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Cognitive Enhancement

By Ronald Steriti, ND, PhD

Cognitive enhancement is a special topic. The articles cited discuss recent research on the use of natural supplements to enhance mental and cognitive performance in healthy subjects. This protocol is written to support people who wish to boost their mental performance so that they may accomplish more in their lives.

Few research articles focus on performance enhancement in healthy people. Most examine drugs and supplements to combat diseases. The same supplements are often used for both, but the motivation is not the same.

Innovative Drug Strategies

Piracetam

Piracetam is considered to be the “father” of nootropic drugs (cognitive enhancers.) Piracetam has been shown to improve a whole series of mental activities, especially higher cortical functions. It can improve your intelligence, concentration, memory and creativity. Piracetam is a cyclic derivative (2-oxo-pyrrolidine acetamide) of the amino acid GABA (gamma amino butyric acid). Although GABA is an inhibitory neurotransmitter, piracetam does not appear to act in the same way. Piracetam has been shown in studies spanning three decades to:

·      enhance memory, particularly when used in combination with choline [1-3]

·      increase attention and cognition [4]

·      improve spatial learning [5]

·      improve the use of glucose by the brain [6, 7]

·      improve brain circulation [8]

·      reduce lipofuscin (age pigment) buildup in the brain [9]

·      act as an antioxidant [10]

One study demonstrated that piracetam facilitates learning and memory in chicks by causing increased plasma levels of corticosterone, which acts on the brain to preserve long-term memories. [11]

Unfortunately, piracetam has not been approved by the FDA for any use, despite it’s long track record and extensive clinical use in Europe. Piracetam is not available in the US, but can be ordered from offshore pharmacies (see below).

The recommended dose of piracetam is 2400 to 4800 g a day.

Hydergine

Hydergine is a popular "smart drug" that people of all ages use to boost cognitive productivity now, and protect against brain aging in the future. The following mechanisms of action have been proposed:

·      Increase blood supply to the brain [12]

·      Increase the amount of oxygen delivered to the brain [12]

·      Increase intelligence, memory, learning, and recall [13]

·      Enhance the use of glucose by brain cells [14]

·      Normalize the brain levels of serotonin [15]

·      Enhance metabolism in brain cells [12]

Hydergine must be obtained by physician prescription. The recommended dosage is 4 to 10 mg a day.

In 5% of people, Hydergine can induce a mild state of nausea. These people should use Sandoz brand Hydergine LC, an enteric-coated capsule that bypasses the stomach and prevents nausea. The problem with these capsules is that they only come in strengths of 1 mg. For the remaining 95% of people for whom Hydergine does not cause nausea, European suppliers sell 5 mg Hydergine tablets that make taking high doses of Hydergine convenient and very economical.

Centrophenoxine

Centrophenoxine (meclofenoxate) is widely used in Europe in combination with piracetam to improve memory and enhance mental energy. Researchers have proposed several mechanisms for Centrophenoxine, including:

·      Increasing activity of free radical scavengers, especially in brain and heart tissues. [16]

·      Providing antioxidant action, possibly due to the DMAE (dimethyl-amino-ethanol) it contains. [17]

·      Increasing acetylcholinesterase activity in the hippocampus and brain. [18]

·      Decreasing the deposition of the age-pigment, lipofuscin, which has been shown to cause neuronal damage.  [19]  

·      Inhibiting total MAO (monoamine oxidase), MAO-A and MAO-B, which  have been shown to damage brain cells.  [20] Recall that

·      Increasing the content of serotonin (5-HT), a key neurotransmitter  that can be damaged by elevated MAO. [21].

·      Significantly increasing the fluidity of brain membranes, which can reverse the dehydration of nerve cells of older animals. [22, 23]

One study found that Centrophenoxine significantly improved learning and retention in male albino rats when administered twice a day for 5 days. [24]

The recommended dose of Centrophenoxine is 250 to 1000 mg a day.

Picamilon

Picamilon is a Russian drug that improves blood flow to cerebral vessels and enhances energy levels. It is a sodium salt of N-nicotinoyl-gamma-aminobutyric acid (GABA).

The recommended dose of Picamilon is 50 to 100 mg three times a day.

Pyritinol

Pyritinol has been used in Europe to enhance neuronal metabolism in order to help restore youthful cognitive function.

A randomized, double-blind crossover study of 12 healthy men who received 600 or 1,200 mg of pyritinol or placebo for 3 days showed significant improvements in the Critical Flicker Fusion and Choice Reaction Time. [25]

The recommended dose of Pyritinol is 200 mg three times a day.

Nutritional Supplements

Ginkgo Biloba

Extracts from ginkgo biloba, the "maidenhair tree", have been shown to thin the blood and improve blood flow to the brain, protect against free radicals, and improve memory. Ginkgo biloba is approved in Germany for the treatment of dementia. There are over 1,200 published studies in the scientific literature on ginkgo biloba extract. [26-28]

One study showed that treating rats with ginkgo biloba extract not only improved their brain function (learning and memory) but also significantly extended their lifespan. [29]

A recent article described a 30-day randomized, double-blind, placebo-controlled clinical trial in which 61 participants were administered a battery of validated neuropsychological tests before and after treatment. Statistical analysis indicated significant improvements in speed of information processing working memory, and executive processing attributable to the ginkgo biloba extract. [30]

An article published in the journal Psychopharmacology described a double-blind, placebo controlled, 14-week, trial of 60 mg of a standardized extract of ginkgo biloba and 100 mg of a standardized extract of Panax ginseng. Two hundred and fifty-six healthy middle-aged volunteers successfully completed the study. The ginkgo/ginseng combination was found to significantly improve an Index of Memory Quality. This effect represented an average improvement of 7.5% and reflected improvements to a number of different aspects of memory, including working and long-term memory. This enhancement to memory was seen throughout the 12-week dosing period. [31]

Another article published in the same journal described another experiment with the same ginkgo and ginseng combination on 20 healthy young people. Compared with the placebo, Ginkgo significantly improved cognitive function, particularly the “speed of attention” factor. [32]

A 6-week, double-blind, fixed-dose, placebo-controlled, parallel-group examined the efficacy of 180 mg of ginkgo biloba extract daily on the cognitive functioning of cognitively intact participants between the ages of 55 and 86 years.  Participants who received the ginkgo biloba extract exhibited significantly more improvement on a task assessing speed of processing abilities (i.e., Stroop Color and Word Test color-naming task) by the end of treatment as compared to participants who received placebo. Trends favoring improved performances in the ginkgo biloba group were also demonstrated in three of the four remaining tasks that involved a timed, speed of processing component, although they did not reach statistical significance. [33]

The recommended dose of ginkgo biloba extract is 120 mg per day.

Acetyl-L-carnitine

Acetyl-L-Carnitine is the biologically active amino acid involved in the transport of fatty acids into the cell's mitochondria for the purpose of producing energy. It has been shown to improve mood, memory, and cognition.

A recently published article reported on research that showed that acetyl-L-carnitine modulated the use of glucose in the brain of rats. [34] It was also shown to improve learning and memory processes in studies conducted with laboratory animals. [35]

The recommended dose of acetyl-L-carnitine is 1,000 to 2,000 mg a day.

DHA

Docosahexaenoic acid (DHA) is a long chain omega-3 fatty acid that is present in high concentrations in the central nervous system. Fish oil contains both EPA (eicosapentaeonic acid) and DHA.

A recent study evaluated the changes in learning associated with a diet deficient in omega-3 fatty acids. Rats were fed a diet deficient in omega-3 fatty acids for two generations. The second generation omega-3-deficient group had 81% less brain DHA (82% less in the olfactory bulb) and made significantly more errors in a series of olfactory-cued, 2-odor discrimination tasks when compared to the group fed adequate amounts of omega-3 fatty acids. [36, 37] Another study found that the second and third generation of rats fed a diet deficient in omega-3 fatty acids took longer to escape from a Morris water maze. [38]

DHA can be found in Life Extension’s Super Max EPA (1,000 mg per tablespoon), Mega EPA (300 mg per softgel). The recommended doses are  2 softgels daily of Mega EPA or 1 tablespoon daily of Super Max EPA.

Choline

Choline is part of the neurotransmitter acetylcholine which is used to send messages between cells. 

One study found that  cytidine (5') diphosphocholine (CDP-choline) had effects on learning and memory similar to meclofenoxate and piracetam. [39]

Choline, lecithin, and phosphatidylcholine are best taken early in the day to maximize improvement in brain productivity throughout the day. Suggested dosage ranges are 2,500 to 10,000 mg a day of choline or 10,000 to 15,000 mg a day of lecithin, and/or 1,200 to 6,000 mg a day of phosphatidylcholine.

Pregnenolone and DHEA

Pregnenolone and DHEA improve brain cell activity and enhance memory. (Pregnenolone is converted into DHEA in the body.) Together, pregnenolone and DHEA help to maintain the brain cells' ability to store and retrieve information in short-term memory.

DHEA is the most plentiful steroid hormone in the human body, but its exact function is unknown. What is known is that its concentration plummets with age: its daily production drops from 30 mg at age 20 to less than 6 mg at age 80. DHEA is naturally synthesized in abundance in young people from pregnenolone in the brain and the adrenal glands. It is known to affect the excitability of neurons in the hippocampus, the part of the brain responsible for memory. Current findings suggest that DHEA enhances memory by facilitating the induction of neural plasticity, the condition that permits the neurons (nerve cells of the brain) to change in order to record new memories.

Pregnenolone, pregnenolone sulfate and DHEA were shown to improve memory retention in tests on laboratory animals. [40]

The suggested supplementation range for pregnenolone is 50 to 150 mg a day in three equal doses. The recommended dosage for DHEA is 25 to 50 mg a day. Women usually need less DHEA than men.

Recommendations

Innovative Drugs

Take one or a combination of the following drugs:

Piracetam (2,400 to 4,800 mg a day)

Hydergine (4 to 10 mg a day)

Centrophenoxine (250 to 1,000 mg a day)

Picamilon (50 to 100 mg three times a day)

Pyritinol (200 mg three times a day)

Supplements

The following supplements were described in this protocol:

Ginkgo biloba extract (120 mg a day)

Acetyl-L-carnitine (1,000 to 2,000 mg a day)

Choline (250 mg a day)

DHA (500-1000 mg a day)

In addition, the following supplements were covered in the Age-Associated Mental Decline Protocol:

Coenzyme Q10  (100 to 200 mg a day)

Hormones, including DHEA, Pregnenolone, Testosterone, Estrogen and Melatonin.

Antioxidants

B vitamins, including methylcobalamin

Vinpocetine (15 mg a day)

References

1.         Senin, U., et al., Aniracetam (Ro 13-5057) in the treatment of senile dementia of Alzheimer type (SDAT): results of a placebo controlled multicentre clinical study. Eur Neuropsychopharmacol, 1991. 1(4): p. 511-7.

2.         Pragina, L.L., et al., [The effect of piracetam and nicergoline on conditioned-reflex memory under conditions of extreme exposure]. Farmakol Toksikol, 1990. 53(3): p. 8-10.

3.         Bartus, R.T., et al., Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol Aging, 1981. 2(2): p. 105-11.

4.         Gallai, V., et al., A clinical and neurophysiological trial on nootropic drugs in patients with mental decline. Acta Neurol (Napoli), 1991. 13(1): p. 1-12.

5.         Canonico, P.L., et al., Repeated injections of piracetam improve spatial learning and increase the stimulation of inositol phospholipid hydrolysis by excitatory amino acids in aged rats. Funct Neurol, 1991. 6(2): p. 107-11.

6.         Heiss, W.D., et al., Abnormalities of energy metabolism in Alzheimer's disease studied with PET. Ann N Y Acad Sci, 1991. 640: p. 65-71.

7.         Heiss, W.D., et al., Effect of piracetam on cerebral glucose metabolism in Alzheimer's disease as measured by positron emission tomography. J Cereb Blood Flow Metab, 1988. 8(4): p. 613-7.

8.         Zykov, V.P., [Cerebral hemodynamics in patients with circulatory encephalopathy]. Zh Nevropatol Psikhiatr Im S S Korsakova, 1992. 92(1): p. 31-4.

9.         Paula-Barbosa, M.M., et al., The effects of piracetam on lipofuscin of the rat cerebellar and hippocampal neurons after long-term alcohol treatment and withdrawal: a quantitative study. Alcohol Clin Exp Res, 1991. 15(5): p. 834-8.

10.       Qian, Z.N., et al., [Effects of piracetam on Na(+)-K(+)-ATPase and monoamine oxidase in rat brain and its antioxidation effect]. Zhongguo Yao Li Xue Bao, 1992. 13(1): p. 48-50.

11.       Loscertales, M., et al., Piracetam facilitates long-term memory for a passive avoidance task in chicks through a mechanism that requires a brain corticosteroid action. European Journal of Neuroscience, 1998. 10(7): p. 2238-2243.

12.       Emmenegger, H. and W. Meier-Ruge, The actions of Hydergine on the brain. A histochemical, circulatory and neurophysiological study. Pharmacology, 1968. 1(1): p. 65-78.

13.       Ditch, M., F.J. Kelly, and O. Resnick, An ergot preparation (hydergine) in the treatment of cerebrovascular disorders in the geriatric patient: double-blind study. J Am Geriatr Soc, 1971. 19(3): p. 208-17.

14.       Nagasawa, H., et al., Effects of co-dergocrine mesylate (Hydergine) in multi-infarct dementia as evaluated by positron emission tomography. Tohoku J Exp Med, 1990. 162(3): p. 225-33.

15.       Markstein, R., Hydergine: interaction with the neurotransmitter systems in the central nervous system. J Pharmacol, 1985. 16(Suppl 3): p. 1-17.

16.       al-Zuhair, H., A. Abd el-Fattah, and M.I. el-Sayed, The effect of meclofenoxate with ginkgo biloba extract or zinc on lipid peroxide, some free radical scavengers and the cardiovascular system of aged rats. Pharmacol Res, 1998. 38(1): p. 65-72.

17.       Zs-Nagy, I., On the role of intracellular physicochemistry in quantitative gene expression during aging and the effect of Centrophenoxine. A review. Arch Gerontol Geriatr, 1989. 9(3): p. 215-29.

18.       Sharma, D. and R. Singh, Centrophenoxine activates acetylcholinesterase activity in hippocampus of aged rats. Indian J Exp Biol, 1995. 33(5): p. 365-8.

19.       Patro, N., S.P. Sharma, and I.K. Patro, Lipofuscin accumulation in ageing myocardium & its removal by meclophenoxate. Indian J Med Res, 1992. 96: p. 192-8.

20.       Stancheva, S.L. and L.G. Alova, [Effect of Centrophenoxine, piracetam and aniracetam on the monoamine oxidase activity in different brain structures of rats]. [Article in Russian]. Farmakol Toksikol, 1988. 51(3): p. 16-8.

21.       Stancheva, S.L., V.D. Petkov, and V.V. Petkov, Effects of the nootropic agents adafenoxate and meclofenoxate on brain biogenic monoamines in aged rats. Acta Physiol Pharmacol Bulg, 1988. 14(1): p. 14-21.

22.       Wood, W.G., et al., Fluidizing effects of Centrophenoxine in vitro on brain and liver membranes from different age groups of mice. Life Sci, 1986. 39(22): p. 2089-95.

23.       Lustyik, G. and I. Nagy, Alterations of the intracellular water and ion concentrations in brain and liver cells during aging as revealed by energy dispersive X-ray microanalysis of bulk specimens. Scan Electron Microsc, 1985. 1: p. 323-37.

24.       Mosharrof, A.H., et al., Effects of meclofenoxate on learning and memory--dependence on the experimental conditions. Acta Physiol Pharmacol Bulg, 1986. 12(3): p. 7-14.

25.       Hindmarch, I., D.M. Coleston, and J.S. Kerr, Psychopharmacological effects of pyritinol in normal volunteers. Neuropsychobiology, 1990. 24(3): p. 159-64.

26.       DeFeudis, F.V. and K. Drieu, Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications. Curr Drug Targets, 2000. 1(1): p. 25-58.

27.       Yoshikawa, T., Y. Naito, and M. Kondo, Ginkgo biloba leaf extract: review of biological actions and clinical applications. Antioxid Redox Signal, 1999. 1(4): p. 469-80.

28.       Diamond, B.J., et al., Ginkgo biloba extract: mechanisms and clinical indications. Arch Phys Med Rehabil, 2000. 81(5): p. 668-78.

29.       Winter, J.C., The effect of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat. Physiology and Behavior, 1998. 63(3): p. 425-433.

30.       Stough, C., et al., Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants. Int J Neuropsychopharmacol, 2001. 4(2): p. 131-4.

31.       Wesnes, K.A., et al., The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers. Psychopharmacology, 2000. 152(4): p. 353-61.

32.       Kennedy, D.O., A.B. Scholey, and K.A. Wesnes, The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology, 2000. 151(4): p. 416-23.

33.       Mix, J.A. and W.D. Crews, Jr., An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults. J Altern Complement Med, 2000. 6(3): p. 219-29.

34.       Aureli, T., et al., Acetyl-L-carnitine modulates glucose metabolism and stimulates glycogen synthesis in rat brain. Brain Research, 1998. 796: p. 1-2.

35.       Bossoni G, C.C., Effect of acetyl-L-carnitine on conditioned reflex learning rate and retention in laboratory animals. Drugs Exp Clin Res, 1986. 12(11): p. 911-6.

36.       Greiner, R.S., et al., Olfactory discrimination deficits in n-3 fatty acid-deficient rats. Physiol Behav, 2001. 72(3): p. 379-85.

37.       Greiner, R.S., et al., Rats with low levels of brain docosahexaenoic acid show impaired performance in olfactory-based and spatial learning tasks. Lipids, 1999: p. S239-43.

38.       Moriguchi, T., R.S. Greiner, and N. Salem, Jr., Behavioral deficits associated with dietary induction of decreased brain docosahexaenoic acid concentration. J Neurochem, 2000. 75(6): p. 2563-73.

39.       Petkov, V.D., et al., Effect of CDP-choline on learning and memory processes in rodents. Methods Find Exp Clin Pharmacol, 1992. 14(8): p. 593-605.

40.       Flood, J.F., M.J. E., and R. E., Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci U S A, 1992. 89(5): p. 1567-71.

 

 

 

 

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