Piracetam

Piracetam (known as (2-oxo-1-pyrrolidine-acetamide) is a synthetic compound of the racetam family, and shares the characteristic 5-carbon oxopyrrolidone ring structure.^[1] Piracetam was the first of the racetam family, and developed by UCB Pharma in Belgium,^[2][1] and is also known as Nootropyl or UCB6215.^[3] It is a nootropic compound, derived from the greek word noos (mind) and tropein (towards); ultimately meaning 'towards the mind'.^[4]

Synthetic molecule designed to enhance brain function. Piracetam is the basic 'racetam' molecule of a family of related compounds

Piracetam tends to share structural similarity to the neurotransmitter GABA, as it is a cyclical derivative; as such it retains two nitrogens in its structure with one amine bearing the two-carbon side chain that has the other nitrogen within it. The skeleton structure and computed minima via conformational analysis (PBE0/6-31G(d,p)) are depicted below; via this article.^[5]

Piracetam does not occur naturally in any food or plant source.

In youth given 1600mg Piracetam orally in a fasted state, a C_max of 27.6+/-1.3ug/mL is reached in 0.90+/-0.15 hours and a 24 hour AUC of 145ug/min/mL is achieved.^[6]

In older individuals, the same fasted 1600mg dose yields a C_max of 32.82+/-3.6ug/mL in a similar (0.86+/-0.14h) T_max, but the 24 hour AUC is extended to 188ug/mL/min; this is thought to be due to a lower urinary excretion rate.^[6]

Due to interactions with a cell membrane (particularily in blood cells), a possibility of Piracetam not following linear excretion and following a loading prinicple is possible;^[7] when excreted, it is exclusively excreted in the urine via glomerular filtration.^[8]

Increased brain oxygen consumption has been noted mostly during periods of insufficient neuronal oxidation following Piracetam ingestion^[9] or incubation with neurons.^[10] As these observations are indicative of glucose consumption, interactions with glucose oxidation were ingestigated and found to be increased in rats^[11] and replicated in humans following two 6g infusions of Piracetam.^[12]

Interestingly, the aforementioned study divided dementia patients into those with Alzheimer's and those without and only in the Alzheimer's group (where glucose consumption is significantly perturbed) was there a statistically significant increase of 8-10% glucose consumption,^[12] suggesting a mechanism unique to cognitively impaired persons.

Piracetam (and Leviracetam) have been found to antagonize an inhibition of glucose uptake into erythrocytes induced by hypnotic drugs (including Melatonin)^[13] which is likely related to membrane fluidity.^[14][13] A possible connection between membrane fluidity and glucose consumption exists, although plausible mechanisms also exist for glucose consumption being enhanced downstream of modulating ion currents and action potentials.^[1]

Overall, Piracetam increases glucose and oxygen consumption in brains which precedes cognitive improvement (as these benefits are global (not favoring certain brain regions) and more significant in cognitively impaired persons, both of which are in accordance with interventions in humans).

The exact mechanisms underlying the enhancement of glucose and oxygen consumption are currently not established

Influences on neurons may be mediated by positively modulating AMPA-gluatmate receptors, which can increase calcium influx into neurons and increase the density of AMPA receptor binding sites.^[15] This mechanism of action is similar to Aniracetam and oxiracetam^[15] and like those two, Piracetam does not significantly act on or modulate the other two glutamate receptor subtypes, NMDA and Kainate receptors,^[15][1] although 500mg/kg to aged mice for 2 weeks may increase the amount of NMDA receptors expressed.^[16] Increased receptor expression has been noted with acetylcholine receptors as well only in aged mice (no effect in youth), suggesting that this is a basic mechanism not unique to glutaminergic receptors.^[17]

Piracetam appears to bind to Glu2 and Glu3 subunits of AMPA receptors, of which Aniracetam binds to Glu3 mostly; binding to Glu2 is a unique site for Piracetam.^[18]

Piracetam shows affinity for two subsets of AMPA (glutamate) receptors, Glu2 and Glu3, and may attenuate the rate of action potentials. It does not appear to directly act upon the other two glutamate receptors (Kainate and NMDA) although the ability of piracetam to possibly increase receptors in general in aged mice may influnce these two receptor classes

Piracetam was initially shown to reduce high voltage-dependent calcium influx into neurons^[19] has been found to inhibit CA_V2.2 calcium channels in some peripheral and central neurons with an IC₅₀ value of 3.4umol/L and a maximal efficacy of 94+/-2% inhibition at 2000umol/L.^[20] The effects of Piracetam were independent of a G-Protein Coupled Receptor (GPRC), were reversible, and were not occluded by noradrenaline (which had some additive benefits with Piracetam).^[20] These effects were noted in superior cervical ganglion cells (large percentage of CA_V2.2 channels) and in CA1 hippocampal neurons, where Piracetam at 10umol/L reduced action potential frequency from 133+/-11% (action potential on regular neurons, with 100% resting levels) to 97+/-10%, excitatory post-synaptic potentials were reduced from 80+/-7% in control to 18+/-5% with Piracetam.^[20] These mechanisms are similar to that of Leviracetam.^[21]

The authors noted a reduction of resting membrane potential after action potential, and suggested that other ion channels could be getting modified by Piracetam.^[20]

May interact with Calcium Channels, where it attenuates excessive neuronal firing

Piracetam is initially formed via using Gamma-Amino Butyric Acid (GABA) and, after losing a molecule, assuming a cyclical shape.^[22] That being said, Piracetam does not appear to interact with GABA receptors.^[23][20]

No significant interactions with GABA receptors despite its origin being a GABA derivative

Piracetam can interact with phospholipid structures due to having high affinity for the polar head of the phospholipid,^[24] which may underlie changes (increases) in membrane fluidity^[25] that may act in a therapeutic manner, as it had no apparent benefit to membrane fluidity in otherwise healthy young brain slices (independent of species tested).^[26]

Membrane fluidity is lessened (rigidity promoting) in instances of oxidative and lipid peroxidative stress, where Piracetam appears to act to normalize fluidity.^[27] A normalization of mitochondrial function secondary to preserving fluidity is noted in instances of excessive oxidative stress^[14] and perturbed fluidity in the mitochondria is associated with states of cognitive decline.^[28][29] As Piracetam is implicated in increasing mitochondrial membrane fluidity in aged brain only^[26] and this preservation of mitochondrial membrane potential is associated with improvements in Aß_1–42 levels and preserving neurite outgrowth in animals.^[30]

Appears to preserve membrane fluidity, which may be due to increasing membrane fluidity in states where fluidity is compromised. These benefits correlate better to instances of cognitive improvement in cognitive degeneration than do AMPA or Calcium channel modulation/inhibition

Piracetam may enhance glutamate release from neuronal synapses, but this effect has not been established in vivo.^[31][23]

One study in 16 otherwise healthy subjects (3:1 male) using 400mg Piracetam taken thrice a day (1200mg total) for a period of 14 days conducted in a matched pair manner (8 given the drug in double-blind manner) noted that while no differences existed at baseline or 7 days in, that 14 days in the Piracetam group was significantly better at a test of backwords word recall; suggesting improvements to short-term working memory.^[32]

One study has noted that, using non-dyslexic persons as a control to test the efficacy of Piracetam in dyslexics, that the apparently healthy controls experienced an 8.6% improvement relative to placebo on measures of verbal learning; this was seen with 4.8g Piracetam over 21 days.^[33]

One study has been conducted on 18 persons aged 50 or above but with no salient signs of cognitive decline, which noted that thrice daily doses of 1600mg (4800mg daily) was associated with general improvement in cognition on a battery of tests, with no specific subset showing a large magnitude of benefit.^[34] This study was single blind and lasted 8 weeks, and the blinding may have failed due to the majority of the subjects receiving Piracetam properly guessing so.

In young and otherwise healthy adults, some (quite weak) cognitive enhancement is apparent. These benefits are more pronounced in populations where cognitive impairment may not be present but optimal cognition is likely not present either (such as 'organic' cognitive decline associated with healthy aging)

A meta-analysis on Piracetam assessing 19 double-blind trials noted a significant benefit associated with Piracetam when it came to persons with some manner of cognitive ailment.^[35] This study built of a 1997 Cochrane Meta-Analysis that assessed 5 studies and found benefit with an Odds Ratio of 2.89 (95% CI of 1.01-8.24) barely showing statistical significance with limited studies,^[36] and noted that when assessing 19 studies that met the inclusion criteria of double-blind and parallel studies (54 in total, excluding 35 including cross-over) noted that in 1,488 persons the Odds Ratio for improvement with Piracetam over Placebo was 3.35 (95% CI of 2.70-4.17) using fixed effects model, and a similar OR and CI were noted for Mantel Haenszel and random effects model.^[35] Excluding the two most statistically influencing studies (one of which is located online^[37]) reduce the OR to 2.50 (95% CI 1.96-3.17).^[35] Numerically, this meta-analysis concluded that the amount of people reporting improvement is 112% higher (60.9% in piracetam and 32.5% in placebo) with piracetam relative to placebo and no effects on cognitive or worsening thereof is reduced 34.4-37.9% relative to placebo (magnitude of improvement not assessed due to hetergeneity of the data).^[35]

This aforemented Meta-Analysis excluded 3 double-blind trials (only one of which is located online^[38]) despite reporting benefit due to note reporting categorical data that could not be put into meta-analysis.^[35] Studies included in meta-analysis that can be located online are cited as follows.^{[39][40][41][42][43][37]}

In a self-report survey from outpatients of cerebrovascular disorders, Piracetam showed a modest memory improvement,^[44][1] a much greater response was seen in in vivo models of traumatic brain injury.^[45]

There appears to be sufficient evidence to indicate that an improvement in cognitive function exists in persons with degenerating cognitive function. Lots of studies not published online or otherwise just presented at symposiums, however, Piracetam may have slightly more benefit in instances of neural trauma when compared to its benefits in organic cognitive decline

One review exists on Dyslexia in particular when it comes to Piracetam^[46] where 4 double-blind crossover studies and 7 double blind studies (encompassing 591 dyslexic or learning disordered boys aged 8-13 and one study with 30 16-21 year old dyslexics) and overall tended to note improvements to verbal learning and comprehension associated with 1.2-3.3g Piracetam daily for up to 8 weeks while other non-verbal parameters measured were much less constant.^[46]

When dyslexic studients are given Piracetam and paired against otherwise healthy peers, a greater increase appears to be apparent with Dyslexic students (15% more than placebo) than with non-dyslexic counterparts (8.6% more than placebo) over a period of 21 days.^[33]

Is associated with improvements to verbal learning and performance in Dyslexics

Piracetam seems to be an effective adjunct therapy to valproate in models of myoclonus epilepsy.^[47]

At least one study noted benefit to Tardive Dyskinesia symptoms, but the benefits were only seen as long as treatment was maintained.^[48]

Piracetam seems to have clinical efficacy, relative to placebo, in reducing the cognitive impairment/dementia seen with aging in vivo,^[35] although many trials are of short duration.^[36]

Acutely, Piracetam seems to have efficacy in alleviating the reduction of cognitive function seen with coronary bypass surgery.^[49][50]

One trial assessing the neuroprotective effects of an acute dose of Piracetam prior to open-heart surgery failed to find a benefit relative to placebo when cognition was assessed 3 days after surgery,^[51] this is in contrast to apparent neuroprotective effects on coronary bypass surgery, which has been noted previously.^[50][52][49]

Piracetam shows promise in alleviating damage done from strokes in animal models,^[53] but according to one systematic review, Piracetam has minimal human evidence to support this claim.^[54]

One study on ischemic cerebrovascular disease in persons suffering from aphasia (impairment of language ability, in this case due to brain hypoxia) using 4.8g Piracetam daily for 6 months after stroke noted that, after assessment via the GAT, NIHSS, mRS and BI rating scales, that while there was significant improvement in regards to auditory comprehension there was no significant influence on the other measured parameters of spontaneous speech, reading fluency, reading comprehension, repetition, and naming when compared to placebo.^[55] These null results are in contrast to previous research, where 6 weeks of 4800mg Piracetam was associated with improvements in 6 languages tests whereas placebo only improved in three,^[56] and one other study assessing brain waves which suggested improvements.^[57]

Mixed evidence on the benefits of Piracetam on recovery of language function after Stroke, with either significant improvement existing or minor trends towards improvement

One study assessing the effects of 4.8g Piracetam on whether or not it could reduce Cocaine dependence found that, after 10 weeks, the Piracetam group was associated with more Cocaine use than placebo and was rated as worse than both placebo and the other tested group, Ginkgo Biloba, which had no effect.^[58]

The lone study assessing cocaine dependence has noted an increased dependency of cocaine dependence associated with Piracetam usage

Piracetam appears to have analgesic properties in response to acute inflammatory hyperalgesia at 30-300mg/kg oral intake (in rats) an hour prior to testing, with dose-dependent reductions in pain reaching up to 41% inhibition of acetic acid induced writhing.^[59] These benefits were thought to be secondary to the antiinflammatory properties of Piracetam.^[59]

There appears to be analgesic properties against acute inflammatory pain

Piracetam has been shown, via self-report, to be somewhat effective at reducing depression associated with cerebrovascular disorders.^[44] These have not been investigated in otherwise healthy persons.

Breath Holding Spells (BHSs) are periods of episodic apnea that sometimes occur in otherwise healthy children (starting at 6-28 months, usually fading by 5-9 years old), where most of the time it is benign yet causes distress to the parent of the unbreathing child (with only 21% of parents, being told it is benign, find relief^[60]); it is thought to be due to the autonomous nervous system^[61] with a relationship between symptoms and diffuse cerebral anoxia.^[23][62][63]

Piracetam is tested for alleviating BHS in children. One study of 40 children (5-60 months; average 32.5) using 50mg/kg Piracetam daily via Stimulan syrup for a period of 4 months was associated with significantly improved symptoms. While both groups had 5-5.5 attacks per month at baseline, placebo maintained at an average 4-5 attacks per month while Piracetam was assocaited with 0-1 attacks, with 72.08% symptoms reduction within one month and 83.85% symptom reduction after 4 months; 5-6 patients seemed to have a delayed response, taking two months to be affected.^[64] This study builds off previous non-blinded studies where Piracetam (50-100mg/kg daily, only 100mg/kg was used if no effect was observed at 4 weeks) over 3-6 months (with supplemental Iron is too low, as that is tied to pathology; no differences between iron treated and untreated groups) abolished BHS in 81% of children, attenuated attacks in 9%, and had no significant effect on 10%.^[65] A much earlier double-blind study with 40mg/kg (divided into two doses daily) Piracetam where 92.3% of children reported benefit; compared to 29.7% of placebo.^[66]

These studies do not seem to report any significant difference between cyanotic or pallid BHS symptoms, benefitting both to equal degrees.^[64][65] Some case studies suggest this may extend to Leviracetam, another Racetam compound.^[67] Additionally, in these studies on children, the doses (50-100mg/kg bodyweight) used for the specified durations are not associated with any observed side effects.^[64][65][66]

Piracetam appears to be highly effective and safe in the treatment of Breath Holding Spells (BHSs) in children, and has not been associated with toxic effects at the dose range of 40-100mg/kg bodyweight

A pilot study in Ataxia where 8 patients were given intravenous doses of 30-60g Piracetam daily (escalating dose) for 14 days (based off a previous case study with high dose Piracetam^[68]) noted improvements in clinician assessment of Ataxia via the International Cooperative Ataxia Rating Scale (ICARS) where score was dropped from 39.4+/-17 to 30.9+/-14.9, a 21% improvement on average.^[69] Significant improvement was seen globally and on posture/gait subscales, but not kinetic functions, speech and oculomotor disorders where it trended to improve the former two with no effect on oculomotor disorders; no side effects were reported by the patients.^[69]

At least one study existed in Schizophrenic patients (n=40) where 4.8g of Piracetam daily for 4 weeks in addition to standard antipsychotic therapy noted minor decreases in global rating of symptoms while a more significant decrease was noted in the subscales of Tardive Dyskinesia; this apparent benefit was mediated by unknown mechanisms.^[48]

Anti-platelet effects of Piracetam have been known to occur in humans for quite some time (1975^[70]) that are apparent in rats at 200mg/kg^[71] and in humans at 4.8-9.6g daily (three doses of 1.6g) with no practically significant efficacy with 1.6 or 3.2g in a day.^[72]

Mechanisms underlying these effects are somewhat elusive, and at least one study has noted that the IC₅₀ values (concentration required to exert 50% effects) are 10-fold higher outside the body in vitro than they are achieved in vivo when measuring extracted serum.^[71]

In hyperactive disorders (acute stroke, Type II Diabetes, Raynaud's phenomenon), a normalization of platelet function occurs.^[73][74] One possibility is the rheological effects of Piracetam (increasing membrane fluidity) normalizing cell function, but other possibilities that have not been excluded are reducing the sensitivity of platelets to ADP or inhibition of Thromboxane A₂ synthesis (a proinflammatory prostaglandin).^[71][72]

Appears to inhibit blood clotting at doses in the higher range for those used in cognitive enhancement (4.8g or above), with the mechanisms currently unknown

One large intervention that was comparative between Piracetam at 4.8g (1600mg thrice a day) and Aspirin (Acetylsalicyclic Acid; ASA) at 200mg thrice a day over the course of 2 years followup in persons who suffered a stroke (n=563) noted that there were no significant differneces between the two groups in regards to preventing death and stroke, but that Piracetam was significantly better tolerated (with 12.5% of persons in Piracetam reporting adverse events, and 21.8% with ASA).^[75] That being said, the apparent non-response to ASA that occurs in some persons^[76] also appears to apply to Piracetam.^[75]

4.8g daily (in three doses of 1.6g) appears to be optimal due to peak efficacy at 1-4 hours post consumption and declining efficacy 8-12 hours after consumption.^[72]

May be effective as prophylaxis after strokes to maintain blood flow, with one study suggesting no significant differences when compared to Aspirin (commonly the first choice for prophylaxis after stroke)

It is known that mediators in the inflammatory pain response (hyperalgesia) are prooxidative molecules, as inflammatory cytokines (such as TNF-α) can cause intracellular increases in prooxidants such as H₂O₂,^[77] peroxynitrate,^[78] and superoxide^[79] mediate the subsequent pain response. Preventing these oxidative molecules either directly (antioxidants) or indirectly via preventing the actions of inflammatory cytokines can reduce hyperalgesia.^[80]

Oral ingestion of 30-300mg/kg Piracetam to rats prior to inflammatory stimuli (carrageenin) was able to reduce myeloperoxidase (MPO) activity at 100mg/kg, and this effect was replicated with localized treatment.^[59] When looking at mechanisms, it appears that piracetam failed to reduce TNF-α levels in serum but prevented TNF-α from inducing secretion of IL-1β and MPO and reducing prooxidative changes.^[59]

Piracetam appears to prevent TNF-α from causing an inflammatory response, which underlies the pain reducing effects of Piracetam by preserving intracellular oxidant status

One study has been conducted in Acute Acoustic Trauama (AAT) with Piracetam (dose not specified) paired with steroid therapy (Prednisone at 25mg IV thrice daily) noted that the combination therapy was able to preserve hearing function in persons dependent on time of intervention; 65% of persons with intervention in under an hour experinced benefit compared to 23.3% (1-24h) and 13.3% (over 24 hours later), with the early intervention outperfoming the latter two groups on auditory tests.^[81] This study investigated Piracetam as the pathology of AAT involves hypoxia in the cochlea,^[82] which Piracetam is though to preserve.

Inhibition of steroid synthesis in general^[83] and an adrenalectomy (removal of the adrenal glands) appears to abolish the memory-enhancing effects of Piracetam^[84] and this learning inhibition is fully reversed when optimal circulating levels of corticosterone (3ug/mL) and aldosterone (30ng/mL) are maintained; suggesting their importance in the signalling of Piracetam.^[85]

Partial restoration of effects are noted with either aldosterone or corticosterone, both of which signal through the mineralocorticoid type I receptor (as blocking with epoxymexrenon abolishes the effects of Piracetam regardless of serum hormone levels)^[86][87] which also appears to exist when the glucocorticoid receptor is selectively blocked.^[86] and the interactions of Racetam compounds and corticosteroids appear to follow a U curve, with higher doses of cortisol attenuating the benefits of Piracetam, with 30-100mg/kg Corticosterone in otherwise normal mice abolishing the effects of Piracetam with no apparent inhibition at 3mg/kg; same effects were noted with supraphysiological levels of 100-300mcg/kg aldosterone.^[88]

One study in chicks that injected Piracetam noted an increase in corticosterone, where a 50mg/kg injection increased corticosterone levels 24.9% after training.^[86]

This inhibition of actions applies to most basic racetam compounds including Aniracetam, Oxiracetam, and Pramiracetam.^[89][84][88]

Corticosteroids and Aldosterone are critical for the memory enhancing effects of Piracetam, probably via the Mineralocorticoid Type I receptor; excessive levels of either hormone abolish the benefits in a similar manner as does no circulating levels

Racetam compounds are typically supplemented alongside cholinergic compounds as their mechanisms are highly interrelated.^[90] Administration of Piracetam causes a decrease in acetylcholine levels in the hippocampus^[91] with unknown mechanisms.^[92]

In a few animal models, choline supplementation has been noted to increase the memory and cognitive effects of Piracetam when coingested.^[93][94] These effects seem to be greatest in models of slight cognitive impairment, such as aging.^[95]

These studies on Piracetam and choline synergism have not been tested in humans.

May augment the relatively poor memory enhancing effects of Piracetam in otherwise healthy animals, but administration of choline alongside Piracetam is not a prerequisite to its efficacy and has not been tested in humans

Chronic alcohol consumption is related to build-up of lipofuscin in brain tissue^[96] of which piracetam has been implicated in reversing (both in rats)^[97] after cessation of alcohol and treatment of piracetam. Piracetam is also implicated in increasing synaptic reorganization^[98] and alleviating further loss of neurons after alcoholism.^[97]

May attenuate some pathology associated with excessive alcohol consumption (alcoholism)

Cinnarizine is an anti-histamine used for motion sickness and that is sometimes combined with Piracetam as a combination product called Fezam (Phezam) or Omaron.^[99][100] It is touted that the ingredients are synergistic with each other in regards to increasing cerebral oxygenation, although the synergism has not been shown experimentally. Both compounds in isolation are effective at preventing hypoxia-related damages however.^[101][102]

Said to be synergistic, this has not yet been demonstrated

Morin is a flavonoid compound found in Maclura pomifera (Osage Orange), tinctoria (Old Fustic), Morus Alba, and Psidium guajava (Guava) that serves as an inhibitor of CYP3A4 and P-Gyp. A 10mg/kg Morin pretreatment for a period of 7 days in rats was able to increase the AUC of a 50mg/kg Piracetam dose 1.5 and increase its C_max by 1.45, but acute Morin ingestion failed to mimic these results.^[103] The authors suggested that a Morin-rich diet could influence pharmacokinetics of Piracetam.

May increase apparent bioavailability when measured in serum due to enzyme inhibition

Asparagus Racemosus at oral doses of 50, 100, and 200mg/kg (an extract concentrated for 62.2% saponins) was not significantly different than 500mg/kg Piracetam in improving spatial memory;^[104] no dose-dependence was seen despite the acetylcholinesterase properties of Asparagus Racemosus being dose-dependent.

100mg/kg Clitorea Ternatea water extract is not significantly different than 50mg/kg Piracetam in memory retention and spatial learning when measured after 9 days, although Piracetam outperformed Clitoria after the first day.^[105]

After hypoxic injury to the brain, 100-200mg/kg Ginger appears to be as effective as Piracetam at 250mg/kg in improving memory recovery over time; both underperformed relative to Aricept (Donepezil).^[106]

Adverse effects, although rare and of short duration^[1] are limited to anxiety, insomnia, drowsiness and agitation. It may be safe for up to 18 months in humans at doses of 3.2g daily^[47] with one year-long study in ambulatory patients with Alzheimer's using 8g daily reporting no side effects.^[43] Piracetam also appears to have clinical usage (and a lack of side effects) when used in youth for the purpose of Breath Holding Spells at oral doses of 50-100mg/kg bodyweight in children aged 5-60 months.^[66][65][64]

In animal models (rodents, dogs, and marmoset), an LD50 failed to be established at the dosage of 8-10g/kg bodyweight in those three species.^[23][107]

Piracetam appears to be quite non-toxic at common doses used, and a few studies exceeding recommended dose (4.8g daily) fail to find toxicity associated with Piracetam

In general, racetams (usually referring to Class I racetams; Pi-, Ani-, and Oxi-) are said to have little side effects and low toxicity rates at commonly used dosages and up to 12g for up to 8 weeks.^{[23][108][109]} However, a possibility for adverse drug-drug interactions persists for Piracetam due to it interacting with blood in an anti-clotting manner (and such, caution should be taken when pairing Piracetam with pharmaceutical blood thinning agents such as Warfarin or potent nutraceutical options).