"Herbal Viagra" Should Be Shunned
By Dónal P. O'Mathùna, PhD. Dr. O'Mathùna is Senior Lecturer in Ethics, Decision-Making & Evidence, School of Nursing, Dublin City University, Ireland; he reports no financial relationship to this field of study.
The arrival of Viagra® on the market in 1998 led to a sexual revolution of sorts. Suddenly, erectile dysfunction (ED) was a legitimate concern that men could discuss with their doctors. Prescriptions for Viagra (sildenafil citrate) increased at record pace. Men with ED found relief, but soon those without diagnosed ED reported benefits too. Viagra works by inhibiting the enzyme phosphodiesterase-5 (PDE-5). A large market developed, and in 2003 two other PDE-5 inhibitors were approved: Cialis® (tadalafil) and Levitra® (vardenafil).1
Interest in Viagra did not go unnoticed by manufacturers of herbal remedies.2 Numerous "herbal Viagra" products claimed to have all the benefits of pharmaceuticals without the side effects. For centuries, extracts of various animal parts, oysters, and many herbs have been recommended to overcome "impotence," the older term for ED.3 To avoid regulatory problems, such products claim to provide male sexual enhancement. Products containing herbs like yohimbe, epimedium, ginseng, Ginkgo biloba, and many others, often in complex multi-herb mixtures, flooded the market.4 By 2006, herbal remedies with names like Stamina-RX, Mentalk, and Sex Gold generated almost $400 million in annual sales.5
Some of these products really worked, which drew attention to their composition. Regulatory agencies tested some samples and found that some "all-natural" and "safe" "herbal Viagra" products contained Viagra itself. This is a serious problem given that PDE-5 inhibitors have well-established side effects. In addition, about two-thirds of those patients with ED also have hypertension and ischemic heart disease, and PDE-5 inhibitors interact negatively with the drugs commonly used to treat these diseases.6 Men who would be warned against using prescription PDE-5 inhibitors might try herbal remedies that could produce the drug interactions they were seeking to avoid.
But how big a problem is this? The literature in this area was reviewed to provide evidence for physicians advising patients who might be using herbal remedies for ED or sexual enhancement. This revealed a massive problem that physicians, patients, and regulatory agencies need to address urgently.
Reviewing the Literature
In 2002, Health Canada ordered a recall of a Chinese herbal remedy that had been on the market since 1999.7 The product was sold to enhance sexual function in men and women, and its label stated it contained five herbs. When tested, it was found to contain a compound that was not of natural origin and was almost identical to sildenafil. Studies published that year reported finding sildenafil in a herbal remedy in Taiwan and herbal soft drinks in Japan.8,9 Both products contained more than 40 mg sildenafil per dose, which falls within the recommended dosage range of Viagra. In addition, the soft drink contained phentolamine, used in hypertensive emergencies and suggested as an oral ED treatment. Over the next couple of years, herbal remedies adulterated with pharmaceutical PDE-5 inhibitors were identified in the United States, the United Kingdom, the Netherlands, Kuwait, Saudi Arabia, Singapore, Korea, China, and Taiwan. More recent studies from France, Italy, and India have brought the total number of studies identifying adulterated sexual enhancement products to 50.
In some cases, concerns arose from patients. For example, a 50-year-old man in the U.K. was taking alpha- and beta-blockers, along with 50 mg sildenafil at least weekly.10 A friend suggested he try an "all natural" herbal remedy, which he did in addition to his sildenafil. The herb worked so well he became suspicious and brought the matter to the attention of his physician who arranged to have the capsules tested by a toxicology lab. They tested 15 capsules and found that all contained sildenafil (50-71 mg per capsule) and 10 of the 15 also contained tadalafil (0.4-2.4 mg). This man was therefore taking more than the recommended dose of sildenafil (100 mg in 24 hours), in addition to about one-quarter the starting dose of tadalafil.11 On top of this, he was at risk of serious drug interactions with his heart medications.
Earlier attempts to identify adulterants were frustrated by the complexity of herbal mixtures. This made standard testing methods unreliable and time-consuming.12 However, since 2006, newer detection methods have led to significant improvements. As a result, adulterants other than the three approved PDE-5 inhibitors have been identified in herbal remedies.
Extent of the Problem
It is difficult to determine exactly how extensively adulteration occurs. Most of the studies report individual products submitted to various food and drug safety authorities. However, a number of studies have collected several products to gain estimates of the extent of adulteration. In the first of these, 40 herbal remedies marketed to improve sexual performance were screened in the United States.4 Of these, 19 (48%) contained PDE-5 inhibitors (eight had sildenafil, 14-60 mg/unit; nine had tadalafil, 4.6-16.9 mg/unit; and two others had analogs). Analogs are chemical variants of the original drugs, often referred to as designer drugs when made illicitly.
In one Canadian study, researchers purchased six products from the Internet and one from a local health food store.13 One contained 30 mg sildenafil and another 20 mg tadalafil (29% of the products). In China, more than 200 products were collected by Chinese authorities from health markets.12 Eighty-one were labeled as natural enhancers of sexual performance. Of these, 28 (35%) were found to contain sildenafil. The concentrations were not reported, but the article stated that in many cases the doses greatly exceeded the recommended daily dose of sildenafil. A French study analyzed 17 products originating from China, Taiwan, Estonia, or Spain.11 Eight of these (47%) were adulterated, five with sildenafil (0.3-120 mg/unit), two with tadalafil (10 and 31 mg/dose), one with vardenafil (16 mg), and two others with analogs (two contained two adulterants).
A 2007 study in Hong Kong collected 26 herbal remedies from convenience stores.14 Fifteen (58%) of these products were adulterated, revealing a trend towards adulteration with analogs: sildenafil was found in one product with the rest containing various analogs. A more recent U.S. study found that 15 of 26 products (58%) were adulterated, 12 of them with analogs.15 A series of raids by the Health Sciences Authority in two red-light districts in Singapore led to 175 sexual enhancement products being sold at makeshift stalls.16 Of these, 134 (77%) were adulterated with pharmaceuticals, 92% of which was sildenafil. More than half of these products contained > 100 mg sildenafil per dose, which exceeds the recommended daily maximum dose. Other pharmaceuticals identified in these herbal remedies included tadalafil, vardenafil, lidocaine, sibutramine, chloramphenicol, and glibenclamide.
Two other studies have found lower incidences of adulteration. An analysis of 90 herbal remedies purchased in Chinatown, New York, found one sample contaminated with sildenafil.17 The study did not report how many of the remedies were recommended for sexual enhancement. A total of five products were adulterated. Another study of Ayurvedic remedies for sexual enhancement sold in India identified only one adulterated product, though it contained 72.5 mg sildenafil.6
PDE-5 inhibitor adulterants have also been found in other products marketed to improve sexual performance. These include herbal drinks and other foods,18 candies,19 soft drinks,8 topical creams,1 and bulk powders used to make dietary supplements.20,21
Types of Adulterants
Up until around 2006, adulterated samples tended to contain one or more of the three approved PDE-5 inhibitors. Since then, adulterated samples have been more likely to contain analogs of these drugs. This has created difficulties with detection. Such designer drugs contain small variations on the structures of the approved drugs.
Producing analogs is one of the strategies used by pharmaceutical researchers to develop new products for testing.14 Some of the adulterants identified have been patented, though not approved for distribution.22 The presence of so many analogs in herbal supplements reveals that knowledgeable chemists are involved in what amounts to a designer drug production system. Analogs are often described in legitimate patents, which are then publicly available on the Internet. For example, 12 of the analogs identified as adulterants were described in earlier patents, which may have guided chemists to synthesize them for use as adulterants.23
By 2009, 14 different analogs of approved PDE-5 inhibitors had been found as adulterants in dietary supplements.11 The literature search for this article revealed seven additional analogs in more recent studies. It is estimated that three or four new analogs are isolated from herbal remedies each year.24
While it is likely that such analogs are active as PDE-5 inhibitors, most have little or no evidence to demonstrate this and are not approved for use. For example, one analog was shown to have potent PDE-5 and PDE-6 inhibitory activity in preliminary in vitro assays.23 The PDE-6 enzyme acts primarily in the human retina, raising concerns about visual side effects. Another adulterant was shown to have similar activity to sildenafil, a second to have half its potency, and a third to be an analog of vardenafil with similar potency.24
In most cases, nothing is known about the side effects of analogs. One analog of vardenafil was found to be more lipid-soluble and metabolically stable than vardenafil.24 This would lead to a longer half-life and increased absorption into the central nervous system, increasing the risk of side effects.
In general, analogs often have different side effects. For example, fenfluramine was an approved weight-loss product until it was taken off the market because of adverse effects. An analog of this drug, N-nitrosofenfluramine has been identified in herbal remedies marketed for weight loss.25 However, nitrosamines are known hepatotoxins. Hundreds of cases of liver toxicity were reported in Japan and Singapore among people taking Chinese herbal remedies later found to contain N-nitrosofenfluramine. At least two deaths occurred, and 11 people required liver transplantation. Presumably, manufacturers of the herbal remedies assumed the analog would have similar effectiveness, but failed to consider the fact that analogs often have differing toxicities.
In addition to PDE-5 inhibitors, other adulterants have been found in herbal remedies marketed for sexual enhancement. These include an investigational selective serotonin reductase inhibitor26 and glibenclamide, used to treat diabetes.27
Adverse Effects
Men taking herbal remedies adulterated with PDE-5 inhibitors are putting themselves at serious risk in a number of ways. Sildenafil and the approved PDE-5 inhibitors are well-known to have adverse effects such as headaches, facial flushing, dyspepsia, visual disturbances, and muscle aches. In addition, sildenafil is contraindicated in men taking drugs commonly used to treat hypertension and ischemic heart disease, including nitroglycerine, doxazosin, and terazosin.6 Other serious drug interactions are possible with erythromycin and HIV protease inhibitors.21
During 2008, men consuming herbal sexual enhancement products in Singapore reported a series of serious adverse effects. As of August 2009, 10 men had died.16 Dozens of other serious adverse events were reported, though many were reversed.27 The products consumed by these men contained sildenafil along with very high doses of glibenclamide. In some cases, the samples contained up to five times the daily recommended dose of glibenclamide.
Little is known about the adverse effects of the analogs of PDE-5 inhibitors, but case reports are raising concerns. In Japan, one case of liver function impairment is thought to have been due to a sildenafil analog.28 In Hong Kong, a young man presented with ataxia after taking a sexual enhancement herbal remedy adulterated with another analog of sildenafil.14
Candies sold as natural sexual enhancement products contained an analog called aminotadalafil along with a previously unknown analog.19 The unknown compound was identified as the product of a chemical reaction between one of the sugar excipients and aminotadalafil. The latter contains a highly reactive chemical group, and points to the risk of unknown reactions occurring with these illicit products.
Recommendations
All patients should be warned against using any herbal remedy or dietary supplement for sexual enhancement, unless verified by a reputable third party. Published studies have found that between one-third and one-half of such "natural" products are adulterated with synthetic chemicals. Earlier in 2010, the U.K. Medicines and Healthcare products Regulatory Agency warned against all such products, adding that its own survey found that 65% of such products were adulterated. Representatives for Pfizer, which manufactures Viagra, told the Associated Press that they found sildenafil in herbal tablets purchased in Thailand, Taiwan, Canada, Australia, New Zealand, Hong Kong, Malaysia, the U.K., and the United States.5 They also found sildenafil in 69% of 3,400 supplements purchased in China.
This is one example of a broader problem with herbal remedies. In May 2010, the Government Accountability Office reported to the U.S. Senate about deceptive and questionable marketing claims on some herbal remedies and their associated websites.29
People who consume sexual enhancement herbal remedies are risking the ingestion of chemicals for which no reliable data exist on their biological or adverse effects. No information is available on the possible contaminants, which may be present as a result of the reactions conducted to make such "designer drugs." Regulation and enforcement is needed to prevent another occurrence of what happened in Singapore. Until then, physicians need to warn all men and boys about the extent of this problem.
References
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