Over 30 years have passed since the "Nootropic Revolution" quietly began with the development of Piracetam (PIR) in the late 1960's. The second wave of this pharmacologic revolution occurred in the late 1970's with the development of Oxiracetam (OXR), Pramiracetam (PRM) and Aniracetam (ANR).
The PIR-nootropics were revolutionary in at least two ways. They combined physiological and medical efficacy with a virtual absence of toxicity and side effects, something rarely seen with more standard medical drugs. More importantly, they offered promise not only in the realm of fighting disease, but also in the virtually unexplored realm of drugs that could not only postpone or even reverse "normal" brain aging, but could even make "normal" brains work better!
The PIR-nootropics have been exhaustively researched, since the first scientific studies on PIR in the late 1960's over 1000 scientific papers on PIR, OXR, PRM and ANR have been published, with about two thirds of them on PIR.
Nootropics - Lack of toxicity
The action of the PIR-nootropics has been studied in a broad range of animals; goldfish, mice, rats, guinea pigs, rabbits, cats, dogs, marmosets, monkeys and humans. The toxicity of PIR and its "cousins" is amazingly low- almost non-existent.
In acute toxicity studies, intravenous doses of PIR given to rats (8g/ Kg body weight) and oral doses given to mice, rats and dogs (10g/ Kg or more) produced no toxicity. This would be equivalent to 560-700 grams (1.23 to 1.54 pounds) for a 154-pound human. Rats given 100-1000mg/ Kg orally for 6 months and dogs given 10,000mg/ Kg orally for one year showed no toxic effect, and no teratogenic (birth defect causing) effects were found, either (Tacconi and Wurtman 1986).
The PIR-nootropics are among the toxicologically safest drugs ever developed.
The four main commercially available "racetam" nootropics all share a pyrrolidine nucleus, while PIR, OXR and PRM also share an acetamide group (see figure one). The racetams (especially PIR and OXR) are also closely related in structure to the amino acid Pyroglutamic Acid (PGA). PGA has been shown in some studies to have weak nootropic activity (Gouliaev and Senning 1994). PGA is naturally present in many human foods, as well as the mammalian brain.
Nootropics - Their structure
The concept and definition of a "nootropic drug" was first proposed in 1972 by C.E. Giurgea, the principal PIR researcher and research co-ordinator for UCB, the Belgian company that launched PIR. "The main features... defining a nootropic drug are: (A) the enhancement, at least under some conditions, of learning acquisitions as well as the resistance of learned behaviors to agents that tend to impair them; (B) the facilitation of interhemispheric flow of information; (C) the partial enhancement of the general resistance of the brain and particularly its resistance to physical and chemical injuries; (D) the increase in the efficacy of the tonic cortico-subcortical control mechanisms; and (E) [absence of the usual negative pharmacologic effects of psychotropic drugs]." (Giurgea and Salama 1977).
Giurgea derived the term "nootropic" from the Greek words "noos" (=mind) and "tropein" (=to turn toward).
Nootropics - Method of action
Schaffler and Klausnitzer (1988) have given an excellent brief overview of some of the chief effects of the PIR-nootropics. "From animal biochemistry it is known that [PIR-nootropics] enhance the brain metabolism by stimulation of oxidative catabolism, increase of ATP-turnover and cAMP levels, enhancement of phospholipid metabolism and protein biosynthesis. [PIR-nootropics have] an impact on the hippocampal release of acetylcholine and on the dopaminergic turnover, too.
Pharmacologically there exist protective effects with regard to several noxes [harmful agents] and an impact on the associative cortical sphere and on hippocampal structures, which are related with learning and memory, especially when the respective functions are impaired. The performatory enhancements are related with an increased arousability of hippocampal pyramid cells, facilitated transmission of the thalamic afferences increased release of hippocampal acetylcholine and enhanced synaptic transmission.
The clinical biochemistry indicates enhancing functions on the utilization of oxygen and glucose under the conditions of decreased brain metabolism, as well as improvements in local perfusion. Due to this profile [PIR-nootropics] can be expected to be of value in the treatment of disease which are related to impairments in the above mentioned features. Such as several types of senile dementia, (e.g. Primary Degenerative Dementia= Alzheimer's type; Multi Infarct [stroke] Dementia), ischaemic [poor brain blood flow] insults, hypoxia, anoxia and toxicologically or dietary based deficiencies." (Footnotes in the original text omitted here).
Nootropics - Animal experiments
From the beginning of PIR research, the ability of the PIR-nootropics to partly or completely prevent or reverse the toxic action of a broad array of chemicals and conditions has been repeatedly demonstrated.
ANR reverses the memory impairment in rats induced by Clonidine. PIR, OXR, PRM and ANR all antagonise the normally lethal neuromuscular blockade induced by Hemicholinium-3 (HC3) in mice.
PIR, OXR and ANR have all attenuated or reversed the Scopalamine (anticholinergic agent)- induced amnesia in rats and mice under a broad range of experimental conditions.
OXR has reversed the typical "spaced out" electroencephalogram (EEG) of healthy humans given Valium, restoring a normal vigilance EEG while maintaining Valium's anti-anxiety effects.
PIR and ANR have ameliorated the amnesia produced by the protein synthesis inhibitor Cycloheximide. PIR, OXR, PRM and ANR all attenuate or reverse the amnesia in mice and rats induced by electroconvulsive shock treatment (ECS) in both passive and active learning conditions.
When mice were given Oxydipentonium, a short acting curare-like agent that induces asphyxia, at a dose sufficient to kill 90-100% of the placebo treated controls, the two groups of PIR treated mice had a 90 and 100% survival rate.
When humans, rats, mice and rabbits have been put under diverse hypoxic experimental conditions, PIR, OXR and ANR have acted to attenuate or reverse the hypoxia-induced amnesia and learning difficulties, as well as to speed up recovery time from hypoxia and reduce the time needed to renormalize the EEG (Gouliaev and Senning 1994, Giurgea and Salama 1977).
Moyersoons and Giurgea reported a classic series of experiments on the protective power of PIR against barbiturate poisoning in 1974. Rabbits connected to EEG machines were given either PIR or saline injections before intravenous (i.v.) administration of the fast acting barbiturates- Secobarbital (SEC).
When PIR was given i.v. one hour before SEC, 10/10 rabbits survived, versus 3/10 survivors given saline. EEG records showed only minimal abnormalities in the PIR rabbits, while the saline rabbits showed massive EEG silence, rapidly followed by death. When given only one-half hour before SEC, 7/11 PIR rabbits survived, versus 3/11 control rabbits.
EEG records of the PIR rabbits showed somewhat more abnormalities than those given one hour PIR pre-treatment, but still far more normal appearing than the saline control rabbits' EEG's.
PIR was also given orally one hour before SEC. 8/9 PIR rabbits survived, while only 3/9 controls survived. The EEG records of both groups were similar to those of the rabbits given PIR and saline i.v. one hour before SEC.
The experiments then treated PIR against a slower acting barbiturate-Allobarbital (ALB), giving the PIR i.v. two minutes after the ALB infusion, 11/13 PIR rabbits survived, while only 2/13 saline control rabbits survived. EEG records of the PIR rabbits again showed electrical silences to be almost absent, and if present, to be shorter and appear later than in the control animals.
In the ALB experiment, one of the two surviving control rabbits actually presented a more normal EEG after ALB than did one of the 11 PIR survivors. Yet an EEG recorded the next morning (about 18 hours later) showed that the control was still asleep, and it was not aroused by a loud noise.
The PIR rabbit, however, was well awake, behaved normally, moved around and its EEG was normal.
Thus, whether given i.v. or orally, and before or after general lethal (to controls) barbiturate infusion, PIR served to protect both life and brain structure and function, as evidenced by EEG records and post recovery behavior.
The rabbit experiments just described are hardly unusual. The PIR-nootropics routinely show an ability to stabilise or normalise the EEG's of humans and animals under a broad range of experimental and medical conditions. The EEG records the electro-chemical activity of large groups of cortical neurons, and thus provides a "macro" picture of brain activity.
Aging, dementia, hypoxia and benzodiazepines all promote a similar shift in EEG frequency patterns. Low frequency delta waves (0-4 cycles per second) and theta waves (4-8 cps) are increased, while alpha waves (8-12 cps) and beta waves (beta-1; 12-20 cps, beta 2; 20-32 cps) diminish. The average frequency of the delta and alpha waves also drops, as compared to healthy normal subjects.
Nootropics - Clinical studies
Giaguinto and colleagues (1986) gave 12 healthy humans 5mg Valium orally at 10PM the night before their experiment. The next morning they were given either i.v. OXR or saline in a double blind crossover experiment.
OXR strongly decreased the excessive delta activity while simultaneously strongly increasing alpha activity, and also induced a modest increase in beta activity. Thus OXR restored the EEG to a pattern indicating in-creased vigilance and alertness, yet without destroying Valium's anti-anxiety effect.
Itil and co-workers (1986) treated four groups of 15 patients suffering mild to moderate dementia with either OXR or placebo for three months. The double blind study used OXR in doses of 800, 1600 and 2400mg daily. Quantitative EEG data indicated that in patients with dementia, OXR had a mode of action similar to other vigilance enhancing compounds.
The majority of patients who had abnormal slow EEG patterns before treatment showed a "normalization" of their brain waves- i.e. a decrease in slow (delta and theta) and an increase in alpha waves. Saletu and colleagues (1985) conducted a four-week double blind trial of OXR (2400mg per day) or placebo in 40 patients (mean age; 80 years) suffering from the "organic brain syndrome of late life."
Their 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 frequency and the centroid of alpha activity after OXR treatment. Their report noted; "The attenuation of the slow activity and the elevation of the alpha and/or slow wave beta activity after [OXR- other studies have shown similar results with PIR and ANR] reflect CNS changes that are just oppositional to those seen in normally and pathologically aging subjects... The increase in delta and theta activities and decrease in alpha activity in normal and pathological aging are due to deficits in the vigilance regulatory systems, which can be counteracted by nootropic drugs."
Nootropics - And the healthy
PIR-nootropics have also shown the ability to improve learning and memory in healthy individuals not suffering from disease or severe age-related degeneration. In 1976 Dimond and Brouwers reported the results of some of a series of seven double blind trials, involving 16 second and third year college students "in excellent health and good physical and mental condition."
Subjects received either 4.8 grams a day PIR or placebo for 14 days. In three different measures of verbal learning and memory, the results showed a highly significant difference in favor of the PIR students over the controls, with confidence levels of P=.01, P=.02 and P=.01.
The authors stated "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."
Giurgea and Salama report the confirmation of Dimond/ Brouwer's work by Wedl and Suchenwirth in 1977. Wedl found significant improvement in mental performance in a group of 17 healthy young volunteers given 3.2 grams per day PIR for five days.
Mindus and colleagues (1976) reported the results of a double blind, crossover trial with 18 healthy middle aged people (median age 56), with no evidence of somatic or mental disease, based on medical records and administration of several intelligence tests (group mean IQ; 120 plus or minus 11).
Most of the subjects were in intellectually demanding jobs, but had reported a slight reduction for some years in their capacity to retain or recall information. After four weeks of 4.8 grams per day PIR, PIR subjects were switched to placebo for four weeks, while the original placebo group then received PIR for four weeks.
Results of a series of paper and pencil tests, as well as computerised tests to measure perceptual motor reactions, showed a clear benefit of PIR over placebo. The three different paper and pencil tests showed superior effects on performance compared to placebo, with confidence levels of P<.001, P<.001 and P<.05. In four of the six computerised tests PIR showed a significant effect over placebo, with confidence levels of P<.05 for three and P<.029 for the fourth. A fifth test showed a clear trend in favor of PIR, with P<.10.
Wilsher and co-workers (1979) related their results with 4.8 grams per day PIR in a double blind, crossover trial to study the benefits of PIR for Dyslexic students.
Interestingly, the 14 healthy student controls, matched for IQ with the dyslexic subjects, demonstrated a significantly better result on a test measuring ability to memorise nonsense syllables while using PIR as com-pared to placebo.
Their improvement from baseline was a 19.5% decrease in the number of trials needed to learn the nonsense syllables while using PIR, versus a 10.9% decrease from baseline while using placebo, P<.05. PIR-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."
Nootropics - Towards the mind
The cerebral cortex in humans and animals is divided into two hemispheres- the left and right cortex. In most humans the left hemisphere (which controls the right side of the body) is the language center, as well as the dominant hemisphere. The left cortex will tend to be logical, analytical, linguistic and sequential in its information processing, while the right cortex will usually be intuitive, holistic, picture oriented and simultaneous in its information processing.
Research has shown most people favor one hemisphere over the other, with the dominant cortex being more electrically active and the non-dominant cortex relatively more electrically silent (when the person is being tested or asked to solve problems, or respond to information).
A bundle of nerve "cables"; the corpus callosum and the anterior commisure link the two cortical hemispheres. In theory these two structures should unite the function of the two hemispheres; in practice they act more like a wall separating them.
This "functionally-split" neurology produces a parallel set of 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 from the Greek word "nous" (the more standard philosophical spelling). Yet in the philosophy of Plato and Aristotle, "nous" did not simply mean "mind." In ancient Greek philosophy, "nous" referred to the faculty of "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.
The Greek philosophers saw the role of philosophy to be a method of developing and perfecting nous/ reason. They understood nous/ reason to be the integrative mind, where logic works complementarily with intuition, and reason and emotion are in harmony.
With a developed nous, one could clearly see and understand "the forest and the trees" simultaneously. From a modern neurological perspective, it is obvious that the cerebral basis for a well-functioning nous would be the effective, complementary, simultaneous integrated function of both cortical hemispheres, with neither hemisphere being automatically dominant or silent.
This in turn would require the corpus callosum and anterior commisure to optimise information flow between the two hemispheres. Research has shown the PIR-nootropics to facilitate such intercerebral information transfer- indeed, it's part of the definition of a "nootropic drug."
Giurgea and Moyersoons reported in 1970 that PIR increased by 25 to 100% the transcallosal evoked responses elicited in cats by stimulation of one hemisphere and recorded from a symmetrical region of the other hemisphere.
Dimond (1976, 1979) used a technique called "dichotic listening" to verify the ability of PIR to promote interhemispheric transfer in humans. In a dichotic listening test, different words are transmitted simultaneously into each ear by headphone. In most people the speech center is the left cortex, because the nerves from the ears cross over to the opposite side of the brain, most people will recall more of the words presented to the right ear than the left ear.
Words received by the right ear directly reach the left cortex speech center, while words presented to the left ear must reach the left cortex speech center indirectly, by crossing the corpus callosum. Dimond's experiments with young healthy volunteers showed that PIR significantly improved left ear word recall, indicating PIR increased inter-hemispheric information transfer.
Okuyama and Aihara (1988) tested the effect of ANR on the transcallosal response of anaesthetised rats. The transcallosal response was recorded from the surface of the frontal cortex following stimulation of the corresponding site on the opposite cortical hemisphere.
ANR at two different i.v. doses (10 and 30mg per Kg) significantly increased the amplitude of the negative wave compared to its level prior to drug, P<.01 and P<.001. The researchers stated that "the present results indicate that Aniracetam.. increased the amplitude of the negative wave, thereby facilitating interhemispheric transfer... Thus, it is considered that the functional increase in interhemispheric neurotransmission by nootropic drugs may be related to the improvement of the cognitive function."
Nootropics - And neurotransmitters
In spite of the many and diverse neurological and psychological benefits they have shown in human, animal and cell studies, the PIR-nootropics are generally considered NOT to be major agonists or inhibitors of the synaptic action of most neurotransmitters.
Thus, major nootropic researchers Pepeu and Spignoli (1990) state; "the pyrrolidinone derivatives [PIR-nootropics] show little or no affinity for CNS receptors for dopamine, glutamate, serotonin, GABA or benzodiazepine... So far, little effect of nootropic drugs has been demonstrated on brain monoamine and amino acid neurotransmitters' metabolism and release."
They also note however that "... a number of investigations on the electrophysiological actions of nootropic drugs have been carried out...Taken together, these findings indicate that the nootropic drugs of the [PIR-type] enhance neuronal excitability within specific neuronal pathways."
Gouliaev and Senning similarly state "... we think that the racetams exert their effect on some species [of 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 racetams act as potentiators of an already present activity (also causing the increase in glucose utilization observed), rather than possessing any activity of their own, 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."
Thus the PIR-nootropics would NOT be prone to the (often-serious) side effects of drugs which directly amplify or inhibit neurotransmitter action e.g. MAO inhibitors, Prozac ®-style "selective serotonin reuptake inhibitors," tricyclic anti-depressants, amphetamines, benzodiazepines, etc.
Nootropics - Side effects and contraindications
The notable absence of biochemical, physiological, neurological or psychological side effects, even with high dose and/ or long term PIR-nootropic use, is routinely attested to in the vast literature on them.
Thus in their 1977 review Giurgea and Salama point out: "Piracetam, while active in previously described situations, is devoid of usual 'routine' pharmacologic activities even in high doses... In normal subjects.. no side effects or 'doping' effects were ever observed. Nor did Piracetam induce any sedation, tranquillisation, locomotor stimulation or psychodysleptic symptomatology.."
Itil and co-workers reported in 1983 that "This investigation has confirmed that [PRM] is a safe and well tolerated compound that can be given in dosages up to 1500mg without significant side effects. In fact side effects were reported more frequently following both placebo and... phenelzine sulfate [an 'active control' drug] than following any of the four [PRM] doses evaluated."
After a major 12 week study with 272 Alzheimer and stroke dementia patients, Maina and colleagues (1989) reported; "Thirty five minor side effects were recorded in 30 patients on [OXR] and 33 unwanted effects in 26 patients on placebo, but none of these was withdrawn from the study... As far as tolerability is concerned, clinical assessments and laboratory evaluations did not reveal any difference between treatments [OXR and placebo]."
Moglia and co-workers (1986) concluded from a study of 43 organic brain syndrome patients "side effects during [OXR] treatment were headache (3 cases), constipation (1 case), sleep disturbances (1 case). Side effects during placebo treatment were headache (2 cases) and constipation (1 case). The side effects spontaneously disappeared and required neither any medication or treatment interruption.
No significant [adverse] change in neurological and laboratory examinations, ECG and EEG could be detected at the end of treatment, both in the [OXR] and in the placebo groups."
When side effects are occasionally reported in the clinical literature on PIR-nootropics, they are usually of a type to suggest slight over stimulation, mainly headaches, agitation, insomnia and irritability.
Yet other studies find these same symptoms to be improved by PIR-nootropics when these symptoms are pre-existing in the patients. Thus Itil (1986) notes, "...[PIR] showed more improvement than [OXR] in factors of paranoid delusion and agitation."
Maina (1989) noted that "[OXR] does not act only by increasing arousal and alertness. If this were the case, there would probably be a worsening of the IPSC-E anxiety and tension [scores]. However, in our study there was actually a decrease in anxiety and tension."
Branconnier (1983), reporting on his group's study of PRM in 32 Alzheimer patients noted that after four weeks' treatment, there was a significant decrease in anxiety-tension (P=.004) and hostility (P=.03), and a clean trend over placebo (P=.08) for PRM to improve existing sleep disturbances.
One potentially limiting factor in obtaining clinical benefit from PIR-nootropics has been bought to light through the research of Mondadori (1992) on steroid interactions with nootropics. Mondadori has shown that either deficient or excessive levels of adrenal steroids can block the memory benefits of PIR-nootropics in animals. High doses of either corticosterone or aldosterone abolish the memory enhancing benefits of PIR-nootropics, while giving corticosterone or aldosterone to rats with no adrenals restores the positive memory effects of nootropics.
Mandadori also notes that cortisol levels are frequently elevated in Alzheimer patients, which might explain the inconsistent results obtained with nootropics in different Alzheimer clinical studies.
Nootropics - Synergy
Since PIR-nootropics act (in part) through subtly amplifying neuronal electrical excitability, they will tend to increase the activity of other drugs that modify neural activity taken simultaneously.
This in turn may increase both the positive action of the other drug, as well as possibly lead to the occasional nootropic over stimulation effects. Thus even caffeine may be sufficiently stimulating to bring on the "nootropic over stimulation effect," especially in those very sensitive to caffeine.
A key normal regulator of neuronal sensitivity is the essential mineral, Magnesium (Mg). Dietary surveys in the Western world routinely show most people to be at least marginally Mg deficient, with many getting half or less of the recommended dietary Mg intake (Wester 1987).
Thus, the occasional over stimulation seen with PIR-nootropics may simply evidence an undetected synaptic Mg deficiency, and Mg supplementation may provide a natural remedy to minimize such over stimulation.
PIR-nootropics have been combined in many clinical and experimental situations with other drugs, almost always with a positive, synergistic effect. Many clinical experiments have demonstrated PIR and OXR to synergise with anti-epileptic medications, especially carbamazepine (Tegretol).
A simultaneous enhancement of the anti-epileptic drug's anti-seizure activity, combined with improvement or elimination of the memory, alertness and comprehension cognitive deficits induced by the anti-epileptic drug, have been found in multiple studies (Chaudhry 1992).
PIR combined with Pentoxifylline (a caffeine analogue cerebral blood flow enhancer) increased both "psycho-intellectual performance" (i.e. measures of cerebral blood flow), significantly more than placebo or either drug alone (Parnetti 1985).
Human and animal studies have shown increased benefit from combining PIR with Choline, the raw material for neuronal production of both the neurotransmitter Acetylcholine, as well as Phosphatidylcholine, a fluidising component of cell membranes (Ferris 1982).
When PIR was combined with Hydergine ® in experiments with mice testing both brain survival time and learning/ memory deficits induced by hypoxia, it was noted that "The effect of the combination was clearly greater than the sum of the effects of the individual agents and indicates that synergism had occurred" (Berga 1986).
A 1994 report looked at the synergy between PIR and intensive speech therapy given to post-stroke aphasic patients; "In general, changes under [PIR] were 160% of the changes observed in patients receiving placebo, while getting the same intensive speech therapy" (Deberdt 1994).
Those wishing to get the maximum benefit from PIR-nootropics may wish to include in their regimen nutrients known to enhance brain structure/ function in various ways.
The B-complex vitamins (including NADH), Lipoic Acid, CoQ10 (Idebenone-ed.), Magnesium and Manganese are all essential to brain ATP energy production through the glycolytic and citric acid cycles and the electron transport side chain.
DMAE (Cyprodenate or Lucidril-ed.) is an excellent Choline precursor that passes the blood brain barrier better than Choline or Lecithin.
Acetyl-L-Carnitine (ALC) enhances the activity of the enzyme Choline Acetyl Transferase (CAT) that combines Acetyl groups with Choline to produce Acetylcholine. ALC also renews the structure and energy generating power of aging neuronal mitochondria.
Phosphatidylserine is a natural neuronal membrane component and stabilizer.
Anti-oxidants, such as vitamins C and E, as well as Pycnogenol or grape seed extract, may protect polyunsaturated fat-rich neuronal and mitochondrial membranes from the damage caused by the inevitable re-lease of large numbers of free radicals, generated through brain mitochondrial energy production.
Nootropics - Their differences
Individual differences of action between PIR, OXR, PRM and ANR are often subtle, and in many studies they show similar modes of action. One intriguing benefit I have seen reported only for PRM, is its ability to increase goal directed and purposive behavior (Branconnier 1983). After trying PRM in my regimen several years ago, I did notice an increase in my tendency to quickly take care of routine household, auto and personal maintenance chores I habitually tended to ignore avoid or postpone.
I have taken PIR for eight years, PRM and ANR for the past two years and OXR for about 9 months. During the past year, my lifelong severe writer's block has gradually disappeared, and my writing output of the past year has exceeded that of the previous decade.
Some studies on dementia comparing PIR and OXR (the two most nearly identical racetams), have suggested that OXR may be more effective in restoring the cognitive deficits of dementia (decreased memory, concentration and alertness). While PIR may be more effective at normalising the emotional problems of dementia such as agitation, tension-anxiety, hostility, insomnia and unco-operativeness.
Quantitatively, PIR is the least potent racetam, with clinical doses typically being 2400mg to 4800mg per day, occasionally even 6000mg to 10,000mg per day.
OXR is usually given 800mg to 2400mg per day.
ANR doses are typically 750mg to 1500mg per day, while PRM has shown benefit even at 150mg to 300mg per day, although 600mg to 1500mg per day is more typical.
PIR and OXR are highly water soluble (96-98%), while ANR and PRM are more fat-soluble. Their lipophilicity may allow for less frequent dosing (once or twice daily) with ANR and PRM, compared to 3 to 4 doses a day with PIR and OXR.
The Japanese, who have contributed much research on it, favor ANR. It is widely used there as an agent to rapidly promote clarity of thought.
Nootropics - Uses and conclusion
During the past 30 years, the PIR-nootropics have been used to treat an amazingly broad range of human ailments and conditions, either alone or with other drugs, with moderate to major benefit.
PIR-nootropics have been used to treat various forms of dementia and "organic brain syndrome." They have been used successfully to treat dyslexia, epilepsy and age-associated memory impairment.
PIR-nootropics have successfully treated post-concussional syndrome, vertigo, alcohol withdrawal, cerebrovascular insufficiency and hypoxia.
They have shown benefit in normalising blood flow parameters; decreased platelet aggregation, increased red blood cell (RBC) deformability, decreased adherence of damaged and sickle cell RBC's to endothelium (blood cell lining) and increased Prostacyclin (PGI2) production and activity.
Yet the most exciting potential benefits of the racetams have yet to be seriously explored in clinical studies.
The racetams are cerebral homeostatic normalizers, neuroprotectants, cerebral metabolic enhancers and brain integrative agents. They enhance brain energy, especially under deficit conditions- e.g. hypoxia, chemical toxicity or impaired cerebral microcirculation.
They preserve, protect and enhance synaptic membrane and receptor structure and plasticity. They enhance brain integration- horizontally, by increased coupling of the cerebral hemispheres; and vertically by enhancing cerebral connection with and tonic control of the limbic system, through nootropics effects on the hippocampus- a major link between cerebrum and limbic system.
This vertical integration increase may help to integrate reason (cerebrum) and emotion (limbic system- sometimes called the "horse brain"). The increased tonic cortico-subcortical control and regulation may also prevent our limbic passions and desires from "running away with us," as in crimes of passion.
In middle aged and older individuals who do not yet suffer any specific neural malady or major mental impairment, nootropics may not only slow down or postpone entropic brain aging, but they may even reverse some mild neural/ mental decline.
Thus a person at 50 might be smarter, have better memory, quicker reflexes and greater vigilance and alertness than when they were 40.
The racetams may literally be safe and effective pharmacologic tools to enhance, protect and optimize truly normal, fully human neuro-psychological structures and function, well into old age.
Nootropics - References
1. P. Berga et al (1986) "Synergistic interactions between Piracetam and [Hydergine ®] in some animal models of cerebral hypoxia and ischaemia" Arzneim Forsch/ Drug Res 36, 1314-20. 2. R.J. Branconnier et al (1983) "The therapeutic efficacy of Pramiracetam in Alzheimer's disease- preliminary observations" Psychopharmacol Bull 19, 726-30. 3. O. Buresova, J. Bures "Piracetam induced facilitation of interhemispheric transfer of visual information in rats" Psychopharmacologia (Berlinr) 46, 93-102. 4. H.R. Chaudhry et al (1992) "Clinical use of Piracetam in epileptic patients" Curr Ther Res 52, 355-60. 5. W. Deberdt (1994) "Interaction between psychological and pharmacological treatment in cognitive impairment" Life Sci 55, 2057-66. 6. S.J. Dimond (1976) "Drugs to improve learning in man" in the neuro-psychology of learning disorders, R. Knight, D. Bakker, eds., 367-79. Univ. Park Baltimore. 7. 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. 8. S.J. Dimond et al (1979) "Some effects of Piracetam.. on chronic schizophrenia" Psychopharmacol 64, 341-48. 9. S.H. Ferris et al (1982) "Combination Choline/ Piracetam treatment of senile dementia" Psychopharm Bull 18, 94-98. 10. S. Giaquinto (1986) "EEG changes induced by Oxiracetam on Diazepam-Medicated volunteers" Clin. Neuropharmacol 9, S79-S84. 11. C. Giurgea, F. Moyersoons (1970) "Differential pharmacological reactivity of three types of cortical evoked potentials" Arch Int. Pharmacodyn Ther. 188, 401-04. 12. C. Giurgea, M. Salama (1977) "Nootropic drugs" Prog. Neuro-Pharmac.1, 235-47. 13. A. Gouliaev, A. Senning (1994) "Piracetam and other structurally related nootropics" Brian Res. Rev. 19, 180-222. 14. T. Itil et al (1983) "Pramiracetam, a new nootropic, a controlled quantitative pharmaco-EEG study" Psychopharm. Bull. 19, 708-16. 15. T. Itil et al (1986) "CNS pharmacology and clinical therapeutic effects of Oxiracetam" Clin. Neuropharmacol. 9, S70-S72. 16. G. Maina et al (1989) "Oxiracetam in the treatment of primary degenerative and multi infarct dementia" Neuropsychobiol. 21, 141-45. 17. P. Mindu et al (1976) "Piracetam induced improvement of mental performance" Acta Psychiat. Scanda. 18. A. Moglia et al (1986) "Activity of Oxiracetam in patients with organic brain syndrome" Clin. Neuropharmac 9, S73-S78. 19. C. Mondadori et al (1992) "Elevated corticosteroid levels block the memory improving effects of nootropics" Psychopharmac. 108, 11-15. 20. F. Moyersoons, C. Giurgea (1974) "Protective effect of Piracetam in experimental barbiturate intoxication: EEG and behavioural studies" Arch. Int. Pharmacodyn Ther 210, 38-48. 21. S. Okuyama, H. Aihara (1988) "Action of nootropic drugs on transcallosal responses of rats" Neuropharmac. 27, 67-72. 22. L. Parnetti et al (1985) "Haemorheological pattern in initial mental deterioration; Results of a long term study using Piracetam and Pentoxi-fylline" Arch Gerontol. Geriatr 4, 141-55. 23. 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. 24. B. Saletu et al (1985) "..Oxiracetam in the organic brain syndrome of late life" Neuropsychobiol 13, 44-52. 25. K. Schaffler, W. Klausnitzer (1988) "..Antihypoxidotic effects of Piracetam using psychophsiological measures in healthy volunteers" Arzneim Forsch. Drug Res. 38, 288-91. 26. 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. 27. P. Wester (1987) "Magnesium" Am. J. Clin. Nutr. 45, 1305-12. 28. C. Wilsher et al (1987) "Piracetam and dyslexia: Effects on reading tests" J. Clin. Psychopharmac. 7, 230-37.