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buff guy standingIn the last article, we covered the research on the neuroprotective and memory-improving capabilities of vinpocetine. We found that vinpocetine has neuroprotective effects in many situations, and there are studies providing evidence that it has utility as a nootropic in humans. We are now going to discuss the mechanisms through which vinpocetine leads to these beneficial effects.

General Effects

We have already gone into some detail on piracetam’s mechanism of action, so a comparison with this drug is a good place to start. As covered previously, while piracetam’s mechanism of action is not fully established, a central effect seems to be alterations at the level of the cell membrane. According to Gabryel et al, who compared the effects of the two drugs in cell cultures, vinpocetine’s mechanism of action is distinctly different [1]. While both of these drugs improve memory, they do so through significantly different mechanisms, lending credence to the idea that their benefits may be additive when taken together.

Unlike piracetam and aniracetam, or any of its individual metabolites, it is believed that vinpocetine operates through multiple, independent mechanisms. Keep in mind that we are referring to the primary mode of action here, so while the racetams may have a number of beneficial properties, they are probably all the result of an individual effect of the drug. In contrast, we will find that vinpocetine has multiple, independent modes of action that result in its activity.

Vinpocetine’s most well-known effects are an increase in cerebral blood flow (CBF) and glucose uptake, both of which can be expected to improve brain function, oxygen delivery, and memory [2]. In the last article in this series, we covered a few studies which demonstrated these effects occurring in stroke patients given vinpocetine.

One of vinpocetine’s more general effects is that it acts as an antioxidant. Reactive oxygen species (ROS) play a central role in many age-related brain disorders [4]. At therapeutic concentrations, vinpocetine has antioxidant effects, whereas piracetam does not [5]. As a fat-soluble antioxidant, vinpocetine’s antioxidant properties are similar to those of vitamin E [6]. An advantage of vinpocetine is that it concentrates this antioxidant effect in the brain, providing it with specific protection.

Ion Channels

Vinpocetine’s most frequently discussed effect is modulation of voltage-dependent sodium and calcium channels, and to a lesser extent, potassium channels.

A number of neuroprotective drugs act primarily through inhibition of sodium channels, as preventing the accumulation of sodium protects neurons in many areas of the brain related to memory and cognition [6-7]. Vinpocetine is a particularly potent inhibitor of voltage-dependent sodium ion channels, and some have postulated this to be its most important effect [8-9]. Veratridine is a neurotoxic drug that increases the concentration of sodium in neurons, and vinpocetine protects against its toxic effect in concentrations that can be achieved through supplementation [7]. While piracetam can protect against the neurotoxic effect of veratridine, it may not do so in pharmacologically relevant doses [10]. Some research suggests that this action of vinpocetine is responsible for its protection of peripheral nerves (recall that vinpocetine can reduce hearing loss and hearing problems) [11].

There are a number of reasons why preventing sodium ion accumulation can be neuroprotective. First, an increase in sodium ions increases the activity of the Na,K-ATPase enzyme, leading to a depletion of cellular ATP. Second, increased intracellular sodium ion concentration can increase glutamate excitotoxicity. Third, an increased concentration of sodium ions can increase the entry of calcium ions into the cell, leading to cellular injury and death [7, 12].

In addition to preventing intracellular calcium ion buildup by blocking sodium ion channels, vinpocetine can selectively block calcium ion channels as well [12]. However, it is not yet fully clear which types of calcium channels vinpocetine affects [7]. Depending on circumstances, vinpocetine can increase intracellular calcium through an unknown mechanism, but this effect also appears to be beneficial [12].

Studies in snail neurons have found vinpocetine to inhibit, augment, or have no effect on potassium ion channels, depending on subtype [13]. The relevance of this effect is not well known, but it may also contribute to the regulation of intracellular calcium [12]. While vinpocetine’s effects on ion channels are complex and varying, the end result is an optimization of ion content within the cell, improving cell function and also preventing cell death.


Most of us are familiar with phosphodiesterase (PDE), an enzyme which inactivates cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). There are a large number of subtypes of phosphodiesterase (at least eleven), and correspondingly, many phosphodiesterase inhibitors with varying effects [14]. Some of the most well-known are tadalafil and sildenafil citrate (Cialis and Viagra), inhibitors of PDE5.

Vinpocetine inhibits both calcium ion/caldomodulin-dependent PDE1 and PDE3 [15-16], but the former effect has been focused on much more, and along with sodium ion channel inhibition, is commonly listed as one of the most important of vinpocetine’s effects. Animal studies indicate that this effect is tissue-specific, occurring primarily in the brain, and to a lesser extent in some other tissues [7]. Out of all of the PDE1 inhibitors that have been identified, vinpocetine is the most selective [17].

PDE inhibition may contribute vinpocetine’s effects in a few ways. It is likely that the increased cerebral blood flow and decreased platelet aggregation is primarily a result of PDE inhibition, as an increase in cAMP will result in vasodilation [6]. Also, vinpocetine’s effect on potassium ion channels is likely to be at least in part due to an increase in cGMP resultant of PDE inhibition [12].


Vinpocetine has a number of effects on neurotransmitters and their receptors, but with the exception of glutamate, they are not usually considered to be all that relevant, and they are generally downstream of ion channel modulation. Vinpocetine does have affinity for alpha adrenergic, peripheral (but not central) GABA-A, and dopamine D4 receptors [3], but whether any of these are relevant is unknown. It may also increase acetylcholine levels, although the literature offers little commentary on this [2].

As is the case with most other nootropics, vinpocetine protects against glutamate excitotoxicity. There is evidence that it acts directly at the receptor level, as it displaces MK-801 [3, 7]. However, once again, it is not known if this effect is relevant at regular doses.


We have now discussed some of the most popular nootropics: piracetam, aniracetam, and vinpocetine. We have also found that taking piracetam (and/or aniracetam) in conjunction with vinpocetine may provide additive benefits, as the primary modes of action are not the same, and both have benefits which the others do not. A combination of piracetam (and/or aniracetam) and vinpocetine provides the foundation for a drug regimen that provides improved memory and learning ability, neuroprotection, and other cognitive benefits.

Questions or comments on this article? Post them in the Avant Labs Forums for live feedback from David Tolson, as well as the Mind and Muscle staff and fellow readers!


1. Neurotoxicology. 2002 May;23(1):19-31. Piracetam and vinpocetine exert cytoprotective activity and prevent apoptosis of astrocytes in vitro in hypoxia and reoxygenation. Gabryel B, Adamek M, Pudelko A, Malecki A, Trzeciak HI.

2. Nutrition. 2003 Nov-Dec;19(11-12):957-75. “Brain-specific” nutrients: a memory cure? McDaniel MA, Maier SF, Einstein GO.

3. Acta Neurol Scand. 2002 Dec;106(6):325-32. PET studies on the brain uptake and regional distribution of [11C]vinpocetine in human subjects. Gulyas B, Halldin C, Sandell J, Karlsson P, Sovago J, Karpati E, Kiss B, Vas A, Cselenyi Z, Farde L.

4. Free Radic Res. 2000 Jan;32(1):57-66. Synaptosomal response to oxidative stress: effect of vinpocetine. Santos MS, Duarte AI, Moreira PI, Oliveira CR.

5. Orv Hetil. 2002 Jan 6;143(1):13-7. [Scavenger effect of various cerebrovascular drugs] [Article in Hungarian]. Horvath B, Marton Z, Halmosi R, Alexy T, Szapary L, Vekasi J, Biro Z, Habon T, Kesmarky G, Toth K.

6. Eur J Pharmacol. 2003 Apr 25;467(1-3):103-9. Pharmacological evidence for a correlation between hippocampal CA1 cell damage and hyperlocomotion following global cerebral ischemia in gerbils. Katsuta K, Umemura K, Ueyama N, Matsuoka N.

7. Brain Res Bull. 2000 Oct;53(3):245-54. Role of sodium channel inhibition in neuroprotection: effect of vinpocetine. Bonoczk P, Gulyas B, Adam-Vizi V, Nemes A, Karpati E, Kiss B, Kapas M, Szantay C, Koncz I, Zelles T, Vas A.

8. Nucl Med Biol. 2002 Oct;29(7):753-9. Cerebral uptake of [ethyl-11C]vinpocetine and 1-[11C]ethanol in cynomolgous monkeys: a comparative preclinical PET study. Gulyas B, Vas A, Halldin C, Sovago J, Sandell J, Olsson H, Fredriksson A, Stone-Elander S, Farde L.

9. Ideggyogy Sz. 2003 May 20;56(5-6):166-72. Asymptomatic ischemic cerebrovascular disorders and neuroprotection with vinpocetine. Hadjiev D.

10. Neurochem Res. 2001 Sep;26(8-9):1095-100. The nootropic drug vinpocetine inhibits veratridine-induced [Ca2+]i increase in rat hippocampal CA1 pyramidal cells. Zelles T, Franklin L, Koncz I, Lendvai B, Zsilla G.

11. J Pharmacol Exp Ther. 2003 Aug;306(2):498-504. Epub 2003 May 01. Vinpocetine is a potent blocker of rat NaV1.8 tetrodotoxin-resistant sodium channels. Zhou X, Dong XW, Crona J, Maguire M, Priestley T.

12. Comp Biochem Physiol C Toxicol Pharmacol. 2001 Feb;128(2):275-80. The nootropic drug vinpocetine modulates different types of potassium currents in molluscan neurons. Solntseva EI, Bukanova JV, Skrebitsky VG.

13. Int J Neuropsychopharmacol. 2002 Sep;5(3):229-37. Selective suppression of the slow-inactivating potassium currents by nootropics in molluscan neurons. Bukanova JV, Solntseva EI, Skrebitsky VG.

14. Eur J Neurosci. 2004 May;19(10):2669-81. Elevation of intracellular cAMP evokes activity-dependent release of adenosine in cultured rat forebrain neurons. Lu Y, Li Y, Herin GA, Aizenman E, Epstein PM, Rosenberg PA.

15. Curr Med Chem. 2003 Apr;10(8):649-61. Large-conductance Ca2+- activated K+ channels:physiological role and pharmacology. Wu SN.

16. J Neurol Sci. 2002 Nov 15;203-204:259-62. Clinical and non-clinical investigations using positron emission tomography, near infrared spectroscopy and transcranial Doppler methods on the neuroprotective drug vinpocetine: a summary of evidences. Vas A, Gulyas B, Szabo Z, Bonoczk P, Csiba L, Kiss B, Karpati E, Panczel G, Nagy Z.

17. Circulation. 2001 Nov 6;104(19):2338-43. Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. Kim D, Rybalkin SD, Pi X, Wang Y, Zhang C, Munzel T, Beavo JA, Berk BC, Yan C.

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