Researchers identified five unapproved drugs in “Brain Boosting” supplements


Supplements that claim to improve mental focus and memory may contain unapproved pharmaceutical drugs and in potentially dangerous combinations and doses, according to a new study published in Neurology Clinical Practice.

Researchers found five such drugs not approved in the United States in the supplements they examined.

The supplements are sometimes called “nootropics,” “smart drugs” or “cognitive enhancers.”

“Over-the-counter cognitive supplements are popular because they promise a sharper mind, but they are not as closely regulated as pharmaceutical drugs,” said study author Pieter A. Cohen, M.D., of Harvard Medical School in Boston, Mass.

“Use of these supplements poses potentially serious health risks.

Not only did we detect five unapproved drugs in these products, we also detected several drugs that were not mentioned on the labels, and we found doses of unapproved drugs that were as much as four times higher than what would be considered a typical dose.”

Cohen said the supplements could be especially risky if used in combination with prescriptions drugs or instead of seeking medical advice.

Table Information provided on the label compared with measured quantity of unapproved drugs in dietary supplements If no amounts provided on the label, no quantity was listed.*Typical pharmaceutical doses are as follows: noopept 10 mg, phenibut 250-500 mg, aniracetam 750 mg, picamilon 50-200 mg and vinpocetine 5-40 mg. ND=Not
detected; NA=Not Applicable; SD=standard deviation

Unlike pharmaceutical drugs that must be proven safe and effective for their intended use before they are marketed to consumers, the law does not require the U.S. Food and Drug Administration (FDA) to approve dietary supplements for safety or effectiveness before they reach the consumer.

The FDA takes action after the products reach the market if they are mislabeled or contain unapproved products.

For the study, researchers searched the National Institutes of Health Dietary Supplement Label Database and the Natural Medicines Database for cognitive supplements that listed drugs similar to piracetam, a drug previously found in supplements but not approved in the U.S.

They were looking for analogs of piracetam, drugs with a similar but slightly different chemical structure. Analogs are sometimes introduced into supplements to circumvent laws.

Researchers identified 10 supplements, eight that promised to enhance mental function, one that was marketed as “workout explosives” and another that had the words “outlast, endure, overcome” on the label.

Researchers examined the contents of each supplement using various methods and measured quantities of each drug present.

In the 10 supplements they examined, researchers detected five unapproved drugs.

Two were analogs of piracetam called omberacetam and aniracetam. The others were the unapproved drugs vinpocetine, phenibut and picamilon.

The FDA has issued a warning that vinpocetine should not be consumed by women of childbearing age.

While all of the risks of these drugs are not known, side effects include increased and decreased blood pressure, agitation, sedation and hospitalization.

All 10 supplements contained omberacetam, which is prescribed in Russia for traumatic brain injury and mood disorders.

A typical pharmaceutical dose would be 10 milligrams (mg). The doses in a recommended supplement serving size were as high as 40 mg, four times greater than in pharmaceutical dosages.

Some supplements contained more than one unapproved drug. One product combined four of the unapproved drugs.

“With as many as four unapproved drugs in individual products, and in combinations never tested in humans, people who use these cognitive enhancement supplements could be exposing themselves to potentially serious health risks,” said Cohen.

“The effects of consuming untested combinations of unapproved drugs at unpredictable dosages are simply unknown and people taking these supplements should be warned.”

Researchers also found that for those products with drug quantities provided on the labels, a majority of the declared quantities were inaccurate.

“The fact that these supplements are listed in official databases does not mean the labeling is accurate or the dosage levels of ingredients in these supplements are safe,” said Cohen.

“U.S. law does not permit unapproved pharmaceuticals to be introduced into dietary supplements, but the law places the burden of eliminating those products on the FDA. The FDA has issued a series of warnings to companies selling supplements with unapproved drugs, yet such drugs remain openly listed on databases as ingredients in supplements.

Our study also raises concerns regarding the quality and legality of supplements listed in supplement databases.”

One limitation of the study was that it didn’t look at all unapproved drugs that are marketed in cognitive supplements.

Source: Garvan Institute of Medical Research


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  7. McCabe DJ, Bangh SA, Arens AM, Cole JB. Phenibut exposures and clinical effects reported to a regional poison center. Amer J Emerg Med 2019;37(11):2066-2071.
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Piracetam (2-oxo-1-pyrrolidineacetamide) (Fig- ure 1) is a cyclic derivative of gamma-aminobutyric acid (GABA), obtained after the loss of one molecule of water followed by ring formation (1).

It is the first representative of the “nootropic” drugs (2).
The term nootropic comes from a Greek word meaning ìacting on the mindî.

Piracetam was synthesized by Giurgea in UCB Laboratories in Belgium. It has been in clinical use since 1972. Since then other pharmaceutical companies have been scrambling to develop their own nootropics (e.g. vinpocetine, aniracetam, pramiracetam, oxirac- etam).

Piracetam might be successfully used to treat senile dementia, vertigo, sickle cell anemia, and numerous other health problems like Alzheimerís disease or stroke (3 – 6).

Piracetam might increase reading comprehension and accuracy in dyslexic children (7).

It has improved alertness, socialization and IQ in elderly psychiatric patients. Piracetam has also been used to treat alcoholism.

In 1991 Paula- Barbosa and colleagues discovered that long-term (12 months) alcohol-feeding to rats significantly increased the formation of lipofuscin (an age-related waste pigment) in brain cells.

Giving high doses of piracetam to the alcohol-fed rats reduced their lipofuscin levels significantly below the control levels (8). In 1997 it was demonstrated that piracetam might reduce the neuronal loss following chronic alcohol consumption (9).

Piracetam Molecule It Is Nootropic Drug Structural Chemical Formula And  Molecule Model Stock Illustration - Download Image Now - iStock
Figure 1. Structure of piracetam (2-oxo-1-pyrrolidineacetamide) ñ prototypical nootropic; a cyclic derivative of GABA.

Piracetam enhances cognition under conditions of hypoxia, and also enhances memory and learning (10). When piracetam is taken with choline, there is a synergistic effect that causes a greater improvement in memory.

The specific pharmacological properties of piracetam were reported almost 30 years ago but its mechanism of action was unknown for a long time.

Piracetam was firstly tested in a model of “central nystagmus” which was sensitive only to anticholinergic and antihistaminic drugs (2, 11).

The current use of piracetam in vertigo might be related to this property.

The subsequent research, however, revealed that piracetam was without anticholinergic or antihistaminic properties (5, 10, 12).
Although piracetam is a derivative of the inhibitory neurotransmitter GABA, the mechanism of its action is not related to that of GABA.

Piracetam has little affinity for glutamate receptors, yet it does have various effects on glutamate neurotransmission.

One subtype of glutamate receptor is the AMPA receptor. Micromolar amounts (levels which are achieved through oral piracetam intake) of piracetam enhance the efficacy of AMPA- induced calcium influx in brain cells.

Piracetam also increases the maximal density of AMPA receptors in synaptic membranes from rat cortex due to the recruitment of a subset of AMPA receptors which do not normally contribute to synaptic transmission (12).

At micromolar levels piracetam potentiates potassium-induced release of glutamate from rat hippocampal nerves (12).
Piracetam is generally reported to have minimal or no side effects.

It is interesting to note, however, that piracetamís occasionally reported side effects of anxiety, insomnia, agitation, irritability and tremor are identical to the symptoms of excessive acetylcholine/glutamate neuroactivity.

In spite of these effects, piracetam is generally not considered to be a significant agonist or inhibitor of the synaptic action of most neurotransmitters.

The piracetam-type nootropic drugs might exert their effect on some species of molecules present in the plasma membrane.

It would seem that they act as potentiators of an already present activity, rather than possessing any neurotransmitter-like activity of their own (12). Thus, piracetam is not prone to the often serious side effects of drugs which directly amplify or inhibit neurotransmitter action, e.g. MAO inhibitors, selective serotonin reuptake inhibitors, tricyclic antidepressants, or ampheta- mines.

It was found that piracetam instead facilitates interhemispheric transfer, enhances the cerebral resistance to noxious stimuli like hypoxia and improves learning and other cognitive functions under normal conditions (13, 14).

However, the improvement of these functions is much more pro- nounced when brain function is impaired by a variety of noxious stimuli (e.g. hypoxia, aging, cerebral injuries).

The in vivo experiments indicate that the cognition-enhancing properties of piracetam are usually more significant in older animals (15, 16). It suggests that the mechanism of action of the nootropic drugs is associated with biochemical alterations in the aged brain.

Therefore nootropics might probably restore or counteract these biochemical changes. Reduced fluidity of brain cell membranes (probably caused by higher membrane concentrations of saturated fatty acids) represents mechanism associated with functional alterations in the aged brain (17) and might be responsible for deficits or dysfunctions of mechanisms of signal transduction (18,19).

Piracetam in aphasia
Most patients after the ischemic stroke regain some of the lost functions. The improvement of sensorimotor function is accompanied by an increased blood flow in impaired brain regions.

Whereas the effect of physiotherapy for the improvement of sensorimotor deficits is unchallenged, the efficacy of speech therapy is still questionable/unclear.

Whether the rehabilitation can be enhanced by adjuvant pharmacotherapy in patients with cerebral disorders is also a matter of speculation (20 – 22). First trials were started in the 1940s and concerned various agents in various neurological disorders (23 – 25).

Figure 2. Levetiracetam is a pyrrolidone derivative and is chemically designated as (S)-α-ethyl-2-oxo-1-pyrrolidineacetamide (27).

Since piracetam improves learning and memory, Kessler et al. investigated in a double-blind, placebo-controlled study whether piracetam improves language recovery in post- stroke aphasia (26). They found that piracetam significantly improves activated blood flow and facilitates rehabilitation of poststroke aphasic patients (26).

Piracetam as an adjuvant to speech therapy improves recovery of various language functions, and this effect is accompanied by a significant increase of task-related flow activation in eloquent areas of the left hemisphere (26).

However, the mechanism by which piracetam enhances recovery from aphasia is still a matter of speculation. Since infracted tissue cannot regenerate, recovery from postroke aphasia must involve regions outside the morphologically damaged area that probably take over language functions lost in acute stroke.

Figure 3. Molecular mechanisms of the inhibition of platelet responses by piracetam, acetylsalicylic acid, ticlopidine, dipiridamol and
GPIIb/IIIa blockers.
There is some evidence that piracetam acts on platelets as an antagonist of thromboxane A2 or as an inhibitor of thromboxane A2 synthetase
together with a reduction in the plasma level of von Willebrandís factor (36). Piracetam also possesses a rheological effect related to its
action on cell membrane deformability (37).
AA – Arachidonic acid; AC – Adenylyl cyclase; ADP – Adenosine diphosphate; βTG – β-thromboglobulin; COX – Cyclooxygenase; DAG
– Diacylglycerol; GPIIb/IIIa – Glycoprotein IIb/IIIa; Gq, Gs – G-proteins; 5-HT ñ Serotonin; IP3 – Inositol-1,4,5-triphosphate; P2Y1, 12 –
ADP-receptor; PAF – Platelet activating factor; PF4 – Platelet factor 4; PG G2, PG H2, PG I2, PG E2 – Prostaglandins G2, H2, I2, E2; PIP2
– Phosphatidylinositol-4,5-diphosphate; PKCa, PKCi – Protein kinase C (active and inactive, respectively); PLA2 – Phospholipase A2;
PLCβ, γ – Phospholipase Cβ, γ; TxA2 – Thromboxane A2

Levetiracetam – derivative of piracetam with antiepileptic properpies

Levetiracetam is the S-enantiomer of α-ethyl- 2-oxo-1-pyrrolidineacetamide (Figure 2).
Although piracetam might be useful in myoclonus and potentiates anticonvulsant action of various antiepileptic drugs (28,29), it was not previously used per se in epilepsy.

Levetiracetam, however, was approved for the add on treatment of partial epilepsy, both in United States and in Europe (27). Levetiracetam has antiepileptogenic and neu roprotective effects, with the potential to slow or arrest disease progression (30).

It may benefit myoclonus in progressive myoclonic epilepsy (31). Although the mechanism of action of levetiracetam is not completely understood, it is suggested that a reduction of potassium currents in neurons may con- tribute to its antiepileptic effect(s) (32).

Piracetam in Alzheimerís disease

Hippocampal membranes of patients with Alzheimerís disease show decreased fluidity which differ from age-specific membrane alterations. Clinical data suggest that long-term piracetam treatment appears to slow the progression of Alzheimerís disease, which was proposed to be explained by restoration of membrane fluidity (19).

Piracetam in stroke

Piracetam has been reported to increase com- promised regional cerebral blood flow in patients with acute stroke and, given soon after onset, to improve clinical outcome (33, 34).

It could be due to the modification of rheological properties of circulating blood by changing platelet responses (aggregation and adhesion) and beneficial effect on red blood cell deformability leading to a puta- tive reduction of ADP release by damaged erythrocytes (35 – 37).

Experimental data suggest that the efficacy of piracetam in secondary stroke prophylaxis is not as good as that of acetylsalicylic acid (ASA) but that piracetam is better tolerated (38). Therefore, piracetam might be an alternative for secondary stroke prophylaxis in patients who cannot be treated by ASA or other antiplatelet drugs.

Piracetam and platelets
Modification of platelet function including inhibition of platelet aggregation by piracetam is known for over 20 years (35). However, the mode of its action is still debated (36 – 39).

Piracetam normalizes hyperactive platelets in various disorders including acute stroke (33, 34), transient cerebral ischemic attacks, Raynaudís phenomenon and diabetes mellitus (36).

Platelet- inhibitory effects have been suggested to be due to a reduced responsiveness to ADP or to inhibition of thromboxane A2 synthesis (37, 40). Piracetam was also reported to have a direct effect on the vascular wall, stimulating prostacyclin production in endothelium with an concomitant reduction of von Willebrandís factor release from WeibelñPalade bodies (37).

The doses necessary to achieve rheological and/or antiplatelet effects are about 2 – 4 times higher than the doses required to obtain nootropic effects (35). However, even at these elevated doses, pirac- etam is well tolerated and only few adverse effects have been recorded in human subjects (5, 10).

The rheological properties of piracetam are thought to be related to plasma membrane alterations such as lipid structure (37). Piracetam incorporates within membranes at the level of the polar heads of the phospholipids. This interaction with the membrane phospholipids restores membrane fluidity and could explain the pharmacological properties of piracetam.

The observation that piracetam binds to the polar head groups of membrane bilayers and induces changes in membrane structure can explain that this drug works not only in the brain but also at the level of blood cells (19).

Its activity is much more pronounced when membranes are impaired (e.g. in aging).

Since changes at the level of the platelet mem- brane seem to be involved into the cascade of events leading to platelet adhesion and aggregation, this membrane-modifying effect might be the primary mechanism of action of piracetam (Figure 3). This mechanism would differentiate piracetam from other drugs used to inhibit platelet aggregation such as ASA, ticlopidine or tirofiban. Ticlopidine, how- ever, as a lipophilic drug might also alter the fluidi- ty of platelet membrane.


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Vinpocetine (14-ethoxycarbonyl-(3a,16a-ethyl)-14,15-eburnamine) is a synthetic derivative of vinca alkaloid vincamine that is an alkaloid extracted from the periwinkle plant, Vinca minor (Fig. 1). Vinpocetine can pass the blood-brain barrier and enter the brain after oral or intravenous administration (Gulyas et al., 2002a, Gulyas et al., 2002b).

The chemical structure, pharmacokinetics, metabolism, and distribution have been previously reviewed in detail (Bonoczk et al., 2000). Vinpocetine, trade name as Cavinton, was originally developed and marketed in Hungary around 1978. Vinpocetine has been clinically used in many Asian and European countries for the prevention and treatment of stroke, senile dementia, and memory disturbances.

In addition, numerous brands of vinpocetine-containing memory pills or products are currently also available worldwide as dietary supplements (

No significant side effects and toxicity have been reported for vinpocetine at therapeutic doses and it is generally thought to be safe for long-term use.

Vinpocetine has thus attracted considerable attention from academic and scientific community as well as pharmaceutical industries to characterize its novel therapeutic functions, mechanism of actions, and pharmacological targets.

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Figure 1
Chemical structures of vincamine and vinpocetine

Pharmacological targets of vinpocetine
Vinpocetine has a number of different cellular targets (Bonoczk et al., 2000, Patyar et al., 2011) (Table 1). Cyclic nucleotide phosphodiesterase 1 (PDE1) is among the first pharmacological target reported for vinpocetine (Ahn et al., 1989, Chiu et al., 1988, Hagiwara et al., 1984, Souness et al., 1989).

PDEs are a superfamily of enzymes that catalyze the degradation of cAMP and/or cGMP, which are grouped into eleven broad families, PDE1–PDE11, based on their distinct kinetic properties, regulatory mechanisms and sensitivity to selective inhibitors (Bender and Beavo, 2006).

PDE1 family members are encoded by three distinct genes, PDE1A, PDE1B and PDE1C with multiple N-terminal and/or C-terminal splice variants (Chan and Yan, 2011).

PDE1 catalytic activity can be stimulated by calcium in the presence of calmodulin, which is the reason that PDE1 is also referred to as Ca2+/calmodulin-stimulated PDE. Ca2+-dependent activation of PDE1 isozymes play critical roles in the crosstalk between Ca2+ and cyclic nucleotide signaling (Yan et al., 2003).

Individual PDE1 isozymes differ in their substrate affinity, Ca2+ sensitivity and tissue/cell distribution. In vitro, PDE1A and PDE1B show much higher substrate affinities for cGMP than cAMP, while PDE1C is equally sensitive for both cGMP and cAMP (Chan and Yan, 2011).

Vinpocetine have distinct inhibitory affinities for different PDE1 isoforms. For instances, vinpocetine inhibits PDE1A or PDE1B at IC50 ≈ 8–20 μM, while PDE1C at IC50 ≈40–50 μM (Loughney et al., 1996, Yan et al., 1996, Yu et al., 1997).

Thus, vinpocetine has higher affinity for PDE1A/1B than for PDE1C. In addition, vinpocetine may also act as a blocker for voltage-dependent Na+ channels. For example, previous studies through patch clamp approaches have shown that vinpocetine blocked voltage-dependent Na+ channels at IC50 values 10–50 μM (Molnar and Erdo, 1995, Sitges et al., 2005, Sitges and Nekrassov, 1999, Zhou et al., 2003).

More recently, vinpocetine was reported to be an inhibitor of IκB kinase (IKK), with an IC50 value around 17 μM (Jeon et al., 2010). IKK plays a critical role in mediating cellular inflammatory responses.

In response to external inflammatory stimuli, a set of IKK complex is activated. The activated IKK complex phosphorylates IκBα, leading to its ubiquitination and degradation. IκB is an inhibitor of NF-κB that is a key transcriptional factor responsible for the expression of variety of proinflammatory mediators, including cytokines, chemokines and adhesion molecules.

NF-κB is liberated due to IκB degradation and then enters the nucleus to activate the transcription of inflammatory molecules (Rothwarf and Karin, 1999). Thus, IKK-mediated phosphorylation of IκBα is the central point in regulating NF-κB-dependent inflammatory response. Therefore, vinpocetine, by inhibiting IKK activity, acts as a novel potent anti-inflammatory agent (Jeon et al., 2010, Medina, 2010).

Table 1

Multiple Molecular Targets of Vinpocetine

TargetsIC50 ValuesTissue/Cell Expression
PDE1 isoformsPDE1A/1B: 8–20 μMBrain: PDE1A, 1B, &1C; Contractile SMCs:
PDE1C: 40–50 μMPDE1A; Proliferating SMCs: PDE1A&1C; Heart: PDE1A%1C; Macrophages: PDE1B
Na+ channel10–50 μMBrain, Heart, vessels
IKK≈ 17 μMMost cell types

Vinpocetine and neurological diseases
Vinpocetine has been initially developed for the treatment of neurological diseases associated with cerebrovascular disorders such as stroke and dementia that are often caused by ischemia or other cognitive deficits.

A number of studies have reported the protective effects of vinpocetine after ischemic injury of the brain in rodents (Jincai et al., 2014, Rischke and Krieglstein, 1991, Sauer et al., 1988) and humans (Bonoczk et al., 2002, Szilagyi et al., 2005, Szobor and Klein, 1976, Vas and Gulyas, 2005, Vas et al., 2002, Zhang et al., 2016).

In addition, vinpocetine appears to be also beneficial for degenerative neuronal disorders such as Parkinson’s disease (PD) (Medina, 2011, Sharma and Deshmukh, 2015), Huntington’s disease (HD) (Gupta and Sharma, 2014), and Alzheimer’s disease (AD) (Heckman et al., 2015, Medina, 2011).

In the brain, vinpocetine improves brain blood flow by acting as a cerebral vasodilator (Bonoczk et al., 2000, Bonoczk et al., 2002, Patyar et al., 2011, Szilagyi et al., Vas et al., 2002, Zhang and Yang, 2015); and enhances cerebral metabolism by increasing oxygen and glucose uptake and stimulating neuronal ATP production (Bonoczk et al., 2000, Bonoczk et al., 2002, Patyar et al., 2011, Szilagyi et al., 2005, Zhang and Yang, 2015).

In a number of neuronal cells or nerve terminals, vinpocetine has also been shown to function as an antioxidant (Deshmukh et al., 2009, Herrera-Mundo and Sitges, 2013, Horvath et al., 2002, Pereira et al., 2000, Santos et al., 2000, Solanki et al., 2011), and prevent neurotoxic calcium and sodium elevation (Sitges et al., 2005, Sitges and Nekrassov, 1999, Tretter and Adam-Vizi, 1998).

It is thus evident that multiple mechanistic actions of vinpocetine through different molecular targets contribute to the neuroprotective effects of vinpocetine.

In addition, vinpocetine also elicits protective effects in other ischemia-related conditions, such as retina (Nivison-Smith et al., 2014, Nivison-Smith et al., 2017, Nivison-Smith et al., 2015), liver (Abdel Salam et al., 2007, Zaki and Abdelsalam, 2013), kidney (Fattori et al., 2017), and skin (Xiao-Xiao et al., 2013).

Vinpocetine and inflammation
Recently, vinpocetine has been demonstrated as a potent anti-inflammatory agent in a variety of in vitro cultured cells such as vascular endothelial cells (ECs) (Jeon et al., 2010), vascular smooth muscle cells (SMCs) (Jeon et al., 2010), monocytes/macrophages (Jeon et al., 2010), neutrophils (Ruiz-Miyazawa et al., 2015), epithelial cells (Jeon et al., 2010, Liu et al., 2014), brain microglial cells (Zhao et al., 2011), and dendritic cells (Feng et al., 2017).

Through directly inhibiting IKK activity, vinpocetine attenuates IKK-mediated phosphorylation of IκB and increases the stability of IκB, which leads to binding of IκB with NF-κB and subsequent suppression of NF-κB-dependent inflammatory molecule expression.

The effect of vinpocetine on antagonizing NF-κB-dependent transcriptional activity is unlikely mediated by targeting PDE1 or Na+ channels as PDE1-selective inhibitor IC86340 and Na+ channel blocker tetrodotoxin had no effect on NF-κB transcriptional activity (Jeon et al., 2010).

The anti-inflammatory effects of vinpocetine have also been revealed in various animal models in vivo. In a rat cerebral ischemia-reperfusion injury model, NF-κB and TNFα levels were found to be associated with changes in brain edema and infarct volume.

Vinpocetine inhibited NF-κB and TNFα expression and decreased the inflammatory response after cerebral ischemia-reperfusion (Wang et al., 2014a).

More importantly, the anti-inflammatory effect of vinpocetine was recently reported a multi-center study involving 60 patients with anterior cerebral circulation occlusion and onset of stroke (Zhang et al., 2017). Patients treated with vinpocetine not only had a better recovery of neurological function and improved clinical outcomes, but also had reduced NF-κB signaling activation and pro-inflammatory mediator expression.

Moreover, vinpocetine is also effective in other animal inflammatory disease models, such as lipopolysaccharide (LPS)-induced inflammatory pain (Ruiz-Miyazawa et al., 2015), LPS-induced lung inflammation (Jeon et al., 2010), mouse otitis media (Lee et al., 2015), and acute kidney injury (Fattori et al., 2017).

Vinpocetine and vascular diseases
The vasorelaxing effect of vinpocetine has also been shown in peripheral vessels from different species, which is likely mediated by inhibiting PDE1 that preferentially hydrolyzes cGMP with high affinities (Ahn et al., 1989, Chiu et al., 1988, Giachini et al., 2011, Hagiwara et al., 1984, Souness et al., 1989).

It has been previously shown that PDE1A was upregulated in a rat model of nitroglycerin (NTG) tolerance, and vinpocetine partially restored the sensitivity of the tolerant vasculature to subsequent NTG exposure (Kim et al., 2001).

PDE1A activation can decrease cGMP levels. Thus, induction of PDE1A in nitrate-tolerant vessels may be one mechanism by which NO/cGMP-mediated vasodilation is desensitized and Ca2+-mediated vasoconstriction is supersensitized. Inhibition of PDE1A activity could be effective to limit nitrate tolerance.

Other PDE1-selective inhibitors such as IC86340 (Miller et al., 2009) and Lu AF41228/Lu AF58027 (Laursen et al., 2017) have been reported to cause vasodilation and/or lower blood pressure in rodents. The role of PDE1A in blood pressure regulation has been more specifically confirmed by the recent finding that PDE1A activity null mice had lower aortic blood pressure (Wang et al., 2017).

Human genetic studies have revealed the association of PDE1A single nucleotide polymorphisms (SNP) with diastolic blood pressure (Bautista Nino et al., 2015, Yan, 2015). Moreover, vinpocetine also augmented the cGMP levels and pulmonary vasodilatory response after NO inhalation in lambs with acute pulmonary hypertension, likely through inhibiting PDE1 (Evgenov et al., 2006).

Genome-wide association analysis has identified PDE1A locus associated with idiopathic pulmonary artery hypertension in a Japanese population (Kimura et al., 2017).

In addition to vasodilation, recent studies have also revealed the novel functions of vinpocetine in other chronic vascular diseases associated with vascular structural remodeling. For example, a recent study by Cai et al. indicated that vinpocetine significantly attenuated vessel wall thickening and neointimal formation in mouse carotid arteries after ligation injury, and markedly suppressed spontaneous remodeling of human saphenous vein explants in an ex vivo culture model (Cai et al., 2012).

A similar study also reported that vinpocetine attenuated balloon injury-induced carotid artery neointimal hyperplasia in diabetic rats (Wang et al., 2014b). In cultured SMCs, vinpocetine inhibited SMC growth through antagonizing reactive oxygen species (ROS) production (Cai et al., 2012, Wang et al., 2014b).

The inhibitory effects of vinpocetine on SMC growth and vascular remodeling appear to be in line with the consequences of specific suppression of PDE1A or PDE1C. Genetically knocking down PDE1A expression through specific RNA interference attenuated vascular SMCs growth and promoted SMC death (Nagel et al., 2006). PDE1C depletion also significantly suppressed SMC growth and migration in vitro (Cai et al., 2015).

In global PDE1C knockout mice that have normal growth rates, feeding patterns, normal nursing and mating behaviors, neointimal formation induced by carotid ligation injury was suppressed ≈75% compared to wild-type control mice (Cai et al., 2015).

However, it remains unknown whether the antioxidant effect of vinpocetine in SMCs is mediated by inhibiting PDE1. Human genetic studies have defined significant associations of PDE1A SNP with carotid intima–media thickness (Bautista Nino et al., 2015, Yan, 2015).

Interestingly, vinpocetine also reduced vascular thrombosis after vascular injury in mice (Cai et al., 2012), which is consistent with previously reported effect of vinpocetine on antagonizing platelet aggregation (Akopov and Gabrielian, 1992). Furthermore, vinpocetine has been shown to attenuate high-fat diet-induced atherosclerosis in ApoE-deficient mice (Cai et al., 2013, Zhuang et al., 2013), as well as prevent atherosclerosis and calcification in rabbit atherosclerosis models (Yasui et al., 1989, Yasui et al., 1990).

Vinpocetine was shown to suppress lipid accumulation in macrophages (Cai et al., 2013) and osteoblastic differentiation of SMCs (Ma et al., 2016), the key events in human vascular atherogenesis. Thus, vinpocetine may represent as a promising drug or supplement for clinical therapy of vascular atherosclerosis and calcification.

Vinpocetine and cardiac diseases
Recent study by Wu et al. investigated the roles of vinpocetine in cardiac hypertrophy, fibrosis, and pathological cardiac remodeling in vitro and in vivo (Wu et al., 2017).

It was shown that vinpocetine significantly suppressed mouse myocardial hypertrophy and cardiac fibrosis in vivo induced by chronic angiotensin (Ang II)-infusion. Mechanistic studies further showed that vinpocetine directly attenuated mouse adult cardiomyocyte hypertrophic growth and cardiac fibroblast activation in vitro, likely in a PDE1-dependent manner.

The finding from this study is consistent with previous reports on PDE1A and PDE1C function in cardiac remodeling with specific genetic approaches. For example, PDE1A and 1C have been shown to be up-regulated in animal hypertrophic hearts induced by isoproterenol (ISO)- or Ang II-infusion and/or failing hearts induced by chronic pressure overload or myocardial infarction, as well as in human failing hearts (Knight et al., 2016, Miller et al., 2011, Miller et al., 2009).

Specific knockdown of PDE1A reduced cardiomyocyte hypertrophy (Miller et al., 2009), and fibroblast activation and extracellular matrix production (Miller et al., 2011).

Similarly, genetic depletion of PDE1C attenuated cardiomyocyte hypertrophy, death, and fibrosis both in vitro and in vivo (Knight et al., 2016). In addition, vinpocetine also elicited inhibitory effects on sodium currents in cardiomyocytes, which may be protective for the heart (Ver Donck et al., 1993, Wei et al., 1997).

However, the role of vinpocetine in cardiomyocyte death remains unknown. Massive cardiomyocyte death is associated with cardiac ischemia/reperfusion injury. Given the anti-apoptotic effects of vinpocetine in various other tissues (Lakics et al., 1995a, Onishchenko et al., 2008, Sonmez et al., 2017) and cell types (Bora et al., 2016, Chen et al., 2007, Erdo et al., 1990, Gabryel et al., 2002, Lakics et al., 1995b, Miyamoto et al., 1989), the protective effects of vinpocetine on cardiomyocyte death and cardiac I/R-injury remain to be investigated.

A recent study found that PDE1A is highly expressed in rabbit cardiac sinoatrial nodal cells and regulates pacemaker function. Therefore, the function of vinpocetine in regulating heart rate deserves to be further investigated.

Conclusion and perspective
Evidently, vinpocetine is a multi-action agent with a variety of pharmacological targets.

Its multi-actions, including vasodilation, anti-oxidation, anti-inflammation, anti-thrombosis, and anti-remodeling, may act together to elicit synergistic therapeutic effects, thereby providing significant benefits to those multifactorial cerebrovascular and cardiovascular diseases.

In addition, vinpocetine is effective for a wide range of pathological conditions. The explanation could be that many diseases share common pathologies that can be improved by vinpocetine, such as antagonizing inflammation in a variety of cell types, protecting different cells from death during ischemia injuries, and stimulating vasodilation to increase blood flow in diverse tissues.

It should be noted that recent findings aimed to explore novel functions of vinpocetine are largely dependent on animal models. Clinical studies in humans are necessary to validate the effectiveness of vinpocetine in preventing pathological vascular and cardiac remodeling as well as in various inflammatory diseases.

Molecular mechanisms underlying some of pharmacological effects of vinpocetine, including metabolic enhancement, anti-oxidation and anti-thrombosis, still remain unclear and need to be further investigated. Successful development of genetic modified animals including gene knockout mice or transgenic mice of PDE1 isoforms, IKK, and the sodium channels would facilitate the elucidation of more precise mechanistic action of vinpocetine.

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Figure 2
Vinpocetine is a multi-action agent with a number of pharmacological targets
Vinpocetine has three major molecule targets including PDE1, voltage-gated Na+ channel, and IKK. PDE1 has been shown to regulate vasoconstriction, vascular and cardiac structure remodeling, and neurotransmission. The Na+ channel is involved in cell toxicity and cell death. IKK plays a critical role in mediating cellular inflammatory response.

reference link :

Phenibut can be described as a phenyl derivative of gamma-aminobutyric acid (γ- aminobutyric acid, or GABA). The compound’s name “pheni-but” is based on its origin of synthesis and its structure, which was first reported by Perekalin et al in the 1960s (Lapin, 2001).

The addition of a phenyl ring to butyric acid enables the compound to cross the blood-brain barrier. Phenibut acts as a GABA agonist, primarily at GABAb receptors, stimulating dopamine release. In contrast, GABA itself does not cross the blood-brain barrier, limiting its use as a viable therapeutic drug to treat anxiety. However, GABA also occurs naturally in the human nervous system.

At this time, GABA is a Controlled Drug B1 under the Misuse of Drugs Act 1975, as it is a substance from which gamma-hydroxybutyrate or GHB (commonly known as Fantasy) can be derived. GHB is a Controlled Drug B1 under the Misuse of Drugs Act 1975.

Phenibut is classified as a GABApentinoid. GABApentinoids are a class of drugs that binds to and blocks the α2δ subunit-containing voltage-dependent calcium channels. This class includes Baclofen which is indicated for skeletal muscle spasticity (eg, Lioresal), Pregabalin which is indicated for neuropathic pain and for the control of epileptic seizures, (eg, Lyrica) and Gabapentin an anticonvulsant, analgesic and anxiolytic for the treatment of anxiety disorders (eg, Neurontin). Baclofen, Pregabalin and Gabapentin are all currently scheduled as Prescription Medicines in Schedule 1 of the Medicines Regulations 1984.

The most common uses expounded for phenibut are as a nootropic (a drug used to enhance memory or other cognitive functions), to reduce anxiety, to improve sleep, increase sexual drive, and increase production of human growth hormone. These last two appear to be academically unsubstantiated.

International Non-proprietary Name (or British Approved Name or US Adopted Name) of the medicine


Chemical names

  • 4-Amino-3-phenylbutyric acid
  • 4-Amino-3-phenylbutanoic acid          [IUPAC name]
  • beta-(Aminomethyl)benzenepropanoic acid
  • beta-(Aminomethyl)hydrocinnamic acid
  • beta-Phenyl-gamma-aminobutyrate
  • beta-Phenyl-gamma-aminobutyric acid
  • beta-phenyl-GABA
  • β-Phenyl-γ-aminobutyrate
  • β-Phenyl-γ-aminobutyric acid

Other names

  • Fenibut / Fenigam
  • Phenigam / Phenigama / Phenygam
  • Phenylgamma
  • PhGaba / Pgaba
  • Noofen

Chemical formula                 Molecular weight

C10H13NO2                                         179.2 gmol-1

Chemical structure

Classification status in other countries (especially Australia, UK, USA, Canada)

Australia – The Advisory Committee on Medicines Scheduling (July 2017) recommended that phenibut be classified as a Schedule 9 prohibited substance, only to be used for research purposes. The TGA’s report on the Committee’s recommendation is included as an attachment to this submission.

USA – Unscheduled. Phenibut is available as a nutritional supplement as it meets the criteria of the Dietary Supplement Health and Education Act 1994 (DSHEA) as a synthetic amino acid derivative. It is usually promoted with health maintenance claims (eg, helps to keep you calm) instead of disease state or condition claims (eg, reduces anxiety) (Cutter 2016, Owen et al, 2016).

United Kingdom – Unscheduled. In 2014, the MHRA seized a large range of cognitive enhancers, including phenibut, on the basis that these were unlicensed medicinal products being supplied for sale (MHRA 2014).

It is unclear if phenibut is caught under the UK’s Psychoactive Substances Act 2016. Some of the reported activities of the substance fall into categories of effects regulated under this Act, such as changes in alertness, mood, empathy, and drowsiness (effects which would apply to many nootropics). Possession of cognitive enhancers is not illegal, although the MHRA’s action indicates that sale without a licence is prohibited (for example, if phenibut was indeed determined to be a cognitive enhancer substance).

Canada – Unscheduled. The Natural and Non-prescription Health Products Directorate of Health Canada has noted that this does not fit their criteria for consideration as a natural health substance as it is not a naturally occurring substance (NHPID 2017). It is available as an unscheduled substance, usually from on-line retailers, health food shops and body-building forums.

Europe – Unscheduled. It is not regulated by the European Medicines Agency. However, some nootropic substances such as piracetam are available only on prescription in some European Union countries and are freely available in others.

Russia – Phenibut is a licensed prescription medication used for a variety of conditions including anxiety, insomnia, post-traumatic stress disorders, depression, stuttering, tics, attention deficit disorders, and vestibular disorders. Russian cosmonauts were reported to have been supplied with the substance to help relieve tension, anxiety and fear (Buckley 2006).

Latvia – as for Russia.

There is no information on the FDA’s Adverse Events Reporting System (FAERS) on Phenibut.

There is no information on phenibut CARM’s adverse reaction database.

On the WHO’s Vigilyze database, there have been 19 ICSRs (Individual Case Safety Report) reported on phenibut since 2012, with a jump in numbers since 2016. The majority of the reports were in people aged 18-44 years from the Americas, and the majority of events were associated with general, nervous system or psychiatric disorders.

Reasons for requesting the classification

Phenibut acts as a full agonist of the GABAb receptor, which is responsible for its sedating effects. At higher doses, phenibut also acts as a GABAa agonist (Shulgina 1986).

Users from various websites and on-line forums (for example, Social Anxiety, Brain Pro,,, reported positive effects:

  • extreme calm
  • increased sociability
  • increased sense of “well-being”
  • mild euphoria
  • variable increase in alertness
  • improved cognition and memory retention

Negative effects reported by users and researchers (Samokhvalov et al 2013; Sankary et al 2017; Joshi et al 2017) are:

  • hangover
  • dependence
  • headache
  • depression, anxiety
  • sedation, particularly from excessive dose or overuse
  • lethargy
  • agitation
  • delirium
  • confusion
  • rarely, tonic-clonic seizures

Most on-line articles and discussions refer to tolerance (reduced effect) with long- term use, and escalating doses are necessary to achieve the effect previously experienced. There are also withdrawal effects, which may include agitation, anger, anxiety, depression, dizziness, hallucination, insomnia, irritability, nausea, tremors.

Withdrawal from phenibut is expected to present like baclofen withdrawal (Alvis and Sobey, 2017) and that of other GABAb agonists and managed with benzodiazepines and supportive care (Maryland Poison Center 2017; O’Connell 2017; American Addiction Centers 2017, Mental Health Daily 2016).

The extent of phenibut use in New Zealand is unknown. However, it is available for sale from on-line retailers such as,,,,,,

Most commercially available phenibut appears to be in the form of the hydrochloride salt, phenibut HCl. Ingestion of phenibut hydrochloride on either an empty stomach or with caffeine (which stimulates gastric secretion) increases the rate of absorption. Phenibut is also commercially available as the free amino acid, which is slower to dissolve and is slightly bitter to the taste. Unlike the hydrochloride salt, the free amino acid can be absorbed intranasally, sublingually, and rectally (Psychonautwiki 2017).

Starting doses vary significantly on the various web user forums (for example,,,,, 200-500 mg has been suggested for nootropic effect. For other effects, including as an anxiolytic, anti-depressant, sleep aid for insomnia, recreational drug, doses of 250- 750 mg up to three times daily have been recommended. Use of up to 3000 mg per day have been reported in some athletes (Tomen, 2017).

Phenibut is reported to also potentiate or improve the effects of tranquilisers, narcotics and neuroleptic medications (Psychonautwiki 2017).

Discussion and conclusions

Nootropic (and other therapeutic) claims are associated with phenibut.

Phenibut has psychoactive effect and could be considered a psychoactive substance under the Psychoactive Substances Act 2013 when sold for the purpose of inducing a psychoactive effect, and its importation could be stopped under that Act. However, the real purpose behind an importation is often difficult to establish when shipments are stopped at the border by Customs. As it is currently an unscheduled substance, the importer may claim that it is being imported for personal therapeutic use.

From the literature, there appear to be some risks associated with its use, most commonly headache, lethargy, dependency and withdrawal symptoms including agitation, irritability, anger. In extreme instances, seizures have been reported.

Phenibut does not meet the moderate risk of harm threshold necessary to be controlled under the Misuse of Drugs Act 1975. Nevertheless, its use and availability should be controlled because of the risk of adverse effects.

The Medicines Classification Committee discussed the nootropic and cognitive enhancing substances racetam and racetam-like structures at the 53rd and 54th meetings and advised that they be classified as prescription medicines. Hence, the classification of phenibut as a prescription medicine would be consistent with the Committee’s approach to nootropic substances, the scheduling of the GABApentinoid class of substances, and the uses and risks associated with the substance.


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2014. seizure-of-experimental-smart-drugs

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Owen DR, Archer JR, Dargan PI. (2016). Phenibut (4-Amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity. Drug and Alcohol Review. 35(5):591-6.

Psychonaut Wiki 2017. Phenibut. Accessed 30 October 2017.

Samokhvalov AV, Paton-Gay CL, Balchand K, Rhem K. (2013). Phenibut dependence. BMJ Case Report


Sankary S, Canino S, Jackson J. (2017). Phenibut overdose. American Journal of Emergency Medicine 35:516e1-516e2. 6757(16)30574-5/abstract

Shulgina GI. (1986). On neurotransmitter mechanisms of reinforcement and internal inhibition. The Pavlovian journal of biological science 21(4):129-40. ( / NCBI).

Tomen D. (2017). Phenibut. Nootropicsexpert website. Accessed 30 October 2017. Vigilyze database (2018). Phenibut. Data accessed. 25 January 2018.


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