Vanadium

Brand names: Metavanadate, Orthovanadate, Sodium Metavanadate, V, Vanadate, Vanadium, Vanadium Chloride, Vanadyl, Vanadyl Sulfate

Usage of Vanadium

Vanadium is a trace element that plays a critical, if not essential, role in the metabolism of carbohydrates, lipids, phospholipids, and cholesterol. Additionally, it is involved in bone mineralization, thyroid and erythrocyte metabolism, cellular calcium movement, and intracellular signaling.(Scibior 2020)

Only 1% to 10% (typically, 0.2% to 2%) of vanadium is absorbed after oral intake due to instability of vanadate ions in stomach acid. Vanadium enters the bloodstream after oral consumption or inhalation and is resorbed in the intestines and lungs, respectively. The overall amount in the body is not affected by transcUTAneous absorption. Normal blood concentrations in healthy adults range from 0.08 to 2 mcg/L. Approximately 80% to 90% is bound to albumin for transport. At low blood concentrations (no more than 1.5 mM), vanadium binds to transferrin (specifically at the ferric iron pocket) for transport, whereas albumin and immunoglobulin G come into play as major transporters with increasing vanadium blood concentrations. Physiologically, the overall and cellular redox status of an individual dictates whether vanadium assumes a cationic, anionic, or Neutral form. Tetra- and pentavalent vanadium are easily interconverted by redox agents, including nicotinamide adenine dinucleotide (NAD+), nicotinamide adenine dinucleotide phosphate, flavin adenine dinucleotide (FAD+), glutathione, and ascorbate. Distribution occurs through the heart, liver, kidney, and spleen, then across the brain, muscle, and adipose tissue, and finally the bones. The skeletal system is the major site of long-term storage, where about 50% of total body vanadium resides; it replaces phosphorus in hydroxyapatite and is retained for about 1 month (half-life of 4 to 5 days). Most of the remaining 50% is deposited in the liver, kidney, and spleen but can also be found in the muscles, lungs, and brain. Insulin may play a role in the metabolism of vanadium, which takes place over 3 phases, with almost 30% of serum levels eliminated in the first 24 hours. The approximate half-life for the rapid, intermediate, and slow metabolic phases are 1 hour, 26 hours, and 10 days, respectively. Up to 99% of daily intake is excreted in the feces, whereas the majority of resorbed vanadium is excreted renally (about 50% after 12 days).(Gruzewska 2014, Rehder 2013, Scibior 2020)

Clinical studies focusing on potential therapeutic application of vanadium supplementation are limited, often with equivocal results; studies have been conducted to improve understanding of the relationship between elevated or low levels of vanadium and various conditions (eg, CNS or renal conditions, systemic lupus erythematosus). Such findings have at times resulted in research focused on the potential benefits/effects of treatments that lower vanadium exposure.

CNS effects

Studies have been conducted to evaluate the cognitive and behavioral changes associated with excess vanadium exposure, as well as underlying mechanisms of action; documented changes include anger, negative mood, hostility, lethargy, and depression/dejection, as well as locomotor problems, tremor, loss of subjective memory, and impaired spatial learning ability. At the cellular level, damage to hippocampal and striatal neurons, dendritic spines, and cell viability have been described.(Folarin 2016, Sun 2017)

Manic-depressive effects

Clinical data

Preliminary data suggest that manic-depressive symptoms may be associated with excess vanadium, particularly depressive symptoms. The mechanism is suspected to be related to the potent reduction of sodium, potassium, and adenosine triphosphatase activity by vanadium. In a small study, 23 patients (10 depressed, 13 manic) received 4 days of a diet with normal vanadium content (approximately 1 to 2 mg vanadium); for the following 10 days, they received a diet containing vanadium in an amount as low as possible. On a double-blind, crossover basis, metavanadate 1.5 mg/day (vanadium 0.7 mg/day) for 5 days followed by ethylenediaminetetraacetic acid (EDTA) (vanadium chelator) 3 g for 5 days, or vice versa, was administered. Global rating scores for depressive symptoms were improved in significantly more patients during the low vanadium phase compared to normal vanadium phase (P<0.05), whereas no significant differences were found between the 2 phases for manic symptoms. Sleep was significantly improved during the low vanadium phase in manic patients (P<0.05), but not in depressed patients. Additionally, 2 female patients, each with a several-year history of cyclic manic-depressive illness resistant to therapy, responded to treatment for the first time in their medical history when administered a low vanadium diet plus EDTA and vitamin C (a vanadium antagonist); 1 woman missed a depressive phase for the first time in a decade and spent significantly less time feeling depressed (P<0.0001) compared with her normal cycle, while her manic phase was unchanged. The second woman treated with the SAMe regimen settled into a mildly hypomanic state within 2 weeks with no depressive phases for 8 weeks. Her normal cycle recurred when treatment was stopped, but upon treatment reinitiation her mild hypomanic state returned.(Naylor 1981)

Memory, learning, and Alzheimer disease

Animal data

Neurobehavioral benefit and harm have been observed in outcomes of animal studies that assessed various vanadium salts, dosing, and durations of exposure.(Folarin 2016, He 2020, Sun 2017) Memory dysfunction was described in mice exposed to oral sodium metavandate 3 mg/kg/day for 12 months. However, reversibility of memory loss was demonstrated when exposure was limited to 3 months, with memory retention comparable to controls documented 9 months later.(Folarin 2016) Similarly, a study in rats exposed to medium and high doses of oral sodium metavandate for 8 weeks showed reductions in memory and learning ability compared with controls; however, the low-dose group was not significantly different than controls.(Sun 2017)

In contrast, cognitive benefit was demonstrated in a mouse Alzheimer disease model with 90-day administration of low or high doses of bis(ethylmaltolato) oxidovanadium (BEOV), an organic vanadium compound that improves uptake of vanadium. The 2 daily doses were equivalent to BEOV 0.206 to 0.274 mg and 1.03 to 1.37 mg, respectively. Both doses ameliorated the learning and memory deficits seen in the untreated mice, and no neurotoxicity or overt side effects were observed.(He 2020)

Clinical data

In a study evaluating whether chronic exposure to vanadium reduces cognitive abilities, significant deficits in attention (P=0.002) as well as visuospatial abilities/motor functioning (P=0.02) were documented in men exposed to vanadium occupationally (n=49) compared with controls (n=49). Maximum urine and serum vanadium levels in exposed men were 95.3 mcg/L and 46.4 mcg/L, respectively, compared with 1.35 mcg/L and 3.12 mcg/L, respectively, for controls. A significant correlation was observed between serum vanadium levels and cognitive deficits.(Barth 2002)

Parkinson disease

Experimental and animal data

Vanadium demonstrated toxic effects on monoaminergic cells in a dose- and duration-Dependent manner using in vitro methods and an in vivo Parkinson disease model. Undifferentiated cells were more sensitive to the toxic effects of acute and long-term (5-day) dosing compared to differentiated cells, which were affected only by chronic administration; the increased sensitivity of the undifferentiated cells was determined to be due to the significantly higher intracellular iron levels (approximately 3-fold; P<0.005). The toxic oxidative effects induced by vanadium were reversed with long-term exposure to synthetic and natural (Aloysia citrodora, Lemon verbena) iron chelators. Existing locomotor deficits in the in vivo (fruit fly) Parkinson disease model were significantly worsened (P<0.01) with administration of subtoxic doses of vanadium and ameliorated with L-dopa. Survival was also significantly decreased (P=0.035) in the model compared with controls; survival was unchanged by L-dopa.(Ohiomokhare 2020)

Diabetes and glucose homeostasis

Animal data

Oral vanadium supplementation in diabetic animal models improved insulin responsiveness in peripheral tissue, promoted normoglycemia, and increased hepatic glycogen synthesis via insulin-like activity, proliferative and restorative effects on pancreatic beta cells, and restoration of mRNA levels of glycolytic hepatic enzymes.(Pirmoradi 2014, Trevino 2019)

Progression of diabetic cataract was mitigated with the administration of oral sodium vanadate in a diabetic rat model with markers of hyperglycemia and weight loss. After 8 weeks of treatment, 0.9 g (0.1 mmol/kg) and 1.8 g (0.2 mmol/kg) doses significantly reduced the progression of cataracts (P<0.05 and P<0.01, respectively) and the higher dose also significantly reduced the opacity index (P<0.05) compared with diabetic controls. The effect appeared to be related to a reduction in sorbitol production via the polyol pathway and not due to reductions in oxidative stress mechanisms. Both doses resulted in significant decreases in blood glucose and prevented significant increases in glycosylated hemoglobin (HbA1c).(Sun 2014)

Clinical data

The effect of vanadium on insulin sensitivity in adults with impaired glucose tolerance was assessed in a small randomized, placebo-controlled study (N=14). Compared with baseline, administration of vanadyl sulfate 50 mg twice daily for 30 days produced similar results to placebo and resulted in no significant changes in body mass index (BMI), blood pressure, insulin sensitivity, glucose concentrations, or lipid parameters. The only exception was a significant increase in mean triglyceride levels with vanadium (1.4 to 1.7 mmol/L; P=0.018) and a slight increase in BMI with placebo (30.7 to 30.9; P=0.043).(Jacques-Camarena 2008)

In a study evaluating the pharmacokinetics and clinical response to vanadyl sulfate (daily doses of 25 mg, 50 mg, or 100 mg for 6 weeks) in patients with type 2 diabetes (N=16), no correlation was found between peak serum vanadium levels and clinical responses related to glycemic control or insulin response. However, a negative correlation was observed between peak serum vanadium levels and glycohemoglobin, as well as glycohemoglobin/globulin composite and Fasting blood glucose variables.(Willsky 2013)

A small crossover experiment in patients with type 1 diabetes (N=5) evaluated effects of vanadyl sulfate on insulin-mediated glucose uptake, glycogen synthesis, and suppression of endogenous glucose production. A low-dose insulin infusion was used to identify any enhanced action on insulin by vanadium. Vanadyl sulfate 100 mg/day for 3 weeks did not enhance the effects of physiologic hyperinsulinemia on glucose or fat metabolism.(Aharon 1998)

A 2008 systematic review found no robust evidence to support routine use of oral vanadium supplementation for glycemic control in adults with type 2 diabetes. Because no high-quality randomized controlled trials or quasi randomized controlled trials could be identified, examination of 5 small, low-quality studies (nonrandomized, within-subject analyses) was conducted; the most common dose employed was vanadyl sulfate 100 mg/day, with 3 of the 5 studies using 50 mg twice daily with meals for 3 or 4 weeks(Boden 1996, Cohen 1995, Halberstam 1996); one study evaluated 25 mg, 50 mg, and 100 mg doses given 3 times daily for 6 weeks; and one study evaluated titration from 50 mg to 150 mg daily (as 3 divided doses).(Goldfine 2000). The studies reported statistically significant improvements from baseline in both mean HbA1c and/or fasting blood glucose that ranged from 0.3% to 1% (P<0.002 to 0.05) and 1.7 to 2.2 mmol/L (P<0.01 to <0.05), respectively. A high incidence of transient GI adverse events was reported for vanadium in all 5 studies.(Smith 2008)

Gastric ulcer

Animal data

Vanadium reversed ischemia-reperfusion gastric erosion and necrosis in a study of rats with induced gastric ulcer. The ulcer score, gastric mucous concentration, and nitrate concentration improved with several doses of vanadium compared with ulcerated controls. The effects were achieved through a reduction in serum and stomach tissue malondialdehyde, upregulation of gastric antioxidant enzyme activities, modulation of the hydrogen/potassium and the calcium ATPase pumps, and suppression of cyclooxygenase (COX-2) and nitric oxide synthase.(Omayone 2020)

High altitude acclimatization

Clinical data

A study in volunteers from the Indian Army (N=16) evaluated effects of oral vanadyl sulfate 5 mg for 6 days on high-altitude acclimatization. Vanadyl sulfate was initiated 3 days prior to airlift of participants to high altitude, then continued for 3 more days during their 12-day stay at high altitude. Vanadyl sulfate did not affect changes in blood pH, PO2, or PCO2 induced by high altitude compared with controls. Blood viscosity was decreased slightly in the vanadium group compared to controls; however, no difference in red blood cell counts was observed between groups. It should be noted that fluid intake was slightly higher in the vanadium group than in controls, but urine output was slightly less. Vanadium supplementation appeared to protect participants against a significant plasma vanadium reduction that was observed in controls at days 3 and 12 at high altitude (ie, after treatment discontinuation). While plasma vanadium levels in controls decreased from 27 ng/mL at sea level to approximately 5 ng/mL on days 3 and 12 at high altitude, levels in the vanadium-supplemented group increased significantly from 31.9 ng/mL at sea level to 37.7 ng/mL on day 3 at high altitude (P<0.05) and remained elevated at 31.7 ng/mL on day 12 at high altitude (P<0.001), which was 9 days after vanadium discontinuation.(Rawal 1997)

Exercise performance

Clinical data

The effect of vanadyl sulfate in 40 healthy weight-training male athletes (N=30) was investigated in a double-blind, randomized, placebo-controlled study. Oral administration of vanadyl sulfate 0.5 mg/kg/day for 12 weeks appeared to improve the "1 repetition maximum" leg extension performance measure (P=0.002) compared with the placebo group. However, no other significant between-group improvements were observed in other performance measures. Additionally, no changes in anthropometric measures, hematological or biochemical indices, liver function tests, blood pressure, or plasma viscosity were observed between groups. Overall, vanadium supplementation was well tolerated; however, excessive fatigue with and without aggressive mood changes were reported by 2 participants in the vanadium group and led to study withdrawal.(Fawcett 1997, Fawcett 1996)

Renal disease

Clinical data

Studies suggest that vanadium accumulates in patients with chronic kidney disease, including adults on hemodialysis. Similar results have been documented in pediatric patients with chronic kidney disease not on dialysis. A median vanadium level of 0.12 mcg/L (range, 0.09 to 0.18 mcg/L) and a maximum level of 3.35 mcg/L were observed in 36 patients 4 to 19 years of age; 89% had at least 1 measured level above the reference level of 0.088 mcg/L. Higher levels were weakly correlated to estimated glomerular filtration rate and less so to the source of drinking water.(Filler 2017)

A systematic review of studies that reported data on trace elements in chronic hemodialysis patients identified increased levels of vanadium greater than those in controls. Data from the 5 studies (N=249) reporting on vanadium levels yielded a pooled standardized mean difference of 3.07 (range, 1.18 to 6.28), with all 5 studies documenting higher concentrations of vanadium in patients on hemodialysis. Variations in techniques and specimens among the studies prevented measurement or estimation of toxic levels; however, accumulation of vanadium was deemed probable. Limitations of the review included poor to moderate study quality, relatively small sample sizes, differing analytical techniques, and varied specimen sources that all led to substantial between-study heterogeneity.(Tonelli 2009)

Systemic lupus erythematosus

Clinical data

Vanadium levels were significantly lower in patients with systemic lupus erythematosus compared with controls (P<0.001). A significant negative correlation was also found between serum vanadium levels and a diagnosis of systemic lupus erythematosus (odds ratio [OR]=0.97; 95% CI, 0.961 to 0.98; P<0.001) but not disease activity.(Pedro 2019)

Vanadium side effects

Occupational exposure to vanadium dust leading to adverse effects, including contact dermatitis, has been reported.(Garcia-Nunez 2019) Four case reports of men developing asthma due to occupational exposure to vanadium compounds exist. Symptoms developing within the first few days included headache; dry mouth; green discoloration of the tongue, fingers, scrotum, and legs; excessive tearing; red edematous nasal mucosa; wheezing; dyspnea; and productive cough that resolved when exposure was stopped. Mild to severe, reversible airflow obstruction was noted, with normal lung function returning within 2 to 6 weeks, depending on duration of exposure.(Musk 1982)

In a small study, excessive fatigue with and without aggressive mood changes were reported by 2 healthy weight-trained athletes taking vanadium and led to discontinuation. Hematological and biochemical indices were within normal limits.(Fawcett 1996)

Before taking Vanadium

Avoid use. Information regarding use in pregnancy and lactation is lacking.

In normal and overweight pregnant women, hair sample vanadium levels were inversely associated with BMI (P=0.011); however, no significant associations were found between maternal BMI and hair trace elements in their children at 9 months. These data are from 159 Siberian mother/child pairs. In contrast, a previous study identified reduced hair vanadium levels in children of obese women as well as a negative correlation between maternal BMI and amniotic fluid vanadium levels.(Skalny 2020)

How to use Vanadium

Clinical data are lacking to provide dosing recommendations. Published studies aim to improve understanding regarding associations between elevated or low levels of vanadium and various conditions.(Barth 2002, Filler 2017, Naylor 1981, Tonelli 2009)

The no-effect level has been set at a daily vanadium intake not exceeding 10 mg/kg body mass to avoid toxic effects.(Rehder 2013)

The pharmacokinetics of orally administered vanadium (as vanadyl sulfate) in patients with type 2 diabetes was similar to kinetic values described previously in healthy adults. Considerable variability was noted among individual patient responses. A dose-dependent increase in peak concentrations in serum and blood continued until steady-state serum concentration was achieved, with 95% of steady state reached in about 20 days.(Willsky 2013)

Warnings

The no-effect level has been set at a daily vanadium intake not exceeding 10 mg/kg body mass to avoid toxic effects.(Rehder 2013)

A case of fatal poisoning was reported in a 24-year-old female who consumed an undetermined amount of ammonium vanadate; death occurred within 24 hours subsequent to unresponsive respiratory distress. Postmortem findings included widespread asphyxia syndrome of the viscera and erosive gastritis. Her blood vanadium level was 6.22 mcg/L, which was about 6,000 times the upper limit of normal.(Boulassel 2011)

Toxic effects with high concentrations of vanadium have been documented in the cardiovascular, digestive, hematopoietic, hepatic, neurological, renal, and respiratory systems, as well as on genes and mitochondria. This is primarily a result of the inhibition of several enzymes, including oxidative phosphorylation, leading to an inhibition of cellular respiration. In addition to a characteristic green tongue, other symptoms of acute or chronic toxicity in humans include heart palpitations, exhaustion, depression, and trembling.(Gruzewska 2014)

Human sperm exposed to various vanadium organic complexes at nanomicromolar concentrations exhibited dose-dependent and irreversible inhibition of sperm motility in vitro. Animal studies with vanadium have demonstrated permanent damage to male reproductive function. Human clinical data on reproductive toxicity specifically for vanadium are lacking; however, even low concentrations of other heavy metals in human, animal, and in vitro studies caused adverse male reproductive effects.(Altamirano-Lozano 2014, Wilk 2017)

Human epidemiological studies of workers exposed to vanadium pentoxide (V2O5) have concluded that vanadium does not cause DNA damage in vivo; however, an increase in micronucleated and necrotic cells was observed in 1 study (N=52).(Altamirano-Lozano 2014)

Data from animal and in vitro studies suggest that dietary antioxidants may help protect humans at high risk of vanadium toxicity via reduction of vanadate to vanadyl and/or formation of stable nonharmful complexes similar to chelation. Some dietary compounds that have shown promise include vitamins C and E, polyphenols (ie, flavonols, flavonones, stilbenes) such as those found in tea and resveratrol, phytosterols (ie, stigmasterol, Beta-Sitosterol), and sulforaphane. Additionally, plant extracts rich in antioxidant compounds that have demonstrated beneficial effects against vanadium toxicity have been identified for Moringa oleifera, Grewia carpinifolia, Camellia sinensis (green tea), Malva sylvestris, and Salvia officinalis (sage).(Zwolak 2020)

What other drugs will affect Vanadium

Drug interaction studies have not been identified.

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