Jermane Krshnan


Vitamin E

Vitamin E is known to have anti-oxidative, anti-inflammatory, anti-obesity, anti-hyperglycemic, anti-hypertensive and anti-hypercholesterolemic properties. 


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The medical information on this site is provided as a resource for information only, and is not to be used or relied upon for any diagnostic or treatment purposes and is not intended to create any patient-physician relationship.  Readers are advised to seek professional guidance regarding the diagnosis and treatment of their medical concerns.


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Definitions and Terminology


Vitamin E

Vitamin E is known to have anti-oxidative, anti-inflammatory, anti-obesity, anti-hyperglycemic, anti-hypertensive and anti-hypercholesterolemic properties. As such it has been proposed as a supplement to offer benefits for these conditions, and particularly metabolic syndrome (MetS), a constellation of medical conditions including central obesity, hyperglycemia, hypertension, and dyslipidemia.

The best option in suppressing the progression of MetS is through a holistic approach, maintaining a healthy lifestyle, including exercise, reduction of stress and a healthy diet. The pathways regulated by vitamin E are critical in the development of MetS and its components, suggesting a supplemental pharmacological approach with vitamin E. The evidence provided by studies on the effects of vitamin E demonstrate the promising potential of vitamin E in preventing the medical conditions associated with MetS.


a-Tocopherol Deficiency and Inadequacy

Vitamin E deficiency is seldom identified in adults and is more frequently found in children, probably because they have limited stores and they are growing rapidly, so deficiency symptoms are more apparent.

It is estimated that >90% of Americans do not consume sufficient dietary vitamin E, as a-tocopherol, to meet estimated average requirements. Inadequate vitamin E status is detrimental: plasma a-tocopherol concentrations <12 mmol/L are associated with increased infection, anemia, stunting of growth, and poor outcomes during pregnancy for both the infant and the mother. When low dietary amounts of a-tocopherol are ingested, tissue a-tocopherol needs exceed amounts available, leading to increased damage to target tissues.

Adequacy of vitamin E status cannot be assessed from circulating a-tocopherol concentrations, but inadequacy can be determined from “low” values. Blood levels of a-tocopherol are very difficult to interpret because as a person ages, plasma lipid concentrations also increase and these elevations in lipids increase the plasma carriers for a-tocopherol, leading to higher circulating a-tocopherol concentrations. However, abnormal lipoprotein metabolism does not necessarily increase a-tocopherol delivery to tissues.

Furthermore, it is important to distinguish between “deficiency” and “suboptimal.” Given the activities of the different vitamin E isormers and their proposed benefits, optimal levels are quite likely to be significantly greater than simply cut-off levels for deficiency since the measurement of the consequences of suboptimal is not possible at this time. Additionally, optimal levels are likely to be dependent on many variables based on a person’s health status.


Better biomarkers of inadequate vitamin E status are needed and urinary excretion of the vitamin E metabolite a-carboxy-ethyl-hydroxychromanol may fulfill this biomarker role. Unfortunately it has not been adequately studied with regard to vitamin E status or with regard to health benefits.


The Family of Vitamin E

Vitamin E is well known for its antioxidant capacity. In actuality, Vitamin E is a family consisting of two forms, the tocopherols and the tocotrienols, each having a small difference in their molecular structure. The tocopherols were first discovered in 1922, specifically alpha-tocopherol, and are the form most familiar to people. Upon discovery in 1986, tocotrienols were first differentiated from tocopherols and found to have different properties. Current research indicates tocotrienols have greater antioxidant potential than tocopherols.

Both tocotrienols and tocopherols comes in four forms: alpha, beta, delta, and gamma but the α- forms of both tocopherols and tocotrienols are considered to be the most metabolically active. All isoforms are biologically active but α-tocopherol is the most biologically active. The most common dietary forms are α- and γ-tocopherol while only α-tocopherol is retained at high levels in plasma and tissues.


Dietary Vitamin E

The average diet contains more tocopherols than tocotrienols. γ-tocopherol is the most common in the US diet due to the higher consumption of soybeans, sesame, and corn oil, and α-tocopherol is the most common in the European diet.

Good sources of tocopherols include:

  • Vegetable oils: olive oil, sunflower oil, rapeseed oil, corn oil, linseed oil, and soybean oil
  • Nut oils
  • Seeds
  • Whole grains


The three most abundant sources of tocotrienols are rice bran (50%), palm oil (75%), and annatto oil (99.9%).

Good sources of tocotrienols include:

  • rice bran oil
  • oats
  • barley
  • hazelnuts
  • rye
  • wheat germ
  • crude palm oil



Each of the eight compounds, has shown to have some degree of antioxidant properties. However, of all the compounds, the alpha-tocopherol (aT) shows the highest physiological concentrations and only tocopherol can correct vitamin E deficiency, which suggests that tocopherol is the form of vitamin E that the body needs most to function efficiently.


Vitamin E and Metabolic Syndrome (MetS)

The benefits of vitamin E supplementation for metabolic syndrome (MetS) was evaluated in a study among MetS subjects who were non-vitamin and non-anti-oxidant users. Participants were treated with α-tocopherol (800 mg/day), γ-tocopherol (800 mg/day), combination of α-tocopherol and γ-tocopherol (800 mg each/day), or placebo for 6 weeks. The combination of α-tocopherol and γ-tocopherol was superior in reducing lipid peroxides, tumor necrosis factor- alpha (TNF-α), malondialdehyde (MDA), 4-hydroxynonenal (HNE), and high sensitivity C-reactive protein (hs-CRP) levels, suggesting their potential benefit for oxidative stress, nitrative stress, and inflammatory response in MetS. 

In addition, a more recent study evaluating adults with MetS aged 20–60 years, supplementing  mixed tocotrienols (400 mg/day) for 16 weeks showed beneficial effects on chronic inflammation (reduced interleukin-6 (IL-6) and TNF-α) and lipid profiles (reduced total cholesterol, LDL-C, and HDL-C).

The above studies alone are not enough to definitively conclude vitamin E impacts MetS and improves quality of life and survival. However, the current documented evidence supports the intake of naturally occurring vitamin E as a dietary supplement to prevent or treat MetS, with tocotrienols being more superior than tocopherols. Essentially, vitamin E (particularly tocotrienols) appears to be a potential medication for treating most of the clinical conditions associated with MetS.

The composition and doses of tocopherols and tocotrienols still need to be evaluated further for optimal benefits and to ensure safety.



Alpha-tocopherol (aT) as an Antioxidant

It has been shown extensively that aT acts as an antioxidant, allowing it to scavenge and remove ROS preventing oxidative damage. It protects polyunsaturated fatty acids present in cell membranes to stabilize cellular membranes them against oxidative damage. Many studies have shown a correlation between aT and reduction of inflammation and enhancement of the immune system functionality. This has stimulated interest in incorporating aT supplementation for various clinical disorders including metabolic syndrome which is associated with lower levels of aT that may indicate that the development and progression of metabolic syndrome could in part be attributed to reduced levels of aT.


Alpha-tocopherol (aT) as an Anti-inflammatory

Recent studies have shown that aT supplementation is capable of reducing inflammatory processes by reducing the expression of inflammatory agents including IL-6, TNF-a and C reactive protein while increasing antioxidant constituents. Furthermore, aT may also inhibit pathways that are activated by ROS which tend to be elevated in obese individuals and various inflammatory diseases and are reduced with aT supplementation. Thus, aT has a plausible role in reducing inflammation induced by ROS-induced oxidative damage and through its effects on immune system functionality.


Alpha-tocopherol (aT) and Arthritis

Oxidative stress is one of the underlying mechanisms contributing to cartilage degeneration in osteoarthritis as evidenced by the reduced antioxidant (including vitamin E) and increased lipid peroxidation products in the circulation and synovial fluid of the patients with osteoarthritis. The benefits of alpha-tocopherol supplementation in slowing the progression of osteoarthritis is still debatable due to the mixed outcomes in the research. High-dose vitamin E supplementation is cautioned due to its potential pro-oxidant effects. Different isoforms of vitamin E may have distinct biological effects on joint health but the studies on isoforms others than alpha-tocopherol are limited. This is a major research gap that should be addressed in future studies to validate the use of vitamin E in tackling osteoarthritis.


Alpha-tocopherol (aT) and Fatty Liver Disease

Fatty liver disease is of interest because the progression of this disorder to more serious forms of the disease is dependent on oxidative damage to lipids, suggesting that inadequate vitamin E intakes may promote disease progression.


Alpha-tocopherol (aT) to Reduce Cholesterol and Triglycerides

Research has has provided promising results for the ability of aT to reduce total cholesterol and triglycerides in metabolic syndrome and in the prevention of obesity-associated atherosclerosis. These benefits of aT are due to the reduction of low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol levels. In animal models of diet induced obesity, aT also diminishes the degree of fat in the liver and circulating triglycerides suggesting a likely role in the prevention of atherosclerosis and fatty liver diseases associated with obesity.


Alpha-tocopherol (aT) and Atherosclerosis

Growing evidence indicates that aT reduces oxidation of cellular membranes and reduces overall lipid content in circulation and within fat cells, suggesting aT may play a role in shifting the metabolic profile of obesity toward normalcy. Changes within fat cells in obese individuals includes an elevation of collagen deposition that may contribute to the systemic inflammation seen in obesity. Supplementation with aT may play a role in downregulating pathways associated with collagen accumulation and abnormal fat cell growth and reduce systemic inflammation.


Alpha-tocopherol (aT) and Type 2 Diabetes (T2DM)

Cumulative studies have indicated that aT supplementation reduces biomarkers of oxidative damage in T2DM patients and improves insulin sensitivity. The elevation in insulin sensitivity is attributed to the anti-inflammatory action of aT in visceral adipose tissue. Also, through scavenging of ROS, aT may may reduce the impact that persistent hyperglycemia has promoting ROS production and inflammation activation. Thus, there may be a role linking aT’s effects on inflammation that may lead to the suppression of the metabolic diseases associated with T2DM.


However,  human and animal studies focused on the effectiveness of aT supplementation in aging-associated diseases, oxidative stress and inflammation have had mixed results, including beneficial and harmful effects. Recent studies suggest that vitamin C, especially in combination with vitamin E, may be helpful in reducing risk of cognitive impairment associated with Alzheimer’s .



Research also suggests independent benefits may be achieved with tocotrienols. For example, the tocotrienols are a much more bioactive form of Vitamin E, possessing 40–60 times more antioxidant activity than tocopherols. Tocotrienols also exhibit potent anti-inflammatory properties, a property that is only very weakly, if at all, observed in tocopherols.

Tocotrienols have diverse properties in addition to antioxidant and anti-inflammatory benefits, including anticancer, neuroprotective and skin protection benefits, as well as improved cognition, bone health, longevity and reduction of cholesterol levels in plasma. Tocotrienols also have been shown to improve lipid profiles, reduce total cholesterol and reduce the volume of white matter lesions in human clinical trials.


Tocotrienols and Cardiovascular Disease (CVD)

Tocotrienols improve ‘inflammaging,’ a chronic low grade inflammation in the absence of other significant medical conditions, a cardiac risk factor in the elderly. They also improve dyslipidemia and mitochondrial dysfunction, thus reducing risk for cardiovascular diseases.

Tocotrienols can  lower blood levels of CRP, 20–50% more effectively than tocopherol and potentially reducing the aging risk of developing cardiovascular disease (CVD).

A new and emerging field of immunocardiology has determined that myocardial and immunological ageing processes are intimately linked and intertwined and related to activity of the immuned cells, CD4+ T cells. Tocotrienols can play a role in immunomodulation of T-cell activity and may potentially provide benefits for the heart by suppressing potentially damaging inflammatory activity by these immunologic cells. 


Tocotrienols and Dyslipidemia

Dyslipidemia is defined as elevated total cholesterol levels or elevated low-density lipoprotein (LDL) cholesterol levels, or low levels of high-density lipoprotein (HDL) cholesterol. Dyslipidemia is an important risk factor for coronary heart disease (CHD) and stroke. Currently, the use of  the “statins” class of drugs (Lipitor, Crestor etc.) is the gold standard for the treatment of hypercholesterolemia.
Cholesterol is produced in the body from the compound HMG-CoA via the enzyme HMG-CoA reductase. Statins mimic the structure of HMG-CoA and acts as a competitive inhibitor, thereby lowering cholesterol levels. Tocotrienols suppress the production of  the enzyme HMG-CoA reductase, thereby lowering cholesterol levels.

While statins are considered the gold standard for treating hypercholesterolemia, they are associated with significant side effects. Although the incidence of these side effects is low they can nevertheless be devastating. The most common side effect is muscle pain and soreness but in more rare and extreme cases, patients may develop rhabdomyolysis, a life-threatening breakdown of muscles.

Additionally, statins have been increasingly shown to have a greater risk to the elderly by increasing the risk of developing diabetes when given high doses of statins. Thus, while one ailment is treated with reduced risk for CVD, the risk for another disease (diabetes) goes higher.

Tocotrienols can reduce triglyceride (TG) and low density lipoprotein-cholesterol (LDL-C) levels by up to 25%. Unlike statins, tocotrienols offer no risk for developing diabetes and in fact quite the opposite effect is seen. Due to its strong antioxidant activity, tocotrienols can reduce oxidative stress in the pancreas and improving insulin secretion. Additionally, tocotrienols can activate the expression of peroxisome proliferator activated receptor γ (PPARγ), a key gene crucial for improving insulin sensitivity. Hence, tocotrienols can also improve diabetes, while improving the risk for cardiovascular diseases.

Of note, when tocopherols (esp. alpha-tocopherol) are added to tocotrienols the activity of tocotrienols are reduced so they should not be taken together.


Clinical Studies with delta-Tocotrienol

Two clinical studies indicate that delta-tocotrienol, combined with antioxidant polyphenols, may curb inflammation and help manage dyslipidemia, triglycerides, or both, and help to lower high-density lipoprotein levels that contribute to the development of atherosclerosis. One placebo-controlled study was conducted in two groups of elderly people over six weeks, one with normal lipid levels, the other elevated. The study product formulation was composed of DeltaGold delta-tocotrienol from annatto along with a B-vitamin (niacin) and polyphenols.

In both groups, supplementation led to a significant drop in C-reactive protein and -glutamyl-transferase (a predictor of non-fatal myocardial infarction and fatal coronary heart disease), while increasing total antioxidant status. In the hypercholesterolemic group, the following also dropped: LDL cholesterol (by 20%-28%) and triglycerides (by 11%-18%). C-reactive protein dropped in healthy elderly subjects (by 21%-29%) and in the hypercholesterolemic elderly (by 31%-48%). No adverse effects were observed.

Of note, combining tocopherols (esp. alpha-tocopherol) with tocotrienols suppresses the benefits of tocotrienols and taking the two together should be avoided.


Statin and Tocotrienol

There has been early research on combining a statin and tocotrienol. One study reported that co-treatment with lovastatin and tocotrienols led to a synergistic effect in improving the lipid profile of hypercholesterol subjects.


Tocotrienols and Atherosclerosis

Atherosclerosis is now well recognised as a chronic in- flammatory disease. It is characterised by the accumulation of lipids and inflammatory cells in the walls of arteries, leading to the formation of atherosclerotic plaque. Vascular wall (endothelium) inflammation is the key factor in the development of atherosclerosis which results in endothelial injury and dysfunction, leading to heart attacks and strokes.

Oxidized LDL (ox-LDL) is a critical factor in the development of atherosclerotic plaque and is due to lipid peroxidation by reactive oxygen species (ROS). Dietary tocotrienols have been shown to inhibit lipid peroxidation and have a preventive role in the development of atherosclerosis. Other antioxidants, particularly CoQ-10, have been shown to protect against ox-LDLs.


Tocotrienols and High Blood Pressure (HBP)

Several recent studies have reported the benefits of dietary antioxidants in reducing blood pressure (BP), including vitamin C and tocotrienols. Studies evaluating tocotrienols in HBP are currently limited to animal studies, but the data results appear promising.


Tocotrienols and Oxidative Stress & Mitochondrial Dysfunction

Mitochondria are intracellular organelles that are the energy producing workhouses inside cells. In the production of energy, free radicals are produced including Reactive oxygen species (ROS) and reactive nitrogen species (RNS).  These free radicals have been clearly established as both potentially harmful, but also potentially beneficial in different circumstances. Both ROS and RNS are normally generated by tightly regulated enzymes such as nitric oxide synthase (NOS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.

The chronic overproduction of ROS/RNS can be damaging to various parts of cell and tissue components and is a phenomenon linked with ageing. This is especially true when it damages important bio-molecules key to sustaining life, including lipids, proteins and DNA.

The free radical theory of ageing proposed in the 1950s and later expanded in the 1970s states that the ageing process accelerates the overproduction of these species, leading to an increased oxidative burden that needs to be cleared by the body, a condition of “oxidative stress.” The longer these ROS/RNS species persist, the higher the likelihood they cause harm by damaging tissues.

In blood vessels oxidative stress contributes to atherosclerosis and in the heart, the deterioration in mitochondrial energetics and function is a major determinant in ageing-related cardiovascular disease, including congestive heart failure. Mitochondrial dysfunction is also proposed as an element if fibromyalgia and other conditions.

See: Mitochondrial Dysfunction


Tocotrienols has been shown to have superior free radical scavenging activity and has been proposed as potentially helpful in suppressing oxidative stress. It should be noted that other natural compounds demonstrating powerful antioxidant and anti-inflammatory effects are likely to be beneficial for oxidative stress: curcumin, CoQ-10,  resveratrol and others, (See: Antioxidants and Oxidative Stress).


Tocotrienols and Anti-Inflammation

Tocotrienols have also been evaluated for their benefit in reducing inflammation. In research studying tocotrienols’ effect on inflammatory markers with dosing of 250 mg/day of tocotrienols (identified as an optimal dose),  C-reactive protein levels were reduced by 40%, and nitric oxide levels, which are aberrant in inflammatory conditions and should be reduced (only in inflammatory conditions), were also lowered by 40% in subjects.


Tocotrienols and Alzheimer’s Disease (AD) 

Tocotrienols are neuroprotective and can address many aspects of Alzheimer’s Disease (AD), including oxidative stress, mitochondrial dysfunction and abnormal cholesterol synthesis. Preclinical studies show that tocotrienol reduces oxidative stress by acting as a free-radical scavenger and by promotion of mitochondrial function and cellular repair. It also prevents cellular glutamate-induced neurotoxicity which is widely implicated in the development of AD. Findings show that vitamin E protects critical fatty acids in the brain from lipid peroxidation and that improved brain vitamin E status is protective for cognitive function.

Compared to alpha-tocopherol, tocotrienols have stronger antioxidant and anti-inflammatory activities. The structure of tocotrienols allows them to be incorporated into the cell membrane better and it has been proposed that their metabolites may be more effective than alpha-tocopherol in preventing AD. However, although tocotrienols have these better activities, alpha-tocopherol levels are higher in the brain after oral administration. At this time it is not possible to conclude which formulation is the most effective against AD.

Epidemiological studies demonstrate a significant inverse relationship between tocotrienol blood levels and the occurrence of AD: higher blood levels correlate with less likelihood of AD. At this time however, there are no clinical trials to show that tocotrienol can delay or prevent the onset of AD. While tocotrienols have the potential to be help prevent AD, additional research is necessary to validate their effiectiveness.


Tocotrienols and Weight Loss

Recent research indicates that tocotrienols may have a positive effect in reducing obesity. It has been shown that tocotrioenols inhibit production of new fat by reducing the accumulation of triglycerides (TGs) and lipid droplets.


Pharmacokinetics of Tocotrienol

Compared to tocopherols, tocotrienols are less orally bioavailable. Tocotrienols are lipid-soluble, so their absorption is enhanced with concurrent intake of dietary fat. Consumption of dietary fat ensures sufficient secretion of bile acids and lipase. Bile acids emulsify tocotrienols into microscopic droplets that provide greater surface area to be digested by lipase and absorbed into the bloodstream.

Since the oral absorption of tocotrienols depends on bile and lipase secretions which may be low and erratic, its absorption often results in poor bioavailability and effectiveness. Because of this, various methods to improve bioavailability such as using self-emulsifying drug delivery system (SEDDS) can be employed to achieve more efficient absorption.

Tocotrienols’ peak blood concentrations are reached in 3 hours after oral ingestion after which they are distributed into most organs, including serum, lung, liver, spleen, colon and adipose tissue. The transport system for vitamin E has been traditionally focused on alpha-tocopherol transport protein (α-TTP), which transports vitamin E from the liver to the blood and has specific affinity towards αTF more than other vitamin E isoforms. However, studies show that the distribution of tocotrienols can be achieved via mechanisms other than α-TTP.

Both tocopherols and tocotrienols accumulate in many tissues, including the liver, adrenal glands, and fat tissue. It is estimated that 90% of the total amount of vitamin E accumulates in the fat. Vitamin E that accumulates in fat tissue consists of about two- thirds of α-tocopherol and one-third of γ-tocopherol.

The metabolism of tocotrienols is similar to tocopherols. The elimination half-life of tocotrienols is  short, approximately 2-4 hours, suggesting a twice daily supplementation dosing schedule.


α-Tocopherol Status and Requirements

The assessment of the human requirement for α-tocopherol is hampered by the rare occurrence of clinical symptoms of deficiency. Symptoms usually only develop in premature babies, infants, and adults with fat malabsorption, liver disease, or genetic diseases.


Recommended Daily Allowance of Vitamin E

Currntly, daily allowance recommendations are 8–15 mg of α-tocopherol or an α-tocopherol equivalent for women and men. There are significant differences in α-tocopherol intake in different countries, varying from 8 to 10 mg/person/day in Finland, Iceland, Japan, and New Zealand, to 20 to 25 mg/person/day in France, Greece and Spain. However, in a study that focused on a comparison of vitamin E intake in different subpopulations, over 80% were below the RDA of 15 mg/day.

The optimum dose and blood levels of tocotrienols required for neuroprotection and other benefits are unknown at this moment.



Blood Levels

The concentration of α-tocopherol in blood (serum) is the main method used to assess α-tocopherol status. Levels of α-tocopherol in serum below 9 μmol/L in men and below 12 μmol/L in women are considered as deficiency. There is strong evidence that men with higher serum α-tocopherol levels (≥14.2 mg/L vs. <9.3 mg/L) have lower overall mortality and lower mortality from cardiovascular disease (CVD), heart disease, stroke, cancer, and respiratory disease. No reference values have been established for the other forms of vitamin E. Additionally, there is a lack of correlation between dietary vitamin E intakes and blood levels of a-tocopherol.

In cancer prevention studies, higher blood levels of α-tocopherol were associated with lower mortality. The lowest total mortality was observed at the concentration of α-tocopherol at the level of 30 μmol/L in the blood serum. Additionally, other results of observational studies showed that at the point of 30 μmol/L and above, the concentration of α-tocopherol in the serum has a positive effect on human health. However, only 21% of reported populations reach this threshold, possibly indicating a generally low vitamin E (α-tocopherol) nutritional status worldwide.

According to some, plasma α-tocopherol concentration is not a reliable marker for the assessment of vitamin E status, especially in subjects with an abnormal lipids profile. Therefore, adjusting α-tocopherol to plasma lipids and lipoproteins is recommended. However, it is not widely used, and it may be a cause of overinterpretation and ambiguity of the described results about α-tocopherol status.

Plasma α-tocopherol concentration may be modified by several factors such as age, gender, lifestyle, low circulating lipid levels, genetic variation and variation in the absorption, metabolism, and excretion of vitamin E, as well as by obesity, metabolic syndrome, or high levels of oxidative stress. Additionally, the assessment of vitamin E status is also difficult because it is a fat-soluble vitamin, which is stored in adipose tissue.

In patients with excess body weight who performed a weight reduction diet for six weeks, asignificant reduction in blood plasma α-tocopherol was found and almost 80% of them levels below 20 μmol/L. This may indicate an increased risk for cardiovascular diseases and low antioxidant protection. It is unclear whether the above-mentioned differences in distribution of the α-tocopherol and other isoforms are due to insufficient intake, changes in metabolism in obese individuals, or due to these two factors.


Obesity and Vitamin E Status

There is a significant relationship between the content of adipose tissue (fat) in the body and the demand and metabolism of tocopherols and tocotrienols, mainly α-tocopherol. An excessive level of adipose tissue creates chronic inflammation with increased production of cytokines, proteins, and immune response mediators, leading to  the  activation of inflammatory pathways.

Chronic, low-grade inflammation in obesity leads to increased oxidative stress and a disrupted balance of oxidants and antioxidants in the body. Bioactive dietary antioxidants such as tocopherols and tocotrienols can prevent damage caused by inflammation and reactive oxygen species, thereby reducing the negative effects of obesity. On the other hand, an excess of adipose tissue may generate in the body an increased demand for antioxidants, which may cause their greater utilization, leading to their decreased concentration in the blood.

More research is needed concerning the relationships between obesity and blood  α-tocopherol, other vitamin E isomers, or their metabolites concentration. Significantly higher blood levels of γ-tocopherol in people with obesity compared with normal body weight and a lack of differences between these two groups for α-tocopherol. It has also been shown that in people with metabolic syndrome and obesity, the level of excreted α-tocopherol metabolites as well as the plasma level of α-tocopherol were lower, and the level of oxidative stress increased.



Tocotrienols and Safety

Palm tocotrienol-rich fraction (TRF) has been labelled “GRAS” (Generally Regarded as Safe) status and determined safe for human consumption by the FDA in 2010.  Clinical trials with doses of approximately 50–400 mg/day for durations of 2 weeks to 18 months reported no adverse effects, even in the elderly.


Tocotrienols and Bioavailability

The amount of vitamin E absorbed depends on the food matrix that supplies it. Alcohol and dietary fiber inhibit the absorption of vitamin E. Studies have shown low bioavailability of vitamin E isoforms from the apples matrix and high bioavailability from bananas and bread matrix.

Tocotrienols’ bioavailability can be enhanced with emulsions that  increase absorption. Another solution for increasing tocotrienols’ bioavailability is to take tocotrienols with a meal.


Tocotrienols and the Future

Research has established that not all vitamin E isomers are the same and that tocotrienols have distinctive functions from tocopherols. There is a growing body of evidence supporting tocotrienols’ benefits for chronic conditions. Given that research indicates that tocopherol does not enhance the function of tocotrienol, but rather antagonizes it,  manufacturers should formulate with delta- and gamma- tocotrienols, without tocopherol or with the lowest amount of alpha-tocopherol possible. It remains early to establish specific recommendations for supplementing with tocotrienols and at what dose.


Comparison between the Effects of Tocotrienol and Tocopherol

The different isomers of Vitamin E possess protective effects on a variety of diseases in varying degrees. Tocotrienols and tocopherols offer many benefits, mainly by alleviating inflammatory response, oxidative stress, mitochondrial dysfunction, and abnormal cholesterol synthesis. The anti-hyperlipidemic, anti-osteoporotic, anti-hyperglycemic, anti-inflammatory, anti-oxidative, neuroprotective, gastroprotective, and cardioprotective effects of Tocotrienols seem to be more superior or as effective compared to tocopherols.


HMGCR inhibition

HMGCR inhibition is one of the biological actions of tocotrienols which is not observed with tocopherols.


Antioxidant Activity

Antioxidant activity is one of the main molecular actions of  the isomers of Vitamin E. Both tocotrienols and tocopherols scavenge free radicals but tocotrienols have better membrane antioxidant activity compared to tocopherols. δ-tocotrienol exerts greater inhibition on lipid peroxidation and ROS production than γ-tocotrienol and α-tocotrienol.


Reducing Cholesterol

The hypocholesterolemic actions between tocotrienols and tocopherols have been compared in several studies. There isvidence that γ-tocotrienol had higher efficacy than mixed tocotrienol (containing 9.9% γ-tocopherol) in lowering TC and LDL-C. It was also found that α-tocopherol is less effective in improving lipid metabolism as compared to TRF (containing a mixture of tocotrienols and tocopherols), γ-tocotrienol, and δ-tocotrienol. In humans, tocotrienols but not α-tocopherol, reduced TC and LDL-C in subjects with mild hypercholesterolemia.


Cardioprotective Effects

In cardiovascular diseases, γ-tocotrienol exhibits the best cardioprotective effect in myocardial ischemia-reperfusion injury model, followed by α-tocotrienol and δ-tocotrienol. In animal studiess, δ-tocotrienol was capable of improving more metabolic abnormalities than γ-tocotrienol, while α-tocotrienol and α-tocopherol were the least effective.


Bone Health

With regards to bone health, previous studies showed that two different forms of vitamin E (palm tocotrienols mixture with α-tocopherol) were comparable in preserving bone microarchitecture and bone density in postmenopausal osteoporosis rat model. Otherwise, some studies reported better outcomes on the skeleton when normal or osteoporotic animals were supplemented with tocotrienols compared to α-tocopherol. In fractured rat model, tocotrienols was also better than α-tocopherol in improving bone strength of the fractured callous in estrogen-deficient rats. Mechanistically, tocotrienols was shown to have more potent anti-inflammatory and anti-oxidative properties, which were responsible for its superior skeletal-promoting effects in animals.


Metabolic Regulation

In terms of metabolic regulation, tocotrienols are more effective than α-tocopherol at similar doses in normalizing body weight and glucose level in diabetic rats. These observations might be attributed to the higher efficacy of tocotrienols in reducing inflammatory response and lipid peroxidation.  α-, γ-, and δ-tocotrienol improve  insulin synthesis, wherein δ-tocotrienol is the most potent isoform, followed by γ- and α-tocotrienol. Additionally, the anti-adipogenic activities of each tocotrienols were reported by following the rank order of γ > δ > β > α-tocotrienol.



In anticancer studies, tocotrienols have significantly greater anticancer activities than their corresponding tocopherol isoforms.


Taken together, vitamin E isomers display beneficial properties in preventing various conditions in general even though the different effects between the isomers of tocotrienols and tocotrienol are present.


Safety of Tocotrienol and Tocopherol

Vitamin E is relatively safe, as has been reported in animal studies, vitamin E is not mutagenic, carcinogenic, or teratogenic. At extremely high doses, way above the usual supplemental dose, bleeding and clotting time in mice were increased, thus the concurrent use of vitamin E isomers with other anticoagulants should be used with caution. Vitamin E supplementation has been associated with hemorrhagic stroke in a meta-analysis. In another human study, oral consumption of high dose of vitamin E (3200 IU/day) is well-tolerated by adults. Since vitamin E, α-tocopherol, and mixed tocotrienols are widely available as over-the-counter supplements, it is hard to regulate their use. but it is important that appropriate doses of vitamin E be employed.




Vitamin E – Tocopherols & Tocotrienols

  1. Tocotrienol is a cardioprotective agent against ageing-associated cardiovascular disease and its associated morbidities. – 2016.pdf
  2. Vitamin E Oxidized LDL.pdf
  3. Tocotrienols – Vitamin E Beyond Tocopherols – 2006.pdf
  4. Tocotrienols, the Vitamin E of the 21st Century: It’s Potential Against Cancer and Other Chronic Diseases – 2010
  5. Metabolism of natural forms of vitamin E and biological actions of vitamin E metabolites – 2022
  6. Tocopherols and Tocotrienols—Bioactive Dietary Compounds; What Is Certain, What Is Doubt? – 2021
  7. Enjoy Carefully: The Multifaceted Role of Vitamin E in Neuro-Nutrition – 2021
  8. Tocopherols, tocotrienols and tocomonoenols: Many similar molecules but only one vitamin E – 2019.pdf
  9. An Interactive Review on the Role of Tocotrienols in the Neurodegenerative Disorders – 2021
  10. Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence – 2020
  11. The Implication of Reactive Oxygen Species and Antioxidants in Knee Osteoarthritis – 2021
  12. Tocotrienols the unsaturated sidekick shifting new paradigms in vitamin E therapeutics – PubMed – 2017
  13. Hidden Hunger of Vitamin E among Healthy College Students: A Cross- Sectional Study – 2021
  14. The Effects of Sesame Consumption on Glycemic Control in Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trial – 2021
  15. Effects of Sesame Consumption on Inflammatory Biomarkers in Humans: A Systematic Review and Meta-Analysis of Randomized Controlled Trials – 2021
  16. Sesame oil and vitamin E co-administration may improve cardiometabolic risk factors in patients with metabolic syndrome a randomized clinical trial – PubMed – 2019
  17. Effects of tocotrienols supplementation on markers of inflammation and oxidative stress: A systematic review and meta-analysis of randomized controlled trials – 2021
  18. Metabolic Syndrome, Cognitive Impairment and the Role of Diet: A Narrative Review – 2022
  19. Mechanistic Effects of Vitamin D Supplementation on Metabolic Syndrome Components in Patients with or without Vitamin D Deficiency – 2020
  20. Vitamin E As a Potential Interventional Treatment for Metabolic Syndrome: Evidence from Animal and Human Studies – 2021
  21. A Review on the Relationship between Tocotrienol and Alzheimer Disease – 2018.pdf
  22. The Role of Vitamin E in Preventing and Treating Osteoarthritis – A Review of the Current Evidence – 2018
  23. The Role of Tocotrienol in Preventing Male Osteoporosis-A Review of Current Evidence – 2019
  24. Association between serum Vitamin E concentrations and the presence of Metabolic Syndrome: A population-based cohort study – 2021
  25. The Role of Tocotrienol in Protecting Against Metabolic Diseases – 2019
  26. Therapeutic Efficacy of Antioxidants in Ameliorating Obesity Phenotype and Associated Comorbidities – 2020
  27. Pharmacology and Pharmacokinetics of Vitamin E: Nanoformulations to Enhance Bioavailability – 2020
  28. Vitamin E inadequacy in humans: causes and consequences – 2014

Systemic Inflammation – Overviews

  1. Systemic Inflammatory Response Syndrome – PubMed – 2022
  2. Chronic inflammation in the etiology of disease across the life span – 2019
  3. Pathophysiology and Therapeutic Perspectives of Oxidative Stress and Neurodegenerative Diseases – A Narrative Review – 2020.pdf
  4. A Pharmacological Rationale to Reduce the Incidence of Opioid Induced Tolerance and Hyperalgesia – A Review – 2018
  5. Pathophysiology of musculoskeletal pain – a narrative review – 2021 Cannabinoids in Chronic Pain: Therapeutic Potential Through Microglia Modulation – 2022
  6. Targeting inflammation as a treatment modality for neuropathic pain in spinal cord injury: a randomized clinical trial – 2016
  7. How Systemic Inflammation Affects Your Brain & Central Nervous System Cannabinoid Receptors and Their Relationship With Chronic Pain: A Narrative Review – 2020
  8. The Neuroimmunology of Chronic Pain: From Rodents to Humans – 2021
  9. Cannabis Has Low Risks, Small Benefits for All Types of Chronic Pain, Say New International Guidelines – 2022
  10. Microglia activation states and cannabinoid system Therapeutic implications – PubMed -2016
  11. Inflamm-aging does not simply reflect increases in pro-inflammatory markers – 2014
  12. Systemic Inflammation Predicts All-Cause Mortality: A Glasgow Inflammation Outcome Study – 2015


Systemic Inflammation – Diet

  1. The Effects of Sesame Consumption on Glycemic Control in Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trial – 2021
  2. Effects of Sesame Consumption on Inflammatory Biomarkers in Humans: A Systematic Review and Meta-Analysis of Randomized Controlled Trials – 2021
  3. Sesame oil and vitamin E co-administration may improve cardiometabolic risk factors in patients with metabolic syndrome a randomized clinical trial – PubMed – 2019
  4. Vitamin C: A Review on its Role in the Management of Metabolic Syndrome – 2020
  5. Obesity–An Update on the Basic Pathophysiology and Review of Recent Therapeutic Advances – 2021
  6. Diet-Derived Antioxidants and Their Role in Inflammation, Obesity and Gut Microbiota Modulation – 2021
  7. The Role of Vitamins in Non-Alcoholic Fatty Liver Disease: A Systematic Review – 2921
  8. Spices, Condiments, Extra Virgin Olive Oil and Aromas as Not Only Flavorings, but Precious Allies for Our Wellbeing – 2021
  9. Anti-inflammatory diet and inflammatory bowel disease: what clinicians and patients should know? – 2021


Oxidative Stress – Overviews  

  1. oxidative-stress-implications-in-the-affective-disorders-main-biomarkers-animal-models-relevance-genetic-perspectives-and-antioxidant-approaches-2016
  2. oxidative-stress-in-health-and-disease-the-therapeutic-potential-of-nrf2-activation-2011
  3. adaptive-cellular-stress-pathways-as-therapeutic-targets-of-dietary-phytochemicals-focus-on-the-nervous-system-2014
  4. oxidative-stress-a-cause-and-therapeutic-target-of-diabetic-complications-2010
  5. a-randomized-trial-of-glutamine-and-antioxidants-in-critically-ill-patients-2013
  6. Inflammation, Oxidative Stress, and Antioxidants Contribute to Selected Sleep Quality and Cardiometabolic Health Relationships – 2015
  7. Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS) – 2014
  8. Oxidative Stress – Harms and Benefits for Human Health – 2017


Oxidative Stress – Aging

  1. Update on the oxidative stress theory of aging – Does oxidative stress play a role in aging or healthy aging? – 2010


Oxidative Stress – Anxiety and Depression

  1. Markers of Oxidative Stress and Neuroprogression in Depression Disorder – 2015
  2. Neuroinflammation and Depression – Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation – 2015
  3. Novel Therapeutic Targets in Depression and Anxiety – Antioxidants as a Candidate Treatment
  4. Oxidative:nitrosative stress and antidepressants: targets for novel antidepressants. – PubMed – NCBI


Oxidative Stress – Cardiovascular

  1. Impaired Oxidative Status Is Strongly Associated with Cardiovascular Risk Factors – 2017
  2. Antioxidants and Cardiovascular Risk Factors – 2018


Oxidative Stress – Diabetic Neuropathy

  1. Oxidative Stress in the Pathogenesis of Diabetic Neuropathy – 2004
  2. Neuroinflammation and Oxidative Stress in Diabetic Neuropathy – Futuristic Strategies Based on These Targets – 2014


Oxidative Stress – Fibromyalgia

  1. Oxidative Stress Correlates with Headache Symptoms in Fibromyalgia – Coenzyme Q10 Effect on Clinical Improvement 2012
  2. Free radicals and antioxidants in primary fibromyalgia: an oxidative stress disorder? – PubMed – NCBI
  3. Current concepts in the pathophysiology of fibromyalgia: the potential role of oxidative stress and nitric oxide. – PubMed – NCBI
  4. Oxidative Stress in Fibromyalgia – Pathophysiology and Clinical Implications – 2011
  5. Oxidative Stress in Fibromyalgia and its Relationship to Symptoms – 2009
  6. Clinical Symptoms in Fibromyalgia Are Better Associated to Lipid Peroxidation Levels in Blood Mononuclear Cells Rather than in Plasma
  7. Evidence of central inflammation in fibromyalgia — Increased cerebrospinal fluid interleukin-8 levels 2012
  8. Oxidative Stress in Fibromyalgia – Pathophysiology and Clinical Implications – 2011
  9. Vitamins C and E treatment combined with exercise modulates oxidative stress markers in blood of patients with fibromyalgia: a controlled clinical … – PubMed – NCBI
  10. Total antioxidant capacity and the severity of the pain in patients with fibromyalgia. – PubMed – NCBI
  11. Stress, the stress response system, and fibromyalgia
  12. Serum prolidase enzyme activity and oxidative status in patients with fibromyalgia. – PubMed – NCBI
  13. Serum ischemia-modified albumin and malondialdehyde levels and superoxide dismutase activity in patients with fibromyalgia. – 2014 – PubMed – NCBI
  14. Pathophysiology and antioxidant status of patients with fibromyalgia. 2011 – PubMed – NCBI
  15. Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients. 2015 – PubMed – NCBI
  16. Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues. – PubMed – NCBI
  17. Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns. 2006 – PubMed – NCBI


Oxidative Stress – Fibromyalgia & Mitochondria

  1. Serum antioxidants and nitric oxide levels in fibromyalgia: a controlled study. 2009 – PubMed – NCBI
  2. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients – implications in the pathogenesis of the disease
  3. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? – PubMed – NCBI
  4. Is Inflammation a Mitochondrial Dysfunction-Dependent Event in Fibromyalgia? – 2012
  5. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia – 2013 – PubMed – NCBI
  6. Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS) – 2014
  7. Oxidative stress and mitochondrial dysfunction in fibromyalgia. – PubMed – NCBIOxidative-Stress-in-Fibromyalgia-and-its-Relationship-to-Symptoms-2009
  8. The-role-of-mitochondrial-dysfunctions-due-to-oxidative-and-nitrosative-stress-in-the-chronic-pain-or-chronic-fatigue-syndromes-and-fibromyalgia-patients-20131


Oxidative Stress – Mitochondria

  1. Mitohormesis: Promoting Health and Lifespan by Increased Levels of Reactive Oxygen Species (ROS) – 2014
  2. The Mitochondrial Basis of Aging and Age-Related Disorders – 2017
  3. Mitochondrion-Permeable Antioxidants to Treat ROS-Burst-Mediated Acute Diseases – 2016 no highlights
  4. Current Experience in Testing Mitochondrial Nutrients in Disorders Featuring Oxidative Stress and Mitochondrial Dysfunction
  5. Mitochondrial biogenesis: pharmacological approaches. – PubMed – NCBI
  6. The mitochondrial cocktail: rationale for combined nutraceutical therapy in mitochondrial cytopathies. – PubMed – NCBI
  7. Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies – Toward Mitochondria-Targeted Clinical Strategies
  8. Daily Nutritional Dose Supplementation with Antioxidant Nutrients and Phytochemicals Improves DNA and LDL Stability


Oxidative Stress – Neurodegenerative Diseases

  1. Oxidative Stress and Neurodegenerative Diseases – A Review of Upstream and Downstream Antioxidant Therapeutic Options – 2009
  2. Neuroprotective Effect of Antioxidants in the Brain – 2020


Oxidative Stress – Pain

  1. Roles of Reactive Oxygen and Nitrogen Species in Pain – 2011
  2. Clinical Relevance of Biomarkers of Oxidative Stress – 2015
  3. The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease – Potential Role of Autonomic Regulation and Epigenetic Mechanisms – 2020
  4. Neuropathic Pain – Delving into the Oxidative Origin and the Possible Implication of Transient Receptor Potential Channels – 2018
  5. Neuroprotective Effect of Antioxidants in the Brain – 2020
  6. Dietary Patterns and Interventions to Alleviate Chronic Pain – 2020


Oxidative Stress – Peripheral Neuropathy

  1. Oxidative stress – A cause and therapeutic target of diabetic complications – 2010

Emphasis on Education


Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.


For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.


Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.


For more information, please contact Accurate Clinic.


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