Ubiquinone vs. Ubiquinol: CoQ10 - Understanding the Difference?

Ubiquinone is also known as Coenzyme Q10 and is commonly abbreviated as CoQ10. Ubiquinone or CoQ10 is currently a very popular nutritional supplement with many purported benefits. So, what exactly is it and what does it do? CoQ10 is a vitamin-like compound that is found in every cell of the human body, hence its name ("ubique" is Latin for "everywhere," and "quinone" is a class of organic compounds). At the risk of some confusion, CoQ10 exists in two different forms or states of oxidation — each of which has a distinct function in the human body - Ubiquinone and Ubiquinol.

• Ubiquinone is the 'oxidised' form of CoQ10 and is located within cellular mitochondria (mitochondria are the energy factories of cells) where it participates in aerobic cellular respiration and generates adenosine triphosphate (ATP) — the key energy source for all of the body's metabolic needs.
• Ubiquinol is the 'reduced' form of CoQ10 and is found outside the cells, in the blood, and on cell membranes where it functions as an antioxidant. As an antioxidant, CoQ10 scavenges free radicals, thus protecting proteins and mitochondrial DNA from oxidative damage. Together, ubiquinone and ubiquinol form a "redox pair" which means that each form can easily be converted to the other by the body.

Where Does CoQ10 Come From

CoQ10 is naturally synthesised by the body but its production decreases with age and illness. A small amount is normally acquired through dietary intake. Meat, fish, nuts, and some oils are the richest nutritional sources of CoQ10, while much lower levels can be found in most dairy products, vegetables, fruits, and cereals. 

CoQ10 was first discovered in 1957 by Dr. Frederick Crane, who isolated the nutrient from the heart of a bull.

The following year, researchers at Merck, Inc. determined its chemical structure and became  the first to produce it. 
Its unique role in the body, however, was not recognised until 1978, when American scientist, Peter Mitchell, developed a theory identifying CoQ10 as an essential element in the synthesis of adenosine triphosphate (ATP) – the body’s main source of cellular energy. Mitchell won a Nobel Prize for his efforts.

Since then, CoQ10 has been the subject of substantial interest in the scientific community, and today, several companies manufacture and distribute coenzyme Q10 as a dietary supplement.

In Australia, dietary supplements are regulated as complimentary medicines. Therefore, premarket evaluation and approval by the Food and Drug Administration (FDA) is not required unless specific disease prevention or treatment claims are made. The FDA can, however, remove dietary supplements from the market that it deems unsafe. The quality of dietary supplements depends on the manufacturer and is not regulated by the FDA.

The government does not require that supplements be standardised, meaning that the amounts or quality of nutrients may vary depending on the batch, manufacturing process or source. However, testing does occur for dietary supplements to ensure they are not mislabelled and that they do not contain contaminants.

Is CoQ10 a supplement?

The line between supplements and therapeutic drugs is not an easy one to define. Vitamins can be treated like drugs (e.g. niacin) and some drugs are re-branded as supplements if they cannot pass the evidence standards to be approved drug products. Natural substances can be marketed as both supplements and drugs (e.g. magnesium) or as drugs alone (e.g. adrenaline). There is not always a clear line, and the variations between countries can be striking. It generally seems to be based more on evaluations of safety than that of efficacy. This may in part explain the varying use of CoQ10 around the world.

It is probably most widely used in Japan, which coincidentally is also the world’s biggest supplier. There, it is apparently used as a routine treatment for congestive heart failure, where it was approved for this purpose almost 40 years ago. It is also used in Europe and in Russia, though the U.S. and Japanese markets make up 85% of the world’s consumption. Supplement or drug, what matters is whether it works and is it safe when it is evaluated using objective standards.

What Is the Hype and What Is the Science Behind CoQ10?

CoQ10 is a touted in the American media as a miracle supplement and a panacea for a vast array of ailments and conditions. Some of the health benefits attributed to CoQ10 include:

• Helping treat high blood pressure and heart disease
• Enhancing immune system function
• Providing an energy boost for people dealing with fatigue
• Reducing high cholesterol levels in the blood, particularly as a adjunct to common cholesterol lowering medications (statins)
• Stabilising blood sugar levels of people with diabetes
• Assisting in the treatment of cancer or the protection of organs from toxic chemotherapy drugs
• Treating gum disease
• Slowing down dementia progression
• Increasing sperm count and motility
• Preventing or treating migraine headaches

Considerable discussion (and confusion) revolves around which form of CoQ10, ubiquinone or ubiquinol, is superior in terms of these benefits and conflicting claims are made for each. It is not uncommon to read that one form is more "active" than the other or, conversely, that the two compounds are interchangeable as supplements because of the body's ability to convert one to the other and vice versa. I will discuss this further below. Lets first look at the research currently available.

What Is the Science-Based Evidence Behind CoQ10?

Congestive heart failure

CoQ10 is known to be highly concentrated in heart muscle cells due to the high energy demands of this cell type. For the past two decades, the great bulk of clinical work with CoQ10 has focused on heart disease, more specifically, congestive heart failure (CHF). Heart failure often develops after other conditions (e.g. coronary artery disease, high blood pressure or diabetes) have damaged or weakened the heart. It describes the state that develops when the heart cannot pump enough blood to meet the metabolic needs of the body.

The term "congestive heart failure" comes from blood backing up into — or congesting — the liver, abdomen, lower extremities and lungs. It has been strongly correlated with significantly low blood and tissue levels of CoQ10. People with CHF commonly experience a relapsing and remitting disease course, with periods of stability and episodes of decompensation (failure to cope with heart damage) leading to worsening symptoms that necessitate hospitalisation. Treatment options for CHF range from less invasive drugs to the extreme of heart transplantation, with each having its own limitations.

CoQ10 was first suggested as treatment for CHF in 1967. Since then, several studies have shown that taking CoQ10 seems to improve symptoms of CHF better than conventional medication. Several studies and meta-analyses have indicated that, for patients with mild to severe CHF (New York Heart Association Class II-IV), the addition of oral CoQ10 to conventional treatments seems to improve the signs and symptoms of CHF such as shortness of breath, leg swelling, and enlarged liver leading to improved quality of life and a decrease in hospitalisation rates. 

Three meta-analyses investigated 38 different clinical trials on the use of CoQ10 in CHF. In a 1997, a meta-analysis of 14 studies, 76% of the patients supplemented with CoQ10 had a greater improvement in their cardiac parameters and 73% had a greater improvement in cardiac output than did the placebo group. In the scientific world, these results are extremely compelling and impressive. In a 2006 meta-analysis of 11 studies, at CoQ10 doses ranging from 60 to 200 mg/day and treatment periods ranging from one to six months, a 3.7% net improvement in the ejection fraction was found, and cardiac output was increased an average of 0.28 L/min. In the most recent 2013 analysis, the results of 13 randomized controlled trials, encompassing 395 participants, revealed that CoQ10 supplementation led to a statistically significant average net increase of 3.67% in the ejection fraction associated with the heart function.

The largest open trial in CHF which involved 2664 patients treated with up to 150 mg of CoQ10 per day showed significant benefit and lack of toxicity.

Results in the other study showed a significant reduction in the intensity of CHF symptoms as early as 2 weeks which was maintained at 4 weeks after onset of therapy. Interestingly, authors observed a similar occurrence of clinical improvement in 192 patients who received CoQ10 as their only therapy.  

CoQ10 supplementation significantly improves survival for even the most severe CHF patients while dramatically reducing the incidence of hospitalisation. 

Hypertension

Depending on the class, various antihypertensive drugs can have adverse effects such as depression, cough, and cardiac and renaldysfunction.

Furthermore,  many patients need to take more than one drug to control their blood pressure, increasing their risk of side effects. Some researchers believe coenzyme Q10 supplementation may reduce the need to take multiple antihypertensive drugs.

As significant deficiency of CoQ10 has been identified in patients with hypertension.  

Researchers found that CoQ10 has the potential in hypertensive patients to lower systolic blood pressure by up to 17 mmHg and diastolic blood pressure by up to 10 mmHg without significant side effects.

Doses used in the trials reported here varied from 34 mg/day in the early trials to 225 mg/day in the later ones. The exact mechanism is not known, but one theory is that it reduces peripheral resistance by preserving nitric oxide. Nitric oxide relaxes peripheral arteries, lowering blood pressure. In some forms of hypertension, superoxide radicals that inactivate nitric oxide are overproduced. CoQ10, with its antioxidant effect, may prevent the inactivation of nitric oxide by these free radicals.Alternatively, coenzyme Q10 may boost the production of the prostaglandin, prostacyclin (PGI2), a potent vasodilator, or it may enhance the sensitivity of arterial smooth muscle to PGI2, or both.

Statin-induced myopathy

Statins (HMG-CoA reductase inhibitors) are currently the most effective medications for reducing low-density lipoprotein cholesterol (the "bad" cholesterol") concentrations and produce remarkable reductions in adverse cardiovascular events (heart attack and ischaemic stroke). Statins can produce potentially life-threatening rhabdomyolysis (breakdown of skeletal muscle fibers with leakage of muscle contents into the circulation), but this severity is extremely rare. Statins are more frequently associated with mild muscle complaints, including myalgia, cramps, and weakness, which may compromise medication compliance and quality of life. 

Cholesterol-lowering drugs inhibit the enzyme, HMG-CoA reductase, which is required for synthesis of cholesterol as well as CoQ10, resulting in a decreased serum CoQ10. Statins inhibit the synthesis of cholesterol by reducing the production of mevalonate, a precursor of both cholesterol and CoQ10. Since both cholesterol and coenzyme Q10 are produced by the same pathway, it is not surprising that statins have been reported to reduce circulating blood and muscle CoQ10 levels. 

How statins produce muscular side effects is not clear. However, one theory suggests that statin myopathy results from mitochondrial dysfunction in muscle caused by CoQ10 deficiency. Insufficient CoQ10 might limit mitochondrial energy production, disrupt normal cellular respiration, and result in the development of myopathy. 

It is hypothesised that statin-induced myopathy resulted from the inability of mitochondria to meet the ATP requirements for skeletal muscle contraction due to CoQ10 depletion. In one study, the results showed that there were no significant differences between the coenzyme Q10 group and the placebo group in the number of patients who tolerated the simvastatin 40mg/d or in the number of patients who remained on simvastatin at any dose. The authors concluded that no significant beneficial effect of CoQ10 supplementation on myalgia symptoms could be demonstrated. The authors did, however, acknowledge that there were only small increases in the myalgia pain scores in each group suggesting that patients in the treatment group may not have experienced sufficiently severe muscle pain to benefit from CoQ10. The role of CoQ10 in statin-related myopathy remains controversial.

Neurodegenerative diseases

Neurodegenerative diseases such as Parkinson's Disease, amylotrophic lateral sclerosis, and Huntington’s Disease are, by definition, associated with a loss of function of neural cells. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases.

Parkinson's Disease

Parkinson's Disease is a progressive disorder of the nervous system characterised by tremour, muscular rigidity, and slow, imprecise movement. These symptoms are considered to be a direct consequence of neurodegeneration and loss of dopaminergic neurons in the substantia nigra.

A randomized, double-blind, placebo-controlled, multicenter study of 80 patients found that 1,200 mg per day of coenzyme Q10 was associated with up to 44 percent less functional decline in patients with Parkinson’s disease, including activities of daily living. 

A study of 28 patients with Parkinson’s disease also demonstrated mild symptom improvement with daily oral dosing of 360 mg of coenzyme Q10. A 2014 phase III randomised, placebo-controlled, double-blind clinical trial at 67 North American sites was conducted.

A total of 600 participants were chosen on the basis of a diagnosis of Parkinson's Disease confirmed within the last 5 years. Subjects were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10 for 16 weeks. At both these higher doses, CoQ10 was generally well tolerated and triggered minimal adverse events, However, disease symptoms progressed just as quickly in both CoQ10 groups as in the placebo group which led to early termination of the study. The investigators concluded that CoQ10 showed no evidence of benefit in early Parkinson's Disease patients.

Huntington's Disease

In 2005, the FDA granted orphan drug status for CoQ10 in the treatment of Huntington's Disease and paediatric congestive heart failure. An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease. In the U.S. and Europe, it is easier to gain marketing approval for an orphan drug, and there may be other financial incentives, such as extended exclusivity periods, all intended to encourage the development of drugs which might otherwise lack a sufficient profit motive.

Mitochondrial cytopathies

In 2000, the FDA granted orphan drug status to CoQ10 for mytochondrial cytopathies. Mitochondrial cytopathies are a diverse group of inherited and acquired disorders that result in inadequate energy production. They can be caused by inheritable genetic mutations, acquired somatic mutations, exposure to toxins (including some prescription medications), and the aging process itself.

Other conditions:

Benefits from CoQ10 have been reported in a number of other conditions.

• Fibromyalgia. Fibromyalgia patients with CoQ10 deficiency showed a significant reduction on symptoms after CoQ10 treatment.
• Male infertility. In a recent study, it has been demonstrated that CoQ10 improves semen quality and pregnancy rate.
• Periodontal disease. CoQ10 serves as an endogenous antioxidant which increases the concentration of CoQ10 in the diseased gingiva and effectively suppresses advanced periodontal inflammation.
• Migraine. Evidence indicates that impaired energy metabolism may be present in brains of migraine sufferers. While general consensus must remain guarded, there is one stand-out study that is worth mentioning because it is of the double-blind, randomised, placebo-controlled variety. This study showed that 100 mg, 3x/day reduced the 50%-responder-rate of migraine attack by 47.6% as compared to placebo.
• Anti-aging. Maintenance of CoQ10 functional levels at cell membranes either by dietary supplementation or by improving endogenous synthesis can be a key strategy to enhance health during aging.
• Cancer. Although CoQ10 is also used for the prevention and treatment of cancer, there is as yet no convincing evidence of its efficacy treatment of this condition spectrum.

What Formulation of CoQ10 Is Best?

It is well-established that CoQ10 (ubiquinone) is not well absorbed into the body, as has been published in many peer-reviewed scientific journals. Ubiquinol is the reduced form of CoQ10, which is known to have higher bioavailability than CoQ10 (ubiquinone). 

The importance of monitoring plasma CoQ10 concentrations in clinical trials involving pharmacologic doses of CoQ10 cannot be overemphasized. Higher than ‘‘normal’’ plasma CoQ10 concentrations appear to be necessary to promote uptake by peripheral tissues and also to cross the blood brain barrier. 

The plasma threshold for the uptake of CoQ10 appears to be different for different tissues. For instance, in one study with congestive heart failure patients, it was reported that those with a plasma CoQ10 value of 2.4l g/mL showed the highest benefit. 

In an earlier study with CHF patients, it was reported that a blood CoQ10 concentration of at least 3.5l g/mL appeared to be necessary before any therapeutic benefit from CoQ10 supplementation could be expected. 

The plasma threshold appears to be much higher for neurodegenerative diseases such as Huntington’s and Parkinson’s, based upon the CoQ10 dosages required to achieve clinical response and also on blood CoQ10 data where available. 

In this context, it may be noted that there are a few studies often cited in the literature where the beneficial effects of CoQ10 supplementation in heart disease could not be demonstrated. Plasma CoQ10 data following CoQ10 supplementation are available only for the first two studies (2.548 lmol/L 10 and 2.029 lmol/L),  and both are below the indicated threshold for heart disease patients. It therefore appears that this could have been at least one factor contributing to the lack of  beneficial effect of CoQ10 in these studies, which could be attributed to both the dosage and also the bioavailability of the products used. 

Plasma CoQ10 is present almost entirely (about 95%) in its reduced form as ubiquinol in healthy subjects. Furthermore, orally ingested CoQ10, whether as ubiquinone or ubiquinol and regardless of the dose, appears in the circulation as ubiquinol with no change or very little change in its redox status. This shows that there is an efficient mechanism to convert orally administered CoQ10 as ubiquinone to ubiquinol in vivo. There is evidence to show that this reduction takes place in the intestine following absorption before CoQ10 enters the lymphatic system. Plasma CoQ10 concentrations and also the net increase over baseline plasma CoQ10 values show a gradual increase with increasing dose of CoQ10 from low/moderate to high doses. Not surprisingly, the efficiency of absorption decreases as the dose increases, and this is particularly striking at high doses. Split dosing is superior to single dosing with pharmacologic doses of CoQ10. Highest plasma CoQ10 concentration reported thus far is 10.7 lmol/L using a solubilised ubiquinol formulation. Whether this value is close to a ceiling for plasma CoQ10 is not known at this time.

Furthermore, whether such high plasma concentrations maximise the therapeutic potential of CoQ10 needs to be explored. Plasma CoQ10 concentrations need to be high (i.e. higher than ‘‘normal’’ values) in order to promote uptake by peripheral tissues and possibly also to cross the blood brain barrier. The plasma threshold for uptake appears to be different for different tissues. Among non-solubilised formulations of CoQ10, ubiquinol has been found to be superior to ubiquinone in its plasma CoQ10 response.

The response following ingestion of solubilised formulations of CoQ10 is much greater indicating their superior bioavailability as compared with non-solubilized powder-based CoQ10 products (compressed tablets, chewable tablets, powder-filled capsules, and softgels containing a suspension in oil). Solubilised formulations of ubiquinol appear to be even better than solubilised ubiquinone.

Thus, comparably high or even higher plasma CoQ10 concentrations may be achieved using much lower doses of the solubilised CoQ10 formulations, and this is of particular importance in neurodegenerative diseases where higher plasma concentrations appear to be necessary for therapeutic benefit.

Is CoQ10 Safe?

Coenzyme Q10 is very safe—no serious adverse effects have ever been reported, even with long-term use. Studies have indicated that these supplements are well tolerated, with relatively few adverse effects or potential drug interactions. However, gastrointestinal effects such as abdominal discomfort, nausea, vomiting, diarrhoea, and anorexia have occurred. Allergic rash and headache have also been reported. In addition, coenzyme Q10’s antiplatelet effect may increase the risk of bleeding for high risk patients.

Because safety during pregnancy and lactation has not been proven, CoQ10 should not be used during these times, like all medications regarding pregnancy, unless the potential clinical benefit outweighs the risks.

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