4. Discussion
’ allergic, allergic, TNF-α, itching, inflammation, allergy, allergic rhinitis, decreased external mobility, nasal congestion, allergies, allergic symptoms, Allergies
INFLAMMATORY RESPONSES, ALLERGIC REACTIONS, INFLAMMATION, ALLERGY, RECRUITMENT, ALLERGIC RHINITIS, ALLERGIES, PATHOGENESIS, ALLERGIES, INFLAMMATORY RESPONSE
Palmitoylethanolamide (PEA) is widely presented in the literature for its analgesic and anti-inflammatory activity for the management of multiple clinical conditions [This study aimed to evaluate the effect of Levagen+ for alleviating allergy symptoms compared to a placebo over a 14-day supplementation period, as measured by the rTNSS. However, the results indicate that there was no significant difference between the Levagen+ and placebo groups in terms of rTNSS scores at baseline or throughout the treatment period. Both groups exhibited a decrease in symptom scores over the 2 weeks, with improvements beginning as early as day 3 for morning scores and day 2 for evening scores. The lack of difference between groups warrants a deeper examination of the study’s findings.One effect to consider is the potentially strong influence of the placebo effect. The fact that both groups showed improvements in symptom scores suggests that psychological factors, such as participants expectations, may have played a substantial role in symptom relief. This highlights the importance of using a robust control group to differentiate the effects of a treatment from those of a placebo.Another consideration is the natural course of allergic symptoms. Allergies typically fluctuate in symptom severity due to their influence by environmental allergen exposure, with both groups showing almost immediate symptom relief, which could be attributed to allergen exposure levels or a strong placebo effect. The results suggest the need for longer-term studies to assess the potential efficacy of Levagen+, or any potential treatment, for allergies to help account for the natural variation in symptoms and any possible placebo effect.With the overall results indicating that both groups had reduced symptoms, participants were sub-grouped to only include those with symptoms classified as a minimum of mild (a score of four or greater) on the baseline rTNSS scores. The sub-group analysis of those with greater symptom scores at baseline showed that Levagen+ led to a significant reduction in symptom scores compared to the placebo at week 2 of treatment (The sub-group analysis suggests that Levagen+ may be more beneficial for individuals with a greater severity of AR symptoms. Currently, mild, and moderate/severe allergic rhinitis have separate treatment plans using either antihistamine (for mild) or corticosteroids (for moderate/severe) [To better explore the potential antihistamine and corticosteroid functions of PEA, blood was collected for an analysis of histamine and inflammation. However, one of the main limitations of this study is that it was conducted during the COVID-19 pandemic. This resulted in participants being unable or unwilling to attend the clinic to have blood samples collected. Of the 101 participants that completed the study, only 36 had blood collected at both the baseline and final points. The low number of participants likely reduced our ability to detect some significant changes in the blood. Despite this, there was a significant difference in the change in plasma histamine detected between the groups. The Levagen+ group showed a reduction in plasma histamine, while the placebo group had an increase. The significant difference in change in plasma histamine supports the notion that Levagen+ supplementation downregulates mast cell activation and thereby inhibits histamine release. The increase in histamine in the placebo group, despite the reduction in reported symptom severity, may indicate a continuation of AR. The findings of this study support the results of Petrosino and colleagues, showing PEA’s mechanistic control to downregulate mast cell activity and histamine release [Along with the histamine reduction, we also showed that plasma pro-inflammatory IL-4, IL-8, and TNF-α and anti-inflammatory marker IL-10 were significantly reduced in the Levagen+ group, but only plasma IL-4 was significantly reduced in the placebo group. The reduction in the pro-inflammatory markers suggests that less inflammation is present, potentially due to the prevention of histamine release from mast cells. The reduction in anti-inflammatory IL-10 suggests that there is no need for an anti-inflammatory cytokine due to a lack of inflammatory signalling. Together, these cytokines play a central role in the pathogenesis of allergic rhinitis by promoting an allergic immune response, inflammation, and the release of allergic mediators. When activated, these cytokines can initiate the production of IgE antibodies and the recruitment of other immune cells, like eosinophils, involved in allergic reactions. This reaction can increase inflammation at the site where the immune reaction has occurred to help combat the noxious stimulus, and it generally results in AR symptoms (i.e., sneezing, nasal congestion, itching, or a runny nose). TNF-α, in turn can amplify the inflammatory response by promoting the activation of other immune cells and the release of additional proinflammatory cytokines. This can further exacerbate the symptoms of AR. Therefore, a reduction in rTNSS symptom scores, along with a reduction in histamine and cytokine production, suggests that Levagen+ may alleviate AR and prevent the release of histamine and subsequent inflammatory responses.There were potentially several limitations to this study that were not foreseen when designing the study. First is the study duration. A 2-week supplementation period was designed, as we felt if the supplement did not work within 2 weeks, it was not worth using. However, we did not factor in, nor foresee, the seemingly strong placebo effect. Possibly a 4- or even 6-week intervention period is required to account for any potential placebo effect or fluctuation in allergy symptoms. A further limitation of this study, as previously mentioned, is that it was conducted during the COVID-19 pandemic. This circumstance resulted in reduced physical activity and potentially lower allergen exposure due to decreased external mobility. Consequently, these factors may have mitigated the severity of participants’ allergic responses, thereby potentially impacting the trial outcomes. Additionally, the increased amount of time individuals spent at home during the pandemic likely facilitated better symptom recovery, possibly contributing to the observed placebo effect.Moreover, owing to the COVID-19 restrictions, we encountered challenges in collecting the desired amount of blood samples. Expanding the blood sample collection and exploring a wider range of inflammatory pathways related to allergic rhinitis (AR) could offer valuable insights into the aetiology of how Levagen+ alleviates AR symptoms.The population selected for this study may have certain limitations. Although participants were screened for a minimum score on the rTNSS, it is possible that the threshold we set was not sufficiently high to consistently confirm the presence of an allergic rhinitis (AR) episode. In future studies, it could be advantageous to include participants from various severity classifications, such as mild, moderate, and severe, to assess the efficacy of Levagen + more comprehensively across different AR severities. Additionally, incorporating a more clinical diagnosis approach in future studies would help ensure that the reported symptoms align accurately with AR, enhancing the study’s reliability.