Racetam Stack: Nootropics That Synergize with Racetams

Finding the perfect racetam stack can be a challenge. We’ve got some fresh ideas about what nootropics to stack with racetams to get the most bang for your buck. Many nootropics individually have subtle effects on cognition. But synergistic effects of multiple nootropics can be much more pronounced, and make all the difference.

Designing a Racetam Stack

1. Glycine and D-Serine

Glycine and D-Serine are non-essential amino acids that activate the glycine binding site of the NMDA receptor. Two molecules of glycine (or d-serine) and two molecules glutamate are actually required for activation of the NMDA receptor. Supplementation with glycine and d-serine is an effective way to boost excitatory transmission without contributing to excitotoxicity because the brain is already well-adapted to using glycine as a neurotransmitter and only a limited amount of glycine enters the brain from dietary supplementation. I’ve achieved the best results from using a 50/50 mixture of the two amino acids.

2. Branched-Chain Amino Acids (BCAA)

A branched-chain amino acid is exactly what it sounds like: it’s an amino acid with an aliphatic side chain containing a branch, such as isoleucine. BCAA supplementation has been reported to rescue sleep/wake deficits in an animal model of mild traumatic brain injury (concussion) by boosting neuronal excitability in the hippocampus [1]. Consider the following abstract:

Sleep disorders are highly prevalent in patients with traumatic brain injury (TBI) and can significantly impair cognitive rehabilitation. No proven therapies exist to mitigate the neurocognitive consequences of TBI. We show that mild brain injury in mice causes a persistent inability to maintain wakefulness and decreases orexin neuron activation during wakefulness. We gave mice a dietary supplement of branched-chain amino acids (BCAAs), precursors for de novo glutamate synthesis in the brain. BCAA therapy reinstated activation of orexin neurons and improved wake deficits in mice with mild brain injury. Our data suggest that dietary BCAA intervention, acting in part through orexin, can ameliorate injury-induced sleep disturbances and may facilitate cognitive rehabilitation after brain injury.

An analogous finding that BCAA supplementation facilitates cognitive recovery after TBI (traumatic brain injury) has been replicated in humans [2].

It is likely a myth that glutamate ingestion from food as monosodium glutamate or MSG encourages excitotoxicity. A review by Williams AN et. al., entitled Monosodium glutamate ‘allergy’: menace or myth? (2009) [3]’ concluded the following:

Despite concerns raised by early reports, decades of research have failed to demonstrate a clear and consistent relationship between MSG ingestion and the development of these conditions.

It is unlikely that dietary glutamate promotes excitotoxicity because glutamate’s entry into the brain is limited by the blood brain barrier (BBB), which requires active transport due to glutamate’s zwitterionic structure. Moreover, glutamate is already ubiquitous in the CNS as it is the most important excitatory neurotransmitter. While adding high concentrations of glutamate to a neuronal cell culture results in excitotoxicity, this represents a poor model of what happens when a human being ingests dietary glutamate.

3. D-Cycloserine

D-Cycloserine is a cyclized version of d-serine with an extra amino group. D-cycloserine is used as a tuberculosis drug, and like d-serine, allosterically activates the NMDA receptor. D-cycloserine may facilitate fear extinction, and shows some promise in the treatment of anxiety and panic disorders. Tentative evidence suggests that D-cycloserine ameliorates some of the cognitive (negative) symptoms of schizophrenia [4], consistent with the notion that hypofunctional glutamate receptors may be a pathognomonic feature of schizophreniform disorders [5]. The evidence for the benefits of d-cycloserine in schizophrenic patients is not unequivocal however, as at least one study reported that d-cycloserine exacerbated negative symptoms of schizophrenia [6].

4. Magnesium Threonate

Magnesium is absolutely essential for the normal functioning of the NMDA receptor. Under physiologic conditions, the divalent magnesium ion occludes the pore of the NMDA channel preventing calcium influx in a voltage-dependent manner. Membrane depolarization rapidly induces dissociation of the magnesium ion from the pore, allowing appropriate calcium influx and signal transduction.

Magnesium is an excellent way for the brain to control the signal-to-noise ratio or gain on excitatory neurotransmission and serves as a very important safeguard against excitotoxicity. Magnesium deficiency is implicated in anxiety disorders and HPA dysregulation [7], and exogenous treatment with magnesium threonate has demonstrated nootropic potential [8]. It remains unclear what role the counter-ion (threonate) plays, and at least one study has demonstrated no benefit of magnesium threonate over other formulations.

Downstream Neuronal Targets

5. Yerba Mate

My experience drinking yerba mate has been overwhelmingly positive. Subjectively (n=1), I experience improved concentration, motivation and verbal fluency.

Yerba mate contains three xanthines: caffeine, theobromine, and theophylline. All three of these xanthines are nonselective phosphodiesterase inhibitors which boost downstream cyclic adenosine monophosphate (cAMP)-dependent signaling. (Phosphodiesterases are a class of enzymes that terminate the action of the second messenger cAMP; inhibiting this enzyme boosts the cAMP signal by protecting it from degradation.)

6. Viagra (Slidenafil)

Slidenafil is a potent phosphodiesterase (PDE)-5 inhibitor that boosts the action of cyclic guanosine monophosphate (GMP). Despite the fact that the PDE4 isoform is probably the most important phosphodiesterase in terms of nootropic effects, tentative evidence suggests that slidenafil enhances cognitive performance in animal models [9], though slidenafil failed to ameliorate cognitive deficits in patients suffering from schizophrenia [10].

It will be interesting to see if patients currently taking slidenafil to manage erectile dysfunction report any subjective cognitive benefits. Consider the following excerpt from the recently published article entitled Phosphodiesterase inhibitors as therapeutics for traumatic brain injury (2015) [11]:

Much of the work regarding the cGMP-PDEs in CNS injury has focused on PDE5, the enzyme inhibited by sildenafil (Viagra) and tadalafil (Cialis). Work from Garcia’s group has shown that the non-selective cGMP-PDE inhibitor, zaprinast, reduced neuronal death after cortical cryoinjury and these beneficial effects were essentially mimicked by the PDE5 selective inhibitor, sildenafil [90, 91]. These effects appeared to be multimodal, with enhanced astrogliosis and angiogenesis in the lesioned area and suppression of microglia infiltration. In glia cells around the lesion site, sildenafil significantly upregulated the expression of neuroprotective metal-binding cysteine-rich proteins, metallothioneins I/II [91]. After cerebral ischemia, tadalafil administration was found to facilitate recovery and improve short-term memory deficits by increasing cGMP levels and reducing neuronal apoptosis [92]. In a middle-aged mouse ischemic brain model, sildenafil significantly increased the number of neural stem cells, as well as their neuronal and oligodendrocyte progeny [93]. Furthermore, after experimental subarachnoid hemorrhage (SAH), PDE5 activity, but not expression, increased with a concomitant decrease in cGMP levels [94]. Post-SAH administration of sildenafil significantly decreased PDE5 activity, restored cGMP levels, decreased cerebral vasospasm and neuronal cell death, and improved functional recovery with minimal physiological side effects [94].

7. Curcumin and resveratrol

Curcumin, curcumin analogues, and resveratrol inhibit phosphodiesterase 5 (PDE5) in vitro *[12] and possibly *in vivo. Curcumin exhibits robust neuroprotective and neurorestorative properties in a wide range of experimental paradigms and under diverse settings, e.g., stroke, traumatic brain injury, neuroanatomic lesioning, neurotoxic exposure, irradiation, dementia, etc.

The most important obstacles with curcumin are its poor bioavailability, rapid metabolism and systemic elimination, poor absorption, and water insolubility. Resveratrol suffers from similar disadvantages including rapid inactivation by hepatic glucuronidation. Pterostilbene may be a more viable methylated isomer of resveratrol. Formulations of curcumin that include bioperine and a lipid emulsion to enhance absorption and inhibit hepatic CYP metabolism are believed to have more promising therapeutic potential in humans.

8. Luteolin

Luteolin is a flavanoid with a yellow crystalline appearance. Luteolin is naturally abundant in artichoke and was popularized with the creation of the chemically-induced long-term potentiation (CILTEP) stack.

While it is unlikely that ingesting artichoke or artichoke extract will result in any meaningful effects in the brain due to rapid and extensive hepatic metabolism of luteolin and poor bioavailability, it remains theoretically possible to develop a luteolin derivative or formulation without these fatal disadvantages. For example, esterification of of luteolin’s three hydroxyl groups would improve lipophilicity (and therefore blood brain barrier permeability). Once inside the brain, esterases could hydrolyze the adduct to regenerate luteolin, effectively “locking” it into the cytosol in a manner analogous to the way glucose is trapped inside intracellular compartments by the enzymatic phosphorylation of C6 via the glycolysis enzyme hexokinase.

The Janus-Faced Glutamate Receptors: NMDA, AMPA and Kainic Acid Receptors

Racetams (such as the pre-eminent Piracetam) and their riskier counterparts–the ampakines–ultimately enhance cognition by modulating glutamatergic excitatory transmission in the brain.

The “big three” glutamate receptors in the central nervous system (CNS) are:

• α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)
• N-Methyl-D-Aspartate receptor (NMDAR)
• Kainic acid receptor.

Piracetam is a positive allosteric modulator of the AMPA receptor. It binds to a subunit of AMPAR inducing a conformational change that increases the open probability of the receptor without any direct activation. The absence of direct activation is important because it means that even if Piracetam or another racetam is bound to AMPAR, a signal won’t transduce across the phospholipid bilayer without glutamate diffusing across the synaptic cleft and also binding to AMPAR. (Glutamate is the endogenous ligand for these receptors. It is the most important excitatory neurotransmitter in the CNS.)

AMPA, NMDA and kainic acid are all potent neurotoxins because they are high-affinity agonists at each of the three glutamate receptors that were named after them. Similarly, domoic acid (associated with amnesic shellfish poisoning) concomitantly activates AMPA and Kainic Acid receptors at nanomolar concentrations in the brain, resulting in profound damage to the hippocampus.

Walking the line between neuroprotection and neurotoxicity

How is it possible that enhanced activation of glutamate receptors can elicit either nootropic effects or excitotoxicity depending on the context?

Furthermore, why is the NMDA *antagonist, *memantine, used to treat dementia and rescue cognitive deficits when other cognitive enhancers (e.g., some racetams and ampakines) have (seemingly) opposite effects, e.g., allosterically activate NMDA receptors?

These questions make conspicuous the fact that both activation or suppression of the glutamatergic system can be either  neurotoxic or neuroprotective depending on the neurochemical milieu in the brain and the pharmacodynamic properties of the drug, including binding affinity (Km), stereochemistry of the ligand and the binding pocket, agonism or antagonism vs. allostery, and off-rate kinetics.

What, then, is the best way to safely augment the LTP-enhancing effects of Racetams without also increasing the risk of excitotoxicity?

(Excitotoxicity occurs when glutamate receptors are excessively stimulated, resulting in an uninterrupted influx of calcium ions and a complex cascade of deleterious downstream consequences culminating in apoptosis or orchestrated cell death.)

Racetams can be effectively augmented by targeting signaling pathways either upstream or downstream of glutamate receptors.

[1] Lim MM, Elkind J, Xiong G, et al. Dietary therapy mitigates persistent wake deficits caused by mild traumatic brain injury. Sci Transl Med. 2013;5(215):215ra173.

[2] Aquilani R, Iadarola P, Contardi A, et al. Branched-chain amino acids enhance the cognitive recovery of patients with severe traumatic brain injury. Arch Phys Med Rehabil. 2005;86(9):1729-35.

[3] Williams AN, Woessner KM. Monosodium glutamate ‘allergy’: menace or myth?. Clin Exp Allergy. 2009;39(5):640-6.

[4] Goff DC, Cather C, Gottlieb JD, et al. Once-weekly D-cycloserine effects on negative symptoms and cognition in schizophrenia: an exploratory study. Schizophr Res. 2008;106(2-3):320-7.

[5] Javitt DC. Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 2010;47(1):4-16.

[6] D-Cycloserine Increases Positive Symptoms in Chronic Schizophrenic Patients When Administered in Addition to Antipsychotics: A Double-Blind, Parallel, Placebo-Controlled Study. Neuropsychopharmacology. 1999;21(2):203.

[7] Sartori SB, Whittle N, Hetzenauer A, Singewald N. Magnesium deficiency induces anxiety and HPA axis dysregulation: modulation by therapeutic drug treatment. Neuropharmacology. 2012;62(1):304-12.

[8] Wang J, Liu Y, Zhou LJ, et al. Magnesium L-threonate prevents and restores memory deficits associated with neuropathic pain by inhibition of TNF-α. Pain Physician. 2013;16(5):E563-75.

[9] Devan BD, Bowker JL, Duffy KB, et al. Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition. Psychopharmacology (Berl). 2006;183(4):439-45.

[10] Goff DC, Cather C, Freudenreich O, et al. A placebo-controlled study of sildenafil effects on cognition in schizophrenia. Psychopharmacology (Berl). 2009;202(1-3):411-7.

[11] Titus DJ, Oliva AA, Wilson NM, Atkins CM. Phosphodiesterase inhibitors as therapeutics for traumatic brain injury. Curr Pharm Des. 2015;21(3):332-42.

[12] Rouse M, Younès A, Egan JM. Resveratrol and curcumin enhance pancreatic β-cell function by inhibiting phosphodiesterase activity. J Endocrinol. 2014;223(2):107-17.