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By Georges Ramalanjaona, MD, DSc, FACEP, MBA
As a dietary supplement, phosphatidylserine (PS) has been used widely in Europe for more than 15 years to treat various forms of dementia and depressive disorders, as well as normal age-related memory impairment. Although relatively unknown in the United States, PS is commercially available and is the best-validated supplement studied (16 controlled and 11 double-blind studies) for age-related memory loss and shows potential benefits in slowing the rate of deterioration of early Alzheimer’s disease.1,2 Furthermore, preliminary research indicates that PS is useful for the treatment of depression in the elderly.3
This report will examine the best, current evidence on the role of PS in the treatment of Alzheimer’s disease, depressive states, and age-related memory loss.
PS is a complex, fat-soluble phospholipid molecule manufactured by the body in a series of steps. It is found only in trace amounts in a typical diet, but in large quantity in green leafy vegetables, fish, and soy. Following oral intake, this substance is absorbed through the gastrointestinal tract and crosses the blood-brain barrier, where it is found in high concentration and is involved in neuronal cell membrane structure and function.4
Experimental animal studies show that PS induces brain biochemical and morphological changes by act-ing on the neurotransmitter system through its effects on membrane properties and the receptor-synaptic system.5,6
Limited human studies confirm that radioactive-labeled PS concentrates highly in the brain, and positron emission tomography scans demonstrate increased glucose utilization and oxygen uptake in the brain, indicative of high metabolism activity following PS ingestion.7,8
|Recent studies on the effects of PS on neuropsychiatric disorders|
|Maggioni M, et all3||crossover, placebo-controlled||10 geriatric women||300 mg/d PO||45 days||Consistent improvement of depressive symptoms, memory, and behavior.|
|Crook T, et al16||randomized, double-blind, placebo-controlled||149 adults||100 mg PO tid||12 weeks||Improvement on neuro-psychological and performance tests vs. placebo.|
|Cenacchi T, et al15||randomized, double-blind, placebo-controlled, multicenter||494 geriatric patients||100 mg PO tid||24 weeks||
Statistically significant improvement in PS-treated group on behavior and cognitive tests vs. placebo.
|Engel RR, et al2||crossover, double-blind, placebo-controlled||33 adults||300 mg/d PO||8 weeks||
Lasting and mild improvement in brain function behavior in PS-treated dementia patients vs. placebo.
|Crook T, et al1||randomized, double-blind, placebo-controlled||51 geriatric patients||300 mg/d PO||12 weeks||
Significant improvement of cognitive test in PS-treated Alzheimer’s patients vs. placebo.
Mechanism of Action
Bovine cortex phosphatidylserine (BC-PS), a pharmacologically active form of PS, enhances catecholaminergic neurotransmission and acetylcholine release and synthesis in brains of aged rats.9 It also prevents age-induced loss of dendritic spines in hippocampal pyramidal neurons and atrophy of cholinergic cells in the basal forebrain of aged rodents.6 As a result, administration of BC-PS improves learning and memory functions in these animals. Also, recent animal studies show BC-PS reverses chemical-induced amnesia.10
In vitro, BC-PS decreases cell death induced by xanthine oxidase.11
In healthy human volunteers, BC-PS neutralizes the adrenocortical activation induced by physical stress. This leads to the release of cortisol, which induces the formation of plaque in brain associated with Alzheimer’s disease (AD).12 It also stimulates release of acetylcholine and produced more relaxing alpha waves as quantitatively assessed by electroencephalogram.7
Overall, the scientific evidence for effectiveness of PS in dementia is very strong (Grade I in evidence-based grading of evidence) and strong (Grade II) for age- associated memory loss.
Eleven randomized, double-blind, placebo-controlled trials involving more than 1,000 patients show that BC-PS is an effective and safe treatment for early AD and other forms of dementia.1,2,13 Results show that patients with AD treated for 8-12 weeks with 300 mg/d of BC-PS display significant improvement on several cognitive measures (memory assessment clinics) vs. placebo. The differences between treatment groups were apparent among patients with less severe cognitive impairment, suggesting that PS may be useful in early stages of AD.
The largest of these studies followed 494 geriatric patients over a six-month period. All of the patients displayed moderate to severe cognitive decline as measured by standardized tests. The results show statistically significant improvements in the PS-treated group (P < 0.05) compared to placebo both in terms of behavioral and cognitive parameters.1 This finding is clinically significant because these patients are representative of the typical geriatric population seen in clinical practice. These results are in agreement with smaller randomized, double-blind, placebo-controlled trials of more than 500 patients with Alzheimer’s or other age-related dementia followed over a short period of time.2,14 These studies consistently show lasting and statistically significant improvement in cognitive tests and brain function behavior in PS-treated dementia and Alzheimer’s patients vs. placebo.
Current literature with good evidence (Grade II) shows that PS improves ordinary age-associated memory loss commonly seen in individuals age 50 and older. Results of a multicenter, fully randomized, double-blind, placebo-controlled trial indicate improvement equivalent to 12 years of de-aging in the PS-treated group taking 300 mg/d of PS for 12 weeks compared to the placebo group on both neuropsychological performance (learning, memory) and clinical global ratings (cognitive, behavioral domains).15,16 Patients with the most severe memory loss showed the most improvement on the parameters. The efficiency of PS compared to placebo was measured on the behavioral and cognitive performance tests of the Plutchik Geriatric Rating Scale and the Buschke Selective Reminding Test at three and six months after therapy.
In addition, further clinical evaluations and laboratory tests showed that BC-PS is well tolerated. These results are clinically important because these patients are representative of the geriatric population commonly seen in clinical practice (i.e., patients with multiple pathologies and on multiple drugs). In this setting, administration of BC-PS together with other drugs failed to show any pharmacological interactions as judged by clinical signs and symptoms for 3-6 months.15
At the time of this publication, there are no known ongoing human clinical trials at the National Institute of Mental Health studying the effects of PS on mental disorders or meta-analyses summarizing the existing effects of PS.
In short-term trials, no adverse events attributable to PS have been noted. In long-term clinical trials, side effects are rare and clinically unimportant, and have been limited to mild gastrointestinal symptoms.15
There is the potential concern that PS may interact with the anticoagulant heparin. This is clinically important for those patients taking heparin for short- or long-term treatment, such as in the prevention or treatment of pulmonary embolus or deep venous thrombosis.
There are no other reported contraindications or precautions with the use of PS for AD and depression.
PS is readily and commercially available as a dietary supplement in the United States, and because it is a natural substance, it is not regulated as a drug by the U.S. Food and Drug Administration.
In the United States, most research has been conducted with PS derived from cow brain tissue. However, due to the concerns about possible infectious disease transmission, soy-based PS supplements are beginning to replace bovine-based PS. Although sales of bovine-based PS have declined because of fear of contracting Mad Cow disease, no such incident has been reported in the United States.
Soy- and bovine-derived PS are not structurally identical (bovine-derived PS contains the omega-3 fatty acid DHA, which is not found in the soy form) and only a few clinical trials have studied the effects of soy-based PS.17 Nevertheless, recent animal studies comparing PS from different sources (egg, soy, and cow brain) have found that injectable soy PS is similar to cow PS in terms of mechanism of action.9
The standard dosage of PS in virtually all the published clinical trials is 100 mg three times a day. Only a few studies have used 200 mg twice a day. After achieving the full therapeutic effects, a lower dosage of 100 mg once daily may be sufficient to maintain good results in long-term studies.
High doses of cow and soy PS (800 mg/d) have been shown to modify the hormonal stress responses to exercise in healthy humans.18 Maximum safe doses in nursing or pregnant woman, children, and adults with severe kidney or liver diseases have not yet been established.
A large body of clinical data from many well-designed clinical trials has demonstrated the effectiveness of PS for the treatment of age-associated memory loss and cognitive decline in early Alzheimer’s disease and depressive disorders (see Table).
Based on short-term and long-term data, PS doses of 300 mg/d appear to be safe and have been associated with infrequent and minor side effects.
PS constitutes an addition to the natural armamentarium available to assist in the symptomatic improvement of patients with senility and dementia.
Based on available data, PS in a total daily dose of 300 mg could be used as a safe and effective alternative to other drugs for treatment of age-related memory loss and cognitive decline of early Alzheimer’s disease. Further clinical trials are needed to compare the relative effectiveness of PS to accepted therapy for the above diseases.
At this time, based on available data, PS cannot be recommended to treat or halt the progression of late-stage Alzheimer’s disease or dementia.
Dr. Ramalanjaona is Associate Chairman for Academic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Education, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.
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2. Engel RR, et al. Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer’s type. Eur Neuropsycho-pharmacol 1992;2:149-155.
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