Vinpocetine (also referred to as ethyl apovincaminate) is derived from the compound Vincamine, which is the principle active ingredient of the plant Vinca Minor (periwinkle) at 25-65% of the total alkaloids; it was first synthesized in 1978 (under the brand name Cavinton) and has since been used for the treatment of cerebrovascular disorders and cognitive impairment.]
The periwinkle plant itself has traditional usage for the treatment of headaches.
Vinpocetine is a synthetic alkaloid that is derived from vincamine, a component of periwinkle plants. It has usage in medicine for neuroprotection following brain injury and usage in the supplement industry for preventing cognitive decline during aging
Vinpocetine ((3α,16α)-eburnamenine-14-carboxylic acid ethyl ester or ethyl apovincaminate) is an alkaloid with a molecular weight of 350.5g/mol which is fully soluble in methanol, dimethyl sulfoxide, and acetone. The structure of vinpocetine is based off of the cis(3S,16S)-eburnamenine skeleton structure, which is the following 5-ringed structure.
Vinpocetine has been noted to have a bioavailability of 6.2-6.7% or so in humans when taken in aqueous solution although it has a much higher bioavailability in rats at around 52%; one human study has suggested that vinpocetine can have a similar bioavailability (56.6+/-8.9%) but this result seems unreliable.
Omeprazole has been found to not significantly influence bioavailability of 2mg/kg vinpocetine although ingesting vinpocetine with a meal can increase bioavailability by 60-100% (relative to fasted conditions). Delivery systems can also increase absorption, including self-emulsifying (1.72-fold) and proliposomes (3.5-fold).
Vinpocetine appears to have decent bioavailability in rats, but poor bioavailability in fasted humans. It may need to be taken alongside food, which increases its bioavailability
Oral administration of a vinpocetine 5mg tablet has resulted in a Cmax of 63.69+/-8.32ng/mL at a Tmax of 1.46+/-0.14h with a half-life of 1.36+/-0.27h and an AUC of 202.48+/-14.48ng/h/mL. It appears in serum fairly rapidly, within 20 minutes (albeit with equally fast metabolism).
When looking at the half-life of vinpocetine, it appears to be reported in the range of 1.46 hours and biphasic; within 2-3 hours post ingestion vinpocetine does not appear to be detectable in the blood anymore.
The volume of distribution appears to be 246.7+/-88.55 1 (3.2+/-0.9L/kg) and total plasma clearance is 66.7+/-17.9L/h (0.88+/-0.20 L/h/kg). Vinpocetine appears to bind extensively to plasma proteins, with numbers ranging from above 86.6% to complete binding.
Vinpocetine itself is rapidly absorbed and rapidly metabolized into cis-apovincamic acid, and vinpocetine itself is not detected in the blood a few hours after oral administration
When looking at the main metabolite (apovincamic acid), it appears to peak within one hour of ingestion to approximately 100ng/mL and normalize within 3-4 hours following ingestion of 5-10mg vinpocetine. Elsewhere, a 10mg dosage of vinpocetine has led to 49.5-51.4ng/mL Cmax at 1.02-1.11h Tmax and vinpocetine has been found to degrade in a fairly constant ratio to its absorption rate (being degraded within 20 minutes of oral ingestion).
cis-apovincamic acid appears to have a rapid spike in the blood due to the rapid conversion of vinpocetine
There does not appear to be appreciable accumulation of vinpocetine in the body following oral ingestion of standard dosages (15-30mg daily).
Vinpocetine is able to effectively penetrate the blood-brain barrier in monkeys and humans. It is rapidly absorbed into the brain (3.18–4.27% of an injected dose within 2 minutes in humans and up to 3.84% of total dose in monkeys) and due to these concentrations exceeding the relative weights of the brain (1.7% and 1.8%, respectively) it is thought that this signifies not only easy permeability but selective accumulation.
Vinpocetine's absorption into the brain via the blood brain barrier is rapid and nearly complete, and vinpocetine appears to accumulate in the brain shortly after ingestion
Vinpocetine appears to be more active and accumulated in the thalamus, basal ganglia, putamen, and visual cortex as assessed by glucose utilization and bioaccumulation and in one case blood flow enhancment. It has been reported to be at 24% higher concentrations in the thalamus (relative to a reference region that did not experience disproportionate accumulation) and 18% higher in the striatum.
Vinpocetine is detectable in the brain, and appears to favor accumulation in some specific neuroorgans (thalamus, striatum, basal ganglia, putamen, and visual cortex)
Vinpocetine appears to be able to be topically absorbed through the skin when a part of a microemulsion to enhance permeability (mostly Labrasol and Transcutol P) and has also been formed into sugar esters proniosomes (converted to niosomes upon hydration, niosomes being a vesicle formed from cholesterol and non-ionic surfactant) which can be topically absorbed, and a patch containing 5mg of vinpocetine has been found to have a Tmax of 11.67+/-1.15h and a Cmax of 12.44+/-1.87ng/mL with a half-life of 13.94+/-1.2h, the overall AUC (417.70+/-50.27ng/h/mL) was approximately double that of oral ingestoin which demonstrates higher bioavailability.
Vinpocetine is reported to be a phosphodiesterase (PDE) inhibitor selective for PDE1 but not further selective among subsets of PDE1 with IC50 values of 19μM, 21μM, or within the aforementioned range. Infrequently, a lower potency of 100μM or so is reported and Ki values have been reported to be in the 15-22.2μM range up to 50.5μM. The large variance is thought to be due to differences between tissue cultures and species. It is a noncompetitive inhibitor with the presence of calmodulin not affecting inhibitory potential and it has been confirmed in vivo albeit at very high doses of 20mg/kg injections.
Vinpocetine has been noted to increase cGMP concentrations (indicative of PDE1 inhibition, as adenylate cyclase was unaffected) at 10μM, with a nonsignificant trend at 1μM. Elsewhere, this has been noted to only occur with noradrenaline or potassium stimulation but not inherently and this increase in cGMP (also downstream of nitric oxide signalling) is thought to underlie the vasodilating effects of vinpocetine.
Inhibition towards cAMP phosphodisterases has been noted to be greater than 300-500μM, and due to the relative inefficacy on other phosphodiesterase enzymes mediating cAMP it is seen as cGMP or PDE1 selective.
Vinpocetine is a noncompetitive inhibitor of PDE1 enzymes, which subsequently raises cGMP concentrations and promotes vasorelaxation. The concentration that this occurs at is plausible, but also may be higher than achieved with oral supplementation (additionally, most literature on PDE1 inhibition is done in vitro only with the limited studies in rats using inpractically high doses)
Vinpocetine appears to be a sodium channel inhibitor at site 2 with an IC50 of 1.6µM and at NaV1.8 (IC50 3.5µM), although it has affinity for NaV1.5 channels, it is significantly weaker (44µM) but still comparable to phenytoin. Vinpocetine has been reported to inhibit batrachotoxin (poison dart frog toxin) binding to sodium channels with an IC50 of 0.34µM.
Vinpocetine can also inhibit L-type calcium channels either directly with an IC50 between 2.1-4.1µM or indirectly via inhibiting sodium channels. These inhibitory effects are thought to underlie some suppressive effects on neurotransmitter release.
Vinpocetine has also been implicated in enhancing potassium current (low-threshold fast inactivating) in the 1-100µM range whereas the slow activating channels are slightly suppressed and calcium dependent potassium channels also suppressed; overall potassium influx is inhibited with vinpocetine usage (76% at 30µM). Potassium channel blockers are associated with memory enhancement (see the memory section on Agmatine for more information), so this is a possible mechanism underlying the supposed cognitive enhancing properties of vinpocetine despite the effects of this in vivo currently being unclear.
Vinpocetine can inhibit sodium and calcium channels, and these mechanisms are thought to underlie the interactions with many neurotransmitters and their release from neurons. Due to occurring at a much lower (more potent) concentration, it is plausible that these mechanisms underlie some of the activity of vinpocetine
Independent of the above two mechanism, vinpocetine may also inhibit IKKβ activation which subsequently impairs NF-kB translocation and subsequent inflammatory processes. This appears to be a direct action independent of sodium and potassium channels as well as independent of known PDE interactions, and has an IC50 of 17.17 μM.
Inhibition of IKKβ is a third mechanism of vinpocetine (albeit not unique among supplements) that underlies antiinflammatory properties of vinpocetine. The practical significance of this towards supplementation is not known
There appear to be interactions with adrenergic receptors directly, including a binding affinity for the adrenergic alpha-1a (2.9µM), alpha-2a (1.9µM), and alpha-2b (0.9µM). The adenosine A1 receptor also has a high affinity for vinpocetine at 8.3µM, and peripheral GABAA receptors (at the benzodiazepine binding site) appear to have an affinity for vinpocetine at 0.2µM (much less potency on central GABAA receptors at more than 10µM)
Appears to have affinity for other receptors, mostly alpha adrenergic receptors and peripheral (but not central) GABAA benzodiazepine receptors. The affinity towards these receptors is quite respectable, and their interactions are probably relevant to nutritional supplementation
It has been noted that TPSO (overview in the GABAergic Neurotransmission section) associates with proteins of the mitochondria and that vinpocetine (25μM) can reduce the loss in mitochondrial membrane potential caused by excitotoxicity which is thought to be in part mediated by TPSO (as other TPSO ligands were also neuroprotective, but to varying degrees).
The impairment of mitochondrial function via beta-amyloid pigmentation appears to be attenuated with vinpocetine, albeit at a very high concentration of 40mM.
Mitochondrial function appears to be supported with vinpocetine in vitro, although it is not ascertained how relevant this information is to oral supplementation. This may just be an outcome associated with the neuroprotective effects of vinpocetine
It has been noted that vinpocetine infusions have failed to significantly increase glucose metabolism in the brain of persons given an infusion of vinpocetine, but that the reduced turnover was nonsignificantly attenuated while elsewhere it has been noted to slightly increase glucose turnover in stroke patients.
There may be a slight increase in glucose consumption of the brain following vinpocetine administration, but there are no studies in otherwise healthy persons using oral supplementation at this moment in time
In six otherwise healthy adults males, an infusion of 20mg vinpocetine (5% dextrose) and measurements over 20 minutes reported a 7% increase in cerebral blood flow relative to placebo. This method of administration (20mg infusion) has been noted to improve blood flow in persons who suffered a stroke without significantly affecting mean arterial pressure. This effect persists over 14 and 90 days and is associated with cognitive protective effects.
According to one PET study, vinpocetine has been noted to increase cerebral microcirculation, which may be related to the ability of vinpocetine to enhance red blood cell (RBC) deformability and thus reduce viscosity of the blood.
In stroke patients or persons with cerebrovascular diseases, there are improvements in oxygenation status with 30-45mg oral vinpocetine (associated with improvements in memory and alertness) and parachymal oxygen extraction.
Vinpocetine appears to enhance cerebral blood flow, which is thought to be secondary to a slight vasodilatory effect. Due to not signficicantly affecting oxygenation inhernetly but increasing blood flow, there is a small increase of oxygenation status of the brain
PDE1 inhibition has been linked to improving cognition in animals exposed to neurotoxins (in these papers, alcohol) which has been confirmed with 20mg/kg injections of vinpocetine; the accumulation of cGMP likely positively regulates neural plasticity (as that is known to occur when eNOS creates cGMP) and does not necessarily require cognitive damage as a prerequisite. As mentioned earlier, it is unsure how relevant the above mechanisms are due to requiring a very high dose of vinpocetine to reach the IC50 concentrations.
Inhibition of sodium and calcium channels is also associated with memory improvement (evidenced by the inhibitor RGH-2716), and due to vinpocetine sharing these properties it is thought that it may be a mechanism underlying memory enhancement from vinpocetine. The interactions of vinpocetine at alpha-adrenergic receptors and augmenting noradrenergic activity in the locus coeruleus also appears to be related to memory enhancement, and the autoinhibition of this effect at 1mg/kg injections (but not lesser amounts) fits in well with the observed bell-curve seen in interventions with vinpocetine.
Another possible mechanism is potentiation of LTP (long term potentiation) which has been noted in vitro in hippocampal slices with a concentration of 0.1µM vinpocetine, although 1µM was slightly less effective and 0.01µM having a nonsignificant trend to augment LTP. This appeared to be additive with similar concentrations of idebenon (a derivative of CoQ10), and although this was not hypothesized by the authors the activation of the locus coeruleus has been noted to increase hippocampal LTP.
Vinpocetine mas mechanisms to increase memory formation. While the most popular mechanisms attributed to vinpocetine (PDE1 inhibition) appears to be overblown and probably not relevant, both the inhibition of sodium channels and the interactions with adrenergic receptors are implicated in increasing memory formation
In rat models of glutaminergic neurotoxicity, vinpocetine and its active metabolite can both preserve memory formation which is hindered in neurotoxic control (assessed by water morris maze, a spatial memory task). Vinpocetine has also shown protective effects against scopolamine induced amnesia, diabetes-induced cognitive impairment, hypoxia induced impairment, and impairment from Rohypnol.
Vinpocetine appears to be protective against toxin-induced amnesia, suggesting an interaction between the neuroprotective effects and memory formation
For studies using water mazes in cognitively healthy rats to assess spacial memory, vinpocetine (10mg/kg) or its active metabolite over five days does not appear to outperform control and a water labyrinth task also fails to show benefit to cognitively healthy young rats (although older rats noted a small amount of benefit).
One study has noted benefits to cognition in rats, specifically retrieval of memory, as assessed by a step-down passive avoidance task in rats given either 18-30mg/kg vinpocetine orally with both higher and lower doses being ineffective. Oddly, the primary metabolite of vinpocetine (apovincamic acid) was ineffective.
Memory scanning speed has been noted to be increased with vinpocetine at 40mg (but not 10-20mg) in otherwise healthy young adult females, but this does not necessarily reflect memory formation (just suggestive thereof).
There is contradictory information as to whether vinpocetine can cause improvements in memory formation and cognition with acute supplementation, but if this is to occur it would with higher dosages (40mg to improve reaction speed, and an estimated human equivalent of 2.88mg/kg for retrieval
Vinpocetine in otherwise healthy adult females (40mg divided into thrice daily dosing) appears to reduce reaction time on memory scanning tests from approximately 610ms to 430ms, whereas 10mg and 20mg were ineffective.
Increased reaction speed, as well as increased processing speed, have been seen in a rehabilitative setting with NFL football players (although highly confounded with Acetyl-L-Carnitine, Fish Oil, Alpha-Lipoic Acid and Huperzine-A) and elsewhere with vinpocetine (10mg) paired with Ginkgo biloba (40mg) and micronutrients.
One study has noted an improvement in reaction speed and performance on a memory test due to increased reaction speed with 40mg vinpocetine, but other studies assessing reaction speed or attention are confounded with the inclusion of other compounds
Vinpocetine is a NaV1.8 sodium channel blocker (3.5µM) and this channel appears to be associated with chronic pain (in the sense that activity of this channel causes pain and inhibition or downregulation reduces pain). Vinpocetine does not appear to inhernetly inhibit the channel, but it has high affinity for activated channels and causes a hyperpolarization and reduced signalling.
Vinpocetine appears to have micromolar affinity towards a variety of alpha-adrenergic receptors including the 1a subset (2.9µM), 2a (1.9µM), 2b (0.9µM) with other adrenergic receptors being classified as 'above 10µM' (and comparatively weaker affinity). Vinpocetine does not appear to inhibit adrenergic activity at 1µM and due to augmenting the noradrenergic firing of the locus coeruleus with an ED50 of 750µg/kg (injections of vinpocetine) it is thought that vinpocetine may be an agonist of the alpha-1 receptor, since this receptor is known to augment firing of the locus coeruleus.
1mg/kg of vinpocetine as injections is able to inhibit the aforementioned potentiation of signalling, but due to affecting more than just adrenergic neurons it is thought to be mediated via a different mechanism.
At least one study has suggested that injections of 2mg/kg can cause beta-adrenergic receptors to have more affinity for their ligands, but this has not been reproduced.
Vinpocetine appears to have affinity for alpha-adrenergic receptors, with a strong enough potency that they are probably relevant following oral ingestion of vinpocetine supplements. Not much is known about how vinpocetine acts with these receptors, but it may be an agonist
Vinpocetine has been implicated in reducing intracellular dopamine concentrations (with an increase in the dopamine metabolite DOPAC) in isolated striatum nerve endings via a mechanisms independent of its interaction with sodium channels and also increasing external DOPAC concentrations. This increase in DOPAC at expense of dopamine is known to occur with MAO activators but this does not appear to be the case with vinpocetine, and an impairment of vesicular storage of dopamine is thought to be the cause.
Vinpocetine does not significantly affect the release rate of dopamine into the synapse invoked by high potassium, although it effectively inhibits the dopamine release caused by sodium channel activators (in accordance with its sodium channel blocking ability), glutamate, and methamphetamine. When there is no significant stressor causing a release of dopamine, basal dopamine kinetics do not appear to be affected as vinpocetine does not appear to be inherently suppressive.
25µM vinpocetine appears to inhibit dopamine uptake into isolated striatal neurons (to 32.9% of untreated control), which was slightly less effective than 1µM of reserpine (18.7%) although 5µM does not appear to alter affinity for the transporter. Vinpocetine (5µM) does not appear to influence dopamine receptor density. Vinpocetine has been noted to have affinity for dopaminergic D2 and D4 receptors (IC50 of 7.9µM), but it is not sure if this is an agonistic or antagonistic property.
Overall, high concentrations of vinpocetine appear to have antidopaminergic properties (reducing vesicular storage without impairing basal release, inhibting dopamine uptake) but it is not sure how relevant this is to oral vinpocetine supplementation due to the concentrations required. There are no studies in living creatures yet
In cells treated with 3-NPA (mitochondrial toxin with particular efficacy in the striatum) vinpocetine at 25µM appears to exert protective effects by trending to normalize dopamine concentrations with a potency similar or slightly lesser than 50µM Vitamin E.
In rats treated with rotenone (to induce Parkinson's like symptoms), oral supplementation of vinpocetine at 3-6mg/kg daily was able to preserve motor function and striatal dopamine concentrations (both to a greater degree than 100-200mg/kg Piracetam) and reduced oxidative parameters with a near normalization of MDA at 6mg/kg.
In response to toxins that normally reduce dopamine levels, oral vinpocetine may exert a protective effect and act to normalize changes in dopamine. The magnitude of neuroprotection seen appears to be greater than many other dietary supplements as it nearly normalizes parameters, and this may be relevant to oral supplementation
Vinpocetine has shown protective effects against glutaminergic excitotoxins and hypoxic/ischemic damage (known to involve excitatory signalling) which appears to extend to its active metabolite, cis-apovincaminic acid.
Vinpocetine has been found to reduce glutamate binding to AMPA receptors, albeit weakly with 27% inhibition at 1µM and 50% inhibition occurring at 100µM. The NMDA antagonist CPP and kainate were not affected by vinpocetine up to this concentration, although since NMDA signalling was attenated a bit it was thought that vinpocetine was a weak and nonselective antagonist of NMDA receptors that was just outcompeted by CPP. Glutamate induced neurotoxicity has also been found to be attenuated with TPSO ligands, but weakly so (and thus this is likely not the mechanism pertaining to vinpocetine in regards to glutaminergic neurotransmission). Furthermore, the NMDA agonist MK-801 has been twice displaced from the membrane by vinpocetine.
It appears that vinpocetine may act at the level of the glutaminergic receptors, and inhibits signalling via AMPA and NMDA (two subsets of glutaminergic receptors) without significantly affecting kainate signalling. The potency at this stage seems to be fairly weak, but may be relevant
Vinpocetine is a sodium channel inhibitor, and it appears to have efficacy on a variety of research drugs that activate sodium channels including 4-aminopyridine, veratridine, with these effects occurring in the 2.5-15μM range and sometimes abolishing neurotransmitter release from the aforementioned drugs. There are less reliable effects in inhibiting potassium-induced neurotransmitter release, either being effective at the standard 15-50μM concentration (44-83% inhibition) (inefficacy also noted at this concentration) or requiring a much higher dose (5mM) to become appreciable.
Vinpocetine appears to reduce neurotransmitter (in this sense, glutamate) release from neurons secondary to inhibiting sodium channels. Although it has mixed evidence assessing the effects of potassium-induced release, drugs that work by the sodium channels are potently inhibited and their neurotranmission reduced
The pro-epileptic drug 4-aminopyridine (induces glutamate release related to a neuronal influx of calcium and sodium and causes seizures) appears to be inhibited in vitro by vinpocetine blocking sodium channels, which also inhibits calcium influx at a concentration of 2.5-25μM and prevents the subsequent glutamate release.
In vitro studies using epileptic toxins and drugs note that vinpocetine is able to confer anti-epileptic effects, and there is some animal evidence to suggest the standard dosages of vinpocetine are able to reduce epileptic potential
Vinpocetine appears to have some actions through peripheral benzodiazepine receptors (also known as the 18kDa translocator protein or TSPO system)  with an IC50 of 0.2µM, the peripheral GABAA receptors are expressed mostly in glial cells (quite limited in neurons) but play less of a role in cognitive relative to central receptors (which vinpocetine has a weaker affinity for, with an IC50 greater than 10µM). This has been confirmed to occur in the brain at an intramuscular dose of 3mg/kg in cynomolgous monkeys, as assessed by studies using vinpocetine to displace the known agonist isoquinoline carboxamide (PK11195).
Vinpocetine appears to be a potent ligand for the peripheral, but not central, GABAA receptor at the benzodiazepine binding site. This appears to occur in the brain following injections, which suggest interactions with glial cell function
Microglia (neuronal support cells) are cells that are activated via inflammatory stressors during stroke and ischemia and the TPSO system (peripheral GABAA receptors) are known to be upregulated in neuroinflammatory states including stroke, aging, and cognitive decline as it is a molecular sensor of neural injury. TPSO expression is thought to be a reliable biomarker of microglia activation.
Antiinflammatory properties have been noted in mice given 5mg/kg vinpocetine daily for a week (injections).
Vinpocetine appears to have anti-inflammatory properties in vitro, and they appear to be relevant during administration of the standard dosages of vinpocetine
The TPSO system (molecular sensor of brain injury and microglia activation) is upregulated in the aging brain that is not afflicted with cognitive degeneration in all tested species including humans but is also upregulated in states of cognitive impairment or neurotrauma. As mentioned elsewhere, vinpocetine has affinity for the TSPO receptor system with an IC50 of 200nM (0.2µM).
The TSPO system (of which vinpocetine is a high affinity ligand for) is known to be upregulated during aging
In ApoE deficient mice given 5mg/kg vinpocetine (injections every other day) for 16 weeks, there appeared to be a near halving of atherosclerotic buildup. This was deemed unrelated to the reduction in blood pressure (usually not associated in this rat model) and was attributed to a concentration dependent reduction in LDL oxidation seen in vitro (30-50µM) which was related to a reduction in the receptor for oxidized LDL (LOX-1). This may be related to the inhibition of IKKβ, as its target (NF-kB) is required in LOX-1 expression.
In ApoE deficient mice, circulating levels of lipoproteins (LDL-C, HDL-C, etc.) do not appear to be significantly influenced.
May reduce LDL oxidation rates and thus artherosclerotic formation independent of actually affecting lipoprotein concentrations. The mechanisms are thought to be related to the antiinflammatory properties of vinpocetine
During the process of atherosclerosis, the vasculature tends to undergo some remodelling associated with increased vascular smooth muscle cell (VSMC) proliferation which serve to further atherosclerosis. Since the antiinflammatory action of inhibiting IKKβ was detected in VSMCs previously and vinpocetine is known to benefit vasculature secondary to its PDE1 properties it has been investigated how vinpocetine acts on VSMC proliferation. Vinpocetine has been implicated in reducing VSMC proliferation at 5mg/kg injections to about 50% of control, which was associated with preventing activation of ERK1/2 from PDGF. As ERK1/2 activation via this means has been noted previously to be activated by oxidation, it was thought that this protective effect was secondary to antioxidative properties (and the effects were mimicked by the antioxidant N-Acetylcysteine).
Oral administration of vinpocetine at 2.1-8.4mg/kg daily for 15 days alongside the hepatotoxin CCL4 was able to dose-dependently reduce the elevations of liver enzymes including ALT (49.3-63.6%), AST (10.5-27.2%), and ALP (52.5-64.9%) with a 82.6% reduction in necrosis at the highest dose; 8.4mg/kg had a potency not significantly different than the comparator of 30mg/kg silymarin (Milk thistle).
Vinpocetine has been noted to protect from antibiotic-induced hearing loss with injections of 2mg/kg, with near absolute protection over the course of 180 days in guinea pigs that may also apply to 4-aminopyridine induced hearing losses.
Vinpocetine has been found to inhibit proliferation of breast cancer cells associated with stoppin the cell cycle at the G0/G1 phase and attenuated activation of PI3K and STAT3; vinpocetine had an inhibitory effect on cell viability with an IC50 of 23.5-32.2µM (range of four cell lines) and was effective in tumor bearing mice given 10-20mg/kg vinpocetine injections at the tumor site.
Vinpocetine has suppressive effects on breast cancer cells, but since this occurs at a high concentration or injections near the tumor it is doubtful how practically relevant this information is
Nitrate is a small molecule found mostly in beets and leafy green vegetables that increases nitric oxide in the body following ingestion. Chronic usage of nitrates or nitrate donors is known to induce a state of tolerance called 'nitrate tolerance' which appear to be associated with an increase in the activity of PDE1A1. Nitric oxide normally acts upon its receptor to increase cGMP concentrations, and PDE1 enzymes (all isoforms) degrade cGMP so an increase of the enzyme acts to normalize cGMP concentrations and thus the effects of nitric oxide. PDE1A1 does not fully explain nitrate tolernace, but plays a role.
Vinpocetine may reduce the tolerance to prolonged nitrate usage and also promote the vasodilating properties of nitrates
When used in hospital settings as IV administration, there have been reports of adverse effects such as death from drastic drops in blood pressure and pulse rate. These effects have not yet been reported for orally supplemented vinpocetine at the standard dosages.
Contact dermatitis to vincamine has been reported, and a case of agranulocytosis (acute reduction in white blood cell count) has been reported and while it was also in a clinical setting it used 15mg vinpocetine daily.
Injections may reduce blood pressure, which are not thought to be relevant to oral ingestion. A lone case study has noted an acute reduction in white blood cell count at a dose that is relevant, but this topic has not been further investigated
Researchers have examined various doses of vinpocetine in a series of animal studies that looked at prenatal toxicity. They have found some worrying results, particularly at higher doses. The following refers to the results of a review.
In one study, groups of 10 time-mated female Sprague Dawley rats were administered doses of 0, 20, 40, 80, 160, or 320 mg/kg of vinpocetine daily from the 6th day of gestation to the 20th. The highest dosed groups tended to have a higher rate of red or brown vaginal discharge. The 0, 20, 40, 80, 160, and 320 mg/kg groups had occurrences of 4, 5, 7, 10, 10, and 9, respectively. Discoloration of nares was found particularly in the 160 and 320 mg/kg groups, and piloerection was found in all rats in the 160 and 320 mg/kg groups. All animals survived.
Maternal body weights were substantially lower in the control group in the 80, 160, and 320 mg/kg groups, notably lower in the 40 mg group, and not lower in the 20 mg/kg group. This was partially due to a reduction in gravid uterine weight, but also independent to some extent. Recording of maternal feed intake was in concordance with this, and vinpocetine reduced consumption in a dose-dependent manner at doses higher than 20 mg/kg.
Percentage of post-implantation loss was (mean + standard error) 5.30 ± 1.78, 18.41 ± 11.70, 27.55 ± 12.35, 100.00 ± 0.00, 90.77 ± 9.23, and 100.00 ± 0.00 for the 0, 20, 40, 80, 160, and 320 mg/kg groups, respectively, the highest 3 being statistically significant. The number of resorptions per litter increased in a dose-dependent fashion, with the 3 highest dosings being statistically significant, and the number of live fetuses per litter declined in a dose-dependent fashion: 13.63 ± 0.53, 11.50 ± 1.78, 10.13 ± 1.85, 0.00 ± 0.00, 1.20 ± 1.20, and 0.00 ± 0.00 for the 0, 20, 40, 80, 160, and 320 mg/kg groups, respectively, the highest 3 being statistically significant.
There weren’t any statistically significant differences in fetal weight or external malformations of examined fetuses, though this was limited by there being either no or very few fetuses in three highest dose groups. Internal malformations weren’t evaluated in this study.
High doses of vinpocetine led to an anorexic effect on pregnant rats and notable fetal toxicity, with a high risk for miscarriages at the upper end of the dose range. It’s not possible to conclude that any of these doses are safe, but there was seen to be a direct dose-dependent effect.
In the follow-up study, groups of 25 time-mated female Sprague Dawley rats were administered doses of 0, 5, 20, or 60 mg vinpocetine/kg daily from the 6th day of gestation to the 20th. It aimed to assess adverse developmental effects so it used smaller doses that wouldn’t lead to as many miscarriages.
Maternal weight was somewhat lower in the 5 and 20 mg/kg groups, and substantially lower in the 60 mg/kg group, which was the only statistically significant reduction. Gravid uterine weight was somewhat lower in the 5 and 20 mg/kg groups and the lowest in the 60 mg/kg group than in the control group, but the only statistically significant difference was in the 60 mg/kg group. Interestingly, feed intake wasn’t different between the 0, 5, and 20 mg/kg groups, and was significantly lower in the 60 mg/kg group, but not by a great deal (nowhere close to the higher doses in the previously mentioned study). The 20 and 60 mg/kg groups saw a large increase in red and/or brown vaginal discharge, but not the 5 mg/kg group.
The number of live fetuses per litter for the various groups was as follows (mean + standard error): 13.95 ± 0.55, 11.95 ± 1.06, 11.86 ± 0.88, and 2.55 ± 1.00 for the 0, 5, 20, and 60 mg/kg groups, respectively, with only the 60 mg/kg group being statistically significantly lower than the control group. Of the live fetuses in the 60 mg/kg group, 82.19% were male, statistically significantly higher than the control group. Percentage post-implantation loss was 3.29 ± 1.33, 10.67 ± 5.29, 11.13 ± 4.65, and 83.13 ± 6.47 which was only statistically significant in the 60 mg/kg group compared with control.
Fetal weight declined a little in the 60 mg/kg group but it wasn’t statistically significant compared with control, and there was no significant difference in external abnormalities in fetuses across all groups. There were various observations of statistically significant increases in abnormalities of organs and skeletons of fetuses from the 5 mg, 20 and 60 mg/kg groups. Overall, it can be said that the risk for fetal abnormalities was possibly higher but roughly comparable to control for 5 mg, and significantly higher for 20 and 60 mg/kg.
Doses of 20 mg/kg or more in rats produced a higher rate of fetal abnormalities, and the 60 mg dose produced a statistically significant reduction in the number of fetuses and in maternal weight.
One other study in groups of 8 time-mated female rabbits used doses of 0, 25, 75, 150, or 300 mg/kg from the 7th day of gestation o the 28th. It found a dose-dependent reduction in maternal body weight for all doses higher than 25 mg/kg and a concomitant decrease in feed consumption. There was no notable maternal pathology. There was a statistically significant reduction in the number of live fetuses per litter in the 300 mg/kg group, and a nonsignificant decline in the 25, and 150 mg/kg groups, but not the 75 mg group. There were no notable differences between groups in fetal malformations of any type.
Very high doses in rabbits caused a higher rate of fetal toxicity and fewer births.
The authors noted that, in another paper, 5 mg/kg in rats produced a plasma level of vinpocetine and its main metabolite roughly equivalent to a single 10 mg dose in humans. While there were no statistically significant differences in fetal toxicity measures for 5 mg/kg up to 20, small increases in risk are compatible with the results, and abnormalities in fetuses were statistically significant or suggestive for many areas in the 20 mg/kg groups or higher. 10-60 mg in humans is a common dose, so while there isn’t sufficient evidence to say that the lower end is harmful during pregnancy, caution would warrant limiting dose to 10 mg or less.
High doses of vinpocetine cause fetal toxicity and reductions in maternal weight and appetite in rats and rabbits. The higher end of usual human doses may lead to these effects, while the lower end of 10 mg hasn’t been sufficiently established to be harmful, but these studies don’t rule out harms in human pregnancy.