Oxiracetam is one of the racetams, and is structurally different from Piracetam due to a single hydroxyl group. It is also used for Nootropic purposes such as enhancing learning in students or preventing against cognitive decline. Like all other racetams, it is a synthetic molecule that is not found in food sources or in nature.
When looking at the evidence for oxiracetam at this point in time it seems to have a fair bit of human evidence for reducing the rate of organic cognitive decline (a natural loss in cognition that occurs during the aging process that is not associated with any disease state) and with dementia, yet the lone study in persons with Alzheimer's showed no apparent benefit with oxiracetam supplementation. When it does aid in cognitive decline, it is somewhat comparable in potency to Alpha-GPC and seems to be slightly more potent than piracetam.
There is currently no evidence to support cognitive enhancement of oxiracetam in young humans with no cognitive impairment looking to increase memory formation.
When looking at animal evidence, oxiracetam appears to very reliably and potently prevent amnesia induced by a variety of anti-cholinergic or anti-glutaminergic compounds (injections of 3-30mg/kg in rats pretty much normalizing memory formation). It has been implicated in increasing memory formation in otherwise healthy and young rats/mice with no apparent cognitive impairment (suggesting that it can be used as a nootropic) but it appears to require at least a five day loading period.
Oxiracetam is a positive AMPA modulator similar in mechanism and potency (but not binding site) to both piracetam and Aniracetam but may have an additional benefit of increasing glutamate, acetylcholine, and D-Aspartic Acid release from activated but not resting neurons. This two-fold sequence (enhancing glutamate release and then positively modulating one of the receptors it signals through) ultimately increases metabolic activity in neuronal cells and memory formation.
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Supplementation of Oxiracetam tends to be in the dosage range of 1,200-2,400mg taken over the course of a day, either in two to three evenly spread dosing periods (such as three doses of 400mg or 800mg).
No studies have assessed whether or not oxiracetam would benefit from being taken with a meal, but it should be taken approximately one hour prior to a learning activity.
The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Oxiracetam has in your body, and how strong these effects are.
|Grade||Level of Evidence|
|A||Robust research conducted with repeated double blind clinical trials|
|B||Multiple studies where at least two are double-blind and placebo controlled|
|C||Single double blind study or multiple cohort studies|
|D||Uncontrolled or observational studies only|
|Level of Evidence ||Effect||Change||Magnitude of Effect Size ||Scientific Consensus||Comments|
Appears to reliably reduce the cognitive decline and related symptoms seen in dementia and other organic brain deterioration states, with particular efficacy towards verbal... show
See 2 studies
Although it has mechanisms and animal evidence to support improvements in memory in healthy youth, all human studies are currently in those with cognitive decline
|C||Functionality in Elderly or Injured|
The one study to note functional capabilities in persons with dementia given oxiracetam failed to find a significant treatment effect
See 2 studies
Appears to favor improvements in verbal fluency in persons with cognitive dementia, despite benefiting most parameters measured
|C||Quality of Life|
The one study to measure subjective quality of life in persons with dementia found a significant improvement with supplementation
|C||Symptoms of Alzheimers|
The lone study in persons with Alzheimer's rather than organic cognitive decline has failed to find any benefit associated with supplementation
Oxiracetam (full name of 4-hydroxy-2-oxo-pyrrolidinoacetamide and classification of ISF-2522) is a synthetic racetam molecule of the pyrrolidinone class with no known food sources, chemically derived from the parent Racetam compound Piracetam (2-oxo-1-pyrrolidinoacetamide) where the difference is the addition of a hydroxyl group upon the 4-carbon. Due to being a racetam molecule, it is commonly supplemented as a Nootropic compound.
Oxiracetam is a GABA analogue that serves to support phospholipid metabolism, positively modulate AMPA receptors, and interacts with neurotransmitter release with benefits to learning of a greater potency than Piracetam.
Oxiracetam is a chemically synthesized nootropic compound of the racetam class, derived from the structure of Piracetam in order to increase potency
Oxiracetam is very structurally similar to Piracetam, differing by only a hydroxyl group on the 4-carbon as shown above
A single oral dose of 800mg oxiracetam is able to reach a Cmax in the blood of s 21.6µg/mL at approximately one hour post ingestion (with another study noting that after 150 minutes the concentration was 8.658µg/mL), and had an overall AUC of 110+/-28µg/h/mL.
Despite the rapid decline, it nears baseline values at 24 hours and a preliminary study was still able to detect plasma levels (136ng/mL) 96 hours after oral ingestion of a single 800mg capsule.
Oxiracetam appears to be absorbed following oral ingestion, and experiences a rapid peak at about an hour post-ingestion followed by rapid declines in serum concentrations
Mechanistically, oxiracetam appears to increase long term potentiation (LTP) in isolated hippocampal slices at 1µM similar to Aniracetam. This increased signalling efficiancy in hippocampal cells is thought to be related to both an increased release of glutamate and D-Aspartic Acid from hippocampal cells when activated at a concentration of 0.01-5µM (without affecting outflow of glutamate or D-AA when the neurons were not activated) and enhancing glutaminergic signalling via AMPA receptors, which oxiracetam is a positive modulator of and AMPA receptors are the ones mediating late expression of LTP.
Although there is a less effective range, 0.1-1µM of oxiracetam also potentiates acetylcholine release from activated neuronal cells in hippocampal slices without affecting basal release and in vivo studies suggest that oxiracetam does not modify resting acetylcholine concentrations in the brain.
Finally, Protein Kinase C (PKC; an intracellular intermediate of memory formation) has been noted to be stimulated in hippocampal cells with oxiracetam both in vitro (200-600nM) and in vivo (47% increase at 100mg/kg injections) which is thought to be downstream of enhanced glutamae release (as activation of both AMPA and NMDA receptors can cause calcium influx into neurons and subsequently PKC activation, and oxiracetam does not have direct effects on calcium channels). The potency of 100mg/kg oxiracetam appears to be comparable to 600mg/kg orally ingested Alpha-GPC (or 50-200nM in vitro) and only in the hippocampus it was comparable to 30mg/kg orally ingested Aniracetam (200nM) and oxiracetam's influence on PKC (membrane bound at least) has been directly correlated to its memory enhancement properties.
May increase long term potentiation in the hippocampus, which is a phenomena thought to promote memory formation. This is possibly related to augmenting the release of excitatory neurotransmitters from activated neurons and enhancing their signalling via AMPA receptors, which then ultimately causes an increase in PKC activation
Studies that use otherwise healthy rodents and assess oxiracetam in memory formation or performance note that 30-100mg/kg is unable to benefit performance in a radial arm maze but is associated with improvements in step down retention, and in older rats acquisition was improved (acquisition in young rats given 3-30mg/kg oxiracetam before a water maze test have failed to find an effect).
Retention on an elevated maze plus test appears to see benefit with 3-30mg/kg oxiracetam in otherwise normal mice despite no inherent effects on acquisition (benefitting naive but not well-trained mice). This is a trend noted in other studies, with those using acute doses in trained rats failing to find benefit at doses up to 100mg/kg and studies using oxiracetam throughout training periods given to naive rats noting that doses as low as 25mg/kg can be effective in improving learning. Some other trials using single day protocols note no significant benefit of oxiracetam treatment while chronic usage tends to cause improvements in memory detectable after 4 months of supplement cessation, and that when benefits do occur they do not occur within prior to 16 hours after learning and instead manifest afterwards.
Errors in a 12-arm radial maze test have been reduced at 100mg/kg oxiracetam, but not lower doses (25-50mg/kg) in rats while overall learning performance was improved at 25mg/kg and 100mg/kg; this differs from a previous study using a less sensitive 8-arm radial maze test finding no benefit with 100mg/kg.
In studies using avoidance tests, avoidance acquisition is enhanced with 5 days treatment of 25-50mg/kg oxiracetam (to a greater degree than Piracetam at 100mg/kg) which has been replicated. Both studies have found a failure of single doses to benefit avoidance acquisition
The aforementioned increase in step down retention seen with oxiracetam also noted a failure of 100mg/kg Piracetam, suggesting more potency with oxiracetam. Other studies note that piracetam tends to be the weakest on learning (when comparing oxiracetam, aniracetam, and pramiracetam).
There may be some inherent improvements in memory formation seen with oxiracetam, but rodent studies suggest they are fairly unreliable
In animal models, oxiracetam has protected against scopolamine-induced amnesia and amnesia induced by NMDA antagonists including MK-801, AP-7, and AP-5 while in vitro glutamate (NMDA) antagonism by kynurenic acid is also inhibited. These anti-amnesiac effects occur in the 3-30mg/kg dosage range (intraperitoneal injections) and the higher dosages tend to abolish amnesia (no significant differences between the toxin with oxiracetam and control). Anti-amnesiac effects occur in both naive and well-trained mice.
The protection against scopolamine amnesia has been replicated in humans at 800-2,400mg oxiracetam taken one hour prior to scopolamine. While the animal studies using scopolamine suggest near absolute protection, the human study failed to note this degree of protection and while all tested doses were effective no dose-depedence was noted. Despite preventing amnesia, oxiracetam does not antagonize the stimulatory effects of scopolamine.
These protective effects are similar to Aniracetam and are near absolute against scopolamine, yet require a lower dosage as the rat studies use 3-30mg/kg of oxiracetam as intraperitoneal injections.
Appears to have potent anti-amnesiac effects against cholinergic antagonists in a much more reliable manner
A pilot study in multi-infarct dementia using twelve persons with cognitive decline given 400mg oxiracetam daily for four weeks (building up to 1,200mg daily) noted hetereogeneous improvements in a dose-dependent manner which seemed to favor psychosocial function rather than cognitive capacity and a later study in similar patients noted a significant improvement in verbal fluency.
Other studies note that in 60 elderly persons with organic cognitive decline given 400mg oxiracetam and building up to a maintenance dosage of 2,400mg for a subsequent six weeks appeared to reduce symptoms of cogntive decline, with oxiracetam being more effective than piracetam at improving memory (less effective at reducing agitation) and in a study of 272 persons with dementia noted benefits on cognitive decline on all three rating scales (IPSC-E, Blessed Dementia Scale and NMIC) while one in 58 persons again confirmed improvement memory formation and verbal skills.
In contrast to the above studies, the lone pilot study in persons with Alzheimer's has failed to find a benefit associated with oxiracetam therapy.
At the standard recommended supplemental dosages, appears to reduce the symptoms of cognitive decline in elderly humans with particular efficacy towards verbal learning. There is a fair bit of evidence towards this, and up to 1,200-2,400mg it appears to give dose and time-dependent benefits
There may not be a benefit towards Alzheimer's disease, and Parkinson's disease is untested
Oxiracetam appears to be active in enhancing signalling through the AMPA glutamate receptor as a positive modulator at 1-100µM (no clear dose dependence) with a KD of 214+/-35nM which is a property similar to both Aniracetam (176+/-7nM) and Piracetam (KD 190+/-51nM). Oxiracetam does not displace aniracetam binding from the AMPA receptor, and when investigating further it is found that these molecules increase the Bmax of the low affinity component of AMPA receptor signalling but not the high affinity component and this increase in Bmax is comparable to the other two mentioned racetams.
Oxiracetam appears to be an AMPAkine similar to Aniracetam and Piracetam, and can enhance signalling through these receptors. At least in regard to this mechanism, all molecules appear to be equally efficacious
The increased signalling efficiancy in hippocampal cells is thought to be related to an increased release of glutamate and D-Aspartic Acid from hippocampal cells when activated at a concentration of 0.01-5µM without affecting outflow of glutamate or D-AA when the neurons were not activated, although 100µM causes a slight increase.
Appears to augment glutamate and D-aspartic acid (agonist at glutamate receptors) release from neurons after neuronal activation, without per se affecting spontaneous release
As mentioned in the memory section, oxiracetam at 3-30mg/kg injections into mice prevents amnesia induced by glutaminergic antagonists MK-801, AP-7, and AP-5. In vitro, the suppression of noradrenaline release caused by NDMA antagonists is prevented with oxiracetam at 1μM (with similar potency to Aniracetam).
Appears to prevent amnesiac effects of glutaminergic antagonists
Oxiracetam has been noted to prevent the reduction in acetylcholine concentrations induced by electroshock therapy in rats, which was accompanied by preventing amnesia. Since phygostigmine (an acetylcholinesterase inhibitor like Huperzine-A) is known to prevent amnesia secondary to preserving acetylcholine concentrations it is hypothesized that the anti-amnesia properties of oxiracetam against cholinergic antagonists like scopolamine are due to preserving acetylcholine concentrations, which has been noted against scopolamine-induced amnesia as well with oxiracetam at 50-100mg/kg (partial preservation in the cortex and hippocampus but not striatum). Aniracetam was noted to be slightly more protective in the hippocampus, but inactive in the cortex.
That being said, this is unlikely to solely explain the antiamnesiac effects since depletion of catecholamines (despite preservation of acetylcholine) abolishes the protective effects of oxiracetam against scopolamine.
The decline in acetylcholine concentrations seen with cholinergic antagonists or amnesiac stressors appears to be prevented to a large degree with oxiracetam, which is thought to play a role in the anti-amnesiac properties (but is likely not the only explanantory factor)
In rats not given anti-cholinergics, both oxiracetam and aniracetam (100mg/kg) fail to significantly modify acetylcholine or choline concentrations in any tested brain region.
Independent of increasing acetylcholine concentrations, oxiracetam appears to increase acetylcholine utilization in the cortex and hippocampus at 100-300mg/kg injections. Repeated daily doses of oxiracetam was noted to increase acetylcholine utilization by 31% relative to control, and appears to be more potent and prolonged than Piracetam.
Furthermore, despite no apparent changes in basal acetylcholine levels in vivo a concentration of 0.1-1µM oxiracetam in hippocampal slices appears to augment acetylcholine release. Basal outflow of acetylcholine from these neurons when not activated was not modified. It is thought that this enhanced release explains the increase in acetylcholine uptake noted with oxiracetam inherently which causes a relative depletion of intracellular acetylcholine levels when choline uptake is blocked (which can be explained by increased release rates).
Despite not influencing resting acetylcholine concentrations in the brain, appears to enhance the efficiency of acetylcholine signalling and the release of acetylcholine from activated neurons
Oxiracetam appears to have psychostimulatory properties as assessed by impaired sleep, which is thought to be related to the cholinergic properties as the cholinergic systems of the brain stem/basal telencephalon facilitate arousal. This arousal effect is thought to at least partly explain the promnesiac (memory enhancing) properties of oxiracetam.
Studies that measure locomotion (a test that responds reliably to amphetamines and naive animals given Caffeine) fail to show a response with oxiracetam and have at times been shown to cause a nonsignificant increase at 100mg/kg, suggesting that the psychostimulatory effect is lesser than other drugs.
Appears to have psychostimulatory properties, although to a relatively small degree
While the stimulatory effects of oxiracetam do not perturb EEG readings during sleep (thought to be reflective of sleep quality), it appears to prolong sleep latency (the time required to fall asleep) in a dose dependent manner reaching a prolongation of 30% at 50mg/kg and 37.9% at 100mg/kg.
Does not appear to impair sleep quality, but does appear to prolong the time required to fall asleep which is due to the psychostimulatory properties
Incubation of 0.01-1µM oxiracetam in hippocampal slices fails to modify the release of noradrenaline upon activation of the neurons, Piracetam was also ineffective on these three neurotransmitters and the lack of effects on noradrenaline replicated even at 10µM.
The inhibition of noradrenaline release from NMDA antagonists seems to be reversed with oxiracetam (1µM), which is due to oxiracetam's ability to reduce the effects of glutamate antagonism. Despite this preservation, oxiracetam does not enhance NMDA-induced noradrenaline release.
Oxiracetam does not appear to influence dopamine release from activated neurons at the standard concentrations of 0.1-1µM but dopamine (as well as the other catecholamines) appear to be implicated in the anti-amnesiac effects of oxiracetam, as the well established protective effect against the anti-cholinergic drug scopolamine does not occur with low dopamine nor noradrenaline concentrations.
The dopaminergic antagonist haloperidol, which is able to cause amnesia (specifically for aversive learning, which dopamine is thought to modulate), has this amnesiac property prevented with preadministration of 50mg/kg oxiracetam. The reduction in locomotor activity commonly seen with dopaminergic antagonists was not prevented with oxiracetam.
The anti-amnesiac effects of oxiracetam appear to extend to preventing the amnesia associated with dopamine antagonists
Oxiracetam (0.01-1µM) in hippocampal slices has failed to modify the release of GABA when the neurons were activated or at rest.
Diazepam (benzodiazepine) induced neuronal cell death appears to be attenuated by oxiracetam between 50-100mg/kg (1500mg/kg augmented damage).
Does not appear to significantly change GABA kinetics
Interestingly, despite oxiracetam having anti-amnesiac properties against dopaminergic, cholinergic, and glutaminergic antagonists it has failed to prevent the amnesia associated with diazepam (an amnesia causing benzodiazepine) at 3-30mg/kg. This differs from the effects of Piracetam, and due to having no explanation at this point in time and a trend to protect from amnesia further studies are required.
Oxiracetam may prevent benzodiazepine induced amnesia, but the lone study assessing this was not enough to confirm whether this property does or does not exist
Oxiracetam does not appear to modify serotonin release from activated neurons at 0.01-1µM nor does an impairment of serotonergic signalling impair the anti-amnesiac effects of oxiracetam against scopolamine.
No significant interactions with serotonin are known to occur with oxiracetam
The organotin neurotoxin trimethyltin which impairs memory formation for up to four years associated with excessive neuronal death in the hippocampus (and other brain regions to a lesser degree) has its toxicity alleviated be pre-treatment, but not post-treatment, of 3-30mg/kg oxiracetam over seven days as assessed by social recognition tests (histology not examined).
At least one study has noted that oxiracetam incubated with astrocytes over a period of two weeks has resulted in an increase in ATP concentration of the cells.
Coingestion of amphetamine with oxiracetam in mice does not suggest an interaction in regards to locomotion (increased per se with amphetamine but not oxiracetam, with the combination not outperforming amphetamines in isolation) yet appeared to be additive or synergistic in regards to avoidance acquisition (learning). This synergism was also noted with amphetamine with Piracetam and has been replicated elsewhere.
Appears to work well with amphetamine compounds in regards to improving cognition and does not affect locomotion, but whether this is an additive effect or synergistic and the mechanisms mediating this require further testing
Nicotine is a cholinergic agonist, and oxiracetam (50mg/kg) paired with nicotine (0.25-1mg/kg) in mice appears to increase the nicotine-induced improvement in step-down latencies (passive avoidance) by 34-74% without significantly modifying locomotion.
On the parameter that oxiracetam seems to reliably improve (avoidance learning), nicotine appears to be additive and/or synergistic with oxiracetam
Phygostigmine is an acetylcholinesterase inhibitor able to independently improve memory formation, but in combination with oxiracetam does not display any apparent additive properties in mice.
Acetylcholinesterase inhibitors are surprisingly not synergistic with oxiracetam, despite increasing acetylcholine concentrations
When looking at human intervention studies, oral supplementation of up to 1,600mg oxiracetam daily in persons with cognitive decline does not have any significant side-effects when compared to placebo.
One study conducted in pregnant mice given 50mg/kg has failed to find teratogenic effects of supplementation when assessing the youth, instead finding an improved performance on a radial maze test (choice accuracy) and grooming behaviour when compared to control.
Limited evidence in pregnant subjects, but the animal research suggests it may even be beneficial
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