enXtra (Alpinia galanga extract)

“A neuroactive botanical that delivers nootropic benefits”

Overview  (refer to SIDI Package_enXtra)

• enXtra is a natural, non-stimulant, water-soluble proprietary extract of Alpinia galanga (part of the ginger/turmeric family), commonly used spice in Asian cooking, with bioactive constituents including polyphenols, tannins, and polysaccharides.
• enXtra harnesses a neuroactive botanical power, that delivers new scientific evidence for nootropic benefits
• enXtra holds 1 mechanistic study, 1 toxicology study in rats, and 5 human clinical studies, clinically shown to promote and sustain mental alertness, support focus and attention, promote positive mood and calmness, and support energy and vigor
• Country of origin: India
• Proposed shelf life of 2 years
• Pre-DSHEA Status
• DNA-authenticated
• Self-affirmed GRAS
• enXtra is nonGMO, gluten free, free of allergens, and contains no artificial or synthetic ingredients

Composition & Dosing

Alpinia galanga extract (Alpinia galanga)(rhizome) Std. to 4% polyphenols, 3% flavonoids, 30% glycosides

Composition:

• 94-97% by weight (active)
• Maltodextrin 2.5-5% by weight (carrier)
• Silicon dioxide 0.5-1% by weight (anti-caking agent)

Clinical dose: 300 mg once daily

enXtra is a trademark of OmniActive Health Technologies Limited.

(SIDI Package_enXtra)

What is special about enXtra?

enXtra is in the ginger/turmeric family that works in the body similar to caffeine. It is a stim-free energy ingredient that provides fast, effective and safe energy with no crash. enXtra improves mental alertness & acuity for up to 5 hours more effectively than caffeine without increasing heart rate, blood pressure, or impacting sleep. (Srivastava, 2017) (Srivastava, 2017 (Sept)), (Srivastava, 2018) (Srivastava, 2020) (Eraiah, 2023)

Natural Medicines Database Safety, Effectiveness & Interaction Analysis

• LIKELY SAFE ...when used orally in amounts commonly found in foods. Alpinia has Generally Recognized as Safe (GRAS) status in the US.
• POSSIBLY SAFE ...when used orally and appropriately in medicinal amounts. Alpinia extract 300 mg daily has been used with apparent safety for 12 weeks.
• PREGNANCY AND LACTATION: There is insufficient reliable information available about the safety of alpinia when used in medicinal amounts during pregnancy and lactation; avoid using.
• When used orally, the most common AE is gastrointestinal effects.
• No moderate/major drug or nutrient interactions found

Safety data

• In one human study, the findings demonstrated the psychostimulant efficacy of enXtra with no safety concerns on long-term usage. (Srivastava, 2020) (see below under human studies for further details)
• A subchronic toxicity study in rats, using a 14-day repeated dose of up to 3,000 mg/kg BW per day of enXtra extract was well tolerated. (Shanmugasundaram, 2022)

Research summary:

Preclinical research:

• Sivanandan, 2018. Molecular docking studies of Alpinia galanga phytoconstituents for psychostimulant activity.

Human Studies

• Srivastava, 2017. Effects of Cymbopogon Flexuosus, Alpinia Galanga, and Glycyrrhiza Glabra on Attention: A Randomized Double-Blind, Placebo-Controlled Pilot Study
• Srivastava, 2017 (Sept). Effect of Alpinia galanga on Mental Alertness and Sustained Attention With or Without Caffeine: A Randomized Placebo-Controlled Study
• Srivastava, 2018. Selective enhancement of focused attention by Alpinia galanga in subjects with moderate caffeine consumption
• Srivastava, 2020. A Randomized Placebo Controlled Clinical Trial Demonstrating Safety & Efficacy of enXtra in Healthy Adults
• Eraiah, 2023. Acute Effects of Alpinia galanga Extract on Mental Alertness, Accuracy and Fatigue in Human Subjects: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study

Totality of the evidence: this search criteria was PubMed, targeted search criteria for all data (note, this type of search does not bring up every branded ingredient study as most are not open access)

• Alpinia galanga = 1,119 results with no filters or specified search criteria
• Alpinia galanga + cognitive= 43 results with no filters
• Alpinia galanga + cognitive = 4 results with an RCT filter

Preclinical research

Sivanandan, 2018. Molecular docking studies of Alpinia galanga phytoconstituents for psychostimulant activity.

Purpose: To explore the mechanism for the neurocognitive enhancing property of enXtra

Design: Molecular docking study comparing a database of molecules present in enXtra against a panel of target proteins responsible for enhancing attention network components

Dosage: N/A

Measurements & Methods: The extract was analysed qualitatively by colour tests for the presence or absence of phytoconstituents with caffeine used as a comparative. (see study for further info on the below methods)

• Qualitative assessment of bioactive components
• GC-MS Analysis
• Molecular Modelling
• Target preparation - 4M48-Dopamine transporter and 4TVK-Acetylcholinesterase were considered for docking.
• Ligand Preparation
• Lipinski’s Rule of Five
• ADME Profile
• GlideScore

Results:

• Six compounds from the enXtra scored high for interacting with the dopamine target protein.
• For acetylcholinesterase target proteins, most of the compounds in enXtra scored higher compared to caffeine
• Through a study model known as molecular docking, it is suggested that enXtra’s active components increase dopamine levels by means of blocking reuptake.

Potential language: Preclinical research suggests enXtra works by increasing dopamine levels

Notes: Reuptake inhibition is achieved when extracellular dopamine not absorbed by the postsynaptic neuron is blocked from re-entering the presynaptic neuron. This results in increased extracellular concentrations of dopamine and increase in dopaminergic neurotransmission.

Human studies

Srivastava, 2017. Effects of Cymbopogon Flexuosus, Alpinia Galanga, and Glycyrrhiza Glabra on Attention: A Randomized Double-Blind, Placebo-Controlled Pilot Study

Purpose: To evaluate the efficacy and safety of natural product extracts in the subjects with caffeine dependence

Population: 70 subjects were assessed, aged 18-40 years with a BMI of 18-25 kg/m2, a resting blood pressure less than or equal to 140/90 mmHg, and habituated to > 400 mg/day caffeine consumption were eligible; subjects were nonsmokers.

• 64 subjects completed the trial

Treatment: 7 groups studied in this 7-day pilot study

• C. flexuosus oil (LG)
• A. galanga (AG1)
• A. galanga (AG2)
• G. glabra (GG1)
• G. glabra (GG2)
• Caffeine (CF)
• Placebo (microcrystalline cellulose)

Design: A randomized, double-blind, placebo-controlled study

• Subjects had to refrain from caffeine products and vigorous physical activity 12 hours prior to the study visit.
• As caffeine abstinence tends to increase sleepiness, consequently reducing the alertness score, the included subjects had to have an Epworth’s sleepiness scale ≥ 10
• A standardized meal was provided on testing days
• On day 1, all the subjects reported to the clinic in the morning hours and the testing began at any early time of the day 8-9:00 am.
• The mean response time, alertness, orientation, and executive attention by ANT was collected after breakfast followed by the administration of the actives
• Post ingestion, data by ANT were collected at 1,3, and 5 hours
• From the days 2-6, the subjects were advised to take two capsules daily until the day 6
• On the day 7 visit, subjects followed the exact schedule as that of day 1.

Composition:

• C. flexuosus oil (LG) = 148.75 mg
• A. galanga water soluble extract (AG1) = 300 mg
• A. galanga water-insoluble extract (AG2) = 300 mg
• G. glabra water soluble extract (GG1) = 500 mg
• G. glabra water-insoluble extract (GG2) = 500 mg
• Caffeine (CF) = 120 mg
• Placebo (microcrystalline cellulose) = 500 mg

Measurements: Mean response time and alertness by Attention network test (ANT)

• Primary: mean response time measured in milliseconds
• Secondary outcomes: scores for alertness, orientation, and execution (ANT)
• ANT is an objective tool that analyses different aspects of the attention network
• The ANT is a combination of a flanker task (with arrows) and a cued reaction time task. Participants indicate the direction of a central arrow that is flanked by four arrows (two per side) pointing in the same direction as the central arrow (congruent condition) or in the opposite direction (incongruent condition), in the neutral condition, either straight lines flank the central arrow or the central arrow is presented alone. The arrows are preceded by one of three types of cues (center cue, double cue, spatially informative cue; all of which are temporally informative) or no cue (a temporally uninformative condition). The center and double cues indicate that the arrow stimulus will occur soon, and the spatially informative cue is 100% predictive of the target location. The software –generated mean response time and attention networks scores in (ms) were used as such for the interpretation without a further need for the data refinement.

Statistically Significant Results:

• In summary, caffeine, AG1 and GG2 demonstrated an improvement in the separate aspects of the attention network.
• Out of all the groups, only 300 mg AGI (enXtra) showed consistent and statistically significant increase in alertness score vs. placebo and baseline at 1, 3, and 5 hours.
• Only caffeine showed a reduction in mean response time at 3 hours; however, it did not show at 5 hours indicating that the effect of caffeine on attention and focus was transient and declines after the 3rd hour

Conclusion: enXtra demonstrated a sustained increase in alertness up to 5 hours

Limitations: Small sample size, the data collected was combined with day 1 and day 7 – with the subjects taking the actives on day 1 (test day), taking active on non-test days (2,3,4,5,) and stopping the active on day 6. On day 7 (test day), the process was repeated exactly the same as day 1. Since there is no Pharmacokinetics data to determine how long enXtra stays in the blood, it is possible (although unlikely)) that a carryover affect may contribute to the statistically significant results.

Strengths: Only right-handed subjects were included to avoid spatial bias; standardized meal was provided. Unlike other studies which report findings on the basis of subjective feelings, this study objectively compared the effects of the IPs on the different aspects of the attention network using ANT, which is the only standardized and validated tool for an independent analysis of the different aspects of the attention network.

Adverse events: Six AEs were reported to be mild; no treatment was required.

Safety evaluation: Determined by evaluating vital parameters (blood pressure and pulse rate).

Potential disclosures

• Mfg supplied material
• Mfg funded study
• Study location: India

Notes: Future studies used a cross over design and washout to eliminate the potential for a carryover effect

Srivastava, 2017 (Sept). Effect of Alpinia galanga on Mental Alertness and Sustained Attention With or Without Caffeine: A Randomized Placebo-Controlled Study

Purpose: To determine the effect of A galanga on mental alertness and sustained attention in comparison with caffeine and placebo in subjects with a habitual caffeine intake

Population: 53 healthy subjects aged 18-40 years, with a BMI between 18-25 kg/m2 with moderate caffeine consumption, a resting blood pressure less than or equal to 140/90 mmHg completed the study

• The participants had a Generalized Anxiety Disorder-7 score < 7, Patient Health Questionnaire-9 score less than or equal to 14 and a Jin Fan’s Attention Network Test alertness score of 50 +- 20 ms.
• Caffeine history was recorded to ensure that the participants were acquainted with caffeine’s stimulant effect and were not caffeine-sensitive
• Subjects reported a sleep diary to ensure adequate sleep through testing days

Treatment: subjects were divided into 4 treatment arms and randomized for allocation to one of the interventional products (IPs) on each study visit, and a similar trend was followed for the subsequent visits. The remaining interventions in consecutive visits were only administered after a sufficient washout period of not less than 5 half-lives of caffeine in the blood to avoid a carryover effect. The subjects receiving only A galanga or caffeine or placebo were co-assigned to an additional placebo capsule to achieve a double-dummy design identical to the caffeine + E-AG-01 regime.

• Placebo = 550 mg microcrystalline cellulose
• E-AG-01 = 300 mg
• Caffeine = 200 mg
• Combination of E-AG-01 with caffeine = 300 mg and 200 mg, respectively

Design: A randomized, double-dummy, double-blind, placebo-controlled cross-over study (4 test days)

• Subjects reported to the clinic during morning hours and the testing began at an early time of the day (8-9 am) for each visit to avoid influence of daily challenges. Time of day was matched for all 4 visits.
• Subjects reported to the clinic following 24-hour abstinence from caffeine-containing products or any psychostimulants prior to all study visits
• Standardized meal was provided on test days
• The baseline data were collected 30 minutes post breakfast followed by the administration of the IP
• The study tools were administered at 1,3-, and 5-hours post-IP administration and the data was collected
• To analyze the effect of the IP on sleep architecture, a second dose of the corresponding IP was supplied in a labeled bottle to be taken before dinner the same night of the clinic visit, and the participants were asked to record all details pertaining to sleep quality and duration of sleep in the sleep diary

Measurements:

• Primary outcome: mental alertness, which is defined as achieving and maintaining a state of high sensitivity to incoming stimuli – conducted using Attention Network Test (ANT) 1.3.0 that also provides a behavioral measure of efficiency of the different components of the attention network separately within a single task.
• Mental alertness in ANT was calculated in terms of the difference score quantified in milliseconds and calculated by subtracting the average double-cue response times (RTs) from the no-cue RTs. Higher scores indicate more efficient functioning of the alerting system.
• Secondary outcomes: sustained attention (assessed by Psychomotor Vigilance Task [PVT]) and sleep architecture (assessed by Karolinska Sleepiness Scale [KSS] score), sleep duration measurement, Groningen’s Sleep Quality Scale [SQS], and sleep diary)
• PVT objectively assesses sustained attention, which might be associated with fatigue-related changes in alertness due to sleep loss, extended wakefulness, and circadian misalignment. The mean reaction time (MRT) is the time taken by a subject to press the response button as soon as each stimuli appeared. Shorter MRT indicates more efficient and sustained attention.
• Subjective sleepiness was based on a subjective questionnaire on a 10-point scale
• Wakefulness was assessed by providing subjects with a stopwatch to record duration of sleep between two assessment sessions. Participants were asked to start the stopwatch before taking a nap and to stop it once they were awake or when they were woken up by the coordinator for an assessment.
• Sleep patterns were assessed by SQS, sleep quality was graded. Lower scores indicate higher subjective quality of sleep and vice versa. Participants were asked to complete the SQS questionnaire at all study visits prior to IP administration. In addition, the participants noted their time of going to bed and rising from the bed in the sleep diary

Results:

• enXtra significantly increased mental alertness at 1, 3, and 5 hrs from baseline and at 3 hrs compared to placebo
• Caffeine significantly increased mental alertness at 1 hr from baseline but decreased at 3 hrs
• enXtra plus caffeine—significantly increased mental alertness at 1 hr but decreased thereafter
• At 5 hours, all groups demonstrated an increase in alertness score; however, this increase was greatest in the enXtra group (from baseline)
• enXtra plus caffeine—significantly increased sustained attention at 1, 3 & 5 hrs as compared with placebo

Conclusion: enXtra increases mental alertness through 5 hours; unlike caffeine that decreased at 3 hrs. This study suggests enXtra improves mental alertness & acuity for up to 5 hours more effectively than caffeine without increasing heart rate, blood pressure, or impacting sleep.

Limitations: somewhat small sample size

Strengths: Unlike the previous study (Srivastava, 2017), researchers took better precaution for a carryover using a washout and crossover design. The researchers state they controlled for carryover by adding a washout period of not less than 5 half-lives of caffeine to assess sleep parameters, there is no Pharmacokinetics data to determine how long enXtra stays in the blood; however, these results confirmed the absence of an influence of any carryover effect in this clinical study of crossover design. Due to the lack of literature pertaining to the effect of A galanga in mentally unstable or depressed individuals, investigators decided to conduct the study in mentally stable population to limit confounding factors and ambiguous results from such a study population.

Adverse events: This study demonstrated a very good safety profile with clinically insignificant safety concerns. Only 1 subject dropped out due to persistent hypertension; otherwise, no effect on BP was noted.

Safety evaluation: vital parameters were taken (heart rate and pulse rate)

Potential disclosures:

• Mfg supplied material
• Mfg funded study
• Study location: India

Notes: Double dummy is a method of blinding where both treatment groups may receive placebo

Srivastava, 2018. Selective enhancement of focused attention by Alpinia galanga in subjects with moderate caffeine consumption

Purpose: The purpose of the secondary analysis of the data from the clinical trial “A Study to Evaluate Efficacy of IP on Alertness and Mental Fatigue” (ClinicalTrials.gov NCT02816827) was to investigate the effect of the Alpinia galanga proprietary extract E-AG-01 (enXtra) on focused attention, in comparison with caffeine and placebo in moderate caffeine habitués.

Population: 59 healthy subjects aged 18-40 years (mean age of 22), with a BMI between 18-25 kg/m2 with moderate caffeine consumption, a resting blood pressure less than or equal to 140/90 mmHg completed the study

• The participants had a Generalized Anxiety Disorder-7 score < 7, Patient Health Questionnaire-9 score less than or equal to 14
• Caffeine history was recorded to ensure that the participants were acquainted with caffeine’s stimulant effect and were not caffeine-sensitive
• Subjects reported a sleep diary to ensure adequate sleep through testing days

Treatment: subjects were divided into 4 treatment arms and randomized for allocation to one of the interventional products (IPs) on each study visit, and a similar trend was followed for the subsequent visits. The remaining interventions in consecutive visits were only administered after a sufficient washout period of not less than 5 half-lives of caffeine in the blood to avoid a carryover effect. The subjects receiving only A galanga or caffeine or placebo were co-assigned to an additional placebo capsule to achieve a double-dummy design identical to the caffeine + E-AG-01 regime.

• Placebo = 550 mg microcrystalline cellulose
• E-AG-01 = 300 mg
• Caffeine = 200 mg
• Combination of E-AG-01 with caffeine = 300 mg and 200 mg, respectively

Design: A randomized, double-dummy, double-blind, placebo-controlled cross-over study (4 test days)

• Subjects reported to the clinic during morning hours and the testing began at an early time of the day (8-9 am) for each visit to avoid influence of daily challenges. Time of day was matched for all 4 visits.
• Subjects reported to the clinic following 24-hour abstinence from caffeine-containing products or any psychostimulants prior to all study visits
• Standardized meal was provided on test days
• The baseline data were collected 30 minutes post breakfast followed by the administration of the IP
• The study tools were administered at 1,3-, and 5-hours post-IP administration and the data was collected
• To analyze the effect of the IP on sleep architecture, a second dose of the corresponding IP was supplied in a labeled bottle to be taken before dinner the same night of the clinic visit, and the participants were asked to record all details pertaining to sleep quality and duration of sleep in the sleep diary

Measurements:

• As a speed-choice task, ANT provides two measures of performance: (a) response time, which is indicative of response speed and, (b) error rate, which suggests task accuracy.
• ANT to measure cognitive efficiency of the alerting, orienting, and executive-control networks

Results:

• Placebo: Demonstrated almost no change in error rate at 1 hour and an increase at 3 and 5 hrs—suggesting a decline in accuracy during task performance
• enXtra: Error rate declined from baseline at 1 hr and continued to remain low at 3 and 5 hrs, suggesting improved accuracy during task performance
• Caffeine: Demonstrated a decrease in error rate at 1 hr and 3 hrs but a subsequent increase at 5 hrs, suggesting a “caffeine-crash” effect. “Crash” is when mental energy and mood generally declines within the first 5 hours after caffeine consumption
• enXtra + caffeine: Error rate decreased at 1 and 3 hours but increased at 5 hrs

Conclusion: enXtra improves focused attention and accuracy during task performance up to 5 hours with no apparent “crash”

Limitations: somewhat small sample size

Strengths: Replicated study with added accuracy measurement. Unlike the previous study (Srivastava, 2017), researchers took better precaution for a carryover using a washout and crossover design. The researchers state they controlled for carryover by adding a washout period of not less than 5 half-lives of caffeine to assess sleep parameters, there is no Pharmacokinetics data to determine how long enXtra stays in the blood; however, these results confirmed the absence of an influence of any carryover effect in this clinical study of crossover design.

Adverse events: none reported

Safety evaluation: vital parameters were taken (heart rate and pulse rate)

Potential disclosures:

• Mfg supplied material
• Mfg funded study
• Study location: India

Notes: Double dummy is a method of blinding where both treatment groups may receive placebo

Srivastava, 2020. A Randomized Placebo Controlled Clinical Trial Demonstrating Safety & Efficacy of enXtra in Healthy Adults

Purpose: To assess the long-term safety (cardiac) and perceivable mental acuity benefits of enXtra in healthy individuals

Population:

• 69 Subjects were included who have a history of moderate caffeine ingestion, aged between 18-60 years with BMI in the range of 18-25 kg/m2.
• Subjects were screened for anxiety and depression using ‘Generalized anxiety disorder (GAD)’ and ‘Patient health questionnaire (PHQ)’
• Subjects blood pressure was between 90-132 mmHg systolic, and 60-88 mmHg diastolic

Treatment: Subjects received enXtra with or without caffeine for a period of 12 weeks

• Received two capsules twice daily for each arm (after breakfast and evening snack)
• Total enXtra was 600 mg/d

Design: Randomized, placebo-controlled study

• Abstinence from caffeine and alcohol or related products prior to scheduled visits was mandatory.
• An additional visit was scheduled at day 90 after 6 days of investigational product (IP) abstinence for evaluating if alertness effect was sustained or if there was any habituation due to continued usage.

Composition:

Measurements: Subjects were assessed for safety and efficacy on day 28, 56, and 84.

• Primary outcome: Electrocardiogram (ECG): carried out at baseline and day 84
• P wave, QRS complex, NN interval, QT variability which is an FDA-mandated primary biomarker for cardiac safety for new and existing drug products was assessed
• At baseline visit, ECG recordings were normal
• Secondary outcomes:
• blood pressure, heart rate, and pulse
• Bond and Lader visual analogue scale: a self-administered scale for evaluation of mood.
• Epworth sleepiness scale (ESS): a self-administered questionnaire used to assess daytime sleepiness.
• Pittsburgh sleep quality index (PSQI)
• Safety assessment: assessed in terms of AEs or serious AEs reported plus (BP, HR, pulse rate)

Results:

• At the end of day 84, there was no significant difference for QT interval in enXtra and enXtra plus caffeine group as compared to placebo group
• At the end of day 84, there was no significant difference in blood pressure, heart rate for the above 3 groups
• At the end of day 84, enXtra and enXtra plus caffeine groups showed significant increases in alertness scores compared to placebo
• At the end of day 84, enXtra and enXtra plus caffeine groups showed significant increases in calmness scores compared to placebo

Conclusion: Long term use of 600 mg enXtra daily is safe and helps maintain mental performance of subjects without affecting ECG and haemodynamics of middle-aged adults

Limitations: Noted by the researchers, ESS and PSQI were not significant and this may be due to the inclusion/exclusion criteria that may have restricted the recruitment of sleep deprived individuals with poor sleep quality; although sample size was sufficient a larger size would have been more ideal. Strengths: equal male to female ratio, good sample size

Adverse events: At least one in each group suffered an AE. None of the events were serious or of severe nature and resolved without any medical intervention

• Most common AEs include headache and heartburn

Safety evaluation: blood pressure, ECG, heart rate, pulse rate

Potential disclosures:

• 600 mg dose of enXtra was used in this study to evaluate the long-term safety
• Mfg supplied material
• It appears the study location was in the US but the research article does not definitely point this detail out.

Notes: The purpose of this study was to evaluate a higher dose of enXtra long term. The previous studies using 300 mg enXtra have proven the efficacy at that dose. This study can be used to substantiate the safety with long-term use of enXtra.

Eraiah, 2023. Acute Effects of Alpinia galanga Extract (AGE) on Mental Alertness, Accuracy and Fatigue in Human Subjects: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study

Purpose: To evaluate the acute effect of AGE on mental alertness, accuracy, and fatigue in healthy subjects

• BMI between 18.5-29.9 kg/m2
• Fatigue score >4, history of consuming < 3 cups of tea/coffee per day
• Post lunch sleepiness by Epworth Sleepiness score > 11 and <17 (or equal to)
• Maintain their usual lifestyle and agreed to refrain from consuming caffeine or caffeine-containing products 12 hour prior to visit days and refrain from vigorous activity

Population: 62 subjects, healthy male and female aged 18–55 years old (mean age of 35)

Treatment: 300mg of AGE or placebo 30 minutes after lunch on Day 1 followed by cross-over treatments on Day 7 (5-day washout)

Design: A randomized, double-blind, placebo-controlled, cross-over clinical trial

• The first visit (Day -7 to -1) was for screening purposes, wherein subjects meeting inclusion criteria and not meeting exclusion criteria were identified, and written informed consent was obtained
• Sixty-two adults were randomized to receive either 300mg of AGE or placebo 30 minutes after lunch on Day 1 followed by cross-over treatments on Day 7. At the third visit (Day 7), subjects were crossed over to receive AGE or placebo as per randomization schedule
• Washout period of 5 days

Composition:

• A. galanga extract (AGE) = 300 mg (enXtra) + 90 mg of cellulose
• Placebo (cellulose) = 390 mg

Measurements:

• Primary outcomes: mental alertness as assessed by Symbol Digit Coding (SDC) test, Shifting Attention Test (SAT), Stroop Test (ST) and Alertness Rating Scale (ARS) of CNS Vital Signs (CVS) from baseline to 0.5, 1-, 2- & 5-hours post supplementation on day 1
• The mean correct responses in the study were calculated by averaging the correct responses data from SDC and SAT, mean errors was calculated by averaging data from SDC, SAT and ST; and mean correct reaction time was calculated by averaging data from SAT and ST. Symbol Digit Coding (SDC) test provides scores for correct responses and errors and covers domains such as complex information, processing accuracy, complex attention, visual perceptual speed, and information processing speed. Shifting Attention Test (SAT) provides scores for correct responses, errors and correct reaction time and covers domains such as executive function, shifting sets: rules, categories and rapid decision making and reaction time.
• Stroop Test (ST) provides scores for simple reaction time, complex reaction time correct, Stroop reaction time correct, Stroop commission errors and covers domains such as simple reaction time, complex reaction time, Stroop reaction time, inhibition/ disinhibition, frontal and executive skills
• Secondary outcomes: evaluation of fatigue, energy, and vigor scores assessed by Visual Analogue Scale to Evaluate Fatigue Severity from baseline to 6-7 hours post dose on day 1 and daytime sleepiness assessed by Epworth Sleepiness Scale from baseline to 0.5, 1-, 2- & 5-hours post supplementation on day 1.
• The visual analogue scale to evaluate fatigue (VAS-F) severity uses 18 items relating to the subjective experience of fatigue validated for adults aged 18-55 years. Each item requires respondents to mark an “X,” representing their current state of mind, on a visual analogue scale extending between two extremes. Each line is 100mm in length; consequently, scores range from 0 to 100. The instrument also has two subscales: fatigue (1-5 and 11-18 items) and vitality (6-10 items). Vigor subscore was taken from the response to question no. 8.
• The ESS is an 8-question self-administered questionnaire. Respondents are asked to rate their normal chances of dozing off or falling asleep while engaged in eight different activities on a 4-point scale (0-3). The ESS score (the sum of 8 item ratings ranging from 0 to 3) can vary from 0 to 24. The higher the ESS score, the greater the person’s average sleep propensity in everyday living (ASP), often known as ‘daytime sleepiness’.
• The same schedule was followed on day 7 after cross-over of study participants and products.

Results:

• SDC results
• Correct responses: A significant increase in correct responses from baseline was reported in the AGE group as compared to placebo at 0.5 and 2-hour time points; was nonsignificant at 1 and 5 hours
• Errors: No significant difference was reported between AGE and placebo groups in reducing errors from baseline at all time points
• SAT test
• Correct responses: A significant increase in correct responses from baseline was seen in the AGE group compared to placebo at 1-hour. Nonsignificant difference from baseline at the other time points
• Errors: A significant decrease in errors from baseline was seen in the AGE group compared to placebo at 1 hour. Nonsignificant difference from baseline at the other time points
• Correct reaction time: Nonsignificant
• Stroop Test
• Simple reaction time: A significant decrease in simple reaction time from baseline was seen in the AGE group compared to placebo at 2 and 5 hours. Nonsignificant difference from baseline at the other time points
• Complex reaction time correct: nonsignificant
• Stroop reaction time correct: nonsignificant
• Stroop commission errors: nonsignificant
• Average correct responses from SDC and SAT showed a significant increase in average correct responses from baseline in AGE group compared to placebo at 0.5 hours. Nonsignificant difference from baseline at the other time points
• Average errors scoring from SDC, SAT, and ST showed a significant decrease in average errors from baseline was seen in the AGE group compared to placebo at 0.5- and 1-hour time points. Nonsignificant difference from baseline at the other time points
• Average correct reaction time from SAT and ST: nonsignificant
• Alertness rating scale: A significant increase in alertness score from baseline was seen the AGE group compared to placebo at 2 and 5 hours. Nonsignificant difference from baseline at the other time points
• 6-7 hours post dose (at the end of the study), a significant reduction in fatigue score from baseline was seen in the AGE group compared to placebo
• 6-7 hours post dose (at the end of the study), a significant reduction in energy score from baseline was seen in the AGE group compared to placebo
• 6-7 hours post dose (at the end of the study), a significant reduction in vigor score from baseline was seen in the AGE group compared to placebo
• Epworth sleepiness scale: A significant decrease in daytime sleepiness from baseline was seen in the AGE group compared to placebo at 1-, 2-, and 5-hours post dose. Nonsignificant difference from baseline at the other time points

Conclusion: AGE supplementation significantly improved aspects of mental energy including mental alertness, reaction time, correct responses, reduction in errors and attention, as early as 0.5 hours and sustained until five hours post dose. AGE demonstrated significant increase in subjective feelings of energy and decreased fatigue levels.

Limitations: somewhat small sample size

Strengths: Although different methods of measuring alertness, attention, accuracy were used in this study, the result outcome was similar to previous reports. Researchers used a 5-day washout period to eliminate any carryover effect.

Adverse events: mild AEs, most common being a headache

Safety evaluation: was assessed by monitoring adverse events, physical examination, and vital signs measurement.

Potential disclosures:

• Mfg supplied material
• Mfg funded study
• Study location: India
• Subjects were of Indian origin

Claim summary:

• Preclinical research suggests enXtra works by increasing dopamine levels
• Clinically demonstrated same-day effect
• Promotes and sustains mental alertness at 1, 3, and 5 hours
• Supports focus, attention, and processing speed at 1, 3, and 5 hours
• Improves focused attention and accuracy during task performance up to 5 hours with no apparent “crash”
• Promotes positive mood and calmness
• Supports energy and vigor
• Provides sustained energy
• Caffeine-free benefits to support a workout later in the day
• Sustains mental alertness and focus better than caffeine
• One clinical study showed enXtra improved aspects of mental energy including mental alertness, reaction time, correct responses, reduction in errors and attention, as early 30 minutes, and sustained until 5 hours post dose
• Does not affect blood pressure or other cardio parameters such as heart rate and pulse rate
• Does not impact sleep
• Long term use of 600 mg enXtra daily is safe without affecting ECG and haemodynamics of middle-aged adults