Efficacy of Functional Foods, Beverages, and Supplements Claiming to Alleviate Air Travel Symptoms: Systematic Review and Meta-Analysis

Airline passengers experience a range of symptoms when travelling on long flights. This review evaluated the efficacy of functional foods, beverages, and supplements claiming to address the effects of air travel for healthy adults. Products were identified in a scoping review of electronic databases, search engines, and grey literature (March to August 2019). A systematic review of the efficacy of product ingredients was conducted using five electronic databases from inception to February 2021. Articles were screened, data extracted, and assessed for risk of bias by two researchers independently. Meta-analysis was performed. Of the 3842 studies identified, 23 met selection criteria: melatonin (n = 10), Pycnogenol (n = 4), various macronutrients (n = 2), caffeine (n = 2), Centella asiatica (n = 1), elderberry (n = 1), Echinacea (n = 1), fluid (n = 1), and Pinokinase (n = 1). Meta-analysis (random effects model) indicated melatonin reduced self-reported jetlag following eastbound (n = 5) and westbound (n = 4) flights: standard mean difference −0.76 (95% CI = −1.06 to −0.45, I2 0%, p < 0.00001) and −0.66 (95% CI = −1.07 to −0.26, I2 45%, p = 0.001), respectively. Pycnogenol also reduced edema scores (n = 3), standard mean −4.09 (95% CI = −6.44 to −1.74), I2 98%, p = 0.0006). Overall, 12 of 183 ingredients contained in 199 products had evidence to support claims.


Introduction
The popularity of international travel has been growing, and over 4.3 billion passengers commuted by air in 2018 [1]. The increasing number of travelers exposed to long-and ultralong-haul flights can experience a range of physiological and psychological symptoms. Despite significant disruptions to international travel due to the COVID-19 pandemic, the rollout of vaccines suggests that long-haul international air travel may soon resume.
Jetlag, the desynchronization of normal circadian rhythm, occurs as a result of rapid travel through multiple time zones [2]. This is characterized by sleep disturbances, daytime fatigue, reduced cognitive and physical performance, and alterations in mood [2,3]. The severity of symptoms worsens following eastward travel over multiple time zones [2].
Air travel has also been associated with several other physical conditions: the sensation of abdominal distention and bloating due to expansion of gases within the gastrointestinal tract at typical aircraft cruising altitudes [4,5], dehydration from low cabin humidity, and the consumption of diuretic beverages commonly served onboard commercial flights such as alcohol. Additionally, the mildly hypoxic cabin conditions combined with dehydration and reduced physical activity result in an increased risk of deep vein thrombosis [5] and edema [6]. The close seating proximity of passengers over long-haul flights increases the possibility of transmission of infectious diseases [7]. Of some concern to cabin crews and frequent travelers is the prolonged exposure to radiation in long-haul flights, and the high altitude of flights may increase an individual's radiation exposure [8].

Scoping Review
The scoping review of available functional foods, beverages, and supplements was conducted from 6 March 2019 until 31 August 2019.

Search Strategy
Functional foods, beverages, and supplements were identified using four databases (Medline, Embase, PsycINFO, and Web of Science) and two search engines (Google and Bing). Search terms were combinations, truncations, and synonyms of terms relating to food and beverages with aviation terms and symptoms associated with flight. Databases were searched from inception until April 2019. A sample search strategy for Medline (via Ovid) is provided in Supplementary Table S1. Due to the large number of records recalled on the Google and Bing search engines, only the first 15 pages from each of the 17 different searches per engine were reviewed according to the default display. The search terms are shown in Supplementary Table S2. Several grey literature publications (PAX International, APEX, and Onboard Hospitality) that circulate articles and advertisements of potentially relevant functional foods, beverages, and supplements were also hand-searched from earliest publicly available issue.

Product Inclusion and Exclusion Criteria
Items identified were investigated further by an online search and were included in the product database if they were (i) stocked or marketed to airlines, airports, or commercial cabin crew; (ii) claimed to be used or developed by commercial cabin crew; (iii) had a scientific publication trialing the product within an air flight simulation setting; (iv) provided instructions for commercial inflight use.
Products were excluded from the database if they were discontinued at the time of the search or did not fulfill the inclusion criteria.

Product Database Formation
Using publicly available material, the following information was recorded in a Microsoft Excel 2011 spreadsheet (Microsoft, Redmond, WA, USA): product information, health claims made, evidence provided by the manufacturer, ingredients, price (per serve in Australian dollars), recommended method of consumption, and nutritional information (per serve and per 100 g).

Ingredient Synthesis of Products within the Database
All ingredients with advertised possible beneficial effects on symptoms relating to flight contained within products included in the database were extracted and categorized into the following categories: vitamins, minerals, macronutrients, and other. These ingredients as well as the consumption method of these products were examined further by systematic literature review.

Search Strategy
The search was conducted from journal inception to the 25 February 2021 in the following electronic databases: Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Medline (including Pre-Medline), and PsycINFO. The reference list of included studies and scientific articles referenced by products in the database were hand-searched for additional records.
The search terms were both the common and scientific names of the ingredients contained in the products in the database combined with synonyms and truncations of aviation terms and the databases' subject headings. The Scottish Intercollegiate Guidelines Network (SIGN) randomized controlled trial study filter [15] was adapted to capture nonrandomized controlled trials and applied to searches conducted in CINAHL, Embase, and Medline with assistance from an academic liaison librarian. The search strategy for Medline (via Ovid) can be found in Supplementary Table S4.

Eligibility Criteria
The following randomized and non-randomized controlled trials were included in order to capture all articles with appropriate control groups according to the following criteria: • Population: healthy adults aged over 18 years without pre-existing health conditions that would impact the primary outcome of the intervention. • Intervention: the administration of a food, beverage, or nutritional supplement to participants at any time before, during, or after a commercial air flight or simulation. • Comparator: an appropriate control or comparison group receiving no intervention, a placebo, or standard management and underwent the same air flight or simulation as the intervention group. • Outcomes: any qualitative or quantitative measurement of physical or cognitive symptoms associated with air travel.
Studies were excluded if they were • Conducted under military or space flight settings, as the conditions of speed and altitude are not comparable to commercial air travel. • Examined a combination pharmacological (other than caffeine and melatonin) or non-pharmacological therapies, whereby the specific effect of the test food, beverage, or nutritional supplement could not be ascertained.

•
Non-English texts. • Full paper was not available.

Study Selection
Titles and abstracts were imported into the EndNote X9 reference management software (Clarivate Analytics, Philadelphia, PA, USA). Duplicates were removed, and titles and Nutrients 2021, 13, 961 4 of 30 abstracts were reviewed by two independent assessors (VC and LW) against the eligibility criteria and assigned into two groups: (i) further review or (ii) excluded. The full text of potentially eligible papers was obtained and reviewed independently (VC and LW), and reasons for exclusion were recorded ( Figure 1). Discrepancies in results were resolved through discussion and a third independent reviewer (MAF) involved when an agreement could not be reached.
• Full paper was not available.

Study Selection
Titles and abstracts were imported into the EndNote X9 reference management software (Clarivate Analytics, Philadelphia, PA, USA). Duplicates were removed, and titles and abstracts were reviewed by two independent assessors (VC and LW) against the eligibility criteria and assigned into two groups: (i) further review or (ii) excluded. The full text of potentially eligible papers was obtained and reviewed independently (VC and LW), and reasons for exclusion were recorded ( Figure 1). Discrepancies in results were resolved through discussion and a third independent reviewer (MAF) involved when an agreement could not be reached. Figure 1. Flowchart of literature search and screening for selection of randomized and non-randomized controlled trials examining the effects ingredients found in functional foods, beverages, and supplements that claim to alleviate flightrelated symptoms. Other sources included a hand search of reference lists of relevant systematic reviews as well as studies listed by products identified in scoping review. Flowchart of literature search and screening for selection of randomized and non-randomized controlled trials examining the effects ingredients found in functional foods, beverages, and supplements that claim to alleviate flight-related symptoms. Other sources included a hand search of reference lists of relevant systematic reviews as well as studies listed by products identified in scoping review.

Data Extraction
The data extraction table designed was guided by the PRISMA statement [13] with some additional elements included. Two reviewers independently extracted the following data in duplicate: study details (author, year, country, funding, and affiliations), participants (characteristics, flight or simulation details, inclusion and exclusion criteria, attrition, and blinding), intervention and comparator details (intervention, sample size, length of intervention and follow-up, and retention rate), and outcomes (qualitative and quantitative measures of symptoms associated with flight and adverse effects).

Data Synthesis and Analysis
The primary outcome of interest was the change in cognitive and physical symptoms associated with air flight. Studies were grouped according to their intervention (and flight direction if applicable). Where possible, for all study arms results were recorded as mean at baseline and post-intervention, with measures of error (SEM or SD) and associated p-values.
A meta-analysis was performed on the edema scores (3 trials) for Pycnogenol studies and visual analogue ratings of jetlag symptoms after melatonin administrations (5 trials eastbound and 4 trials westbound) for studies of similar design using Cochrane RevMan (version 5.4, The Cochrane Collaboration). A random effects model and standardized mean difference (Cohen d) was applied. Data were presented graphically as forest plots by intervention (and flight direction for melatonin). Studies were grouped according to the timing of administration of melatonin as either prior to flight or at bedtime on the day of or following flight. Asymmetry could not be assessed by funnel plot analysis as there were fewer than 10 studies included in the meta-analyses [16]. Missing data required for the meta-analysis were obtained from a previous publication [2] or imputed as per the Cochrane Systematic Review Handbook [16].

Quality Assessment
Risk of bias was assessed independently by the two reviewers (VC and LW) using the appropriate Cochrane Collaboration Tool-Risk of Bias for Randomized Control Trials II [17] or Robins I for Other Non-Randomized Interventions [18].
Grading of Recommendations Assessment, Development and Evaluation system [19] was not performed as initially proposed in the published protocol [14]. This diversion from the protocol is explained in the Discussion section.

Scoping Review
A total of 199 functional foods, beverages, and supplements were included in the database. Of which, 55.8% were unique (n = 111) and the remaining were the same product but of a different flavor (n = 47, 23.6%), portion size (n = 40, 20.1%), or part of a package (n = 1, 0.5%).
A total 183 ingredients were advertised to deliver the improvements to health and wellbeing of these products. As shown in Table 2, the majority of products (66.7%) promoted at least one herbal compound or supplement as an ingredient purporting to have beneficial effects. Pycnogenol was reported in 6.3% of all products, 2.7% for caffeine, and 12.6% for melatonin. However, 24.3% of products identified did not provide a full ingredient list. The majority of evidence to support claims made by products was primarily in the form of generalized statements with no peer reviewed publications referenced (79.3%) and lay testimonies from consumers (54.1%). A small proportion of products (n = 15) provided some form of scientific evidence, most of these were not conducted within flight settings (n = 6) or did not have results published (n = 2) at the time that the scoping review was completed. Of the remaining products, results were published in the form of a letter (n = 1), subsection of a review paper (n = 1), or conference abstracts (n = 3). Only 2 out of the 199 products referenced peer reviewed publications of studies that were conducted within appropriate air flight settings.

Study Selection
As shown in Figure 1, a total of 4741 articles were obtained by database searching. A further 42 studies were identified through hand searching reference lists and articles referenced by products included within the scoping review database. After removal of duplicates, 3842 records were screened by title and abstract, of which 3776 were excluded. The remaining 66 studies underwent full-text review. Twenty-three studies met the eligibility criteria and were included in this review. The remaining 43 studies were excluded with reasons provided (Figure 1 and Supplementary Table S3).
The characteristics of the interventions categorized by the two different test conditions are reported in Table 3 for studies conducted within flight conditions and Table 3 for studies conducted in simulated flight conditions.
Participant characteristics and intervention procedures varied across studies. All supplements were administered in the form of a tablet, pill, or capsule. The results were collected <2 h following their flight (n = 4) [33,34,36,37] or participants were followed up over a period of 28 h to four weeks. The percentage of participants followed up was reported by 17 studies and ranged between 72% and 100%. The compliance of participants to allocated intervention was only reported in four studies [20][21][22]32] and ranged between 60% and 97%.

Characteristics of Studies Conducted in Simulated Flight Settings
The five studies conducted in a simulated flight setting are outlined in Table 3. These interventions studied the effects of caffeine [28,39], fluid [40], fiber [4], and macronutrients [41]. Four studies used computer simulations [38][39][40][41], and one used a simulated flight altitude [4]. The length of flight simulations was reported in all studies and ranged from 10 min to 8 h.
All studies were RCTs. The interventions were administered in food form [4,41], liquid form [38,40], or as a tablet/pill [39]. Two studies reported performing a power calculation to determine sample size [40,41]. Participant characteristics and intervention procedures varied across studies. The results were collected for all participants immediately following the flight simulation. Full compliance with procedures (100%) was reported in three interventions [4,38,39].
The key outcomes are reported according to the test conditions: Table 4 details the characteristics of studies conducted within flight conditions and Table 4 for studies conducted in simulated flight conditions.

Key Outcomes of Studies Conducted within Flight Settings
The key outcomes of studies conducted within flight settings are outlined in Table 4. Supplementation with Centella asiatica appeared to reduce the rate of ankle swelling and edema [20]. Pinokinase seemed to reduce the edema score and incidence of deep vein thrombosis in high-risk subjects [33]. One of the four studies examining the effects of Pycnogenol reported a reduction in the incidence of deep vein thrombosis and superficial venous thrombosis [36]. Elderberry supplementation did not seem to reduce the incidence of cold diagnosis; however, it appeared to reduce symptom score [21]. Administration of Echinacea reported a reduction in participants reporting respiratory illness [22].

Key Outcomes of Studies Conducted within Simulated Flight Settings
They key outcomes of studies conducted in simulated flight settings are summarized in Table 4. One of the studies studying caffeine found possible beneficial effects during sustained wake times [39]. The other study found no significant effects of caffeine dosage on flight performance [38]. Participant scores appeared to be negatively impacted by dehydration but not significantly influenced by high-or low-fluid diets [40]. Participants on a high-fat or high-carbohydrate diet seemed to achieve better flight scores than those consuming a high-protein diet [41].
Higher-fiber diets appeared to be associated with slower gastric emptying and higher reported gastrointestinal symptoms in flight altitude simulations when compared to participants on low-fiber diets [4].
Adverse effects were only reported for the study examining fiber on gastrointestinal symptoms [4], and no other adverse effects were reported by the other studies conducted in simulated flight settings.
3.2.7. Impact of Melatonin on Self-Reported Jetlag Following Westbound Travel Four papers (five interventions) [23][24][25][26] studied the effects of melatonin on jetlag symptoms in westbound travel (n = 3 both directions and remaining intervention in westward direction only) using visual analogue scales (see Table 4). The dosage of melatonin ranged between 0.5 mg and 5.0 mg and was administered prior to departure (n = 3) or at bedtime upon arrival (n = 1).

Key Outcomes of Studies Conducted within Simulated Flight Settings
They key outcomes of studies conducted in simulated flight settings are summarized in Table 4. One of the studies studying caffeine found possible beneficial effects during sustained wake times [39]. The other study found no significant effects of caffeine dosage on flight performance [38]. Participant scores appeared to be negatively impacted by dehydration but not significantly influenced by high-or low-fluid diets [40]. Participants on a high-fat or high-carbohydrate diet seemed to achieve better flight scores than those consuming a high-protein diet [41].
Higher-fiber diets appeared to be associated with slower gastric emptying and higher reported gastrointestinal symptoms in flight altitude simulations when compared to participants on low-fiber diets [4].
Adverse effects were only reported for the study examining fiber on gastrointestinal symptoms [4], and no other adverse effects were reported by the other studies conducted in simulated flight settings.

Impact of Melatonin on Self-Reported Jetlag Following Westbound Travel
Four papers (five interventions) [23][24][25][26] studied the effects of melatonin on jetlag symptoms in westbound travel (n = 3 both directions and remaining intervention in westward direction only) using visual analogue scales (see Table 4). The dosage of melatonin ranged between 0.5 mg and 5.0 mg and was administered prior to departure (n = 3) or at bedtime upon arrival (n = 1).
The meta-analysis was performed on all four studies (five interventions). A random effects model was used to combine studies examining the effect of melatonin on selfreported jetlag following westbound flight. Figure 2 presents the forest plot, and the overall effect size between intervention and placebo group was −0.66 (95% CI = −1.07 to −0.26, I2 45%, p = 0.001). Subgroup analysis between administration prior to flight (effect size: −0.64, 95% CI = −1.29 to 0.00, I2 66%, p = 0.05) and on day of or after flight (effect size: −0.67, 95% CI = −1.26 to −0.07, I2 28%, p = 0.03) showed similar trends.  Diamond represents overall effect size, squares indicate percentage weighting of each study to overall effect size and 95% confidence intervals shown using horizontal lines.

Impact of Melatonin on Self-Reported Jetlag Following Eastbound Travel
Nine interventions examined the effect of melatonin on jetlag symptoms following eastbound travel (n = 3 both directions [23][24][25] and n = 6 in eastward direction only [27][28][29][30][31][32]). Seven interventions assessed jetlag with a visual analogue scale [23][24][25][26][27][28][29]31]; one used the Columbia jetlag scale [30]; the other asked about jetlag symptoms on a three-point scale [32]. One study applied the Liverpool jetlag questionnaire in addition to the visual analogue scale [29]. Dosage of melatonin varied between studies ranging from 0.5 mg to 8.0 mg. Administration schedules of melatonin differed between study protocols with studies providing melatonin to participants prior to departure (n = 3) or only at bedtime (n = 6) on the day of flight or after arrival.
A meta-analysis was completed on five comparable studies, but four had to be excluded because the mean and variance measures were not reported or able to be calculated [29][30][31][32]. Authors were not contacted for additional information, as studies were published over 19 years prior to this review. A random effects model was used to combine studies examining the effect of melatonin on self-reported jetlag following eastbound travel. Figure 3 presents the forest plot, and the overall effect size between intervention and placebo group was −0.76 (95% CI = −1.06 to −0.45, I 2 = 0%, p < 0.00001). Subgroup analysis between melatonin administration prior to flight (effect size: −0.88, 95% CI = −1.26 to −0.49, I 2 0%, p < 0.00001) and on the day of or after flight (effect size: −0.56, 95% CI = −1.06 to −0.07, I 2 0%, p = 0.03) showed similar trends.
3.2.8. Impact of Melatonin on Self-Reported Jetlag Following Eastbound Travel Nine interventions examined the effect of melatonin on jetlag symptoms following eastbound travel (n = 3 both directions [23][24][25] and n = 6 in eastward direction only [27][28][29][30][31][32]). Seven interventions assessed jetlag with a visual analogue scale [23][24][25][26][27][28][29]31]; one used the Columbia jetlag scale [30]; the other asked about jetlag symptoms on a three-point scale [32]. One study applied the Liverpool jetlag questionnaire in addition to the visual analogue scale [29]. Dosage of melatonin varied between studies ranging from 0.5 mg to 8.0 mg. Administration schedules of melatonin differed between study protocols with studies providing melatonin to participants prior to departure (n = 3) or only at bedtime (n = 6) on the day of flight or after arrival.
A meta-analysis was completed on five comparable studies, but four had to be excluded because the mean and variance measures were not reported or able to be calculated [29][30][31][32]. Authors were not contacted for additional information, as studies were published over 19 years prior to this review. A random effects model was used to combine studies examining the effect of melatonin on self-reported jetlag following eastbound travel. Figure 3 presents the forest plot, and the overall effect size between intervention and placebo group was −0.76 (95% CI = −1.06 to −0.45, I 2 = 0%, p < 0.00001). Subgroup analysis between melatonin administration prior to flight (effect size: −0.88, 95% CI = −1.26 to −0.49, I 2 0%, p < 0.00001) and on the day of or after flight (effect size: −0.56, 95% CI = −1.06 to −0.07, I 2 0%, p = 0.03) showed similar trends.

Impact of Pycnogenol on Edema
Three studies investigated the impacts of Pycnogenol on edema [34,35,37]. Dosages ranged from 100 mg to 200 mg and were administered within 2-3 days (n = 2) [34,35] or 3 h of departure (n = 1) [37]. Standard management of regular water consumption and exercise was employed in one study in all intervention groups [34].
The meta-analysis was performed on all three studies. One study [34] provided subgroup results according to participant risk of developing edema and deep vein thrombosis i.e., low, moderate, or high risk. A random effects model was used to combine studies examining the effect of Pycnogenol on edema. Figure 4 presents the forest plot, and the effect size between intervention and placebo group was −4.09 (95% CI = −6.44 to −1.74, I2 98%, p = 0.0006). Diamond represents overall effect size, squares indicate percentage weighting of each study to overall effect size and 95% confidence intervals shown using horizontal lines.

Impact of Pycnogenol on Edema
Three studies investigated the impacts of Pycnogenol on edema [34,35,37]. Dosages ranged from 100 mg to 200 mg and were administered within 2-3 days (n = 2) [34,35] or 3 h of departure (n = 1) [37]. Standard management of regular water consumption and exercise was employed in one study in all intervention groups [34].
The meta-analysis was performed on all three studies. One study [34] provided subgroup results according to participant risk of developing edema and deep vein thrombosis i.e., low, moderate, or high risk. A random effects model was used to combine studies examining the effect of Pycnogenol on edema. Figure 4 presents the forest plot, and the effect size between intervention and placebo group was −4.09 (95% CI = −6.44 to −1.74, I2 98%, p = 0.0006).

Risk of Bias of Included Studies
The majority of RCTs were rated as high risk of bias (n = 13) as many did not report performing intention to treat analysis (domain 2) nor manage missing data appropriately (domain 3), as shown in Figure 5. Reporting bias could not be accurately discerned as only two of the RCTs provided details of their trial registration (domain 5).

Risk of Bias of Included Studies
The majority of RCTs were rated as high risk of bias (n = 13) as many did not report performing intention to treat analysis (domain 2) nor manage missing data appropriately (domain 3), as shown in Figure 5. Reporting bias could not be accurately discerned as only two of the RCTs provided details of their trial registration (domain 5). Similarly, most non-RCTs were rated as serious risk of bias, as many did not adjus for confounding variables adequately (domain 1) nor report methodology to handl missing data (domain 5), indicated in Figure 6. Additionally, three studies had missin participants that were not accounted for in their analysis.  [4,[20][21][22][23][24][25][26][27]30,33,34,[36][37][38][39][40][41].
Similarly, most non-RCTs were rated as serious risk of bias, as many did not adjust for confounding variables adequately (domain 1) nor report methodology to handle missing data (domain 5), indicated in Figure 6. Additionally, three studies had missing participants that were not accounted for in their analysis.

Discussion
A range of functional foods, beverages, and supplements was identified with 111 unique products included in the database as part of the scoping review, 93.7% of which made one or more health claims. Limited evidence was found to support claims made for such products. Only 12 out of 183 ingredients had scientific evidence trialing their use in flight settings or simulations across the 23 studies identified in the systematic review.
Melatonin had the greatest number of studies. Melatonin appears to have beneficial effects on self-reported jetlag following both east-and westbound flights. However, timing of melatonin ingestion may play a role because administration prior to flight appeared more effective than when administered on the day of or post flight. Travelers may have experienced more beneficial effects of the preflight melatonin following eastbound travel as it is often reported to be more severe than in the westerly direction [10]. This review employed a random effects model using standardized mean difference as study protocols, and outcome measurement was different between studies. Despite differences in methodology, the meta-analyses findings of this review for melatonin parallel those of a similar Cochrane review [2], which utilized a fixed effect model with mean difference. The meta-analysis of the effects of melatonin in this review also included the results of two additional papers in the westbound [25,26] and one in the eastbound [25] direction.
All studies included in the melatonin meta-analyses used a visual analogue scale to assess jetlag as these research studies were conducted prior to the development of the other measurement methods i.e., Liverpool scale (2000 [42]) or the Columbia scale (1999 [30]). A single subjective rating of jetlag on a visual analogue scale has limitations but remains useful for capturing the passengers' experience of jetlag [43].
Most studies examining melatonin were classified as having a high risk of bias. Those employing an RCT design often did not report performing intention to treat analysis nor manage missing data appropriately. Of the two studies that were classified as non-RCT, they did not control for confounding variables.
Pycnogenol supplementation had favorable effects on edema. However, the majority of the studies examining this compound appear to have originated from the same group. No studies examining Pycnogenol adequately reported if their participants were blinded to intervention arm nor control for confounding variables (for non-randomized controlled

Discussion
A range of functional foods, beverages, and supplements was identified with 111 unique products included in the database as part of the scoping review, 93.7% of which made one or more health claims. Limited evidence was found to support claims made for such products. Only 12 out of 183 ingredients had scientific evidence trialing their use in flight settings or simulations across the 23 studies identified in the systematic review.
Melatonin had the greatest number of studies. Melatonin appears to have beneficial effects on self-reported jetlag following both east-and westbound flights. However, timing of melatonin ingestion may play a role because administration prior to flight appeared more effective than when administered on the day of or post flight. Travelers may have experienced more beneficial effects of the preflight melatonin following eastbound travel as it is often reported to be more severe than in the westerly direction [10]. This review employed a random effects model using standardized mean difference as study protocols, and outcome measurement was different between studies. Despite differences in methodology, the meta-analyses findings of this review for melatonin parallel those of a similar Cochrane review [2], which utilized a fixed effect model with mean difference. The meta-analysis of the effects of melatonin in this review also included the results of two additional papers in the westbound [25,26] and one in the eastbound [25] direction.
All studies included in the melatonin meta-analyses used a visual analogue scale to assess jetlag as these research studies were conducted prior to the development of the other measurement methods i.e., Liverpool scale (2000 [42]) or the Columbia scale (1999 [30]). A single subjective rating of jetlag on a visual analogue scale has limitations but remains useful for capturing the passengers' experience of jetlag [43].
Most studies examining melatonin were classified as having a high risk of bias. Those employing an RCT design often did not report performing intention to treat analysis nor manage missing data appropriately. Of the two studies that were classified as non-RCT, they did not control for confounding variables.
Pycnogenol supplementation had favorable effects on edema. However, the majority of the studies examining this compound appear to have originated from the same group. No studies examining Pycnogenol adequately reported if their participants were blinded to intervention arm nor control for confounding variables (for non-randomized controlled interventions). They also introduced selection bias as they did not use intention to treat analysis for the RCTs. Despite the meta-analysis showing beneficial effects, it should be noted that due to the high level of heterogeneity (for Pycnogenol), a limited number of studies, and high risk of bias, the results should be interpreted with caution.
The remaining 14 studies examined the effects of caffeine, Centella asiatica, elderberry, Echinacea, Pinokinase, and diets containing various levels of fluid, macronutrients, or fiber. All interventions only had one study examining its effects, with the exception of caffeine that had two studies. None of these ingredients were tested under both flight and simulation conditions.
The majority of studies were rated as high risk of bias, and consequently the results of the included papers should be interpreted with caution. There is an insufficient evidence base to make a definitive judgement for their usage within air flight settings.
In Australia, the efficacy of low-risk complementary medicines is not assessed prior to sale, and products that are typically considered food can in some instances make health claims and not be classified as a therapeutic good [44,45]. This reflects why the majority of the products identified in this study did not provide high-quality scientific evidence to justify the health claims made.
Most interventions were well tolerated with no adverse effects reported by participants. Supplementation with elderberry resulted in some reports of cold and flu symptoms. Those administered with Echinacea reported vomiting, headache, heart burn, diarrhea, tingling, and in some instances burning of the tongue and mouth. Melatonin was the least welltolerated with seven out of ten studies reporting some adverse effects, the most common being headache, nausea, and diarrhea.
The majority of studies did not report their sources of funding; therefore, it was difficult to assess conflicts of interest. Five studies reported some affiliations with industry; one indicating involvement with supply, design, and publication; one for the supply of materials; one on the recruitment of participants; and two were unclear on its impact on published results. This may pose a risk of bias that might be favored towards beneficial effects of these compounds [46]. Five studies indicated they received funding sources with low risk of conflict of interest.
One of the major limitations of our review is the limited number of high-quality studies free from a high risk of bias and with adequate sample size to demonstrate effects. The studies included in the meta-analysis mostly had a small number of participants and were of poor quality as rated by the Cochrane risk of bias tools. As such the GRADE approach to make recommendations was abandoned (despite initially intended). The study protocols were often poorly reported with respect to duration, direction, and type of flight test (computer simulations and air flights). As a result, no subanalysis of the effects of flight duration on the efficacy of melatonin for jetlag could be conducted. As the body of evidence grows, further examination of the impacts of these varied conditions may be assessed in a manner not currently possible.
To our knowledge this is the first extensive review examining the efficacy of functional foods, beverages, and supplements that claim to alleviate symptoms experienced in air flight. The systematic review was limited to studies published in English and may have missed studies in other languages. However, the search strategy employed was comprehensive (spanning 674 lines in Medline via Ovid) conducted across multiple electronic databases.

Conclusions
Overall, from the range of functional foods, beverages, and supplements identified in the scoping review, there is limited research performed within flight or simulation settings to assess claims made. Of the studies available, Pycnogenol and melatonin may have beneficial effects on edema and jetlag, respectively. However, due to the poor quality and small number of studies, no recommendation for the use of these products can be made until more research emerges.

Supplementary Materials:
The following are available online at https://www.mdpi.com/2072-664 3/13/3/961/s1, Table S1. Electronic database search strategy: Medline (via ovid) for scoping review of functional foods, beverages and supplements for flight related symptoms, Table S2. Search engine search strategy for scoping review of functional foods, beverages and supplements for flight related symptoms, Table S3. Full text articles excluded (n = 43) with reasons, Table S4. Electronic database search strategy: Medline (via Ovid) for systematic review.