Noopept

1.0 Introduction

1.1 The Landscape of Nootropics and Cognitive Enhancement

The pursuit of cognitive enhancement has led to the exploration of a diverse class of neuroactive compounds collectively termed “nootropics,” or “smart drugs”.1 This category is broad, encompassing substances with varied mechanisms and regulatory statuses. It can be stratified into three main groups: 1) Prescription stimulant drugs, such as amphetamine salts (Adderall) and methylphenidate (Ritalin), which primarily modulate dopaminergic and noradrenergic pathways to improve attention and are approved for conditions like Attention-Deficit/Hyperactivity Disorder (ADHD) 1; 2) Synthetic compounds, including the racetam family (e.g., piracetam) and their derivatives, which often target glutamatergic and cholinergic systems to influence synaptic plasticity 1; and 3) Natural compounds and dietary supplements, such as caffeine,

Bacopa monnieri, and Ginkgo biloba, which exert their effects through various pathways including antioxidant action, improved cerebral blood flow, and modulation of neurotransmitter systems.2

The use of these substances, particularly outside of clinical supervision, raises significant societal and ethical questions regarding fairness, coercion in academic and professional environments, and the long-term safety of altering brain chemistry for non-therapeutic purposes.2 Within this complex landscape, N-phenylacetyl-L-prolylglycine ethyl ester, or Noopept, occupies a unique and controversial position.

1.2 Development and Classification of Noopept

Noopept (developmental code GVS-111) was synthesized in Russia in 1996 at the Zakusov State Research Institute of Pharmacology.4 It was developed as a dipeptide analogue of piracetam, the prototypical nootropic agent, based on an innovative drug design approach that uses short-peptide structures to mimic the activity of nonpeptide molecules.6 Although it shares structural motifs with the racetam class, such as a pyrrolidine ring, it technically lacks the defining 2-oxo-pyrrolidine nucleus and is therefore pharmacologically distinct.4 Initial preclinical investigations revealed that Noopept was approximately 1000 times more potent than piracetam on a dose-by-dose basis and possessed a broader spectrum of activity, influencing not only the early stages of memory formation but also memory consolidation and retrieval.6

1.3 Chemical Profile and Global Regulatory Status

Noopept is chemically identified by its IUPAC name, Ethyl 1-(phenylacetyl)-l-prolylglycinate, and its chemical formula, C17H22N2O4.8 Its global regulatory status is characterized by a profound and telling fragmentation. In Russia, Noopept is classified as a medicinal drug and is available without a prescription, indicating a level of acceptance and perceived safety within that country’s healthcare system.8 In stark contrast, in the United States, it is considered an unapproved “New Drug” as defined by 21 U.S. Code § 321(p)(1).8 Consequently, its inclusion in dietary supplements or food is unlawful, and it has not undergone the rigorous safety and efficacy evaluation required by the Food and Drug Administration (FDA).8 Other nations have taken even stricter stances; for instance, Hungary has added Noopept to its list of controlled psychoactive substances, prohibiting its production and sale.8

This regulatory divergence creates a fundamental paradox that is central to understanding the current state of knowledge on Noopept. On one hand, its status as a medicine in Russia has generated a body of clinical research, such as the widely cited Neznamov & Teleshova trial, which forms the primary basis for its therapeutic claims.10 On the other hand, its unapproved status in the West has driven its use into a gray market of online vendors and unregulated supplements.11 This bifurcation has resulted in two parallel and often conflicting narratives: one portraying Noopept as a legitimate therapeutic agent for cognitive disorders, and another viewing it as a risky, unproven “smart drug” of unknown purity and safety. Law enforcement agencies frequently intercept large bulk quantities of raw Noopept material on the illegal market, underscoring the scale of its unregulated distribution.13 Any scientific evaluation of Noopept must therefore navigate this complex landscape, critically assessing the available clinical data while acknowledging the significant public health risks posed by its uncontrolled availability.

2.0 Pharmacokinetics

2.1 Absorption, Distribution, and Blood-Brain Barrier Penetration

Noopept demonstrates excellent oral bioavailability, a key characteristic for a centrally-acting agent. Preclinical studies in rats have shown that an oral dose of 50 mg/kg achieves serum concentrations and excretion kinetics comparable to a 5 mg/kg injection, indicating efficient absorption from the gastrointestinal tract.4 Following oral administration, it reaches maximum plasma concentration (Cmax) rapidly, with a time to maximum concentration (Tmax) of approximately 7 minutes in rats.4 Despite its ability to cross the blood-brain barrier, the parent molecule, N-phenylacetyl-L-prolylglycine ethyl ester, has an exceptionally short biological half-life. In rodent models, its half-life is estimated to be only around 6.5 minutes, and the compound is often undetectable in brain tissue shortly after administration.4 This rapid clearance presents a pharmacological puzzle: how can a substance with such a fleeting presence in the body exert sustained and cumulative cognitive effects? The answer lies in its metabolism.

2.2 The Central Role of Cycloprolylglycine (cPG) as the Primary Active Metabolite

The key to understanding Noopept’s pharmacology is recognizing that it is a prodrug—an inactive or less active precursor that is converted into an active drug within the body.8 Upon absorption and distribution to the brain, Noopept is rapidly metabolized into the endogenous dipeptide cycloprolylglycine (cPG).4 Studies have confirmed that brain concentrations of cPG increase significantly one hour after Noopept administration, long after the parent compound has been eliminated.9 This establishes cPG as the primary active metabolite responsible for the majority of Noopept’s observed nootropic and neuroprotective activities.

This mechanism positions Noopept as a highly efficient “Trojan Horse” delivery system. The ethyl ester and N-phenylacetyl groups likely enhance its lipophilicity, facilitating passage across the blood-brain barrier, after which it releases its active cPG payload directly within the central nervous system. However, this model is complicated by a critical paradox observed in preclinical research. While subchronic administration of Noopept over nine days leads to a cumulative anti-amnesic effect in rats—with the percentage of animals showing memory improvement increasing from 70% to 90%—direct injections of cPG do not produce this build-up effect.4 In fact, the efficacy of direct cPG administration appeared to decrease over the same period, with the rate of memory improvement falling from 50% to 33%.4

This discrepancy suggests that the therapeutic profile of Noopept is not solely attributable to the presence of cPG, but rather to the specific kinetics of its delivery and release. A bolus injection of cPG may lead to rapid saturation or downregulation of its target receptors, inducing tolerance and diminishing its effect over time. In contrast, Noopept, once inside the brain, may be sequestered within neurons or glial cells and metabolized into cPG at a slow, controlled rate. This would create a “depot” effect, providing a sustained, low-level release of cPG directly into the synaptic microenvironment. Such a controlled release mechanism could be essential for driving the long-term neuroplastic changes, such as the upregulation of neurotrophic factors, without triggering the rapid desensitization observed with direct cPG administration. Therefore, Noopept should be viewed not merely as a simple prodrug, but as a sophisticated delivery and controlled-release system, where the metabolic conversion process itself is integral to its unique pharmacological profile.

3.0 Mechanisms of Action

The biological effects of Noopept, mediated primarily through its active metabolite cycloprolylglycine (cPG), are multifaceted and involve the modulation of several critical neurotransmitter and signaling systems. Its actions converge on pathways that govern synaptic plasticity, neuronal survival, and cellular resilience. The following table summarizes these interconnected mechanisms.

Table 1: Summary of Noopept’s Mechanisms of Action

System	Primary Target	Mediator	Observed Effect	Associated Benefit
Glutamatergic	AMPA Receptors	Cycloprolylglycine (cPG)	Positive Allosteric Modulation	Enhanced Synaptic Plasticity (LTP), Improved Learning
Neurotrophic	TrkB/TrkA Receptors	BDNF & NGF	Increased Gene Expression	Neurogenesis, Neuronal Survival, Neurorestoration
Cholinergic	α7 Nicotinic Acetylcholine Receptors (on interneurons)	Noopept	Receptor Sensitization, Increased GABAergic Tone	Improved Attention, Anxiolysis
Neuro-protective	Multiple (Mitochondria, Inflammatory Pathways, Glutamate Receptors)	Noopept & cPG	Reduced Oxidative Stress, Anti-inflammatory Action, Attenuation of Excitotoxicity & Apoptosis	Increased Cell Viability in Pathological States

3.1 Primary Action on the Glutamatergic System

The glutamatergic system is the principal excitatory network in the central nervous system, and its receptors are fundamental to synaptic transmission, plasticity, learning, and memory.14 Noopept’s most significant effects are exerted through its modulation of this system.

3.1.1 Cycloprolylglycine: A Positive Allosteric Modulator of AMPA Receptors

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are ionotropic glutamate receptors that mediate the majority of fast excitatory synaptic transmission in the brain.14 When activated by glutamate, they allow an influx of sodium ions, causing a rapid depolarization of the postsynaptic membrane.15 Compelling evidence indicates that Noopept’s active metabolite, cPG, functions as a positive allosteric modulator of these receptors. This means it binds to a site on the receptor distinct from the glutamate binding site and enhances the receptor’s response to glutamate.

Direct electrophysiological evidence comes from studies on freshly isolated rat cerebellar Purje cells, where the application of cPG at physiological concentrations was shown to significantly enhance transmembrane currents mediated by AMPA receptors.16 This finding was further substantiated by computational modeling, which demonstrated that cPG can dock effectively at the known binding site for piracetam on the GluA3 subtype of the AMPA receptor.17 This has led to the classification of cPG as an endogenous “ampakine”—a substance that potentiates AMPA receptor function.17 The functional relevance of this interaction is underscored by experiments showing that the neuroprotective effects of cPG are entirely dependent on AMPA receptor activation; when these receptors are blocked by antagonists like DNQX or GYKI 52466, the protective effects of cPG are abolished.18

3.1.2 Downstream Effects on NMDA Receptors and Long-Term Potentiation (LTP)

The potentiation of AMPA receptors by cPG has profound downstream consequences for synaptic plasticity, particularly through its interplay with the N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are unique “coincidence detectors” that are critical for Long-Term Potentiation (LTP), the primary cellular mechanism underlying the formation of memories.14 For an NMDA receptor channel to open, two conditions must be met simultaneously: the neurotransmitter glutamate must be bound to the receptor, and the postsynaptic membrane must be sufficiently depolarized to expel a magnesium ion (Mg2+) that otherwise blocks the channel at resting potential.15

The sustained influx of sodium ions through AMPA receptors provides this necessary depolarization.15 By enhancing AMPA receptor currents, cPG makes it more likely that a given glutamatergic signal will achieve the threshold of depolarization required to unblock NMDA receptors. Once unblocked, NMDA receptors allow an influx of calcium ions (Ca2+), which act as a crucial second messenger, triggering a cascade of intracellular signaling events that lead to a lasting strengthening of the synapse, or LTP.19 Therefore, Noopept facilitates learning and memory not by acting directly on NMDA receptors, but by sensitizing the AMPA receptors that “prime” the neuron for NMDA-dependent plasticity.4

3.2 Stimulation of Neurotrophic Factors

Noopept’s acute effects on synaptic transmission are complemented by long-term effects on neuronal structure and survival, mediated by the upregulation of key neurotrophic factors, or neurotrophins. These proteins are essential for the growth, maintenance, and survival of neurons.

3.2.1 Upregulation of Brain-Derived Neurotrophic Factor (BDNF)

Brain-Derived Neurotrophic Factor (BDNF) is a critical protein that supports the survival of existing neurons, encourages the growth and differentiation of new neurons and synapses (neurogenesis and synaptogenesis), and is integral to LTP.22 Preclinical studies have consistently shown that chronic (28-day) administration of Noopept leads to a significant increase in the expression of BDNF mRNA and protein levels, particularly in the hippocampus, a brain region vital for memory consolidation.9 The metabolite cPG is also independently shown to increase BDNF levels, suggesting it is the primary mediator of this effect.9 This neurotrophic action is functionally linked to Noopept’s neuroprotective properties, as the protective effects of cPG are dependent on the activation of the BDNF receptor, Tropomyosin receptor kinase B (TrkB).8

3.2.2 Increased Expression of Nerve Growth Factor (NGF)

In addition to BDNF, chronic treatment with Noopept has also been demonstrated to increase the expression of Nerve Growth Factor (NGF) in the rat hippocampus.24 NGF is another essential neurotrophin that plays a crucial role in the survival and maintenance of neurons, particularly cholinergic neurons, which are important for attention and memory.25 This dual action on both BDNF and NGF expression contributes to Noopept’s potential for neurorestoration and its ability to support cognitive function over the long term.

These findings reveal that the glutamatergic and neurotrophic mechanisms of Noopept are not independent but are linked in a unified “Glutamate-to-Growth” signaling cascade. The initial, acute event is the positive modulation of AMPA receptors by cPG. This enhanced glutamatergic activity serves as the trigger for the subsequent, long-term synthesis and release of neurotrophins like BDNF.16 BDNF then binds to its corresponding TrkB receptor, initiating downstream intracellular pathways that result in structural changes at the synapse, enhanced neuronal survival, and neurogenesis.18 This elegant, two-stage mechanism provides a compelling explanation for how Noopept can produce both immediate cognitive-enhancing effects (via enhanced synaptic transmission) and sustained neuroprotective and neurorestorative benefits (via structural changes driven by neurotrophins).

3.3 Cholinergic System

The cholinergic system, which uses acetylcholine as its primary neurotransmitter, is critically involved in cognitive processes such as attention, learning, and memory. Noopept appears to exert a subtle but significant modulatory effect on this system.

3.3.1 Sensitization of α7 Nicotinic Acetylcholine Receptors on Interneurons

Research using electrophysiological recordings in rat hippocampal slices has revealed that Noopept increases inhibitory tone in the CA1 region.27 Specifically, it increases the frequency of spontaneous inhibitory postsynaptic currents (IPSCs) in pyramidal neurons.27 This effect is not direct; rather, it is mediated by the activation of inhibitory interneurons that synapse onto these pyramidal cells. The mechanism was pinpointed through pharmacological blockade: the application of α-bungarotoxin and methyllycaconitine, both selective antagonists of the α7 nicotinic acetylcholine receptor (α7-nAChR), completely abolished Noopept’s effect.28 This demonstrates that Noopept acts on α7-nAChRs located on these inhibitory interneurons. By sensitizing these receptors, Noopept enhances their response to acetylcholine, leading to an increased release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This resulting increase in hippocampal inhibitory activity is believed to contribute to Noopept’s observed anxiolytic (anti-anxiety) effects.27

3.4 Neuroprotective Pathways

Beyond its specific actions on neurotransmitter systems, Noopept exhibits a range of general neuroprotective effects that contribute to its therapeutic potential in conditions involving neuronal stress and damage.

3.4.1 Attenuation of Glutamate-Induced Excitotoxicity

Excitotoxicity is a pathological process in which excessive stimulation of glutamate receptors leads to a massive influx of calcium ions, triggering a cascade of events that result in neuronal injury and death.19 This process is a key contributor to the damage seen in ischemic stroke and traumatic brain injury. Multiple

in vitro studies have demonstrated that Noopept pretreatment can protect neurons from glutamate-induced toxicity and subsequent calcium overload, thereby preserving cell viability.6 This anti-excitotoxic action is a cornerstone of its neuroprotective profile.

3.4.2 Antioxidant, Anti-inflammatory, and Anti-Apoptotic Effects

Noopept and its metabolite cPG also combat neuronal damage by mitigating cellular stress at multiple levels. In cellular models of Alzheimer’s Disease, Noopept has been shown to reduce the accumulation of intracellular reactive oxygen species (ROS), thereby inhibiting oxidative damage.5 It also enhances mitochondrial membrane potential and suppresses the mitochondrial apoptotic pathway, which is a form of programmed cell death.5 Furthermore, cPG has demonstrated anti-inflammatory properties, reducing the expression of the pro-inflammatory cytokine interleukin-6 (IL-6) while increasing the expression of the anti-inflammatory cytokine interleukin-4 (IL-4) in a model of amyloid-beta infusion.9 This combination of antioxidant, anti-inflammatory, and anti-apoptotic actions provides a robust, multi-pronged defense against the cellular insults that characterize neurodegenerative diseases and brain injury.

4.0 Potential Therapeutic Applications

The multifaceted mechanisms of action of Noopept suggest a broad range of potential therapeutic applications, from mitigating age-related cognitive decline to treating neurodegenerative diseases. However, the clinical evidence supporting these applications is limited and primarily originates from studies conducted in Russia.

4.1 Mild Cognitive Impairment (MCI) of Vascular and Traumatic Origin

The most significant clinical data for Noopept comes from a comparative study conducted by Neznamov and Teleshova, which evaluated its efficacy in patients with mild cognitive impairment (MCI) resulting from either cerebrovascular disease or traumatic brain injury (TBI).10 This study serves as the primary evidence base for its clinical use in Russia.

Table 2: Overview of the Neznamov & Teleshova (2009) Comparative Trial

Parameter	Details
Patient Population	53 patients (41 completed) with mild cognitive disorders of vascular or post-traumatic origin.31
Study Design	Open-label, comparative clinical trial.31
Noopept Group	31 patients initially enrolled; treated with 10 mg twice daily (20 mg/day).31
Piracetam Group	22 patients initially enrolled; treated with 400 mg three times daily (1200 mg/day).31
Duration	56 days.31
Cognitive Outcomes	Both groups showed improvement in cognitive function. Noopept demonstrated a more pronounced effect on restoring cognitive functions, particularly in patients with post-traumatic cognitive deficits.31
Vegetative / Autonomic Outcomes	Noopept showed a clear advantage over piracetam in normalizing autonomic nervous system function, leading to significant reductions in headaches, dizziness, sleep disturbances, and anxiety-related symptoms.31
Safety/Tolerability	Both treatments were generally well-tolerated. The incidence of side effects in the Noopept group was 1.8-fold lower than in the piracetam group. Piracetam was associated with more pronounced undesirable psychostimulatory effects.31
Limitations	The study was open-label (not blinded), lacked a placebo control group, and had a relatively small sample size. These factors limit the generalizability of the findings and introduce a high risk of bias.

4.1.1 Analysis of the Neznamov & Teleshova (2009) Comparative Trial

The findings from this trial suggest that at a daily dose of 20 mg, Noopept is not only effective in improving cognitive function in patients with MCI but may be superior to a 60-fold higher dose of piracetam (1200 mg) in certain domains.31 The authors reported that Noopept had a more pronounced anxiolytic (anti-anxiety) and neuroprotective effect. It was particularly effective in addressing the cognitive deficits associated with TBI and demonstrated a significant ability to improve autonomic nervous system function, leading to better sleep and a reduction in somatic complaints like headaches and dizziness.31 The superior tolerability profile, with nearly half the incidence of side effects compared to piracetam, is also a notable finding.33 A separate open-label Russian study involving 60 stroke patients reported similar significant improvements in cognitive functions after two months of treatment with 20 mg of Noopept daily, further supporting its potential in cerebrovascular-related cognitive impairment.32 Despite these positive results, the methodological limitations of these studies—particularly the lack of blinding and a placebo control—mean they should be considered preliminary. They provide a strong rationale for further investigation but do not constitute definitive proof of efficacy by modern clinical trial standards.

4.2 Preclinical Models

While clinical data is sparse, a significant body of preclinical research points to Noopept’s potential in treating major neurodegenerative diseases.

4.2.1 Alzheimer’s Disease (AD)

Alzheimer’s disease is characterized by the extracellular accumulation of amyloid-beta (Aβ) plaques and the intracellular formation of neurofibrillary tangles composed of hyperphosphorylated tau protein. In vitro studies using PC12 cell lines (a common neuronal model) have shown that Noopept provides robust protection against Aβ-induced toxicity.5 Pretreatment with Noopept improved cell viability, reduced levels of reactive oxygen species, prevented calcium overload, and suppressed the mitochondrial pathway of apoptosis (programmed cell death).5 Critically, Noopept was also shown to decrease the hyperphosphorylation of tau protein at the Ser396 site and to restore the normal morphology and neurite outgrowth of cells exposed to Aβ.6 These findings suggest that Noopept can target multiple core pathological mechanisms of AD.

4.2.2 Parkinson’s Disease (PD)

Parkinson’s disease pathology is linked to the misfolding and aggregation of the protein α-synuclein into toxic oligomers and Lewy bodies. Research has shown that Noopept can modulate the amyloid assembly process of α-synuclein.11 It appears to promote the rapid sequestration of toxic oligomeric species into larger, more stable fibrillar aggregates, which may be less cytotoxic.11 In a genetic rat model of PD (PINK1 knockout rats), intranasal administration of a formulation containing Noopept and Forskolin was shown to significantly reverse motor symptoms, loss of muscle strength, and the neurodegeneration of midbrain dopamine neurons.11 These preclinical results are promising and suggest that Noopept warrants further investigation as a potential disease-modifying therapy for synucleinopathies.

4.3 Anxiolytic (Anti-Anxiety) Properties

Separate from its cognitive-enhancing effects, Noopept consistently demonstrates anxiolytic properties in preclinical models.6 This effect appears to be genotype-dependent, being more pronounced in animal strains that exhibit high baseline levels of anxiety, such as BALB/c mice.36 The anxiolytic action is believed to stem from at least two of its core mechanisms. As detailed in section 3.3, its modulation of α7-nAChRs on hippocampal interneurons leads to an increase in inhibitory GABAergic transmission, which is a well-established mechanism for reducing anxiety.27 Additionally, some research suggests that Noopept’s activation of Hypoxia-inducible factor 1 (HIF-1) may play a role, as HIF-1 can influence the protein responsible for controlling GABA receptors.8 The active metabolite, cPG, has also been independently shown to produce an anxiolytic effect in rodent studies, confirming that this property is central to the drug’s profile.9

5.0 Safety, Tolerability, and Critical Concerns

The evaluation of Noopept’s safety profile is complicated by the dichotomy between its regulated use in one country and its unregulated status elsewhere. While clinical data provides some insight into its tolerability, significant theoretical risks and public health dangers remain.

5.1 Adverse Events from Clinical Trials

The primary source of human safety data comes from the open-label Neznamov & Teleshova trial.31 In this study, Noopept was generally well-tolerated, especially when compared to piracetam. The reported adverse events were typically mild and included sleep disturbances (reported in 5 of 31 patients), irritability (3/31), and an increase in blood pressure (7/31).9 The authors noted that the overall incidence of side effects was 1.8 times lower than in the piracetam group, which was associated with more significant psychostimulatory effects like agitation.31 While this suggests a favorable tolerability profile in a supervised clinical context, the data is derived from a small, non-blinded study, and a comprehensive safety assessment is still lacking.

5.2 Potential Risks and Psychiatric Side Effects

A critical concern that is often overlooked in discussions of Noopept is the potential for serious psychiatric adverse effects. While no formal case reports have been published specifically linking Noopept to psychosis or mania, its fundamental mechanisms of action suggest that such a risk is biologically plausible. The very processes that underlie its therapeutic potential—the potentiation of glutamatergic neurotransmission and the enhancement of synaptic plasticity—represent a double-edged sword.

The brain’s excitatory systems are tightly regulated to maintain homeostasis. Dysregulation of glutamatergic pathways, particularly involving NMDA receptors, is strongly implicated in the pathophysiology of psychiatric disorders such as schizophrenia and bipolar disorder. While Noopept’s enhancement of AMPA receptor function is intended to facilitate healthy learning and memory, this powerful modulation could, in susceptible individuals, push a vulnerable neural system past a homeostatic tipping point. By “revving up” the machinery of synaptic plasticity, it could potentially lead to aberrant circuit formation, contributing to symptoms of paranoia, psychosis, or hypomania.

This is not merely a theoretical concern. Case reports have linked other nootropics, including its parent compound piracetam, to the induction of psychotic symptoms, including auditory and visual hallucinations, in vulnerable individuals.39 Other cognitive enhancers like citicoline have been associated with psychosis and paranoia in case reports.40 Given that Noopept is significantly more potent than piracetam and acts on the same fundamental systems, it is logical to infer that a similar, if not greater, risk exists. The absence of specific case reports for Noopept may be a function of underreporting or its relatively niche status in Western medicine, not an inherent absence of risk. Therefore, unsupervised use, especially in individuals with a personal or family history of mental illness, carries a significant and underappreciated danger of psychiatric destabilization.40

5.3 Public Health Challenge

The most immediate and significant danger associated with Noopept stems from its sale in unregulated markets. As an unapproved drug in the US and many other countries, it is primarily available through online vendors who operate outside the purview of regulatory bodies like the FDA.8 This creates a high-risk environment for consumers.

Independent laboratory analyses of over-the-counter “cognitive enhancement” supplements purchased online have revealed alarming and dangerous findings. A 2020 study published in Neurology: Clinical Practice found that products labeled as containing racetam analogues frequently contained wildly inaccurate dosages, with some exposing consumers to amounts up to four times greater than typical pharmaceutical doses.12 More disturbingly, these supplements were often found to be cocktails of multiple unapproved drugs. Some products contained undeclared substances like phenibut (a GABAB agonist with high abuse potential) and vinpocetine.11 Consumers are therefore not only using a substance with a limited and unverified safety profile but are often unknowingly ingesting an untested combination of potent neuroactive chemicals. The health effects of consuming such unpredictable and unverified drug combinations are entirely unknown, posing a serious public health threat.11

6.0 Synthesis and Future Research Directions

6.1 Noopept’s Pharmacological Profile

N-phenylacetyl-L-prolylglycine ethyl ester (Noopept) is a potent synthetic nootropic agent with a complex and sophisticated pharmacological profile. It functions primarily as a prodrug for the endogenous neuropeptide cycloprolylglycine (cPG), which mediates the majority of its biological effects. Its mechanism is initiated by the positive allosteric modulation of AMPA-type glutamate receptors, an action that facilitates NMDA receptor-dependent long-term potentiation and underpins its acute cognitive-enhancing properties. This glutamatergic activity triggers a downstream cascade that, with chronic administration, leads to the upregulation of key neurotrophins, including BDNF and NGF. This “Glutamate-to-Growth” pathway promotes long-term synaptic plasticity, neurogenesis, and neuronal survival, forming the basis of its neurorestorative potential. Complementing these core actions are a distinct anxiolytic effect, mediated by the sensitization of α7 nicotinic acetylcholine receptors on hippocampal interneurons, and a suite of broad-spectrum neuroprotective properties, including anti-excitotoxic, antioxidant, and anti-inflammatory effects. While preclinical data is robust and promising, the clinical evidence remains sparse and requires rigorous validation.

6.2 Knowledge Gaps and Future Clinical Investigations

The current body of research on Noopept is characterized by a profound disconnect between the promising, detailed preclinical evidence and the limited, dated, and methodologically flawed clinical data. To bridge this gap and determine the true therapeutic value and safety of Noopept, a structured and rigorous program of clinical investigation is urgently required. The following research directions are proposed:

Phase I Clinical Trials: There is a critical need for modern, well-controlled Phase I trials in healthy human volunteers. These studies should be designed to definitively establish the human pharmacokinetics of both Noopept and its primary metabolite, cPG. Key objectives would include determining its half-life, dose-linearity, metabolic pathways, and safety profile in a controlled setting.
Double-Blind, Placebo-Controlled Efficacy Trials: The findings of the Neznamov & Teleshova study must be validated through large-scale, multicenter, double-blind, randomized, placebo-controlled trials. These trials should focus on patient populations with mild cognitive impairment of vascular or post-traumatic origin, using standardized and validated cognitive assessment tools such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and comprehensive neuropsychological test batteries as primary endpoints.
Exploratory Studies in Neurodegenerative and Neurological Disorders: Given the strength of the preclinical data, well-designed pilot studies are warranted to explore Noopept’s potential as a disease-modifying or symptomatic treatment in early-stage Alzheimer’s disease. Its neurorestorative and anti-inflammatory properties also suggest potential utility as an adjunctive therapy in post-stroke rehabilitation, an area where preliminary Russian data already exists.32
Long-Term Safety and Psychiatric Risk Assessment: Prospective, long-term observational studies or extended clinical trials are necessary to evaluate the safety of chronic Noopept administration. These studies should specifically monitor for cardiovascular effects (e.g., changes in blood pressure) and, crucially, include structured psychiatric assessments to quantify the risk of adverse events such as psychosis, mania, or anxiety in both the general population and in individuals with a predisposition to mental illness.

Until such research is conducted, Noopept will remain a compound of significant scientific interest but unproven clinical utility and uncertain safety, with its unregulated availability posing a continued risk to public health.