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

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

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.

Study Overview

• Status: Completed
• Conditions: Cognitive Change
• Intervention / Treatment: Dietary supplement: Zanthozylum armatum; Dietary supplement: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Tyne And Wear
    • Newcastle upon Tyne, Tyne And Wear, United Kingdom, NE1 8ST
      • Northumbria University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo	Dietary supplement: Placebo; sunflower oil matched for appearance
Active Comparator: Zanthozylum armatum; fruit extract	Dietary supplement: Zanthozylum armatum; Zanthozylum armatum MCT oil extract

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Northumbria University
• Collaborators: Mibelle AG

Publications and helpful links

General Publications

• Gilani SN, Khan AU, Gilani AH. Pharmacological basis for the medicinal use of Zanthoxylum armatum in gut, airways and cardiovascular disorders. Phytother Res. 2010 Apr;24(4):553-8. doi: 10.1002/ptr.2979.
• Kalia NK, Singh B, Sood RP. A new amide from zanthoxylum armatum. J Nat Prod. 1999 Feb;62(2):311-2. doi: 10.1021/np980224j.
• Nakamura T, Komai N, Isogami I, Ueno K, Ikegami F, Ono K, Yano S. Memory and learning-enhancing effect of Daikenchuto, a traditional Japanese herbal medicine, in mice.Journal of Natural Medicines 60(1): 64-67, 2006

Helpful Links

• Link to study site website

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2018
• Primary Completion (Actual): November 16, 2018
• Study Completion (Actual): November 16, 2018

Study Registration Dates

• First Submitted: September 13, 2018
• First Submitted That Met QC Criteria: September 13, 2018
• First Posted (Actual): September 17, 2018

Study Record Updates

• Last Update Posted (Actual): January 24, 2019
• Last Update Submitted That Met QC Criteria: January 23, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: cognitive performance; mood; NIRS; Zanthozylum armatum; Nepalese pepper
• Other Study ID Numbers: 53BS1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No