Nefiracetam is a cognitive enhancer (Nootropic) of the Racetam class, derived initially from the parent molecule Piracetam but it shares most structurally similarity to Aniracetam. Both nefiracetam and aniracetam are fat soluble racetam drugs for the purpose of memory enhancement or the treatment of cognitive decline.
In regards to acute usage, a single dosage of nefiracetam does not appear to significantly affect memory formation. Nefiracetam appears to be able to increase memory formation when taken daily over a prolonged period of time (7 days or longer), which has been repeatedly shown in animal studies with some limited human evidence suggesting the same. Prolonged supplementation is also associated with a higher rate of neurogenesis, which is not seen acutely.
The mechanisms of nefiracetam seem to be linked back to two pathways. One of these pathways is prolonging the opening of calcium channels (tied into PKA and a Gi/o protein) which enhances signalling of a receptor independent of the synapse, and the other pathway seems to be tied into PKC and CAMKII which then augments signalling through cholinergic receptors (which then releases most excitatory neurotransmitters from the presynaptic level in a manner similar to Nicotine).
The former pathway (calcium channels) appears to be critical for long-term potentiation, whereas the latter pathway (PKC/CAMKII) appears to be vital for neuronal signal enhancement.
Some other minor pathways include being a partial agonist at the Glycine binding site of the NDMA receptor (may enhance signalling when there are subpar levels of glycine, but attenuates excessive signalling) and increasing affinity of the muscarinic acetylcholine receptors for its ligand, acetylcholine.
Nefiracetam is a cogntive enhancer that appears to promote memory formation, and it does so via enhancing signalling of acetylcholine and glutamate at the synapse and then prolonging the calcium in the activated neuron. It does not appear to work acutely, but requires daily supplementation
In regards to the potential toxicity of nefiracetam, it does appear to be reliably toxic in dogs at doses that are much higher than the recommended supplemental dosage; lower doses seem to be free from toxicity, and these lower doses barely fit into the recommended dosage range.
That being said, there is evidence to suggest that this toxicity is exclusive to canines as it has not been detected in rats nor monkeys. There is insufficient human testing to absolutely confirm that it isn't a concern for humans, but the limited human evidence at this point in time using the recommended nefiracetam dosages do not find any significant complications.
Nefiracetam is highly toxic to dogs, but this does not appear to extend to monkeys nor rodents. While it has not been completely confirmed to be harmful or harmless in humans, the standard supplemental dosages do not appear to be associated with overt toxicity in preliminary studies
Supplementation of nefiracetam appears to be in the 150-450mg range over the course of a day (usually divided into three even doses). Animal studies using acute doses tend to note most benefits in the 3-10mg/kg range, and this correlates to a human dose of 0.48-1.6mg/kg (for a 150lb person, 33-110mg) which is similar to the aforementioned human doses.
Although single doses of nefiracetam do not appear to promote cognition, it is able to affect the brain within 30-60 minutes following oral ingestion. It is not certain whether nefiracetam needs to be taken prior to cognitive training.
The Human Effect Matrix looks at human studies (excluding animal/petri-dish studies) to tell you what effect Nefiracetam 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
||Magnitude of Effect Size
|C||Stroke Recovery Rate||
No significant influence on the recovery rates from stroke has been noted.
Nefiracetam (N-(2,6-dimethylphenyl)-2-(2-oxopyrrolidine-1-yl)-acetamide or codename DM-9384) is a hydrophobic derivative of Piracetam, and like all Racetam compounds nefiracetam is synthetically created. Nefiracetam is currently in production from Daiichi Sankyo (Japan based pharamceutical company) for the treatment of Alzheimer's disease.
Among all possible mechanisms attributed to nefiracetam it is mostly referred to as a calcium channel opener and secondary to that an excitatory signal enhancer, as well as a partial agonist at the Glycine binding site of NMDA receptors.
Nefiracetam is a pyrrolidinone nootropic that has a structure somewhat comparable to the parent racetam, Piracetam. It is more structurally different than Aniracetam or Oxiracetam (very similar to Piracetam) but retains some properties
The structure of nefiracetam is basically the structure of Piracetam, although a phenyl group with two methyl groups has been added to the amine of Piracetam. This structure is somewhat similar to Aniracetam (pictured below) although the amine group of piracetam is preserved in nefiracetam's structure.
Nefiracetam can dose-dependently (5-50nM) inhibit neuronal toxicity from sodium channel openers (veratridine) with 50nM and 500nM performing equally at around 75% cell preservation relative to control.
Nefiracetam can protect from sodium channel opening drugs (neurotoxic)
G-proteins are small intracellular signalling molecules that are coupled to G-protein coupled receptors (GPRCs), and two of them (GS known as cholera sensitive and Gi/Go known as pertussin sensitive) seem involved with nefiracetam signalling. In particular, abolishing the actions of GS seems to prevent activation of neurotransmitter release and activation of presynaptic acetylcholine receptors.
G-Proteins are those involved in the signalling of certain receptors, many of which are neurological targets. They appear to mediate the effects of nefiracetam. The stimulation of acetylcholine receptors presynaptically (which causes neurotransmitter release) is dependent on the GS protein
Calcium influx into a neuron is vital in the development of long term potentiation (LTP) and while calcium channels are less implicated than glutaminergic receptors they still are a potential influence. Since calcium is involved in the signalling from stimulatory receptors (acetylcholine and glutamate), ion receptor modulators are thought to influence cognition yet provide a novel mechanism of action.
Nefiracetam acts on long-lasting L-type calcium channels (active mostly at 1µM with 204.8+/-12.9% of control, but in the range of 0.1-10µM by 123.7-136.2%) without affecting the transient components. This is similar to Aniracetam, although more potent (aniracetam peaks at 10µM and 160.8+/-14.1%) and is similar to how dibutyryl cyclic AMP acts as they are additive but cannot mutually exceed saturation.
This augmentation of long-lasting calcium signalling appears to be coupled to the G0/Gi protein, with its inhibition abolishing the observed signal enhancement. Inhibiting calcium channels also prevents the learning enhancement and anti-amnesiac effects of nefiracetam,
Nefiracetam appears to augment calcium signalling through a neuron associated with the G0/Gi protein
PKCα is a major hippocampal PKC isoform involved in LTP and nefiracetam treatment potentiates PKC autophosphorylation in a concentration curve that mimicks the one seen with calcium influx (peak at 10nM). This increase in PKCα increased phosphorylation of its target proteins (MARCKS and NR1) and is inhibited by PKC inhibitors used in previous studies.
PKCα activation has been confirmed following oral ingestion of 1mg/kg nefiracetam to mice (to around 125% of control), and appears to be activated in both cognitively injured as well as control mice. PKC activation is dependent on glutaminergic signalling (blocking metabotropic receptors or NMDA receptors abolishes its effects).
Activation of PKCα appears to be a vital intermediate of how nefiracetam induces memory formation and cognitive enhancement, and this appears to be dependent on glutamate receptor activation
CaM Kinase II autophosphorylation is increased in a concentration dependent manner between 10-1000nM without alterations in protein content, and this is independent of synapsin I phosphorylation (a synaptic marker). Similar to PKC, inhibiting CAMKII appears to abolish the enhancement of neuronal signalling (glutaminergic in this study) and abolishes long-term potentiation in hippocampal neurons. CAMKII activation is dependent on glutaminergic signalling, as blocking either the metabotropic receptors or the NMDA receptor blocks its activation.
CAMKII has also been confirmed to be activated in response to 1mg/kg oral ingestion of nefiracetam to mice (to almost 150% of control), with efficacy in both cognitively injured mice as well as normal controls.
CAMKII also appears to be a critical intermediate in memory formation, and is similar to PKC in the sense that it is dependent on glutamintergic signalling
The anti-amnesiac effects of nefiracetam on protein synthesis inhibition are abolished with scopolamine, suggesting a role for muscarinic acetylcholine receptors; acetylcholine has per se been noted to be protective against amnesia from protein synthesis inhibitors and nefiracetam can preserve acetylcholine concentrations during amnesiac toxin administration.
Acetylcholine signalling is vital for the anti-amnesiac effects of nefiracetam
In elderly rabbits, improvements in performance on delay eyeblink conditioning have been noted with nefiracetam. Since this model (delay eyeblink conditioning) is highly depending on cholinergic firing in the septohippocampal region and nefiracetam is known to be dependent on the hippocampus in this task it is thought that this is evidence for cholinergic requirements in the learning effects of nefiracetam.
The cognitive enhancing properties of nefiracetam appear to be associated with cholinergic neurotransmission
It has been noted that 5mg/kg nefiracetam has been able to increase QNB (3-Quinuclidinyl benzilate, a ligand) binding to muscarinic receptors, indicating an increase in Bmax (138.7% of control). QNB is known to bind to the acetylcholine binding site.
Oral intake of nefiracetam has been noted to increase the ability of ligands to bind to the muscarinic acetylcholine binding sites
Presynaptic acetylcholine receptors have their signalling potentiated with nefiracetam (1-10μM) in hippocampal cells, which encourages glutamate release and LTP (not seen with piracetam or aniracetam). This increase in neurotransmitter release appears to be secondary to α4β2 receptor activation at 10nM, and it is both ineffective without acetylcholine and inactive on neurons that do not respond to acetylcholine. This enhancement of presynaptic acetylcholine activity is PKC dependent but not inhibited by G-protein inhibition.
An increased release of acetylcholine (200-211% of baseline within 10-30 minutes, lasting 60 minutes) has been confirmed in the prefrontal cortex of rats fed 1mg/kg nefiracetam (human dose of 0.16mg/kg) with 3-10mg/kg being similarly effective. While the release is sensitive to tetradotoxin it is not affected by scopolamine and longer term studies using 10mg/kg have failed to note alterations in basal acetylcholine concentrations (in healthy rats and in brain damaged rats).
Nefiracetam may enhance acetylcholine signalling at the presynaptic level, encouraging more acetylcholine release (among other neurotransmitters such as glutamate). This has been confirmed in a living model orally given nefiracetam, and appears to be linked to both memory formation (LTP) and the PKC protein
When looking at studies that do not differentiate receptor subtype, signalling is suppressed by normal concentrations of nefiracetam (0.1-10μM) in a reversible manner for about 30 minutes (PKA sensitive) and augmented by higher concentrations (100-1000μM) via a Gi/Go sensitive mechanism. It is thought that two different pathways modulate the observed effects, and the inhibition fades at 70 minutes in.
Via interactions with the GS protein (not Gi/Go) and independent of PKA/PKC, nefiracetam can stimulate α4β2 acetylcholine signalling in a reversible manner, which appears to occur at concentrations as low as 1nM (aniracetam at 0.1nM) and still some efficacy at 10nM to 10μM. Potentiation still occurs at acetylcholine saturation of this receptor, and seems to occur in the 200-300% of baseline range. Other studies looking at this particular receptor note that it is PKC sensitive similar to the α7 receptor. This stimulation does not appear to be upstream of the effects of PKC as blocking the α4β2 receptor does not prevent PKC activation, and potentiation of α4β2 receptors has failed in HEK cells suggesting the machinery for augmentation is not present (other studies use corticol neurons or PC12).
In regards to the fast acting α7 nicotinic acetylcholine receptors, nefiracetam has shown irreversible inhibition at 1-100μM, albeit weakly (2.8-20.1% inhibition) which increased the EC50 value of acetylcholine on this receptor without affecting maximal activation. The α7 receptor interactions seem PKC sensitive (and is not responsible for activating PKC either) and in studies expressing all receptors its selective inhibition doesn't seem to affect anything.
Signalling of nicotinic acetylcholine receptors is significantly modified by nefiracetam incubation, but both inhibition and augmentation have been noted. The inhibitory pathways seem more tied into Gi/Go and PKA (and the enhancement of calcium signalling) whereas the augmenting pathways seem to be more tied into GS and PKC
Nefiracetam (1-10μM) has been noted to active presynaptic acetylcholine receptors in hippocampal neurons, which is known to stimulate the release of neurotransmitters of which include glutamate (among most others).
Wholly possible that presynaptic activities of nefiracetam on acetylcholine can result in an increase in glutamate release, and thus more activity at the postsynaptic level. This is a possible pro-glutaminergic effect that is independent of the receptor interactions
NMDA induced currents have been noted to be augmented in rat corticol neurons (associated with the Glycine binding site) and was later confirmed to enhance NMDA signalling via PKC dependent means at a concentration of 10nM to the range of 160-180% of control and independent of NDMA concentration. This is likely related to PKC reducing the effects of a Magnesium block on NMDA receptors (seen with nefiracetam and elsewhere in general) which glycine does not do and nefiracetam incubation has been noted to reduce the potentiating effects of glycine with 3μM glycine being comparable to 10nM nefiracetam yet the combination slightly lower.
Oddly, unlike acetylcholine the increase in hippocampal firing seen with nefiracetam is not dependent on NMDA receptors as blocking them fails to abolish the effects.
The aforementioned interactions with the glycine receptor are similar to that of a partial agonist (higher affinity but lower potency outcompeting glycine), which is plausible as it has been reported some NMDA-mediated effects are not abolished by inhibiting Gi/o proteins. The glycine binding site is thought to be the active one as, aside from the aforementioned interactions, binding to the NMDA site have been ruled out and directly blocking the site inhibits the effects of nefiracetam on NDMA receptors despite preserving PKC activity.
Nefiracetam appears to modulate signalling via the glycine binding site of the NMDA receptor, and it is thought to be a partial agonist (rather than allosteric modulator) since it does not work nicely with other ligands such as glycine. This does not appear to be vital for long-term potentiation
AMPA and Kainate currents are not significantly influenced by 10nM nefiracetam, but this nonsignificant trend on AMPA can reach significant if the concentration is increased up to 1000nM. The effects on AMPA are likely dependent on CAMKII activation but it is uncertain how AMPA receptors influence memory formation from nefiracetam since 1000nM nefiracetam (higher activation of AMPA receptors) is not associated with long term potentiation (LTP) like 10-100nM is.
While kainate receptors appear to be wholly affected, AMPA receptors are but weakly affected at the standard concentrations of nefiracetam. With higher concentrations, the AMPA receptors begin to take more of the glutaminergic load which seems to be reduced via NDMA (due to being in the descending area of the bellcurve)
250-500nM of nefiracetam appears to be able to attenuate glutamate-induced neurotoxicity in vitro by reducing glutamate-induced cell death by about 26% and elsewhere an in vitro ischemia test (mediated by excessive NDMA activation) noted that 10nM of nefiracetam was able to reduce NDMA currents to 30% of control and reduce calcium influx. Concentrations as high as 1µM still seem effective, although it doesn't seem significantly more potent than 10nM.
At higher levels of neuronal activation (where excitotoxicity is a concern), nefiracetam appears to attenuate NMDA signalling and is thus protective against excessive glutamate levels
Nefiracetam does not appear to have any affinity for the GABAA nor benzodiazepine binding sites of central receptors in the active range, this inefficacy is also seen with aniracetam and Oxiracetam and nefiracetam has failed to modify the binding of muscimol to GABAA receptors in the normal concentration range but can force a displacement at an inpractically high concentration of 8.07M. Despite not actively binding onto central receptors, nefiracetam appears to enhance signalling of GABA on GABAA receptors when GABA itself is in low concentrations yet acts in a suppressive manner at higher concentrations. This interaction with receptor signalling is linked to the Gi/o protein and PKA.
GABA does not appear to have affinity for the GABA receptors themselves in the relevant concentration range, yet due to the interactions with the Gi/o protein it may modulate signalling (enhancement at low concentrations, suppression at higher concentrations)
Without alterations in basal GABA efflux, potassium-evoked GABA release may be enhanced following nefiracetam administration
10mg/kg nefiracetam has been noted to increase GABA uptake into synaptic neurons by 36% within one hour of oral therapy to rats, with 1-3mg/kg barely being effective and an in vitro test failing to replicate the uptake.
GABA uptake into neurons may be enhanced following administration of nefiracetam. This has failed to occur in vitro, and may be due to a nefiracetam metabolite
The anti-amnesiac effects of nefiracetam on memory impairment from protein synthesis inhibitors are abolished with GABA receptor inhibitors and agonists at these receptors have previously been noted to be protective against amnesia induced by protein synthesis inhibitors. In brain damaged rats (cerebral ischemia), the reductions seen in GABA have been reversed in the cortex and hippocampus with 10mg/kg nefiracetam.
10mg/kg nefiracetam daily for seven days was associated with an increase in glutamate decarboxylase activity without inherent alterations in GABA concentrations (hippocampus and cortex) and the decrease in this enzyme activity seen with cerebral injury is also reversed at the same dose, although this latter study failed to confirm the findings of the former.
GABA concentrations in the brain may be modified by nefiracetam administration, with an increase in turnover rates (no inherent alteration in basal concentrations) in otherwise healthy rodents and a preservation of GABA under amnesiac periods where GABA would be reduced
In regards to peripheral type benzodiazepine receptors (its activation capable of causing seizures), oral nefiracetam is able to inhibit convulsive activity from agonists of these receptors with an EC50 value of 17.2mg/kg (a potency greater than aniracetam) and 75% inhibition at 50mg/kg which is thought to be due to inhibiting ligand binding in the concentration range (IC50) of 150–200µM. In this model, piracetam and oxiracetam are either weakly effective or ineffective.
Nefiracetam appears to inhibit ligand binding and signalling through peripheral type benzodiazepine receptors, which may underlie some anti-epileptic properties. Nefiracetam appears to be more potent than other racetam drugs, but less potent than Vinpocetine
The alterations in dopamine concentrations in the gerbil brain following ischemia do not appear to be reliably influenced by nefiracetam at 10-30mg/kg as pretreatment.
A reduction in dopamine and HVA concentrations has been noted in the hippocampus at 30mg/kg to 63% of baseline, but not 10mg/kg, in gerbils following acute treatment. This was met with an increase in DOPAC concentrations. Elsewhere, a slightly increase in dopamine in the striatum has been reported in rats but an in vivo microdialysis failed to find any alterations in free moving rats.
Dopamine uptake into synaptosomes does not appear altered in the 1-10nM range of nefiracetam.
While interactions with dopaminergic neurotransmission cannot be ruled out (since activation of nicotinic acetylcholine receptors presynaptically can release dopamine), dopamine does not appear to be a major target for nefiracetam and the neuroprotective effects do not seem to interact with dopamine too much
Nefiracetam (10-30mg/kg, but not 1-3mg/kg) is able to counteract an ischemia-induced loss of serotonin in the striatum (no effect in other brain regions).
3-10mg/kg nefiracetam given 30 minutes prior to 8-OH-DPAT injections (5-HT1A agonist) was able to attenuate some of the abnormaliries noted in a choice recognition task (% correct and omission, choice reaction time and motor activity unaffected) similar to 10-100mg/kg aniracetam. As these receptors (5-HT1A) are thought to suppress neuronal activity
Serotonin uptake into synaptosomes does not appear altered with 1-10nM nefiracetam.
Similar to dopamine, while serotonergic interactions with nefiracetam cannot be ruled out they do not appear to be a major target of the nootropic
Nefiracetam is thought to contribute to learning processes due to enhancing long term potentiation (LTP) via a PKC dependent pathway, enhancing NMDA-dependent LTP at low concentrations and AMPA dependent LTP at higher concentrations. Furthermore, increased acetylcholine release has been noted in vivo and learning appears to be associated with acetylcholine signalling in the hippocamps suggesting both stimulatory pathways (glutaminergic and cholinergic) are recruited.
Furthermore, immunohistological analysis has noted an increase in dentate polysialylated cell frequency following chronic ingestion of nefiracetam at 1-9mg/kg (as well as some other cognitive enhancers) which is a phenotype similar to that seen with cognitive training. This may be related to an observed augmentation of neuronal growth factor seen in vitro with max efficacy at 100nM (lower doses not tested) and was confirmed with 9mg/kg (but not 3mg/kg) in rats over 40 days.
Due to the enhancement of both glutaminergic and cholinergic pathways, nefiracetam is thought to possess cognitive enhancing properties
In otherwise healthy rats, administration of nefiracetam (3-30mg/kg) has been unable to significantly alter step down latency and acute usage of 1-10mg/kg has failed to facilitate the acquisition process of avoidance response. Elsewhere, 10mg/kg has failed to modify escape latency acutely in rats (healthy controls used in a study on cerebral ischemia) and 10-30mg/kg has failed to alter performance in a water maze test after a single oral dose.
Nefiracetam appears to increase the rate of acquisition on novel tastes in the 3-10mg/kg range, although with repeated testing it eventually performs similar to control; the authors suggested that nefiracetam aids in novel memory consolidation. This same novel object task has been noted to be unaffected with 1mg/kg in mice elsewhere.
Acute usage of nefiracetam for the purpose of cognitive enhancement, unlike Pramiracetam, rarely if ever causes an increase in memory formation in research animals
For studies over a longer periods of time, 15mg/kg of nefiracetam for 38 days (postnatal day 41 to 79) has noted an increase in spatial memory formation. This prolonged requirement of nefiracetam's nootropic potential has been noted in rabbits previously and a previous study that noted a failure of nefiracetam to benefit avoidance acquisition at 3-10mg/kg acutely noted benefit with seven days of supplementation.
Adding nefiracetam to cognitive training failed to outperform either in isolation.
Nefiracetam appears to promote cognition in otherwise healthy and young animals when taken daily over a prolonged period of time (minimum of seven days it seems), although the one study to combine nefiracetam with cognitive training failed to find an additive effect
In rats given cerebral ischemia, 10mg/kg nefiracetam daily (preliminary study said it was more effective than 3mg/kg) is able to partially reverse the impairment of spatial memory seen with injury.
In rats with cerebral injuries of sorts, nefiracetam appears to be neuroprotective and can restore memory function
The amnesia induced by protein synthesis inhibitors appears to be attenuated with nefiracetam either pretraining (3-30mg/kg) or posttraining (5-15mg/kg), with more protective effects from preloading and trended to be more protective than aniracetam. This has been noted elsewhere and anti-amnesiac effects have also been reported with nefiracetam on a variety of other drugs of cholinergic, GABAergic, or dopaminergic neurotransmission including Alcohol and even extends to some endogenous compounds such as β-amyloid proteins as well as carbon monoxide.
Against scopolamine in particular (cholinergic amnesiac), the amnesiac effects have been noted to be reduced with nefiracetam at 1-30mg/kg with maximal effects (67% protection) at 10mg/kg, which outperformed aniracetam (33% peak efficacy in the range of 1-30mg/kg). This has been noted in other studies and species such as rabbits and can be traced back to its influence on high-voltage calcium channels.
In response to electroshocks, nefiracetam is able to reduce the subsequent amnesia in the dosage range of 1-3mg/kg with higher doses having no protective effect. The same mechanisms are thought to underlie the ability of nefiracetam to attenuate seizures against various stressors (possibly less potent than Levetiracetam) and due to occurring at a lower range than other pharmaceutical goals they may be related to acting on sodium channels in an inhibitory manner (active in the 5-50nM range).
Nefiracetam appears to possess anti-amnesiac properties, with slightly more efficacy than Aniracetam based on the animal evidence. The breadth of these anti-amnesiac effects appears to be quite large and affects most things that induce amnesia, and it can be traced back to the influence on calcium channels (opening them)
Nefiracetam has noted antidepressant effects previously in rats associated with CAMKII activation at 1mg/kg.
In persons with strokes who suffer from depression, supplementation of 600-900mg nefiracetam has once failed to have any significant effect on HAM-D scores over 4 weeks (duplicated in Medline).
In stroke patients who suffer from depression also meeting diagnostic criteria for apathy (as assessed by the apathy rating scale, apathy from stroke is a common symptom), supplementation of 600-900mg of nefiracetam twice daily (300-450mg each time) for four weeks was able to reduce apathy in a dose-dependent manner in a way not related to depression nor cognition.
May reduce apathy scores in persons who suffered from a stroke, with no apparent benefit to depressive symptoms. It is unsure how apathy is affected in otherwise healthy persons
In Alzheimer's, both glutaminergic and cholinergic neurons are downregulated, leading to the usage of proglutaminergic and cholinergic molecules (with the standard being acetylcholinesterase inhibitors). Nefiracetam is thought to have a role in these disease states since both glutaminergic and cholinergic signalling are linked to intracellular calcium influx.
In persons with dementia related to cerebrovascular disorders, supplementation of nefiracetam at 150, 300, and 450mg daily (divided into three equal doses) has noted that reports of symptoms being "moderately improved or more" increased by 24.5%, 28.4% and 41.7% (study cannot be located online, but mentioned both here and here) said to have efficacy comparable to idebenone (a CoQ10 analogue).
May have a therapeutic role in Alzheimer's and Dementia, but this has not been well investigated. Preliminary evidence seems promising
180-300mg/kg of nefiracetam in male beagle dogs has been noted to reduce serum testosterone within one week of supplementation, with no dose dependence noted and a single dose of nefiracetam able to suppress testosterone within four hours.
300mg/kg nefiracetam to male beagle dogs appears to increase circulating estrogen concentrations in serum within one week (maintaining magnitude over four weeks), with 180mg/kg only effective after four weeks and to a lesser degree.
The single dose toxicity of nefiracetam (LD50 values) is 1940-2005mg/kg for mice, 1182-1408mg/kg for rats, and greater than 500mg/kg for beagle dogs.
In human studies doing standard toxicology testing and looking for clinical side-effects, dosages of 600-900mg nefiracetam for four weeks do not appear to be significantly different from placebo.
In general, the limited human evidence does not suggest any toxicity associated with the recommended dosages of nefiracetam
In male beagle dogs fiven 180mg/kg or 300mg/kg of nefiracetam for four weeks, histological examination of the testicles has noted alterations to germ cells (degeneration and reduced count) and both spermatids and the seminiferous tubules but no alterations to Leydig or Sertoli cells and testicular weight was unaltered. These adverse changes were dose-dependent, while the increase in malformed sperm was time and dose dependent (there seemed to be an unreliable suppression of sperm motility) and elsewhere alterations in sperm have been noted to occur at 60mg/kg, but not 20mg/kg in the same species and a 52 week study noted that 30mg/kg was also safe.
60-90mg/kg or higher in dogs (both sexes) seems to be the minimum dosage to induce renal necrosis and may occur within one week of treatment. These pathological changes appear to be due to metabolic products of nefiracetam, namely the 3-hydroxylation and subsequent sulfation byproduct which then inhibits renal prostaglandin synthesis. It has been reported that this effect occurs in dogs but not rats nor monkeys, insinuating that it does not apply to human consumption.
Studies conducted in canines repeatedly note that doses above 60mg/kg or so can very rapidly and severely cause renal necrosis and lesions in the kidney tissue, as well as reduce sperm production and testosterone concentrations. It is thought that these effects are unique to dogs, and do not apply to humans (and have been confirmed to not occur in monkeys and rats)
If the above information were to be converted into human dosages, the 30mg/kg safe range would translate to a human dose of 16.2mg/kg and the lowest observed toxic dose (60mg/kg) would be 32.4mg/kg. The former dosage, for a 150lb human, is approximately 1,100mg daily.
If the toxicity is assumed to apply to humans, then the highest confirmed safe dose appears to be within the recommended supplemental dosages. However, the therapeutic index (safety buffer between toxic and effective dosages) seems to be very small
(Common misspellings for Nefiracetam include DM9384, nefracetam, nefiracetm)
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