Abstract

The objective of this study was to evaluate the scientific evidence on stevia, including expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing. This review serves as a clinical support tool. Electronic searches were conducted in 10 databases, 20 additional journals (not indexed in common databases), and bibliographies from 50 selected secondary references. No restrictions were placed on the language or quality of the publications. All literature collected pertained to efficacy in humans, dosing, precautions, adverse effects, use in pregnancy and lactation, interactions, alteration of laboratory assays, and mechanisms of action. Standardized inclusion and exclusion criteria were used for selection. Grades were assigned using an evidence-based grading rationale. Based on the availability of scientific data, two indications are discussed in this review: hypertension and hyperglycemia. Evaluation of two long-term studies (1 and 2 years in length, respectively) indicates that stevia may be effective in lowering blood pressure in hypertensive patients, although data from shorter studies (1-3 months) did not support these findings. A pair of small studies also report positive results with respect to glucose tolerance and response, although the relatively low methodological rigor of these experiments limits the strength of these findings. Further investigation is warranted in both indications.

What is stevia?
Stevia is a tropical plant native to South America. Its extract has up to 300 times the sweetness of sugar. Although some people complain of its staying power in the mouth or its sometimes licorice-like aftertaste, it is a popular natural alternative sweetener. As a sweetener, it is low glycemic and has added benefits in potentially helping to control obesity, enhance glucose tolerance, and reduce blood pressure. You would think that with this kind of pedigree, it would qualify as the perfect sugar substitute and be approved for use as an alternative sweetener everywhere. You would be half right. It is widely used throughout Asia (particularly Japan) and South America — not so in the US, most of Europe, and Canada, where it is banned as a food additive. In the United States, and Canada it’s allowed as a supplement, but not in food. In Europe, it’s only allowed as an additive to animal feed.

This whole separation thing between food additives and supplements as seen in the US and Canada is actually very nebulous — and deliberately so. Although the rulings as written by the various government agencies might appear clear, government authorities choose to interpret them as the mood suits. A good example is the recent censure of Celestial Seasonings teas. Celestial Seasonings followed the letter of the law by labeling their Zingers tea an herbal supplement and including a supplements facts panel on the label, but as it turns out, that didn’t matter. To quote from the FDA notice, “Notwithstanding your use of the term ‘Herbal Supplement’ to identify the product and your use of a supplement facts label for nutrition labeling, your Zingers Tangerine Orange Tea is subject to regulation as a conventional food and not a dietary supplement… Therefore, your stevia-containing Zingers Tangerine Orange Tea is adulterated within the meaning of section 402(a)(2)(C) of the Act.”

To better understand the situation, let’s take a more detailed look at stevia.

What are the studies that support it?
In fact, stevia has been studied extensively. In addition to the studies cited above showing its benefits in regard to obesity, glucose tolerance, and high blood pressure, there are numbers of other studies proving its safety. For example, a 1991 study in Thailand found that even at doses 1,000 times normal human dosage, hamsters demonstrated no difference in growth rate or sexual performance — even through three generations.

In 2004, researchers at the KU Leuven (Belgium) organized an international symposium on ” The Safety of Stevioside.” Scientists from all over the world who attended concluded that stevioside is safe:

* Stevioside is not carcinogenic. On the contrary, studies in Japan have proven that stevioside reduces breast cancer in rats as well as skin cancers in animals models.

* Stevioside is not absorbed by the human gut. Only bacteria of the colon degrade stevioside to steviol. Part of this steviol is absorbed through the intestine but is quickly metabolized to steviol glucuronide and excreted in the urine. No free steviol is detected in the blood.

* Although steviol showed a weak mutagenic activity in one very sensitive strain of bacteria, even high concentrations of oral steviol were harmless (up to 2 g/kg body weight)!

What are the problematic studies?

So is everything rosy for stevia? Not necessarily. There have been some problematic studies. For example:

* A 1984 study found that although stevioside was not cancer causing, steviol, a metabolite of stevioside, is indeed mutagenic in the presence of a specific metabolic activation system — although subsequent studies have either not found it so, or found the effect to be so low as to be insignificant (1, 2). And again, as discussed earlier, any steviol that passes through the intestinal tract is metabolized to steviol glucuronide and excreted in the urine. In fact, some studies have shown that stevia may actually be cancer preventive.

* There were also studies that indicated stevia might negatively affect fertility in rats, but those studies were later refuted by more reliable studies involving higher numbers of rats and more controlled protocols. And this merely reinforces the results of numerous other studies.

The bottom line is that there is no compelling evidence that stevia in any reasonable dosage causes cancer. In fact, it is worth noting that the incidence of cancer in Japan is very low, although stevioside has been used there for over 25 years. And as for the fertility issue, there is no meaningful laboratory evidence that stevia has any effect on male or female fertility, nor on the development or state of the fetus. And again, despite a quarter of a century of use in Japan, there is no actual evidence of any negative effect on fertility or any other aspect of health for that matter.

It should also be noted that all of the problematic studies have used purified stevia at levels far, far, far higher than would ever happen in a normal human diet. Is this important (after all, testing for mutagenic effects at high doses is standard procedure)? The problem is that just because it’s standard doesn’t make it meaningful. Keep in mind that even things that are healthy can become deadly if taken in large amounts. For example, if you have 100 times the normal dosage of protein each day, you will destroy your liver in short order. If you have a 100 times the normal dosage of water, you will die in a single day — in a rather messy explosion.

The bottom line here is that all of the problematic studies have been conducted on rats and hamsters with absurdly high doses. In the real world, stevia has been in use with hundreds of millions of people throughout Asia and South America for as much as a quarter of a century. We’re talking billions of doses and no sign of increased cancer or lowered fertility. If only the alternative sweeteners that the regulators allow could match that kind of track record.

What are the absurdities of the regulators’ positions on sweeteners?
But all that aside, it would at least be understandable if the regulators played with a fair deck and applied equal standards to all alternative sweeteners. But they do not.

Aspartame
* According to the FDA’s own audit on aspartame, the Bressler Report, aspartame triggers brain tumors, mammary tumors, pancreatic tumors, ovarian tumors, pituitary adenomas, uterine tumors, etc. A senior FDA toxicologist, the late Dr. Adrian Gross, who tried to prevent the approval of aspartame, told Congress that it violated the Delaney Amendment because it triggered brain tumors (Congressional Record SID835:131 – 8/1/85).

* Aspartame has also been shown to trigger birth defects and miscarriages — not just if the mother uses it, but the father also.

* Before aspartame was approved in beverages in 1983, the National Soft Drink Association created a THIRTY PAGE PROTEST (that was later read into the Congressional Record) declaring that aspartame was NOT stable, and that it could actually make unwary users FATTER!

The bottom line on aspartame is that its safety record and evaluation record do not even come close to matching the safety of stevia. In fact, FDA’s own evaluation committees rejected aspartame. But in 1983, the Commissioner of the FDA, Dr. Arthur Hull Hayes, overrode his own committees and approved NutraSweet (aspartame) for soft drinks two months before leaving office. A couple of months later, after he had retired from the FDA, he accepted a position as Senior Medical Advisor to Burson Marsteller, the public relations firm that promoted NutraSweet for G.D. Searle, NutraSweet’s manufacturer — at the rate of $1,000 per day. An unfortunate coincidence, one might say.

Sucralose
If you think that sucralose, the new darling of the regulatory agencies, has better science behind it than aspartame, you would be sadly mistaken. As Dr. Mercola points out, as of 2006:
“Only six human trials have been published on sucralose. Of these six trials, only two of the trials were completed and published before the FDA approved sucralose for human consumption. The two published trials had a grand total of 36 total human subjects.The longest trial at this time had lasted only four days and looked at sucralose in relation to tooth decay, not human tolerance.”

In addition, pre-approval research shows that sucralose causes up to 40% shrinkage of the thymus gland and enlarges the liver and kidneys.

High fructose corn syrup
And, of course, high fructose corn syrup, the number one sweetener used in the world today is a health disaster.

What lies in the future?
One has to wonder why aspartame, sucralose, and high fructose corn syrup — all with proven major negative health effects — are approved by regulatory agencies in the US, Canada, and Europe and are currently in widespread use; whereas stevia is not. Not to be cynical, but perhaps the companies behind aspartame, sucralose, and high fructose corn syrup (G.D. Searle, Royal DSM, Tate and Lyle, and ADM) have a political clout that small independent stevia producers cannot muster for a non-patentable natural sweetener.

If that’s true, we can be fairly sure that we will never see stevia approved for commercial use in Europe, Canada, and the US until one of those large corporate entities finds a way to patent it. But wait! Forgive my cynicism! Cargill and Coca Cola are doing just that even as we speak! I think we can look forward to an approval of stevia — in a patented form — in the not too distant future. Will this version be safer? No, of course not. It will merely have a different name, Rebiana. Oh yes, and Coke and Cargill will back it. In the world of nutrition regulation, it appears that money talks… and real nutrition walks. It’s enough to give you high blood sugar, tiny thymuses, brain tumors, and shrunken sex glands!

Conclusion

I originally titled this article the Stevia Shibboleth. A shibboleth, as described in the Bible, was a secret word used by the ancient Gileadites to identify outsiders who were unable to pronounce the word correctly. In a sense, we can see that stevia is being used as a shibboleth by regulatory agencies to separate the insiders (the large commercial entities with major political influence) from the outsiders (the purveyors of all-natural healthy products). And just as the Gileadites put outsiders who failed the test to death, so it would seem our regulators would do the same to manufacturers such as Celestial Seasonings who fail the modern Shibboleth test and pronounce their sweetener: stevia.

This article was originally written as a newsletter which is read by tens of thousands of people in over 120 countries. Of those thousands of subscribers, six have email addresses that carry the @fda.gov ID. This particular issue was written for them — and for the other handful of subscribers who represent the European regulatory agencies.

Guys, as long as you approve aspartame, sucralose, and high fructose corn syrup as healthy and refuse to allow stevia to be used, calling it unsafe, despite all reasonable evidence to the contrary, you will have no credibility among thinking people. It is tantamount to an open admission that approval has nothing to do with safety — only what’s bought and paid for.

Since we’re running a Biblical motif with our shibboleth reference, let’s conclude with another for our regulator friends. To paraphrase Moses, “Let my stevia go!”

The drugs come with ‘an unacceptable risk’ of causing type 2 diabetes, and they are only half as effective as newer hypertension drugs such as the ACE inhibitors, according to practice guidelines issued by the National Institute for Health and Clinical Excellence (NICE) last month.

The announcement, described as the ‘most significant’ in NICE’s history, was forced on the advisory group by reports last autumn that beta-blockers had killed tens of thousands of hypertension patients when a more benign and effective therapy was available.

The dangers of beta-blockers were already being highlighted 16 years ago.

One study discovered that hypertension patients who suddenly stopped taking a beta-blocker were very likely to suffer a heart attack and death (JAMA, 1990; 263), while another study, published eight years ago, discovered they were no more effective than a sugar pill (JAMA, 1998; 279: 1903–7).

But it has been the continued revelations from ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) that finally forced NICE’s hand. ASCOT, which recruited 19,257 hypertension patients aged between 40 and 79 years, has been pointing out for years both the dangers and shortcomings of the beta-blockers, but NICE decided to form a review committee only after a damning study was published in September 2005 (Lancet, 2005; 366: 895–906).

This trial established that the beta-blockers were reducing the risk of stroke by 19 per cent compared with the 38 per cent effectiveness of the ACE inhibitors. Beta-blockers were also responsible for the deaths of 3 per cent more patients than other anti-hypertensives.

Beta-blockers (beta-adrenergic antagonists) are designed to decrease the heart’s need for blood and oxygen by reducing its workload. They also help the heart to beat more regularly.

Nobel prize winner Sir James Black developed the drug in the 1950s as a way of combating heart diseases such as angina after he realized that adrenaline, our ‘fight or flight’ hormone, puts a sudden demand on the heart.

Adrenaline triggers the release of glucose reserves into the blood. They bind to receptors on the membrane of the heart cells that cause the heart to beat faster. The hormone also constricts arteries to increase the rate at which blood is pumped around the body.

It took another ten years before the first beta-blocker—propranolol—was licensed for use. Ironically, Black and his team at Glasgow never developed it as an antihypertensive, but it was quickly used as this and for many other conditions that can be worsened by a sudden restriction of the arteries.

Within just a few years of it appearing on the market, propranolol was being used to treat migraine, glaucoma, tremor, hyperthyroidism, and performance anxiety and enhancement.

Propranolol quickly established itself as the beta-blocker for all ills. Not surprisingly, the American Association of Poison Control Centers (AAPCC) each year receives reports of 2.4 million adverse reactions to the drug in the USA alone, and 1,184 fatalities associated with the drug.

Tragically, it is also the ‘drug of choice’ for people attempting suicide, while its widespread use means that almost every home has some, and 510 children under the age of six die every year after swallowing drugs prescribed for their parents.

What now for the beta-blocker? The drug industry has a wonderful way of reinventing drugs that have been finally discredited, and the beta-blockers are no exception.

One researcher at Baylor College of Medicine in Houston, Texas, believes they could be the answer to osteoporosis. Prof Gerard Karsenty believes that the drug could block bone destruction (Nature, 20 Feb 2005), a theory that has been supported by another trial, which found that people taking beta-blockers also suffered fewer fractures (JAMA, 2004; 292: 1326–32).

And psychiatrists at Cornell University believe they could be used to help suppress disturbing memories in people who witnessed a traumatic event such as 9/11 or the London terrorist bombings. Propanolol has the ability to block the neurotransmitters involved in laying down memory, and so it could be used for victims of post-traumatic stress disorder (PTSD), the researchers postulate.

The Cornell team wants to recruit 60 volunteers who would be prepared to take the drug whenever they experienced a PTSD symptom, such as increased heart rate or breathing difficulties.

It’s a therapy that has not been met with universal approval.

Dr Paul McHugh, a psychiatrist at Johns Hopkins University in Baltimore, says: “If soldiers did something that ended up with children getting killed, do you want to give them beta-blockers so that they can do it again?”

Bryan Hubbard

Researchers from Boston University Medical Center focused their attention on 72 of the 459 participants in the original DASH trial who had stage I ISH (140-159 mmHg). In the eight-week DASH study, participants’ blood pressures were measured on entry into the study and again after randomisation into one of three diet groups. The three diets were: a typical American diet (control); a diet rich in fruits and vegetables; and the DASH diet, which is rich in fruits, vegetables and low-fat dairy foods.

The DASH diet lowered systolic blood pressure significantly more than the control diet (211.2 mmHg, p < 0.001), and the fruit and vegetable diet (28.0 mmHg, p < 0.01).

Overall, say the researchers, the nutritional approach using the DASH diet translates to an overall drop in blood pressure from 146/85 mmHg to 134/82 mmHg – a response comparable to that seen with standard treatment with antihypertensive drugs (Hypertension, 2001; 38: 155-8).

Patients on short acting antagonists were nearly four times as likely to suffer a serious reaction, and possibly death, compared to those given long acting drugs.

The discovery of a major difference between the two types of calcium antagonists is an important one, but the researchers were quick to point out that their findings did not mean that the long acting agents were necessarily safe (The Lancet, 1997; 349: 594-8).

A four year regimen can produce a “significant” reduction in blood pressure, and this was achieved with an average weight loss of just 7.9 lbs (3.6 kg), one glass of alcohol less a week, and the introduction of a diet low in cholesterol and fats.

Researchers from the University of Minnesota studied 902 men and women, aged between 45 and 69, suffering from mild (stage 1) hypertension. Each was given one of six drug treatments as well.

All showed tremendous improvements, including those taking a placebo, which indicates that the major factor was the diet and exercise programme.

See WDDTY 5.11 for our special report on hypertension.

!AJAMA, May 22, 1996.

A study of 54 women with high blood pressure in their 26th week of pregnancy by James’s University Hospital in Leeds showed that women treated in a day care unit fared far better than controls in treating their condition.

The control group spent nearly five times longer as inpatients than the day care group, were 8.8 times more likely to be admitted to hospital, 4.9 times more likely to have labour induced and 11.4 times more likely to develop protein in the urine.

These results throw by the board the widespread medical belief that enforced bed rest for hypertense pregnant women without protein in the urine is the treatment of choice.

“The frequencies of proteinuria, preterm delivery and perinatal death were not reduced by bed rest,” concluded the study.

In this small study, 41 adults receiving no more than two antihypertensive drugs were initially assigned to a diet providing 12.5 per cent of energy from protein and 15 g of fibre/day.

After four weeks on this diet, the participants were randomly assigned to either continue with the low-fibre diet, switch to one supplemented with 66 g of soy protein (providing 25 per cent of their total energy) or an additional 12 g of soluble fibre in the form of psyllium, or both, for a further eight weeks.

Those who consumed the high-fibre, high-protein diet achieved the largest decreases in blood pressure, with their systolic blood pressure dropping by an average of 10.5 mmHg compared with the control subjects.

The investigators documented ‘significant independent effects of fibre and protein on 24-hour systolic blood pressure and awake systolic blood pressure, and a significant effect of protein on asleep systolic blood pressure’.

As long as a patient does not have an impaired kidney function, concluded the researchers, an increased intake of protein and fibre, particularly with fruits and vegetables as sources of soluble fibre, should be considered as a means of controlling hypertension (Hypertension, 2001; 38: 821-6).

A team from the University of Kuopio collected data from 1449 men and women over an average period of 21 years. These subjects were 65-79 years of age in 1998, when they were reexamined, and had been previously examined when they were 40-64 years of age.

The researchers concluded that, in midlife, those with a systolic blood pressure of 160 mmHg or more, or a blood cholesterol concentration of 6.5 mmol/L or more, had more than twice the risk of developing Alzheimer’s than those with normal systolic blood pressure and blood cholesterol.

Subjects who had both risk factors in midlife had a risk of developing Alzheimer’s disease that was 3.5 times greater than in those with only one of the risk factors alone.

The team also found that a high diastolic blood pressure in midlife had no effect on Alzheimer’s risk.

Previous studies have shown evidence of an association between Alzheimer’s disease and midlife cardiovascular factors in single sex groups, but this, say the researchers, is the first population based study to investigate the connection in both sexes (BMJ, 2001; 322: 1447-51).

In a related study, scientists at Stanford University School of Medicine, in California, suggest there may be a link between sleep disordered breathing (SDB) and an increased risk of developing Alzheimer’s. The reason for this, say the researchers, is the presence of the e4 allelic variant of apolipoprotein E (apoE), a protein involved in fat metabolism.

Data were collected from participants as part of an ongoing population study of sleep disorders in middle aged adults that began in 1989. After adjusting for factors such as age, sex, body mass index and ethnic group, subjects with apoE e4 had a significantly higher probability of moderate to severe SDB than those without the e4 allele 12 per cent versus 7 per cent.

Since the e4 variant predisposes individuals to cardiovascular problems as well as Alzheimer’s disease, the researchers hint that all three conditions may be connected in a way we simply don’t yet fully understand (J Am Med Assoc, 2001; 285: 2888-90).

Finnish researchers have also confirmed the connection between e4 in the very elderly and an increased risk of Alzheimer’s. Of those who had the e4 allele, 71 per cent developed Alzheimer’s versus only 22 per cent of those who did not (Neurology, 2001; 56: 1690- 6).

That conclusion comes from an observational study carried out in the North of England which abstracted records from 18 general practices over three years. In this investigation, 196 out of 224 male and female patients who were taken off antihypertensive medication were followed up.

It was found that 43, or 22 per cent, of these patients continued to have normal blood pressure even though they remained off medication for the whole of the investigation. The study also found that, of these 43 patients, there were twice as many men as women with normal blood pressure while off medication.

Apart from sex, no other differences were seen between the group which stayed off medication and those who restarted.

Those who redeveloped high blood pressure tended to do so early on, within three months of stopping medication (Br J Gen Pract, 1999; 49: 977-80).