Centrophenoxine (Meclofenoxate)
1. Identity and Chemical Profile
Meclofenoxate (International Nonproprietary Name; BAN), also known as centrophenoxine, is a cholinergic nootropic used as both a dietary supplement and, in certain countries, a pharmaceutical drug in the treatment of symptoms of senile dementia and Alzheimer's disease. It is also sold under several brand names, including Lucidril, Cerutil, Helfergin, Atsefen, and Closete.
Centrophenoxine is a synthetic compound developed in the 1950s. It is essentially an ester combining two molecules: dimethylaminoethanol (DMAE) and parachlorphenoxyacetic acid (pCPA). DMAE is a natural compound thought to be a precursor to acetylcholine and a component of cell membranes, while pCPA is a synthetic auxin-like plant hormone analog.
The DMAE component is a natural substance found in some foods — particularly fish and seafood — and is produced in small amounts in the brain. pCPA is a synthesized version of a plant growth hormone. DMAE on its own does not easily cross the blood-brain barrier; combining DMAE with pCPA seems to help this bioavailability issue.
Common Names and Synonyms
- Meclofenoxate (INN/BAN; pharmacopeial name)
- Centrophenoxine (common supplement name)
- Brand names: Lucidril, Cerutil, Helfergin, Closete, Atsefen, Amipolen, Analux, Brenal, Cellative, Cerebron, Licidril, Lucidryl, Lutiaron, Marucotol, Proserout, Proseryl, Ropoxyl
Centrophenoxine has been marketed under the brand names Amipolen, Analux, Brenal, Cellative, Centrophenoxin, Cerebron, Cerutil, Closete, Helfergin, Licidril, Lucidryl, Lutiaron, Marucotol, Proserout, Proseryl, and Ropoxyl.
Available Forms
Centrophenoxine is available either as a powder or in capsules that usually contain 200–500 mg each. Centrophenoxine is available as a supplement in capsules that contain 200–300 mg each. It is available as a prescription drug (Lucidril®) in some countries and widely available online as a dietary supplement or bulk powder in many regions, including the United States.
Centrophenoxine is also a component of Antagonic-Stress®, a combination therapy patented internationally for purported effects on managing stress, aging, and age-related diseases; the formulation also includes methionine, aspartate, fructose, vitamin B1, vitamin B6, nicotinic acid, magnesium, zinc, and sulfate.
2. Historical Development and Early Use
Centrophenoxine was developed in 1959 by scientists at the French National Scientific Research Center as a treatment for Alzheimer's disease, insufficient blood flow to the brain, and age-related cognitive decline. Research has shown centrophenoxine to be a powerful memory booster and anti-aging agent.
Centrophenoxine was initially investigated and used, particularly in Europe, for treating age-related cognitive decline, dementia (like Alzheimer's disease), and recovery after stroke or head injury. In Japan and some European countries, it is prescribed for the treatment of age-related memory loss, but is available over the counter as a dietary supplement in the US and Canada, where it is most frequently used for its cognitive-enhancing properties.
Meclofenoxate HCL powder for injection has also been indicated for the following conditions: coma; skull and brain trauma; following a stroke; encephalopathy; mental disorders (in combination with psychotropic agents); mental and psychomotor retardation in children; brain intoxication; alcohol psychoses; neuritis and polyneuritis.
Centrophenoxine has no traditional botanical or ethnomedicinal history in the classical sense — it is a fully synthetic pharmaceutical compound created in the mid-twentieth century, not derived from historical herbal traditions. Its "traditional" use context is clinical pharmacology in Europe and Japan from the 1960s onward.
3. Key Constituents and Active Compounds
The main mechanism of action of meclofenoxate is generally believed to be cholinergic in nature. As an efficient transporter of DMAE, meclofenoxate encourages the production of choline in the brain, which is then synthesized into acetylcholine. The more acetylcholine neurotransmitters in the brain, the better and more efficient the cognitive functions will be.
DMAE (Dimethylaminoethanol)
Centrophenoxine contains DMAE, a natural substance found in some foods (fish, seafood) and in small amounts in the brain. It is a source of choline, and is believed to have stimulating effects on the brain. Researchers speculate that DMAE may increase acetylcholine (ACh) levels in the brain by inhibiting choline metabolism in peripheral tissues, thereby preventing the use of choline by other tissues and increasing choline levels in the bloodstream.
pCPA (Parachlorphenoxyacetic Acid)
The pCPA component of centrophenoxine is similar to plant auxins — plant hormones that increase RNA and protein production in growing plants. This analogy between pCPA and plant growth hormones has led researchers to hypothesize that it contributes to increased neuronal RNA and protein synthesis in a comparable manner.
4. Mechanisms of Action
Centrophenoxine is classified as a cholinergic, a substance that delivers or enhances the action of choline. Choline is the precursor of the neurotransmitter acetylcholine, strongly associated with many aspects of cognitive function. Though centrophenoxine has been the subject of decades of research, its precise mechanisms of action are still not entirely understood.
4.1 Cholinergic Enhancement
The main mechanism of action of meclofenoxate is generally believed to be cholinergic in nature. As an efficient transporter of DMAE, meclofenoxate encourages the production of choline in the brain, which is then synthesized into acetylcholine. Centrophenoxine, also known as meclofenoxate, has been used as a dietary supplement for its potential memory-boosting abilities. It has properties similar to acetylcholine, which is a neurotransmitter important to memory and learning.
4.2 Lipofuscin Reduction
Lipofuscins are waste products, composed mostly of lipids, that build up in the brain as we age. Lipofuscins have been implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease.
Centrophenoxine reduced lipofuscin deposits (studied both biochemically and histochemically), indicating that the drug inhibited lipofuscin accumulation by elevating the activity of antioxidant enzymes. In a key preclinical study published in the scientific literature, lipofuscin accumulation and its removal by chemical interference in neurons of the anterior hypothalamus of senile guinea pigs was investigated. Centrophenoxine (80 mg/kg body weight) was administered intramuscularly to senile guinea pigs for 30–90 days. Electron microscopic examination of the anterior hypothalamus of the control senile animals showed considerable accumulation of pigment. Drug administration for longer than 70 days caused dissolution and removal of the pigment by phagocytic cells.
In a cell culture study indexed on PubMed, cells from neonatal rat cerebral hemispheres were dispersed by trypsin and cultured for 32 days. Histochemical, fluorescence, and electron microscopic analyses demonstrated that lipofuscin pigments increased in neuronal and non-neuronal cells in primary culture according to the lapse of time. When centrophenoxine was added to the medium, the accumulation of lipofuscin pigments in neurons was significantly reduced. However, the effects of these agents were not detected in non-neuronal cells.
In another animal study, researchers investigated whether centrophenoxine could prevent lipofuscin formation if given early in life before the onset of pigmentogenesis. The study showed that the drug did not stop lipofuscin formation in 1-month-old mice, but there was a consistent decrease in the pigment in the neurons of the cerebral cortex and hippocampus of treated animals compared to age-matched controls. The degree of reduction was largely dependent on the duration of treatment, and a significant diminution was noted after treatment for five months or more.
4.3 Antioxidant Activity
Centrophenoxine increases antioxidant enzymes, and by scavenging free radicals it protects neurons from toxic oxidative stress. Six weeks of administration of centrophenoxine (once a day in doses of 80 mg/kg and 120 mg/kg) to experimental animals produced increases in the activity of superoxide dismutase (SOD), GSH-peroxidase, and GSSG-reductase in particulate fractions from all three brain regions studied.
4.4 RNA and Protein Synthesis Enhancement
In one study, centrophenoxine treatment in old rats restored the rate of RNA synthesis to levels found in rats that were half as old. By enhancing RNA synthesis, centrophenoxine can in turn increase protein turnover in neurons. Centrophenoxine also increases neuronal RNA and protein production. RNA (derived from DNA in the cell nucleus) instructs neurons how to form proteins which help encode memory, as well as repair cell damage. Brain RNA and protein production normally drop with age, and especially when large lipofuscin deposits form around the cell nucleus — one of the main sites where lipofuscin accumulates in old age. Centrophenoxine reverses this age-related drop.
4.5 Glucose and Oxygen Metabolism
Centrophenoxine stimulates brain-wide metabolism. It increases the availability of oxygen and glucose in neurons and glia both in vitro and in vivo. Some studies suggest centrophenoxine can enhance glucose uptake and oxygen consumption in brain tissue, improving cellular energy production (ATP).
4.6 Neuronal Membrane Stabilization
Centrophenoxine primarily acts as an efficient delivery system for DMAE into the brain. Its mechanisms likely involve modulation of the cholinergic system, stabilization of neuronal membranes, potent antioxidant activity, and, notably, the reduction of age-related lipofuscin pigment accumulation.
5. Scientific Evidence by Area of Use
5.1 Cognitive Function in Healthy Elderly Individuals
A double-blind study of the effects of meclofenoxate on memory performance of fit, able, elderly subjects was carried out. A number of performance measures designed to measure various aspects of memory function were employed. These revealed that meclofenoxate appears to increase the consolidation of new information into long-term memory, but does not affect other aspects of remembering. It was also found that significantly more of the subjects receiving meclofenoxate reported an increased level of mental alertness. This study, published by Marcer and Hopkins in Age and Ageing (1977), involved 76 healthy elderly participants and administered 600 mg of centrophenoxine twice daily.
In the 1977 study, 76 healthy elderly participants were divided into two groups and took a placebo or 600 mg of centrophenoxine twice daily. The centrophenoxine-treated group demonstrated better memory performance on a free-recall test, suggesting it facilitates the ability to transfer new information into long-term memory. Also, in a post-trial questionnaire, significantly more of the subjects taking centrophenoxine reported increased levels of alertness and well-being.
Centrophenoxine was reported to help promote the formation of long-term memories and increased alertness, according to one study in 60 healthy but elderly human subjects.
Centrophenoxine has insufficient and inconclusive clinical evidence overall. The most comprehensive and well-conducted study was a 74-person double-blind, randomized controlled trial that examined the effects of a 9-month centrophenoxine therapy on cognitive skills. After treatment, the centrophenoxine group outperformed the placebo group on a memory test called delayed free recall, which was linked to the consolidation of new knowledge into long-term memory.
The largest and most well-carried-out study used treatment at 600 mg twice daily on cognitive functions. The centrophenoxine group performed significantly better than placebo in delayed free recall, suggesting that the treatment may improve consolidation of new information.
Evidence strength for healthy elderly: This is the area with the most historical clinical research, primarily from European studies conducted decades ago. The main supportive finding — improvement in delayed free recall — comes from one well-designed study, but it has not been extensively replicated in modern trials. Evidence is preliminary.
5.2 Dementia and Alzheimer's Disease
A double-blind clinical trial from 1989 investigated the effects of centrophenoxine on memory in 50 participants with moderate dementia. The researchers gave the group a placebo or 2 grams of centrophenoxine for eight weeks. The centrophenoxine-treated group showed a 48% improvement in memory functions, compared to just 28% in the placebo group. In addition to improving cognition testing after eight weeks, centrophenoxine also significantly increased intracellular water content in the treated group.
However, the ADDF analysis of this trial notes caveats: A double-blind randomized controlled trial of 50 dementia patients examined the effects of 8 weeks of centrophenoxine treatment (2 g/day). There was high variability in cognitive performance and only intra-individual analyses could be performed; 48% of the centrophenoxine group (10/21) displayed improvements in memory functions while only 28% (7/25) of the placebo group showed improvement. But more people on the centrophenoxine group (5) significantly worsened compared to the placebo group (1). The authors concluded that centrophenoxine may be a useful and safe drug in treating dementia, but these claims are not supported by statistics, which were not carried out rigorously.
Another double-blind randomized trial of 63 mild-to-moderate Alzheimer's patients compared the effects of centrophenoxine (1560 mg/day for 3 months) with a combination treatment (Antagonic-Stress®) that included centrophenoxine plus methionine, aspartic acid-Mg, fructose, vitamin B1, vitamin B6, nicotinic acid, and zinc sulfate. There was no placebo control, but both treatments were able to improve cognitive functions compared to baseline, and the Antagonic-Stress® treatment was significantly superior to centrophenoxine alone in attention, memory, intelligence IQ, verbal IQ, performance IQ, and full IQ.
Another smaller double-blind clinical study in 28 people with memory deficits reported that 3 weeks of centrophenoxine treatment did not show statistically significant effects on any of the 8 measures of memory or mental concentration.
More recently, a randomized controlled trial of 242 patients with mild cognitive impairment tested the effects of DMAE, which is the active component of centrophenoxine. The study found no significant difference in memory, executive function, or attention versus placebo.
Evidence strength for dementia/Alzheimer's: Although multiple clinical trials have tested the effects of centrophenoxine, the studies were of suboptimal quality and the results were inconclusive. Based on 6 randomized clinical trials — 3 in dementia patients, 2 in healthy elderly people, and 1 in head trauma patients — the clinical evidence for centrophenoxine is weak and inconclusive. Clinical evidence is weak and many studies have shown a lack of cognitive benefit.
5.3 Head Trauma and Cerebrovascular Disease
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. 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.
A 1968 double-blind controlled trial (Ito et al.) examined the effects of Lucidril (meclofenoxate) in post-traumatic syndrome, especially dizziness. In a clinical trial with head trauma patients, 8 out of 63 subjects experienced mild side effects: 2 thirst, 2 blurred vision, 1 nausea, 1 heartburn, 1 diarrhea, and 1 insomnia, though it was unclear whether these were related to treatment.
In a rat model, a study examined the effects of centrophenoxine on chronic cerebral hypoperfusion-induced deficits in rats. Chronic hypoperfusion was performed by permanent bilateral ligation of the common carotid arteries, and the Morris water maze was used to measure spatial memory performance. The conclusion was that the abilities of centrophenoxine to attenuate memory deficits and neuronal damage after ischemia may be beneficial in cerebrovascular type dementia. This is preclinical evidence only.
Evidence strength for head trauma/cerebrovascular: Limited; one early RCT exists, and preclinical data (animal models of stroke and ischemia) is more abundant. Clinical evidence base is very thin.
5.4 Neuroprotection — Animal and In Vitro Evidence
In rats with various types of brain injury, centrophenoxine was reported to reduce the damage caused by free radicals, and may have prevented some cognitive deficits that sometimes result from elevated oxidative stress.
Lab studies show centrophenoxine may protect brain cells. It fights damaging processes linked to strokes and other brain injuries. Key findings include: reduction of inflammation in the brain, prevention of cell death after oxygen loss, and lowering of oxidative stress.
Most of the impressive centrophenoxine research cited online comes from animal studies. The leap from evidence that it cleared lipofuscin in rat brains to the conclusion that it will make human users cognitively sharper is a much bigger gap than supplement marketers acknowledge.
5.5 Memory Enhancement in Preclinical Models
A 1978 study investigated the effects of centrophenoxine on learning and memory in aged female mice. The researchers administered 80 mg/kg of centrophenoxine daily for three months and subsequently tested memory and learning with a T-maze. Compared to untreated mice, the centrophenoxine-treated group completed the memory task in significantly fewer trials. These positive results were correlated with reductions in neuronal lipofuscin pigments in both the cerebral cortex and hippocampus.
6. Body Systems and Health Areas Associated with Centrophenoxine
- Central Nervous System / Cognition: Primary application; memory consolidation, alertness, and general cognitive function have been studied clinically.
- Cholinergic System: Centrophenoxine is classified as a cholinergic, a substance that delivers or enhances the action of choline, the precursor of acetylcholine.
- Cellular Aging and Lipofuscin Clearance: Its potential to clear cellular waste (lipofuscin) gives it a unique "anti-aging" profile among cognitive enhancers.
- Neuronal Membrane Integrity: Meclofenoxate also increases cellular membrane phospholipids.
- Cerebrovascular System: Research, primarily preclinical, has examined its effects in stroke and chronic cerebral ischemia models.
- Brain Energy Metabolism: Centrophenoxine stimulates brain-wide metabolism, increasing the availability of oxygen and glucose in neurons and glia in vitro and in vivo.
7. Dosage Forms and Doses Reported in Studies
Clinical trials that tested the effects of centrophenoxine on cognitive functions have used daily doses of 1,200 mg in healthy elderly participants and doses of up to 2,000 mg in dementia patients.
The specific doses used in published human trials are as follows:
- 600 mg twice daily (1,200 mg/day) in the Marcer and Hopkins (1977) double-blind study of 76 healthy elderly participants.
- 2 g (2,000 mg) per day for 8 weeks in the 1989 double-blind trial of 50 participants with moderate dementia.
- 1,560 mg/day for 3 months in the double-blind randomized trial of 63 mild-to-moderate Alzheimer's patients.
- 1,500 mg/day (DMAE pyroglutamate, V0191) for 24 weeks in the large double-blind RCT of 242 prodromal Alzheimer's patients (this trial used DMAE directly, not centrophenoxine, but DMAE is centrophenoxine's active metabolite).
- Trials in elderly patients with dementia or age-related cognitive impairment reported use of doses often at 600 mg to 2,000 mg daily compared to placebo.
In studies with healthy elderly participants, daily dosages of 1,200 mg have been used safely. Studies with dementia patients have used daily dosages up to 2,000 mg.
Centrophenoxine is available as a supplement in capsules that contain 200–300 mg each.
8. Safety Considerations and Known Interactions
8.1 General Tolerability
Most studies have reported that side effects with centrophenoxine are mild, including nausea, headache, dizziness, gastrointestinal issues, and mild stimulant effects. However, a few studies testing DMAE, the active component of centrophenoxine, have raised safety concerns.
One trial in 63 mild-to-moderate Alzheimer's patients noted that toxicity was "very low," though no details were provided on the number of patients who experienced adverse events and their nature. Another trial in 50 moderate Alzheimer's disease patients reported that there were no signs of toxic side effects encountered during the trial, and 3 dropouts were due to comorbidities not related to the treatment.
8.2 Cholinergic Side Effects
Centrophenoxine can raise acetylcholine levels. An excess of acetylcholine could cause mild side effects like nausea, headache, gut issues, and sleeplessness.
Some reported side effects include stomach upset, body odor, drowsiness, confusion, increased blood pressure, moderate depression, and irritability.
8.3 Serious Adverse Events (DMAE-Related)
A double-blind RCT of 242 prodromal Alzheimer's patients reported that DMAE pyroglutamate treatment (V0191; 1,500 mg/day) for 24 weeks was associated with adverse events in 43.5% of people on the drug and 29.6% of people on placebo. And 8.1% of people in the V0191 group and 4.8% in the placebo group had adverse events leading to discontinuation. Most frequent adverse events were bronchitis (higher in placebo), UTI, headache, and diarrhea. There were 3 serious adverse events: cardiorespiratory arrest, cardiac failure with fatal outcome, and grand mal convulsion in the V0191 group. The investigators could not exclude the possibility that these events were related to treatment. It should be noted this trial used DMAE directly (not centrophenoxine itself), but since centrophenoxine metabolizes to DMAE, this finding is considered relevant to its safety assessment.
8.4 Contraindications: Teratogenicity
Teratogenicity represents a potential harm. Females of child-bearing age should avoid centrophenoxine, as DMAE has been shown to produce neural tube defects in mouse embryos grown in vitro. Embryos were unable to convert choline into phosphatidylcholine, which is critical for neural tube formation.
Pregnant women should avoid centrophenoxine because its DMAE component may cause birth defects.
8.5 Psychiatric and Neurological Contraindications
People with major depression, bipolar disorder, seizure disorders, or Parkinson's disease should probably avoid this drug, as too much acetylcholine can worsen these conditions, according to many scientific and clinical reports.
Centrophenoxine is contraindicated in people with severely high blood pressure.
8.6 Drug Interactions
Drug interactions are currently unknown. No entries were found in the major drug-interaction databases reviewed in the Alzheimer's Drug Discovery Foundation analysis. Centrophenoxine can theoretically interact with other medications, especially those affecting neurotransmitter levels (like acetylcholine).
8.7 Long-Term Safety
While a number of centrophenoxine's potential effects have been studied, much of this research is still in a relatively early stage, and in most cases it is difficult to come to any firm conclusions about its relative efficacy and safety in healthy human users. This is a common situation for many so-called "nootropic" supplements and compounds, as these tend not to receive as much scientific attention as other drugs, such as pharmaceutical medications that are used by doctors to treat specific medical conditions.
The long-term safety of centrophenoxine has not been extensively studied.
9. Overall Evidence Assessment
While claims about centrophenoxine's ability as a nootropic agent have not been fully established in clinical trials, some studies do strongly suggest that it is indeed effective in improving memory retention and recall.
Clinical evidence is weak and many studies have shown a lack of cognitive benefit. Three other randomized controlled trials in dementia patients produced inconclusive results. A smaller 3-week study in 28 people with memory problems found no statistically significant effects on any of eight different memory measures. And the largest relevant trial — 242 patients taking DMAE (centrophenoxine's active metabolite) for 24 weeks — showed no significant improvement in memory, executive function, or attention versus placebo.
Much of the clinical research remains inconclusive due to small sample sizes and varying quality of the studies. 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 its efficacy in treating populations with specific diseases.
References
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