The randomized trials assessed outcomes at 90 days [1]. Post-viral smell recovery is slow in general, which is also why uncontrolled reports are hard to interpret: some recovery happens on its own.
Why do two randomized trials disagree?
They measured different things. The larger trial compared score improvements between groups [1]. The later one asked whether improvements crossed a threshold of clinical meaningfulness and found no between-group difference on that measure [2]. Both can be accurate descriptions of the same underlying effect.
References
- Di Stadio A, D’Ascanio L, Vaira LA, et al. Ultramicronized Palmitoylethanolamide and Luteolin Supplement Combined with Olfactory Training to Treat Post-COVID-19 Olfactory Impairment: A Multi-Center Double-Blinded Randomized Placebo-Controlled Clinical Trial. Curr Neuropharmacol (2022). PMID 35450527
- Gellrich J, Czaplewski J, Hähner A, Hummel T. Palmitoylethanolamide and Luteolin for Postinfectious Olfactory Disorders: How Clinically Meaningful Is Its Effect?. ORL J Otorhinolaryngol Relat Spec (2024). PMID 38861957
- Capra AP, Ardizzone A, Crupi L, et al. Efficacy of Palmitoylethanolamide and Luteolin Association on Post-Covid Olfactory Dysfunction: A Systematic Review and Meta-Analysis of Clinical Studies. Biomedicines (2023). PMID 37626685
- Rankin L, Fowler CJ. The Basal Pharmacology of Palmitoylethanolamide. Int J Mol Sci (2020). PMID 33114698
- O’Byrne L, Webster KE, MacKeith S, et al. Interventions for the treatment of persistent post-COVID-19 olfactory dysfunction. Cochrane Database Syst Rev (2022). PMID 36062970
- LoVerme J et al. The search for the palmitoylethanolamide receptor. Life sciences (2005). PMID 15963531
- Im DS GPR119 and GPR55 as Receptors for Fatty Acid Ethanolamides, Oleoylethanolamide and Palmitoylethanolamide. International journal of molecular sciences (2021). PMID 33494185
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