Category: dementia

Cerebrolysin in dementia treatment

Cerebrolysin: a review of its use in dementia


Adis, a Wolters Kluwer Business, Auckland, New Zealand.


Cerebrolysin is a parenterally administered, porcine brain-derived peptide preparation that has pharmacodynamic properties similar to those of endogenous neurotrophic factors. In several randomized, double-blind trials of up to 28 weeks’ duration in patients with Alzheimer’s disease, Cerebrolysin was superior to placebo in improving global outcome measures and cognitive ability. A large, randomized comparison of Cerebrolysin, donepezil or combination therapy showed beneficial effects on global measures and cognition for all three treatment groups compared with baseline. Although not as extensively studied in patients with vascular dementia, Cerebrolysin has also shown beneficial effects on global measures and cognition in this patient population. Cerebrolysin was generally well tolerated in clinical trials, with dizziness (or vertigo) being the most frequently reported adverse event. Although further studies with Cerebrolysin, including longer term trials and further exploration of its use in combination with cholinesterase inhibitors, are needed to more clearly determine its place in the management of Alzheimer’s disease and vascular dementia, available data suggest that Cerebrolysin is a useful addition to the treatment options available for dementia.

[PubMed – indexed for MEDLINE]

BUY ALFA LIPOIC ACID 24ml 600mg amps here



To evaluate the efficacy and safety of high-dose α-lipoic acid in the treatment of diabetic polyneuropathy with regards to sensory symptoms and nerve conduction velocity.


A total of 236 diabetics with symptomatic polyneuropathy were enrolled into this 5-center, randomized, double-blind and placebo-controlled study of α-lipoic acid 1800 mg daily (n = 117) or matching placebo (n = 119) for 12 weeks. The primary outcome was total symptom score (TSS). Secondary end points included nerve conduction velocity, individual symptom score, HbA1c and safety parameters. The above parameters were reviewed and recorded at zero point and after treatment for 2, 4, 8, 12 weeks separately.


73.27% patients with symptomatic polyneuropathy improved after treatment with α-lipoic acid for 12 weeks versus 18.27% with placebo. TSS declined by 2.6 ± 2.3 with α-lipoic acid. And it was more than 0.7 ± 1.4 versus placebo (P < 0.05). TSS decreased quickly after treatment with α-lipoic acid for 2 weeks (P < 0.05). And it was better than placebo. Individual symptom scores of pain, extremity numbness, burning sensation or resting abnormal sensations were significantly diminished as compared to those before treatment and placebo group (all P < 0.05). Nerve conduction velocity had no change. HbA1c further decreased at the end of trial after α-lipoic acid treatment (P < 0.05). The incidence rates of adverse effects were 25.4% vs 11.8% in the treatment and control groups. The major manifestation was burning sensation from throat to stomach (12.7%).


Oral treatment with high-dose α-lipoic acid for 12 weeks may improve symptoms in patients with diabetic polyneuropathy. Dose of 600 mg thrice daily for 2 weeks has marked effects with a reasonable safety.

[PubMed – indexed for MEDLINE]
Age is an important predictor of neuromuscular recovery after peripheral nerve injury. Insulin-like growth factor 1 (IGF-1) is a potent neurotrophic factor that is known to decline with increasing age. The purpose of this study was to determine if locally delivered IGF-1 would improve nerve regeneration and neuromuscular recovery in aged animals. Young and aged rats underwent nerve transection and repair with either saline or IGF-1 continuously delivered to the site of the nerve repair. After 3 months, nerve regeneration and neuromuscular junction morphology were assessed. In both young and aged animals, IGF-1 significantly improved axon number, diameter, and density. IGF-1 also significantly increased myelination and Schwann cell activity and preserved the morphology of the postsynaptic neuromuscular junction (NMJ). These results show that aged regenerating nerve is sensitive to IGF-1 treatment.
Keywords: aging, IGF-1, nerve injury, nerve regeneration, neuromuscular junction
Age is thought to be the most important predictor of neuromuscular recovery after peripheral nerve injury.1 Of the 18 million extremity injuries recorded annually in the USA, >50% occur in patients 45 years of age or older.2 Children often regain near-normal function after nerve injury,3,4 but adults or aged patients have slow or absent neuromuscular recovery. Over half of patients >50 years of age do not achieve any functional recovery following nerve repair,1 resulting in impaired activities of daily living. Aging is known to affect the structure and function of the peripheral nerve,5,6 but the exact etiology of age-related impairment in regeneration is unknown, although delayed axonal regeneration7,8 and instability of the neuromuscular junction (NMJ) have been implicated.9
Insulin-like growth factor 1 (IGF-1) is a single-chain, 70-amino-acid polypeptide, with a molecular mass of 7.6 kDa, similar in structure to pro-insulin, and is highly conserved across species.10 IGF-1 plays a significant role in neuronal development, 11,12 recovery from neuronal injury,13,14 neuronal survival,15 and neurite outgrowth following crush injury.16 In vitro studies have suggested that IGF-1 is produced locally by non-neuronal cells following injury and stimulates regeneration.17 Hansson et al. first showed that IGF-1 is secreted from Schwann cells in an autocrine fashion after peripheral nerve injury.13 IGF-1 has been shown to affect multiple facets of Schwann cell function in vitro, which likely contributes to improved nerve regeneration, 18 including proliferation,19 mobilization, myelination,20 and Schwann cell–axon interaction. IGF-1 knockout mice have defects in neurologic development21 in addition to impaired recovery from neuronal injuries.22 Thus, there is substantial evidence that IGF-1 plays a key role in neuromuscular recovery following injury.
Age and developmental stage are the major determinants of IGF-1 levels. IGF-1 levels peak during puberty, initiating and maintaining the pubertal growth spurt.23 Following the pubertal growth spurt, IGF-1 levels decline24 at a rate of approximately 14% per decade.25,26 With continued aging, IGF-1 concentrations fall to levels of 20–80% of values for young adults,27 concordant with the decline in functional recovery following nerve transection and repair in aged adults.1
Given the wide-ranging effects of IGF-1 on nerve regeneration and the known decline in IGF-1 with age, we sought to determine whether IGF-1 replacement would improve nerve regeneration in aged animals. Previously, we found that increasing systemic IGF-1 via pulsatile growth hormone injection did not improve nerve regeneration (unpublished data). Thus, the purpose of this study was to examine the effects of IGF-1 locally delivered to a nerve transection site in aged rats, and to evaluate neuromuscular recovery, axonal regeneration, myelination, Schwann cell activity, and the resulting changes at the NMJ. The hypothesis was that age-related decline in neuromuscular recovery following transection would be ameliorated by IGF-1 administered to the regenerating nerve.
Animal Model
Thirty-two Fischer 344 × Brown Norway rats were obtained from the National Institute of Aging colony at the Harlan Sprague-Dawley facility (Indianapolis, Indiana). The animals were divided into two groups: young adult (8 months) and aged (24 months). Each age group was subdivided into saline and IGF-1 treatment groups. There were 6 young adult saline, 6 young adult IGF, 10 aged saline, and 10 aged IGF-1 animals. Animals underwent nerve transection and repair, as detailed in what follows, and were then killed after 12 weeks.
Surgical Procedure
Each animal was anesthetized with isoflurane, and an incision was made over the posterior aspect of the left thigh. Under the operating microscope, the sciatic nerve was exposed, and the tibial nerve was isolated and transected 1 cm from its insertion into the gastrocnemius. The nerve stumps were placed at opposing ends of a custom-made T-tube and the middle arm was attached to a minipump (Fig. 1). The minipump was buried subcutaneously under the skin of the back. The nerve conduit portion of the T-tube was made from 1016-µm internal diameter, semiporous tubing (Micro-Renathane; Braintree Scientific, Braintree, Massachusetts), and the T-arm was constructed of Silastic tubing (Dow Corning, Midland, Michigan). An Alzet 2004 mini-osmotic pump (Durect Corp., Cupertino, California) delivered either normal saline or IGF-1 at a rate of 0.25 µl/h. Half of the animals received recombinant human IGF-1 (Bachem AG, Torrance, California) at a 0.10-µg/µl (100 µg/ml) concentration. Thus, final IGF-1 delivery was 0.025 µg/h, modeled after previous studies of IGF-1 infusion.28 The other animals received normal saline only. The subcutaneous pumps were replaced under anesthesia after 6 weeks. At 12 weeks after nerve transection and repair, tissue was harvested, and the animals were overdosed with isoflurane and perfused with fixative.

Diagram of experimental setup. The tibial nerve was transected 1 cm from the insertion into the gastrocnemius and allowed to relax to create a 7-mm gap. A custom-made T-tube device was interposed between the nerve ends and secured with a 9-0 nylon suture. (more …)
Animals were group-housed and allowed food and water ad libitum. All experiments were conducted under a protocol approved by the institutional animal care and use committee. The animals were housed in an appropriate facility in accordance with standards established by the Association for Assessment and Accreditation of Laboratory Animal Care.
Muscle and Tissue Harvest
At study termination, the animals were anesthetized with isoflurane, and the gastrocnemius was harvested. The muscle was cleaned, rinsed, flash frozen in liquid nitrogen, and stored at −80°C. Following removal of the gastrocnemius, the animals were transcardially perfused with warm saline followed by ice-cold 4% paraformaldehyde. The regenerated nerve was then removed and immersion-fixed in 2.5% glutaraldehyde.
Nerve Histomorphometry
The midpoint of the regenerated nerve was secondarily fixed in 1% osmium tetroxide, embedded in resin, sectioned to 1 µm, and stained with toluidine blue. All images were acquired microscopically (AxioImager M1; Carl Zeiss, Jena, Germany) using AxioVision version 4.5 software. Images were imported into ImageJ (National Institutes of Health, Bethesda, Maryland) for analysis. For the peripheral nerve, the following measurements were taken: nerve diameter; nerve cross-sectional area; axon number; axon density (axons per mm2); average axon diameter; and the average g-ratio (ratio of axon diameter to fiber diameter). Nerve diameter and nerve area were measured on 100× or 200× images. For axon number and axon density, two or three non-overlapping 400× fields were obtained from each of the four quadrants of the nerve. For average axon diameter and the average g-ratio, three or four non-overlapping 1000× fields were obtained from each of the four quadrants of the nerve. In each 400× high-power field, the myelinated axons were counted, and the area sampled was calculated, yielding axon density. For axon diameter and g-ratio, a minimum of 100 nerve fibers were analyzed. In order to focus analysis on motor neurons, axons <1 µm were not measured. For axon diameter, the measurement was from made from the inner table of the myelin sheath and did not include the myelin layer. The g-ratio was calculated by measuring axon diameter and total fiber diameter.
mRNA Expression of GAP43
The lateral gastrocnemius was pulverized, and total RNA was extracted with Trizol (Sigma-Aldrich, St. Louis, Missouri). Quantity and purity of the RNA was assessed using a spectrophotometer (ND-1000; NanoDrop Technologies, Wilmington, Delaware), and quality of RNA was assessed by microcapillary gel electrophoresis (Model 2100 Bioanalyzer; Agilent Technologies, Santa Clara, California) prior to downstream applications. The mRNA was transcribed to cDNA using oligo-dT primers (Invitrogen, Carlsbad, California) and Superscript II (Invitrogen, Carlsbad, California). Primers were obtained from Applied Biosystems for GAP43 (NM_017195.3). Relative quantitative reverse transcript–polymerase chain reaction (qRT-PCR) was then performed (Model 7900HT; Applied Biosystems) with a 384-well block. Muscle creatine kinase (MCK) was used as an endogenous control, as it has been shown to be stably expressed in skeletal muscle with age.29
Histology of Postsynaptic NMJs
The medial gastrocnemius was pinned to resting length and immersed in isopentane cooled with dry ice. The muscle was sectioned on a cryotome longitudinally in 25-µm sections. The sections were permeabilized with 0.1% Triton X-100 for 20 minutes, and then treated with AlexaFluor 488–conjugated α-bungarotoxin (1:200; Invitrogen, Carlsbad, California) for 1 hour. Sections were rinsed and fixed in 1% paraformaldehyde for 1 hour. Confocal images were obtained on a laser scanning confocal microscope (Zeiss 510) with argon and helium–neon lasers. Slice thickness was set at ≤1.2 µm. Slices were then merged to create the final image. The NMJs were then qualitatively evaluated.
Statistical Analysis
All data were imported into SigmaStat version 3.11 (Systat Software, Inc., San Jose, California) for analysis. For each outcome measure, a two-way analysis of variance (ANOVA) model was established with age and treatment as the independent variables. Post hoc pairwise comparisons were made with the Student–Newman–Keuls test. Transformations to ranked sums were made when the data were nonparametric. Type 1 error was set at 0.05.
IGF-1 Increases Axon Number, Diameter, and Density in Regenerated Nerve of both Young and Aged Animals
Examination of the peripheral nerve revealed that, in aged saline-treated nerves, there were fewer total axons, fewer axons per mm2, and less myelination than in young saline-treated nerves. IGF-1 had a marked effect on both young and aged animals, increasing axon number, diameter, and density, in addition to increasing myelination (Fig. 2). Quantitative data are presented in Figure 3. For the number of axons per nerve, IGF-1 increased total axon number in both young and aged animals; however, this was only statistically significant for aged animals. For axon density, IGF-1 increased axon density in both young and aged animals; however, this was only statistically significant for aged animals. For average axonal diameter, there was a significant increase in average axonal diameter in both young and aged animals when they were treated with IGF-1. There was no difference between the young IGF-1 group and aged IGF-1 group for number of axons per nerve, axon density, and average axonal diameter.

Cross-section of regenerated nerve segment. After 3 months, the regenerated nerve segment was removed, sectioned to 1 µm, stained with toluidine blue, and viewed at 1000×. (A) Young saline, (B) aged saline, (C) young IGF-1, and (D) aged (more …)

Effect of age and IGF-1 on axon number, density, and diameter. Quantification of histologic images reveals a significant effect of IGF-1 on (A) axons per nerve, (B) axon density (axons per mm2), and (C) average axonal diameter. Although there were differences (more …)
IGF-1 Increases Myelination and Schwann Cell Activity in Regenerated Nerve of both Young and Aged Animals
Three parameters of Schwann cell activity and myelination were examined: (1) myelin thickness; (2) axon/fiber ratio (g-ratio); and (3) GAP43 mRNA expression, a marker of Schwann cell activity. 30,31 We found that IGF-1 significantly affected all measured aspects of Schwann cell activity and myelination (Fig. 4). For myelin thickness and g-ratio, this effect was not age-dependent. However, for GAP43 expression, aged animals had a greater response to IGF-1 than young animals (Fig. 4C).

Effect of age and IGF-1 on measures of myelination. Quantification of histologic images revealed a significant effect of IGF-1 on multiple facets of myelination and Schwann cell function. (A) Myelin thickness was significantly increased in IGF-1–treated (more …)
IGF-1 Preserves Morphology of Postsynaptic NMJs in Aged Animals
The postsynaptic NMJs were stained with fluorescent-labeled α-bungarotoxin and qualitatively examined using laser scanning confocal microscopy (Fig. 5). In saline-treated young animals, the postsynaptic NMJs were highly contiguous, complex, and had deep gutters, similar to uninjured control NMJs (images not shown). In young IGF-1 animals, the NMJs were very similar to those in the young saline group. In the aged saline group, numerous NMJs displayed a loss of complexity, with markedly more shallow gutters, and a loss of perimeter and endplate area. This is consistent with the morphology of denervated NMJs.32,33 In contrast, in the aged IGF-1 animals, the complexity, gutter depth, and overall morphology more closely resembled that of young animals.

Response of the neuromuscular junction to saline or IGF-1 treatment. (A) Young saline, (B) aged saline, (C) young IGF-1, and (D) aged IGF-1. The postsynaptic NMJ was stained with fluorescent-labeled α-bungarotoxin and imaged under a confocal microscope. (more …)
In this study we sought to determine whether IGF-1 would improve neuromuscular recovery after nerve injury during aging. We found that IGF-1 improved nerve regeneration by acting on the axons and Schwann cells, and secondarily on the NMJs. These results suggest that there is no loss of sensitivity to IGF-1 with age and that IGF-1 can improve regeneration after nerve injury during aging.
Previous studies have examined the effect of systemically administered IGF-1 during neuromuscular recovery in neonatal rats. Vergani et al. found that systemic IGF-1 promoted neuronal survival following crush injury and improved muscle reinnervation.34 Kanje et al. found that locally delivered IGF-1 following crush injury in juveniles led to improved sensory function.35 Tiancgo et al. found that IGF-1 locally delivered to an end-to-side repair improved muscle function in young rats.36 To the authors’ knowledge, the current study is the first to examine the effect of IGF-1 during nerve regeneration in aged animals.
Axonal outgrowth is central to nerve regeneration, and IGF-1 is a well-documented promoter of motor neuron survival,37 axonal growth,38 and axonal branching.18 In the regenerating nerve, IGF-1 is a key promoter of initial sprouting and subsequent elongation of axons39 (for review, see Rabinovsky2). Although there has been extensive investigation of the effect of IGF-1 on neuron outgrowth and survival, nearly all of the studies were performed in vitro or in embryonic animals. Thus, it is not known how increased age affects the neuronal response to IGF-1. In this study we found that, for metrics of neuronal trophism, aged animals had a robust response to IGF-1 treatment, increasing axonal number, diameter, and density in the regenerated nerve segment. Thus, the neuronal response to IGF-1 of the regenerating axon does not appear to be limited due to age.
The Schwann cell is a key factor in promotion of nerve regeneration. The effect of IGF-1 on Schwann cells has also been studied. IGF-1 is known to promote Schwann cell survival,40 motility,41 proliferation, 42 and myelination.43 However, the physiology of Schwann cells from aged animals is largely unknown. This study has addressed some of the parameters of Schwann cell function in vivo, particularly myelination and GAP43 expression. GAP43 is upregulated in nearly all myelinating Schwann cells of the distal stump following axotomy.31 Expression of GAP43 is postulated to play a role in the interaction between the regenerating axon and Schwann cell.30 In this study, we found that GAP43 expression was significantly upregulated in both young and aged animals with IGF-1 treatment. In addition, GAP43 expression was higher in aged animals treated with IGF-1 than in similarly treated young animals, suggesting that age increases sensitivity to IGF-1 for this aspect of Schwann cell function. However, due to pooling of the whole muscle mRNA, in this study we could differentiate between an increase in Schwann cell number and an increase in activity. Furthermore, because the sample was from muscle, the increase in GAP43 expression was due to intramuscular neurons, terminal Schwann cells, or both. GAP43 expression in the regenerated segment itself was not assayed. In addition to GAP43 activity, IGF-1 increased myelination in the regenerated nerve, independent of the increase in axon diameter. Thus, at the Schwann cell level, age does not impair the response to IGF-1 and results in an increased regenerative response.
Failure to achieve reinnervation of the muscle is thought to contribute to impaired neuromuscular recovery after nerve injury.44 In this study we found by histologic examination that the motor endplate regained an innervated, pre-injury morphology in all but the aged saline group. This failure to reinnervate may have been due to delayed nerve regeneration or instability of the postsynaptic NMJ, both of which have been shown to occur with aging.9 In this study, treatment with IGF-1 may have accelerated axonal regeneration, leading to earlier reinnervation of the muscle, and thus preservational of the postsynaptic NMJ.
One limitation of our study is the lack of functional and electrical assessments. Functional recovery is the gold standard for clinical outcomes in human subjects, but, historically, functional recovery in rodent models has been difficult to assess.45 In rats, there is a poor correlation between functional, electrophysiologic, and histologic outcomes. 46 In this study, electrical measures of function were performed and showed a trend toward improvement with IGF-1 treatment, but this was not statistically significant (data not shown). Nonetheless, we were able to demonstrate that IGF-1 improved nerve regeneration in aged animals.
An important strength of our study is the in vivo comparison between young adult and aged rats after a complete nerve transection. Previous studies of IGF-1 on nerve regeneration utilized in vitro, neonatal, or juvenile animal models. In addition, many previous studies utilized crush injury models. Crush injuries in rodents typically have a near 100% rate of recovery and do not accurately model clinical scenarios wherein neuromuscular recovery is often very poor. Although previous studies have helped to answer many questions about the effects of IGF-1, this study is the first to examine in vivo the effects of age and IGF-1 on neuromuscular recovery following nerve transection.
Overall, our study has provided substantial evidence that locally delivered IGF-1 improves neuromuscular recovery after nerve injury in aged animals. We showed that, when local IGF-1 levels were equally supplemented in young and aged animals, nerve regeneration and NMJ preservation were similar, suggesting that IGF-1 may be a contributing factor in age-related impairment of neuromuscular recovery. However, our study has not conclusively demonstrated that IGF-1 deficiency is the immediate cause of age-related impairments in neuromuscular recovery after injury.


The therapeutic effect of Cerebrolysin in the treatment of dementia and brain injury has been proposed because of neurotrophic properties of this compound. Since an increased kynurenine metabolism has been documented in several brain pathologies including dementia the aim of the present study was to investigate the biochemical properties of Cerebrolysin with respect to kynurenic acid (KYNA) formation in an in vitro study. KYNA is an endogenous metabolite of the kynurenine pathway of tryptophan degradation and is an antagonist of the glutamate ionotropic excitatory amino acid and of the nicotine cholinergic receptors. The activities of the KYNA synthesizing enzymes kynurenine aminotransferases I, II and III (KAT I, KAT II and KAT III) in rat liver, and rat and human brain homogenates were analysed in the presence of Cerebrolysin. KAT I, II and III activities were measured using a radio-enzymatic method in the presence of 1 mM pyruvate and 100 µM [H3]l-kynurenine. Cerebrolysin, dose-dependently and significantly reduced KAT I, KAT II and KAT III activities of rat liver homogenate. Furthermore, Cerebrolysin exerted a dose-dependent inhibition of rat and human brain KAT I, KAT II and KAT III activities, too. The inhibitory effect of Cerebrolysin was more pronounced for KAT I than for KAT II and KAT III. The present study for the first time demonstrates the ability of Cerebrolysin to lower KYNA formation in rat liver as well as in rat and human brain homogenates. We propose Cerebrolysin as a compound susceptible of therapeutic exploitation in some disorders associated with elevated KYNA metabolism in the brain and/or other tissues. We suggest that the anti-dementia effect of Cerebrolysin observed in Alzheimer patients could be in part due to Cerebrolysin induced reduction of KYNA levels, thus modulating the cholinergic and glutamatergic neurotransmissions.

Abbreviations: KYNA, kynurenic acid, KAT, kynurenine aminotransferase, NMDA, N-methyl-d-aspartate, EAA, excitatory amino acid, CNS, central nervous system

Keywords: Kynurenic acid, Kynurenine aminotransferases, NMDA receptor, Cholinergic receptor, Dementia, Cerebrolysin


Cerebrolysin Review
Wise Young, Ph.D., M.D.
W. M. Keck Center for Collaborative Neuroscience
Rutgers University, Piscataway, New Jersey 08540-8087
Originally posted 1 April 2006, minor revisions (10 Feb 2009)

Cerebrolysin is a peptide mixture isolated from pig brain. A neurotrophic peptidergic mixture produced by standardized enzymatic breakdown of lipid-free porcine brain proteins, cerebrolysin is composed of 25% low molecular weight peptides (<10K DA) and 75% free amino acids, based on free nitrogen content [1]. The mixture has relatively high concentrations of magnesium, potassium, phosphorus, and selenium [2], as well as other elements [3, 4]. While the drug has antioxidant properties, it is much less than trolox or vitamin E [5]. The active ingredient(s) in the mixture are not known. Two concentrates of the peptide fraction of cerebrolysin are being tested, one called EO21 and the other N-PEP-12 [6].

Multiple clinical trials have reported that cerebrolysin is beneficial in Alzheimer’s disease, stroke, and other neurological conditions. The drug has been studied since the early 1970’s. Double-blind placebo controlled trials have reported sustained improvements and slowing down of progressive memory loss, cognition impairment, mood changes, and motor and sensory symptoms of stroke and neurodegenerative diseases ( The drug has been approved for treatment of Alzheimer’s disease in the United States. Ebewe Pharmaceutical ( makes the drug. Over 176 articles have been published since 1973 on the subject of cerebrolysin treatment of various neurological disorders. I will review this literature below.

Chronic Stroke. In 1990, Ischenko & Ostrovskaia [26] compared the effects of cerebrolysin and various other agents on blood viscosity in 128 patients with circulatory encephalopathy. They found that cerebrolysin marked increased blood viscosity and suggesting that the drug be cautiously used in patients with ischemic blood circulation disorders. In Austria, Kofler, et al. [27] studied contingent negative variation (CNV) in 41 geriatric patients with moderate “organic brain syndrome” and showed that 10 infusions of cerebrolysin plus multi-vitamin infusions increased CNV amplitudes, compared to the placebo group that received multivitamin alone. Kofler, et al. also did psychometric measures in 27 patients with organic brain syndrome and treated with a course of ten cerebrolysin treatments, compared to 14 clinically comparable patients, showing significant improvements in the cerebrolysin treated group. In 1991, Vereschchagin, et al. [28] treated 30 patients with multi-infarct dementia and compared them with 30 patients that received placebo. Cerebrolysin improved memory, abstract thinking, and reaction time of the patients, confirmed with EEG-mapping. Pruszewicz, et al. [29] gave cerebrolysin to severe central hearing loss and observed improvement in 36%. In 1996, Iakno, et al. [30] treated 20 patients with vascular dementia and showed EEG effects and the most improvement in patients with the least cognitive deficit. In 2004, Gafurov and Alikulova [31] treated 2 groups of patients with ischemic brain hemispheric stroke and reported that cerebrolysin improved both groups.

Pediatric Treatments. Several Russian groups have been using cerebrolysin to treat neurological disorders in children. In 1998, Gromova, et al. [2] gave cerebrolysin to 36 3-8 year old children with minimal cerebral dysfunction. Gruzman, et al. [32] used intravenous cerebrolysin injections to treat resistant forms of night enuresis in children. In 2000, Sotnikova, et al. [33] found that cerebrolysin (1 ml per 10 kg) increased CD19+ cells and CD4+ lymphocytes with normalization of serum IgG and IgA levels and CD16+ cells (NK) at one month after treatment, in children (age 3-8 years) with minimal cerebral dysfunction; in addition, cerebrolysin activated T helper cells in vitro. Sukhareva, et al. [34] treated 120 children (age 4-15 years) with “neurosensory hypoacusis” with “pharmacopuncture” injecting cerebrolysin and several other drugs. They reported that the treatment improved speech intelligibility, headache, and other problems in 85% of cases. Sotnikova [35] gave cerebrolysin (1 ml/10kg) intramuscularly for one month to children with attention deficit syndrome, reporting that this resulted in “a simultaneous normalization of neurological and immune disorders and a reduction in the illness rate.” In 2003, Krasnoperova, et al. [36] gave cerebrolysin (0.1 ml daily for 5 days) to 19 children with childhood autism and 8 with Asperger’s syndrome (aged 2-8 ) and found positive effects in all the patients with Asperger’s syndrome and 89% of the patients with autism. Guseva and Dubovsakia [37] treated 646 children (age 8 weeks to 18 years) with optic nerve disease by giving retrobulbar cerebrolysin once daily, in combination with microcirculatory drugs, in the irrigation system, or just microcirculatory drugs alone through the irrigation system, reporting that cerebrolysin treatment improved vision.

Extrapyramidal hyperkinesis. This is a motor syndrome that results from neuroleptic (dopaminergic) drugs used to treat various neurological disorders including Parkinson’s disease, schizophrenia, and depression. In 1997, Kontsevoi, et al. [38] did an open-label study of cerebrolysin treatment of 30 Parkinson patients who had prolonged extrapyramidal complications from neuroleptic therapy, finding that cerebrolysin markedly reduced severity of extrapyramidal symptoms in 46.6% of the patients and partial response in 26.6%. In 1999, Panteleeva, et al. [39] gave cerebrolysin and magme B6 (a drug) to 51 patients with diagnoses of schizophrenia or depression, suffering from extrapyramidal and somato-vegetative effects of neuroleptic and anti-depressive drugs. Both drugs reduced the hyperkinetic and cardiovascular side effects of neuroleptic drugs. In 2004, Lukhanina, et al. [40] examined the effects of cerebrolysin on EEG activity of 19 patients with Parkinson’s disease and 18 healthy controls, They found twofold improvements in CNV mean amplitudes, strengthening of postexcitatory inhibition in the auditory system after paired stimulation, and other measures. An open-label prospective study in Russia assessed 25 patients with childhood autism (ages 3-8 ) who received 2 therapeutic courses of cerebrolysin. The patients all demonstrated a significant improvement in mental function, cognitive activity, attention during task performance, perception, and fine motor function [41].

Alzheimer’s Disease. In 1994, Ruther, et al. [42] did a double-blind placebo control study of cerebrolysin treatment of 120 patients with moderate Alzheimer’s dementia and found modest beneficial effects. In 1997, Rainer, et al. [43] treated 645 demented patients with 30 ml of cerebrolysin daily for an average of 17.8 days, reporting that the treatment improved clinical global impression in 80% of the patients and significantly more in younger and less afflicted patients. In 1998, several reviewers [44, 45] pointed out cerebrolysin as a potential therapy for Alzheimer’s disease. Windisch, et al. [46] called for clinical trials to ascertain whether cerebrolysin induces repair in chronic brain injury and whether the effects are long lasting. In 1999, Roshchina, et al. [47] found that cerebrolysin (30 ml) enhanced the beneficial effects of amridin (80 mg daily for 10 weeks) in 20 patients with Alzheimer’s, compared to 23 patients treated only with amiridin. In 2000, Bae, et al. [48] did a double-blind placebo-controlled multicenter study of cerebrolysin in 53 men and women with Alzheimer’s disease. They found that the cerebrolysin significantly improved cognitive deficits and global function in patients with mild to moderate dementia. Based on these results, Molloy and Standish [49] suggested that cerebrolysin be given to patients with Alzheimer’s disease. Ruther, et al. [50] evaluated 101 patients 6 months after completion of a 4-week course of 30 ml cerebrolysin or placebo, showing a clear sustained beneficial effect of cerebrolysin over placebo. Windisch [51] reviewed the literature and concluded that three placebo-controlled double-blind randomized studies had shown significant improvements of cognitive performance, global function, and activities of daily patients with Alzheimer’s disease, indicating a “powerful disease modifying activity” of cerebrolysin. In 2001, Ruether, et al. [52] did a 28-week, double-blind, placebo-controlled study of 4- week cerebrolysin treatment in 149 patients with Alzheimer’s disease, showing a 64.5% responder rate on the clinical global impression compared to 41.4% in the placebo group, as well as a 3.2 point difference in the ADAS-cog scale. The effects were maintained for 3 months after end of treatment. The treatment was repeated after a 2-month therapy-free period and improvements were maintained [53]. In 2002, Muresanu, et al. [54] showed that cerebrolysin improved activities of daily living in patients with Alzheimer’s disease. Panisset, et al. [55] randomized 192 patients with Alzheimer’s disease to cerebrolysin (30 ml, 5 days per week, 4 weeks) or placebo, finding that cerebrolysin is well tolerated and significantly improved global score for 2 months after end of active treatment. Gavrilova, et al. [56] correlated ApoE4 genotype in patients with mild-to-moderate Alzheimer’s disease and efficacy of cerebrolysin therapy and cholinergic (exelon) therapy. A 4-month treatment showed that 1.7 fold higher response rate to cerebrolysin than the exelon group but further analysis revealed that those with genotype ApoE4(-) had 3- fold higher effect from cerebrolysin than people with ApoE4(+) genotype. Roshchina, et al. [57] did a neuropsychological evaluation of Alzheimer patients treated with two doses cerebrolysin (10 or 30 ml) over 19 months. Patients receiving the higher dose showed better cognitive function and less disease progression. In 2006, Alvarez, et al. [58] did a 24-week double-blind placebo-controlled study of 10, 30, and 60 ml of cerebrolysin (5 days a week for the first four weeks and then 2 infusions per week for 8 weeks). The results indicate a reversed U-shaped dose response relationship. The 10 ml dose improved cognitive performance but, while the 30 and 60 ml dose did not further improve cognitive function, the higher doses showed significantly better global outcome impression scores. Thus, many clinical trials have confirmed long-term beneficial effects of cerebrolysin in people with Alzheimer’s disease.

Acute Stroke. In 1994, Gusev, et al. [59] treated 30 patients with acute ischemic strokes with daily intravenous doses of 10, 20, 30 ml for 10 days, reporting that the treatment accelerated recovery in those with moderate strokes, compared to control subjects. In 1995, Domzai & Zaleska [60] treated 10 patients with acute middle cerebral artery strokes with 15 mg/day of cerebrolysin for 21 days and found similar recovery compared to a larger group of 108 patients given other drugs. Sidorenko, et al. [61] treated patients with partial optic atrophy with retrobulbar injections of cerebrolysin and apparently saw “favorable” effects in 50% of cases, compared to only 25% of control untreated patients. In the same year, Koppi & Barolin [62, 63] compared 318 stroke patients that received standard hemodilution with 100 patients that received hemodilution with cerebrolysin; reporting the cerebrolysin accelerated recovery. In 1998, Funke, et al. [64] did a remarkable double-blind placebo-controlled study showing that cerebrolysin increased parietal EEG signal in 48 healthy subjects subjected to transient brain ischemia, comparing 10, 30, and 50 ml doses. In 2004, Skvortsova, et al. [65] randomized 36 patients (age 45-85 years) with ischemic stroke of the carotid territory to cerebrolysin (10 ml/day or 50 ml/day) or placebo on day 3 of the stroke. They found EEG improvement in 72.7% of the treated patients. Ladurner, et al. [66] randomized 146 patients to placebo or cerebrolysin within 24 hours after stroke and examined at various times up to 90 days later. While the cerebrolysin group showed no significant improvement in clinical neurological scores, the Barthel Index, or Clinical Global Impression when compared to the placebo Cerebrolysin Review – Wise Young – Page 6 group, patients on cerebrolysin showed significant better cognitive function on the Syndrome Short Test.

Other Conditions. Cerebrolysin has been reported to be beneficial in several other neurological conditions, including diabetic neuropathy, glaucoma, neurosurgical procedures, Rett syndrome, vascular dementia, and traumatic brain injury In 1997, Bisenbach, et al. [67] treated 20 patients with type II diabetes, giving them 20 ml of cerebrolysin-infusion daily over 10 days, comparing with an age matched placebo control group. Cerebrolysin treatment resulted in significant subjective improvement of painful diabetic neuropathy for at least 6 weeks. In 2000, Lunusova [68] used cerebrolysin to treat patients with persistent glaucoma, reporting that the treatment (along with others) arrested the glaucomatous process, improved visual acuity, and extended visual field. In 2000, Matula and Schoeggl [69] suggested that cerebrolysin may be useful for preventing neurological deficits such as confusion, disorientation, or cognitive deficits after neurosurgery. Deigner, et al. [70] suggested that cerebrolysin may act in neurodegenerative diseases by preventing neuronal apoptosis. In 2001, Gorbachevskaya, et al. [71] gave cerebrolysin to 9 girls with Rett syndrome (age 2-7 years). Treatment resulted in increased behavioral activity, attention level, motor function, and non-verbal social communication, as well as EEG. In 2001, Vereshchagin, et al. [72] gave cerebrolysin for 28 days (15 mg/day) annually for 2 years to 42 patients with vascular dementia in a double-blind placebo-controlled study. The trial suggested stabilization of cognitive loss and prevention of progression of vascular dementia. Alvarez, et al. [73] used cerebrolysin to treat patients with brain trauma and found significant improvement in patient’s clinical outcomes during the first year with no adverse events. In 2005, Wong, et al. [74] reported a beneficial effect of cerebrolysin on moderate and severe head injury patients. At 6 months after treatment, 67% of the patients in the cerebrolysin group attained good outcome (GOS 3-5) compared to a historical cohort. Cerebrolysin has been reported to be beneficial for a wide variety of neurodegenerative disorders [75, 76], organic mental disorders [77], multiple sclerosis [78], anti-aging [79], and ischemic encephalopathy [80].

Animal Studies

Early animal studies did not shed much light on the mechanism(s) of cerebrolysin. In 1975, Lindner, et al. [81] applied the hydrolysate to cultures of chick peripheral and central neurons and found that high concentrations reduced nerve fiber growth but increased migration of non-neuronal cells. Zommer & Kvandt [82] gave doses of 0.005-0.025 ml of cerebrolysin to neonatal rats and found earlier differentiation of cytoarchitectonic fields in cerebral cortex, as well as early accumulation and increase in granular secretions in the pituitary gland of the animals. In 1976, Trojanova, et al. [83] reported that single injections of cerebrolysin given intraperitoneally to rats did not change their resistance to anoxia but repeated (5x) dosing increased resistance of young female rats (35 day old) to anoxia and that higher doses also increased resistance of adult rats to anoxia, compared to control mixtures of amino acids, oligopeptides, and nucleotides.

Neural Development and Cerebral Metabolism. By the 1980’s, several groups reported the cerebrolysin affected neuronal development and cerebral metabolism in animals. In 1981, Wenzel, et al. [84] reported that cerebrolysin treatment significantly increased the number of dendritic spines in the dentate gyrus (hippocampus) of neonatal rats. In 1985, Windisch & Poiswanger [85] treated rats for 3, 5, 7 or 14 days and examined cerebral protein, lactic acid, and oxygen consumption of brain homogenates, finding that higher doses (2.5 ml/kg) significantly increased respiratory activity of the homogenates. These effects apparently were most prominent in young rats up to 4 weeks and then in older 12-18 month old rats [86].

Experimental Demyelination and Immune Modulation. In 1991, Bespalova, et al. [87] assessed brain cerebrosides, sulfocerebrosides and gangliosides in rats subjected to experimental demyelination and treated with cerebrolysin. Zuber [88] examined the effects of cerebrolysin on brain phospholipids in rats with experimental demyelination. In 1992, Belokrylov and Malchanova [89] reported that treatment with cerebrolysin increased the number of Thy-1 positive cells and in vivo immune responses. In 1998, Grechko [90] compared cerebrolysin with a number of other peptide immunomodulators drugs and found that cerebrolysin had greater effect on free open-field group behavior of animals than most.

Hippocampal lesions. In the early 1990’s, several groups studied the effects of cerebrolysin on recovery from fimbria-fornix lesions. In 1992, Akai, et al. [91] of Kinki University in Osaka, Japan examined the effects of cerebrolysin (FPF1070) on septal cholinergic neurons after transection of the fimbria-fornix in rat brain. They found that intraperitoneal injections of the aqueous mixture of protein-free solution (containing 85% free amino acid and 15% small peptides) stimulated growth of embryonic dorsal root ganglion cultures. Apparently, the FPF1070 mixture prevented degeneration and atrophy of injured cholinergic neurons. In 1996, Francis-Turner & Valouskova [92, 93] compared intraperitoneal cerebrolysin with different concentrations of intraventricular infusions with NGF and bFGF on amnesia induced by fimbria-fornix transections. Cerebrolysin treatment or cerebrolysin combined with bFGF eliminated retrograde amnesia in the rats. In 1998, Cruz, et al. [94] showed the cerebrolysin (2.5 mg/kg x 7 days) had only a modest effect on glutathione related enzymes after fimbria-fornix transection. However, Gonzalez, et al. [95] found that cerebrolysin preserved SOD and CAT activity in the brain after a septohippocampal lesion.

Blood-Brain Barrier. In 1995, Boado [96] at UCLA reported that cerebrolysin transiently increased the glucose transporter GLUT-1 expression in blood-brain-barrier (BBB) within 2 hours and then a reduction at 20-48 hours, suggesting that cerebrolysin modulates expression of BBB-GLUT-1 expression. Boado [97] then used a luciferin-luciferase reporter gene to show that cerebrolysin markedly increased the BBB-GLUT1 expression and that the mechanism did not involve phosphokinase C. In 1998, Boado [98, 99] showed that cerebrolysin increased GLUT-1 expression via mRNA stabilization. In 1999, Boado, et al. [100] showed that acute or chronic administration of cerebrolysin increases the transport of glucose from blood to brain. In 2000, Boado [101] further showed that cerebrolysin stabilized GLUT1 transporter mRNA by increasing p88 TAF. In 2000, Gschanes, et al. [102] showed that both cerebrolysin and its peptide fraction EO21 increased the abundance of GLUT1 transporter in the brains of both old and young rats. In 2001, Boado [103] showed that cerebrolysin markedly increases the expression of BBB-GLUT1 reporter genes containing regulatory cis-elements involved in stabilization and translation, increases glucose uptake by the BBB, and increases GLUT1 protein expression.

Hippocampal slices. In Toronto, Baskys, et al. [104] assessed cerebrolysin effects on hippocampal slices, finding that it suppressed synaptic responses in CA1 neurons but not dentate gyrus neurons. Xiong, et al. [105, 106] found that cerebrolysin caused presynaptic inhibition that can be blocked with adenosine A1 receptor blockers and, since cerebrolysin does not contain detectable amounts of adenosine, proposed that cerebrolysin acted indirectly perhaps be release of endogenous adenosine. Cerebrolysin also appears to inhibit hippocampal responses by activating the GABA-B receptor [107]. Meanwhile, in 1995, Zemkova, et al. [108] of the Czech Republic, found that cerebrolysin potentiates GABA-A receptors in culture mouse hippocampal slices and that this could be blocked by bicucullin (a GABA-A receptor blocker). Ischemia. In 1993, Sugita, et al. [109] assessed the effects of FPF1070 (cerebrolysin) on delayed neuronal death in the gerbil global ischemia model. They measured the formation of hydroxyl free radicals in the brain and found that both DMSO (a hydroxyl free radical scavenger) and FPF1070 significantly reduced delayed neuronal death and evidence of hydroxyl radicals in the brains, proposing that hydroxyl radical scavenging may be the mechanism of cerebrolysin effect. In 1996, Schwab, et al. [110] assessed the effects of cerebrolysin on cytoskeletal proteins after focal ischemia in rats. In 1997, Schwab, et al. [111] compared the effects of hypothermia and cerebrolysin, finding that the latter enhanced the neuroprotective effects of the former. Cerebrolysin also improved EEG signal and motor activity of rats after mild forebrain ischemia [112]. Gschanes, et al. [113] found that cerebrolysin improved spatial memory and motor activity in rats after ischemic-hypoxic injury. In 1998, Schwab, et al. [114] showed that cerebrolysin reduced the size of cerebral infarct and microtubule protein loss after middle cerebral artery occlusion. In 2005, Makarenko, et al. [115] compared different fractions of cerebrolysin on a bilateral hemorrhagic rat stroke model. They found the most pronounced effects for the cerebral-1 fraction and particularly the 1.2 subfractions.

Spreading depression, hypoxia, and hypoglycemia. In 1998, Bures, et al. [116] showed that cerebrolysin (2.5 mg/kg daily x 10 days) remarkably protected the hippocampus against damage during repeated spreading depressions. Koreleva, et al. [117] compared the effects of MK801 and cerebrolysin on focal ischemia, finding that cerebrolysin increased amplitude of evoked spreading depression. In the same year, Gannushkina, et al. [118] studied the effects of cerebrolysin on 389 rats after bilateral common carotid occlusion, showing that the treatment did not increase blood flow but increased EEG recovery that may enhance ischemia damage. In 1999, Buresh, et al. [119] reported that cerebrolysin completely prevented hypoxia induced loss of CA1 neurons in the hippocampus. Koroleva, et al. [120] found that cerebrolysin treatment protected the hippocampus against carbon monoxide poisoning and spreading depression. In 2000, Veinbergs, et al. [121] pre-treatment with cerebrolysin was necessary to provide significant neuroprotection for kainic acid injections. In 2003, Patockova, et al. [122] showed that cerebrolysin significantly reduced lipid peroxidation induced by insulin hypoglycemia in the hearts and brains of mice.

Alzheimer’s disease. In 1999, Masliah, et al. [123] showed that cerebrolysin ameliorates performance deficits and neuronal damage in apolipoprotein E-deficient mice (a model of Alzheimer’s disease). In 2002, Rockenstein, et al. [124] treated transgenic mice expressing human amyloid precursor protein (APP751) under the Thy-1 promoter. Cerebrolysin significantly reduced the amyloid burden in the frontal cortex of 5-month-old mice, as well as the levels of A-beta (1-42). In 2003, Rockenstein, et al. [125] showed that cerebrolysin is neuroprotective in a transgenic mouse expressing human mutant amyloid precursor protein (APP) under the Thy1 promoter, start 3 or 6 months after birth. The treatment significantly ameliorated performance deficits and protected neurons. Rockenstein, et al. [126] investigated various gene expression and found no change in BACE1, Notch1, Nep, and IDE but did find higher levels of active cyclin-dependent kinase-1 (CDK5) and glycogen synthetase kinase-3 beta (GSK3beta).

Memory. In 1996, Hutter-Paier, et al. [127-130] reported that a single injection of cerebrolysin improved passive avoidance reactions in rats after transient cerebral ischemia. Gschanes & Windisch [131] likewise found that cerebrolysin improved spatial navigation in rats after transient brain ischemia. In 1998, Gschanes and Windisch [132] assessed the effects of cerebrolysin on spatial navigation in old (24-month) rats and found that cerebrolysin and EO21 (the concentrated peptide fraction of cerebrolysin) both improved spatial learning and memory of the rats. In 1999, Gschanes and Windisch [133] found that cerebrolysin or EO21 also improved spatial learning and memory in young rats, lasting up to 3 months after treatment stopped. In 1998, Valouskova and Francis- Turner [134] reported that cerebrolysin restored learning capability in rats when given 4 months after brain lesions. In 1999, Reinprecht, et al. [135] gave cerebrolysin or EO21 to 24-month old rats and found that the peptide mixtures improved cognitive performance of the rats and increased number of synaptophysin-immunostaining in the hippocampus. In 1999, Valouskova and Gschanes [136] compared NGF, bFGF, and cerebrolysin on rat performance in the Morris water maze test after bilateral frontoparietal cortical lesions, showing that cerebrolysin had a significant beneficial effect that declined to control levels by 8 months. Windolz, et al. [137] found that cerebrolysin or EO21 increased synaptophysin immunoreactivity in the brains of 6-week old rats. Eder, et al. [138] reported that cerebrolysin increased expression of the glutamate receptor subunit 1 (GluR1).

Spinal Motoneurons and Injury. Haninec, et al. [139] reported that insulin-like growth factor I (IGF-I) and cerebrolysin improves survival of motoneurons after ventral root avulsion. Either IGF-1 or cerebrolysin were effective when given intrathecally to the spinal cord. In 2004, Haninec, et al. [140] showed that BDNF and cerebrolysin both increased reinnervation of the rat musculocutaneous nerve stump after avulsion and its direct reconnection with the C5 spinal cord segment. BDNF was better than cerebrolysin. In 2005, Bul’on, et al. [141] studied the effects of cytoflavin or cerebrolysin in rats after spinal cord compression injury. The neuroprotective effects of cytoflavin were greater than for cerebrolysin.

Cell Cultures. In 1998, Hutter-Paier, et al. [142] showed that cerebrolysin counteracted the excitotoxic effects of glutamate and hypoxia [143] in cultured chick cortical neurons. In 1999, Lombardi, et al. [144] applied cerebrolysin to cultures of rat astrocytes and microglia, showing that the peptide mixture prevented microglial activation after LPS activation and reduced interleukin-1b expression. Mallory, et al. [145] reported that cerebrolysin applied to the human teratocarcinoma cell line (NT2) markedly increased expression of synaptic-associated proteins, suggesting that it has synaptotrophic effects mediated through regulation of APP expression. Alvarez, et al. [146] likewise showed that cerebrolysin reduced microglial activation both in vitro and in vivo. Satou, et al. [147] reported that cerebrolysin had a inverted U-dose response on neurite growth and suggested that cerebrolysin has different effects depending on the subpopulation of neuron. Wronski, et al. [148] showed that cerebrolysin prevented MAP2 loss in primary neuronal cultures after brief hypoxia. Cerebrolysin also inhibits the calcium-dependent protease calpain [149]. In 2001, Hartbauer, et al. [1] showed that cerebrolysin is anti-apoptotic in embryonic chick cortical neuronal cultures and stimulates outgrowth and protection of neurites [150]. In 2002, Gutmann, et al. [151] showed cerebrolysin protects cultured chick cortical neurons from cell death from a wide variety of causes, including glutamate, iodoacetate, and ionomycin; they propose that cerebrolysin stabilizes calcium ionic homeostasis. Safarova, et al. [152] showed that cerebrolysin improved survival of PC12 cells in serum-free medium, reducing apoptosis from 32% to 10%. In 2005, Schauer, et al. [153] found that a single addition of cerebrolysin to culture medium resulted in significant protection of tissue cultures against ischemia and hypoxia for up to 2 weeks. The treatment can even be delayed as long as 96 hours and still have beneficial effects. In 2006, Riley, et al. [154] applied cerebrolysin to organotypic brain slices and showed that the most pronounced neuroprotective effects of other drugs was seen when the drug was added both before and after glutamate.

Discussion and Summary

On the surface, cerebrolysin seems to be the worst sort of “drug” to investigate. First, it is not clear what cerebrolysin actually contains. Second, it is difficult to imagine why an intravenous injection of an extract of enzyme-digested pig brain proteins, composed of 25% low molecular weight peptides and 75% free amino acids, would be helpful. While we know that many peptides and amino acids act as growth factors and neurotransmitters, the blood brain barrier prevents the movement of peptides and amino acids from the blood to the brain. Third, if peptides and amino acids readily crossed the blood brain barrier, our brains would be subject to the whims of every steak and meal that we eat.  Finally, cerebrolysin is digested proteins from pig brain. It should be quite immunogenic to inject all these foreign peptides intravenously. Immunogenic reactions are complex and not well understood. Thus, in theory and from the viewpoint of safety, cerebrolysin should not only be ineffective but may pose significant risks.

Early 1970’s anecdotal clinical reports in Russia did not contribute to the credibility of cerebrolysin. It was being used in patients with cerebral arteriosclerosis, infantile cerebral palsy, and dementia. None of the studies were adequately controlled and the outcomes were vague and it all just seemed too good to be true. Likewise, early animal and cell culture studies likewise did not provide much information. However, in Russia, cerebrolysin was widely used and tried on many different kinds of diseases, mostly hopeless and poorly documented. This is of course a natural tendency. If a safe and effective therapy exists for a condition, that therapy would of course be the first choice of doctors. Conditions that have no known effective therapies are the ones that are most likely to be treated by cerebrolysin.

Animal studies turned the tide of skepticism. In the early 1980’s, the work of Wenzel, et al. [84] showing changes in neuronal synapses and Windisch & Poiswanger [85] reporting dose-related effects of cerebrolysin on cerebral metabolism suggested that the hydroxylate was doing something to the brain. Cerebrolysin also appeared to affect brain phospholipids [88] and may even have some effects of the immune system [89]. By the 1990’s, several groups reported remarkable effects of cerebrolysin on hippocampal lesions, preventing degeneration and atrophy of cholinergic neurons [91] and amnesia [92, 93], In 1995, Boado [96] showed that cerebrolysin remarkably upregulates the glucose transporter in the blood brain barrier, through a specific mechanism involving stabilization of the GLUT1 mRNA and associated not only with increase in GLUT1 protein but also increased glucose transport across the blood-brain-barrier [100].

Many clinical trials have now reported that cerebrolysin is an effective and safe therapy for many neurological disorders, ranging from stroke to Alzheimer’s disease. The drug’s primary effect seems to be on hippocampal function. Some studies suggest that cerebrolysin may be modestly neuroprotective in stroke and facilitates recovery from stroke. The side effects of the drug seem to be negligible. There are efforts underway to develop an oral version of the drug but the vast majority of the studies involve daily intravenous injections. The apparently broad spectrum of neuroprotective and neuroreparative effects of the drug both in the acute and chronic phases of brain injury suggest that this drug should be useful for both acute and chronic stroke and traumatic brain injury. Several studies suggest that the drug stabilizes excitability of the brain and can reduce hyperkinetic syndromes associated with neuroleptic drugs used for Parkinson’s disease. It may also be useful for preventing progressive deterioration in Parkinson’s disease although no clinical trial has addressed this issue yet.

An impressive array of clinical trials support beneficial effects of cerebrolysin on Alzheimer’s disease, beginning with Ruther, et al. [42] with 120 patients in 1994 and Rainer, et al. [43] with 645 patients in 1997. In 1999, Roshchina, et al. [47], Bae, et al. [48], and Ruther, et al. [50] confirmed these results. The effects of the cerebrolysin are not only statistically but also clinically significant [54]. The cerebrolysin responder rate on global clinical impression scale was 64.5% compared to 41.4% in placebo treated patients [52]. Several clinical trials also showed a clear dose-response [58] and several animal studies [6] are suggesting that the active ingredient is in the peptide fraction and not the amino acid fraction of cerebrolysin. People with genetic causes of the disease appear to be more responsive to cerebrolysin [56]. More interesting, the drug effects appear to last many months or even years after treatment has stopped [52, 53, 55]. This long-lasting effects suggest that cerebrolysin is not merely improving the balance of neurotransmitters or increasing the excitability of neurons, although EEG studies suggest that changes of excitability do occur with cerebrolysin treatment. Thus, it seems that cerebrolysin may be stimulating repair or perhaps even neuronal replacement in the brain. One interesting possibility is the cerebrolysin may be stimulating stem cells in the brain and repair processes that we do not understand.

Some clinical evidence suggest that cerebrolysin may be beneficial for other neurological conditions, including extrapyramidal hyperkinesis associated with neuroleptic therapy [38-40], with acute [65, 66] and chronic [28, 30, 31] stroke, diabetic neuropathy [67], Rett syndrome [71], vascular dementia [72], brain trauma [73, 74], organic mental disorders [77], multiple sclerosis [78], anti-aging [79], ischemic encephalopathy [80], and other neurodegenerative disorders [75, 76], Little data is available concerning the effect of the drug on spinal cord injury. Only one recent study is available regarding cerebrolysin therapy of a rat spinal cord compression model and it suggests a modest effect of the drug compared to another antioxidant. More studies are needed to ascertain the benefits of cerebrolysin for both acute and chronic spinal cord injury.


NOOTROPIL (UCB) 3G 15 ml amp infusion $10

Piracetam – the original nootropic
by James South MA

Piracetam (technically known as 2-oxo-pyrrolidone) was developed in the mid-1960’s by UCB pharmaceutical company of Belgium. It was originally used to treat motion sickness. (1) Between 1968 and 1972, however, there was an explosion of Piracetam research which uncovered its ability to facilitate learning, prevent amnesia induced by hypoxia and electroshock, and accelerate electroencephalograph return to normal in hypoxic animals. (1) By 1972 700 papers were published on Piracetam. (1) Yet already by 1972 Piracetam’s pharmacologic uniqueness led C.E. Giurgea, UCB’s principal Piracetam researcher and research coordinator, to formulate an entirely new category of drugs to describe Piracetam: the nootropic drug. (2)

According to Giurgea, nootropic drugs should have the following characteristics:

1) they should enhance learning and memory.
2) They should enhance the resistance of learned behaviors/memories to conditions which tend to disrupt them (e.g. electroconvulsive shock, hypoxia).
3) They should protect the brain against various physical or chemical injuries (e.g. barbiturates, scopalamine).
5) They should ”increase the efficacy of the tonic cortical/subcortical control mechanisms.”
6) They should lack the usual pharmacology of other psychotropic drugs (e.g. sedation, motor stimulation) and possess very few side effects and extremely low toxicity. (3)

As research into Piracetam and other nootropics (e.g. pyritinol, centrophenoxine, oxiracetam, idebenone) progressed over the past 30 years, section 5) of Giurgea’s original definition has been gradually dropped by most researchers. (3) Nonetheless, the nootropic drugs represent a unique class of drugs, with their broad cognition enhancing, brain protecting and low toxicity/ side effect profiles. It is an interesting comment on the AMA/FDA stranglehold on American medicine that as of January 2001, not a single nootropic drug has ever been given FDA approval for use in the U.S.

Piracetam has been used experimentally or clinically to treat a wide range of diseases and conditions, primarily in Europe. (Although much of the research on Piracetam has been published in English, a large amount of Piracetam research has been published in German, French, Italian, and Russian.)

Piracetam has been used successfully to treat alcoholisrn/ alcohol withdrawal syndrome in animals and man. (4,5,19) Piracetam has brought improvement, or slowed deterioration, in “senile involution” dementia and Alzheimer’s disease. (6,7) Piracetam has improved recovery from aphasia (speech impairment) after stroke. (8) Piracetam has restored various functions (use of limbs, speech, EEC, slate of consciousness) in people suffering from acute and chronic cerebral ischemia (decreased brain blood flow). (9,10) Piracetam has improved alertness, co-operation, socialization, and IQ in elderly psychiatric patients suffering from “mild diffuse cerebral impairment.” (11)

Piracetam has increased reading comprehension and accuracy in dyslexic children. (8,12) Piracetam increased memory and verbal learning in dyslexic children, as well as speed and accuracy of reading, writing and spelling. (13,14) Piracetam potentiated the anticonvulsant action of various anti-epileptic drugs in both animals and man, while also eliminating cognitive deficits induced by anti-epileptic drugs in humans. (15,16) Piracetam has improved mental performance in “aging, nondeteriorated individuals” suffering only from “middle-aged forgetfulness.” (17) Elderly outpatients suffering from “age-associated memory impairment” given Piracetam showed significant improvement in memory consolidation and recall. (8) Piracetam reversed typical EEC slowing associated with “normal” and pathological human aging, increasing alpha and beta (fast) electroencephalograph activity and reducing delta and theta (slow) electroencephalograph activity, while simultaneously increasing vigilance, attention and memory. (17A)

Piracetam reduced the severity and occurrence of major symptoms of “post-concussional syndrome,” such as headache, vertigo, fatigue and decreased alertness (18), while it also improved the state of consciousness in deeply comatose hospitalized patients following head injuries. (19) Piracetam has successfully treated motion sickness and vertigo. (1) Piracetam “is one of the best available drugs for treating myoclonus [severe muscle spasms] of cortical origin.” (20) Piracetam has successfully treated Raynaud’s syndrome (severe vasospasm in hands and/or feet), with “a rapid and marked improvement. The efficacy of Piracetam has been maintained in several patients already followed for 2-3 years.” (21) Piracetam has been used to inhibit sickle cell anemia, both clinically and experimentally. (11) Piracetam has improved Parkinson’s disease, and may synergize with standard L-dopa treatment. (1) A key part of Piracetam’s specialness is its amazing lack of toxicity. Piracetam has been studied in a wide range of animals: goldfish, mice, rats, guinea pigs, rabbits, cats, clogs, marmosets, monkeys, and humans. (1,19) In acute toxicity studies that attempted to determine Piracetam’s “LD50” (the lethal dose which kills 50% of test animals), Piracetam failed to achieve an LD50 when given to rats intravenously at 8gm/kg bodyweight. (1) Similarly, oral LD50 studies in mice, rats, and dogs given 10gm Piracetam/kg bodyweight also produced no LD50! (1) This would he mathematically equivalent to giving a 70 kg (154 pound) person 700gm (1.54 pounds) of Piracetam! As Tacconi and Wurtman note, ”Piracetam apparently is virtually non-toxic. Rats treated chronically with 100 to 1,000 mg/kg orally for 6 months and dogs treated with as much as 10g/kg orally for 1 year did not show any toxic effect. No teratogenic (birth deformity) effects were found, nor was behavioral tolerance noted.” (22) Thus, Piracetam must be considered one of the toxicologically safest drugs ever developed.

From the earliest days of Piracetam research, the ability of Piracetam to partly or completely prevent or reverse the toxic action of a broad array of chemicals and conditions has been repeatedly demonstrated. Paula-Barbosa and colleagues discovered that long-term (12 month) alcohol-feeding to rats significantly increased formation of lipofuscin (an age-related waste pigment) in brain cells. Giving high dose Piracetam to the alcohol-fed rats reduced their lipofuscin levels significantly below both the control and alcohol/no Piracetam rats’ levels. (4) Piracetam antagonized the normally lethal neuromuscular blockade (which halts breathing) induced by mice by intravenous hemicholinium-3 (HC-3) (23), and Piracetam also blocked the lethal neuromuscular blockade induced in cats by d-tubocurarine. (1) Piracetam reversed learning and memory deficits in mice caused by the anti-cholinergic substance, HC-3. (23) When mice were given oxydipentonilim, a short-acting curare-like agent which halts breathing, at a dose sufficient to kill 90% of one group and 100% of another group of placebo-treated controls, the two groups of Piracetam-treated mice had a 90% and 100% survival rate. (19)

Rapid synthesis of new protein in brain cells is required for memory formation. Piracetam has ameliorated the amnesia induced by rodents by cycloheximide, a protein synthesis inhibitor. (1)

Hexachlorophene is a toxic chemical that induces edema, membrane damage, and increased sodium /decreased potassium in brain cells. (Hexachlorophene was used in shampoos, soaps and other personal care products until about a decade ago.) Rats were fed hexachlorophene orally for 3 weeks, then given Piracetam or one of 5 other drugs by injection for 6 days. Hexachlorophene seriously disrupted the rats’ ability to navigate a horizontal ladder without frequently falling off the rungs. Piracetam reduced the fall rate 75% compared to saline-injected controls on the first day of treatment. None of the other drugs came close to that improvement. (24)

Piracetam increases the survival rate of rats subjected to severe hypoxia. (1,25) When mice, rats and rabbits have been put under diverse experimental hypoxic (low oxygen) conditions, Piracetam has acted to attenuate or reverse the hypoxia-induced amnesia and learning difficulties, while speeding up post-hypoxic recovery time and reducing time to renormalize the EEC}. (1,2,25) When a single 2400mg dose of Piracetam was given to humans tested under 10.5% oxygen (equivalent to 5300m./17,000 ft. altitude), eye movement reflexes were enhanced, while breathing rate and choice reaction time were reduced by Piracetam. (26)

Electro convulsive shock (electro convulsive shock) is a powerful disruptor of learning and memory. When a group of rats were taught to avoid a dark cubicle within their cage there was 100% retention of the learned behavior 24 hours later.

Giving a maximal electro convulsive shock right after learning caused the learning-retention rate to drop lo 20% 24 hours later in the control group, while Piracetam-treated electro convulsive shock rats still had a 100% retention of the avoidance behavior 24 hours later. (2) Other experiments with mice and rats show Piracetam’s ability to attenuate or reverse electro convulsive shock-induced amnesia. (19.27)

When given the fast acting barbiturate secobarbital, combined with Piracetam injected 1 hour before the secobarbital, 10 of 10 rabbits survived, with only minimal abnormalities in their electroencephalograph records. The electroencephalograph records the electrical activity of large groups of corticol neurons, and also reflects cerebral oxygen/glucose metabolism and blood flow. (25)

Only 3 of 10 rabbits given) secobarbital with saline injection survived, and most of that groups’ electroencephalograph records showed rapid onset of electrical silence, followed quickly by death. When secobarbital was given to rabbits combined with oral Piracetam, 8 of 9 survived, with only 3 of 9 saline-fed controls surviving. The electroencephalograph records of both groups were similar to those of the rabbits given i.v. Piracetam and saline. (28)

By the 1980s neuroscientists had discovered that brain cholinergic neural networks, especially in the cortex and hippocampus, are intimately involved in memory and learning. Normal and pathological brain aging, as well as Alzheimer’s-type dementia were also discovered lo involve degeneration of both the structure and function of cholinergic nerves, with consequent impairment of memory and learning ability. (29)

During this same period a growing body of evidence began to show that Piracetam works in part through a multimodal cholinergic activity. Studies with both aged rats and humans which combined Piracetam with either choline or lecithin (phosphatidyl choline), found radically enhanced learning abilities in rats, and produced significant improvement in memory in Alzheimer’s patients. (30-35)

Yet giving choline or lecithin alone (they are precursors for the neurotransmitter acetylcholine) in these studies provided little or no benefit, while Piracetam alone provided only modest benefit.

Animal research has also shown that Piracetam increases high-affinity choline uptake, a process that occurs in cholinergic nerve endings which facilitates acetylcholine formation. (23,29) “High-affinity choline uptake rate has been shown to be directly coupled to the impulse flow through the cholinergic nerve endings and it is a good indicator of acetylcholine utilization nootropic drugs (including Piracetam) activate brain cholinergic neurons” (29) HC-3 induces both amnesia and death through blocking high-affinity choline uptake in the brain an din peripheral nerves that control breathing. Since Piracetam blocks HC-3 asphyxiation death and amnesia, this is further evidence of Piracetam’s pro-high-affinity choline uptake actions. (23,29)

Scopalamine is a drug that blockades acetylcholine receptors and disrupts energy metabolism in cholinergic nerves. When rats were given Scopalamine, it prevented the learning of a passive avoidance task, and reduced glucose utilization in key cholinergic brain areas. When rats given Scopalamine were pretreated with 100/kg Piracetam, their learning performance became almost identical to rats not given Scopalamine. (36) The Piracetam treatment also reduced the Scopalamine depression of glucose-energy metabolism in the rats’ hippocampus and anterior cingulate cortex, key areas of nerve damage and glucose metabolism reduction in Alzheimer’s disease.(36)

German researchers added to the picture of Piracetam’s cholinergic effects in 1988 and 1991. Treatment for 2 weeks with high dose oral Piracetam in aged mice elevated the density of frontal cortex acetylcholine receptors 30-40%, restoring the levels to those of healthy young mice. A similar decline in cortex acetylcholine receptors occurs in “normal” aging in humans. (37) The same group of researchers then discovered that there is a serious decline in the functional activity of acetylcholine receptors in aged mice; with many receptors becoming “desensitized” and inactive. Oral treatment with high dose Piracetam also partially restored the activity of acetylcholine cortex nerves, as measured by the release of their “second messenger,” inositol-1-phosphate. (38)

Glutamic acid (glutamate) is the chief excitatory neurotransmitter in the mammalian brain. Piracetam has little affinity for glutamate (glutamate) receptors, yet it does have various effects on glutamate neurotransmission. One subtype of glutamate receptor is the AMPA receptor. Micromolar amounts [levels which are achieved through oral Piracetam intake] of Piracetam enhance the efficacy of AMPA-induced calcium influx [which “excites” nerve cells to fire] in cerebeller [brain] cells. Piracetam also increases the maximal density of [AMPA glutamate receptors] in synaptic membranes from rat cortex due to the recruitment of a subset of AMPA receptors which do not normally contribute to synaptic transmission.” (1) Further support for involvement of the glutamate system in Piracetam’s action is provided by a Chinese study which showed that the memory improving properties of Piracetam can be inhibited by ketamine, an NMDA (another major subtype of glutamate receptor) channel blocker. (1) Furthermore, high dose injected Piracetam decreases mouse brain glutamate content and the glutamate/GABA ratio, indicating an increase in excitatory nerve activity (1)

At micrornolar levels, Piracetam potentiates potassium-induced release of glutamate from rat hippocampal nerves. (1)

Given that acetylcholine and glutamate are two of the most central “activating” neurotransmitters and the facilatory effects of acetylcholine/glutamate neural systems on alertness, focus, attention, memory and learning. Piracetam’s effects on acetylcholine/glutamate neurotransmission must he presumed to play a major role in its demonstrated ability to improve mental performance and memory. Although Piracetam is generally reported to have minimal or no side effects, it is interesting to note that Piracetam’s occasionally reported side effects of anxiety, insomnia, agitation, irritability and tremor (18) are identical to the symptoms of excess acetylcholine/glutamate neuroactivity.

In spite of the many and diverse neurological/psychological effects Piracetam has shown in human, animal and cell studies, Piracetam is generally NOT considered to he a significant agonist (direct activator) or inhibitor of the synaptic action of most neurotransmitters. Thus, major nootropic researchers Pepeu and Spignoli report that “the pyrrolidinone derivatives [Piracetam and other racetams] show little or no affinity for central nervous system receptors for dopamine, glutamate; serotonin, GABA or benzodiazepine.” (23) 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 [Piracetam-type] enhance neuronal excitability [electrical activity] within specific neuronal pathways.” (23)

Grau and colleagues note that “there exist papers giving data of bioelectric activity as affected by Piracetam, and suggesting that it acts as a non-specific activator of the excitability. [i.e. brain electrical activity] thus optimizing the functional state of the brain.” (25)

Gouliaev and Senning similarly state “we think that the racetams exert their effect on some species [of molecule] present in the cell membrane of all excitable cells, i.e. the ion carriers or ion channels and that they somehow accomplish an increase in the excitatory (electrical) 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 [neurotransmitter-like] 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 toward stimulation.” (1)

Thus Piracetam is NOT 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 antidepressants, amphetamines, Ritalin®, benzodiazepines (Valium), etc.

A key finding on Piracetam in various studies is its ability to enhance brain energy, especially under deficit conditions. Energy (ATP) is critical to the brain’s very survival; it typically uses 15-20% of the body’s total ATP production, while weighing only 2-3% or so of bodyweight. Brain cells must produce all their own ATP from glucose (sugar) and oxygen – they cannot “borrow” ATP from other cells. Branconnier has observed that “evidence from studies of cerebral blood flow, oxygen uptake and glucose utilization have shown that brain carbohydrate metabolism is impaired in a variety of dementias and that the degree of reduction in brain carbohydrate metabolism is correlated with the severity of the dementia.” (39) In a 1987 study, Grau and co-workers gave saline or Piracetam i.v. to rats who were also fed i.v. radioactive deoxygilicose to help measure brain metabolism. Compared to saline controls, Piracetam rats had a 22% increase in whole brain glucose metabolism, while the increase in 12 different brain regions ranged from L6 to 28%. (25) This increase in brain energy metabolism occurred under normal oxygen conditions.

In 1976 Nickolson and Wolthuis discovered that Piracetam increased the activity of adenylate kinase in rat brain. Adenylate kinase is a key energy metabolism enzyme that converts ADP into ATP and AMP and vice versa. It comes into play especially when low brain oxygen begins to reduce mitochondrial ATP production. As existing ATP is used up, ADP is formed. Under the influence of adenylate kinase, 2ADP becomes ATP plus AMP. Thus Piracetam-activated adenylate kinase can slow down the drop in ATP in oxygen-compromised brains. This helps explain Piracetam’s ability to prevent abnormalities in animals subjected to hypoxia or barbiturates. When oxygen levels return toward normal, adenylate kinase can convert AMP into ADP, which can then be used in the reactivated mitochondria to make more ATP. This accounts for the ability of Piracetam to speed up recovery from hypoxia seen in animal studies. (40)

In their 1987 study with rats, Piercey and colleagues found that Piracetam could restore scopalamine depressed energy metabolism modestly in many brain areas, and significantly in the hippocampus and anterior cingulate cortex. (36)

Piracetam has also been shown to increase synthesis and turnover of cytochrome b5, a key component of the electron transport chain, wherein most ATP energy is produced in mitochondria. (22) Piracetam also increases permeability of mitochondrial membranes for certain intermediaries of the Krebs cycle, a further plus for brain ATP production. (25) In his 1989 paper on cerebral ischemia in humans, Herrschaft notes that the Herman Federal Health Office has conducted controlled studies that indicate a “‘significant positive” effect of Piracetam (4.8 – 6gm/day) to increase cerebral blood flow, cerebral oxygen usage metabolic rate and cerebral glucose metabolic rate in chronic impaired human brain function – i.e. multi-infarct dementia, senile dementia of the Alzheimer type, and pseudo-dementia. (9)

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 that most people favor one hemisphere over the other, with the dominant hemisphere being more electrically active and the non-dominant hemisphere relatively more electrically silent, when a person is being tested or asked to solve problems or respond to information. The two cortical hemispheres are linked by a bundle of nerve fibers: the corpus callosum and the anterior commisure. In theory these two structures should unite the function of the two hemispheres. In practice they act more like a wall separating them.

From a neurological perspective, the cerebral basis for a well-functioning mind would he the effective, complementary, simultaneous integrated function of both cortical hemispheres, with neither hemisphere being automatically or permanently dominant. This in turn would require the corpus callosum and cerebral commisure to optimize information flow between the two hemispheres. Research has shown Piracetam to facilitate such inter-cerebral information transfer-indeed, it’s part of the definition of a “nootropic drug.”

Giurgea and Moyersoons reported in 1972 that Piracetam 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. (41) Buresova and Bures, in a complex series of experiments involving monocular (one-eye) learning in rats, demonstrated that “Piracetarn enhances transcommisural encoding mechanisms and some forms of inter-hemispheric transfer.” (42)

Dimond and co-workers used a technique called “dichotic listening” to verily the ability of Piracetam 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. This occurs because 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 from the right cortex. Dimond’s research with healthy young volunteers showed that Piracetam significantly improved left ear word recall, indicating Piracetam increased interhemispheric transfer. (43)

Okuyama and Aihara tested the effect of aniracetam, a Piracetam analog, 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. The researchers reported that “the present results indicate that Piracetam…increased the amplitude of the negative wave, thereby facilitating inter-hemispheric transfer. Thus, it is considered that the functional increase in interhemispheric neuro-transmission by nootropic drugs may be related to the improvement of the cognitive function [that nootropics such as Piracetam and aniracetam promote].” (44)

The notable absence of biochemical, physiological, neurological or psychological side effects, even with high dose and/or long-term Piracetam use, is routinely attested to in the Piracetam literature. Thus in their 1977 review Giurgea and Salama point out: “Piracetam is devoid of usual ‘routine’ pharmacologic activities [negative side effects] even in high doses. In normal subjects no side effects or ‘doping’ effects were ever observed. Nor did Piracetam induce any sedation, tranquilization, locomotor stimulation or psychodysleptic symptomatology.” (19) Wilshen and colleagues, in their study on 225 dyslexic children, note that “Piracetam was well tolerated, with no serious adverse clinical or laboratory effects reported.” (12) In this particular study (as in many others), the incidence of (mild) side effects was higher in the placebo group than in the Piracetam group! In his 1972 8 week study on 196 patients with “senile involution” dementia, Stegink reported that “No adverse side effects of Piracetam [2.4gm/day] were reported.” (6) In their study of 30 patients treated for one year with 8gm Piracetam/day, Croisile and colleagues observed that “Few side effects occurred during the course of the study – one case of constipation in the Piracetam group…. Piracetam had no effect on vital signs, and routine tests of renal, hepatic, and hematological functions remained normal. No significant changes in weight, heart rate, or blood pressure occurred….” (7)

Yet as noted in the section on glutamate, because Piracetam is a cholinergic/glutamatergic activator, there is the potential for symptoms related to cholinergic/glutamatergic excess to occur, especially in those unusually sensitive to Piracetam. Such symptoms – anxiety, insomnia, irritability, headache, agitation, nervousness, and tremor – are occasionally reported in some people taking Piracetam. (11,18) Reducing dosage, or taking magnesium supplements (300-500mg/day), which reduce neural activity, will frequently alleviate such “overstimulation” effects. Persons consuming large amounts of MSG (monosodium glutamate) and/or aspartame in their diet should be cautious in using Piracetam, as should those who are highly sensitive to MSG-laden food (the “Chinese restaurant syndrome”). Caffeine also potentiates Piracetam’s effects, as do other nootropics such as deprenyl, idebenone, vinpocetine, and centrophenoxine, and it may be necessary to use Piracetam in a lower dosage range if also using any of these drugs regularly. Those wishing to augment Piracetam’s cholinergic effects may wish to combine it with cyprodenate or centrophenoxine, which are much more powerful acetylcholine enhancers than choline or lecithin.

B complex vitamins, NADH, lipoic acid, Co Q10, or idebenone, and magnesium will enhance Piracetam’s brain energy effects. In the clinical literature on Piracetam, dosages have ranged from 2.4 gm/day (6,11) up to 8gm/day (7,21), continued for years (7,21). Piracetam has a relatively short half-life in the blood, although there is some short-term bioaccumulation in the brain. (1,22) Piracetam is therefore usually taken 3-4 times daily. 1.6 gm, 3 times daily, or 1.2 gm 3-4 times daily is a fairly typical Piracetam dosage, although some people report noticeable improvement in memory and cognition from just 1.2 gm twice daily.