The Story and Science of Piracetam

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Piracetam, the original Racetam was created as a cognitive enhancer. It is similar to GABA, a neurotransmitter from which it is derived, and it has been used to treat cognitive decline. A fair amount of evidence shows that it can enhance cognition in people who have had a decline in such. However, there is not much in the way of studies of piracetam in people who haven’t experienced such a decline.^[1]

Piracetam was created in 1964 by a Belgian pharmaceutical company named UCB. The lead scientist was Dr. Corneliu E. Giurgea, who came up with the term nootropic to describe piracetam and other similar compounds. In the 1970’s, UCB released Nootropil, the trade name for Piracetam. Nootropil is currently used in Europe.^[2]

Mechanisms of Action

The basic mechanism of piracetam is not well established. However, it does appear to be non-sedative and non-stimulatory.^[3] The following are some seeming mechanisms of action.

Oxygen and glucose consumption

Piracetam increases the brain’s oxygen and glucose consumption, which may be responsible for the cognitive enhancement seen in those who are impaired. ^[4]
A study that looked at patients with Alzheimer’s Disease and unclassified dementia showed that piracetam increased brain glucose consumption by 8-10% in people with Alzheimer’s. No such increase was seen in the group who had unclassified dementia. ^{[5] [6]}

Glutamate receptors

Neurotransmitters carry information between neurons. The part of the neuron that receives neurotransmitters is called a “receptor.” The glutamate receptor, as the name implies, is the receptor for the neurotransmitter, glutamate. Glutamate is not only our main excitatory neurotransmitter, but it is also the precursor of GABA, our main inhibitory neurotransmitter. In very simple terms, an inhibitory neurotransmitter has a calming effect on the brain, while an excitatory neurotransmitter has a stimulant effect, and the body needs both in the right quantities to operate correctly.

Glutamate receptors are important for forming memories and learning. AMPA receptors are a type of glutamate receptors that are involved in memory storage. Piracetam acts upon the Glu2 and Glu3 AMPA glutamate receptors. Acting upon the Glu2 subtype of AMPA receptors seems to be a unique site for Piracetam. ^[7] Piracetam does not seem to interact with the Kainate and NMDA glutamate receptors.^[8]

GABA receptors

As you may have guessed, GABA receptors are the neuronal receptor sites for the neurotransmitter, GABA. Despite being a GABA derivative, Piracetam does not interact with GABA receptors as best we know. ^{[9] [10]}

Increase in cellular membrane fluidity

Piracetam may restore brain mitochondrial cell membrane fluidity ^[11] and presumably enhance brain cell function.

Mitochondrial dysfunction may have a causative role in Alzheimer’s Disease ^{[12] [13]}. One in-vitro study looked at the hippocampus membranes of Alzheimer’s patients and noted that the fluidity of these cells improved with Piracetam. ^[14] Findings that Piracetam may improve the fluidity of mitochondrial membranes and thus mitochondrial function have been supported in animal models of Alzheimer disease and aging. These findings may explain some of Piracetam’s cognitive effects in aging and brain dysfunctions. ^[15]

It is still unclear what this means to healthy young people. Piracetam seems to improve cell membrane fluidity in the brains of aged rats, but not in young rats.^[16]

Anti-platelet effect

Piracetam seems to have an antiplatelet effect ^{[17][18][19] [20] [21] [22] [23]} when administered in doses that have been used for cognitive improvement ^{[24] [25] [26] [27]}. The mechanism for such is not clear.

Conditions for which it has been used

Memory & Cognition in the Elderly

There appears to be a fair bit of evidence that Piracetam may improve memory and cognition in those who are cognitively impaired.

• A meta-analysis of 19 double-blind, placebo-controlled trials using Piracetam in 1,488 elderly patients with cognitive impairment or dementia showed that the amount of individuals who improved was 112% higher with Piracetam vs. placebo. The studies included in this meta-analysis looked for clinically meaningful improvement. Waegemans et al concluded that this meta-analysis provided compelling evidence of piracetam’s efficacy in a diverse group of aged cognitively impaired people.^[28]
• However, Flicker et al concluded that there was not enough evidence to support the use of Piracetam for dementia or cognitive impairment and that many of the piracetam trials for dementia were flawed.^[29]

Memory & Cognition in Healthy Subjects

There is weak evidence of cognitive benefit in young and healthy adults. Such benefit seems more apparent where cognition is not optimal, but there is not frank impairment (e.g., age-related decline). ^[30]

• One small double-blinded study showed that Piracetam improved backward word recall, which implies short-term memory enhancement.^[31]
• Another study showed that healthy people improved their verbal learning by 8% vs. placebo over 21 days.^[32]
• Yet another study seemed to indicate that Piracetam improved cognition in 18 people over age 49 who had no sign of cognitive impairment. ^[33]

Dyslexia

Piracetam has been associated with improvements in verbal learning and comprehensive in boys with dyslexia or learning disorders.

• A review of 11 double-blinded studies with nearly 600 boys aged 8 to 13 who had learning disorders or dyslexia showed that Piracetam improved comprehension and verbal learning.^[34]
• In one study, Piracetam improved verbal learning by 15%. ^[35]

Coronary Artery Bypass Surgery

Piracetam seems to prevent reduced cognition associated with coronary bypass surgery in some ^{[36] [37] [38]} but not all ^[39] studies.

Stroke

Human evidence is mixed on whether Piracetam can benefit recovery from stroke. ^{[40] [41] [42] [43][44]}

Safety

Piracetam appears fairly non-toxic. Adverse effects seem to be rare and of limited duration and limited to agitation, anxiety, clinical depression, drowsiness, headache, hyperkinesia, hypersexuality, insomnia, irritability, libido increase, nervousness, somnolence, tremor, and weight gain ^[45]. Piracetam appeared to be safe for as much as 18 months in Alzheimer’s patients. The LD50 is 5.6 grams/kg of body weight for rats and 20g/kg for mice.

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Summary

A fair amount of evidence shows that Piracetam can enhance cognition in those who are impaired and that it has an excellent safety profile. However, clinical studies of Piracetam in people who haven’t experienced cognitive decline is scant.

Although how Piracetam works is not entirely clear, interaction with AMPA receptors may be one of the routes of actions. Besides, there is evidence that it increases acetylcholine production as well as enhance the brain’s consumption of glucose and oxygen and improve fluidity of mitochondrial cell membranes.