Neuronal Correlates of Neurexan® Action in Mildly to Moderately Stressed Probands (NEURIM)

Neuronal Correlates of Neurexan® Action in Mildly to Moderately Stressed Probands - A Randomized, Placebo-controlled, Double-blind, Cross-over Trial of Mode of Action and Response Prediction by Functional Magnetic Resonance Imaging MRI

The purpose of this study is to explore the effect of Neurexan® on the brain response when participants undergo an emotional stressful condition in verum compared to placebo.

Study Overview

• Status: Completed
• Conditions: Acute Stress Reaction
• Intervention / Treatment: Drug: Neurexan; Drug: Placebo

Detailed Description

A randomized placebo-controlled, double-blind, two-period crossover study with an explorative design. 40 healthy males aged 31-59 years will be included in the study. Participant allocation to either Neurexan® or Placebo at study start is randomized with a ratio of 1:1, i.e. 20 Neurexan® first to 20 Placebo first individuals. Participants receive totally three tablets of either Neurexan® or Placebo per treatment period orally.

• Study Type: Interventional
• Enrollment (Actual): 53
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Magdeburg, Germany
    • Clinical Affective Neuroimaging Laboratory (CANLAB)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 31 years to 59 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Male
2. Age between ≥31 to ≤59 years
3. Fluent in German language
4. Nonsmoker
5. Able to understand the explanations and instructions given by the study physician
6. Willing to adhere to the prohibitions and restrictions specified in this protocol
7. Healthy on the basis of clinical laboratory tests, physical examination, medical history, vital signs performed at Screening Visit
8. Magnetic Resonance Imaging (MRI) compatible
9. Participants must have signed a written informed consent document prior to any study procedure indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study
10. Screening Scale for Chronic Stress of the Trier Inventory for Chronic Stress (TICS-SSCS) Score ≥ 9 and ≤ 36
11. Perceived Stress Scale (PSS) > 9

Exclusion Criteria:

1. Current or past history of psychotic features or a diagnosis of any psychiatric disorder as defined in the Diagnostic and Statistical Manual of Mental Disorder 4th edition (DSM-IV) Axis I (recurrent major depression, panic disorder, social phobia, obsessive-compulsory disorder; alcohol dependency; schizophrenia and mania)
2. History of depressive episodes during the last 3 months prior to Screening Visit
3. Use of any psychotropic medication or suffering from severe psychiatric illness during the last 3 months prior to Screening Visit
4. Intake of prescription drugs for sleeping disorders or nervousness within one month prior to Screening Visit
5. Intake of over the counter (OTC) medication for the treatment of sleeping disorders or nervousness within the last (one) week prior to Screening Visit
6. High chronic stress as verified with the TICS-SSCS (> 36)
7. Low chronic stress as verified with the TICS-SSCS (< 9) and PSS ≤ 9
8. Participants with Blood Pressure (BP) ≥ 160/100 on day 0 and at randomization
9. Participants with treated hypertension
10. Known allergies and/or hypersensitivity to ingredients of Neurexan® (Passiflora incarnata, Avena sativa, Coffea arabica, Zincum isovalerianicum, lactose monohydrate, magnesium stearate) or Placebo (Lactose monohydrate, magnesium stearate)
11. Known Lactose intolerance
12. Use of any psychological stress-management intervention within the last 4 weeks prior to Screening Visit
13. History of substance, drug, including nicotine, or alcohol abuse within the preceding 3 months prior to Screening Visit
14. Alcohol, drug, nicotine intake within the last 24 hours before day 0 and at randomization - confirmed by positive screening tests
15. Body Mass Index (BMI) > 30 kg/m2
16. Works regularly nights shifts
17. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic or hematologic disease as defined by clinical screening interview
18. Any somatic disease or other condition the Investigator or their duly assigned representatives believes could affect the ability of the individual to complete the study or the interpretation of the study results
19. Participants with medical illness that may have influenced brain morphology and/or physiology (e.g. uncontrolled hypertension, diabetes)
20. Participants with a history of one or more seizures without a clear and resolved aetiology
21. Participants with claustrophobia
22. Participants with tinnitus
23. Clinically significant acute illness within 7 days prior to randomization
24. Presence of metallic (ferromagnetic) implants (heart pacemaker, aneurysm clips), tattoos or piercings
25. Have received an experimental drug or used an experimental medical device (participation in any other clinical trial) within the last 30 days before study inclusion
26. Participants whose ability to speak for themselves lacks or can be doubted

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neurexan first, then Placebo; Participants received a single dose of three Neurexan tablets on trial Day 1. Following a washout period of 7 to 35 days, they received a single dose of three placebo tablets on trial Day 2.	Drug: Neurexan; 0.6 mg / tablet; Other Names: Nx4; Drug: Placebo; Neurexan-matched Placebo tablet
Experimental: Placebo first, then Neurexan; Participants received a single dose of three Placebo tablets on trial Day 1. Following a washout period of 7 to 35 days, they received a single dose of three Neurexan tablets on trial Day 2.	Drug: Neurexan; 0.6 mg / tablet; Other Names: Nx4; Drug: Placebo; Neurexan-matched Placebo tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Functional Magnetic Resonance Imaging (fMRI) Task Data: BOLD Activation Changes Within Amygdala During Negative Faces in the Hariri Face Matching Task Between Placebo and Neurexan Treatment	The neuronal drug effect was assessed by measuring changes in amygdala activity between placebo and Neurexan using fMRI 1 hour after treatment. The left amygdala was prespecified as region of interest for emotional processing and social stress. Amygdala activation in response to negative emotional faces versus neutral forms in the Hariri task was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation explained by a variable, here negatives faces or forms. Beta values serve as index of neural activity, the higher the beta value, the higher the activity. A paired t-test analysis of extracted beta values for the left amygdala was performed comparing placebo and Neurexan treatment. Amygdala hypersensitivity to negative stimuli is associated with anxiety disorders and increased stress sensitivity, while a reduction in amygdala activation may indicate a calming or modulating effect of the intervention.	1 hour after taking a single dose of Neurexan or placebo
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Global Functional Connectivity Density of the Amygdala at Rest	Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Highly connected functional hubs were identified by global functional connectivity density (gFCD) analysis. The number of voxels with a positive rsFC larger than the predefined threshold of r > 0.6 at a whole brain level was evaluated. gFCD was calculated for each voxel as the total number of significant correlations between this voxel and all voxels in gray matter. The gFCD value in each voxel was divided by the global mean value to improve normality. The larger the number of significant correlations, the greater the gFCD strength. Changes in gFCD strength of the amygdala from pre-dose to 1-hour post-dose were compared between the Neurexan and Placebo conditions using a within-subject repeated-measures ANOVA with main effects of time (pre- vs. post-dose) and drug (placebo vs. Nx4) and their interaction (time x drug).	1 hour after taking a single dose of Neurexan or placebo
Functional Magnetic Resonance Imaging (fMRI) Task Data: Stress Network Activation in Response to Psychosocial Stress Induction.	The neuronal drug effect was assessed by measuring activity changes within a predefined stress network, comprising the anterior cingulate cortex, medial orbitofrontal cortex, hippocampus, amygdala, and hypothalamus, between placebo and Neurexan using fMRI. Stress network activation in response to psychosocial stress induced by the ScanSTRESS paradigm was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation that is explained by a variable, in this case mental rotation or simple matching of figures. Beta-estimates serve as an index of neural activity, the higher the beta value, the higher the activity. The paradigm contrast (stress-control) for each participant was taken to a second level analysis of all voxels comprised by an ACC mask. A voxelwise paired t-test, controlled for multiple comparison, compared placebo and verum conditions. The endpoint was assessed approximately 1.5 hours post-dose after a single dose of Neurexan or placebo.	1.5 hours after taking a single dose of Neurexan or placebo
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Whole-Brain Functional Connectivity of the Amygdala at Rest	Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Left centromedial amygdala (CeMA) was defined as the seed based on probabilistic cytoarchitectonic maps. The time course of the average BOLD signal within the seed was correlated with the signals in each voxel in the whole brain. The Pearson correlation coefficients were transformed to Z values (Fisher's Z), resulting in a map representing voxel-wise strength of rsFC to the seed region. Changes in left CeMA rsFC from pre-dose to post-dose, evaluated as binary connectivity coefficients, were compared between the Neurexan and Placebo conditions.	1 hour after taking a single dose of Neurexan or placebo
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Baseline Activity of the Amygdala at Rest as Measured by Amplitude of Low-Frequency Fluctuations (ALFF)	The time series in each voxel of the rs-fMRI data were converted to the frequency domain using a Fast Fourier Transform (FFT), and the power spectrum was obtained. The square root of the power spectrum was computed and then averaged across each predefined frequency band. This averaged square root was taken as amplitude of low frequency fluctuation (ALFF). A ratio of the power spectrum of low-frequency range to that of the entire frequency range, i.e. the fractional ALFF (fALFF), was computed. High fALFF in the amygdala may reflect hyperactivity and could serve as a marker for heightened stress sensitivity. To examine the effect of drug on rs-metrics (RS1) while taking baseline rs-metrics before drug administration (RS0) as control variable, mean fALFF values of the amygdala were compared between placebo and Neurexan.	1 hour after taking a single dose of Neurexan or placebo

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Normalized EEG frontal frequency changes associated with normalized HRV in verum relative to placebo conditions.		Day 1 and Day 2
High morning cortisol and alpha-amylase level predicts increased subjective stress response (VAS, STAI-XI), effect which is reversed in verum but not in placebo condition.	Individual cortisol and alpha-amylase level at 8 timepoints during the MRI visits, VAS (tensions and nervousness) at 7 timepoints, and STAI-X1 at 6 timepoints will be computed as the area under the curve. The relation between change in cortisol, VAS (tension and nervousness) and personality traits (TCI), coping to stress (ABI, FKK), self-esteem (Rosenberg Self-Esteem), and childhood traumatic experiences (CTQ) will be investigated by the use of non-parametric correlations analysis. Changes in subject reported outcome instruments and stress response by morning cortisol and alpha amylase will be evaluated within the framework of formal crossover analyses. Due to unknown distributions, the analysis will be of nonparametric nature.	Day 1 and Day 2
Reduced subjects stress perception as assessed with STAI-XI, VAS after MIST task in verum relative to placebo condition.	The analysis is already described under point "Outcome 8" and "Outcome 10" of secondary outcome measures.	Day 1 and Day 2
Personality traits assessed with TCI predicted stress response.	It will be investigated how personality traits (TCI), anxiety level (STAI), depressive symptoms (BDI-II), self-esteem, subject's coping strategies as well as cognitive processes predict stress response and the relation with Neurexan® efficiency. Regression analyses will be conducted on resting state functional connectivity in placebo and verum conditions. These exploratory analyses are hypothesis generating in order to confine follow up investigations.	Screening Visit

Collaborators and Investigators

• Sponsor: Biologische Heilmittel Heel GmbH
• Investigators: Principal Investigator: Martin Walter, PD Dr Med., Clinical Affective Neuroimaging Laboratory, Univ. Magdeburg, Germany

Publications and helpful links

General Publications

• Krylova M, Alizadeh S, Izyurov I, Teckentrup V, Chang C, van der Meer J, Erb M, Kroemer N, Koenig T, Walter M, Jamalabadi H. Evidence for modulation of EEG microstate sequence by vigilance level. Neuroimage. 2021 Jan 1;224:117393. doi: 10.1016/j.neuroimage.2020.117393. Epub 2020 Sep 21.
• Herrmann L, Vicheva P, Kasties V, Danyeli LV, Szycik GR, Denzel D, Fan Y, Meer JV, Vester JC, Eskoetter H, Schultz M, Walter M. fMRI Revealed Reduced Amygdala Activation after Nx4 in Mildly to Moderately Stressed Healthy Volunteers in a Randomized, Placebo-Controlled, Cross-Over Trial. Sci Rep. 2020 Mar 2;10(1):3802. doi: 10.1038/s41598-020-60392-w.
• Mayer K, Krylova M, Alizadeh S, Jamalabadi H, van der Meer J, Vester JC, Naschold B, Schultz M, Walter M. Nx4 Reduced Susceptibility to Distraction in an Attention Modulation Task. Front Psychiatry. 2021 Nov 29;12:746215. doi: 10.3389/fpsyt.2021.746215. eCollection 2021.
• Chand T, Alizadeh S, Li M, Fan Y, Jamalabadi H, Danyeli L, Nanni-Zepeda M, Herrmann L, Van der Meer J, Vester JC, Schultz M, Naschold B, Walter M. Nx4 Modulated Resting-State Functional Connectivity Between Amygdala and Prefrontal Cortex in a Placebo-Controlled, Crossover Trial. Brain Connect. 2022 Nov;12(9):812-822. doi: 10.1089/brain.2021.0189. Epub 2022 Jun 10.
• Nanni-Zepeda M, Alizadeh S, Chand T, Kasties V, Fan Y, van der Meer J, Herrmann L, Vester JC, Schulz M, Naschold B, Walter M. Trait anxiety is related to Nx4's efficacy on stress-induced changes in amygdala-centered resting state functional connectivity: a placebo-controlled cross-over trial in mildly to moderately stressed healthy volunteers. BMC Neurosci. 2022 Nov 24;23(1):68. doi: 10.1186/s12868-022-00754-4.
• Herrmann L, Kasties V, Boden C, Li M, Fan Y, Van der Meer J, Vester JC, Seilheimer B, Schultz M, Alizadeh S, Walter M. Nx4 attenuated stress-induced activity of the anterior cingulate cortex-A post-hoc analysis of a randomized placebo-controlled crossover trial. Hum Psychopharmacol. 2022 Sep;37(5):e2837. doi: 10.1002/hup.2837. Epub 2022 Feb 25.
• Chand T, Alizadeh S, Jamalabadi H, Herrmann L, Krylova M, Surova G, van der Meer J, Wagner G, Engert V, Walter M. EEG revealed improved vigilance regulation after stress exposure under Nx4 - A randomized, placebo-controlled, double-blind, cross-over trial. IBRO Neurosci Rep. 2021 Sep 25;11:175-182. doi: 10.1016/j.ibneur.2021.09.002. eCollection 2021 Dec.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2015
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: October 28, 2015
• First Submitted That Met QC Criteria: November 9, 2015
• First Posted (Estimated): November 11, 2015

Study Record Updates

• Last Update Posted (Actual): June 24, 2025
• Last Update Submitted That Met QC Criteria: June 10, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Keywords: Stress, amygdala, functional MRI, Hariri paradigm, TSST
• Additional Relevant MeSH Terms: Trauma and Stressor Related Disorders; Mental Disorders; Wounds and Injuries; Fractures, Bone; Stress Disorders, Traumatic; Fractures, Stress; Stress Disorders, Traumatic, Acute
• Other Study ID Numbers: C1501; 2015-001802-32 (EudraCT Number)

Plan for Individual participant data (IPD)

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