Pramiracetam: The ultimate smart-drug?

Technically speaking a “smart-drug” should be called a “nootropic.” This was a term originally coined by Dr. Giurgea in the 1970’s and taken from Greek to mean; “acting on or towards the mind.” (1,9) In the medical sense a nootropic is restricted to a particular specialist class of drugs (2), but today the public are more likely to use the term “smart drug” to refer to any substance that has a positive effect on memory and cognition.

Ever since the publication in the 1990’s of Dean, Morgenthaler and Fowkes best selling books; Smart Drugs and Nutrients (3) and Smart Drugs II (4) the term “smart drugs” has become much more familiar.

The first true smart-drug was piracetam and it was first developed nearly 40 years ago, heralding a "revolution" in pharmacology. This then continued with the development of piracetam’s “cousins;” oxiracetam, aniracetam and pramiracetam. (figure 1)

Nootropics are revolutionary for two reasons, firstly they combine efficacy with extremely low toxicity and few side effects, (something rarely seen with “regular” drugs), plus they also offer promise to postpone or help reverse brain aging, and they may even be able to make "normal" brains work better!

What is clear from even a brief check of the international drug database PubMed, is that nootropics have been exhaustively researched. Since the first scientific studies began in the late 1960's over 1000 scientific papers have now been published. (4)

Lack of toxicity

The action of the nootropics has been studied extensively in both animals and humans and one thing stands out, the toxicity of piracetam and its "cousins" is almost non-existent.

For example, in acute toxicity studies, intravenous doses of piracetam given to rats (8 g./ Kg. body weight) and oral doses given to mice, rats and dogs (10 g./ Kg. or more) have produced no toxicity. (6) This would be equivalent to 700 grams for a 70 Kg. (154 lb) human and therefore can be claimed to be “safer than salt.” It is apparent that nootropics are among the toxicologically safest drugs ever developed.

After examining the manufacturer’s leaflets for aniracetam, oxiracetam, piracetam and pramiracetam (20-24), the listed side effects are limited to excitability, headache, nausea, agitation, insomnia and anxiety, with most of those being mainly attributable to over dosage.

Method of action

Nootropics enhance brain metabolism by stimulating oxidative catabolism, increasing energy levels (by improving ATP-turnover and cAMP levels), and enhancing phospholipid metabolism and protein biosynthesis. In addition they also appear to have an impact on the hippocampal release of acetylcholine and dopamine, but they do not significantly impact the release (or inhibition) of neurotransmitters, which may be a clue to their very rare occurrence of side effects (7).

Gouliaev and Senning stated; "..we think that [nootropics] exert their effect on some [molecule] present in the membrane of all excitable cells, i.e. the ion carriers or ion channels, and that they somehow accomplish an increase in the excitatory response. It would therefore seem that the [nootropics] act as potentiators of an already present activity (also causing the increase in glucose utilization observed), rather than possessing any activity of their own, [this is] in keeping with their very low toxicity and lack of serious side effects. The result of their action is therefore an increase in general neuronal sensitivity towards stimulation." (8)

The most unique method of action of nootropics is the increase of communication across the corpus callosum (figure 2). This is the bundle of nerves that separate the two hemispheres of the brain. Nootropics appear to be able to enhance the communication across this network, improving intra-hemisphere contact. (26,27,28) Some have inferred that this represents the ability to have new ideas (the right brain being artistic and creative) and putting them into action, (the left brain being logical and analytical). In other words, effectively connecting the Yin and Yang parts of the cerebellum.

These methods indicate that nootropics enhance potentiation and sensitize the activity of receptors, something very much in line with the model of improvement for the “neuroendocrine theory of aging.” (25)

Benefits

In the 3+ decades that nootropics have been available in Europe, they have been used to treat an amazingly broad range of human ailments and conditions. These include:

  • Being used successfully to treat alcoholism. (9,10,11)


  • Improving or slowing deterioration in senile dementias such as Alzheimer's disease. (12,13)


  • Enhancing alertness, co-operation, socialization and IQ in elderly patients. (14)


  • Improving reading and accuracy in dyslexia, as well as the speed of reading, writing and spelling. (15,16)


  • Reducing the severity and occurrence of the symptoms of headache, especially those associated with concussion. (18)


  • Successfully treating motion sickness and vertigo. (19)


  • Boosting mental performance in "aging, non-deteriorated individuals" suffering only from "forgetfulness." (17)

In regard to that last statement, nootropics have been found to boost learning, concentration and intelligence even in young people!

In a unique experiment, Dimond and Brouwers reported the results of a series of 7 double blind trials, involving 16 second and third year college students, all of them in excellent health and good physical and mental condition. After a period of 14-days, the authors reported on those receiving the nootropic by stating; “the fact is that piracetam improves verbal learning and in this it would appear to be a substance which is.. capable of extending the intellectual functions of man.. our subjects were not senile, suffering from generalized brain disorder, confusional states, or any other pathology of the brain... It is therefore possible to extend the power which [individuals gifted with high intelligence and good memory] possess to still higher levels despite the fact that the range of their achievement is already high." (24)

This is a remarkable statement and is a clear indication of the potential of nootropics in antiaging/ preventative medicine.

The cousins

Individual differences of action between piracetam, oxiracetam, aniracetam and pramiracetam and often subtle.

The Japanese, who have contributed much research on aniracetam favor it as an agent to rapidly promote clarity of thought.

One interesting benefit reported only for pramiracetam, is its ability to increase goal directed and purposive behavior (30).

Some studies on dementia comparing piracetam and oxiracetam (the two that are most chemically identical), have suggested that oxiracetam may be more effective in restoring the cognitive deficits of dementia (decreased memory, concentration and alertness). While piracetam may be more effective at normalizing the emotional problems of dementia such as agitation, tension-anxiety, hostility, insomnia and uncooperativeness.

piracetam and oxiracetam are highly water soluble, while aniracetam and pramiracetam are more fat-soluble. This fact may allow for less frequent dosing (once or twice daily) with aniracetam and pramiracetam, compared to 2 to 3 doses a day with piracetam and oxiracetam.

Quantitatively, piracetam is the least potent racetam, with clinical doses typically being 2400 mg. to 4800 mg. per day. oxiracetam is usually given 800 mg. to 2400 mg. per day. Aniracetam doses are typically 750 mg. to 1500 mg. per day, while pramiracetam has shown benefit even at 150 mg. to 300 mg. per day, although 600 mg. to 1200 mg. per day is more typical.

In fact, one study (31) showed significant intelligence and memory enhancement in Alzheimer’s patients with just 150 mg. of pramiracetam daily, whilst the equivilant piracetam dose would have been 2400 mg. to 4800 mg. This indicates that when compared mg. to mg. pramiracetam could be up to 15-times more potent than piracetam.

Conclusion

Nootropics are a proven way to help improve concentration, memory, learning and attention. They have a long record in Europe of assisting with numerous disorders for the young and old alike.

Although there wasn’t time to elaborate in this short article, there is also strong evidence that nootropics often work well, (i.e. they can be synergistic) when taken with some other substances such as acetyl-l-carnitine, centrophenoxine and hydergine etc.

There are a number of subtle differences between piracetam and its later derivatives. Often to get the best for an individual patient, some informed experimentation is required. But whilst oxiracetam and piracetam may be the most similar and aniracetam and pramiracetam the most “different,” it is clear when compared mg. to mg. that pramiracetam can be considered, at least by its potency alone, to be the “ultimate smart drug.”

References

1. Giurgea, C. (1973) "The nootropic approach to the pharmacology of the integrative activity of the brain" Cond. Reflex 8, 108-115.

2. South J, (1998) “Reviewing the smart drugs” International Antiaging Bulletin, Spring v3 i4, International Antiaging Systems.

3. Dean W, Morgenthaler J, (1990) “Smart Drugs and Nutrients.” Health Freedom Publications.

4. Dean W, Morgenthaler J, Fowkes S.W. (1993) “Smart Drugs II.” Health Freedom Publications.

5. PubMed drug database www.pubmed.gov National Library of Medicine and National Institute of Health.

6. M. Tacconi, R. Wurtman (1986) "Piracetam, physiological disposition and mechanisms of action" in Advances in Neurology V43; Myoclonus, S. Fahn, ed. 675-685, Raven Press.

7. G. Pepeu, G. Spignoli (1990) "Neurochemical actions of nootropic drugs" in Advances in Neurology V51; Alzheimer's disease, R. Wurtman ed. 247-52, Raven Press.

8. A. Gouliaev, A. Senning (1994) "Piracetam and other structurally related nootropics" Brian Res. Rev. 19, 180-222.

9. C. Giurgea, M. Salama (1977) "Nootropic drugs" Prog. Neuro-Pharmac.1, 235-47.

10. Paula- Barbosa, M. et al (1991) "The effects of Piracetam on lipofuscin of the rat cerebellar and hippocampa; neurons after long-term alcohol treatment and withdrawal" Alcoholism: Clin Exp Res 15, 834-38.

11. Skondia, V. & Kabes, J. (1985) "Piracetam in alcoholic psychoses: a double-blind, crossover, placebo controlled study" J Int Med Res 13, 185-87

12. Stegink, A. (1972) "The clinical use of Piracetam, a new nootropic drug" Arzneim-Forsch/Drug Res 22, 975-77.

13. Croisile, B. et al (1993) "Long-term and high dose treatment of Alzheimer's disease" Neurol 43, 301-05.

14. Chouinard, G. et al (1983) "Piracetam in elderly psychiatric patients with mild diffuse cerebral impairment" Psychopharmacol 81, 100-06.

15. DeBerdt, W. (1994) "Interaction between psychological and pharmacological treatment in cognitive impairment" Life Sci 55, 2057-66

16. Wilsher, C. et al (1987) "Piracetam and dyslexia: effects on reading tests" J Clin Psychopharmacol 7, 230-37

17. Mindus, P. et al (1976) "Piracetam-induced improvement of mental performance" Acta Psychiat Scand 54, 150-60.

18. Hakkrainen, H. & Hakamies, L. (1978) " Piracetam in the treatment of post-concussional syndrome" Eur Neurol 17, 50-55.

19. Gouliaev, A. & Senning, A, (1994) "Piracetam and other structurally related nootropics" Brain Res Rev 19, 180-222.

20. Aniracetam manufacturer’s leaflet (Ampamet), Menarini.

21. Oxiracetam manufacturer’s leaflet (Neuromet), GlaxoSmithKline.

22. Piracetam manufacturer’s leaflet (Nootropil), UCB.

23. Pramiracetam manufacturer’s leaflet (NeuPramir), Lusofarmaco.

24. S.J. Dimond, E. Brouwers (1976) "Increase in the power of human memory in normal man through the use of drugs" Psychopharmacol 49, 307-09.

25. Dilman, V., Dean, W., (1992) “The neuroendocrine theory of aging and degenerative disease.” Center for Biogerontology, Pensacola, Florida.

26. Buresova, O. & Bures, J. (1976) "Piracetam induced facilitation of interhemispheric transfer of visual information in rats" Psychopharmacologia 46, 93-102.

27. Dimond, S. et al (1979) "Some effects of Piracetam on chronic schizophrenia" Psychopharmacol 64, 341-48.

28. Okuyama, S. & Aihara, H. (1988) "Actions of nootropic drugs on transcallosal response of rats" Neuropharmacol 27, 67-72.

29. South, J. “Nootropic drugs and nutrients, pathway to brain rejuvenation.” 1st Monte Carlo Antiaging Conference www.antiaging-conference.com

30. R.J. Branconnier et al (1983) "The therapeutic efficacy of Pramiracetam in Alzheimer's disease- preliminary observations" Psychopharmacol Bull 19, 726-30.

31. Poschel, BPH, Marriott JG, Gluckman MI, (1983) “Pharmacology underlying the cognition activating properties of pramiracetam.” Psycopharmacology Bulletin, Vol. 19, No. 4, pp 708-16.

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