Centrophenoxine

Risk-Benefit Analysis

Forever Healthy Foundation gGmbH

Amalienbadstraße 41

D-76227 Karlsruhe, Germany

Version 1.5 - October 5, 2022

Mario Alvarez-Martinez, PhD
Gabriel Borden, MD

Preface

This risk-benefit analysis (RBA) is part of Forever Healthy's "Rejuvenation Now" initiative that seeks to continuously identify new rejuvenation therapies and systematically evaluate them on their risks, benefits, procedures and potential application.

Special thanks are extended to the whole Rejuvenation Now team at Forever Healthy for their friendly contributions.

Section 1: Overview 

Motivation

Centrophenoxine (CPH) is a compound consisting of dimethylaminoethanol (DMAE) and para-chlorophenoxyacetic acid (pCPA), joined by a chemical bond. DMAE can be converted by cells into choline, which is a precursor of membrane phospholipids, neurotransmitters, and other important biomolecules. The pCPA component enhances the penetration of CPH across the blood-brain barrier (Miyazaki et al., 1976).

CPH supplementation is hypothesized to increase brain acetylcholine levels, protect neurons from oxidative damage, improve cognitive function, and reduce age-related lipofuscin accumulation.

Key questions

This analysis seeks to answer the following questions:

• Which benefits result from CPH supplementation?
• Which risks are involved in CPH supplementation (general and method-specific)?
• What are the potential risk mitigation strategies?
• Which method or combination of methods is the most effective for CPH supplementation?
• Which of the available methods are safe for use?
• What is the best therapeutic protocol available at the moment?
• What is the best monitoring protocol currently available?

Impatient readers may choose to skip directly to Section 6 for the Presentation of Results and tips on practical application.

Recommended reading/viewing

General introduction

The following site offers information on CPH supplementation at a consumer level and is useful as an introduction to the topic:

• Centrophenoxine: potential uses & side-effects - selfdecode.com

Scientific overview 

The following scientific review provides a more detailed overview of the topic of CPH supplementation:

• Centrophenoxine (Meclofenoxate) - alzdiscovery.org

Section 2: Methods

Analytic model

This RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development (Sarac et al., 2012).

Literature search

A literature search was conducted on PubMed, the Cochrane Library, Google Scholar and the China National Knowledge Infrastructure (CNKI) using the search terms shown in Table 1 and included articles available as of September 4, 2022. Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms.

Inclusion criteria: Any human study that used CPH supplementation was included.

Exclusion criteria: We excluded animal and in vitro studies, as well as trials that used CPH in combination with other molecules if the effect of CPH could not be isolated.

For the assessment of hypothetical risks, selected animal and in vitro studies were also considered.

Table 1: Literature search 

Abbreviation list

Section 3: Existing Evidence

Summary of results from clinical trials (humans)

Our search terms identified 1707 studies, of which 150 were relevant to this analysis (see Table 2). We also chose to include the clinical studies summarized in chapter 4 (Herrschaft, 1992) from the book Neuro-Psychopharmaka Ein Therapie-Handbuch (Riederer et al., 1992) in our analysis, despite being unable to access the majority of the original papers (see Table 3).

Some trials from the Chinese literature, mostly comparing CPH to traditional Chinese medicine (TCM), reported only a qualitative superiority of the comparator, at least in the online open-access portion (abstract). These results were not included in our analysis, but are included in Table 2.

The overall quality of the evidence is low. Although most of the selected studies are randomized controlled trials (RCTs) and comparative trials, a large proportion of the available studies are only available as abstracts, many of those from the Chinese literature. In addition, several studies have methodological limitations, such as lack of statistical analysis and generally short-term study periods, or are conducted in elderly populations with high dropout rates due to death and morbidity.

Table 2: Clinical trials

Table 3: Herrschaft summary

Section 4: Risk-Benefit Analysis

Decision model

Risk and benefit criteria

The decision profile is made up of risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and type and are assessed according to magnitude, likelihood, duration and perceived importance. The risk criteria are organized by category and type and are assessed according to severity, frequency of occurrence, and difficulty of detection and mitigation. Each criterion is assigned a numerical value for each assessment category:

1 = low

2 = moderate

3 = high

The numerical values for the criterion are then summarized, serving as the justification for the weighting in the following column.

Weight

The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). The value in the summary column is divided by 4 to result in a weight between 1 → 3.

Score

Each criterion is assessed according to the performance of CPH supplementation against the comparator (physiological aging) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior), and +1 (superior) to the comparator.

Uncertainty

Uncertainty is determined according to the amount and quality of the evidence, availability of full text articles & supplementary data, number of participants and whether methodological flaws, conflicting studies, or conflicts of interest (i.e. funding) are present. Evidence that is based on RCTs is initially upgraded by 1 point, evidence from open-label trials is considered neutral, and evidence that is based on observational studies is downgraded by 1 point. The uncertainty is then further valued using the above-mentioned criteria to result in an uncertainty score.

Weighted score

The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted according to the uncertainty score. Weighted scores are upgraded where the uncertainty score is low (positive) or downgraded where the uncertainty score is high (negative).

Benefit assessment

We identified a total of 59 benefits associated with CPH. The benefits were mostly observed in aged or diseased populations, were of small magnitude and were not demonstrated to persist after the treatment period.

Table 4: Benefit assessment

For even more detailed information on our analysis, see Supplementary Data.