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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:

Decreased awakening time in alcohol intoxication

An RCT (n=150) in patients with acute alcohol intoxication reported that the CPH group experienced a shorter time to regain consciousness compared to those receiving routine treatment (Ji, 2009).

An RCT (n=120) in patients treated with naloxone for acute alcohol intoxication reported a 33.8% shorter mean awakening time (3.05 hours vs. 4.61 hours) in the group with CPH added to the treatment (Hu et al., 2013).

Another RCT (n=96) in patients with acute ethanol intoxication treated with naloxone reported a 22.2% shorter mean awakening time (3.18 hours) in the group also treated with CPH (Sun et al., 2010). Identical data (except n=76) were reported in another journal with different authors and year (Xu et al., 2014).

Three other RCTs (n=150; n=63; n=60) in patients with acute alcohol intoxication and treated with naloxone reported shorter awakening time for the group also receiving CPH (Liao, 2019; Shi, 2017; Yang & Li, 2012).

Two comparative trials (n=80; n=40) in patients with acute alcohol intoxication did not observe any difference in awakening time when comparing CPH against naloxone (Huang, 2011; Chen et al., 2006).

Decreased duration & severity of acute delirium in alcohol withdrawal

Thirteen open clinical studies, published between 1961 and 1967, reported a shortening of the acute phase of delirium in alcohol withdrawal syndrome using CPH at high doses. Three controlled studies reported a similar effect of CPH, and clomethiazole or haloperidol, on the duration and symptom severity of the delirium (Herrschaft, 1992).

Clinical improvement in CO poisoning

An RCT (n=72) in patients given HBO therapy for acute CO poisoning reported greater efficacy in the group also treated with i.v. CPH (500 mg/day) for 14 days (Zheng et al., 2011).

Another RCT (n=59) in patients treated with HBO and standard management, for severe acute CO poisoning, reported a superior improvement in clinical symptoms as well as imaging (MRI or CT) findings in the group also receiving CPH (Lv & Yuan, 2010).

An RCT (n=60) in patients with delayed encephalopathy following CO poisoning reported a higher effective rate and higher cure rate in the group receiving i.v. CPH in addition to HBO and standard management. The group including CPH also enjoyed shorter times to effective response and cure (Hou, 2010).

Improved recovery after anesthesia

An RCT (n=60) in elderly female patients recovering from general anesthesia reported a shorter extubation time, better Steward Awakening Score and shorter time in the post-anesthesia care unit in the i.v. CPH group compared to the control group (Mao, 2013).

A similar RCT (n=60) from the same author in elderly female patients recovering from general anesthesia reported a shorter time to open eyes in response to a verbal stimulus, shorter extubation time, better Steward Awakening Score and shorter time in the post-anesthesia care unit in the CPH group (250 mg i.v.) compared to the placebo group (Mao et al., 2019).

However, both RCTs reported that the Mini-Mental State Examination (MMSE) scores were reduced postoperatively vs. preoperative baseline scores and there was no significant difference between the CPH groups and the controls.

Psychiatry & psychology

Improvement/stabilization in attention & concentration

A DB-RCT (n=52) in patients with neurasthenic syndromes reported an improvement in the d2 test of attention in the subgroup with psycho-reactive disturbances (n=32) after 4 weeks of CPH supplementation (2 g/day) compared to placebo (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 psychometric examinations (d2 test) (Vehreschild et al., 1975).

An RCT (n=20) in abstaining chronic alcoholics reported an increase in concentration measured by the Pauli test after a single oral dose of CPH (250 mg) relative to controls. However, sustained mental effort and arithmetic speed did not improve (Vojtechovsky et al., 1970).

A parallel DB-randomized comparative trial (n=63; 31 using CPH) in elderly patients with mild to moderate "senile dementia of Alzheimer type" reported a 19.5% improvement (from 8.2 to 9.8) in attention/concentration evaluated by the digit symbol subtest from the Wechsler Adult Intelligence Scale (WAIS) after 3 months of oral CPH supplementation (1520 mg/day). Attention/concentration increased by 53.3% (from 7.5 to 11.5) with AS supplementation, which contained the same amount of CPH (Popa et al., 1994).

An open-label trial (n=20) on patients with qualitative consciousness disorders reported that CPH (750-2500 mg/day, orally) improved attention (Molčan et al., 1978).

A triple-blind RCT (n=24) in female patients with "senile dementia" reported no benefit of CPH supplementation (800 mg/day) for 12 weeks on the occupational therapy scale, which includes attention span (Bower & McDonald, 1966). A crossover DB-RCT (n=28) conducted in elderly participants with chronic mental confusion due to a variety of causes (>60 years of age), found no significant improvement in mental concentration after 4 weeks of CPH (1200 mg/day) (Oliver & Restell, 1967).

Improved short-term memory

An open-label trial (n=20) in patients with qualitative consciousness disorders reported that CPH (750-2500 mg/day, orally) improved short-term memory (Molčan et al., 1978).

A crossover RCT in abstaining chronic alcoholics (n=6) with marked memory disturbances (chronic Korsakoff psychoses) reported an improvement in short-term memory, evaluated by the Benton Visual Retention Test, with administration of 750 mg CPH (for 12 days) compared to placebo, which was given to the same subjects for 12 days before or after CPH. However, the same study did not report any change in "recent memory" in abstaining chronic alcoholics (n=20) following a single oral dose of CPH (250 mg) compared to separate controls receiving placebo (Vojtechovsky et al., 1970).

A DB-RCT (n=76) in elderly subjects with age-related cognitive decline reported no effect of 9 months of oral CPH supplementation (1200 mg/day) compared to placebo in immediate free-recall (Marcer & Hopkins, 1977).

A crossover DB-RCT (n=28) conducted in elderly participants with chronic mental confusion due to a variety of causes (>60 years of age), found no significant improvement in short-term memory assessed by the Benton Visual Retention Test after 4 weeks of CPH (1200 mg/day) (Oliver & Restell, 1967).

Another crossover DB-RCT (n=9) in subjects with mild to moderate Alzheimer's dementia also found no significant difference in verbal and short-term memory, assessed by the word list recall and digit span test, respectively, between subjects receiving CPH (1200 mg/day) and controls (Harris & Dowson, 1986).

A DB-RCT (n=50) in nursing home residents with moderate dementia reported a 21.2% improvement in memory assessment (including immediate word list reproduction) in the CPH group (2 g/day oral for 8 weeks) compared to 9.0% in the placebo group (Pék et al., 1989). However, our calculations revealed that this difference was not significant.

Improved long-term memory & learning

A DB-RCT (n=76) in elderly subjects with age-related cognitive decline reported a 2.9% improvement (from 63.4 to 65.3) in the delayed free-recall test after CPH supplementation (1200 mg/day oral for 9 months), compared to a decrease of 9.8% (from 63.4 to 57.2) in the placebo group (Marcer & Hopkins, 1977). In the same trial, 14 participants who had declined to take any tablets because they felt they were already in good health, agreed to participate in the assessments as untreated controls. Those patients (13 completed the study) performed the memory tests as well as the CPH-treated group.

A DB-RCT (n=12) in female patients with mild to moderate dementia reported a median absolute increase of 35.0 in percentile rank (from 52.5 to 87.5) in a pictorial paired-associate learning task in the CPH group (600 mg/day for 6 weeks) compared to a decrease of 11.0 (from 54.5 to 43.5) in the control group. All members of the pair in the treatment group did better than the control member of the pair (Gedye et al., 1972).

A parallel DB-randomized comparative trial (n=63; 31 using CPH) in elderly patients with mild to moderate "senile dementia of Alzheimer type" reported a memory-learning increase of 22.1% (from 82.0 to 100.1 on the Wechsler Memory Scale (WMS)) after 3 months of oral CPH supplementation (1520 mg/day) compared to approximately a 33.6% increase (from 81.3 to 108.6) in the AS group. Both improvements correspond to an increase in memory, from mild cognitive impairment to average (Popa et al., 1994).

An open-label trial (n=10) in sleep-deprived abstaining chronic alcoholics (5 young, 5 middle-aged) reported an increase in a paired-associate learning test in the CPH-treated group relative to controls at 3 days of sleep deprivation only in the middle-aged group but not in the young (average ages: 44 and 26, respectively). However, no statistical significance was claimed (Vojtechovsky et al., 1969).

A crossover RCT (n=6) in abstaining chronic alcoholics with memory disturbances reported an increase in learning evaluated by a paired-associate learning test and memory quotient assessed by the WMS in response to 12 days' administration of 750 mg/day CPH, compared to placebo, which was administered to the same patients for a 12-day period before or after CPH treatment (Vojtechovsky et al., 1970).

A study (n=62) in patients with "senile dementia" reported an improvement in long-term memory and learning after CPH supplementation (1200 mg/day) for 12 months (Herrschaft, 1992).

A DB-RCT (n=50) in nursing home residents with moderate dementia reported a 21.2% improvement in memory assessment (including word list reproduction after 30 minutes) in the CPH group (2 g/day oral for 8 weeks) compared to 9% in the placebo group (Pék et al., 1989). However, our calculations revealed that this difference was not significant.

A crossover DB-RCT (n=28) conducted in elderly participants with chronic mental confusion due to a variety of causes (>60 years of age), found no significant improvement in long-term memory after 4 weeks of CPH (1200 mg/day) (Oliver & Restell, 1967).

Another crossover DB-RCT (n=9) in subjects with mild to moderate Alzheimer's dementia also found no significant improvement on a questionnaire on temporal orientation and remote memory between subjects receiving CPH (1200 mg/day) and controls (Harris & Dowson, 1986).

Improved memory of unspecific type

A DB-RCT (n=222) in patients with VaD reported an increase in memory after 4 weeks of CPH supplementation (600-1200 mg/day) compared to the control group. Two other DB-RCTs in patients after an ischemic cerebral infarction reported an improvement in memory, among other benefits, following 4 weeks of CPH treatment (900-2000 mg/day) (Herrschaft, 1992).

A randomized comparative trial (n=80) in patients with mild/moderate "senile dementia" reported an improvement in memory function after 6 months of oral CPH supplementation (900 mg/day) compared to salvia and vitamins C and E (Zhou, 2002).

A case series (n=120) in cerebrovascular accident patients reported an efficacy of 81.7% (98/120) in treating memory loss with oral CPH (200-300 mg/day for 1 week, optionally increased to 400-900 mg/day thereafter) (Zhao, 2004).

However, a multicenter crossover DB-RCT (n=51 completed the study) in patients with head injury sequelae reported a non-significant reduction in memory disturbance after 2 weeks of CPH supplementation (900 mg/day) (Itoh et al., 1968).

Improved general cognition & mental performance

In an RCT (n=124) in ACH patients, an improved Montreal Cognitive Assessment score was reported for the CPH group relative to controls after 1 month of treatment (Hou et al., 2019).

A clinical trial (n=80), in cerebral infarction patients treated with salvia or salvia plus oral CPH (900 mg/day), reported improved MMSE scores in the CPH group over 1 month of treatment (Zhu et al., 2003a; Thomas et al., 2008).

A parallel DB-randomized comparative trial (n=63; 31 using CPH) in elderly patients with mild to moderate "senile dementia of Alzheimer type" assessed several components of general intelligence after CPH or AS supplementation for 3 months, both containing the same amount of CPH (1520 mg/day). In the CPH group, verbal performance increased by 9.0% (from 100 to 109), cognitive performance increased by 9.7% (from 93 to 102) and full IQ by 8.2% (from 97 to 105), and the WAIS deterioration index decreased by 28.6% (from 14 to 10). However, the AS group was superior in all these assessments (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 in cognitive function relative to controls receiving salvia and vitamins C and E, though clinical efficacy in severe disease was poor (Zhou, 2002).

A randomized comparative trial (n=40) in patients with mild to moderate VaD reported a total effective rate of 80% (16/20) with respect to cognitive score in the group receiving a "short course" of i.v. CPH (300 mg), an absolute advantage of 10% over vitamin B6 (Yao et al., 2006).

An open-label trial (n=56) in patients with VaD treated with CPH, 600 mg/day for 12 weeks, reported a mean improvement of 4.69 points out of 30 on the MMSE, a 15.6% increase relative to the range (0-30) (Fu et al., 2007). Another open-label trial (n=30) in patients with VaD reported that 57% (17/30) of patients improved in the MMSE after CPH supplementation (600 mg/day) for 10 weeks when compared to baseline (Zhang & Wang, 2007).

A DB-randomized comparative trial (n=60) in patients with VaD reported a general effectiveness rate on cognition capacity of 80% (24/30) after 2 weeks of CPH supplementation, a 10% absolute advantage vs. vitamin B6 (Chen, 2007b).

In two trials in healthy younger subjects, CPH showed a mild but inconsistent positive effect on cognitive performance (Herrschaft, 1992).

Our calculation from the participant-level data of a DB-RCT (n=50) in nursing home residents with moderate dementia (Pék et al., 1989) shows a significant negative effect of CPH (2 g/day for 8 weeks) on mental performance. The CPH group had a worsening score in performance tests according to the Nuremberg Geronto-psychological Inventory (the number connection test, digit-symbol and maze test), while the placebo showed no significant change (-19.4% vs. +3.4%).

A triple-blind RCT (n=24) using CPH (800 mg/day for 12 weeks) in female patients with "senile dementia", found no statistical change in the psychiatric rating scale, which includes intellectual functioning (Bower & McDonald, 1966).

A crossover DB-RCT (n=9) in subjects with mild to moderate Alzheimer's dementia also found no significant improvement in the digit symbol test of the WAIS between subjects receiving CPH (1200 mg/day) and controls (Harris & Dowson, 1986).

Decreased depression

A single-blind RCT (n=69) in patients with depression reported a lower average score on the Hamilton Depression Scale after 6 weeks of oral CPH supplementation compared to before treatment scores, and was not different from the group treated with fluoxetine. Both groups additionally received lithium (Tang & Zhou, 2006).

An RCT (n=51) in patients with depression reported an improvement in 92.9% of the patients, of which 71.4% markedly improved, after i.v. CPH treatment. The group additionally including oral tricyclic antidepressants experienced similar efficacy, faster response, and an absolute advantage in marked response rate of 16.1% (Xing et al., 1996).

An observational study in patients with depression reported that the dose of tricyclic antidepressants was reduced when CPH was added to the therapy, and the combined treatment was more effective than either treatment separately (Qiu & Zhang, 2003).

However, an RCT (n=48) in patients with depression after cerebral infarction found no significant difference when CPH (300 mg/day i.v. for 2 weeks, then 600 mg/day oral) was added to fluoxetine (21/25 of the patients improved) compared to fluoxetine alone (17/23) after 6 weeks of treatment (Bian et al., 2006).

Improved behavior & mood

A DB-comparative trial (n=63; 31 using CPH) in patients with mild to moderate "senile dementia of Alzheimer type" (n=31), comparing CPH (1560 mg/day) to AS over 3 months, found that CPH-only supplementation was associated with improved SCAG scores of 23.3% in interpersonal relationships, 28.3% in affective disorders, and 18.5% in apathy (corresponding to score decreases of 3.7, 3.6 and 2.4 points, respectively) though in all areas the AS group showed superior improvements. Similar results were obtained on the corresponding subscales of the self-assessed SASG (Popa et al., 1994).

An open-label trial (n=20) in participants with qualitative consciousness disorders reported that doses of 750 to 2,500 mg/day of CPH alleviated states of agitation (Molčan et al., 1978). A randomized comparative trial (n=80) in Alzheimer's patients reported improved psychoneurological function in a subgroup with mild/moderate disease receiving 900 mg/day CPH (oral) for 6 months compared to the conventionally treated group receiving salvia and vitamins C and E (Zhou, 2002).

A DB-RCT (n=222) in patients with VaD reported an improvement in affective lability after 4 weeks of CPH supplementation (600-1200 mg/day) compared to the control group. Another DB-RCT (n=250) in outpatients with overwork syndrome with emotional deficits reported a 60% improvement after 4-5 weeks CPH supplementation (600 mg) compared to 40% in the placebo group. Two trials in healthy young participants reported a mild but inconsistent positive effect on mood. Two other DB-RCTs reported a 10-25% improvement rate in acute and chronic sequelae following ischemic cerebral infarction after four weeks of CPH treatment (900-2000 mg/day); improved affectivity and drive were among the benefits observed (Herrschaft, 1992).

A case series (n=20) in dementia patients of mixed type reported that symptoms of nocturnal delirium, hostility, and fugue were most responsive to treatment, though somatic and neurological symptoms did not improve (500 mg/day i.v. CPH for 4 weeks) (Tamai & Torii, 1990).

On the other hand, a DB-RCT (n=106) which evaluated clinical symptoms of patients with cerebrovascular diseases reported that CPH (oral, 900 mg/day for 4 weeks) was not effective in improving psychiatric symptoms (Hasegawa et al., 1976).

A multicenter crossover DB-RCT (n=51 completed the study) in patients who experienced persistent symptoms following a head injury sustained from 4 days to 5 years prior to enrollment assessed the effect of CPH supplementation (900 mg/day) for 2 weeks and reported no benefit of CPH over placebo for nervous instability and irritability (Itoh et al., 1968).

Our analysis of patient-level data from a DB-RCT (n=50) in nursing home residents with moderate dementia (Pék et al., 1989) indicated that a psychologist's evaluation scale of patients' behavior trended to inferiority during CPH treatment compared to controls.

A triple-blind RCT (n=24) using CPH (800 mg/day for 12 weeks) in female patients with "senile dementia", found no statistical change in the psychiatric rating scale, which includes emotionality, communication and manifest overt behavior (Bower & McDonald, 1966).

Improvement in neuroses

A DB-RCT reported that a subgroup (n=32) of patients with "psycho-reactive neurotic disturbances" reported improvements according to subjective evaluation by doctors and patients in the CPH group (2 g/day) over 4 weeks of treatment. A descriptive self-assessment also showed improvement (Pieschl et al., 1983).

On the other hand, an open-label study (n=88) in patients with neuroses reported that i.v. CPH (125 mg, single dose) was indistinguishable from saline in effect (Ziolko, 1961).

Sleep & consciousness

Favorable sleep changes in adults

An open-label trial in patients with a sleep disorder reported a general improvement in 93% of the patients after CPH supplementation (600 mg/day). Of the patients who improved, "14 cases were cured, 11 cases were markedly effective and 13 were effective" (Ti et al., 2002).

A case report (n=1) of one male patient with recurrent episodes of hypersomnolence due to Kleine‐Levin syndrome reported a relief of all symptoms after 3 days of CPH use (Wan & Bao, 1985).

However, a triple-blind RCT (n=24) in female patients with "senile dementia" reported no benefit of CPH supplementation (800 mg/day) for 12 weeks on the nurses' rating scale, which assesses psychopathology and nursing care requirements, including sleep (Bower & McDonald, 1966).

Another clinical trial (n=12) reported that 750 mg CPH daily prolonged the time to fall asleep and reduced the duration of sleep stages 3 and 4, though rapid eye movement phases were unaffected (Brezinova et al., 1970).

Increased EEG vigilance and somatosensory evoked potential (SSEP) amplitudes

A review of pharmaco-electroencephalographic studies of several drugs in healthy young volunteers reported an enhancement and stabilization of EEG vigilance with a single dose of CPH, corresponding to increased alpha waves in the range above 9.5 Hz and a decrease in slow waves. However, "a constant relationship to dose level could not be determined" (Kinoshita, 1990; Herrschaft, 1992).

One clinical trial (n=12) assessed the effects of CPH on EEG vigilance in the course of sleep deprivation in abstinent chronic alcoholics. During 127 hours of sleep deprivation, participants who received 1 g of oral CPH maintained EEG arousal to stimuli for longer than untreated controls (Brezinova et al., 1970).

An open-label study (n=10) in apallic head trauma patients found a significant increase in the N20 amplitude of the median nerve SSEP in 80.0% (8/10) participants after 2 weeks of daily treatment (2 g) with i.v. CPH. The authors also remarked that responsiveness to various external stimuli improved (Umlauf et al., 1983). Low N20 amplitude predicts poor outcomes in coma patients (Soest et al., 2021).

Stroke

Clinical improvement in ACH

Six RCTs in patients with ACH reported general clinical improvement after CPH supplementation.

An RCT (n=124) reported that CPH had an effective rate of 87.1% (54/62) after one month of treatment, an absolute advantage of 32.3% over controls (Hou et al., 2019).

An RCT (n=123) reported an efficacy rate of 78.05% (32/41) in the CPH group (Ma & Zhou, 2021).

An RCT (n=80) reported a total rate of clinical efficacy in the CPH group of 95.00% (38/40), an absolute advantage of 20.0% over controls (Zhang, 2018b).

Another RCT (n=62) reported an "apparent effect rate" an absolute 22.6% higher (61.29%; 19/31 vs. 38.71%; 12/31), and improvement rate 32.3% higher (87.10%; 27/31 vs. 54.85%; 17/31) in the CPH group vs. controls after 4 weeks of supplementation (Lv & Huang, 2008).

Another RCT (n=266) reported a higher effective rate in the CPH group (250 mg/day i.v. for 2 weeks) compared to the placebo group (Lu et al., 2007).

A DB-RCT (n=82) reported a superior general improvement in patients receiving CPH compared to controls in patients with ACH (Cooperation Study Group on Acute Cerebrovascular Diseases, 1978).

Clinical improvement in cerebral infarction

An RCT (n=156) in patients with ACI reported an absolute 9.0% higher rate of "obvious improvement" in the group receiving 300 mg/day i.v. CPH for 14 days (38.5%; 30/78). The CPH group also experienced an absolute 14.8% advantage in total effective rate (88.46%; 69/78) (Wang & He, 2007).

An RCT (n=40) in patients with ACI reported an absolute 20% higher effective rate (85%; 34/40) for the group receiving CPH for 3 weeks in addition to conventional treatment (mainly oral aspirin, i.v. Danhong and dehydrating agent) (Lin, 2014).

Two DB-RCTs reported a 10-25% improvement rate in acute and chronic sequelae following ischemic cerebral infarction after four weeks of CPH treatment (900-2000 mg/day); reduced fatigue was among the benefits observed (Herrschaft, 1992).

A randomized comparative trial (n=120) in diabetics who had suffered a cerebral infarction reported effective rates of 76.7% (46/60) and 88.3% (53/60) for the group treated with conventional care and CPH (500 mg/day i.v. for 2 weeks) and the group additionally receiving TCM, respectively (Liang & Wang, 2012).

A comparative trial reported that CPH improved the clinical state of patients with cerebral infarction; the comparator group receiving ephedrine improved as well (Stoica et al., 1974).

However, a DB-RCT (n=82) reported an inferior effect of CPH compared to controls in patients with ACI (Cooperation Study Group on Acute Cerebrovascular Diseases, 1978).

Clinical improvement in cerebrovascular disease of unspecified type

An open-label trial (n=15) using CPH in post-stroke patients reported that 40.0% (6/15) of participants showed "excellent" improvements, 60.0% (9/15) of patients demonstrated "marked" improvements, and all patients improved at least some in "psychic activity" [mental activity] and initiative as well as cooperation in motor rehabilitation and speech re-education after 6 weeks of treatment (Budinova-Smela & Mimrova, 1975).

A case series (n=120) in elderly stroke patients reported efficacy for oral CPH (200-300 mg/day for 1 week, optionally increased to 400-900 mg/day thereafter) in the following areas: headache 80.0% (96/120); dizziness 75.8% (91/120); tinnitus 75.0% (90/120); weakness 80.8% (97/120); limb numbness 68.3% (82/120); gait instability 71.7% (86/120); slurred speech 48.3% (58/120); urinary and fecal incontinence 78.3% (94/120) (Zhao, 2004).

However, a DB-RCT (n=106) in patients with cerebrovascular disorders reported no difference in global judgment in the group administered 900 mg/day oral CPH for 4 weeks compared to the placebo group (Hasegawa et al., 1976). An RCT (n=130) in elderly patients with cerebrovascular disease reported CPH to be lacking in effect (Robinson, 1978).

Decreased neurological deficit in ACH

Four RCTs and one observational study in patients with ACH reported an improvement in neurological function after CPH treatment.

An RCT (n=80) reported a 35.7% better (lower) score (11.7 vs. 18.2) on the National Institutes of Health Stroke Scale (NIHSS) in the CPH group compared to the control group, an advantage of 15.5% relative to the NIHSS range (0-42) (Zhang, 2018b).

An RCT (n=62) reported an average 33.3% lower (9.6 vs. 14.4) neurological functional deficit score in the CPH group after 4 weeks of supplementation compared to the control group (Lv & Huang, 2008).

Another RCT (n=266) reported a better improvement rate and score on the NIHSS on days 7, 14 and 28 of CPH treatment (250 mg/day i.v., given in addition to routine therapy) (Lu et al., 2007).

Another RCT (n=123) reported that, in two treatment groups receiving cattle encephalon glycoside and ignotin, the group also receiving CPH had a lower average NIHSS score (Ma & Zhou, 2021).

A retrospective observational study (n=51) in patients treated with standard care, reported that the group treated additionally with CPH had a lower average NIHSS score (You, 2020).

Decreased neurological deficit in ACI

An RCT (n=198) in patients with an initial NIHSS score between 8 and 22, reported that the group receiving 250 mg/day i.v. CPH for 14 days showed a significantly improved NIHSS score on days 3, 7, 14, and 28 relative to controls receiving routine care (Lu et al., 2006).

Another RCT (n=60) in conventionally treated participants reported a superior improvement in the group additionally treated with CPH (300 mg/day i.v. for 2 weeks) (Ji et al., 2007).

An RCT (n=92) treated with TCM reported a lower NIHSS in the group also receiving CPH for 3 weeks (Dai et al., 2009).

An RCT (n=71) reported a 28.7% higher (97.8%, 34/35 vs. 76.0%, 25/36) effective rate, based on the change in neurological deficit, in the group receiving oral CPH in addition to conventional care (Chen et al., 2003).

An RCT (n=40) in patients with ACI reported a better average score on a modified NIHSS assessment for the group receiving CPH in addition to conventional treatment (Lin, 2014).

However, an RCT (n=48), in which both groups received fluoxetine, reported a 15% absolute advantage in the rate of neurological recovery (80%) in the group additionally receiving CPH (300 mg/day i.v. for 2 weeks, then 600 mg/day orally), but the difference was not significant (Bian et al., 2006).

Decreased volume of brain edema in ACH

An RCT (n=80) in patients with ACH reported a 31.0% decrease (18 vs. 26.1 mL) in cerebral hematoma volume in the CPH group compared to the control group (Zhang, 2018b).

An RCT (n=124) in conventionally treated patients with ACH reported a lower volume of cerebral hematoma after 1 month of CPH supplementation (Hou et al., 2019).

Improved ADL in acute cerebral damage

An RCT (n=80) in patients with ACH reported a 28.4% higher (75.86 vs. 59.08) ADL score in the CPH group compared to the control group (Zhang, 2018b).

An RCT (n=40) in conventionally treated patients with ACI reported a 10.1% higher (75.2 vs. 65.1) Barthel Index, relative to the index range (0-100) in the group also supplemented with CPH for 3 weeks (Lin, 2014).

In a clinical trial (n=80) of adults less than one month after a cerebral infarction, a 3% higher score (37 vs. 34) relative to the Barthel Index range was reported for the group receiving oral CPH (900 mg/day) in addition to salvia injections for one month (Zhu et al., 2003a; Thomas et al., 2008)

Trials reporting a qualitative benefit of CPH supplementation in acute cerebral damage:

Traumatic brain injury (TBI) & coma

Restoration of consciousness level

An RCT (n=80) in patients with ACH reported a 31.7% higher score (12.8 vs. 9.0) relative to the Glasgow Coma Scale (GCS) in the CPH group compared to the control group (Zhang, 2018b).

Another four RCTs (n=266; n=200; n=102; n=100) in patients with ACH and TBI reported qualitatively higher GCS scores in groups in which CPH (250-600 mg/day i.v. for 2 weeks) was added to conventional treatment (Lu et al., 2007; Gao et al., 2008; Ma, 2018; Gao et al., 2006).

A retrospective study (n=300) in intensive care unit (ICU) patients with impaired consciousness who were treated with CPH (1000 mg/day for 14 days) reported a 22.9% improvement (from 11.82 to 14.57) relative to the GCS range (3-15) within 6-10 days; only 6 patients did not improve following treatment (Bassem et al., 2018).

However, a DB-RCT (n=82) reported that CPH was superior to the control group in improving consciousness in patients with cerebral hemorrhage, but inferior to control in patients with cerebral infarction, though the authors suggested this difference may have been due to an uneven distribution of severity between groups (Cooperation Study Group on Acute Cerebrovascular Diseases, 1978).

Another DB-RCT (n=106) in patients with cerebrovascular disorders reported a non-significant improvement in promoting "early awakening" in the group administered 900 mg/day oral CPH for 4 weeks (Hasegawa et al., 1976).

Recovery from TBI

An RCT (n=102) in TBI patients reported a higher effective rate, lower mortality and fewer complications in patients treated with 600 mg/day CPH in addition to conventional treatment (Ma, 2018).

A case series (n=26) in TBI patients reported that "18 cases were cured, 6 cases were effective, 1 case was improved" following i.v. CPH treatment (Han, 2005).

A case series (n=13) reported a "significant curative effect" in 84.6% (11/13) of the patients with post-traumatic neurological syndrome treated with CPH (Xing & Yang, 1991).

An RCT (n=200, divided in 4 groups) in TBI patients reported that the group receiving both CPH and naloxone experienced better efficacy and had a better prognosis than those receiving either treatment singly, or conventional treatment only. There was no difference between the CPH and naloxone groups (Guo et al., 2011).

However, a multicenter crossover DB-RCT (n=51) in patients who experienced persistent symptoms following a head injury sustained from 4 days to 5 years prior to enrollment assessed the effect of CPH supplementation (900 mg/day) for 2 weeks and reported no benefit of CPH over placebo for global judgment for efficacy (Itoh et al., 1968).

Urinary

Decreased clinical symptoms in enuresis

An RCT (n=70) in patients with VaD, and treated with huperzine A, reported a beneficial effect on post-stroke incontinence with the addition of CPH supplementation (600 mg/day for 3 months, orally) (Bian et al., 2004).

A clinical trial (n=80) in cerebral infarction patients treated with salvia reported an absolute 45.0% higher improvement rate (77.5%; 31/40) in urinary incontinence in patients additionally receiving CPH (900 mg/day) (Zhu et al., 2003a; Thomas et al., 2008).

A comparative trial (n=400) in patients with enuresis (age not reported) treated with CPH or TCM reported effective rates of 75.5% (151/200) and 89% (178/200) for the two groups, respectively (Bai et al., 2002).

Another comparative trial (n=60) treating post-stroke incontinence reported increased bladder capacity and maximum forced urinary pressure and bladder compliance relative to baseline as well as an overall effective rate of 73.3% (27/30) in the CPH-only group. The effective rate and urodynamic indexes were superior, however, in the comparator group additionally receiving TCM (Zhou et al., 2013).

A case series (n=14) in patients with clozapine-induced enuresis reported "good efficacy" with CPH treatment (Zhu & Ren, 1997). A case series (n=5) in female schizophrenia patients with clozapine-induced enuresis (age 15-26 years) reported that symptoms were relieved after 2-6 days of oral CPH (100-900 mg/day, orally) in 4/5; the other patient eventually responded as well, though after the cessation of CPH treatment (Yan, 1990). A case series (n=120) in elderly patients with various symptoms of stroke sequelae reported an effective treatment rate of 78% (94/120) for incontinence after 3 months of oral CPH supplementation (200-300 mg/day for 1 week, optionally increased to 400-900 mg/day thereafter) (Zhao, 2004).

Risk assessment

We identified 16 risks that have occurred in clinical trials with CPH supplementation. CPH was generally well tolerated and safe. However, some severe risks were observed at high doses, although the causal role of CPH has not been established. Additionally, we included 1 hypothetical risk that appeared in an ex vivo study.

Table 5: Risk assessment

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

Central nervous system (CNS)

Impaired recovery after cerebral infarction

A DB-RCT (n=82) reported that general improvement and consciousness showed a tendency to be inferior in the CPH compared to the control group in patients with cerebral infarction but not in patients with cerebral hemorrhage. However, the authors reported that differing disease severity of the groups could be the reason for the different levels of improvement (Cooperation Study Group on Acute Cerebrovascular Diseases, 1978).

Neurological adverse events (AEs)

A multicenter crossover DB-RCT (n=51 completed the study, of 63 originally enrolled) in patients with head injury sequelae reported blurred vision and thirst in 7.84% (4/51) of the patients after 2 weeks of CPH supplementation (900 mg/day) (Itoh et al., 1968).

An open-label study (n=56) in patients with VaD reported mild side effects, such as dizziness and headache (and nausea), in 14.3% (8/56) of the patients after CPH supplementation (600 mg/day) for 12 weeks (Fu et al., 2007).

Parkinsonism

An open-label trial (n=12) studying the effect of CPH on patients suffering from tardive dyskinesia reported that one patient developed signs of parkinsonism (masked face, muscle rigidity, bradykinesia, loss of arm swing, and difficulty in speaking and turning). Symptoms appeared 3 months after starting CPH (1200 mg daily) and increased "day-by-day". Approximately 1 month following withdrawal of CPH, the described parkinsonism symptoms diminished, and involuntary movements never reappeared (Izumi et al., 1986).

Increased jitteriness/agitation

An open-label trial in 10 older adults (mean age 64 years) reported that 50.0% (5/10) of the patients in the CPH group (3 g/day for 12 months) complained of a very small increase in jitteriness compared to controls (the number of controls was not reported) (Schmid & Schlick, 1979).

Insomnia

A multicenter crossover DB-RCT (n=51 completed the study) in patients with head injury sequelae reported insomnia in one patient after 2 weeks of CPH supplementation (900 mg/day). However, in the same trial insomnia was presented as a sequela of head injury and there was no overall benefit of CPH supplementation over placebo (3/51 vs. 2/51) (Itoh et al., 1968).

An open-label study (n=30) in patients with VaD reported insomnia in 6.67% (2/30) of the patients after CPH supplementation (600 mg/day) for 10 weeks (Zhang & Wang, 2007).

Epileptic seizures

A randomized comparative trial (n=41 in the CPH group) in patients with cerebral circulatory disturbances reported epileptic seizures in several patients treated with CPH, that were not observed in patients treated with piritinol (n=107) or piriditol (n=77) (Wasilewski et al., 1981).

Worsening general cognition in older adults

Our calculation from the participant-level data of a DB-RCT (n=50) in nursing home residents with moderate dementia (Pék et al., 1989) shows a negative effect of CPH (2 g/day for 8 weeks) on mental performance in a cognitive function test including the numbers-connection test, digit-symbol and maze test. The CPH group had a worsening average score in the performance tests according to the Nuremberg Geronto-psychological Inventory, while the placebo group showed no significant effect (-19.4% vs. 3.4%).

Decreased mental performance/learning in children

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. 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) (Teichmann & Schwebke, 1973).

Gastrointestinal (GI)

Increased nausea

A multicenter crossover DB-RCT (n=51 completed the study) in patients with head injury sequelae reported nausea, heartburn or diarrhea in 5.88% (3/51) of the patients after CPH supplementation (900 mg/day) for 2 weeks (Itoh et al., 1968).

An open-label study (n=30) in patients with VaD reported nausea in 6.67% (2/30) of the cases after CPH supplementation (600 mg/day) for 10 weeks (Zhang & Wang, 2007).

Another open-label study (n=56) in patients with VaD also mentioned nausea after CPH supplementation (600 mg/day) for 12 weeks (Fu et al., 2007).

Increased gastric pain

An open-label trial, with 10 older adult (mean age 64 years) participants in the treatment group, reported mild gastric pain in 40.0% (4/10) of the patients after high doses of CPH intake (3 g/day), which disappeared after 20 minutes (Schmid & Schlick, 1979).

General

Unspecified AEs

A DB-RCT (n=106) in psychiatric patients reported side effects in 9.4% (5/53) of the patients in the CPH group (900 mg/day oral for 4 weeks) compared to 5.7% (3/53) in the placebo group (Hasegawa et al., 1976).

An RCT (n=40) in patients who had suffered a cerebral infarction reported that 10.0% (2/20) experienced unspecified AEs in the treatment group receiving CPH in addition to conventional care (mainly oral aspirin, i.v. Danhong and dehydrating agent), while the control group receiving conventional care alone recorded none. The difference was not significant (Lin, 2014).

A randomized comparative trial (n=102) in children with enuresis reported adverse reactions in 13.73% (7/51) of the patients in the CPH group, compared to 3.92% (2/51) in the TCM group receiving Wuzi Yanzong + CPH, but the difference was not significant (Ma et al., 2020).

Increased mortality in elderly

A DB-RCT (n=50) in nursing home residents with moderate dementia (mean age of 77.4 years old) reported that 12.0% (3/25) of the patients in the CPH group (2 g/day oral for 8 weeks) died (mean age 85 years) during the study, compared to none in the placebo group. Pneumonia and atherosclerosis were common in these deaths and the authors mentioned that the "treatment with 2 g/day per person may represent a kind of metabolic load in some cases, especially for the older patients." However, the authors found no connection with CPH. In addition, within 10 days after the test finished, 12.0% (3/25) of the patients in the placebo group died from similar causes (Pék et al., 1989).

A book chapter summarized two unpublished clinical trials (n=260; n=30) in patients with cerebrovascular disease and organic dementia, reporting mortality in the CPH and control groups of 8.46% (11/130) vs. 3.08% (4/130) and 46.7% (7/15) vs. 6.7% (1/15), respectively. Five of the deaths in cerebrovascular patients were from cardiovascular causes, and unpublished World Health Organization data suggesting that CPH may induce fatal disturbances of the cardiac rhythm were also mentioned (Robinson, 1978).

The populations studied, typically hospitalized or institutionalized patients with dementia or cerebrovascular disease, suffer from a high background death rate, making attribution of excess mortality to CPH unclear.

Hepatic

Increased alanine aminotransferase (ALT) levels

A multicenter DB-randomized comparative trial (n=456 completed the full analysis set) in children with enuresis reported abnormal ALT levels in 1.75% (2/114) of the patients after CPH supplementation (100 mg/day oral) for 28 days (Hu et al., 2008).

However, a multicenter crossover DB-RCT (n=51 completed the study) in patients with head injury sequelae did not find any abnormal change in the laboratory tests (blood, liver function, urine) after 2 weeks of CPH supplementation (900 mg/day) compared to placebo (Itoh et al., 1968). An open-label trial in 10 older adults (mean age 64 years) administered oral CPH (3 g/day for 12 months) reported that no harmful changes to liver function were observed (Schmid & Schlick, 1979).

Immune

Allergic reaction

A case study reported an allergic reaction in one patient after CPH intake (Chen & Wu, 2005).

Psychiatric

Increased mood alterations in patients with neurological disorders

An open-label trial (n=88) in patients with neurosis reported a dysphoric reaction (mood change in the form of sadness) and crying after a single dose of i.v. CPH (125 mg) in 46.4% (13/28) of the patients with neurosis compared to 5.0% (1/20) in healthy individuals (Ziolko, 1961).

Urinary

Increased blood urea nitrogen (BUN), creatinine, and urination

A case study in a woman with hypertension, sequelae of cerebral infarction and hyperlipidemia reported urinary frequency, urgency and incontinence, as well as elevated BUN (7.10 mmol/L) and creatinine in the high normal range (88 μmol/L) with CPH administration (500 mg i.v.). Her symptoms improved with CPH cessation and her condition stabilized after 3 days (Chen & Zheng, 2010).

Hypothetical risks

Glucose-6-phosphate dehydrogenase (G6PD) and catalase inhibition

An ex vivo study in human red blood cells reported that pCPA exposure for 1 hour decreased G6PD and catalase activity by ~20% and ~30%, respectively, while GSH-Px, glutathione reductase and Cu/Zn-SOD were not significantly affected. According to the authors, even if the G6PD reduction was lower than that observed in patients with G6PD deficiency, pCPA concentration was very low (1 ppm) and therefore, this could pose a risk in patients with G6PD deficiency (Alicigüzel et al., 2001). A concentration of 1 ppm would be equivalent to ~1 mg/L in plasma, which is easily achieved after CPH oral intake in humans (see Absorption).

Section 5: Pharmacodynamics & Pharmacokinetics

Mechanism of action

Although the precise mechanisms underlying the effects of CPH on humans have yet to be clarified, they have been attributed primarily to (1) increasing acetylcholine levels, (2) scavenging free radicals, and (3) removing lipofuscin, in addition to some other hypotheses.

CPH is an ester of DMAE and pCPA. pCPA is structurally related to auxins, a family of plant hormones. Binding pCPA and DMAE via an ester linkage facilitates the penetration across the blood-brain barrier (Miyazaki et al., 1976). The health benefits of CPH have been mainly attributed to its DMAE component, which is also naturally found in the brain.

DMAE (dimethyl-ethanolamine) is a close structural analog to choline (trimethyl-ethanolamine), which in turn is the building block for acetylcholine and phospholipids in cell membranes. DMAE (Haubrich et al., 1975) and CPH (Georgiev et al., 1979) have been shown in animal studies to increase acetylcholine levels in the brain. However, other preclinical studies failed to show an increase in acetylcholine following DMAE or CPH administration (Zahniser et al., 1977). It seems that conversion of DMAE to choline occurs in the liver but does not occur in the brain (Miyazaki et al., 1976).

Both the DMAE and the pCPA portions of CPH act as antioxidants by scavenging ·OH radicals and protecting neurons from oxidative damage (Zs.-Nagy & Floyd, 1984). CPH supplementation increased the activity of the antioxidant enzymes SOD, GSHPx, and glutathione reductase in rat brains (Roy et al., 1983) as well as serum levels of SOD and GSHPx in humans with acute CO poisoning (Zheng et al., 2011) and alcohol intoxication (Tang & Dong, 2018).

The anti-aging effect of CPH has been attributed, at least in part, to its ability to remove lipofuscin, a conglomerate of insoluble lysosomal waste products that accumulate during the aging process (Dowson, 1989). In vitro studies showed an association between the reduction of lipofuscin by long-term CPH administration and increased rates of RNA synthesis and glucose uptake in glial cells (Ludwig-Festl et al., 1983). CPH increases protein RNA levels in aged rat brain (Zs.-Nagy & Semsei, 1984).

However, other studies found that CPH slowed accumulation of but did not eliminate preexisting lipofuscin (Terman & Welander, 1999), or had no effect on lipofuscin levels at all (Katz & Robison, 1985). Histological studies indicate that nervous tissue from patients with "senile dementia" does not have increased lipofuscin levels as compared to age-matched controls, calling the role of lipofuscin accumulation in the etiology of dementia into question (Mann & Sinclair, 1978).

Additionally, CPH has been shown to restore the intracellular potassium permeability in neurons, rehydrate cells and decrease microviscosity of lipid membranes, countering many of the negative age-associated changes purported in the membrane hypothesis of aging (Zs.-Nagy, 2014).

Absorption

A bioequivalence study (n=21) between tablets and capsules in healthy volunteers reported maximal plasma concentration for pCPA and DMAE (26 μg/mL and 266 μg/L, respectively) after a single oral dose (300 mg) of the reference CPH formulation (Nan et al., 2021). Another bioequivalence study (n=24) in healthy volunteers reported a pCPA maximal plasma concentration (13 μg/mL at 2 hours after ingestion) after a single dose (200 mg) of oral CPH intake (Zou et al., 2008). Pharmacokinetics parameters from capsules and tablets were shown to be bioequivalent (Zou et al., 2008; Li et al., 2010).

A study in mice reported that over 90% of C-14 initially present in the pCPA moiety of a radiolabeled 3 mg oral CPH dose was recovered from the urine by 3 days post-ingestion, suggesting efficient initial absorption (Mitta et al., 1967).

CPH may possibly be better absorbed in a fed vs. fasted state, according to an in silico model (Omachi et al., 2019; pubchem.gov).

Distribution

Administration to mice of CPH labeled with C-14 in the DMAE moiety resulted in a similar brain signal intensity shortly after infusion compared to mice administered CPH with the pCPA component labeled, suggesting that CPH enters the brain as an intact ester. At 4 hours, brain pCPA concentration became negligible but blood concentrations remained elevated. In contrast, the concentration of DMAE remained high in the CNS at 24 hours following CPH infusion, but had disappeared from the blood by 5 minutes (Miyazaki et al., 1971; Miyazaki et al., 1976). Autoradiograms of mice administered radiolabeled DMAE or pCPA alone did not show substantial localization to the brain (Miyazaki et al., 1971).

In mice, the absolute brain concentration of DMAE (~89 mg/kg) derived from CPH is tenfold higher compared to the administration of an equimolar infusion of labeled DMAE (Miyazaki et al., 1976), and a thousandfold greater than the endogenous DMAE concentration in the human brain (Honegger & Honegger, 1959).

Outside the CNS, pCPA localization was relatively nonspecific, distributing to tissues as well as remaining in the blood. DMAE additionally distributes to bone (transiently), liver, kidney, submaxillary gland, adrenal gland, bladder, brown fat and the GI tract.

Metabolism

CPH has been shown to rapidly undergo hydrolysis into its components in human plasma in vitro, suggesting CPH may separate into pCPA and DMAE before penetrating the blood-brain barrier (Yoshioka et al., 1987). However, another in vitro study using human plasma suggested that a fraction of absorbed CPH may remain protected from hydrolyzation by binding to serum albumin, extending the half-life of intact CPH to several minutes (Ohta et al., 1985). Studies in mice suggested that CPH rapidly penetrates the brain as an intact ester after i.v. administration (Miyazaki et al., 1971; Miyazaki et al., 1976).

The same radiolabeling experiments demonstrated that the DMAE component of CPH is subsequently phosphorylated, and ultimately largely incorporated into membrane phospholipids. In the brain, phosphatidyl-DMAE is more readily formed, peaking at approximately 16 hours, and persisting through at least 24 hours. The appearance of radiolabeled phosphatidylcholine was slower, approaching half the abundance of phosphatidyl-DMAE at 24 hours. Brain choline activity in the lipid fraction was unaffected, leading the authors to conclude that the site of incorporation of radiolabeled DMAE into phosphatidylcholine was outside the CNS.

Conversely, in the liver, phosphatidylcholine was formed efficiently from labeled DMAE, with phosphatidyl-DMAE making only a minor contribution to the lipid fraction (Miyazaki et al., 1971; Miyazaki et al., 1976).

A study in rats injected intraperitoneally with 0.4-2 mmol/kg CPH (approximate human equivalent dose: 160-800 mg) reported markedly increased CNS levels of choline, as well as, to a lesser degree, acetylcholine (Wood & Peloquin, 1982). However, this increase was interpreted to represent a pharmacological effect on endogenous choline metabolism rather than direct methylation of DMAE to choline, based on the work of previous authors with DMAE (Jope & Jenden, 1979, Zahniser et al., 1977). Selective ablation of neurons with kainic acid did not alter the increase in choline, suggesting that the surplus choline was extraneuronal.

Excretion

DMAE and pCPA are found in the urine after oral CPH intake in humans. However, intact CPH is not detected (Guddat et al., 2006).

A human study (n=1) reported pCPA in the urine after oral CPH intake (250 mg) with a maximal concentration of 145 μg/mL at 48 hours (Rubio et al., 2021). A bioequivalence study in healthy volunteers reported the half-life of pCPA in humans, ingested as a 200 mg dose of CPH, to be 6 hours (Zou et al., 2008). A study in mice showed the same half-life for pCPA as the previous human study, though the dose was not specified. The half-life for DMAE in mice was shown to be 1h (Herrschaft, 1992).

A study in humans reported that after injection of 1 g of DMAE alone, 33% was excreted unchanged, while the remaining portion may have been retained as an input to anabolic pathways (Haneke & Masten, 2002). Further studies in rats and mice that were administered oral C-14-labelled DMAE reported significant recovery of label in exhaled air as carbon dioxide (up to 5% and 22%, respectively) (NTP Report 2020), a known excretion path for choline breakdown products (Tolbert & Okey, 1952). However, DMAE, at least when administered alone, is mainly excreted through urine, with 57% recovered in the urine after 24 hours in rats (Schipkowski et al., 2019).

At 24 hours after i.v. CPH administration in mice, the blood and brain concentration of pCPA became negligible. There is also pCPA uptake by other tissues such as adrenal glands, kidneys and urinary bladder, suggesting again renal excretion (Miyazaki et al., 1971). This is consistent with the results from a Japanese study in mice showing almost complete excretion of unchanged pCPA via the urine within 24 hours (Mitta et al., 1967). On the other hand, at 24 hours DMAE remained in the brain and was still being incorporated into the lipid fraction, at a higher level than 5 minutes after injection (Miyazaki et al., 1971).

These studies in mice concluded that DMAE distribution is specific and blood clearance is very rapid due to the brain uptake, whereas pCPA remains high in the blood and distribution is not specific, although complete clearance occurs in 24 hours.

Type, composition, dose and duration

Type and composition

CPH, also known as meclofenoxate, is available in many countries online as a dietary supplement in capsules (250-500 mg/capsule) or in powder (50-100 g/container). However, in the UK (Tormen, 2016) and in some European countries such as Germany, Hungary and Austria or in Japan, CPH requires a medical prescription (Haavisto, 2008). In several clinical trials, i.v. CPH was administered. We found two pharmaceutical formulations currently available, Lucidril (250 and 500 mg tablets) and Luciforte (500 mg ampoules), both manufactured by Minapharm Pharmaceuticals (Cairo, Egypt).

CPH exhibits poor stability, possibly hydrolyzing within several days in tablet form, depending on temperature, humidity, and tablet components (Yoshioka et al., 1982). A recent study that tested commercially available CPH supplements from several manufacturers reported that over half of the samples contained less than 60% of the quantity of CPH claimed (Cohen et al., 2022). Lack of stability is apparently responsible for CPH currently being marketed more often as a supplement instead of a drug, at least in Western countries (Guddat et al., 2006).

Dose and duration recommendations by manufacturers and experts

The leaflet for Lucidril, a commercially available pharmaceutical form of CPH from Minapharm, recommends an oral dose of 1 g/day for at least one month of continued supplementation, in the form of 2 tablets of 250 mg in the morning and 2 tablets at noon or no later than 4 pm, while asserting that the magnitude of the effect depends to a large extent on the duration of the treatment. Indications for treatment are cerebral aging, cerebral atherosclerosis, as well as neurological or psychological sequelae of head injury (minapharm.com).

Minapharm's recommendations for its i.v. formulation, Luciforte, range from 1-3 g daily for 10-14 days (acute cerebrovascular accident) to 1 g twice daily for 3 days (rapid deterioration) to 1-2 g as a single dose at the end of anesthesia (minapharm.com). Intramuscular application is described in the leaflet for Luciforte, however, no clinical studies were identified using this route of administration.

In a therapy handbook on neuro-psycho-pharmaceuticals, the recommended adult oral dose is 500 mg in the morning and at noon, or in severe cases 1000 mg twice daily. The recommended dose for children up to 10 years of age is 200-600 mg daily. Administration with food is recommended to mitigate potential GI side effects, and before 4 pm to prevent sleep disturbances (Herrschaft, 1992).

The same book recommended an i.v. dose for acute onset, severe cerebral impairment of 1-6 g daily in 3-4 divided doses per day, up to 12 g daily in cases with loss of consciousness, noting that the usual i.v. therapy duration is 10-14 days; infusions should not be administered faster than 1 g/L per hour (Herrschaft, 1992).

A leading researcher on CPH, who has published over a dozen studies on the subject over a period of several decades, anecdotally reported that he and a small group of others have been taking 500 mg/day CPH orally since 1976, beginning at approximately 40 years of age, with subjectively good results and without side effects (Zs.-Nagy, 2014).

Dose and duration used in clinical trials

The doses used in the clinical trials range from 60 mg/day up to 3 g/day, with no particular benefits associated with any specific dose. Lower doses are reported in neonatal encephalopathy (60-120 mg/day i.v.) or children with enuresis (100-400 mg/day orally), and higher doses in the elderly (600-2000 mg/day orally and i.v.). In pathological states such as cerebrovascular diseases, TBI and alcohol or pesticide intoxication, i.v. doses between 250 and 600 mg/day have been used with positive results (see Table 2).

The duration of CPH supplementation in human studies ranges from a single acute dose up to 21 months, with 2-4 weeks being the most common duration (see Table 2). Clinical trials in patients with cerebrovascular disease and in patients with dementia or cognitive decline, which are two of the most common applications for CPH, commonly lasted between 2 and 12 weeks and between 3 and 9 months, respectively.

Common dosing regimens used in clinical trials:

The highest dose (3 g/day orally) is found in a small open-label trial in 10 older adults (mean age 64 years) subjects for one year, in which gastric pain and agitation were reported in half of the patients, but no abnormalities in bone marrow, renal or hepatic function were found (Schmid & Schlick, 1979). Another trial employed 2 g/day orally for 8 weeks in old patients with dementia (Pék et al., 1989; Fülöp et al., 1990). However, some individuals experienced a worsening of mental performance, which suggests that high doses could represent a metabolic strain, especially in the elderly (Pék et al., 1989). The highest i.v. dose was 2 g/day for 2 weeks in comatose patients (Umlauf et al., 1983).

Toxicity/safety considerations

Human trials with CPH report that toxicity is very low, with doses up to 1500 mg/day being safe and well tolerated in the clinical trials. However, high doses might cause some side effects.

One high-dose trial (3 g/day) in older adults (mean age 64 years) noted effects consistent with a mild uncoupling of oxidative phosphorylation: increased O2 consumption, reduced fasting glucose, and weight loss (Schmid & Schlick, 1979). Uncoupling effects have also been observed with a pCPA analog, 4-chloro-2-methylphenoxyacetic acid (MCPA), which is used as an herbicide. Phenoxy compounds generally are thought to disrupt the function of lipid membranes, interfere with acetyl coenzyme pathways, and uncouple oxidative phosphorylation. In isolated rat mitochondria, uncoupling effects are observed in MCPA beginning at concentrations of ~0.1 mM (approximately 20 mg/L) (Zychlinski & Zolnierowicz, 1990). Comparable plasma concentrations of pCPA are easily achieved by modest oral dosing (Zou et al., 2008).

The authors of another high-dose trial in patients with dementia speculated that the worsening mental status of several patients may have been due to the "metabolic load" placed by 2 g/day CPH (Pék et al., 1989).

The oral CPH median lethal dose (LD50) is 1750 mg/day in mice and 865-2600 mg/kg in rats (pubchem.gov CPH; pubchem.gov CPH-HCl), which would correspond to 140-422 mg/kg (10-30 g for 70 kg) in humans based on interspecies dose conversion (Janhavi et al., 2019). Intravenous LD50 doses have been reported for mice (330 mg/kg) and rabbits (150 mg/kg) (pubchem.gov CPH-HCl; pubchem.gov CPH), again scaling to approximately 27-49 mg/kg (1.9-3.4 g for 70 kg) of i.v. CPH in humans.

Drug interactions

• any medication containing citicoline (minapharm.com).

• anticholinergics, cholinergics, and acetylcholinesterase (AChE) inhibitors generally

Hypothetically, as CPH has been reported to speed recovery from general anesthesia (see: Recovery from anesthesia), it could possibly lighten, or reduce the duration of anesthesia as well.

Note: CPH may complicate monitoring the response to thyroid hormone replacement therapy for primary hypothyroidism as it has been reported to suppress elevated thyroid stimulating hormone (TSH) levels in this setting (euthyroid subjects were unaffected, however) (Shimomura, 1978; Kobayashi et al., 1980).

Section 6: Presentation of Results

The following "tornado" diagram summarizes the results of the previous sections:

• The risk-benefit criteria are listed in the category column

• The weighted score after factoring in uncertainty is shown as a numerical value

• The weight of the criteria is proportional to the width of the columns
  
  

• Risk and benefit criteria are assigned to either low (1-1.66), medium (1.67-2.33), or high (2.34-3) weighted categories based on the results of the assessment in Table 4 and Table 5

• The diagram is filterable by category so the main risks and benefits for each system can be viewed
  
  

To view the tornado diagram as a pdf please click on the thumbnail below:

Open

For those who would prefer to view the document in excel, we have included the original .xls file.

CPH - RBA - v1.5.xlsx

Main benefits

The main benefits seen in clinical trials of CPH supplementation are:

• improved condition of the newborn in SGA fetuses

• restoration of consciousness level

• decreased neurological deficit, decreased volume of brain edema, and better overall clinical improvement in ACH

• decreased neurological deficit and better overall clinical improvement in ACI

• improved ADL in acute cerebral damage

• improved biomarkers in cerebrovascular disease

• improved recovery in acute severe organophosphate poisoning and alcohol intoxication
  
  

• better clinical course in HIE

• decreased dizziness

Main risks

The main risks seen in clinical trials of CPH supplementation are:

• decreased general cognition in older adults

• increased mortality in elderly

• decreased mental performance/learning in children

Section 7: Practical Application

Suggested treatment protocol

We do not recommend CPH for the healthy population. However, if one decides to supplement, see the protocol below:

• follow the risk mitigation strategies and be aware of the general contraindications

• choose a qualified physician

• start with 250-500 mg/day of oral CPH in 1 or 2 doses

• should preferably be taken in the morning or in the afternoon

• if well-tolerated and no side effects are experienced, but the desired clinical effect is not achieved, the dose can be progressively increased, but exceeding 1500 mg/day may increase side effects

Risk mitigation strategies

• do not exceed recommended dose

• if GI symptoms arise, take the supplement with food or lower the dose

• if sleep disturbance occurs, concentrate CPH intake in the morning or lower the dose

• if cholinergic symptoms or common side effects occur, discontinue the treatment for two weeks or until symptoms subside
  
  

• if side effects were not serious, can resume the treatment, reducing the dose or taking CPH every other day
  
  

• if short-term side effects occur (i.e. 20 minutes of gastric discomfort post-ingestion), consider dividing the dose

• CPH should be stored in a dry place as it is rapidly degraded to DMAE and pCPA under humid conditions, and should be discarded after the manufacturer's expiration date

Contraindications

• strong

  • children
    
    

  • early pregnancy
    
    

  • previous episodes of epilepsy

  • psychiatric disorders, as increased acetylcholine may exacerbate (Higley & Picciotto, 2014)

  • pre-existing heart disease (cardiovascular disease, congestive heart failure or arrhythmias)

  • athletes competing at a high level, as CPH is on the WADA prohibited list as a stimulant

  • G6PD deficiency

  • pronounced condition of excitement (minapharm.com)

• relative

  • concurrent use of choline-related drugs or others with potential interaction

  • renal disease that may impair the excretion
    
    

  • elderly and frail patients

  • high estimated cardiovascular risk with one of the established tools

  • sexually active women of child-bearing age

  • anemia

Treatment monitoring

• initial (for clearance to begin use)
  
  

  • before beginning CPH supplementation, we recommend further evaluation (electrocardiogram and/or echocardiogram) by a qualified specialist in cases of:
    
    

    • symptoms of arrhythmia or heart failure

    • strong family history of cardiac risk
      
      

    • concerning auscultatory findings

    • previous use of cardiotoxic medication

  • kidney function (plasma creatinine, glomerular filtration rate and proteinuria)

  • G6PD activity and Beutler test for NADPH (medscape.com), especially in men (i.e. monitor complete blood count), where the condition is more prevalent (Minucci et al., 2009)

  • EEG in cases of possible seizure risk

• baseline and ongoing (for safety)
  
  

  • periodically re-evaluate cardiac risk and monitor for symptoms of developing heart disease
    
    

  • standard liver function test

  • serum catalase

• for effectiveness

  • WAIS-IV to assess cognitive function in the general population (Bowden et al., 2011); can repeat every 3 months but be aware of normal test:retest changes for cognitive tests

  • serum markers for oxidative stress (MDA, GSH-PX or SOD) and inflammation (high-sensitivity CRP, TNF-α, IL-6)

  • if effect on sleep and vigilance is of interest or concern, consider EEG, smartphone sleep tracker application, or polysomnography

• in hypothyroidism, be aware of possible TSH reduction (Shimomura, 1978; Kobayashi et al., 1980)

Section 8: Conclusion

There is moderate evidence that centrophenoxine may benefit patients hospitalized for injury to the brain from either vascular or traumatic origin, especially in acute cerebral hemorrhage. Improvements were reported in several areas: neurological deficits, edema volume, consciousness, activities of daily living and general clinical evaluation. Several possible mechanisms may impart benefit: increased cerebral blood flow, reduced inflammation, reduced oxidative stress, and generally increased anabolism and glucose utilization. Therefore, we can recommend the consideration of centrophenoxine as an adjunct to conventional care in acute and chronic cerebrovascular disease and traumatic brain injury.

Centrophenoxine may possibly exert a beneficial effect in organophosphate poisoning, hypoxic-ischemic encephalopathy and during late pregnancy in small for gestational age fetuses. However, these benefits were only supported by a few trials, which suffered from the general limitations listed above, and in the case of small for gestational age fetuses, lack of peer review.

However, despite several decades of use since it was first synthesized, the clinical utility of centrophenoxine in healthy individuals remains unclear, primarily because the vast majority of published trials test the efficacy of centrophenoxine in treating study populations with specific diseases. Additionally, for a large proportion of studies, only an abstract is freely available, the original language is not English, or the treatment centrophenoxine is evaluated against is not a proper control.

Centrophenoxine is marketed as a general anti-aging supplement, however, we found no evidence in humans to support this purported benefit. Preclinical studies on the effect of centrophenoxine on longevity in animals are also scant.

The evidence regarding the use of centrophenoxine as a cognitive enhancer is inconsistent (see cognitive benefits). Many studies employed a wide battery of tests, often reporting a narrow but significant positive result among many assessments that did not change, or occasionally worsened. Most studies were small (n<30), conducted in older adults with significant cognitive impairment, often in frail clinical condition, and suffered from high dropout rates.

Some serious adverse events could occur with centrophenoxine supplementation at high doses, especially in elderly and frail patients, those who have a history of cardiac conditions, and in other populations noted in contraindications, otherwise, the clinical trials we reviewed reported that centrophenoxine supplementation is well tolerated and generally safe.

However, although low doses are unlikely to cause harm, we conclude that, in the healthy population, the evidence for any benefits of centrophenoxine supplementation is not sufficiently compelling to overcome the precautionary principle. If one does decide to supplement with centrophenoxine, risk mitigation strategies should be followed and treatment monitoring should be performed regularly, as offered in Practical application above.