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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:

• 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.

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) in the CPH group compared to the control group (Zhang, 2018b).

In an RCT (n=124) in ACH patients, lower IL-6, tumor necrosis factor alpha (TNF-α), high-sensitivity CRP, and IL-1 levels were reported in the CPH group relative to controls after 1 month of treatment (Hou et al., 2019).

An RCT (n=60) in patients with ACI reported lower CRP in the CPH group (300 mg/day for 2 weeks) compared to the control group (Ji et al., 2007).

A retrospective observational study (n=51) in ACH patients reported lower CRP, TNF-α, and IL-6 in the group receiving CPH for 1 month in addition to standard care (You, 2020).

Movement disorders

Improved reflexes in cerebral palsy

An open-label trial (n=71, with an additional 33 normal controls) reported that myotensiometric and electromyography examinations demonstrated that the plantar postural reflex, grasp reflex, and arthrokinetic reflexes of knee and hip were improved (Bradna, 1967).

Decreased involuntary movement in tardive dyskinesia

An open-label trial (n=12) in psychiatric patients with abnormal involuntary movements induced by neuroleptics reported a 44.7% reduction (from 38 to 21) in the abnormal involuntary movement (AIM) scale after 12 weeks of CPH supplementation (600-1200 mg/day). A decrease in the AIM scale was observed in 63.6% (7/11) of the patients, from which 4 (36.4%) improved markedly, 1 (9.1%) moderately and 2 (18.2%) slightly; involuntary movements reappeared 4-8 weeks after the cessation of the treatment. In the additional patient, CPH treatment was started 1 week after the appearance of dyskinesia, which diminished slightly after 2 weeks of treatment (900 mg/day) and disappeared completely from the third week after CPH treatment (1200 mg/day) through the following 3 months (Izumi et al., 1986).

However, a multicenter DB-RCT (n=60) in patients with tardive dyskinesia reported no effect after 8 weeks of CPH supplementation (900 mg/day) compared to placebo (Yagi et al., 1990).

Decreased amyotrophic lateral sclerosis (ALS) symptoms

A parallel comparative trial (n=26) in patients with ALS reported that 30.8% (4/13) of the patients improved, 53.8% (7/13) of the patients were unaffected by CPH (up to 300 mg/day orally, or 250 mg/day i.v.) and 15.4% (2/13) worsened. However, a group of 13 patients treated with trypan red experienced a similar disease course. At one year follow-up, both the CPH and trypan red groups did not show any improvement and the disease progressed (Sercl & Kovarik, 1963).

Musculoskeletal

Increased bone mineral density

A randomized comparative trial (n=100) in patients with diabetes who suffered a cerebral infarction reported an increase in bone mineral density after 21 days of i.v. CPH (500 mg/day) (Li et al., 2019).

Decreased shoulder stiffness

A DB-RCT (n=222) in patients with VaD reported an improvement in shoulder stiffness after 4 weeks of CPH supplementation (600-1200 mg/day) compared to the control group (Herrschaft, 1992).

A DB-RCT (n=106) which evaluated clinical symptoms of patients with cerebrovascular diseases noted only some early effectiveness of oral CPH (900 mg/day for 4 weeks) in improving shoulder stiffness, however the improvement was not significant (Hasegawa et al., 1976). A multicenter crossover DB-RCT (n=51 completed the study) in patients with head injury sequelae reported no benefit of CPH supplementation (900 mg/day for 2 weeks) over placebo in shoulder stiffness (Itoh et al., 1968).

Neurological symptoms

Decreased ischemia-induced orthostatic hypotension & abnormal catecholamine response

An open-label trial (n=25) studied the effect of a 10-day course of 800 mg/day CPH in patients with orthostatic hypotension due to brainstem ischemia. Initially aberrant posture-induced catecholamine secretion patterns resolved concurrently with CPH supplementation. However, though patients' orthostatic blood pressure drop was less marked after treatment, the authors reported that this could not be correlated significantly with the restoration of the catecholamine response (Stoica & Enulescu, 1991).

Decreased dizziness

A multicenter crossover DB-RCT (n=51) in patients with head injury sequelae reported a decrease in dizziness in 64.0% (16/25) of the patients after 2 weeks of CPH supplementation (900 mg/day) compared to 24.0% (6/25) with placebo, an absolute advantage of 40.0% for CPH (Itoh et al., 1968).

A case series (n=120) in elderly stroke patients reported an effective treatment rate of 76% (91/120) for dizziness after 3 months of oral CPH supplementation (200-300 mg/day for 1 week, optionally increased to 400-900 mg/day thereafter) (Zhao, 2004).

One study (n=25) in patients with VaD reported a decrease in dizziness after 6 weeks of CPH supplementation (600-900 mg/day) (Herrschaft, 1992).

Decreased headache

An open-label study (n=30) in patients with cerebrovascular disease reported an improvement in headache symptoms in 84.6% of the patients after 3 months of CPH supplementation (600 mg/day) (Lin, 2001).

A case series (n=120) in elderly patients with various symptoms of stroke sequelae reported an effective treatment rate of 80% (96/120) for headache after 3 months of oral CPH supplementation (200-300 mg/day for 1 week, optionally increased to 400-900 mg/day thereafter) (Zhao, 2004).

One study (n=25) in patients with VaD reported a decrease in headache after 6 weeks of CPH supplementation (900-600 mg/day) (Herrschaft, 1992).

However, a multicenter crossover DB-RCT (n=51 completed the study, of 63 originally enrolled) in patients with head injury sequelae did not find any significant effect of 2 weeks of CPH supplementation (900 mg/day) on headache. A decrease in headache was reported in only 37.1% (13/35) of patients in the CPH group, compared to 51.4% (18/35) in the placebo group (Itoh et al., 1968).

Increased heart rate variability (HRV) in ACI

A randomized comparative trial (n=141) observed that HRV indexes were lower in patients with ACI compared to healthy subjects (n=50). After 15 days of CPH supplementation (n=46), HRV indexes in patients with infarction increased compared to patients receiving piracetam (n=45) (Liu et al., 2008).

Decreased vertigo

A randomized comparative trial (n=48) in patients with vertigo reported that CPH is effective and faster in resolving vertigo symptoms compared to nimodipine (Chen, 2007a).

Decreased visually-triggered gaze saccade latency in post-traumatic cervical syndrome

An open-label study (n=12) in patients with post-traumatic cervical syndrome reported that a single i.v. injection of CPH (250 mg) shortened, by approximately 100 milliseconds (~20-25% of total reaction time), a delay to initiate visually triggered gaze saccade present in this patient population when evoked by nuchal stimulation (Maeda & Ishii, 1984).

Improved cortical blindness

A case report (n=2; one of them was a child) in patients with cortical blindness reported satisfactory results after CPH treatment (Yang & Feng, 1987).

Perinatal & pediatric

Improved general cognition & mental performance in children

In two placebo-controlled studies in children with oligophrenia (intellectual disability), an increase in mental tempo was registered to a slight extent under CPH medication (300-500 mg/day) (Herrschaft, 1992).

An open-label trial (n=35) in intellectually disabled children aged 6-14 reported approximately 50% of patients showed an advancement in mental age with CPH treatment over 5-6 months with improvement more likely in serious cases; an improvement in psychomotor ability was also noted in 60% (Colpin, 1970).

However, a crossover DB-RCT (n=18) in children with behavior consistent with a modern diagnosis of attention deficit hyperactivity disorder (ADHD) reported a 9.9% lower score on the Pauli test following oral CPH supplementation for 18 days (200 mg/day for 7 days and 600 mg/day for 11 days) compared to placebo; the participants completed an average 634 math problems on the assessment following the placebo phase, but only 571 after the CPH phase, having completed an average 562 problems (589 according to our calculations) on a baseline assessment. The study also reported a trend toward a higher error rate for the CPH phase (3.4% vs. 2.0% for placebo). The performance curves for the CPH phase, over the approximately hour-long test, showed that participants' work rate tended to drop during the later part of the assessment (Teichmann & Schwebke, 1973).

Improved long-term memory & learning in children

Two trials reported a positive effect in children with dyslexia regarding learning ability and improvement of long-term memory (Herrschaft, 1992).

However, a crossover DB-RCT (n=18) in children with behavior consistent with a modern diagnosis of ADHD reported a 9.9% lower score on the Pauli test following oral CPH supplementation for 18 days (200 mg/day for 7 days, followed by 600 mg/day for 11 days) and a smaller score increase compared to placebo. While the Pauli test is primarily a test of concentration and mental performance, examinees typically experience a test:retest score increase, which was reduced or abolished for the CPH phase of this study (Teichmann & Schwebke, 1973).

Improved behavior & mood in children

Two RCTs in children with an intellectual disability reported that affective interest increased to a "slight extent" in those treated with CPH (300-500 mg/day) compared to placebo (Herrschaft, 1992).

An open-label trial (n=35) in intellectually disabled children aged 6-14 reported an improvement in social maturity in 30% of those treated with CPH over 5-6 months (Colpin, 1970).

However, a DB-RCT (n=40) in children with intellectual disability reported no difference between CPH (increasing stepwise oral dosing from 200-1000 mg/day over 4 weeks) and placebo in response to examiner, play activity, response to verbal requests, and school and ward behavior (Kirman, 1961).

A crossover DB-RCT (n=18) in children with ADHD reported no significant improvements associated with CPH treatment (200 mg/day for 7 days and 600 mg/day for 11 days) to various aspects of behavior as assessed by blinded parents and teachers (Teichmann & Schwebke, 1973).

Decreased clinical symptoms in pediatric enuresis

Nineteen randomized comparative trials in children with enuresis reported benefits after 2-4 weeks of CPH supplementation. In all the trials, CPH was used as a control and was compared against TCM, which was uniformly reported to be numerically superior to CPH supplementation, although not significantly so in some cases. In sixteen of these trials that reported quantitative data, an average of 73.0% (519/711) of patients experienced reduced incontinence after CPH supplementation. These trials are shown in a table below. Three of the trials did not report any numerical value but reported a beneficial effect of CPH supplementation on incontinence (Wang, 2020; Zhang & Zhang, 2017; Yu et al., 2020).

One study additionally reported a recurrence rate, 55.6% (10/18) at 3 months' follow-up, with CPH treatment (Li, 2010).

From all the trials, only two studies reported the dose: one trial reported 100 mg/day 30 minutes before bedtime (Hu et al., 2008) and the other trial reported 300 mg/day divided into three doses (Wang, 2015).

A DB-RCT (n=40) in intellectually disabled children reported no difference in continence between CPH and placebo (Kirman, 1961).

Three trials compared CPH to standard Western treatments for pediatric enuresis, desmopressin and sleep alarms, and reported CPH to be inferior (Tong, 2011; Jin et al., 2009; Yang et al., 2007).

Table of studies that reported an effective rate of CPH in pediatric enuresis:

Decreased sleep arousal threshold in pediatric enuresis

A multicenter DB-randomized comparative trial (n=446) in children with enuresis reported an improvement in depth of sleep compared to baseline after oral CPH supplementation (100 mg/day 30 minutes before bedtime) for 28 days (Hu et al., 2008).

Two randomized comparative trials (n=102; n=68) in children with enuresis reported a decrease in arousal threshold or an improvement score of "sleep-wake disorder" after CPH supplementation. In both trials, CPH was used as a control and compared against TCM, which was shown to be superior to CPH (Ma et al., 2020; Wang, 2020). One of these trials also reported an increase in anti-diuretic hormone after CPH supplementation (Ma et al., 2020).

Clinical improvement in hypoxic-ischemic encephalopathy (HIE)

An RCT (n=156) in neonates with HIE reported an absolute 67.9% greater improvement rate in the combined group receiving CPH in addition to conventional therapy (84.6%; 66/78) (Pu & Liu, 2008).

A similar RCT (n=88) reported a 25.5% absolute advantage over controls in the proportion of patients with generally improving neurological symptoms, 95.8%, in the group treated with CPH (Guo, 2013).

Another RCT (n=98) in neonates with HIE reported an absolute 16.3% greater average clinical improvement rate (97.96%; 48/49) in the group treated with CPH in addition to monosialotetrahexosylganglioside. The group receiving both agents also had a higher average neonatal behavioral neurological assessment score, and experienced improvement earlier than controls (Hui & Zhang, 2022). The same study reported a lower IL-6, IL-8, TNF-α and NSE in the group receiving CPH.

An RCT (n=92) reported that 89.6% (43/48) of the cases with HIE were cured, improving clinical symptoms and CBF dynamics, with CPH supplementation (60-100 mg/day) for 7 days, superior to the cure rate in the control group (Xiang & Wang, 2005).

An RCT (n=60) in neonates with HIE reported an absolute advantage of 23.3% in improvement rate for the group in which CPH was added to conventional treatment (86.67%; 26/30). Additionally, the absolute risk of sequelae and morbidity-mortality were lower by 13.3% and 6.67%, respectively, in the CPH group compared to the control group (Wang, 2011).

An RCT (n=120) in neonates with HIE reported higher effectiveness for the group treated with CPH in addition to HBO (Fang et al., 2010).

A randomized comparative trial (n=100) in children with HIE reported an effective rate of 90% (45/50) in the treatment group receiving i.v. CPH, an absolute advantage of 16% over controls receiving breviscapine; both groups additionally received cerebrolysin and massage therapy (Wu, 2010). The same study reported that the percentage increases in CBF for the anterior cerebral, middle cerebral, and basilar arteries were greater in the CPH group compared to the breviscapine group, with absolute differences between groups of 23.0%, 15.6%, and 29.1% for the three vessels, respectively.

Improved condition of the newborn in small for gestational age (SGA) fetuses

A DB-RCT (n=293) in pregnant women with intrauterine growth retardation reported a 44.8% higher (1597 g vs. 2312 g) weight of the premature newborn (in those delivered between the 31st and 36th week) in the CPH-treated group (1500 mg/day, initiated in the 26 week of pregnancy) compared to the placebo group. Overall gestation was 11.3% longer in the CPH group. The absolute risk of acidosis (measured from the umbilical artery) was 11% lower in the CPH-treated group; 92% of the newborns were normal and healthy (as evaluated by the Apgar score) in the CPH group compared to 84% in the placebo group. However, statistical analysis was not reported in this study (Neumann & Zienert, 1993).

Poisoning & anesthesia

Improved recovery in acute severe organophosphate poisoning

An RCT (n=85) in patients with acute organophosphate poisoning reported a 57.7% lower (123 hours vs. 291 hours) mechanical ventilation time and a 16.9% lower absolute risk (4/43 vs. 11/42) of delayed peripheral neuropathy in the CPH group (500 mg/day i.v. for 14 days) compared to the control group treated with i.v. glucose (Huang & Zhang, 2006).

An RCT (n=58) in children with acute severe organophosphate poisoning reported that 86.6% (26/30) of the cases survived in the CPH group (120-200 mg/day i.v.), an absolute advantage of 22.3% vs. controls (Li, 2009).

Clinical improvement in alcohol intoxication

Ten RCTs and one comparative trial in patients with acute alcohol intoxication reported general clinical improvement after CPH supplementation.

An RCT (n=150) reported that the CPH group outperformed the group receiving routine treatment in the resolution of symptoms (Ji, 2009).

Another RCT (n=63) in patients treated with naloxone reported an absolute 16.4% higher improvement rate (90.63%; 29/32) in the group additionally receiving CPH (Shi, 2017).

Five RCTs in patients with acute alcohol intoxication reported a shorter mean time to symptom disappearance when CPH was combined with naloxone compared to naloxone alone. Time to symptom disappearance was reduced by an average of ~37% in the combined group compared to naloxone alone; these trials are shown in a table below. Another two RCTs (n=150; n=60) reported a qualitatively more rapid symptom resolution when CPH was added to naloxone treatment (Liao, 2019; Yang & Li, 2012).

An RCT (n=76) reported a general improvement in 100% of the patients after treatment with CPH and naloxone in addition to conventional care (Xu et al., 2014). However, treatment with only naloxone added to conventional treatment also had an effective rate of 100%.

A randomized comparative trial (n=117) reported a general improvement in 81.03% (47/58) of the patients after CPH supplementation compared to 96.61% (57/59) for the group additionally receiving TCM (Tang & Dong, 2018).

A randomized comparative trial (n=1716) reported no difference in clinical cure rates when CPH and naloxone were compared (Hou, 2009). Two comparative trials (n=80; n=40) did not observe any difference in time to symptom disappearance when comparing CPH against naloxone (Huang, 2011; Chen et al., 2006). While naloxone is not an established treatment for alcohol intoxication in Western countries, it is apparently in regular use for this indication in China. East Asians exhibit a higher prevalence of the alcohol flush reaction, which is blocked by naloxone (Chan, 1985).

Table of studies that reported a reduction in time to symptom disappearance during alcohol intoxication: