Nootropics: A Guide to Cognitive Enhancement

The use of "smart drugs" to boost cognitive performance is fast becoming common place. With literally thousands of compounds on the market, it is difficult to know where to begin. The spectrum of such substances is vast, and encompasses everything from vitamin and mineral preparations, to commercial pharmaceuticals. We will begin our discussion with one of the fastest growing classes of cognitive enhancers--nootropics.

I have begun work on an e-book on nootropics which will be complete in 6 months. This being said, I will not have time to update this blog until after its completion. In the mean time, feel free to stop by at www.MemTrax.net and sign up for a FREE memory testing profile. Keep in mind MemTrax is still in the Beta phase for now. Beta mobile app coming soon!

In 1964, a new compound, piracetam, was synthesized by Romanian chemist/psychologist, Dr Corneliu E. Giurgea. Giurgea coined the term nootropic in 1972, a term he would later used to describe his discovery, piracetam. The term nootropic derives its meaning from the Greek words nous, meaning "mind", and trepein, meaning "to bend". Three years after coining the term, Giurgea established criteria which must be met in order for a substance to be considered a true nootropic.

Giurgea's Nootropic Criteria:

1.) Enhances learning and memory.

2.) Promote the resistance of learned behaviors to conditions which are known to disrupt them. Example: hypoxia (oxygen deficiency).

3.) Protect the brain from physical or chemical injury.

4.) Enhance the tonic cortical/subcortical control mechanisms

5.) Exhibit few side effects and extremely low toxicity, while lacking the pharmacology of typical psychotropic drugs (motor stimulation, sedation etc).

Since Giurgea's original criteria were first published, there has been little agreement as to what truly constitutes a nootropic compound. The most well defined criteria to date was established by Skondia in 1979. Skondia utilizes a metabolic approach, taking into account the pharmacological mode of action.

Skondia's Nootropic Criteria:
I. No direct vasoactivity
- A. No vasodilation
- B. No vasoconstriction

II. EEG activity: No change in basic rhythm
- A. Quantitative EEG: Increased power spectrum (beta 2 and alpha)
- B. Qualitative EEG: Decreased delta waves and cerebral suffering

III. Must pass blood-brain barrier
- A. Under normal conditions
- B. Under pathological conditions

IV. Must show metatolic activity in:
- A. Animal brain metabolism
- 1. Molecular
- 2. Physiopathological
- B. Human brain metabolism (clinical evaluation)
- 1. A-V differences
- a. Increased extraction quotients of O2
- b. Increased extraction quotients of glucose
- c. Reduced lactate pyruvate ratio
- 2. Regional cerebral metabolic rates (rCMR)
- a. Increased ICMR of O2
- b. Increased rCMR of glucose
- 3. Regional cerebral blood flow: Normalization

V. Minimal side effects

VI. Clinical trials must be conducted with several rating scales designed to objectify metabolic cerebral improvement.

Nootropic activity has been primarily claimed for a relatively new class of compounds which belong to the pyrrolidinone class, are lactams and are cyclic GABA derivatives. Very few chemicals claiming to poses nootropic activity belong to other chemical classes and/or share no structural correlates with the pyrrolidinones.

Despite the close structural relationship with GABA, nootropics such as oxiracetam and piracetam do not interact with GABA recptors. While gamma-lactams are very similar to the folded conformation of GABA, the "active" conformation on post synaptic receptors is in fact the extended form. All known products with significant binding affinity for GABA receptors are zwitterions. The folded form seems to serve a role in various transport mechanisms.

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1. Giurgea, C.: Vers une pharmacologie de l'activitk intkgrative du cerveau. Tentative du concept nmtrope en psychopharmacologie actual. Pharrnacol. 25: 115, 1972.

*Translation: Pharmacology of integrative activity of the brain. Attempt at nootropic concept in psychopharmacology.

2. Giurgea, C.: Differential experimental definition of nootropic drugs. Proc. Symp. "Nooanaleptic and Nootropic Drugs," Rome, September 17, 1975, p. 83.

3. Giurgea CE, Greindl MG, Preat S (1983). "Nootropic drugs and aging". Acta Psychiatr Belg 83 (4): 349-58. PMID 6660010

4. Skondia, V.: Criteria for clinical development and classification of nootropic drugs. Clin. Ther. 2: 316, 1979.

5. Fink,M.:Contributiontoan"objective"classificationofpsychoactivedrugs.1lthC.1.N.PCongress, July 1978, Vienna.

6. Krogsgaard-Larsen, P. and Johnston, G.A.R.: Structure activity studies on the inhibition of GABA binding to rat brain membranes by muscimol and related compounds. J. Neurochem. 30: 1377, 1978.

7. Krogsgaard-Larsen, P. and Cristensen, A.V.: GABA agonists and antagonists. Annual Reports in Med. Chem., Chapter 5, 15: 41, 1980, Academic Press.

8. Brehm, L., Krogsgaard-Larsen, P. and Jacobsen, P.: GABA uptake inhibitors and structurally related "Pro Drugs." In: "GABA Neurotransmitters," ed. by P. Krogsgaard-Larsen. Copenhagen: Publ. Munksgaard, 1979, p. 247.

9. Callery, P.S., Stogniew, M. and Geelhaar, A,: Detection of the "in vivo" conversion of 2-pyrrolidinone to gamma-aminobutyric acid in mouse brain. Biomed. Mass Spectrom. 6: 23, 1979.

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Acetylcholinesterase (AChE) is an enzyme that breaks down the neurotransmitter acetylcholine into choline and acetate. This action serves to terminate synaptic transmission at both the neuromuscular junction and cholinergic nervous system. Mammalian acetylcholinesterase is encoded by the AChE gene and undergoes alternative splicing and post translational modifications to produce three known isoforms. The AChET isoform is the major form, and is found in the brain, muscle and other tissues, where it is anchored in the intercellular or neuromuscular junction.

In 2007, Dori et al, demonstrated that the AChER form may be involved in the stress response, and possibly inflammation. This form has yet to be discovered in humans, but may in the future help to explain the pathology of Alzheimer's disease. Two years later, Shaked et al, published in the journal Immunity, an article entitled MicroRNA-132 Potentiates Cholinergic Anti-Inflammatory Signaling by Targeting Acetylcholinesterase, states that "findings identify the AChE mRNA-targeting miR-132 as a functional regulator of the brain-to-body resolution of inflammation, opening avenues for study and therapeutic manipulations of the neuro-immune dialog." While further studies must be performed, the initial findings are exciting to say the least.

***MORE TO COME***
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AChE cannabis http://pubs.acs.org/doi/abs/10.1021/mp060066m

Dori A, Ifergane G, Saar-Levy T, Bersudsky M, Mor I, Soreq H, Wirguin I (2007). "Readthrough acetylcholinesterase in inflammation-associated neuropathies.". Life Sci 80 (24-25): 2369-74. doi:10.1016/j.lfs.2007.02.011. PMID 17379257.

Massoulié J, Perrier N, Noureddine H, Liang D, Bon S (2008). "Old and new questions about cholinesterases.". Chem Biol Interact 175 (1-3): 30-44. doi:10.1016/j.cbi.2008.04.039. PMID 18541228.

Shaked I, Meerson A, Wolf Y, Avni R, Greenberg D, Gilboa-Geffen A, Soreq H (2009). "MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase". Immunity 31 (6): 965-73. doi:10.1016/j.immuni.2009.09.019. PMID 20005135
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Carnitine is a vitamin like amino acid derivative, and is present in nearly all cells of the body. First isolated from meat extracts in 1905, carnitines role in human physiology remained unknown until 1952, when a group of researchers determined it to be a growth factor for the meal worm Tenebrio molitor. From this discovery, carnitine became known as vitamin Bt. This prompted researchers to reinvestigate the role of carnitine in humans, and soon after determined it to be essential in the breakdown of fats to produce energy. Carnitine is no longer considered a vitamin, as it is synthesized in the body, primarily the liver and kidneys, from the essential amino acids L-methionine and L-Lysine. The synthesis of carnitine requires the cofactors vitamin B6 (in the active form pyridoxal phosphate, PLP), niacin (vitamin B3, nicotinic acid), vitamin C and iron.

Carnitine is responsible for the transport of long-chain fatty acids, across the inner mitochondrial membrane, where they are released and used for beta oxidation (energy production, ATP). In addition, carnitine serves several other key physiological functions, including the conversion of keto-acid analogues of the branched chain amino acids. This function is vital during periods of starvation/fasting and exercise.

While carnitine is available in several forms, the acetyl-L-carnitine (ALCAR also called LAC) form is preferred for Alzheimer's disease and cognitive effects. Acetyl-L-carnitine shares great structural similarity to acetylcholine. This led researchers to investigate the role of carnitine in Alzheimer's disease. Calvani et. al. demonstrated in 1993, that acetyl-L-carnitine does in fact mimic acetylcholine, and is beneficial to both Alzheimer's patients and elderly patients with impaired memory or depression. It does so by enhancing energy production, stabilizing cell membranes and by mimicing or increasing acetylcholine function.

This finding prompted De Falco, et. al, to study the effects of carnitine on Down's syndrome, as both are characterized by cholinergic transmission deficits. Sure enough, patients demonstrated statistically significant improvements in attention and visual memory. For the treatment of Down's syndrome, a dosage of 10 milligrams per pound of body weight appears adequate.

Dosage: 1,500-4,000 mg/day in divided doses.

Interactions: Carnitine works synergystically with both pantethine and CoQ10. Daily choline supplementation assists in the conservation of carnitine, by lowering urinary carnitine excretion significantly (20mg choline/kg body weight).

Safety: Acetyl-L-carnitine exhibits no significant side effects.

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1. Bremer J, Carnitine--metabolism and function. Physiol Rev 63. 1420-1480, 1983.

2. Bamji MS, Nutritional and health implications of lysine carnitine relationship. Wld Rev Nutr Diet 44, 185-211, 1984.

3. Bowman B, Acetyl-carnitine and Alzheimer's disease. Nutrition Reviews 50, 142-144, 1992.

4. Calvani M, et al., Action of acetyl-L-carnitine in neurodegeneration and Alzheimer's disease. Ann NY Acad Sci 663, 483-486, 1993.

5. Carta A, et al., Acetyl-L-carnitine and Alzheimer's disease. Pharmacological considerations beyond the cholinergic sphere. Ann NY Acad Sci 695, 324-326, 1993.

6. Carter HE, et al., Chemical studies on vitamin BT isolation and characterization as carnitine. Arch Biochem Biophys 38, 405-416, 1952.

7. De Falco FA, et al., Effect of the chronic treatment with L-acetylcarnitine in Down's syndrom. Clin Ther 144, 123-127, 1994.

8. Daily JW III; Sachan DS, Choline supplementation alters carnitine homeostasis in humans and guinea pigs. J Nutr 125, 1938-1944, 1995.

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First synthesized in 1964 Piracetam is legal to import into the United Kingdom without a prescription and remains an uncontrolled substance in the United States. Piracetam is a derivative of the neurotransmitter GABA (Gamma Amino Butyric Acid). Piracetam is chemically related to Pyroglutamic Acid(pyrrolidine Carboxylic Acid). Pyroglutamic acid is found in cerebrospinal fluid and is formed by post translational modification through the deamination of N-terminal glutamine to pyroglutamic acid.

Piracetam enhances brain metabolism by increasing blood and oxygen flow as well as glucose utilization (the primary fuel of the brain). By interacting with the polar head groups of the phospholipid bilayer, Piracetam increases cell membrane fluidity. This helps to support healthy neuron structure, and thus communication. Piracetam also exhibits significant antioxidant properties.

Effects can usually be felt within an hour or up to several days later. It may take up to a month for full effects to be noticed. Typical dose is between 800mg to 6 grams. Should be taken in cycles, first daily for 2-3 months, followed by 1 month off.

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Galantamine is a natural plant alkaloid, used to treat mild to moderate Alzheimer's disease, and other cognitive deficits of vascular origin. Galantamine derives its name from the snowdrop (genus Galanthus) from which it was first isolated. Galantamine is one of over 20 new drugs released on the market between 2000 and 2005, of natural origin; however, due to the scarcity of the various plant species which produce the alkaloid, and low alkaloid yeild (.1% to .2 % dry weight) galantamine is now produced on a commercial scale via synthetic synthesis (although this may change in the near future: Click to Learn More .)

Galantamine is a competitive reversible cholinesterase inhibitor.

***MORE TO COME***
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Chida, Noritaka; Kato, Tomoaki; Yamada, Hisako (2010). "Total Synthesis of (+)- and (-)-Galanthamine". Heterocycles 82: 563. doi:10.3987/COM-10-S(E)27

Chin Y-W, Balunas MJ, Chai HB, Kinghorn AD. Drug Discovery From Natural Sources. AAPS Journal. 2006; 8(2): E239-E253. DOI: 10.1208/aapsj080228

Magnus, Philip; Sane, Neeraj; Fauber, Benjamin P.; Lynch, Vince (2009). "Concise Syntheses of (%u2212)-Galanthamine and (±)-Codeine via Intramolecular Alkylation of a Phenol Derivative". Journal of the American Chemical Society 131 (44): 16045-16047. doi:10.1021/ja9085534. PMID 19835379

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While aniracetam is a chemical analogue of piracetam, aniracetam is fat soluble, making its effects more potent and longer lasting. Aniracetam stimulates the Corpus Callosum, a region of the brain which connects and unites the two hemispheres; Piracetam also exhibits this effect. Aniracetam is sought after for its potent AMPA receptor enhancing properties, namely enhances focus and concentration. Aniracetam is commonly reported to be one of the "best" anxiolytic (anti-anxiety) nootropics.

Effects can be felt within an hour to several day. Typical doses range from 750-1500mg/day taken with meals.

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Oxiracetam is a potent water soluble analogue of Piracetam. Oxiracetam is the fastest acting of all the racetams. The nootropic effect of oxiracetam is reported to be much stronger than Piracetam or Aniracetam. Oxiracetam helps to increase brain ATP (universal biological energy currency) levels, as well as increase levels of acetylcholine in the hippocampus, striatum, and cerebral cortex via increased Choline Acetylcholinetranferase activity.

Effects can be felt within a few hours. Typical doses range between 800-1600mg/day.

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