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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



   

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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:


Scientific overview 

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


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 

Search terms

Database
Number of publications

Number of
Relevant studies

centrophenoxine OR meclofenoxate OR meclophenoxate OR lucidril OR brenal OR centrophenoxin OR cerebron OR cerutil OR helfergin OR licidril OR lucidrylPubMed562150
centrophenoxine OR meclofenoxate OR meclophenoxate OR lucidril OR brenal OR cellative OR centrophenoxin OR cerebron OR cerutil OR closete OR helfergin OR licidril OR lucidrylCochrane Library62
centrophenoxine OR meclofenoxate OR meclophenoxate OR lucidril OR amipolen OR analux OR brenal OR cellative OR centrophenoxin OR cerebron OR cerutil OR closete OR helfergin OR licidril OR lucidryl OR lutiaron OR marucotol OR proserout OR proseryl OR ropoxylGoogle Scholar6610
(first 300 results screened)
centrophenoxine OR meclofenoxate OR meclophenoxate OR lucidril OR lucidrylCNKI782
meclofenoxate OR centrophenoxine OR centrophenoxin OR meclophenoxate OR cerutil OR lucidril OR luciforte OR helferginclinicaltrials.gov1
Other sources
A manual search of the reference lists of the selected papers
PubChem entries for centrophenoxine, p-chlorophenoxyacetic acid, meclofenoxate, meclofenoxate hydrochloride
Book: Neuro-Psychopharmaka: Ein Therapie Handbuch Band 5 Parkinsonmittel and Nootropika (Herrschaft, 1992) - available online excerpts only; book in German


Abbreviation list


Abb

Full text

ACHacute cerebral hemorrhage
ACIacute cerebral infarction
ADHDattention deficit hyperactivity disorder
ADLactivities of daily living
AEsadverse events
AIMabnormal involuntary movement
ALSamyotrophic lateral sclerosis
ALTalanine aminotransferase
ASAntagonic-Stress
BUNblood urea nitrogen
CBFcerebral blood flow
CNScentral nervous system
COcarbon monoxide
CPHcentrophenoxine
CRPC-reactive protein
DBdouble-blind
DB-RCTdouble-blind randomized controlled trial
DMAEdimethylaminoethanol
EEGelectroencephalogram
G6PD

glucose-6-phosphate dehydrogenase

GCSGlasgow Coma Scale
GIgastrointestinal
GSH-Pxglutathione peroxidase
HBO
hyperbaric oxygen
HIEhypoxic-ischemic encephalopathy
HRV
heart rate variability
ICU
intensive care unit
ILinterleukin
i.v.intravenous
LD50median lethal dose
MCPA4-chloro-2-methylphenoxyacetic acid
MDAmalondialdehyde
MMSEMini-Mental State Examination
NIHSSNational Institutes of Health Stroke Scale
NSEneuron-specific enolase
pCPA

para-chlorophenoxyacetic acid (4-chlorophenoxyacetic acid)

RCT
randomized controlled trial
salvia
Salvia miltiorrhiza
SGA
small for gestational age
SODsuperoxide dismutase
SSEPsomatosensory evoked potential
TBItraumatic brain injury
TCMtraditional Chinese medicine
TNF-αtumor necrosis factor alpha
TSHthyroid stimulating hormone
VaDvascular dementia
WAISWechsler Adult Intelligence Scale
WMSWechsler Memory Scale

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.


Category Benefit type 

Magnitude

Likelihood

Duration

Importance to patientSummaryWeightScoreUncertaintyWeighted score
1Dementia & cognitive decline↑ clinical improvement/stabilization in dementia & cognitive decline

1

2

1

2

61.5+1

1 RCT: Marcer & Hopkins, 1977; Pieschl et al., 1983; Vehreschild et al., 1975

2 Comparative/Open-label: Popa et al., 1994; Yang, 2015; Yang & Zhang, 2016; Herrschaft, 1992; Zhou, 2002

3 Observational: Tamai & Torii, 1990

Conflict: Bower & McDonald, 1966; Pék et al., 1989

0.75
2Dementia & cognitive decline
↑ ADL in dementia & cognitive decline
1


1


1


2


51.25+1

1 RCT: Marcer & Hopkins, 1977

2 Open-label: Fu et al., 2007

Conflict: Zhang & Wang, 2007; Pék et al., 1989; Bower & McDonald, 1966

0
3Dementia & cognitive decline↑ clinical improvement in corpus callosum degeneration

1

2

1

3

7
1.75
+1

2 Open-label: Dai & Li, 2012

0.5
4Dementia & cognitive decline↓ neurological deficit in VaD

1

2

1

3

71.75+1

1 RCT: Bian et al., 2004

2 Comparative: Chen, 2007b; Yao et al., 2006

1.25
5Dementia & cognitive decline↑ clinical improvement in VaD

1

2

1

3

71.75+1

1 RCT: Bian et al., 2004

2 Comparative/Open-label: Niu & Li, 2008; Fu et al., 2007; Zhang & Wang, 2007; Herrschaft, 1992

3 Observational: Tamai & Torii, 1990; Richter, 1983; Ma, 2014

1.25
6General CBF

1

3

1

2

71.75+11
7General clinical improvement in chronic cerebrovascular disease

1

1

1


1


41+10
8Metabolism & biochemistry↓ age-related intracellular water loss

1

1

1

1

41+1

1 RCT: Fülöp et al., 1990

0.75
9Metabolism & biochemistry

↑ blood oxygen saturation & consumption

1

1

1

1

41+12 Comparative/Open-label: Tang & Dong, 2018; Schmid & Schlick, 1979

Conflict: Xie & Min, 2013

0
10Metabolism & biochemistry↓ fasting glucose levels

1

1

1

1

41+10
11Metabolism & biochemistry↑ normalization of blood glucose dynamics

1

1

1

1

41+1

2 Comparative: Stoica et al., 1974

0
12Metabolism & biochemistry↑ oxidative stress mitigation

2

1

1

1

51.25+1
2 Comparative: Tang & Dong, 2018
1.25
13Metabolism & biochemistry↑ energy

1

1

1

1

41+10
14Metabolism & biochemistry

biomarkers in cerebrovascular disease

2


1

1

2

6
1.5
+1

1 RCT: Zhang, 2018b; Hou et al., 2019; Ji et al., 2007

3 Observational: You, 2020

1.5
15Movement disorders↑ reflexes in cerebral palsy

1

1

1

2

51.25+1

2 Open-label: Bradna, 1967

0
16Movement disorders↓ involuntary movements in tardive dyskinesia

2

2

2

2

82+1

2 Open-label: Izumi et al., 1986

Conflict: Yagi et al., 1990 

0
17Movement disorders ALS symptoms

1

1

1

2

51.25+1

2 Comparative: Sercl & Kovarik, 1963

0
18Musculoskeletal↑ bone mineral density

1

1

1

1

41+1

2 Comparative: Li et al., 2019

0
19Musculoskeletal shoulder stiffness

1

1

1

1

41+10
20Neurological symptoms↓ ischemia-induced orthostatic hypotension & abnormal catecholamine response

1

1

1

1

41+1

2 Open-label: Stoica & Enulescu, 1991

0

21Neurological symptoms↓ dizziness

1

2

1

2

61.5+1

1 RCT: Itoh et al., 1968

2 Open-label: Herrschaft, 1992

3 Observational: Zhao, 2004

1.5
22Neurological symptoms↓ headache

1

2

1

2

61.5+1

2 Open-label: Lin, 2001; Herrschaft, 1992

3 Observational: Zhao, 2004

Conflict: Itoh et al., 1968

0
23Neurological symptoms HRV in ACI

1

1

1

2

5
1.25
+1

2 Comparative: Liu et al., 2008

0
24Neurological symptoms vertigo

1

1

1

2

5
1.25
+1

2 Comparative: Chen, 2007a

0
25Neurological symptoms↓ visually-triggered gaze saccade latency in post-traumatic cervical syndrome

2

2

1

1

6
1.5
+1

2 Open-label: Maeda & Ishii, 1984

0
26Neurological symptoms clinical improvement in cortical blindness

1

1

1

2

5
1.25
+1

3 Observational: Yang & Feng, 1987

0
27Perinatal & pediatric↑ long-term memory & learning in children

1

1

1

2

51.25+10
28Perinatal & pediatric↑ general cognition & mental performance in children

1

2

1

2

61.5+10
29Perinatal & pediatric↑ behavior & mood in children

1

1

1


1
4
1
+1

2 Open-label: Herrschaft, 1992; Colpin, 1970

Conflict: Kirman, 1961; Teichmann & Schwebke, 1973

0
30Perinatal & pediatric
↑ clinical improvement in HIE

1


2

2

3

82+11.5
31Perinatal & pediatric↑ condition of the newborn in SGA fetuses

2

2

2

2

8
2
+1

1 RCT: Neumann & Zienert, 1993

1.75
32Perinatal & pediatric↓ clinical symptoms in pediatric enuresis

1

2

1

1

5

1.25+11
33Perinatal & pediatric↓ sleep arousal threshold in pediatric enuresis

1

1

1

1

4

1
+10
34Poisoning & anesthesia↑ recovery in acute severe organophosphate poisoning

2

2

2

3

9
2.25
+1

1 RCT: Huang & Zhang, 2006; Li, 2009

1.5
35Poisoning & anesthesia clinical improvement in alcohol intoxication

2 

1

1

1

5
1.25
+1

1 RCT: Liao, 2019; Shi, 2017; Hu et al., 2013; Yang & Li, 2012; Sun et al., 2010 (identical data in Xu et al., 2014); Wu & Zhang, 2008; Mai, 2013; Ji, 2009

2 Comparative: Tang & Dong, 2018; Huang, 2011; Chen et al., 2006; Hou, 2009

1
36Poisoning & anesthesia awakening time in alcohol intoxication

2

1

1

2

6
1.5
+1

1 RCT: Shi, 2017; Liao, 2019; Hu et al., 2013; Sun et al., 2010 (identical data in Xu et al., 2014); Yang & Li, 2012; Ji, 2009

2 Comparative: Huang, 2011; Chen et al., 2006

1.5
37Poisoning & anesthesia↓ duration & severity of acute delirium in alcohol withdrawal

2

1

1

2

6
1.5
+1

2 Open-label: Herrschaft, 1992 

0.5
38Poisoning & anesthesia clinical improvement in CO poisoning

1

1

1

3

6
1.5
+1

1 RCT: Zheng et al., 2011; Lv & Yuan, 2010; Hou, 2010

1
39Poisoning & anesthesia recovery from general anesthesia

1

1

1

1

41+1

1 RCT: Mao et al., 2019; Mao, 2013

0.75
40Psychiatry & psychology↑ improvement/stabilization in attention & concentration

1

1

1

2

51.25+11
41Psychiatry & psychology↑ short-term memory

1

1

1

2

51.25+10
42Psychiatry & psychology↑ long-term memory & learning

2

2

1

2

71.75+11
43Psychiatry & psychology↑ memory of unspecific type

1

2

1

2

61.5+1

2 Comparative/Open-label: Zhou, 2002; Herrschaft, 1992

3 Observational: Zhao, 2004

Conflict: Itoh et al., 1968

0
44Psychiatry & psychology↑ general cognition & mental performance

2

2

1

2

71.75+11
45

Psychiatry & psychology

↓ depression

2

1

1

2

6
1.5
+1

1 RCT: Xing et al., 1996; Tang & Zhou, 2006

3 Observational: Qiu & Zhang, 2003

Conflict: Bian et al., 2006

0.25
46

Psychiatry & psychology 

↑ behavior & mood

1

1

1

2

5
1.25
+1

2 Comparative/Open-label: Popa et al., 1994; Zhou, 2002; Molčan et al., 1978; Herrschaft, 1992

3 Observational: Tamai & Torii, 1990

Conflict: Pék et al., 1989; Bower & McDonald, 1966; Itoh et al., 1968; Hasegawa et al., 1976

0.25
47

Psychiatry & psychology

↓ neuroses

1

1

1

2

5
1.25
+1

1 RCT: Pieschl et al., 1983

Conflict: Ziolko, 1961

0.25
48Sleep & consciousness↑ favorable sleep changes

1

2

1

2

6
1.5
+1

2 Open-label: Ti et al., 2002

3 Observational: Wan & Bao, 1985

Conflict: Bower & McDonald, 1966; Brezinova et al., 1970

0
49Sleep & consciousness

↑ EEG vigilance and SSEP amplitudes

1

1


1


1


4
1
1

2 Comparative/Open-label: Kinoshita, 1990; Herrschaft, 1992; Brezinova et al., 1970; Umlauf et al., 1983

0
50Stroke

neurological deficit in ACH

2

1

2

3

8
2
+1

1 RCT: Lu et al., 2007; Zhang, 2018b; Lv & Huang, 2008; Ma & Zhou, 2021

3 Observational: You, 2020

1.5
51Stroke

↓ neurological deficit in ACI

1

2

2

3

7
1.75
+1

1 RCT: Lu et al., 2006; Ji et al., 2007; Dai et al., 2009; Lin, 2014; Chen et al., 2003

Conflict: Bian et al., 2006

1.5
52Stroke

↓ volume of brain edema in ACH

2

1

2

3

8
2
+1

1 RCT: Zhang, 2018b; Hou et al., 2019

1.5
53Stroke

↑ clinical improvement in ACH

1

2

1

3

7
1.75
+1

1 RCT: Lv & Huang, 2008; Hou et al., 2019; Zhang, 2018b; Ma & Zhou, 2021; Cooperation Study Group on Acute Cerebrovascular Diseases, 1978

1.5
54Stroke

↑ clinical improvement in cerebral infarction

1

2

1

3

7
1.75
+1

1 RCT: Wang & He, 2007; Lin, 2014

2 Comparative/Open-label: Stoica et al., 1974; Liang & Wang, 2012; Herrschaft, 1992

Conflict: Cooperation Study Group on Acute Cerebrovascular Diseases, 1978

1.5
55Stroke

↑ clinical improvement in cerebrovascular disease of unspecified type

2

2

1

3

8
2
+1

2 Open-label: Budinova-Smela & Mimrova, 1975

3 Observational: Zhao, 2004

Conflict: Robinson, 1978; Hasegawa et al., 1976

0
56Stroke

ADL in acute cerebral damage

2

1

2

2

71.75+1

1 RCT: Zhang, 2018b; Lu et al., 2006; Hou et al., 2019; Zhu et al., 2003a; Chen et al., 2003; Ji et al., 2007; Lin, 2014

3 Observational: You, 2020

1.5
57TBI & coma consciousness level

2

2

2


3

92.25+1

1 RCT: Cooperation Study Group on Acute Cerebrovascular Diseases, 1978; Zhang, 2018b; Ma, 2018; Lu et al., 2007; Gao et al., 2008; Gao et al., 2006

2 Open-label: Umlauf et al., 1983

3 Observational: Bassem et al., 2018

Conflict: Cooperation Study Group on Acute Cerebrovascular Diseases, 1978; Hasegawa et al., 1976

1.75
58TBI & coma↑ recovery from TBI

1

2

2

3

8
2
+1

1 RCT: Ma, 2018; Guo et al., 2011

3 Observational: Han, 2005; Xing & Yang, 1991

Conflict: Itoh et al., 1968

1
59Urinary↓ clinical symptoms in enuresis

1

1

1

2

5

1.25+10.5


Dementia & cognitive decline


Clinical improvement/stabilization in dementia & cognitive decline

A double-blind randomized controlled trial (DB-RCT) (n=76) in elderly subjects with age-related cognitive decline observed a self-reported beneficial effect of CPH supplementation (1200 mg/day oral for 9 months) in a patient questionnaire in 67% of the treatment group, compared to 42% in the placebo group. However, there were no differences in the health assessment (Marcer & Hopkins, 1977).

A DB-RCT (n=52) reported superiority of CPH supplementation (2 g/day) over placebo in a subgroup (n=32) of patients with "psycho-reactive neurotic disturbances" in subjective evaluations, including the judgment of doctors as well as patients after 4 weeks of treatment (Pieschl et al., 1983).

In another trial (n=62), patients (45-75 years) suffering from an idiopathic progressive reduction in cerebral capacity were given CPH (600 mg/day) for 6-21 months; for a 6-8 week period, 28 of these participants were administered a placebo instead as part of a DB-RCT. The study reported that, while taking CPH, no increase in patients' symptoms was observed, according to clinical electroencephalogram (EEG) before and after treatment (Vehreschild et al., 1975).

A double-blind (DB) comparative trial (n=63; 31 using CPH) in patients with "senile dementia of Alzheimer type" reported improvements relative to baseline in the somatic dysfunction subscales of the Sandoz Clinical Assessment-Geriatric (SCAG) and Sandoz Self-Assessment Scale-Geriatric (SASG) of 23.0% (from 11.3 to 8.7 points) and 20.0% (from 11.5 to 9.2 points), respectively, over a 3-month course of oral CPH (1560 mg/day). The comparator group taking Antagonic-Stress (AS), with the same amount of CPH/day in addition to vitamins, minerals, amino acids and fructose, showed superior improvements (Popa et al., 1994).

 A randomized comparative trial (n=80) in patients with Alzheimer's dementia (50 with mild-moderate disease and 30 with severe disease) reported that the group administered oral CPH, 900 mg/day for 6 months, improved significantly relative to controls receiving Salvia miltiorrhiza (salvia) and vitamins C and E, though clinical efficacy in severe disease was poor (Zhou, 2002).

Two comparative trials (n=72; n=76) in patients with cerebral atrophy reported an effective rate of 72.22% (26/36) and 68.42% (26/38), respectively, after 3 months of CPH treatment, however, the groups receiving gastrodin injection experienced higher effective rates, 94.44% (34/36) and 94.74% (36/38) (Yang, 2015; Yang & Zhang, 2016).

Two DB-RCTs reported changes in the physician’s overall assessment with CPH treatment in patients with Alzheimer’s dementia. One reported an improvement in the CPH group (1000 mg/day for 6 weeks) of 58% compared to 42% in the control group. However, the other trial reported only a positive trend after CPH treatment (1200 mg/day) for 12 months (Herrschaft, 1992).

A case series (n=20; 11 with Alzheimer's dementia) reported that patients treated with 500 mg/day intravenous (i.v.) CPH for 4 weeks experienced moderate to marked symptomatic improvement in 81.8% (9/11), mild improvement in one (9.09%), and no benefit in another (9.09%), however, the authors remarked: "the improvement rate was considered low." Symptoms of nocturnal delirium, hostility, and fugue were most responsive to treatment, while somatic and neurological symptoms generally did not respond (Tamai & Torii, 1990).

A DB-RCT (n=50) in nursing home residents with moderate dementia reported a self-rating improvement in 25.0% (6/24) of the cases in the CPH group over 8 weeks of treatment with 2 g/day orally, compared to 28.0% (7/25) of the cases in the placebo group. The health status according to the rating of the medical doctor was reported as positive in 8.0% (2/25) of the patients from the placebo group, compared to 37.5% (9/24) in the treatment group (Pék et al., 1989). However, our calculations revealed that neither of these differences were significant.

In contrast, a triple-blind RCT (n=24) using CPH (800 mg/day for 12 weeks) in female patients with "senile dementia", found no significant change in the rating of clinical symptoms by nurses, occupational therapists, and psychiatrists (Bower & McDonald, 1966).


Improved activities of daily living (ADL) in dementia & cognitive decline

A DB-RCT (n=76) in elderly subjects with age-related cognitive decline reported that the improvement in memory function observed in the CPH group (1200 mg/day oral for 9 months) led to an improvement in day-to-day activities in several cases. However, no statistical significance was claimed (Marcer & Hopkins, 1977).

An open-label study (n=56) in patients with vascular dementia (VaD) reported an improvement in ADL after CPH supplementation (600 mg/day) for 12 weeks (Fu et al., 2007).

Another open-label study (n=30) in patients with VaD showed that although most of the patients improved in their daily living ability after CPH supplementation (600 mg/day) for 10 weeks, the change did not reach significance (Zhang & Wang, 2007).

A triple-blind RCT (n=24) in female patients with "senile dementia" did not report any benefit of CPH supplementation (800 mg/day) for 12 weeks in the Nurses' rating scale, which assesses psychopathology and nursing care requirements, including daily life activities (Bower & McDonald, 1966).

In addition, our calculation from the participant-level data from a DB-RCT (n=50) in nursing home residents with moderate level dementia (Pék et al., 1989) shows no impact of CPH (2 g/day for 8 weeks) compared to placebo (7.9% improvement in the treatment group vs. 6.4% in placebo) on the observation scale for daily activities.


Decreased neurological deficit in VaD

An RCT (n=70) in patients with mild to moderate VaD treated with huperzine A reported an absolute 34.3% higher improvement rate in neurological deficits (57.14%; 20/35) in the group additionally administered oral CPH (600 mg/day for 3 months) (Bian et al., 2004).

A DB-randomized comparative trial (n=60) in patients with VaD reported an improvement in neurological function in 80% (24/30) of the patients after 2 weeks of CPH supplementation compared to 60% (18/30) in the control group supplemented with vitamin B6 (Chen, 2007b).

A comparative trial (n=40) in patients with mild to moderate VaD reported an absolute 20% higher total effective rate of 80% (16/20; markedly effective in 60%, effective in 20%) with respect to neurological deficit score in the group receiving a "short course" of i.v. CPH (300 mg), compared to 60% (12/20; markedly effective in 30%, effective in 30%) in the control group receiving 200 mg of vitamin B6 (Yao et al., 2006).


Clinical improvement in VaD

An RCT (n=70) in patients with mild to moderate VaD treated with huperzine A reported an absolute 28.6% higher improvement rate in dementia symptoms (65.71%; 23/35) in the group additionally administered oral CPH (600 mg/day for 3 months) (Bian et al., 2004).

An open-label trial (n=56) in patients with VaD treated with CPH, 600 mg/day for 12 weeks, reported a mean increase of 0.82 points on the Clinical Dementia Rating Scale, a 27.3% improvement relative to the scale range (from 0 to 3) (Fu et al., 2007).

An open-label study (n=30) in patients with VaD, reported an "effective rate" of 66.67% (20/30) on the Clinical Global Impression scale after CPH supplementation, 600 mg/day for 10 weeks, compared to baseline (Zhang & Wang, 2007).

A randomized comparative trial (n=80) in patients with VaD reported an effective rate of 60% (24/40) for the CPH group, an absolute 20% lower than the group also receiving TCM (Niu & Li, 2008).

Two DB-RCTs (n=160; n=25) in patients with VaD reported a significant improvement in the physician’s overall assessment associated with 6 weeks of CPH treatment (500-900 mg/day) (Herrschaft, 1992).

A retrospective observational study (n=50) in patients with VaD reported several clinical indicators were significantly improved after treatment and concluded that CPH has "...outstanding clinical therapeutic effect on patients with VaD" (Ma, 2014). Another observational study (n=31) reported that CPH supplementation (1250 mg/day for 8 weeks) positively influenced clinical symptoms in patients with cerebral insufficiency (Richter, 1983).

A case series (n=20, 9 with VaD) reported moderate to marked symptomatic improvement in 33.3% (3/9), mild improvement in 33.3% (3/9), and no benefit in 33.3% (3/9) treated with 500 mg/day i.v. CPH for 4 weeks. Symptoms of nocturnal delirium, hostility, and fugue were most responsive to treatment (Tamai & Torii, 1990).


Clinical improvement in corpus callosum degeneration

An open-label trial (n=21) in patients treated with CPH (300-750 mg/day) for corpus callosum degeneration due to chronic alcoholism reported that 42.86% (9/21) of the patients were cured, 33.33% (7/21) improved, 14.29% (3/21) were unchanged, and 9.52% (2/21) died (Dai & Li, 2012).


General


Increased cerebral blood flow (CBF)

An open-label trial (n=18) in patients with cerebrovascular disease reported average increases in total and gray matter CBF of ~9% and 11.4%, respectively, 15 minutes after a single i.v. dose of CPH (1000 mg). No significant increase was reported when the dose was reduced to 500 mg, or in white matter with either dose (Herrschaft et al., 1974).

A randomized comparative trial (n=102) in patients with acute cerebral infarction (ACI) reported an increase in CBF after CPH supplementation compared to baseline and compared to controls receiving citicoline (Chen, 2010).

One trial in patients with ACI and another in patients with VaD reported a positive effect of CPH on CBF and cerebral metabolism (Herrschaft, 1992).


Clinical improvement in chronic cerebrovascular disease

A randomized comparative trial that tested several agents (n=41 in the CPH group) in patients with cerebral circulatory disturbances reported moderately good results with CPH use. Decreased intensity of neurotic complaints, labyrinthine-cerebellar signs, pyramidal signs, anxiety and fears, improvement of recent memory, attention and psychomotor activity were among overall benefits mentioned, but not attributed to any specific trial drug (Wasilewski et al., 1981).


Metabolism & biochemistry


Decreased age-related intracellular water loss

A DB-RCT (n=50) in nursing home residents with moderate dementia reported a mean absolute increase of 2.4% (from 64.9% to 67.1% in males and from 64.5% to 67.1% in females) in intracellular water content after 8 weeks of CPH supplementation (2 g/day), while only a slight increase was reported in the placebo group (Fülöp et al., 1990).


Increased blood oxygen saturation & consumption

A randomized comparative trial (n=117) in patients with acute alcohol intoxication reported an increase in blood oxygen saturation and arterial oxygen content after 3 days of i.v. CPH administration (600 mg/day) compared to before treatment. However, superior results were reported for the group additionally treated with TCM (Tang & Dong, 2018).

An open-label trial with 10 older adults (mean age 64 years) in the treatment group reported an increase in maximal oxygen consumption after 12 months of CPH supplementation (3 g/day) compared to the control group (the number of controls was not reported) (Schmid & Schlick, 1979).

However, an RCT (n=60) in elderly female patients recovering from general anesthesia did not report any significant difference in oxygen saturation between 3 groups treated with nalmefene, CPH (250 mg), or their combination (Xie & Min, 2013).


Decreased fasting glucose levels

An open-label trial with 10 older adults (mean age 64 years) in the treatment group reported a decrease in fasting blood glucose levels but no change in an oral glucose tolerance test after 12 months of CPH supplementation (3 g/day) compared to the control group (the number of controls was not reported) (Schmid & Schlick, 1979).


Normalization of blood glucose dynamics

A comparative trial reported that stroke patients' blood sugar dynamics and vanillylmandelic acid excretion in response to hypoglycemia normalized in most patients given CPH (Stoica et al., 1974).


Improved oxidative stress mitigation

An RCT (n=72) in patients with acute carbon monoxide (CO) poisoning, and treated with hyperbaric oxygen (HBO), reported a higher serum level of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and lower malondialdehyde (MDA) in the group additionally treated with CPH (500 mg/day for 2 weeks) (Zheng et al., 2011).

A randomized comparative trial (n=117) in patients with acute alcohol intoxication reported an increase in SOD and GSH-Px after 3 days of i.v. CPH administration (600 mg/day) compared to before treatment. However, superior results were reported for the group additionally receiving TCM (Tang & Dong, 2018).


Improved energy

An open-label trial (n=10) in sleep-deprived abstaining chronic alcoholics (5 young, 5 middle-aged) reported an increase in "the biological reactions of energy rich phosphates" in the CPH-treated group at 3 days of sleep deprivation in the middle-aged group. However, no statistical significance was claimed (Vojtechovsky et al., 1969).


Improved biomarkers in cerebrovascular disease

An RCT (n=80) in patients with acute cerebral hemorrhage (ACH) reported a 53.37% reduction in high-sensitivity C-reactive protein (CRP; 9.0 vs. 19.3 mg/L), a 34.31% reduction in neuron-specific enolase (NSE; 13.4 vs. 20.4 μg/L) and a 52.78% reduction in interleukin-6 (IL-6; 8.5 vs. 18.0 pg/mL)