Cognitive and Cerebral Blood Flow Effects of Zanthozylum Armatum Fruit Extract in Healthy Adults Aged 30 - 55

Study Overview
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Brief Summary
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Zanthozylum armatum (Z. armatum)-otherwise known as Nepalese pepper, or timut-is an perennial shrub found in India and across Southeast Asia. Preparations of the bark, fruit and seeds of Z. armatum have been extensively used in traditional Indian medicine. Preliminary data have indicated that preparations of Z. armatum may also be beneficial to cognitive function. The study aims to investigate the effects acute and chronic consumption of Z. armatum on cognitive function and cerebral blood flow.

Detailed Description
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Zanthozylum armatum (Z. armatum) is an perennial shrub found in India and across Southeast Asia. Preparations of the bark, fruit and seeds of Z. armatum have been extensively used in traditional Indian medicine. For example, the fruits and seeds have been employed as an aromatic tonic in fever and dyspepsia and the essential oil of the fruits has exhibited antibacterial, antifungal and anthelmintic properties. Furthermore, the dried fruits are used as spice, especially in Nepalese and Sichuan cuisine with increasing popularity across Europe. With regard to physiological effects relevant to brain function, Z. armatum has also been traditionally used as a cardio-depressant; these vasodilatory properties have recently being linked to its antagonistic effect on calcium ion channel function as demonstrated in isolated rabbit aorta tissue. In addition, the observed anti-inflammatory and antioxidant effects of preparations of Z. armatum may serve to beneficially impact cognition with chronic administration. Although direct effects of Z. armatum on brain function have yet to be assessed; Zanthozylum fruit comprises one constituent of the traditional Japanese herbal medicine Daikenchuto (DKT) where some data do exist. In a series of trials investigating the effects of DKT on learning and memory function in mice, it was established that the extract of Zanthozylum fruit contained in DKT alone that was associated with reductions in escape latency in the Morris Water Maze task. Interestingly, the authors also revealed that it was the amide hydroxy-ɑ-sanshool (HAS) isolated from the Zanthozylum fruit extract that was associated with these effects, speculating that the effect of HAS on escape latencies was due to a facilitation effect of HAS on acetylcholine release. Given the evidence of potentially relevant mechanisms of action and initial evidence of cognitive effects of HAS in murine models, the aim of this study is to assess the acute and chronic effects of Z. armatum on cognitive function, mood, and cerebral blood flow in healthy adults aged 30 to 55 years.

Official Title
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The Acute and Chronic Cognitive and Cerebral Blood Flow Effects of Zanthozylum Armatum Fruit Extract: a Double Blind, Randomized, Placebo Controlled, Parallel Groups Study in Healthy Humans

Conditions
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Cognitive Change

Intervention / Treatment
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* Dietary Supplement: Zanthozylum armatum
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must self-assess themselves as being in good health Aged 30 to 55 years at the time of giving consent Are proficient in English equivalent to IELTS band 6 or above Exclusion Criteria: Have any pre-existing medical condition/illness which will impact taking part in the study NOTE: the explicit exceptions to this are controlled (medicated) hypertension, arthritis, asthma, hay fever, high cholesterol and reflux-related conditions. There may be other, unforeseen, exceptions and these will be considered on a case-by-case basis; i.e. participants may be allowed to progress to screening if they have a condition/illness which would not interact with the active treatments or impede performance Are currently taking prescription medications or dietary supplements including omega fatty acids / fish oils NOTE: the explicit exceptions to this are hormone replacement treatments for female participants where symptoms are stable, those medications used in the treatment of arthritis, high blood pressure, high cholesterol and reflux-related conditions; and those taken 'as needed' in the treatment of asthma and hay fever. As above, there may be other instances of medication use which, where no interaction with the active treatments is likely, participants may be able to progress to screening Have planned a surgery requiring general anaesthesia Have high blood pressure (systolic over 159 mm Hg or diastolic over 99 mm Hg) Have a Body Mass Index (BMI) outside of the range 18-35 kg/m2 Are pregnant, seeking to become pregnant or lactating Have learning difficulties, dyslexia Have a visual impairment that cannot be corrected with glasses or contact lenses (including colour-blindness) Smoker or regular consumption of nicotine containing products e.g. patches, gum, vaping Have a history of alcohol or drug abuse Excessive caffeine intake (>500 mg per day) Have food intolerances/sensitivities, especially against citrus fruits Have any health condition that would prevent fulfilment of the study requirements Are unable to complete all of the study assessments Are currently participating in other clinical or nutrition intervention studies, or have in the past 4 weeks Do not have a bank account (required for payment) Are non-compliant with regards treatment consumption

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Zanthozylum armatum<br>fruit extract | Dietary Supplement: Zanthozylum armatum<br>* Zanthozylum armatum MCT oil extract<br>|
| Placebo Comparator: Placebo<br>placebo | Dietary Supplement: Placebo<br>* sunflower oil matched for appearance<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary memory score | This is a composite measure derived from summing the z score performance on the following cognitive tasks: immediate word recall, delayed word recall, delayed picture recognition, delayed word recognition, delayed name to face recall (-1 to 1 where higher is better). | Chronic (57 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| STAI-trait total score | State-trait anxiety inventory 'trait' score (20-80; higher is more anxious) | Baseline | 
| STAI-state total score | State-trait anxiety inventory 'state' score (20-80; higher is more anxious) | Chronic (57 days) | 
| Secondary memory score | This is a composite measure derived from summing the z score performance on the following cognitive tasks: immediate word recall, delayed word recall, delayed picture recognition, delayed word recognition, delayed name to face recall (-1 to 1 where higher is better). | Acute (45, 180, 300 minutes post-dose) | 
| Secondary memory score | This is a composite measure derived from summing the z score performance on the following cognitive tasks: immediate word recall, delayed word recall, delayed picture recognition, delayed word recognition, delayed name to face recall (-1 to 1 where 1 is better). | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Working memory score | This is a composite measure derived from summing the z score performance on the numeric working memory task and Corsi block-tapping task (-1 to 1; where higher is better) | Chronic (57 days) | 
| Working memory score | This is a composite measure derived from summing the z score performance on the numeric working memory task and Corsi block-tapping task (-1 to 1; where higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Working memory score | This is a composite measure derived from summing the z score performance on the numeric working memory task and Corsi block-tapping task (-1 to 1; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Speed of memory score | This is a composite measure derived from summing the z score reaction times on the numeric working memory task, the delayed name/face recall task, the delayed picture recognition task, and the delayed word recognition task (-1 to 1; where lower is better). | Acute (45, 180, 300 minutes post-dose) | 
| Speed of memory score | This is a composite measure derived from summing the z score reaction times on the numeric working memory task, the delayed name/face recall task, the delayed picture recognition task, and the delayed word recognition task (-1 to 1; where lower is better) | Chronic (57 days) | 
| Speed of memory score | This is a composite measure derived from summing the z score reaction times on the numeric working memory task, the delayed name/face recall task, the delayed picture recognition task, and the delayed word recognition task (-1 to 1; where lower is better). | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Accuracy of attention score | This is a composite measure derived from summing the z score accuracy performance on the choice reaction time and Rapid visual information processing tasks (-1 to 1; where higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Accuracy of attention score | This is a composite measure derived from summing the z score accuracy performance on the choice reaction time and Rapid visual information processing tasks (-1 to 1; where higher is better) | Chronic (57 days) | 
| Accuracy of attention score | This is a composite measure derived from summing the z score accuracy performance on the choice reaction time and Rapid visual information processing tasks (-1 to 1; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Speed of attention score | This is a composite measure derived from summing the z score reaction times on the choice reaction time and Rapid visual information processing tasks (-1 to 1; where lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Speed of attention score | This is a composite measure derived from summing the z score reaction times on the choice reaction time and Rapid visual information processing tasks (-1 to 1; where lower is better) | Chronic (57 days) | 
| Speed of attention score | This is a composite measure derived from summing the z score reaction times on the choice reaction time and Rapid visual information processing tasks (-1 to 1; where lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Immediate word recall task correctly identified words | total number (0-15; where higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Immediate word recall task correctly identified words | total number (0-15; where higher is better) | Chronic (57 days) | 
| Immediate word recall task correctly identified words | total number (0-15; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Immediate word recall task error responses | total number (can be any number; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Immediate word recall task error responses | total number (can be any number; lower is better) | Chronic (57 days) | 
| Immediate word recall task error responses | total number (can be any number; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Delayed word recall task correctly identified words | total number (0-15; where higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Delayed word recall task correctly identified words | total number (0-15; where higher is better) | Chronic (57 days) | 
| Delayed word recall task correctly identified words | total number (0-15; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Delayed word recall task correctly error responses | total number (can be any number; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Delayed word recall task correctly error responses | total number (can be any number; lower is better) | Chronic (57 days) | 
| Delayed word recall task correctly error responses | total number (can be any number; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Picture recognition accuracy | (%; 0-100; where higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Picture recognition accuracy | (%; 0-100; where higher is better) | Chronic (57 days) | 
| Picture recognition accuracy | (%; 0-100; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Picture recognition reaction time | (ms; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Picture recognition reaction time | (ms; lower is better) | Chronic (57 days) | 
| Picture recognition reaction time | (ms; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Word recognition accuracy | (%; 0-100; where higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Word recognition accuracy | (%; 0-100; where higher is better) | Chronic (57 days) | 
| Word recognition accuracy | (%; 0-100; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Word recognition reaction time | (ms; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Word recognition reaction time | (ms; lower is better) | Chronic (57 days) | 
| Word recognition reaction time | (ms; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Name to face recall correct responses | number (0-24; higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Name to face recall correct responses | number (0-24; higher is better) | Chronic (57 days) | 
| Name to face recall correct responses | number (0-24; higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Name to face recall reaction time | (ms; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Name to face recall reaction time | (ms; lower is better) | Chronic (57 days) | 
| Name to face recall reaction time | (ms; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Peg and ball task planning time | (ms; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Peg and ball task planning time | (ms; lower is better) | Chronic (57 days) | 
| Peg and ball task planning time | (ms; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Peg and ball task completion time | (ms; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Peg and ball task completion time | (ms; lower is better) | Chronic (57 days) | 
| Peg and ball task completion time | (ms; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Peg and ball task errors | number (can be any number, lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Peg and ball task errors | number (can be any number, lower is better) | Chronic (57 days) | 
| Peg and ball task errors | number (can be any number, lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Corsi blocks accuracy | Average scores from the last five correctly completed trials from the corsi block-tapping task | Acute (45, 180, 300 minutes post-dose) | 
| Corsi blocks accuracy | Average scores from the last five correctly completed trials from the corsi block-tapping task | Chronic (57 days) | 
| Corsi blocks accuracy | Average scores from the last five correctly completed trials from the corsi block-tapping task | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Choice reaction time accuracy | (%; 0-100; where higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Choice reaction time accuracy | (%; 0-100; where higher is better) | Chronic (57 days) | 
| Choice reaction time accuracy | (%; 0-100; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Choice reaction time reaction time | (ms; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Choice reaction time reaction time | (ms; lower is better) | Chronic (57 days) | 
| Choice reaction time reaction time | (ms; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Numeric working memory accuracy | (ms; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Numeric working memory accuracy | (%; 0-100; where higher is better) | Chronic (57 days) | 
| Numeric working memory accuracy | (%; 0-100; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Numeric working memory reaction time | (ms; lower is better) | Acute (45, 180, 300 minutes post-dose) | 
| Numeric working memory reaction time | (ms; lower is better) | Chronic (57 days) | 
| Numeric working memory reaction time | (ms; lower is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Serial 3 subtractions total responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; higher is better | Acute (45, 180, 300 minutes post-dose) | 
| Serial 3 subtractions total responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; higher is better | Chronic (57 days) | 
| Serial 3 subtractions total responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; higher is better | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Serial 3 subtractions total error responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Acute (45, 180, 300 minutes post-dose) | 
| Serial 3 subtractions total error responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Chronic (57 days) | 
| Serial 3 subtractions total error responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Serial 7 subtractions total responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; higher is better | Acute (45, 180, 300 minutes post-dose) | 
| Serial 7 subtractions total responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; higher is better | Chronic (57 days) | 
| Serial 7 subtractions total responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; higher is better | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Serial 7 subtractions total error responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Acute (45, 180, 300 minutes post-dose) | 
| Serial 7 subtractions total error responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Chronic (57 days) | 
| Serial 7 subtractions total error responses | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Rapid visual information processing accuracy | (%) - calculated from the 3 cycles of the Cognitive Demand Battery (%; 0-100; where higher is better) | Acute (45, 180, 300 minutes post-dose) | 
| Rapid visual information processing accuracy | (%) - calculated from the 3 cycles of the Cognitive Demand Battery (%; 0-100; where higher is better) | Chronic (57 days) | 
| Rapid visual information processing accuracy | (%) - calculated from the 3 cycles of the Cognitive Demand Battery (%; 0-100; where higher is better) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Rapid visual information processing reaction time | (ms) - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Acute (45, 180, 300 minutes post-dose) | 
| Rapid visual information processing reaction time | (ms) - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Chronic (57 days) | 
| Rapid visual information processing reaction time | (ms) - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Rapid visual information processing false alarms | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Acute (45, 180, 300 minutes post-dose) | 
| Rapid visual information processing false alarms | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Chronic (57 days) | 
| Rapid visual information processing false alarms | number - calculated from the 3 cycles of the Cognitive Demand Battery; lower is better | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Mental fatigue | visual analogue scale (%) - calculated from the 3 cycles of the Cognitive Demand Battery (0-100; higher indicates more fatigue) | Acute (45, 180, 300 minutes post-dose) | 
| Mental fatigue | visual analogue scale (%) - calculated from the 3 cycles of the Cognitive Demand Battery (0-100; higher indicates more fatigue) | Chronic (57 days) | 
| Mental fatigue | visual analogue scale (%) - calculated from the 3 cycles of the Cognitive Demand Battery (0-100; higher indicates more fatigue) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Subjective mood - Alert | derived from Bond Lader visual analogue scales (0-100; higher is more alert) | Acute (45, 180, 300 minutes post-dose) | 
| Subjective mood - Alert | derived from Bond Lader visual analogue scales (0-100; higher is more alert) | Chronic (57 days) | 
| Subjective mood - Alert | derived from Bond Lader visual analogue scales (0-100; higher is more alert) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Subjective mood - Content (visual analogue scale) | derived from Bond Lader visual analogue scales (0-100 higher is more content) | Acute (45, 180, 300 minutes post-dose) | 
| Subjective mood - Content | derived from Bond Lader visual analogue scales(0-100 higher is more content) | Chronic (57 days) | 
| Subjective mood - Content | derived from Bond Lader visual analogue scales(0-100 higher is more content) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Subjective mood - Calm | derived from Bond Lader visual analogue scales (0-100 higher is more calm) | Acute (45, 180, 300 minutes post-dose) | 
| Subjective mood - Calm | derived from Bond Lader visual analogue scale (0-100 higher is more calm) | Chronic (57 days) | 
| Subjective mood - Calm (Bond Lader visual analogue scale) | derived from Bond Lader visual analogue scale (0-100 higher is more calm) | Superimposed chronic (57 days plus 45, 180, 300 minutes post-dose) | 
| Cerebral blood flow during performance of cognitive tasks | Measured (in umol) using quantitative near infrared spectroscopy (higher indicates increased blood volume) | Acute (120, 150 minutes post-dose) | 
| Cerebral blood flow during performance of cognitive tasks | Measured (in umol) using quantitative near infrared spectroscopy (higher indicates increased blood volume) | Superimposed chronic (57 days plus 120, 150 minutes post-dose) | 
| Cerebral blood flow at rest | Measured (in umol) using quantitative near infrared spectroscopy (higher indicates increased blood volume) | Acute (120, 150 minutes post-dose) | 
| Cerebral blood flow at rest | Measured (in umol) using quantitative near infrared spectroscopy (higher indicates increased blood volume) | Chronic (57 days) | 
| Cerebral blood flow at rest | Measured (in umol) using quantitative near infrared spectroscopy (higher indicates increased blood volume) | Superimposed chronic (57 days plus 120, 150 minutes post-dose) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NIRS, mood, cognitive performance, Zanthozylum armatum, Nepalese pepper