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Ultimate Guide to Nootropics | Part 2 | Racetams: The Original Nootropic Family

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Ultimate Guide to Nootropic Racetams

What Makes Up a Racetam?

In 1964, a group of researchers in Belgium, headed by Dr. Corneliu Giurgea, developed a drug designed to induce sleep and help treat motion sickness. They based their creation off the endogenous neurotransmitter GABA, which is used by the body to reduce neuronal excitability and stress. While the synthesized compound, called piracetam, failed to provide any sleep-inducing qualities, the scientists did find its potential for enhancing cognitive processes, giving birth to the first nootropics, and leading Giurgea to coin the term “nootropic.”

Racetam Chemical Structure

The  racetam family has since seen numerous new additions, all characterized by a shared 2-Pyrrolidone base structure; which is a lactam, or cyclic amide. The structure is easily recognizable as a 5 sided cyclic ring with a carboxyl group and open nitrogen. This open nitrogen makes it possible to attach other functional groups, which leads to a very wide variety of compounds in the racetam family. No matter how complex they get, or how those changes affect their pharmacodynamics in the body, at the heart of all racetams is the 2-Pyrrolidone base structure.

Racetam Structures

Let’s Take a Closer Look at Some Popular Racetams.

Piracetam

                                                                                          Piracetam Chemical Structure

The parent compound of the racetam family,  piracetam, is an odorless slightly bitter white powder. It is a cyclic derivative of GABA, but does not act like GABA in the body. It is a positive allosteric modulator of the NMDA and AMPA receptors, which are your body’s excitatory receptors that are normally bound to by glutamate. An allosteric modulator is a compound that does not bind to the main site of a receptor, but binds to a second site; which allows it to modulate the receptor’s function. This allows piracetam to modulate, both up and down, the signaling of the NMDA and AMPA receptors, but still allows them to be bound to by agonists/antagonists. So in the case of the NMDA/AMPA receptors, piracetam increases the excitability when they are bound to by glutamate, facilitating enhanced neuronal transmission.

Piracetam affects multiple neurotransmitter systems, like acetylcholine, glutamate, and kainite, thereby increasing oxygen and blood flow to modify neuronal, cognitive, and vascular functions. It also improves cell membrane permeability, increasing ATP metabolism and usage. Piracetam also improves the mitochondrial electron transport chain, which facilitates the Krebs cycle. It’s these varied effects that lead to the improvements seen in the available research.

Benefits of Piracetam

While Piracetam is not as potent as some of its other family members, it has some very unique benefits. Some  potential benefits of piracetam include:

  • Preventing cognitive decline – Six clinical studies show that piracetam may be particularly useful in preventing the cognitive decline that comes with aging and the aggression associated with that decline.
  • Improve memory recall – The compound may increase short-term memory recall.
  • Treat breath holding spells (BHS) – Breath holding spells affect about 5 percent of children between infancy and five years old. Piracetam has been shown in some cases to treat severe cases of BHS.
  • Protection from ischemia and cerebral trauma- Multiple studies have shown the neuroprotective and antithrombotic effects of piracetam in cases of ischemic stroke and other instances of lowered oxygen delivery to the brain.

Piracetam is water soluble, very stable, and does not metabolize in the body in any meaningful amounts. It is one of the safest compounds out there, and is often touted as being safer than table salt. The fact that it lacks functional groups that are lipid-soluble makes its blood brain barrier permeability lower than other racetams. However, it does pass the blood-brain barrier and acts in a protective manner on the brain.

Piracetam Properties:

Normal Dosage Range: 800mg to 2.4g
Bioavailability: ~100% via oral administration
Biological Half-Life: 4-5 hours
Metabolism: Renal (excreted mostly unchanged in urine)
Molar Mass: 142.16 g/mol
LogP (water/lipid solubility): -1.75 (Water Soluble)
Solubility in Water (at 25C): 72mg/ml
Melting Point: 147-157 Celsius
Chemical Formula: C 6H10N2O2
CAS: 7491-74-9

Aniracetam

                                                                                       Aniracetam Chemical Structure

Aniracetam is an odorless white fluffy powder that has a very mildly bitter taste. It differs from piracetam in the addition of a p-Anisyl group. Aniracetam was first synthesized in the 1970s by Hoffmann-La Roche. It is an AMPAkine nootropic, which acts primarily on the AMPA receptors, and decreases the rate of receptor desensitization. It is more potent than piracetam, and is more lipid soluble. This means that more of it passes the blood brain barrier. It has shown to be more anxiolytic (anxiety-reducing) than piracetam. This is most likely due to its major metabolite, N-anisoyl-GABA. Aniracetam has been shown to increase dopamine and serotonin levels in the prefrontal cortex, basolateral amygdala, and dorsal hippocampus of the mesocorticolimbic system. Like piracetam, it increases the uptake and usage of acetylcholine in the brain.

How Does Aniracetam Work? 

Aniracetam is rapidly and completely absorbed in the gastrointestinal tract on an empty stomach. It does not need to be taken with food or fat to absorb, like many sites incorrectly claim. The reason most claim Aniracetam needs fats to absorb is because it is fat soluble, and there is a widespread misconception that fat soluble substances need fat to be bioavailable. This is not only incorrect, but it can in fact lower bioavailability, by allowing some fat-soluble compounds to be excreted in higher amounts in feces. The reason aniracetam’s effects are short-lived, only lasting 2-4 hours, is that it is rapidly and completely metabolized in the liver after absorption.

Aniracetam is metabolized into three major metabolites: N-anisoyl-GABA, P-Anisic Acid, and 2-pyrrolidinone. 70% of a dose of aniracetam becomes N-anisoyl-GABA, also called 4,p-Anisaminobutyric acid. Studies have shown that injecting N-anisoyl-GABA directly into the brain leads to similar cognitive effects as aniracetam, and is thus considered an active metabolite. So while aniracetam’s biological half-life is very short, N-anisoyl-GABA continues to act on the body and brain for a bit longer. Aniracetam has very little binding to plasma proteins, so it does not build up in the body. Many sites claim all fat soluble compounds build up in the body. However, that more has to do with its protein binding rather than lipid solubility.

Potential Benefits of Aniracetam

As a modulator of AMPA receptors, aniracetam is currently being studied as a treatment for depression and disorders of the central nervous system, including Alzheimer’s. More generally, aniracetam may increase blood flow in the area of the brain associated with collective and holistic thinking. Holistic thinking differs from analytical thinking by the method in which it approaches a problem. Analytic thinking involves understanding a system by thinking about its parts, and how they work together to produce larger-scale effects. Holistic thinking involves understanding a system, by sensing its large-scale patterns and reacting to them. Thus, aniracetam may help people analyze the bigger picture, and could help form new perspectives on everyday problems. Some studies suggest that aniracetam may also help in memory formation, improved judgment, and increased neural plasticity.

Some benefits of aniracetam include:

  • Ability to  reduce stress by enhancing the effects of cortical GABA
  • Decreases the rate of receptor desensitization of AMPA receptors
  • Increases blood flow and activity in brain regions associated with holistic thinking
  • Is a positive allosteric modulator of the AMPA receptors
  • Improve mood by modulating the breakdown of dopamine and serotonin

Aniracetam Properties 

Normal Dosage Range: 750mg to 1.5g
Bioavailability: ~100% via oral administration (on an empty stomach)
Biological Half-Life: 1-2.5 hours
Metabolism: Hepatic (rapidly metabolized in liver) CYP3A4
Molar Mass: 219.237 g/mol
LogP (water/lipid solubility): 1.11 (Lipid Soluble)
Solubility in Water (at 25C): 2.47mg/ml
Melting Point: 121-122 Celsius
Chemical Formula: C 12H13NO3
CAS: 72432-10-1

Oxiracetam 

                                                                                    Oxiracetam Chemical Structure

Oxiracetam is an odorless white powder with a sweet and slightly bitter flavor. It is very similar in physical properties to piracetam, as the only difference between them is the addition of a hydroxyl group. This addition makes it more potent than piracetam, needing much smaller dosages, and makes it more stimulating. It works through similar mechanisms to both piracetam and aniracetam, modulating AMPA receptors and increasing acetylcholine usage, but it can also affect D-aspartic acid (D-AA). This can potentially lead to increased metabolic activity in neuronal cells, which may be another reason people feel it is more stimulating than piracetam.

Is Oxiracetam More Potent Than Piracetam? 

Many sites state that oxiracetam is more potent than piracetam because it passes the blood-brain barrier better. However, there is no evidence of this. The concentration of oxiracetam in cerebrospinal fluid is 5.3% of blood serum levels, meaning that while it does pass the blood-brain barrier, it is not in higher amounts than piracetam (5.5%). This is to be expected, because a hydroxyl group will actually lower lipid solubility, making it slightly less likely to pass a lipid membrane-like the blood brain barrier. If you compare the LogP of oxiracetam (-1.29) to the LogP of piracetam (-1.75), you can see why they are similar in blood-brain barrier permeability, and why oxiracetam is slightly less water soluble than piracetam. Therefore, the increase in potency of oxiracetam compared to piracetam is due to pharmacodynamic receptor affinities, not pharmacokinetics. Some studies have shown that piracetam and oxiracetam act on peripheral mechanism as well, like the adrenergic system. So the blood-brain barrier permeability would not affect increases in potency toward peripheral mechanisms. The most likely scenario is that both central and peripheral mechanisms are at play with piracetam and oxiracetam.

How Does it Work?

Oxiracetam is a positive allosteric modulator of the AMPA receptors. However, it binds to a different binding site than that of piracetam and aniracetam. So while they act similarly in effects, they do not compete for the same binding site. This means that taking oxiracetam together with piracetam and aniracetam can lead to improved effects, without competitive inhibition of each other’s actions. This is why many people find taking oxiracetam at the same time as piracetam to be more effective than each individually. Like some other racetams, oxiracetam is a choline uptake enhancer and increases the utilization of acetylcholine. Some people benefit from the addition of a  choline source, like alpha GPC or CDP choline when using a racetam. However, that combination is not a requirement if your dietary intake of choline is sufficient. One should always be aware that depression is a common side effect of stronger choline sources. So only add in a stronger choline source if you are getting headaches, or consider a less potent one like choline bitartrate.

Some  benefits of oxiracetam include:

  • Enhances the release of excitatory neurotransmitters
  • More potent than piracetam, and binds to a different AMPAR binding site
  • Reduces the rate of cognitive decline in elderly
  • Enhances the release of D-aspartic acid and stimulation of protein kinase C (PKC)
  • Increases memory formation in young and healthy

Oxiracetam Properties: 

Normal Dosage Range: 500mg to 1g
Bioavailability: ~75-80% via oral administration (on an empty stomach)
Biological Half-Life: 3-7 hours, depending on renal function
Metabolism: Renal/Hepatic (50% excreted unchanged in urine)
Molar Mass: 158.155 g/mol
LogP (water/lipid solubility): -1.29 (Water Soluble)
Solubility in Water (at 25C): 31mg/ml
Melting Point: 160-166 Celsius
Chemical Formula: C 6H10N2O3
CAS: 62613-82-5

Pramiracetam

                                                                            Pramiracetam Chemical Structure

Pramiracetam is a white to beige odorless powder, which is extremely bitter in taste. It also has a very low melting point (116-118F), which makes it stickier than most racetams. It differs from piracetam structurally by the addition of a 2-(diisopropyl amino)ethyl group. This extra functional grouping alters the potency and effects of the compound. It is more anti-amnesiac than piracetam, and acts as a central nervous system stimulant. It is a high-affinity choline uptake enhancer and increases nitric oxide synthase activity in the cerebral cortex. Similar to piracetam, the memory consolidation effects of pramiracetam can be abolished by an adrenalectomy. This indicates that adrenal function is crucial to getting the benefits of either compound.  Pramiracetam has been shown to lead to acute  nootropic effects after oral dosing in healthy humans.

Like aniracetam, pramiracetam is widely touted as a fat-soluble compound. As such, most sites incorrectly state that it needs to be taken with fat to absorb. However, like aniracetam, this is not true. Pramiracetam is rapidly and completely absorbed in the GI tract on an empty stomach. It does not need to be taken with fat to absorb. Also, pramiracetam is actually very water soluble (180mg/ml at 25C); more water soluble than other  racetams in its family. However, it also has lipid soluble functional groups on the structure. This means that pramiracetam is both water and fat-soluble, making it ideal for both absorption and blood-brain barrier permeability. It is also widely distributed in tissues around the body and reaches steady state plasma levels after 24-48 hours of chronic dosing.

Studies show that pramiracetam can:

  • Increase cerebral blood flow
  • Improve long-term memory and spatial learning
  • Increase high-affinity choline uptake
  • Increase nitric oxide synthase in the cerebral cortex
  • Reduce the effects of amnesiac drugs

Pramiracetam Properties 

Normal Dosage Range: 600mg to 1.2g
Bioavailability: ~98% via oral administration on empty stomach
Biological Half-Life: 5 hours
Metabolism: Renal (excreted mostly unchanged in urine)
Molar Mass: 269.383 g/mol
LogP (water/lipid solubility): ACD LogP -1.4, ALogP 0.49 (Both water/lipid soluble)
Solubility in Water (at 25C): 180mg/ml (very water soluble)
Melting Point: 47-48 Celsius (116-118F)
Chemical Formula: C 14H27N3O2
CAS: 68497-62-1

Phenylpiracetam

                                                                                                        Phenylpiracetam Chemical Structure

Phenylpiracetam is an odorless white powder that is very bitter in taste. It differs from piracetam in the addition of a phenyl functional group. A phenyl grouping is a six-sided cyclic ring consisting of benzene, minus a hydrogen, leaving an open carbon bond available to attach as a functional group on a molecule. With the added phenyl group, the phenylpiracetam structure becomes more like phenylethylamine, which is the base structure many stimulants are made of. Because of this, phenylpiracetam acts a lot more as a central nervous system stimulant and enhances physical performance. It is much more potent than piracetam, only needing 100-200mg doses. Also, unlike piracetam, phenylpiracetam exhibits a specific anticonvulsant action. So while in lower dosages phenylpiracetam is a psychostimulant and antidepressant, large dosages act as a psychodepressant. Phenylpiracetam is a selective dopamine transporter inhibitor and moderately stimulates striatal dopamine release. In addition, racemic phenylpiracetam has been shown to lower micromolar binding affinity to the nicotinic acetylcholine receptors.

Phenylpiracetam has very low water solubility but is slightly lipid soluble. The phenyl ring likely provides active transport across the blood-brain barrier, making it reach the brain in higher amounts. It exists in two enantiomers R and S. The R-enantiomer being the more potent of the two. Phenylpiracetam is rapidly and completely absorbed in the GI tract on an empty stomach and is not metabolized in any meaningful amounts. It is excreted mostly unchanged in urine and sweat.

Potential Benefits of Phenylpiracetam

In terms of benefits, phenylpiracetam, like other members of the  racetam family, may curb the rate and symptoms of organic cognitive decline. Some studies suggest that the compound may help to improve cognition in those suffering from epilepsy, due to its anticonvulsant effects; which is a shared trait of its cousin levetiracetam. Those who have recently suffered a stroke may also recover more quickly from physical and cognitive symptoms. Phenylpiracetam is one of the more potent racetams by weight and is the most stimulating of the family. The R-enantiomer in particular is very effective at psycho- stimulation and antidepressant effects, due to the dopamine transporter affinities.

Some benefits of phenylpiracetam include:

  • Rapid mood boosting effects
  • More neuroprotective than piracetam
  • Enhanced physical performance and cold tolerance
  • Improved mental stimulation and focus
  • May improve immune system during times of stress

Phenylpiracetam Properties: 

Normal Dosage Range: 100mg to 200mg
Bioavailability: ~100% via oral administration on empty stomach
Biological Half-Life: 3-5 hours
Metabolism: Renal (excreted mostly unchanged in urine and sweat)
Molar Mass: 218.3 g/mol
LogP (water/lipid solubility): .16 (slightly lipid soluble)
Solubility in Water (at 25C): 1-2mg/ml (very low water solubility)
Melting Point: 149-152 Celsius
Chemical Formula: C 12H14N2O2
CAS: 77472-70-9

Coluracetam

                                                                                         Coluracetam Chemical Structure

Coluracetam is an odorless white to cream colored fluffy powder, with a very bitter taste. It was developed in Japan in 1993 as a selective choline uptake enhancer. It differs from the structure of piracetam by the addition of a bulky dimethyl-tetrahydrofuro-quinolinyl grouping. This addition makes is a very potent high-affinity choline uptake (HACU) enhancer. That is the process of drawing choline into a neuron to then be synthesized into acetylcholine. Increasing the rate of high-affinity choline uptake is associated with increased activity in cholinergic neurons, which results in cognitive enhancement. Also, during its phase 2a clinical trials, it showed promise in the treatment of major depressive disorder (MDD). In addition, chronic dosing of coluracetam protects the brain from glutamate-induced neurotoxicity. It is rapidly metabolized in the body, and has a short half-life. However, its memory enhancing effects last 24 hours after dosing. This is most likely due to the improvements in cholinergic transmission lasting much longer than the half-life of the compound itself. Chronic dosing of coluracetam leads to much more potent memory improvements and a neuroprotective action that is not seen in acute dosing. So regular use of coluracetam leads to more benefits than occasional dosing.

Potential Benefits of Coluracetam  

There is very little pharmacokinetic data on coluracetam. It is orally active. However, bioavailability is likely low. Some researchers have found sublingual administration to be more effective than oral. It is rapidly metabolized in the body and has a short half-life. However, its effects last up to 24 hours after the last dose and increase in effect the longer it is taken. It does not build up in the body, so the memory improvements and neuroprotection are likely downstream mechanisms related to its high-affinity choline uptake enhancement. Its acute memory enhancing effects are not very potent, but build over time. It shows most promise in boosting mood and protecting from glutamate-induced neurotoxicity.

Some benefits of coluracetam include:

  • Ability to boost mood and combat depression
  • Long-lasting cognitive improvements after chronic dosing
  • Protection from glutamate-induced neurotoxicity with chronic use
  • Little side effects and does not build up in the body

 Coluracetam Properties:

Normal Dosage Range: 20mg to 40mg
Bioavailability: Not measured. Likely low via oral. Suggest sublingual
Biological Half-Life: Very short (effects last 24 hours, due to HACU)
Metabolism: Hepatic (rapidly metabolized)
Molar Mass: 341.404 g/mol
LogP (water/lipid solubility): 1.98 (lipid soluble)
Solubility in Water (at 25C): <1mg/ml (very low water solubility)
Melting Point: 232-234 Celsius
Chemical Formula: C 19H23N3O3
CAS: 135463-81-9

Fasoracetam

                                                                             Fasoracetam Chemical Structure

Fasoracetam is a white to beige powder with a bitter taste. Its structure is fairly different than other racetams, with the acetamide grouping off the 5 position of the 2-Pyrrolidone ring, rather than the open nitrogen off the 1 position like other racetams in its family. In addition to that, fasoracetam has an added piperidine grouping off the acetamide. These structural changes make its effects very unique in the racetam world. Fasoracetam modulates adenylate cyclase activity by stimulating the metabotropic glutamate receptors (mGluRs). It is also a high-affinity choline uptake enhancer, and stimulates central cholinergic activity. In addition, fasoracetam upregulates GABAb receptors. This is why many people have turned to it to help slow or reverse tolerance to compounds that agonize GABAb; like phenibut. However, it does not bind directly to GABAb, but still reverses the memory deficits from GABAb agonist baclofen. GABA receptors have been demonstrated to be negatively coupled to adenylate cyclase via PTX-sensitive G-proteins. So this is how Fasoracetam reverses memory issues caused by baclofen and phenibut, and up-regulates GABAb receptors. It modulates adenylate cyclase, which are coupled to GABA by other G-proteins, leading to expression changes in GABAb receptors. Fasoracetam may also possess G-dependent stimulatory action on cyclic adenosine monophosphate (cAMP) formation, which is the signal transduction pathway that controls memory consolidation and long-term potentiation (LTP).

How Does it Work?

Fasoracetam is rapidly and completely absorbed through the GI tract on an empty stomach. Eating food around the time of dosing negatively impacts its absorption, so it should be taken during a fasting state. It is not extensively metabolized in the liver, and is mostly (90%) excreted unchanged in urine by way of the kidneys. Creatine levels have been shown to affect clearance rates, which leads to elderly people having higher plasma levels. Higher creatine levels means faster clearance of fasoracetam from plasma. Peak plasma levels are reached in 1 hour, and the plasma half-life is 2-3 hours. Two major metabolites added up to 6% of the fasoracetam dose, and are called LAM-162 und LAM-79. LAM-162 is an oxidative metabolite with C-N cleavage of the piperidine ring. LAM-79 is a metabolite with a hydroxyl group added to the 4 position of the piperidine ring. Serum protein binding for fasoracetam is 3.3%, meaning it will not build up in the body over time.

Potential Benefits of Fasoracetam

Since fasoracetam has been shown to modulate cAMP signaling and enhance high affinity choline uptake, it shows promise as a novel cognitive enhancer. In addition, it has shown potent antidepressant activity, due to its upregulation of GABAb receptors. Fasoracetam is also currently in trials for treating attention deficit hyperactivity disorder.

Fasoracetam’s benefits include:

  • Rapid alleviation of symptoms of depression
  • Potential for treatment of ADHD
  • Reversal of memory deficits from phenibut and baclofen
  • Upregulation of GABAb receptors
  • Modulation of cAMP and high-efficiency choline uptake
  • Potent anti-amnesiatic effects, memory improvements, and long-term potentiation

Fasoracetam Properties:

Normal Dosage Range: 20mg to 40mg
Bioavailability: 80% to 90% depending on creatine levels
Biological Half Life: 2-3 hours
Metabolism: Renal and hepatic (excreted 90% unchanged in urine)
Molar Mass: 196.25 g/mol
LogP (water/lipid solubility): -1.37 (water soluble)
Solubility in Water (at 25C): 50mg/ml
Melting Point: 152 Celsius
Chemical Formula: C 10H16N2O2
CAS: 110958-19-5

Which Racetam Will You Be Choosing? 

The racetam family of compounds is considered one of the key components of the nootropics world, and the original nootropic, piracetam, was the compound that led Dr. Corneliu Giurgea to coin the term. What started out as an attempt to improve GABA, and make a better sleep inducer, led to an entire family of cognitive enhancing compounds. While their effects and potencies vary wildly, they all share the same 2-Pyrrolidone base structure. There are now many other compounds in the nootropics world, but the racetam family of compounds are a staple to most people’s stacks.

Nootropics Depot offers an advanced racetam sample pack featuring coluracetam, fasoracetam, phenylpiracetam, and pramiracetam in powder form. However, beginners might prefer the basic nootropics sample pack, which includes aniracetam, piracetam, oxiracetam, and noopept, all in pre-measured capsules for easier ingestion. We will soon be releasing an advanced racetam capsule sample pack too, for those that prefer capsules to powders.

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