Nootropics - reviewing piracetam and analogues by James South M.A.

Over 30 years have passed since the Nootropic !evolution "uietly began with the development o# $iracetam in the late medical e##icacy with a virtual absence o# to%icity and side e##ects& something rarely seen with more standard medical drugs. More importantly' they o##ered promise not only in the realm o# #ighting disease' but also in the virtually une%plored realm o# drugs that could not only postpone or even reverse normal brain aging' but could even ma(e normal brains wor( better) *he $iracetam-nootropics have been e%haustively researched& since the #irst scienti#ic studies on $iracetam in the late +,-0.s over +000 scienti#ic papers on $iracetam' O%iracetam' $ramiracetam' and Aniracetam have been published with about two thirds o# them on $iracetam. *he action o# the $iracetam-nootropics has been studied in a broad range o# animals& gold#ish' mice' rats' guinea pigs' rabbits' cats' dogs' marmosets' mon(eys and humans. *he to%icity o# $iracetam and its cousins is ama/ingly low- almost non-e%istent. 0n acute to%icity studies' intravenous doses o# $iracetam given to rats 12g3 4g bodyweight5 and oral doses given to mice' rats' and dogs 1+0g3 4g or more5 produced no to%icity. *his would be e"uivalent to 6-0-700 grams 1+.83 to +.69 pounds5 #or a +69 pound human. !ats given +00-+000mg3 4g orally #or - months and dogs given +0'000mg3 4g orally #or one year showed no to%ic e##ect' a teratogenic 1birth de#ect causing5 e##ects were #ound' either 1*acconi and :urtman +,2-5. *he $iracetam-nootropics are among the to%icologically sa#est drugs ever developed. *he #our main commercially available racetam nootropics all share a pyrrolidine nucleus' while $iracetam' O%iracetam' and $ramiracetam' also share an acetyl group. *he racetams 1especially $iracetam and O%iracetam5 are closely related in structure to the amino acid $yroglutamic Acid. $yroglutamic Acid has been shown in some studies to have wea( nootropic activity 1;ouliaev and Senning +,,95. $yroglutamic Acid is naturally present in many human #oods' as well as the mammalian brain. *he concept and de#inition o# a nootropic drug was #irst proposed in +,78 by <.=. ;iurgea' the principal $iracetam researcher and research coordinator #or ><?' the ?elgian company that launched $iracetam. *he main #eatures... de#ining a nootropic drug are 1A5 the enhancement' at least under some conditions' o# learning ac"uisitions as well as the resistance o# learned behaviors to agents that tend to impair them&

1?5 the #acilitation o# interhemispheric #low o# in#ormation& 1<5 the partial enhancement o# the general resistance o# the brain and particularly its resistance to physical and chemical in@uries& 1A5 the increase in the e##icacy o# the tonic cortico-subcortical control mechanisms& and 1=5 Babsence o# the usual negative pharmacologic e##ects o# psychotropic drugsC. ;iurgea'and Salama +,775. ;iurgea derived the term nootropic #rom the i words noos 1Dmind5 and tropein 1Dto turn toward5. Scha##ler and 4lausnit/er 1+,225 have given an e%cellent brie# overview o# some o# the chie# e##ects o# the $iracetam-nootropics. Erom animal biochemistry it is (nown that B$iracetam-nootropicsC enhance brain metabolism by stimulation o# o%idative catabolism' increase o# A*$-turnover and cAM$ levels' enhancement o# phospholipid-metabolism and protein biosynthesis. B$iracetam-nootropics haveC an impact on the hippocampal release o# acetylcholine and on the dopaminergic turnover' too. $harmacologically there e%ist protective e##ects with regard to several no%es Bharm#ul agentsC and an impact on the associative cortical sphere and on hippocampal structures' which are related with learning and memory' especially when the respective #unctions are impaired. *he per#ormatory enhancements are related with an increased arousability o# hippocampal pyramid cells' #acilitated transmission o# the thalamic a##erences' increased release o# hippocampal acetylcholine and enhanced synaptic transmission. *he clinical biochemistry indicates enhancing #unctions on the utili/ation o# o%ygen and glucose under the conditions o# decreased brain metabolism' as well as improvements in local per#usion. Aue to this pro#ile B$iracetam-nootropicsC can be e%pected to be o# value in the treatment o# disease which are related to impairments in the above mentioned #eatures' such as several types o# senile dementia' 1e.g. $rimary Aegenerative AementiaD Al/heimerFs typeG Multi 0n#arct Bstro(eC Aepantia5' ischaemic Bpoor brain blood #lowC insults' hypo%ia' ano%ia and to%icologically or dietary based de#iciencies. 1Eootnotes in the original te%t omitted here5. Erom the beginning o# $iracetam research' the ability o# the $iracetam-nootropics to partly or completely prevent or reverse the to%ic action o# a broad array o# chemicals and conditions has been repeatedly demonstrated. Aniracetam reverses the memory impairment in rats induced by <lonidine. $iracetam' O%iracetam' $ramiracetam' and Aniracetam all antagoni/e the normally lethal neuromuscular bloc(ade induced by Hemicholinium-3 1H<35 in mice. $iracetam' O%iracetam' and Aniracetam have all attenuated or reversed the Scopalamine 1anticholinergic agent5- induced amnesia in rats and mice under a broad range o# e%perimental conditions. O%iracetam has reversed the typical spaced out electroencephalogram o# healthy humans given Ialium' restoring a normal vigilance electroencephalogram while

maintaining Ialium.s anti-an%iety e##ects. $iracetam and Aniracetam have ameliorated the amnesia produced by the protein synthesis inhibitor <yclohe%imide. $iracetam' O%iracetam' $ramiracetam' and Aniracetam all attenuate or reverse the amnesia in mice and rats induced by electroconvulsive shoc( treatment in both passive and active learning conditions. :hen mice were given O%ydipentonium' a short acting curare-li(e agent which induces asphy%ia' at a dose su##icient to (ill ,0-+00J o# the placebo treated controls' the two groups o# $iracetam treated mice had a ,0 and +00J survival rate. :hen humans' rats' mice and rabbits have been put under diverse hypo%ic e%perimental conditions' $iracetam' O%iracetam' and Aniracetam have acted to attenuate or reverse the hypo%ia-induced amnesia and learning di##iculties. as well as to speed up recovery time #rom hypo%ia and reduce the time needed to renormali/e the electroconvulsive shoc( treatment 1;ouliaev and Senning ;iurgea and Salama +,775. A classic series o# e%periments on the protective power o# $iracetam against barbiturate poisoning was reported by Moyersoons and ;iurgea in +,79. !abbits connected to electroconvulsive shoc( treatment machines were given either $iracetam or saline in@ections be#ore intravenous 10.I.5 administration o# the #ast acting barbituratesSecobarbital. :hen $iracetam was given 0.I. one hour be#ore Secobarbital' +03+0 rabbits survived versus 33+0 survivors given saline. =lectroconvulsive shoc( treatment records showed only minimal abnormalities in the $iracetam rabbits' while the saline rabbits showed massive electroconvulsive shoc( treatment silence' rapidly #ollowed by death. :hen given only one-hal# hour be#ore Secobarbital' 73++ $iracetam rabbits survived versus 33+ + control rabbits. =lectroconvulsive shoc( treatment records o# the $iracetam rabbits showed somewhat more abnormalities than those given one hour $iracetam pre-treatment' but still #ar more normal appearing than the saline control rabbits. electroconvulsive shoc( treatment. $iracetam was also given orally one hour be#ore Secobarbital. 23, $iracetam rabbits survived while only 33, controls survived. *he electroconvulsive shoc( treatment records o# both groups were similar to those o# the rabbits given $iracetam and saline 0.I. one hour be#ore Secobarbital. *he e%periments then treated $iracetam against a more slow acting barbiturate Allobarbital' giving the $iracetam 0.I. two minutes a#ter the Allobarbital in#usion ++3+3 $iracetam rabbits survived' while only 83+3 saline control rabbits survived electroconvulsive shoc( treatment. !ecords o# the $iracetam rabbits again showed electrical silences to be almost absent' and i# present' to be shorter and appear later than in the control animals.

0n the Allobarbital e%periment' one o# the two surviving control rabbits actually presented a more normal electroconvulsive shoc( treatment a#ter Allobarbital than did one o# the survivors eleven $iracetam survivors.. Ket an electroconvulsive shoc( treatment recorded the ne%t morning 1about +2 hours later5 showed that the control was still asleep' and it was not aroused by a loud noise. *he $iracetam rabbit' however' was well awa(e' behaved normally' moved around and its electroconvulsive shoc( treatment was normal. *hus' whether given 0.I. or orally' and be#ore or a#ter general lethal 1to controls5 barbiturate in#usion' $iracetam served to protect both li#e and brain structure and #unction' as evidenced by electroconvulsive shoc( treatment records and post recovery behavior. *he rabbit e%periments @ust described are hardly unusual. *he $iracetam-nootropics routinely show an ability to stabili/e or normali/e the electroconvulsive shoc( treatment.s o# humans and animals under a broad range o# e%perimental and medical conditions. *he electroconvulsive shoc( treatment records the electro-chemical activity o# large groups o# cortical neurons' and thus provides a macro picture o# brain activity. Aging' dementia' hypo%ia and ben/odia/epines all promote a similar shi#t in electroconvulsive shoc( treatment #re"uency patterns. Low #re"uency delta waves 10-9 cycles per second5 and theta waves 19-2 cps5 are increased' while alpha waves 12-+8 cps5 and beta waves 1beta-+& +8-80 cps' beta 8& 80-38 cps5 diminish. *he average #re"uency o# the delta and alpha waves also drops' as compared to healthy normal sub@ects. Nootropics - clinical studies ;iaguinto and colleagues 1+,2-5 gave +8 healthy humans 6mg Ialium orally at +0$M the night be#ore their e%periment. *he ne%t morning they were given either 0.I. O%iracetam or saline in a double blind crossover e%periment. O%iracetam strongly decreased the e%cessive delta activity while simultaneously strongly increasing alpha activity' and also induced a modest increase in beta activity. *hus O%iracetam restored the electroconvulsive shoc( treatment to a pattern indicating increased vigilance and alertness' yet without destroying Ialium.s anti-an%iety e##ect. 0til and co-wor(ers 1+,2-5 treated #our groups o# +6 patients su##ering mild to moderate dementia with either O%iracetam or placebo #or three months. *he double blind study used O%iracetam in doses o# 200' +-00 and 8900mg daily. Muantitative electroconvulsive shoc( treatment data indicated that in patients with dementia' O%iracetam had a mode o# action similar to other vigilance enhancing compounds. *he ma@ority o# patients who had abnormal slow electroconvulsive shoc( treatment patterns be#ore treatment showed a normali/ation o# their brain waves- i.e. a decrease in slow 1delta and theta5 and an increase in alpha waves. Saletu and colleagues 1+,265 conducted a #our wee( double

blind trial o# O%iracetam 18900 mg per day5 or placebo in 90 patients 1mean age& 20 years5 su##ering #rom the organic brain syndrome o# late li#e. *heir results showed a clear trend towards a decrease in delta and theta wave activity' an increase in alpha and beta wave activity' as well as an increase in the dominant #re"uency and the centroid o# alpha activity a#ter O%iracetam treatment. *heir report notedG *he attenuation o# the slow activity and the elevation o# the alpha and3or slow wave beta activity a#ter BO%iracetam - other studies have shown similar results with $iracetam and AniracetamC re#lect <NS changes that are @ust oppositional to those seen in normally and pathologically aging sub@ects... *he increase in delta and theta activities and decrease in alpha activity in normal and pathological aging are due to de#icits in the vigilance regulatory systems which can be counteracted by nootropic drugs. Nootropics - and the healthy $iracetam-nootropics have also shown the ability to improve learning and memory in healthy individuals not su##ering #rom disease or severe age-related degeneration. 0n +,7- Aimond and ?rouwers reported the results o# some o# a series o# seven double blind trials' involving +- second and third year college students in e%cellent health and good physical and mental condition. Sub@ects received either 9.2 grams a day $iracetam or placebo #or +9 days. 0n three di##erent measures o# verbal learning and memory' the results showed a highly signi#icant di##erence in #avor o# the $iracetam students over the controls' with con#idence levels o# $D.0+' $D.08 and $D.0+. *he authors stated the #act is that $iracetam improves verbal learning and in this it would appear to be a substance which is.. capable o# e%tending the intellectual #unctions o# man.. our sub@ects were not senile' su##ering #rom generali/ed brain disorder' con#usional states' or any other pathology o# the brain... 0t is there#ore possible to e%tend the power which Bindividuals gi#ted with high intelligence and good memoryC possess to still higher levels despite the #act that the range o# their achievement is a high. ;iurgea and Salama report the con#irmation o# Aimond3 ?rouwer.s wor( by :edl and Suchenwirth in +,77. :edl #ound signi#icant improvement in mental per#ormance in a group o# +7 healthy young volunteers given 3.8 grams per day $iracetam #or #ive days. Mindus and colleagues 1+,7-5 reported the results o# a double blind crossover trial with +2 healthy middle aged people 1median age 6-5' with no evidence o# somatic or mental disease' based on medical records and administration o# several intelligence tests 1group mean 0M& +80 plus or minus ++5. Most o# the sub@ects were in intellectually demanding @obs' but had reported a slight reduction #or some years in their capacity to retain or recall in#ormation. A#ter #our wee(s o# 9.2 grams per day $iracetam' $iracetam sub@ects were switched to placebo #or #our wee(s' while the original placebo group then received $iracetam #or #our wee(s.

!esults o# a series o# paper and pencil tests' as well as computeri/ed tests to measure perceptual motor reactions' showed a clear bene#it o# $iracetam over placebo. *he three di##erent paper and pencil tests showed superior e##ects on per#ormance compared to placebo' with con#idence levels o# $N.00+' $N.00+ and $N.06. 0n #our o# the si% computeri/ed tests $iracetam showed a signi#icant e##ect over placebo' with con#idence levels o# $N.06 #or three and $N.08, #or the #ourth. A #i#th test showed a clear trend in #avor o# $iracetam' with $N.+0. :ilsher and cowor(ers 1+,7,5 related their results with 9.2 grams per day $iracetam in a double blind' crossover trial to study the bene#its o# $iracetam #or dysle%ic students. 0nterestingly' the +9 healthy student controls' matched #or 0M with the dysle%ic sub@ects' demonstrated a signi#icantly better result on a test measuring ability to memori/e nonsense syllables while using $iracetam as compared to placebo. *heir improvement #rom baseline was a +,.6J decrease in the number o# trials needed to learn the nonsense syllables while using $iracetam' versus a +0.,J decrease #rom baseline while using placebo. $N.06. $iracetam-nootropics may increase learning and memory in healthy individuals' where they are not merely attenuating or reversing pathology' through their distinctive power to promote what has been termed hemispheric super-connection. *he cerebral corte% in humans and animals is divided into two hemispheres- the le#t and right corte%. 0n most humans the le#t hemisphere 1which controls the right side o# the body5 is the language center' as well as the dominant hemisphere. *he le#t corte% will tend to be logical' analytical' linguistic and se"uential in its in#ormation processing' while the right corte% will usually be intuitive' holistic' picture oriented and simultaneous in its in#ormation processing. !esearch has shown most people #avor one hemisphere over the other' with the dominant corte% being more electrically active and the nondominant corte% relatively more electrically silent 1when the person is being tested or as(ed to solve problems' or respond to in#ormation5. *he two cortical hemispheres are lin(ed by a bundle o# nerve cables & the corpus callosum and the anterior commisure. 0n theory these two structures should unite the #unction o# the two hemispheres& in practice they act more li(e a wall separating them. *his #unctionally-split neurology produces a parallel set o# dichotomies in consciousness& logic vs. intuition& reason vs. emotion& analysis vs. synthesis& parts vs. whole& words vs. pictures& science vs. art and religion' etc. As noted earlier' the word nootropic is derived #rom the ;ree( word nous 1the more standard philosophical spelling5. Ket in the philosophy o# $lato and Aristotle' nous did not simply mean mind. 0n ancient ;ree( philosophy' nous re#erred to the #aculty o# higher mind or reason' as opposed to the more concrete' sensory oriented mind which humans share even with the lower animals. And reason did not merely mean logic or analysis.

*he ;ree( philosophers saw the role o# philosophy to be a method o# developing and per#ecting nous3 reason. *hey understood nous3 reason to be the integrative mind' where logic wor(s complementarily with intuition' and reason and emotion are in harmony. :ith a developed nous' one could clearly see and understand the #orest and the trees simultaneously. Erom a modern neurological perspective it is obvious that the cerebral basis #or a well-#unctioning nous would be the e##ective' complementary' simultaneous integrated #unction o# cortical hemispheres' with neither hemisphere being automatically dominant or silent. *his in turn would re"uire the corpus callosum and anterior commisure to optimi/e in#ormation #low between the two hemispheres. !esearch has shown the $iracetamnootropics to #acilitate such intercebral in#ormation trans#er- indeed' it.s part o# the de#inition o# a nootropic drug. ;iurgea and Moyersoons reported in +,70 that $iracetam increased by +00J the transcallosal evo(ed responses elicited in cats by stimulation o# one hemisphere and recorded #rom a symmetrical region o# the hemisphere. ?uresova and ?ures 1+,7-5 in a comple% series o# e%periments involving monocular 1one-eye5 learning in rats' demonstrated that ...$iracetam enhances transcommisural encoding mechanisms... and some #orms interhemispheric trans#er... Aimond 1+,7-' +,7,5 used a techni"ue called dichotic listening to veri#y the ability o# $iracetam to promote interhemispheric trans#er in humans. 0n a dichotic listening test' di##erent words are transmitted simultaneously into each ear by headphone. 0n most people the speech center is the le#t corte%' because the nerves #rom the ears cross over to the opposite side o# the brain' most people will recall more o# the words presented right ear than the le#t ear. :ords received by the right ear directly reach the le#t corte% speech center' while words presented to the le#t ear must reach the le#t corte% speech center indirectly' by crossing the corpus callosum. Aimond.s e%periments with young healthy volunteers showed that $iracetam signi#icantly improved le#t ear word recall' indicating $iracetam increased interhemispheric in#ormation trans#er. O(uyama and Aihara 1+,225 tested the e##ect o# Aniracetam on the transcallosal response o# anaesthetised rats. *he transcallosal response was recorded #rom the sur#ace o# the #rontal corte% #ollowing stimulation o# the corresponding site on the opposite cortical hemisphere. Aniracetam at two di##erent 0.I. doses 1+0 mg and 30mg per 4g5 signi#icantly increased the amplitude o# the negative wave compared to its level prior to drug' $N.0+ and $N.00+. *he researchers stated that the present results indicate that Aniracetam.. increased the amplitude o# the negative wave' thereby #acilitating interhemispheric trans#er... *hus' it is considered that the #unctional increase in interhemispheric neurotransmission by nootropic drugs may be related to the improvement o# the cognitive #unction. 0n spite o# the many and diverse neurological and psychological bene#its they have shown in human' animal and cell studies' the $iracetam-nootropics are generally considered

NO* to be ma@or agonists or inhibitors o# the synaptic action o# most neurotransmitters. *hus' ma@or nootropic researchers $epeu and Spignoli 1+,,05 state& the pyrrolidinone derivatives B$iracetam-nootropicsC show little or no a##inity #or <NS receptors #or dopamine' glutamate' serotonin' ;A?A' or ben/odia/epine... So #ar' little e##ect o# nootropic drugs has been demonstrated on brain monoamine and amino acid neurotransmitters. metabolism and release. *hey also note however that ... a number o# investigations on the electrophysiological actions o# nootropic drugs have been carried out... *a(en together' these #indings indicate that the nootropic drugs o# the B$iracetam-typeC enhance neuronal e%citability within speci#ic neuronal pathways. ;ouliaev and Senning similarly state ... we thin( that the racetams e%ert their e##ect on some species Bo# moleculeC present in the membrane o# all e%citable cells' i.e. the ion carriers or ion channels and that they somehow accomplish an increase in the e%citatory response... 0t would there#ore seem that the racetams act as potentiators o# an already present activity 1also causing the increase in glucose utili/ation observed5' rather than possessing any activity o# their own' in (eeping with their very low to%icity and lac( o# serious side e##ects. *he result o# their action is there#ore an increase in general ne sensitivity towards stimulation. *hus the $iracetam-nootropics would NO* be prone to the 1o#ten serious e##ects o# drugs which directly ampli#y or inhibit neurotransmitter c e.g. MAO inhibitors' $ro/ac-style selective serotonin reupta(e inhibitors' tricyclic antidepressants' amphetamines' ben/odia/epines' etc. *he notable absence o# biochemical' physiological' neurotogical' psychological side e##ects' even with high dose and3 or long term nootropic use' is routinely attested to in the vast literature on them. *hus in their +,77 review ;iurgea and Salama point outG $iracetam active in previously described situations' is devoid o# usual .re pharmacologic activities even in high doses... 0n normal sub@ects.. no side e##ects or .doping. e##ects were ever observed. Nor did $iracetam induce any sedation' tran"uilli/ation. locomotor stimulation or psychodysleptic symptomatology.. 0til and co-wor(ers reported in +,23 that *his investigation has con#irmed that B$ramiracetamC is a sa#e and well tolerated compound that can be given in dosages up to +600 mg without signi#icant side e##ects. 0n #act side e##ects were reported more #re"uently #ollowing both placebo and... phenel/ine sul#ate Ban .active control. drugC than #ollowing any o# the #our doses evaluated. A#ter a ma@or +8 wee( study with 878 Al/heimer and stro(e dementia patients' Maina and colleagues 1+,2,5 reported& *hirty #ive minor side e##ects were recorded in 30 patients on BO%iracetamC and 33 unwanted e##ects in 8- patients on placebo' but none o# these was withdrawn #rom the study... As #ar as tolerability is concerned' clinical assessments and laboratory evaluations did not reveal any di##erence between treatment and placeboC.

Moglia and co-wor(ers 1+,2-5 concluded #rom a study o# 93 organic syndrome patients that side e##ects during BO%iracetamC treatment headache 13 cases5' constipation 1+ case5' sleep disturbances 1+ Side e##ects during placebo treatment were headache 18 case constipation 1+ case5. *he side e##ects spontaneously disappears re"uired neither medication nor treatment interruption. No signi#icant BadverseC change in neurological and laboratory e%1 lions' =<; and ==; could be detected at the end o# treatment' both in the BO%iracetamC and in the placebo groups. :hen side e##ects are occasionally reported in the clinical literature on $iracetam-nootropics. they are usually o# a type to suggest slight over-stimulation' mainly headaches' agitation' insomnia and irritability. Ket other studies #ind these same symptoms to be improved by $iracetam-nootropics when these symptoms are pre-e%isting in the patients. *hus 0til 1+,2-5 notes' ...B $iracetamC showed more improvement than BO%iracetamC in #actors o# paranoid delusion and agitation. Maina 1+,2,5 noted that BO%iracetamC does not act only by increasing arousal and alertness. 0# this were the case' there would probably be a worsening o# the 0$S<-= an%iety and tension BscoresC. However' in our study there was actually a decrease in an%iety and tension. ?ranconnier 1+,235' reporting on his group.s study o# $ramiracetam in 38 Al/heimer patients noted that a#ter #our wee(s. treatment' there was a signi#icant decrease in an%iety-tension 1$D.0095 and hostility 1$D.035' and a clean trend over placebo 1$D.025 #or $ramiracetam to improve e%isting sleep disturbances. One potentially limiting #actor in obtaining clinical bene#it #rom $iracetam-nootropics has been bought to light through the research o# Mondadori 1+,,85 on steroid interactions with nootropics. Mondadori has shown that either de#icient or e%cessive levels o# adrenal steroids can bloc( the memory bene#its o# $iracetam-nootropics in animals. High doses o# either corticosterone or aldosterone abolish the memory enhancing bene#its o# $iracetam-nootropics' while giving corticosterone or aldosterone to rats with no adrenals restores the positive memory e##ects o# nootropics. Mandadori also notes that cortisol levels are #re"uently elevated in Al/heimer patients' which might e%plain the inconsistent results obtained with nootropics in di##erent Al/heimer clinical studies. Nootropics - Synergy. Since $iracetam-nootropics act 1in part5 through subtly ampli#ying neuronal electrical e%citability' they will tend to increase the activity o# other drugs that modi#y neural activity ta(en simultaneously. *his in turn may increase both the positive action o# the other drug' as well as possibly lead to the occasional nootropic over-stimulation e##ects. *hus even ca##eine may be su##iciently stimulating to bring on the nootropic over stimulation e##ect' especially in those very sensitive to ca##eine. A (ey normal regulator o# neuronal sensitivity is the essential mineral' Magnesium. Aietary surveys in the :estern world routinely show most people to be at least marginally Mg de#icient' with many getting hal# or less o# the recommended dietary Magnesium inta(e 1:ester +,275. *hus' the occasional over stimulation seen with $iracetam-nootropics may simply evidence an undetected synaptic Magnesium de#iciency' and Magnesium supplementation may provide a natural remedy to minimi/e such over stimulation

$iracetam-nootropics have been combined in many clinical and e%perimental situations with other drugs' almost always with a positive' synergistic e##ect. Many clinical e%periments have demonstrated $iracetam and O%iracetam to synergi/e with antiepileptic medications' especially carbama/epine 1*egretol5. A simultaneous enhancement o# the anti-epileptic drug.s anti-sei/ure activity' combined with improvement or elimination o# the memory' alertness and comprehension cognitive de#icits induced +G anti-epileptic drug' have been #ound in multiple studies 1<haudhry $iracetam combined with $ento%i#ylline 1a ca##eine analogue cerebral #low enhancer5 increased both psychointellectual per#ormance measures o# cerebral blood #low5' signi#icantly more than place either drug alone 1$arnetti +,265. Human and animal studies have shown increased bene#it #rom combining $iracetam with <holine' the raw material #or neuronal production o# be neurotransmitter Acetylcholine' as well as $hosphatidylcholine' a #luidi/ing component o# cell membranes 1Eerris +,285. :hen $iracetam was combined with Hydergine in e%periments with mice both brain survival time and learning3 memory de#icits induced po%ia' it was noted that *he e##ect o# the combination was greater than the sum o# the e##ects o# the individual agents and indicates that synergism had occurred 1?erga +,2-5. A +,,9 report loo(ed at the synergy between $iracetam and intensive speech therapy given to post-stro(e aphasic patients& 0n general' changes under B$iracetamC were +-0J o# the changes observed in patients receiving placebo' while getting the same intensive speech therapy 1Ai +,,95. *hose wishing to get the ma%imum bene#it #rom $iracetam-nootropics may to include in their regimen nutrients (nown to enhance brain structure #unction in various ways. *he ?-comple% vitamins 1including NAAH5' Lipoic Acid' <oM+0' Magnesium' and Manganese are all essential to brain A*$ energy production through the glyolytic and citric acid cycles and the electron transport side chain. AMA= is an e%cellent <holine precursor passes the blood brain barrier better than <holine or Lecithin. Acetyl L-carnitine enhances the activity o# the en/yme 1<holine Acetyl *rans#erase 1<A*5 that combines Acetyl groups with <holine to produce Acetylcholine. Acetyl L-carnitine also renews the structure and energy generating power o# aging neuronal mitochondria. $hosphatidylserine is a natural neuronal membrane component and stabili/er. Antio%idants' such as vitamins < and =' as well as $ycnogenol or grape seed e%tract' may protect polyunsaturated #at-rich neuronal and mitochondrial membranes #rom the damage caused by the inevitable release o# large numbers o# #ree radicals' generated through brain mitochondrial energy production. Nootropics - their di##erences 0ndividual di##erences o# action between $iracetam' O%iracetam' $ramiracetam' and Aniracetam are o#ten subtle' and in many studies they show similar modes o# action. One intriguing bene#it 0 have seen reported only #or $ramiracetam' is its ability to increase

goal directed and purposive behavior 1?ranconnier +,235. A#ter trying $ramiracetam in my regimen several years ago. 0 did notice an increase in my tendency to "uic(ly ta(e care o# routine household' auto and personal maintenance chores 0 habitually tended to ignore' avoid or postpone. 0 have ta(en $iracetam #or eight years' $ramiracetam and Aniracetam #or the past two years and O%iracetam #or about , months. Auring the past year' my li#elong severe writer.s bloc( has gradually disappeared' and my writing output o# the past year has e%ceeded that o# the previous decade. Some studies on dementia comparing $iracetam and O%iracetam 1the two most nearly identical racetams5. have suggested that O%iracetam may be more e##ective in restoring the cognitive de#icits o# dementia 1decreased memory' concentration and alertness5' while $iracetam may be more e##ective at normali/ing the emotional problems o# dementia 1agitation' tension-an%iety' hostility' insomnia' uncooperativeness5. Muantitatively' $iracetam is the least potent racetam' with clinical doses typically being 8900 mg to 9200 mg per day' occasionally even -000 mg to 00'000 mg per day. O%iracetam is usually given 600 mg to 8900 mg per day. Aniracetam doses are typically 760 mg to +600mg per day' while $ramiracetam has shown bene#it even at +60 mg to 600 mg per day' although -00 mg to +600 mg per day is more typical. $iracetam and O%iracetam are highly water soluble 1,--,2J5' while Aniracetam and $ramiracetam are more #at soluble. *heir lipophilicity may allow #or less #re"uent dosing 1once or twice daily5 with Aniracetam and $ramiracetam' compared to 3 to 9 doses a day with $iracetam and O%iracetam. Aniracetam is #avored by the Japanese' who have contributed much research on it. 0t is widely used there as an agent to rapidly promote clarity o# thought. Nootropics - uses and conclusion Auring the past 30 years' the $iracetam-nootropics have been used to treat an ama/ingly broad range o# human ailments and conditions' either or with other drugs' with moderate to ma@or bene#it. $iracetam-nootropics have been used to treat various #orms o# dementia and organic brain syndrome. *hey have been used success#ully to treat dysle%ia' epilepsy and age-associated memory impairment. $iracetam-nootropics have success#ully treated post-concussional syndrome' vertigo' alcohol withdrawal' cerebrovascular insu##iciency and hypo%ia. *hey have shown bene#it in normali/ing blood #low parameter creased platelet aggregation' increased red blood cell 1!?<5 de#ormability' decreased adherence o# damaged and sic(le cell !?<.s dothelium 1blood cell lining5 and increased $rostacyclin 1$;+85 production and activity. Ket the most e%citing potential bene#its o# the racetams have yet seriously e%plored in clinical studies.

*he racetams are cerebral homeostatic normali/ers' neuroprotectants' cerebral metabolic enhancers and brain integrative agents. *hey enhance brain energy' especially under de#icit conditionG hypo%ia' chemical to%icity or impaired cerebral microcirculation. *hey preserve' protect and enhance synaptic membrane and receptor structure and plasticity. *hey enhance brain integration- hori/ontally' by increased coupling o# the cerebral hemispheres& and vertically by enhancing cerebral connection with and tonic control o# the limbic system' through nootropics e##ects on the hippocampus- a ma@or lin( between cerebrum and system. *his vertical integration increase may help to integrate reason 1cerebrum and emotion 1limbic system- sometimes called the horse brain 5. *he increased tonic corticosubcortical control and regulation may prevent our limbic passions and desires #rom running away with us as in crimes o# passion. 0n middle aged and older individuals who do not yet su##er any speci#ic neural malady or ma@or mental impairment' nootropics may not only slow down or postpone entropic brain aging' but they may even reverse mild neural3 mental decline. *hus a person at 60 might be smarter' have better memory' "uic(er re#le%es and greater vigilance and alertness than when they were 90. *he racetams may literally be sa#e and e##ective pharmacologic tools to enhance' protect and optimi/e truly normal' #ully human neuropsychological structures and #unction' well into old age. HOM= !=E=!=N<=S to order www.piracetam.com

+. $. ?erga et al 1+,2-5 Synergistic interactions between $iracetam and BHydergineC in some animal models o# cerebral hypo%ia and ischaemia Ar/neim Eorsch3 Arug !es 3-' +3+9-80. 8. !.J. ?ranconnier et al 1+,235 *he therapeutic e##icacy o# $ramiracetam in Al/heimerFs disease- preliminary observations $sychopharmacol ?ull +,'78--30. 3. 0. ?uresova' J. ?ures $iracetam induced #acilitation o# interhemispheric trans#er o# visual in#ormation in rats $sychopharmacologia 1?erlinr5 9-',3-+08. 9. H.!. <haudhry et al 1+,,85 <linical use o# $iracetam in epileptic patients <urr *her !es 68' 366--0. 6. :. Aeberdt 1+,,95 0nteraction between psychological and pharmacological treatment in cognitive impairment Li#e Sci 66' 8067---. -. S.J. Aimond 1+,7-5 Arugs to improve learning in man in the neuropsychology o# learning disorders' !. 4night' A. ?a((er' eds.' 3-7-7,. >niv. $ar( ?altimore.

7. S.J. Aimond' =. ?rouwers 1+,7-5 0ncrease in the power o# human memory in normal man through the use o# drugs $sychopharmacol 9,' 307-0,. 2. S.J. Aimond et al 1+,7,5 Some e##ects o# $iracetam on chronic schi/ophrenia $sychopharmacol -9'39+-92. ,. S.H. Eerris et al 1+,285 <ombination <holine3 $iracetam treatment o# senile dementia $sychopharm ?ull +2' ,9-,2. +0. S. ;ia"uinto 1+,2-5 ==; changes induced by O%iracetam on Aia/epam-Medicated volunteers <lin. Neuropharmacol ,' S7,-S29. ++. <. ;iurgea' E. Moyersoons 1+,705 Ai##erential pharmacological reactivity o# three types o# cortical evo(ed potentials Arch 0nt. $harmacodyn *her. +22'90+-09. +8. <. ;iurgea' M. Salama 1+,775 Nootropic drugs $rog. Neuro-$harmac. +.836-97. +3. A. ;outiaev' A. Senning 1+,,95 $iracetam and other structurally related nootropics ?rian !es. !ev. +,' +20-888. +9. *. 0til et al 1+,235 $ramiracetam' a new nootropic' a controlled "uantitative pharmaco-==; study $sychopharm. ?ull. +,' 702-+-. +6. *. 0til et al 1+,2-5 <NS pharmacology and clinical therapeutic e##ects o# O%iracetam <lin. Neuropharmacol. ,' S70-S78. +-. ;. Maina et al 1+,2,5 O%iracetam in the treatment o# degenerative and multi in#arct dementia Neuropsychobiol. 8+. +9+ +7. $. Mindus et al 1+,7-5 $iracetam-induced improvement o# mental per#ormance Acta $sychiat Scand 69' +60--0. +2. A. Moglia et al 1+,2-5 Activity o# O%iracetam in patients with organic brain syndrome <lin. Neuropharmac ,' S73-S72. +,. <. Mondadori et al 1+,,85 =levated corticosteroid levels bloc( the memory improving e##ects o# nootropics $sychopharmac. +02' + +-. 80. E. Moyersoons' <. ;iurgea 1+,795 $rotective e##ect o# $iracetam in e%perimental barbiturate into%icationG ==; and behavioural studies Arch. 0nt. $harmacodyn *her 8+0. 32-92. 8+. S. O(uyama' H. Aihara 1+,225 Action o# nootropic drugs on transcollosal responses o# rats Neuropharmac. 87. -7-78.

88. L. $arnetti et al 1+,265 Haemorheological pattern in initial mental deterioration& !esults o# a long term study using $iracetam and $e#ylline Arch ;erontol. ;eriatr9' +9+-66. 83. ;. $epeu. ;. Spignoli 1+,,05 Neurochemical actions o# nootropic drugs in Advances in Neurology I6+& Al/heimerFs disease. !. :u ed. 897-68' !aven $ress. 89. ?. Saletu et al 1+,265 O%iracetam in the organic brain syndrome o# late li#e Neuropsychobiol +3' 99-68. 86. 4. Scha##ler' :. 4lausnit/er 1+,225 Antihypo%idotic e##ects o# $iracetam using psychophsiological measures in healthy volunteers Ar Eorsch. Arug !es. 32' 822-,+. 8-. M. *acconi' !. :urtman 1+,2-5 $iracetamG physiological disposition and mechanism o# action in Advances in Neurology I93& Myocio Eahn' ed. -76--26' !aven $ress. 87. $. :ester 1+,275 Magnesium Am. J. <lin. Nutr. 96' +306-+8. 82. <. :ilsher et al 1+,275 $iracetam and dysle%ia-.e##ects on reading tests J. <lin. $sychopharmac. 7' 830-37. ALL 0NEO!MA*0ON 0S =A><A*0ONAL ANA SHO>LA NO* !=$LA<= *H= AAI0<= OE KO>! $HKS0<0AN. *he above article is copyrighted and may not be copied without the written permission o# 0nternational Antiaging Systems' Les Autelets Suite A' Sar( ;K, 0SE' <hannel 0slands' >4.