Centrophenoxine Research, Benefits, and Side effects
In an era defined by the relentless pursuit of cognitive advancement, nootropics have emerged as the beacon for many seeking enhanced mental prowess. These cognitive-enhancing substances, both synthetic and natural, promise sharper memory, heightened concentration, and improved overall brain function. Whether it’s a student bracing for critical exams, an entrepreneur navigating the cutthroat world of business, or a senior citizen aiming to counter the cognitive effects of aging, nootropics offer a tantalizing potential for brain optimization.
Among these cognitive enhancers, centrophenoxine has emerged as a standout compound, capturing the attention of both the scientific community and self-proclaimed brain hackers [1].
Historical context
Centrophenoxine, also known as meclofenoxate, traces its roots back to the 1950s, when it was first synthesized by coupling DMAE (dimethylaminoethanol) and pCPA (para-chlorophenoxyacetic acid) together using an esterification reaction. It was thought that pCPA would help shuttle DMAE across the blood-brain barrier more readily than DMAE could shuttle itself. DMAE is structurally like choline but lacks one of choline’s methyl groups [2].
Initially developed in France, its original application wasn’t primarily for cognitive enhancement. Instead, it was meant to be a treatment for Alzheimer’s disease and other age-related cognitive disorders. Researchers were drawn to its potential benefits in brain health, primarily due to its apparent ability to aid in the removal of lipofuscin deposits, waste products that build in brain cells and are often linked to aging [2].
Its primary uses evolved over the years. Beyond its application in treating cognitive disorders, it was also studied for its potential in enhancing the overall health of the brain, especially in the elderly. The interest grew as researchers noted its potential role in increasing acetylcholine, a neurotransmitter vital for memory and learning [3].
However, it was the entry of centrophenoxine into the nootropic community that solidified its place in cognitive enhancement discussions. As nootropics became more popular in the latter part of the 20th century, centrophenoxine began to be recognized not just as a treatment for disorders but also as a proactive supplement for brain optimization in healthy people. Research on rats even suggests that centrophenoxine has a positive effect on neuroplasticity, further bolstering its appeal. Its ability to potentially boost cognitive function while offering anti-aging benefits makes it particularly attractive [4].
Word of mouth, supported by both scientific and anecdotal evidence, propelled centrophenoxine into the limelight. It became a staple for many nootropic enthusiasts, often forming part of a “stack”: a combination of nootropics taken together to amplify their effects. Over the decades, its reputation has remained relatively consistent, with new generations of cognitive enhancer enthusiasts still turning to this time-tested compound for its perceived benefits [5, 6].
Mechanism of action
Upon ingestion, centrophenoxine undergoes swift absorption, making its first pass through the liver via the portal vein. In the liver, the compound undergoes hydrolysis, a process catalyzed by liver esterases, which splits it back into DMAE and pCPA [7].
The metabolic journey of DMAE, post-liberation from pCPA, remains a subject of interest and speculation. One hypothesis posits that DMAE could be methylated by S-adenosyl methionine (SAMe), converting it to choline. Although there is some evidence hinting at this transformation, this evidence is limited [8]. SAMe, which can be found ubiquitously in the body, plays a pivotal role in numerous biochemical processes, acting as the principal methyl donor [9].
While it’s evident that centrophenoxine can readily traverse the blood-brain barrier more than DMAE can, the studies establishing this used intravenous administration. Hence, these results might not directly extrapolate to oral administration scenarios, as it bypasses the metabolic steps in the liver [10].
One study’s findings illuminated the intricate relationship between DMAE and choline. DMAE seems to have an edge in brain transport, perhaps because it competes with, and even hampers, the transportation of choline across the blood-brain barrier. Further research by Ceder suggests that when DMAE is ingested orally, it doesn’t necessarily accumulate in the brain but rather maintains equilibrium between plasma and spinal fluid concentrations [11, 12].
Early indications, primarily from animal studies, hint that DMAE could be integrated into neuron cell membranes as part of phosphatidyl choline, though this notion requires more rigorous validation [13, 14]. Additionally, free DMAE showcases a protective side, acting as a free radical scavenger that shields cell membranes from oxidative harm [15, 16]. This defense mechanism aligns with the “Membrane Hypothesis of Aging,” which theorizes that progressive, cumulative damage to cellular membranes, leading to lipid peroxidation and other detrimental changes, underpins aging [17].
The fate of choline
DMAE is most likely to be converted to choline, which has many fates in the human body. Choline is essential to various biological processes and can be funneled down several metabolic pathways [18]. One of the primary roles of choline in the nervous system is to serve as a precursor to the neurotransmitter acetylcholine. Acetylcholine plays vital roles in memory formation, muscle control, and various other neurological functions [19].
Choline is integral to the formation of phosphatidylcholine and sphingomyelin, two major phospholipids that make up cellular membranes. These molecules are essential for cellular integrity and function [20].
Choline can be oxidized to form betaine, which participates in crucial metabolic pathways in the liver, particularly the conversion of homocysteine to methionine [21]. Choline is a component of platelet-activating factor (PAF), a signaling molecule involved in processes like inflammation and blood clotting. Beyond its role as a precursor, choline itself is involved in cellular signaling and is a component of cell structures [22].
Given the diverse potential roles of choline, centrophenoxine’s cognitive-enhancing and neuroprotective effects could arise from various pathways. It might enhance acetylcholine synthesis, support cell membrane integrity, modulate inflammation, or play roles in other choline-associated processes [18].
Centrophenoxine and lipofuscin
Lipofuscin is often termed the “age pigment.” It’s a complex, indigestible cellular waste product that accumulates primarily within the lysosomes of post-mitotic cells, such as neurons and cardiac muscle cells. Comprised of oxidized proteins, lipids, and metals, lipofuscin is a visible marker of cellular aging and oxidative stress [23].
As cells age, their ability to degrade and recycle damaged cellular components, particularly within the lysosome (the cell’s recycling center), diminishes. Over time, this leads to the build-up of these indigestible residues, forming granules of lipofuscin [23].
In the brain, excessive accumulation of lipofuscin can interfere with cellular functions, potentially contributing to neurodegenerative diseases. It can occupy a significant volume of the cell, pushing functional components aside and interfering with normal cellular operations [23].
The presence of lipofuscin is often correlated with cellular senescence and aging, making it a common histological indicator of age-related changes in tissues [24].
Beyond being a mere waste product, lipofuscin can render lysosomes dysfunctional, thereby hampering a cell’s ability to degrade waste efficiently. This can lead to a vicious cycle of increased waste accumulation [23].
Several studies have investigated the effects of centrophenoxine on lipofuscin accumulation. Many of these have demonstrated a reduction in lipofuscin content in various tissues, particularly in the brain, upon administration of centrophenoxine [25-29].
Proposed mechanisms
While the exact mechanism remains unclear, some hypotheses suggest that centrophenoxine may enhance the efficiency of cellular waste clearance processes or may even protect cells from oxidative damage, thus reducing the initial formation of lipofuscin [30]. If centrophenoxine indeed reduces lipofuscin, this could have significant implications for its potential as an anti-aging therapy, especially concerning age-related cognitive decline. However, there are no studies suggesting that centrophenoxine or DMAE topical creams reduce the appearance of age spots.
Elevating acetylcholine levels
Acetylcholine (ACh) is a vital neurotransmitter responsible for various neural functions. It plays a central role in cognitive processes such as memory, attention, and learning. Beyond the brain, ACh is also crucial for muscle control and other peripheral nervous system tasks [31].
Choline’s conversion to acetylcholine involves specific enzymes. There’s potential for centrophenoxine to influence these enzymatic processes, either by upregulating their activity or by ensuring that they have sufficient substrates for ACh production [32].
Besides synthesis, neurotransmitter function also depends on effective release, receptor interaction, and breakdown. There’s evidence that compounds related to centrophenoxine can influence these aspects of neurotransmitter turnover, possibly optimizing the use of acetylcholine in the synaptic cleft [33].
Implications for cognitive health
Given acetylcholine’s pivotal role in cognitive functions, strategies to elevate its levels or enhance its effectiveness are of immense interest in neuroscience and nootropics. If centrophenoxine does boost acetylcholine levels or its efficacy, users might experience enhancements in memory retention and the ability to grasp new information. Improved acetylcholine activity often correlates with heightened attention and focus, which are crucial for tasks that demand prolonged concentration [19].
Many neurodegenerative diseases, like Alzheimer’s, are characterized by disrupted acetylcholine function. While centrophenoxine is not a treatment for such conditions, understanding its action on acetylcholine could provide insights for future research [34].
While there are indications that centrophenoxine could influence cholinergic activity in the brain (activity related to choline), definitive evidence, particularly from human studies, is not robust. The exact mechanisms by which centrophenoxine exerts its cognitive and anti-aging effects remain a topic of research and debate.
Various studies have supported the claims that centrophenoxine possesses neuroprotective qualities, especially against age-related cognitive decline. Its potential to reduce lipofuscin deposits in brain cells remains a focal point of this research [7, 35-37].
Research in both animals and humans has shown potential benefits in memory and learning processes. The precise magnitude and nature of these benefits can vary, but the underlying theme is that centrophenoxine has the potential to enhance certain cognitive functions [38,39].
Oxidative stress, a factor in neurodegeneration, has been another area of interest. Some studies suggest that centrophenoxine can counteract oxidative stress, though the exact mechanisms and efficacy are still subjects of exploration [16].
The long-term effects of centrophenoxine require more robust research. While short-term studies and anecdotal evidence have generally found the compound to be safe, comprehensive long-term studies remain somewhat sparse [7].
Overstated anti-aging claims
While centrophenoxine has been proposed as an effective agent in reducing lipofuscin accumulation in cells, its efficacy is debated [29]. Many of the foundational studies on centrophenoxine’s impact on lipofuscin were conducted in the 1960s, 1970s, and 1980s, and there’s a lack of recent large-scale, double-blind clinical trials to validate these findings. The precise mechanism by which centrophenoxine acts to decrease lipofuscin remains unclear.
Furthermore, while animal studies have shown promise [28], the results might not directly translate to humans. Some people contend that lipofuscin accumulation is a natural aging process and may not necessarily be detrimental [40]. Lastly, potential side effects like insomnia and dizziness raise concerns about the net benefits of the drug [41].
Comparisons with other nootropics
As the nootropic market has expanded, many newer compounds have been introduced, leading to debates about where Centrophenoxine stands in efficacy compared to these newer entrants [6, 42-44].
Like with many nootropics, individual responses to centrophenoxine can vary widely. This has led to some skepticism, as some users report profound benefits while others notice minimal to no effects.
Side effects
While many users tolerate centrophenoxine well, some side effects have been reported, albeit infrequently. As with many nootropics that influence neurotransmitter levels, headaches can occasionally manifest. This may be due to changes in cholinergic activity or simply individual responses to the compound [45].
Some users have reported feelings of nausea, especially when taken on an empty stomach. Centrophenoxine can be taken with meals to mitigate this potential side effect. Given its stimulating effects on the brain, certain people might experience restlessness or difficulty sleeping, especially if taken later in the day. To counteract this, some research suggests taking centrophenoxine earlier in the day or adjusting the dosage [41].
Less commonly, some users have reported symptoms like dizziness and stomach upset. As always, monitoring individual responses and consulting with a healthcare professional is crucial [47].
In clinical trials, centrophenoxine has been generally well-tolerated. Severe risks at high doses have been observed, but it has not been firmly established that centrophenoxine was the cause.
Vulnerable groups
There is limited data on centrophenoxine’s effects during pregnancy or breastfeeding. As a precaution, it’s typically recommended that women in these categories avoid taking this compound [48].
There have been infrequent reports of increased blood pressure with centrophenoxine use. People with histories of hypertension should be cautious and monitor their blood pressure regularly [39].
Centrophenoxine may interact with certain medications, especially those that affect neurotransmitter levels, including antidepressants or other nootropics. People who take medications should speak with healthcare professionals before taking centrophenoxine [49].
There’s some evidence suggesting that excessive cholinergic activity could make it easier for people to have seizures. Therefore, people with histories of seizures or related conditions should approach with caution [50].
In conclusion, while centrophenoxine is generally well-tolerated, there are a few potential side effects and contraindications. While centrophenoxine has a storied past within the nootropic community, its exact benefits and mechanisms remain subject to ongoing debate. While some people advocate for its cognitive and anti-aging properties, critical evaluation and further research are essential. The true impact of centrophenoxine on cognitive health remains an open question.
Aside: the cost of choline
Centrophenoxine is not a cost-effective source of choline but may function as a relatively expensive substitute for vegans, who do not eat eggs or meat. Choline derived from entrophenoxine is 13 times as expensive as choline derived from eggs and 5 times as expensive as choline derived from chicken breast [51, 52].
Literature
[1] Shabanov, P.D. The Origins and Background of the Creation of the Nootropics Concept. Neurochemical Journal 2023 17:2 2023, 17, 163–168
[2] Thuillier, J, Rumpf, P Thuillier, G. [Derivatives of Acids Regulators of Plant Growth. I. Pharmacologic Properties of the Dimethylaminoethyl Ester of p-Chlorophenoxyacetic Acid (235 ANP)]. C R Seances Soc Biol Fil 1959, 153, 1914–1918.
[3] Georgiev, V.; Chavdarov, D.; Petkov, V.; Kirilov, B. Effect of Centrophenoxine on Acetylcholine Release in Perfused Cerebral Ventricles of Cats under Dynamic Electrophysiological Control. Acta Physiol Pharmacol Bulg 1979, 5, 59–66.
[4] Bertoni-Freddari, C.; Giuli, C.; Pieri, C. The Effect of Acute and Chronic Centrophenoxine Treatment on the Synaptic Plasticity of Old Rats. Arch Gerontol Geriatr 1982, 1, 365–373,
[5] Stancheva, S.L.; Alova, L.G. [Effect of Centrophenoxine, Piracetam and Aniracetam on the Monoamine Oxidase Activity in Different Brain Structures of Rats]. Farmakol Toksikol 1988, 51, 16–18.
[6] Krapivin, S. V.; Voronina, T.A. A Comparative Neurophysiological Study of Nootropic Drugs Piracetam and Centrophenoxine. Farmakologiya i Toksikologiya 1987, 50, 17–20.
[7] Herrschaft, H. Meclofenoxat. Neuro-Psychopharmaka Ein Therapie-Handbuch 1999, 567–579, .
[8] Mato, J.M.; Lu, S.C. Role of S-Adenosyl-L-Methionine in Liver Health and Injury. Hepatology 2007, 45, 1306–1312,
[9] Bottiglieri, T.; Hyland, K.; Reynolds, E.H. The Clinical Potential of Ademetionine (S-Adenosylmethionine) in Neurological Disorders. Drugs 1994, 48, 137–152
[10] Miyazaki, H.; Nambu, K.; Minaki, Y.; Hashimoto, M.; Nakamura, K. Comparative Studies on the Metabolism of Beta-Dimethylaminoethanol in the Mouse Brain and Liver Following Administration of Beta-Dimethylaminoethanol and Its p-Chlorophenoxyacetate, Meclofenoxate. Chem Pharm Bull (Tokyo) 1976
[11] Millington, W.R.; McCall, A.L.; Wurtman, R.J. Deanol Acetamidobenzoate Inhibits the Blood-Brain Barrier Transport of Choline. Ann Neurol 1978, 4, 302–306.
[12] Ceder, G.; Schuberth, J. 2-Dimethylaminoethanol (Deaner) in Body Fluids. Journal of Pharmacy and Pharmacology 2011, 29, 373–374.
[13] Segawa, T.; Kamata, M.; Hara, S.; Totani, Y. Antioxidative Behavior of Phospholipids for Polyunsaturated Fatty Acids of Fish Oil .III. Synergistic Mechanism of Nitrogen Including Phospholipids for Tocopherol.
[14] Katyal, S.L.; Lombard, B. Quantitation of Phosphatidyl N-Methyl- and N,N-Dimethylaminoethanol in Rat Liver. Lipids 1976, 11, 513–516
[15] G, M.; MB, A.; HD, M.; S, P. New Insights on Dimethylaminoethanol (DMAE) Features as a Free Radical Scavenger. Drug Metab Lett 2012
[16] Zs.-Nagy, I.; Floyd, R.A. Electron Spin Resonance Spectroscopic Demonstration of the Hydroxyl Free Radical Scavenger Properties of Dimethylaminoethanol in Spin Trapping Experiments Confirming the Molecular Basis for the Biological Effects of Centrophenoxine. Arch Gerontol Geriatr 1984, 3, 297–310
[17] Zs.-Nagy, I. A Membrane Hypothesis of Aging. J Theor Biol 1978, 75, 189–195
[18] Corbin, K.D.; Zeisel, S.H. Choline Metabolism Provides Novel Insights into Non-Alcoholic Fatty Liver Disease and Its Progression. Curr Opin Gastroenterol 2012, 28, 159.
[19] Hasselmo, M.E. The Role of Acetylcholine in Learning and Memory. Curr Opin Neurobiol 2006, 16, 710–715.
[20] Sanders, L.M.; Zeisel, S.H. Choline: Dietary Requirements and Role in Brain Development. Nutr Today 2007, 42, 181
[21] Ueland, P.M. Choline and Betaine in Health and Disease. Journal of Inherited Metabolic Disease 2010 34:1 2010, 34, 3–15
[22] Brailoiu, E.; Chakraborty, S.; Cristina, G.; Unterwald, E.M.; Abood, M.E.; Taylor, C.W. Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP 3-Evoked Ca 2+ Signals through Sigma-1 Receptors Choline Potentiates IP 3-Evoked Ca 2+ Release by Activating Sigma-1 Receptors d Bradykinin Stimulates Ca 2+ Release by Stimulating Formation of IP 3 and Choline d Choline Uptake by a Specific Transporter Potentiates IP 3-Evoked Ca 2+ Release. Cell Rep 2019, 26, 330–337
[23] Jung, T.; Bader, N.; Grune, T. Lipofuscin: Formation, Distribution, and Metabolic Consequences. Ann N Y Acad Sci 2007, 1119, 97–111
[24] Sohal, R.S.; Brunk, U.T. Lipofuscin as an Indicator of Oxidative Stress and Aging. Adv Exp Med Biol 1989, 266, 17–26; discussion 27
[25] Jung, T.; Bader, N.; Grune, T. Lipofuscin: Formation, Distribution, and Metabolic Consequences. Ann N Y Acad Sci 2007, 1119, 97–111,
[26] Katz, M.L. Potential Reversibility of Lipofuscin Accumulation. Arch Gerontol Geriatr 2002, 34, 311–317
[27] Terman, A.; Welander, M. Centrophenoxine Slows Down, but Does Not Reverse, Lipofuscin Accumulation in Cultured Cells.
[28] Riga, S.; Riga, D. Effects of Centrophenoxine on the Lipofuscin Pigments in the Nervous System of Old Rats. Brain Res 1974, 72, 265–275.
[29] Nandy, K.; Bourne, G.H. Effect of Centrophenoxine on the Lipofuscin Pigments in the Neurones of Senile Guinea-Pigs. Nature 1966 210:5033 1966, 210, 313–314,
[30] Terman, Alexei. Mechanisms of Lipofuscin/Ceroid Accumulation and Its Impact on the Function of Lysosomal System.
[31] Beers, W.H.; Reich, E. Structure and Activity of Acetylcholine. Nature 1970 228:5275 1970, 228, 917–922
[32] Lindner, M.; Bell, T.; Iqbal, S.; Mullins, P.G.; Christakou, A. In Vivo Functional Neurochemistry of Human Cortical Cholinergic Function during Visuospatial Attention. PLoS One 2017, 12.
[33] Chothia, C. Interaction of Acetylcholine with Different Cholinergic Nerve Receptors. Nature 1970, 225, 36
[34] Muir, J.L. Acetylcholine, Aging, and Alzheimer’s Disease. Pharmacol Biochem Behav 1997, 56, 687–696
[37] Clinical Study of Meclofenoxate Hydrochloride in the Treatment of Vascular Dementia
[38] Marcer, D.; Hopkins, S.M. The Differential Effects of Meclofenoxate on Memory Loss in the Elderly. Age Ageing 1977, 6, 123–131,.
[39] Fisman, M.; Mersky, H.; Helmes, E. Double-Blind Trial of 2-Dimethylaminoethanol in Alzheimer’s Disease. Am J Psychiatry 1981, 138, 970–972,.
[40] Kakimoto, Y.; Okada, C.; Kawabe, N.; Sasaki, A.; Tsukamoto, H.; Nagao, R.; Osawa, M. Myocardial Lipofuscin Accumulation in Ageing and Sudden Cardiac Death. Sci Rep 2019, 9..
[41] Itoh, H.; Kudo, Y.; Kabeshima, Y.; Nobushia, S.; Komine, K.; Sato, Y. Double-blind Controlled Trial of Lucidril (Meclofenoxate) in The Post-Traumatic Syndrome, Especially Dizziness Psychiatry Clin Neurosci 1968, 22, 23–42.
[42] Zheleva-Dimitrova, D.; Balabanova, V.; Awale, S.; Malík, M.; Tlustoš, P. Nootropic Herbs, Shrubs, and Trees as Potential Cognitive Enhancers. Plants 2023, Vol. 12, Page 1364 2023, 12, 1364,
[43] Shabanov, P.D. The Origins and Background of the Creation of the Nootropics Concept. Neurochemical Journal 2023 17:2 2023, 17, 163–168
[44] Solmaz, G.D.; Erbas, O. Nootropics as Cognitive Enhancers: Pharmacological Properties and Therapeutic Use. Journal of Experimental and Basic Medical Sciences 2023, 4, 052–061,
[45] Safety and Efficacy of Meclofenoxate in Treatment of Patients with Vascular Dementia
[47] Fisher, M.C.; Zeisel, S.H.; Mar, M.H.; Sadler, T.W. Perturbations in Choline Metabolism Cause Neural Tube Defects in Mouse Embryos in Vitro. FASEB J 2002, 16, 619–621
[48] Uses of Citicoline
[49] Wasilewski, R.; Lebiediewa, N.; Kozlowa, E.; Wolkow, W. [Comparative Evaluation of Psychoactive Drugs Used in Patients with Subacute and Chronic Cerebrovascular Disorders]. Neurol Neurochir Pol 1981, 15, 447–451.
[50] Walmart.Com https://www.walmart.com/cp/groceries-essentials/1735450 (accessed on 28 September 2023).
