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From the June 4th, 1997 issue of Smart Drug News [v5n9].
Copyright (c) 1997, 2009. All rights reserved.
Smart Drug Update:
The Case for PiracetamOne of the current focal points for the emergence of smart drugs into popular consciousness and mainstream use is the application of piracetam to Down’s syndrome (DS). This application has generated lots of controversy within DS circles for several reasons: 1) piracetam is not FDA approved, 2) US physicians are generally unfamiliar with its use, and 3) major establishment DS organizations have a policy that DS is fundamentally untreatable.
US physicians and scientists associated with these DS organizations are actively discouraging piracetam’s use. Allegations of elevated seizure risks and possible long-term side effects from piractam are being made. However, the complete lack of such effects during more than two decades of worldwide clinical experience with piracetam suggest that political and ideological considerations are the sole basis of these anti-piracetam policy positions. Indeed, the increasing use of piracetam and targetted nutritional intervention (TNI) is putting these matters to the test. This article will specifically focus on the use of piracetam in DS-related conditions [see v2n10, v3n4, v4n10, v5n1 for previous articles].
Piracetam’s earliest use in Down’s syndrome (DS) was in Spain and Portugal in 1974 in a comparative study (using historic case controls) of Dromia (a 5-hydroxytryptophan-containing product) and Noostan (a brand of piracetam) in 26 children from age 3 months to 12 years of age [Fialmo, 1976]. This study was obscurely published, not indexed in any computer database, and remained largely unknown in the US.
In the early 90s, Dixie Tafoya, the mother of a child with DS, read Smart Drugs & Nutrients and realized that piracetam’s beneficial effects on various learning disabilities might address some of her daughter’s developmental problems [see SDN v3n4]. Piracetam’s almost complete lack of toxicity [Reynolds, 1996; Dukes, 1996] coupled with its ability to 1) enhance the higher (telencephalic) functions of the brain, 2) enhance interhemispheric communication through the corpus calosum, 3) enhance memory and learning in both animals and humans, and 4) prevent memory loss and learning difficulties induced by drugs, stress and trauma [reviewed by Vernon and Sorkin, 1991] made it seem an ideal prospect for DS therapy. Her daughter responded dramatically, and piracetam use has been spreading through the DS community ever since.
In 1995, Dr. Fialmo’s study of Dromia and piracetam was rediscovered in the US. It showed universal benefits in motor development, mental development, speech, affective social (emotional) development, scholastic achievement, and EEG changes indicating improved hemispheric synchronization (see Figure 1). The gains in speech were especially dramatic.
One of piracetam’s most unique and conspicuous features is its extremely low toxicity. The classical measure of drug toxicity, the LD-50 (the dose causing death for 50% of test animals), is not applicable; standard dosing methods (oral, intravenous injection, intraperitoneal injection) cannot deliver enough piracetam to kill laboratory animals. Doses of greater than 20 g/day have been given to people suffering from myoclonic seizure disorders, without serious side effects [Karacostas et al., 1993]. The recommended dose of piracetam for infants with myoclonic seizures is 10-20 g/day (approximately 1-2 rounded tablespoons), a phenomenally high dose by normal drug standards.
Piracetam is absorbed rapidly and completely following oral intake, and it is excreted predominantly unchanged in the urine. Peak plasma levels are reached in less than an hour. However, brain concentrations rise more slowly. It may take days for piracetam to reach peak levels.
Piracetam is absorbed rapidly and completely following oral intake, and it is excreted predominantly unchanged in the urine. Peak plasma levels are reached in less than an hour. However, brain concentrations rise more slowly. It may take days for piracetam to reach peak levels in the brain, and days for it to fall after discontinuation. Additional information about piracetam can be obtained by reading the Smart Drug Update on piracetam [see SDN v1n10] and the piracetam chapters in Smart Drugs & Nutrients and Smart Drugs II.
Allegations of increased seizure risk from piracetam have been made by a few US physicians associated with establishment DS organizations. This is of special concern due to a higher-than-normal incidence of seizures in DS individuals. The basis of these allegations of seizure risk is enhanced cellular calcium influx from piracetam, an in vitro (test-tube) finding whose applicability to real life must be seriously questioned in the face of decades of clinical experience to the contrary [see SDN v5n8p10]. In fact, piracetam has mild anti-seizure activity, and it protects against memory and cognitive deficits caused by seizures.
Piracetam is used as an adjunctive therapy for epilepsy. Although its effects on epilepsy are not considered sufficiently substantive when used alone, piracetam does potentiate the antiepileptic activity of other drugs. Some newer “racetam” analog drugs appear to have stronger anticonvulsant activity.
Piracetam is recognized throughout most of the world as a treatment of choice for myoclonus, a seizure-like condition characterized by uncontrolled muscle twitching or jerking. This application of piracetam has been thoroughly researched from a clinical perspective. Piracetam has orphan drug status in the US for treatment of myoclonus.
In a recent study of 60 patients, piracetam was found to be “effective in myoclonus, especially that of cortical origin” when used either singly and with other drugs [Ikeda et al., 1996]. Although this study was open-label, a blinded video inspection was employed. Piracetam was of positive benefit to handwriting, feeding, sleep, attention deficit, depression, gait ataxia (incoordination), and convulsions, but not to dysarthria (articulation difficulty). This latter finding is somewhat paradoxical, given that enhancement of speech and language skills is generally the rule rather than the exception. There was also “no positive correlation between clinical and electrophysiological [EEG] improvement,” suggesting that piracetam works through a different mechanism than standard anticonvulsant drugs.
In an earlier study, myoclonic patients with positive clinical responses to piracetam (2.4 to 16.8 g/day) were studied in a placebo-controlled, double-blind, two-week, cross-over trial. Of 21 patients with “disabling spontaneous, reflex or action myoclonus due to various causes,” 10 had to be rescued from the placebo phase of the study due to severe exacerbations of their myoclonus [Brown et al., 1993]. No patients required rescuing from the piracetam arm. Piracetam improved motor function scores, writing ability, functional disability scores, global assessment scores, and visual tests. The authors concluded, “Piracetam, usually in combination with other antimyoclonic drugs, is a useful treatment for myoclonus of cortical origin.”
The dose of piracetam may be quite large in some circumstances and still be well tolerated. In one case of accidental electrocution, spastic tetraparesis (limb paralysis) and spontaneous myoclonus (muscle twitching) in both arms were successfully controlled by 24 g/day piracetam, administered intravenously [Karacostas et al., 1993]. The myoclonic movements returned three days after the piracetam was discontinued six weeks into therapy, and were almost abolished when the piracetam was resumed.
A review of the treatment of myoclonus with piracetam covering “62 case reports, 3 open trials and 2 double-blind trials, covering 171 patients” has been published [Van Vleymen and Van Zandijcke, 1996]. A clinical review of the symptoms and diagnosis of myoclonus, progressive myoclonus epilepsy and other epilepsies, and the use of piracetam and 5-hydroxytryptophan in recent clinical trials, has also been published in Nurse Practitioner [Tate, 1995].
One of the effects common to many anti-seizure medications and
therapies is
Brain membranes may be especially sensitive to changes in membrane fluidity. They have an especially high degree of polyunsaturation, containing high levels of EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), which have 5 and 6 double bonds respectively. These highly unsaturated fatty acids increase the fluidity of brain membranes, but they also make them especially sensitive to free radicals and oxidative stress, a putative risk factor resulting from overexpression of superoxide dismutase (SOD), an antioxidant enzyme which is encoded on the 21st chromosome. The overexpression of SOD increases production of hydrogen peroxide {see SDN v4n10].
The latter fatty acid, DHA, is found in relatively high levels in human breast milk, but not in soy or cow’s milk. Infant formulas manufactured in the US do not contain DHA, but many in other parts of the world do. The lack of DHA in early infancy, and/or its peroxidation, may have deleterious effects on cognitive development. The higher-than-normal incidence of nursing difficulties in DS infants may make them more at risk from this problem.
Piracetam mitigates oxidative stress and fluidizes brain membranes. The membrane fluidizing effects of piracetam have been reported in both rodents and man. The age-related decrease in brain fluidity seen in aged rats is partially corrected by administration of piracetam. However, in young rats, piracetam caused no measurable fluidization [Mueller et al., 1997]. This suggests that piracetam has a normalizing or self-limiting effect on brain membrane fluidity. In other words, if fluidity is normal, nothing happens, if fluidity is abnormal, it is normalized. This finding may be of particular interest in DS due to the possibility of abnormal fluidity changes in early infancy and childhood. Although this has yet to be measured directly, various signs of decreased membrane fluidity are evident (seizure risks are high in infants, and they have been observed to increase over time).
Hypoxia is a condition of low oxygen levels in the tissues. Hypoxia can be caused by lack of oxygen in the air (hypobaric or high-altitude conditions), decreased oxygen-carrying capacity of the blood (anemia or carbon monoxide toxicity), by impaired circulation (ischemia, heart attacks, blood clots, etc.), or other causes.
For decades, piracetam has been studied as an anti-hypoxia agent. This may have special application to DS due to developmental delays in the closing of the heart muscle wall between the right and left sides of the heart. This results in the mixing of blood from the right side of the heart (which pumps oxygen-depleted blood to the lungs) with blood on the left (which pumps oxygenated blood to the rest of the body). This effectively diminishes oxygen delivery capacity and exposes affected individuals to some degree of chronic hypoxia.
Hypoxia has an adverse effect on cognitive functioning, which piracetam effectively prevents [see SDN v1n10]. Hypoxia is also associated with increased lipid peroxidation, which is inhibited by piracetam and antioxidants [Nagornev et al., 1996]. This effectively increases human resistance to high altitude. In aged patients with ischemic heart disease, the combination of piracetam and tocopherol acetate (vitamin E) provides better control of angina pain, increases exercise tolerance, and positively influences hemodynamic measurements [Pimenov et al., 1997]. These observations confirmed earlier work [Pimenov et al., 1992].
Hypobaric hypoxia of pregnant rats causes memory impairment and learning delays (in both passive and active tasks) in newborn pups. Postnatal piracetam (200 mg/kg/day) in the second and third weeks of life partially corrected behavioral disturbances and physical development, but not adaptive behavior, caused by this prenatal hypoxia [Trofimov et al., 1993].
The adverse role that oxidative stress can play in cognitive functioning can also be blocked by piracetam. Craniocerebral trauma in rabbits causes 1) increased free radical activity, 2) decreased antioxidant function, and 3) increased lipid peroxidation throughout the brain. These effects are prevented by piracetam or amphetamine (which are stimulants), but not by phenobarbitol (a CNS depressant) [Promyslov and Demchuk, 1995]. The lack of any direct antioxidant effect of piracetam or amphetamine in an in vitro model suggests that the antioxidant effect is entirely mediated by secondary metabolic effects of these compounds.
Although piracetam has obvious theoretical applications to the hypoxic conditions typical of heart disease, Russian doctors and scientists appear to be the only researchers pursuing this application.
In 1995, Dasaeva published the results of a study of hypertensive subjects under job-related stress (i.e., “nervous and emotional stress” in their work environment). Piracetam “appeared to improve psychic state, mental performance and the occupationally important function of memory” without any adverse effect on attention. A follow-up report on the use of piracetam with reserpine (an antihypertensive medication that is also used as an antipsychotic agent) found that piracetam reversed the adverse effects of reserpine on activity, memory and cognitive function [Dasaeva and Vermel, 1996]. The authors stated that the combination of piracetam and reserpine “is thought effective for inpatient treatment of hypertensive subjects exposed to psychoemotional stress.”
In elderly patients with stable effort angina, piracetam (2.4-5.2
g/day) improved several metabolic and hormonal indices. Low-density
lipoprotein cholesterol in serum decreased, as did triglycerides. There
were also improvements in glucose tolerance (reduced hyperglycemia
and hyperinsulinemia) [Pimenov
Piracetam’s hypoxia-protective effects may be maximized under more extreme conditions. In a rat study of experimentally induced heart attacks, piracetam (400 mg/kg) and sodium oxybutyrate (GHB) (200 mg/kg) normalized aortic blood flow acceleration during exercise and increased overall survivability [Tsorin et al., 1993]. Yet neither piracetam nor GHB had any significant effect on cardiac contractility at rest.
Piracetam may also be of benefit to other hypoxia-related conditions. In a Russian clinical study of 155 patients with destructive pulmonary tuberculosis, the effectiveness of conventional antibacterial therapy (isoniazid, rifampicin, streptomycin) was enhanced by the addition of chemotherapeutic drugs (pirazinamid or ethambutol) and vitamin therapy. There was additional enhancement of efficacy from the addition of antioxidant therapy (tocopherol acetate or galascorbin) with anti-hypoxants (piracetam, calcium pangamate and piriditol) [Savula et al., 1993].
The regulation of biological responses to oxygen free radicals, whether due to low or high oxygen levels, is mediated by tissue hormones called prostaglandins. These powerful hormones are created by the interaction of oxygen free radicals and polyunsaturated fatty acids (PUFAs). In a series of complicated metabolic transformations, the oxidized PUFAs are converted stepwise into various prostaglandins which mediate such injury-related biological responses as platelet aggregation (to maximize clotting in bleeding areas and minimize it in others), vasoconstriction (to minimize blood loss), immune cell activation (to absorb necrotized tissue and prevent infection), vasorelaxation (to maximize blood flow during repair) and blood pressure. The proper coordination of these events is necessary for proper response to traumatic injury and for effective healing.
The prostaglandin cascade often results in collateral damage to otherwise healthy tissues immediately adjacent to damaged tissue. Piracetam has been shown to moderate this damage. In a study of animal burn wounds, piracetam (200 mg/kg IM) or hyperbaric oxygen were both found to protect the basal epidermal cells (the “living” skin layer) from necrosis (death) [Germonpre et al., 1996].
The high incidence of heart defects in DS infants has raised questions about how concurrent piracetam use may affect surgical risks. The standard response of US cardiovascular surgeons (and hospitals) is to insist that piracetam be discontinued prior to surgery. There are obvious legal and liability justifications for this policy, but are there medical reasons for this recommendation? In other words, would piracetam increase or decrease survivability in open heart surgery?
The anti-hypoxic, neuroprotective and anti-inflammatory effects of piracetam would seem to offer significant potential benefits to persons facing surgical trauma, especially when it is heart surgery which might entail periods of interruption of blood flow to the brain. Several research teams across the world have been investigating aspects of this issue.
In a randomized study of patients with severe or recurrent venous thrombosis, pir- acetam has shown a beneficial potentiating antithrombotic effect when administered with anticoagulants (heparin or vitamin K antagonist) [Moriau et al., 1995]. This effect is partially attributed to an anti-platelet effect characterized by 1) inhibition of thromboxane (a prostaglandin), and 2) reduction in fibrinogen and plasma factor VIII (von Willebrand’s factor) [Moriau et al. 1993]. It was also attributed to various rheological (blood flow) effects due to increased deformability of cell membranes (red cell, white cell and platelet). Increased deformability allows red blood cells to better squeeze through through microcapilaries throughout the tissues of the body.
In healthy adults, these rheological effects are observed at single
doses of 9.6 g and 4.8 g, but not at 3.2 g and 1.6 g. Since the
standard dose of piracetam is 0.8 to 1.6 g three times daily, standard
use may be below a rheological threshold.
Piracetam (400 mg/kg) has also been reported to have beneficial effects on the maturation of blood cells in rats [Nyagolov et al., 1993]. Increased iron incorporation into newly formed red blood cells, increased reticulocytes (a red cell precursor), and increased maturation of erythroblasts (a red cell progenitor cell line located in bone marrow) were all indications of piracetam-induced erythropoiesis (the generation of new red blood cells). A similar pro-maturation effect was seen in white blood cells (small lymphocytes and granulocytes).
Piracetam’s ability to enhance learning abilities may be directly related to its effect on membrane fluidity. In rat studies, 300 mg/kg of piracetam administered once daily enhanced brain fluidity and active avoidance learning only in old animals [Mueller et al., 1997]. There was no measurable effect on either parameter in young animals.
Piracetam is quite effective in reducing memory loss and learning deficits in rats caused by kindling (induction of epileptic-like seizures by toxic chemicals). Kindled rats show decreased active avoidance learning. Of vinpocetine (0.1 and 1.0 mg/ kg), methylclucamine orotate (225 and 450 mg/kg), meclofenoxate [centrophenoxine] (100 mg/kg) and piracetam (100 mg/kg), only piracetam was effective in preventing kindling-induced learning deficits regardless of the timing of administration (i.e., either before or after kindling) [Becker and Grecksch, 1995]. None of these drugs had any significant effect on the severity of induced seizures. Piracetam also prevents amnesia in kindled rats [Genkova-Papazova and Lazarova-Bakarova, 1996].
Learning deficits in rats caused by prenatal alcohol exposure are partially corrected by post-natal piracetam administration [Trofimov et al., 1996].
The possibility of synergy between biologically based therapies (i.e., nutrition and/or drugs) and cognitive therapies (e.g., training, physiotherapy, speech therapy, memory exercises, etc.) deserves close consideration. The standard early intervention therapy for DS children is a form of educational training which can augment environmental influences on development and enhance cognitive potential. Synergy between Ginkgo biloba and memory training [see SDN v1n10p7] has now been confirmed with ginkgo (160 mg/day) and piracetam (2.4 or 4.8 g/day) [Deberdt, 1994]. These studies suggest that nootropic drugs and memory training enhance different cognitive functions and act complementarily. Deberdt writes, “This potentiation is very clear in the treatment of dyslexic children.” While the dyslexic placebo group achieved only half the normal progress in reading accuracy and comprehension during a normal school year, the piracetam group (3.3 g/day) achieved a full year of progress.
Piracetam has a specific language-enhancing effect. This effect
has been observed in studies of adults and children with learning
disabilities, and it has recently been confirmed in a double-blind,
placebo-controlled study of aphasic infants and young children (of
up to three years of age) [Huber
In a 12-week, randomized, double-blind, placebo-controlled pilot study of 158 adult stroke patients undergoing rehabilitation, recovery was significantly enhanced by piracetam. Recovery in a subset of aphasic individuals was also significantly enhanced (P=0.02) [Enderby et al., 1994].
Piracetam offers the potential of addressing a host of DS-related conditions without imposing any significant toxicity. It has been demonstrated to augment cognitive, learning and memory abilities, to decrease oxidative and hypoxic stress, and to stabilize cells in the blood and central nervous system. The degree to which these benefits may accrue to DS individuals needs to be thoroughly investigated.
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see also sidebar on sickle cell disease and Angelman syndrome.
