“Vitamin E is dangerous!” “Herbal products have no evidence!” ______ does not treat or cure advanced cancer“? “Supplements don’t do anything, so don’t waste your money!” For almost 30 years I have watched not just patients, but especially some influential clinicians generalize, embellish, and misconstrue data on dietary supplements. This type of commentary just mirrors the lack of objective education in this area, does nothing to improve the clinician and patient relationship, and arguably sends countless individuals to less credible sources for information and misguided sales pitches (as it did through the years for many of my own family members). At the same time, I have watched many in the supplement industry embellish data and supplement efficacy and promote a “we vs. them” contentious milieu that only continues to confuse the public. Again, this acrimonious dichotomy or profound polarization does nothing for overall patient care [1].

A good example of the ongoing dual cacophony was a New York (NY) Times front-page article on quality control testing of dietary supplements. The New York State attorney general (NYAG) accused four national retailers (GNC, Target, Walgreens, and Walmart) of selling dietary supplements that were fraudulent and, in numerous cases, “contaminated with unlisted ingredients” [2]. A total of four out of every five products tested contained none of the herbs advertised on the label! And it seemed for critics of the supplement industry this added fuel to the ongoing fire while advocates for the industry fought back and stated that the NY state attorney general’s office commissioned an independent testing group that actually performed the wrong test. And they have proof that exactly what is advertised in their products is what is in the products [3]. The NY investigation and accusation was based on testing of herbal products using “DNA barcoding .” It is a very reliable method, but here is the key—it needs to be performed on the appropriate material. In other words, herbal extracts found in many supplements contain DNA but it is often of a low quality and broken down or degraded to a level that could make it really difficult to prove what is in the bottle based on this specific testing method. There is a chance that the supplement companies were primarily in compliance and the NY office was too quick in reaching a verdict. The problem at the time of this writing is that there has been no communication or release of the testing commissioned by the NYAG. In fact, NYAG has now shifted some of the focus on health claims made by these supplement companies and also quality control. This has all the makings of a reality TV show. Recently, research out of Canada showed similar findings of quality control issues but they also utilized DNA barcoding [4]. Regardless of who is right or who is wrong or semi-wrong there is little doubt that many supplements still have issues so perhaps the end will justify the mean with the NYAG situation. Even if the NYAG investigation was botched there appeared to be gluten for example found in “gluten free” advertised supplements.

Thus, I wanted to provide multiple rules or steps, questions I am asked, or really observations that have helped me when making a recommendation or finding the right product for patients that are as true today as they were almost 25+ years ago. This is critical because timeless advice is needed in this field rather than the need or desire to be attracted to the latest and greatest option only to be disappointed or taken to the cleaners so to speak. These will help you (health care professional, patient, …) in getting something desperately needed when reviewing the latest “groundbreaking” (how cliché are those words) supplement or dietary or lifestyle changes, and that is something called “objectivity .” This what is desperately needed in the teaching of integrative medicine and especially dietary supplements, which is a business today, and I am glad it is a business because it initiating more and more research and interest, but the down side of that business is the nebulousness or demarcation of objectivity and subjectivity (of course conventional medicine is also as guilty at times of this problem). More and more health care professionals then ever before are selling or recommending supplements and get paid for doing so, and more and more consumers are selling them. This does not disqualify their expertise but makes it more difficult than ever before for a non-polarizing, non-royalty, or non-endorsing objective and experienced current up-to-date source of information, although I had my brief moments over my long career of having been often tempted or even succumbing temporarily to a disease called “JD” or “judgmental dysfunction ,” but at least I (or others) quickly reminded me of how to find the cure, which is actually appreciating the honor or privilege and trust you hold and earned over time with the public, patients, and health care professionals. Here in this chapter at least you will find that source of current information that I wish I had when I was starting my career as a complete greenhorn.

• The difference between a clinically effective drug and supplement is perception and not reality. So, what are the rules or even politics of what becomes a supplement or a drug? What about FDA current Good Manufacturing Practices ( cGMP) now required by supplement companies in the USA? Does that help to give a supplement drug like quality?

In the words of the FDA: “A dietary supplement is a product intended for ingestion that contains a dietary ingredient intended to add further nutritional value to (supplement) the diet. A dietary ingredient may be one, or any combination, of the following substances: a vitamin, a mineral, an herb or other botanical, an amino acid, a dietary substance for use by people to supplement the diet by increasing the total dietary intake, a concentrate, metabolite, constituent, or extract …” [5]. What?! And keep in mind that dietary supplements are not intended to diagnose, treat, cure or prevent and disease, but the FDA states that some supplements can be used to “help you reduce your risk of disease” [5]. What?!

Okay, now from those definitions above try and tell me the difference of what can become a supplement or a drug? It is pretty nebulous, which is why for example you can sell fish oil or omega-3 in the USA or you can also get it as a prescription drug (Epanova^®, Lovaza^®, Vascepa^® …) [1]. Thus, in my opinion the difference is usually researched based or the requirements of strict clinical trials for FDA approval (a drug) or no trials needed at all (a supplement) and political with an “us” versus “them” mentality which is why it is tough to regulate. In other words, in Congress you have staunch past and current advocates of legislation to maintain supplements as a standalone category (Senator Hatch from Utah, Senator Harkin from Iowa … Republican and a Democrats joined together). And then you have others politically that are on the other side that are more quiet in general but try and monitor public concern, and since most Americans take supplements of some kind and most politicians I have met (hundreds over the years) consume supplements, then I think it is an unpopular position politically to suggest supplements should be tested or regulated like drugs.

The idea that there is no enforced safety net for pills that you consume is a little concerning. So, with some public pressure mounting on quality control the FDA came up with current good manufacturing practices (cGMP or GMP) rule many years ago, in 2007, that supplement companies are supposed to follow. However, if I told you the speed limit was 55 MPH but you knew there were few cops on the highways to enforce this law, then what speed would you drive? In other words, FDA does not have the person power to enforce cGMP so some companies say they are cGMP, but the public has no idea until they are actually inspected by the FDA or an outside third party (for example like NSF or USP). So, there are still a small number of companies operating with an “innocent until they catch me doing something wrong” mentality.

Still, I do not believe supplements should become prescriptions but at the same time anyone that wants to start a supplement company should have to abide by some credible third party independent quality control group like NSF. It makes no sense that tomorrow I could simply set up the “Dr Moyad supplement company” and there would be no one that could stop me or require me in some credible manner to prove that what I was proffering was at least safe (and do not get me started on the scientific part that also requires zero proof for some companies to start selling pills).

On the other side of the debate, you have the anti-drug movement folks and this is a reality. Some drugs today are so ridiculously and embarrassingly expense that this is why the name “big pharma” has become part of the US vernacular or lexicon and that term is obviously not complimentary. I had a colleague of mine at Harvard (notice how I threw in the word Harvard to impress the reader on my personal regular range of peers or colleagues) lean over to me at a lecture and tell me that sildenafil (Viagra ) was 40 dollars a single pill (at the time) for some men suffering from a medical condition (erectile dysfunction ) after prostate surgery for example [1]. And by the way there is no justification for some of these prices such as Viagra’s cost because research and development (R&D) was not that expensive for this once shelved drug to justify this ongoing cost. So, thanks to higher drug prices and I am sure numerous other reasons like shifting the profit to another source, there is also a strong movement that is anti-big pharma, which helps keep strong political advocacy in favor of NOT changing the supplement rules because what is the perceived antithesis of big pharma? In my opinion, the mom and pop supplement company or holistic practitioner just trying to sell their natural products to help people, and look at big pharma deliberately or personally getting in the way like some vendetta, or try to minimize the little alternative guy or gal (of course sarcasm because some of the biggest supplement companies are now pharmaceutical brands from Bayer to Pfizer and some of the biggest out of pocket profiting is from selling your own line of supplements/recommending them).

Supplements are a many billion-dollar industry (arguably 35–40 billion/year) [6, 7], and in some ways (ironically) it has taken on its own big pharma feel, and money doesn’t talk but shouts! So, in reality there are massive money and political movements behind keeping things status quo. When I started 30 years ago in supplements and even in medical school, doctors would tell me all the time that a supplement might not help but “can’t hurt” but we know that is not true anymore. They can help, hurt or do nothing (just like any other pill). The sheer amount of profit in the industry combined with the lack of good objective education to health care professionals and the public, and throw in the political forces, and you have somewhat of a blurred line between what can become or mimic a supplement and/or a drug. The bottom line again, is that the real difference to me is perception and reality, and also one is required to pass some threshold of evidence and the other does not have to pass a threshold of evidence (it is up to the individual company in the case of a supplement if they even want to risk their business model with something as silly as research—again sarcasm).

So, remember, there is no difference between an effective supplement and a drug. Some of the most widely used supplements in the USA are treated like regulated drugs in other countries. Ever heard of melatonin [1]? Alpha-Lipoic Acid [1]? S-adenosyl-methionine (SAM-e) or Zinc gluconate [1]?!

Under the FDA Code of Federal Regulations , title 21, volume 2, the rules for dietary supplements are quite clear despite voluminous language. Under part 101, subpart F and section 101.93 (I am not kidding here) and stated under number 2 part C “Text for disclaimer.” It states that the rules are “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.” The problem with this language is it also serves to provide a confusing chasm between reality and perception for families or individuals dealing with minor to devastating diseases. I often tell audiences that most of the effective supplements in the USA are actually prescription drugs or regulated like drugs in other countries such as S-adenosyl-methionine (SAM-e ) for depression or osteoarthritis [8–10]. Thus, the line between an effective drug and supplement is only perception and not reality. Instead, what is permitted by the FDA for dietary supplements are what is known as “structure/function claims ” (as long as some level of anemic general evidence is provided), which are non-disease claims and companies are allowed to suggest that something contributes or benefits “general well-being” or reduces “nutrient deficiency” or how a nutrient acts to “maintain such structure or function” [11].

In my experience, many companies have tried to follow structure/function claims by mentioning one of three words in advertising, so for example the suggestion that a supplement product may “maintain” or “promote” or “support” prostate health. For example, saw palmetto can advertise that it “supports prostate health,” which is not only confusing vernacular to the consumer, but it is arguably now completely inaccurate (see below) [1, 12]. Thus, again these rules do not serve to provide clarity for clinicians and patients but rather perplexity. The current rules or system are scientifically confusing and health care professionals in everyday practice need to better educate the public and patients. Therefore, it is imperative to review a series of situations where supplements are utilized like a drug or not (clear demarcation), and why not allow over-the-counter exceptions or situation where some companies could advertise the benefits (especially when a part of clinical guidelines for a specialty) especially if they were part of the objective phase-3-like trial, while not allowing any suggestion of benefit for other products that have clearly failed phase-3-like trials. The solution does not have to be that difficult and it does not imply that supplements have to be strictly regulated by the government. I am talking about rewarding the research (more on this later)!

Alzheimer Disease (AD) or completely different medical conditions known as “NAFLD” (non-alcoholic fatty liver disease ) and “NASH” (non-alcoholic steatohepatitis ) have somE-thing in common— vitamin E

Individuals with mild to moderate Alzheimer disease taking 2000 IU of vitamin E (dl-alpha-tocopheryl acetate or “synthetic” vitamin E from DSM Nutritional Products, Heerlen, Netherlands) per day in addition to standard medications—the acetylcholinesterase inhibitors (AChEI ) drugs, experienced an over 6 month reduction in functional decline and reduced caregiver time by 2 h a day in one of the longest and best clinical trials conducted in the USA (known as the “TEAM-AD VA cooperative randomized trial ” and published January 1, 2014 in the Journal of the American Medical Association) [13]. It is noteworthy that this is the second such phase-3-like trial to demonstrate this clinical benefit in Alzheimer patients with 2000 IU of vitamin E (again dl-alpha-tocopherol from Hoffman-LaRoche, Nutley, NJ) daily and the first trial was published on April 24, 1997 in the New England Journal of Medicine [14]!

AD patients need more options as exemplified by the recent Cleveland Clinic report that 99.6 % (244 out 245) of the Alzheimer’s clinical trials have failed over the past decade [15], so why not? It is remarkable that no vitamin E supplement company is able to advertise these results (not even the company that provided the product for the clinical trial) so the only individuals that potentially suffer from this lack of objective information are the patients afflicted by Alzheimer disease and the other individuals that care about or for them.

It is also disconcerting that some practitioners have not been recommending vitamin E to Alzheimer patients because these supplements have been suggested to have shown some toxicity in other areas of medicine [16], so why utilize them in Alzheimer disease? This myopic thinking again somehow places an effective supplement for a devastating disease in a different category than how things would be treated for an effective drug with some standard limitations. If acetylcholinesterase inhibitors showed some toxicity in other disease scenarios, which they have significantly done already in mild cognitive impairment or Alzheimer patients (nausea, vomiting and diarrhea) [17, 18], then would practitioners quit using all these medications? This appears doubtful because the benefit exceeds the risk for many patients, which is similar to the situation with vitamin E. Additionally, in the TEAM-AD VA Cooperative Trial and in the first phase 3 trial published in 1997, the adverse effects of vitamin E were similar overall to placebo [13, 14]. Interestingly, vitamin E supplements have not shown an ability to prevent Alzheimer’s or help those with mild cognitive impairment (MCI) at a dosage of 2000 IU per day (from DSM Nutritional Products, Heerlen, Netherlands) [19], but for those with mild to moderate or moderately severe impairment from Alzheimer’s it should be discussed with a physician.

Interestingly, this situation and benefit is arguably similar to a different disease scenario occurring with NAFLD (non-alcoholic fatty liver disease) or NASH (non-alcoholic steatohepatitis) where 800 IU daily (400 IU twice a day) of vitamin E appears to have benefited children/young adults (age 8–17 years) and more clearly benefited adult patients from two major clinical trials (PIVENS trial used “natural” form vitamin E or d-alpha-tocopherol from Nature Made^®, Pharmavite, LLC, Mission Hills or Northridge, CA and TONIC children/young adult trial also used Nature Made^® vitamin E at the same dosage and form used in the PIVENS trial) [1].

Individuals with intermediate to advanced stages of age-related macular degeneration (AMD) are now recommended to use a dietary supplement as one of the primary treatments for this disease, which can also prevent vision loss. The exact formulation recommended by the National Eye Institute (NEI) was derived from two phase-3 government funded trials known as AREDS1 (supplements provided by Bausch & Lomb, Bridgewater, NJ) conducted at 11 medical centers and AREDS2 [supplements from DSM Nutritional Products, Inc., Sisseln, Switzerland manufactured the constituents of the AREDS2 formulations and raw materials for active ingredients and placebos were produced into tablets (lutein + zeaxanthin) and gelatin capsules (EPA + DHA ethyl esters) by Tishcon Corp, Westbury, NY and Alcon Research Ltd, Fort Worth, TX provided raw materials for the four AREDS-type supplements and added into gelatin capsules Banner Pharmacaps Europe BV (Tilburg, the Netherlands)] conducted at 82 medical centers [20–22]. The following dosage is now a standard clinical recommendation for ophthalmologists dealing with AMD:

(Note: The lutein source was Tagetes erecta/Aztec marigold and zeaxanthin was synthesized at DSM via a patented process and omega-3’s EPA + DHA failed to show a benefit in the AREDS2 clinical trail and all participants taking a multivitamin were required to switch to Centrum Silver^®, now Pfizer, New York, NY, which was also provided to them, and in the AREDS1 trial the multivitamin allowed was Centrum^®, Whitehall-Robins Healthcare, Madison, NJ and now Pfizer.)

Interestingly, this and a similar formula have not shown an ability to prevent this disease but appear to help those with the intermediate to advanced stages. Thus, it is critical that I reiterate the fact that this has become one of the primary or standard treatments for AMD (dry and wet form) along with conventional medicine to help preserve vision. Again, no direct advertisements or benefits are allowed by the companies that provided these products for the clinical trial despite the fact that they are a standard part of medical treatment. I am often frustrated by the fact that I am educating some patients with macular degeneration about these results and the specific formulation that they require, and immediately with the approval of their ophthalmologist they are utilizing these pills. There must be a better method of general education, right?

Aging is not a medical condition per se, but some in the antiaging movement appear to be advertising that they are combating the aging process. High on this list is a dietary supplement known as “resveratrol.” Resveratrol is a supplement that can cost 50–100 dollars a month and it is touted to have dramatic antiaging effects like increasing telomere length and other impressive vernacular, but the reality outside of the laboratory, is that many of the recent human studies have been a large disappointment. And even when preliminary clinical trials on the supplement were published [23], or a large pharmaceutical company (GlaxoSmithKline) invested heavily (arguably up to 750 million dollars for a resveratrol-like compound) it also turned out to be a preliminary disappointment [24]. I often tell patients to save their money until someone can actually prove it does something besides shrink your wallet, which ultimately can increase your stress and can accelerate the aging process [1, 25]. Why some practitioners are allowed to sell these expensive supplements and others out of their office, and profit from an overall lack of consistent beneficial evidence is concerning, especially based on the ongoing recent evidence [26]. Thus, when a supplement has drug-like efficacy it should be allowed to advertise to patients but at the same time if it fails to show overall efficacy then not even structure–function claims should be permitted.

BPH (Benign Prostatic Hyperplasia or non-cancerous prostate enlargement )—the story of saw palmetto and two phase-3-like and very well-done trials, or the story of chronic non-bacterial prostatitis: a tale of two urologic cities

One of the largest past reviews of clinical studies of saw palmetto for benign prostatic hyperplasia (BPH) found some interesting results in 1998 [27]. This analysis reviewed a total of 18 randomized trials (n = 2939 men) and found that most of the studies were limited by their short duration and study design. However, the existing evidence suggested that this herbal product improves urologic symptoms and flow measures. Compared with the FDA approved drug finasteride for this condition, saw palmetto produced similar improvement in urinary tract symptoms and urinary flow, with less side effects. However, saw palmetto had only been compared to current drug therapies for a maximum of approximately 12 months (still not a bad endorsement). More data was needed on this herbal product. Interestingly, the dosage of saw palmetto used in most randomized trials at this point in time was 320 mg/day and this dosage had no effect on PSA levels.

Four years after this notable 1998 review was published another one by similar authors added three new trials with 230 added male participants that translated into a meta-analysis of 21 randomized trials and the conclusions were similar stating that “The results of this update are in agreement with our initial review” [28]. In other words that saw palmetto could be an option that works as well as some pharmacologic agents but with less side effects.

The authors then updated their original meta-analysis again in 2009 and came to this conclusion “Serenoa repens was not more effective than placebo for treatment of urinary symptoms consistent with BPH” [29]. Next, in 2012 another follow-up review by similar authors concluded with the following comment on subjective and objective benefits of saw palmetto by noting: “Serenoa repens therapy does not improve LUTS or Q(max) compared with placebo in men with BPH, even at double and triple the usual dose” [30].

What happened that caused such a reversal in a long-standing recommendation or endorsement for saw palmetto? In the more recent meta-analysis for example there were nine new trials added to the analysis that included 2053 more men (about 65 % increase), and overall there were 5222 subjects from 30 randomized trials of a 4–60 week duration utilized for example [29, 30].

However, the answer to the question of what caused such a reversal in the saw palmetto enthusiasm lies in what is known as well-done non-biased or objective phase-3-like research. The first trial was a US government funded trial called “STEP” (The Saw palmetto for Treatment of Enlarged Prostates ) [31], followed by the results of a more recent trial called “CAMUS” (Complementary and Alternative Medicine for Urological Symptoms ) [32]—two outstanding phase-3 like trials that arguably should have settled the majority of the debate on saw palmetto itself.

The STEP trial was simply a very well done clinical trial [31], and the researchers and participants in this study should be commended for being a part of one of one the better herbal studies ever completed in medicine. Saw palmetto enjoys a tremendous amount of sales around the world. Some areas of Europe have made this herbal product a prescription, but in the USA there are literally hundreds of over-the-counter (OTC) brands. Florida and several coastal states are some of the largest exporters of this herbal product. This herbal product is so well known that it continues to be one of the more popular supplements taken by men to prevent prostate cancer despite having no relevant evidence that it prevents prostate cancer [33, 34]. Okay, another reason why a structure and function claim such as “supports prostate health” can confuse the public even more than it can clarify, and this is very concerning, because saw palmetto again never had any credible data that it reduces the risk of prostate cancer. So, then why are all these men taking it? Is it because they do not get enough saw palmetto in their diet, or could it be that when something supports prostate health it is very logical to assume that it may have some research against prostate disease prevention, including cancer? Regardless, all of the preliminary data was for the improvement of BPH symptoms. Some researchers suggest it has a finasteride (a drug approved for BPH) type effect, but unlike finasteride (also known as Proscar^® ) it has not been shown to have any impact on PSA levels. Regardless, there was an ample need to conduct a non-industry or non-biased supported clinical trial to determine if saw palmetto really does have some efficacy. And of course I was pulling for saw palmetto to work and work well given the lack of low cost options with reduced side effects at the time.

The STEP trial was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and by the National Center for Complementary and Alternative Medicine (NCCAM) [31]. In the STEP trial a total of 225 men with moderate-to-severe BPH symptoms were randomized to saw palmetto extract at a dosage of 160 mg twice a day (320 mg a day total) or placebo [31]. The primary outcomes were the change in score on the American Urological Association Symptom Index (AUASI , a subjective measurement completed by patients) and the maximal flow rate (an objective measure completed by the physician). There were also a number of secondary outcomes including: change in the prostate size, urine volume left in the bladder after urinating, quality of life, laboratory values and side effects. When the trial ended after 12-months of treatment there was no difference between saw palmetto and placebo in all the major areas of study including:

Interestingly, critics abound from these trials and it appears will do anything to shred a major well-done objective phase-3-like clinical trial. For example, some of the popular alternative medicine consumer books and websites had espoused for years the use of a saw palmetto with either 80–95 % combination of fatty acids and sterols or 85–95 % fatty acids and greater than 0.2 % sterols. The herbal extract used in this trial demonstrated consistent 90–92 % fatty acids and 0.33 % sterols and this was actually verified [31], which means it was right on target or even above the standards of what has been recommended in the past for effectiveness. Even the placebo had an odor similar to saw palmetto so that the participants could not tell the difference, which is always needed in a well-done clinical trial but had not been done in several past saw palmetto trials so I believe some of the participants could tell the difference. The placebo contained polyethylene glycol-400, which is a bitter-tasting liquid with an oil makeup. It contained no free fatty acids, and a brown coloring agent was used in order to ensure no difference in appearance between saw palmetto and placebo.

Some critics then argued that the study should have tested men with mild BPH symptoms or larger prostate glands. Perhaps including men with more mild BPH symptoms and not those with moderate-to-severe BPH would have been a better study, and perhaps men with larger prostates would have also been a better group. The reason for this is due to the suggestion that saw palmetto works similar to a drug (finasteride ) that shrinks larger prostate glands. However, again in defense of the researchers in this trial, studying only mild BPH would have been filled with problems such as a large placebo effect, and the encouragement of medicating a condition that for many men needs no immediate intervention (aka overtreatment). Regardless, when the researchers looked at the small number of men with more or less symptoms than the average or with small or larger prostate glands there was still no difference between saw palmetto and placebo [31].

Additionally, what also did not receive attention from this trial was the fact that all of the potential participants in this trial were first placed in a 1-month, single-blind, placebo run-in phase and were not permitted in the trial unless they took 75 % or more of the placebo capsules [31]. In other words, in order to really determine who was committed to being compliant with the pills throughout this entire trial, the participants had to take placebo pills for 1-month prior to the start of the official study. It is interesting that there was actually a significant despite small improvement (or decrease) in symptom scores (AUASI ) during this 1-month period! This demonstrates the impressiveness of the placebo effect, especially with BPH and it has to be accounted for, and the researchers made a good effort accounting for it.

Critics also complained of the short length of the trial. Yet this trial was one of the longest saw palmetto versus placebo trials in the history of medicine. The majority of the past trials were about 3 months or shorter [27, 28]. BPH trials of 6 months to 1 year or more are more than adequate to determine if a medication is effective. The researchers could have done this trial over 6 months, but in my opinion 1-year was the perfect duration to determine if saw palmetto was better than placebo. In fact, participants had eight clinic visits during the trial [31], which was also more than sufficient to determine the impact of saw palmetto.

If the STEP trial results were a surprise then the CAMUS results were arguably even more surprising in my opinion because of the higher doses of saw palmetto utilized [32]. Basically, the CAMUS researchers found that low (320 mg), moderate (640 mg), and high doses (960 mg) of saw palmetto given over 72 weeks did not work better than a placebo for BPH/LUTS. Saw palmetto was again as safe as a placebo, but not more effective than a placebo in the follow-up North American study to the STEP trial. CAMUS was a double-blind, multicenter, placebo-controlled randomized trial conducted at 11 North American clinics including Ontario, Canada [32]. A total of 369 men, approximate mean age, AUASI, peak urinary flow rate, and PVR (post-void residual) of 61 years, 14.5, and 14.9 ml/s and 41 ml were given escalating doses of saw palmetto or placebo over 72 weeks. Again, the intervention consisted of 1–3 chocolate covered gelcaps (320 mg each), and the starting dosage was 320 mg/day with a dose escalation at 24 (640 mg/day) and 48 weeks (960 mg/day) with the trial ending at 18-months of intervention compared to placebo. The saw palmetto used in CAMUS consisted of 85–95 % fatty acids, and it was a lipidic ethanolic extract of ripe, dried saw palmetto berries manufactured by Rottapharm/Madaus, Cologne, Germany, and sold as PROSTA-URGENIN UNO capsules. The placebo contained 375 mg of polyethylene glycol and a matched weight (475 mg), and participants were told to take all gel caps at same time.

Again, in the CAMUS trial the baseline and 72-week results found no significant differences between saw palmetto and placebo for any parameter [32]. For example, no differences were found for all of the following (impressive list):

Many items actually favored placebo except for the difference in AUASI for non-Caucasian participants, which favored saw palmetto (non-significantly). Some critics suggested the extraction process of saw palmetto was faulty resulting in an impure product. However, the STEP trial used a carbon dioxide extraction procedure for their saw palmetto preparation [31], compared to an ethanolic extraction procedure in the CAMUS trial [32]. In other words, some internet criticisms of the extraction procedure for saw palmetto after the STEP trial was addressed in the CAMUS trial and did not produce better results. This is again a beautiful testament to the researchers for these trials (many of them I know and respect, as is the case with many of the other clinical trials in this book that I thought I would mention to mildly impress the reader).

Interestingly, the most notable saw palmetto supplement/drug in the world (Permixon^® ) with the most positive clinical research (popular in Europe) apparently either did not or could not participate in this trial [35–38], despite being requested to participate by the North American researchers. Thus, the researchers were left with another agent from a different manufacturer in this trial, which again arguably demonstrated that North American saw palmetto rigorous studies do not demonstrate efficacy of this herbal product compared to placebo. However, should researchers discount the more positive European studies utilizing Permixon? Not necessarily, but since the most notable product outside the USA are not for sale in the USA, then both the STEP and CAMUS trial suggests that saw palmetto should not be allowed to make any prostate health claim without some future positive research. This would seem appropriate based on the fact that two of the most rigorous trials ever done in medical history showed no benefit over placebo. Regardless of the type of supplement and whatever the medical condition, if most of the rigorous trials result in failure then why is a structure/function claim still permitted?

Still, in order to maintain objectivity in this discourse, patients are left with unmet needs when it comes to prostate enlargement prescription FDA approved medications because numerous men are not able to tolerate them or they could be dangerous for some elderly men [39]. And recent costly drug combinations approved by the FDA did not even include a placebo arm and were still given FDA approval [40]? Also, in discussions with some of the researchers from the CAMUS trial there appeared to be no volunteers (despite being requested) from the pharmaceutical world to be placed up against saw palmetto or placebo when the original trial was being designed. Again, the patients get lost in this shuffle, so BPH is an area of medicine that would benefit from some dietary supplement that works modestly or moderately better than a sugar pill. And although there are some candidates like beta-sitosterol [25], it has been difficult to initiate more recent and rigorous clinical trials to determine if these agents are truly effective. Instead, high-priced combinations of ingredients are used in prostate health supplements that include beta-sitosterol and some of these companies use the old beta-sitosterol clinical data (normally a low cost single ingredient) as evidence as to why their product is effective? However, their product contains countless compounds and beta-sitosterol is just one of them and yet they are allowed to promote their product using the publications of beta-sitosterol as a stand-alone intervention? What?! This issue is not only symptomatic of some urologic supplements but symptomatic of the larger disease found with supplements in almost every medical specialty [1]. Some are bad and should never be allowed any claim, and others do not get the credit they deserve because research does not get rewarded enough in the world of dietary supplements so let’s reward some more research before finishing this section.

On the other hand, it is fascinating and perplexing that in another area of urology, chronic non-bacterial prostatitis there are some dietary supplements (Cernilton pollen extract from a variety of sources such as Graminex LLC products, Deshler, OH; and quercetin generic and quercetin complexes from Farr Labs, Beverly Hills, CA such as Prosta-Q and Q-Urol) with adequate clinical evidence and no consistently effective FDA approved drugs [1, 25, 41, 42]. And countless clinicians from the Mayo Clinic to UCLA utilize and recommend these dietary supplements and yet no one is allowed to advertise their benefits?! And chronic non-bacterial prostatitis, by the way, consists of the vast the majority of the global cases of prostatitis, not infectious prostatitis [25].

Interestingly, there is no supplement that has shown evidence to reduce the risk or recurrence of these two common cancers. And, in f act, there is now plenty of evidence to suggest that getting too many supplements when completely healthy could increase the risk of these cancers, especially prostate cancer. For example, higher-dosages of selenium supplements (200 μg or more) when already ingesting ample selenium from dietary sources could increase the risk of aggressive prostate cancer [25, 43]. Additionally, the evidence of vitamin E supplements and an increased prostate cancer risk as well as potentially high-dose folic acid cannot be ignored [25]. Currently, there is no single supplement that could be considered to have ample evidence in the area of breast cancer prevention or recurrence. And the past 30 years are replete with supplements that claimed such a potential distinction or were deemed to potentially benefit by “experts” in the field. However, the evidence for dietary supplements to reduce the risk of side effects or treat side effects from breast and prostate cancer treatment are impressive (see Chap. 7).

Fish oil has been touted for countless conditions but overall has failed most recent clinical trials from cardiovascular disease prevention to macular degeneration [22, 44, 45]. However, it continues to garner increasing research and recommendations in the area of dry eye syndrome [46–49], which is commendable because prescription drugs for this condition can be quite expensive. In the most recent meta-analysis of seven independent studies and almost 800 participants concluded with the following: “Consequently, our findings suggest that omega-3 fatty acids is an effective therapy for dry eye” [49].

These studies have attracted enough interest to initiate a large phase-3 like trial in collaboration with the National Eye Institute (NEI) at over 20 medical centers (2000 mg EPA and 1000 mg DHA) to determine if omega-3 can improve moderate to severe dry eye disease. This trial is known as “DREAM” (Dry Eye Assessment and Management Study ) [50]. It will be interesting because the placebo contains olive oil, which also has some known anti-inflammatory properties (a controversial choice). Ophthalmologists are using this option in clinical practice but again how do patients in general discover this information [1]? And what of a cancer patient that experiences this specific problem as a side effect from conventional treatment. Why not try this low-cost option?

Interestingly, the American Heart Association (AHA ) guidelines suggest 2–4 g of EPA + DHA (omega-3 from marine sources) per day provided as capsules under a physician’s care for hypertriglyceridemia (500 mg/dl+) or simply “patients who need to lower triglycerides” [51]. Currently, three omega-3 prescription drugs have been approved by the FDA for the reduction of triglycerides and they include: Lovaza (approved in 2004), Vascepa (2012), and Epanova (2014) [52, 53]. However, the question remains whether low-cost over-the-counter omega-3 products (fish oil) are the same, better, or worse at lowering triglycerides compared to the more expensive prescription brands. In my experience, there is no difference except in price and the perception of quality control assurance, but most of the over-the-counter fish oil products have outstanding quality control based on serendipity [25]. This is due to the finding that fish oils are usually derived from short-lived nontoxic harboring fish such as anchovies, sardines, and mackerel. Most of the krill, shrimp, salmon, and even green-lipped mussel fish oils are also well-known for their high quality control, and ease of use/utilization compared to larger fish oils pills, but also high price in some cases, and lack of an impressive number of more rigorous trials with hard clinical endpoints found with low cost (aka cheap) fish oil supplements [1]. And if there is a reason to take fish oil but one needs to avoid large pills, then a children’s flavored liquid easily suffices in terms of taste, quality control, concentration, and ease of use compared to any many fish oil pills or capsules.

l-citrulline (an amino acid derived from watermelon rind) is arguably the most promising supplement for ED at 1500 mg/day because it can significantly raise nitric oxide (NO) levels better than the most commonly used products for this same purpose (l-arginine) [25, 54]. And preliminary clinical research demonstrates that it (l-citrulline free form) may be an adequate option for mild or moderate ED. Many other supplements touted for ED have little to no research. And in many parts of the USA some of ED prescription drugs are approximately 10–40 dollars a single pill. This will moderately change with sildenafil becoming generic but in the meantime other viable options to be utilized with and without prescription medications are being utilized by physicians. l-citrulline malate (or even free form) also has the potential to help with legal athletic enhancement (improve muscle blood flow/oxygenation and remove metabolic waste products to allow muscles to function longer) [55]. And since the only primary dietary source of citrulline is watermelon rind, supplementation is the only option for a medical condition [1, 25].

Individuals with high cholesterol that cannot tolerate statin drugs have the option of using red yeast rice extract (RYR) . However, in one of the more bizarre rulings by federal officials companies are NOT allowed to standardize the active ingredient known as “monacolin K ” (basically identical to isolated lovastatin ), which is responsible for the lowering of LDL cholesterol in RYR [25].

A meta-analysis of 9625 patients in 93 randomized trials involving three different commercial variants of RYR has summarized this alternative option for patients [56]. The mean reduction in total cholesterol, LDL, triglyceride, and increase in HDL was respectively the following: −35 mg/dl (−0.91 mmol/L), −28 mg/dl (−0.73 mmol/L), −36 mg/dl (−0.41 mmol/L), and +6 mg/dl (+0.15 mmol/L).

“Xuezhikang ” is a commercial RYR product evaluated in a large, randomized, placebo-controlled clinical trial with robust endpoints [57]. The China Coronary Secondary Prevention Study (CCSPS) enrolled 4870 participants (3986 men, 884 women) with a previous myocardial infarction (MI ) , and a baseline mean total cholesterol, LDL, triglyceride, and HDL of approximately 208 mg/dl (5.38 mmol/L), 129 mg/dl (3.34 mmol/L), 165 mg/dl (1.85 mmol/L), and 46 mg/dl (1.19 mmol/L). Participants received RYR 600 mg twice daily (1200 mg total, monacolin K 2.5–3.2 mg/capsule) or matching placebo and followed for 4.5 years. The trial was conducted from May 1996 to December 2003 in 65 hospitals in China. The primary end point was nonfatal MI or death from coronary or cardiac causes. Secondary end points included total mortality from CV disease, total all-cause mortality, need for coronary revascularization procedure, and change in lipid levels. Fasting blood samples were drawn at baseline, 6–8 weeks after randomization, and at 6-month intervals. There were two interim analyses, and the second one demonstrated a significant difference for the primary endpoint. The study was stopped in June 2003. A total of 98 % of the participants completed the study. It is of interest that a plethora of clinical endpoints were significantly reduced with the exception of a nonsignificant reduction in fatal MI (see Chap. 4 ). Cancer mortality and all-cause mortality were reduced. Lipids were also modestly and significantly reduced. No serious adverse events were observed during this trial. Total adverse events and treatment cessation numbers were similar for RYR and placebo. The number needed to treat (NNT ) to prevent a primary end-point over the 4.5 year duration of the trial is 21, which favorably compares to the NNT range (19–56) observed in previous secondary prevention trials [58]. Subsequent subgroup evaluations from the CCSPS trial have found equivalent benefits with RYR among diabetics [59], elderly (mean age 69 years) [60], and hypertensive participants [61]. Potential anticancer benefits found in the overall trial with RYR were also found among the elderly (significant reduction in cancer deaths) [57, 60], and included a 51 % reduction in cancer incidence [60]. Thus, the data has been consistent that RYR reduces lipid parameters, especially LDL [62–64], and appears to have a favorable impact on clinical endpoints [57]. Reviews of past studies in statin intolerant patients have demonstrated efficacy and safety [65], including a preliminary study in breast cancer patients where RYR was a primary ingredient in one supplement [66], so it could be an interesting current or future option in some cancer patients. The catch … searching for a supplement used in a positive clinical trial that one can rely on and some are mentioned in this text (for example, Sylvan Bioproducts at www.​sylvaninc.​com/​bio/​healthCare.​html).

There are currently no effective dietary supplements that can consistently increase low testosterone in men [12], and even when testosterone pills were utilized in drugs in many other countries there were health concerns, which is arguably why this form of testosterone was never FDA approved in the USA [1, 25]. In fact, many of the best selling supplements in this category contains fenugreek (Trigonella foenum-graecum), which has not only not worked consistently, but actually showed a significant reduction in free testosterone in one study [67]. Fenugreek was famous/infamous over a decade ago when female breast enhancement supplements used this as their primary ingredient (and it did not work in this situation either) [25]. Fenugreek the food has health benefits but the supplement being linked to testosterone or even estrogen consistent increase needs quality research and I am not optimistic despite the fact that having a supplement to increase testosterone would be well-received if safe because some forms of prescription testosterone replacement are expensive.

Melatonin is a well-known supplement that can help with jet lag but it can also help with occasional bouts of insomnia and has an excellent safety record [1]. Most melatonin supplements are immediate release, which means they do not remain in the body for long (short half-life), but they have still demonstrated efficacy. Currently there is another option known as PR (prolonged release) melatonin that has shown some benefit and is regulated like a drug in some European countries (known as “Circadin^®”) and it is approved in multiple counties for primary insomnia for individuals 55 years and older [68].

The preliminary benefit in utilizing melatonin for breast cancer patients with insomnia or even depressive symptoms with similar side effects to placebo also should be preliminarily impressive (for example one 3 mg melatonin supplement from Rugby Laboratories—a subsidiary of Watson Laboratories in Duluth, GA, USA—used in a Harvard study, or another 6 mg melatonin from Pharma Nord, Vejle, Denmark) [69, 70]. It is critical to continue to find short-term insomnia solutions especially since some of the prescription drugs have come under some scrutiny lately (for example eszopiclone and FDA concerns) because in rare situations higher dosages can lead to fugue states or “impairment,” where the person performs activities, such as driving a vehicle, and does not recall them [71]. And it should be kept in mind that unintentional prescription drug abuse is a leading cause of mortality in the USA with opioids, antianxiety and then insomnia prescription drugs as the top three (in that order) medications that the CDC has identified as a source of this epidemic issue [1].

Prescription drugs and painkillers work well for some migraine sufferers but what does a patient do when suffering from them regularly in terms of prevention? The American Academy of Neurology (AAN) guidelines recommend butterbur extract (Petadolex^® brand licensed to multiple companies including Linpharma Inc., Oldsmar, FL—not identified by AAN, but utilized in the clinical trials) as having class A evidence (one of its highest recommendations) as a method to prevent migraine [72]. Additionally higher dosages of vitamin B2 (generic riboflavin) have excellent preliminary data (Level B recommendation) [72]. Yet how exactly does the patient figure all of this out without a reputable and highly specific source [1]?

There are no effective treatments that slow the progression of this disease but few realize that one of the most interesting options being utilized now by some clinicians and tested in large clinical trials is inosine (from initial research funded by the Michael J. Fox Foundation, US Government/NIH and others and called “SURE-PD” Trial and inosine supplements were obtained from Kyowa Hakko USA Inc., New York, NY) to slow the progression of this disease by raising uric acid levels (making sure patients are monitored carefully by a health care professional because taking too much can increase the risk of kidney stones ) [1, 73]. Inosine is also receiving research currently in Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS) [1].

Creatine monohydrate is commonly associated with exercise enhancement but it was also being studied at 10 g a day in arguably one of the largest and well done trials in PD to potentially slow clinical decline and improve quality of life (45 clinical sites in the USA and Canada for a minimum of 5 years) [74]. After reviewing the data from an interim analysis of 955 patients enrolled at least 5 years in this trial there was no observation of efficacy, so the study was appropriately stopped [75].

Chronic antibiotic use for the prevention of recurrent UTIs may have efficacy but also have potential toxicity and the development of resistance. Cranberry dietary supplements have worked as well as cranberry juice in preventing UTI for individuals that suffer from recurrent UTIs but this is still preliminary data [76, 77]. Regardless, cranberry supplements only contain a few calories whereas cranberry juice contains about 125–150 calories per 8 ounces, which can increase your weight and waist, which in the long-term could theoretically increase the risk of UTIs [25]. Supplements with higher concentrations of the active ingredients, PAC-A (proanthocyanidin A) , need more research [77, 78], but are arguably an option being utilized currently for antibiotic-intolerant patients based on benefit over risk ongoing research [25, 77–79]. Looking for reasonable priced supplement with a higher concentration of PAC or especially PAC-A is important since there is no stand out product from a major clinical trial (numerous products exist in Europe such as Anthocran, Cysticlean, Monoselect Macrocarpon-enteric-coated that are regulated).

Green coffee bean extract , Garcinia cambogia, acai berry … there are a countless list of weight loss supplements that are controversial. However, protein powder isolates (no sugar or lactose) contain as much as 25 g of protein per 100 calories far exceeds what can be accomplished with almost any protein bar or dietary option [1]. It should be “first do no harm” when dealing with weight loss and dietary supplements. Research continues to accumulate that this or another protein powder is a potential option to encourage weight/waist loss and enhance lean muscle mass in association with resistance exercise/exercise and moderate calorie reduction from an analysis of 14 randomized trials [80]. Cancer patients experiencing sarcopenia from treatment should at least be informed of this data. Additionally, alpha-lipoic acid (ALA) has received some interesting rigorous trial results and it may just function as a less potent metformin mimic (see Chap. 6), but ALA is a regulated drug in many countries but it is a supplement in the USA (from multiple easy to access companies) [1].

Excuse the distraction for a moment on the discussion of plant sterols (also see Chap. 4), but it is not only educational on some specific dietary supplements and nutrient added to foods and beverages (plant sterols and stanols) to lower cholesterol, but demonstrates what has become somewhat common when utilizing someone else’s research to promote a new product that in and of itself has little to no research.

Phytosterols are found in a variety of plants and plant oils [81]. Phytosterols are similar in structure to cholesterol except for minor structural differences. They are not synthesized in humans and minimally absorbed, excreted more rapidly from the liver compared to cholesterol, and not found in high concentrations in human tissues. The main phytosterols found in diet are sitosterol, stigmasterol, and campesterol. Beta-sitosterol is arguably the phytosterol found in largest quantity in the diet (please keep this in mind). Phytosterols block the uptake of exogenous cholesterol from dietary and bile sources in the intestinal tract. LDL cholesterol is reduced by phytosterols, and HDL and triglycerides are not impacted. The blockage of cholesterol absorption may produce a relative cholesterol pool reduction that is followed by up regulation of cholesterol synthesis and LDL receptors, which can increase LDL removal. This is somewhat similar to how some healthy dietary fats found in many healthy foods such as almonds or pistachios may also reduce LDL and improve some health outcomes [82, 83].

An ample quantity (over 40) of clinical trials utilizing phytosterols themselves has been conducted that have ranged from 1 to 12 months in duration [81, 84, 85]. Plant sterols added to foods such as yogurt, margarine, orange juice, mayonnaise, olive oil, and milk have been shown to reduce LDL by approximately 10–15 % (mean of 10–11 %) when approximately 2000 mg or more per day is ingested. And 1600–3000 mg of plant sterol supplemental or tablet consumption can also reduce LDL approximately 4–15 %. Plant sterols may also reduce the absorption of some fat-soluble vitamins, so there has been some debate as to whether multivitamin consumption should occur with the use of these products, and I agree that one multivitamin per day should also be encouraged.

It is interesting that the primary mechanism of action of these sterols via cholesterol uptake reduction and a minor anti-inflammatory mechanism suggests, in my opinion, that they are weaker or less potent mimics of the drug ezetimibe (Zetia^® ), which can reduce LDL by approximately 20 % with 10 mg dose [86, 87]. Laboratory research suggests ezetimibe favorably impacts prostate tissue and reduces prostate enlargement [88]. Ezetimibe is also commonly added to statin therapy or other lipid lowering agents to achieve synergistic impacts and more favorably reduce LDL [86, 87]. Thus, it should not be surprising that beta-sitosterol by itself or with other lipid lowering medications could reduce non-cancerous prostate enlargement (BPH) symptoms. For example, despite some data to suggest no impact of statins on established BPH over a short period of time [89, 90], other epidemiologic and past laboratory studies suggest potentially favorable impacts on BPH prevention and progression with cholesterol lowering prescribed medications [91–94]. What does this have to do with supplements in general? No problem, we will arrive at this point very soon.

There were two critical and similar reviews that were published in 1999 that has allowed beta-sitosterol supplements to become a potential option for BPH [95, 96]. It is interesting that since this time period no other definitive clinical trials (positive or negative) have been published. The first systematic review was by Wilt et al. and appeared in BJU international that identified studies from 1966 to 1998 [95]. A total of four clinical trials that included 519 men met the inclusion criteria [97–100]. All four trials were randomized, double-blind, placebo-controlled that included men with mild to moderate symptomatic BPH, and the intervention was given from 4 to 26 weeks. Beta-sitosterol significantly improved symptom scores and flow measures compared to placebo. Beta-sitosterol had no impact on prostate size. Gastrointestinal side effects were the most common side effects and occurred in 1.6 % of men on beta-sitosterol compared to 0 % on placebo. Erectile dysfunction was reported in approximately 0.5 % of men on beta-sitosterol and none on placebo. The authors of this systematic review concluded that beta-sitosterol “improves urological symptoms and flow measures,” but that more long-terms studies and standardization of beta-sitosterol preparations were needed. The beta-sitosterol utilized in these studies were known by the names “Harzol ,” “Azuprostat ,” or “WA184 ” (standardized like drugs in other countries), usually derived from South African star grass (Hypoxis rooperi or from species of Picea or Pinus). Studies used primarily purified extracts and three studies used “nonglucosidic B-sitosterol” again from 60 to 195 mg/day (two of these studies used Azuprostat, 65 mg TID or 195 mg/day with a 70 % beta-sitosterol content). The preparation generally contained 50 % or higher amounts of B-sitosterol.

The second review was published in 2000 and consisted of similar authors compared to the first review [96], except there may be the potential for beta-sitosterol to reduce getting up at night (nocturia) approximately one less time. The positive results observed in these trials compare with results from pharmaceutical agents. Although beta-sitosterol was considered the active ingredient in these clinical trials this has not been definitively proven but it is reasonable to conclude that it is the most likely or primary efficacious ingredient.

The clinical question is why not just utilize beta-sitosterol as a stand-alone cost-effective single ingredient pill as a patient or recommend it as a clinician? Beta-sitosterol is a heart healthy low-cost ingredient. However, the dosage recommended in cholesterol treatment guidelines is 2000–3000 mg a day to reduce LDL by 6–15 %, and in fact in these National Cholesterol Education Panel recommendations it states that the following: “Plant stanol/sterol esters (2 g/day) are a therapeutic option to enhance LDL cholesterol lowering” [101]. This should be kept in mind when consulting with patients about beta-sitosterol because it is important to be able to discuss the efficacious dosages from the older 1990 prostate studies (20–65 mg TID) compared to the evidence-based hearth healthy guidelines of just plant stanol/sterols to reduce LDL cholesterol (2000–3000 mg/day). Regardless, using just beta-sitosterols or plant sterols by themselves make clinical sense right, but perhaps does not make cents but dollars.

Currently there appears to be multiple costly prostate healthy products that patients are paying as much as 30–50 dollars or more per 1–2 months that appear to have diverse and numerous ingredients but promote their product utilizing the research mentioned earlier. This was not the research on their product but the research someone else conducted. This has ethical issues in some cases because it is my perception and reality that the patients believe the product being sold to them at a high price was the exact product utilized in the research! However, again this is not the case and more importantly they are a variety of other ingredients in these products that combined have never been tested in any clinical trial or any single rigorous clinical trial. For example, imagine if I sold you aspirin and then I sold you aspirin with ten other ingredients in the same pill and utilized the research on aspirin itself to sell the more expensive 10-item pill! Oh, and I also added a celebrity endorsement to promote the product with real verve. And this is exactly what has been done by some (small number but vociferous and profitable) companies in the supplement business, but one would hope that patients and clinicians would be wise enough to simply just recommend low-cost aspirin? Yet this is not the case in my opinion because they are not aware of what is happening in terms of the “bait and switch here.” Thus, in this example I would simply just recommend beta-sitosterol from food or the lower priced single ingredient or primarily generic “plant sterol” supplement pill compared to any other product, and this would save the patient a large sum of money and would follow the research and it would appear to be the most ethical route. These tactics are not utilized only in prostate health products but throughout the supplement spectrum by a select number of companies so just being aware of this one teachable example, which can pave the way for future objectivity, success, and cost-savings for your patients. As I was writing this chapter coincidentally I observed multiple other celebrity endorsed weight loss and other products that are costly and utilize one ingredient or several from some other groups research and surround that ingredient with others that do not contain arguably any reliable clinical research (the beat goes on unless it is stopped at the grass roots or patients and health care professional level).

Plant sterols are an interesting option and they arguably will continue to garner positive data. For example, the early research in breast cancer suggests that this and other compounds in this class are heart healthy and breast healthy [102]. And lowering cholesterol by blocking the uptake of cholesterol from food is now again a legitimate pharmaceutical option (again ezetimibe or Zetia), especially after the recent conclusion of the IMPROVE-IT clinical trial of over 18,000 patients in a randomized, double-blind that included a placebo and statin arm versus statin and ezetimibe [103], and has preliminary anticancer effects via favorable lipid changes or a reduction in inflammation [104]. Please see Chap. 4 for more on this and other lipid lowering products (such as PCSK9 inhibitors) that will be utilized in clinical trials with cancer patients in the future.

• Remember, the primary goal with patients should be pill-free or the minimum number of pills needed ( MNPN) and NOT to encourage a self-medication personality.

The concept or belief that a pill is needed regardless of evidence or safety should be antiquated, but it is not. Patients should be instructed that based on an extensive evaluation of benefit-versus-risk a pill (supplement or prescription) should be considered. Ingesting countless pills, without evidence for this practice, I have found no different from an addict self-medicating for the pleasure derived from his or her drug of choice. The plethora of other negative outcomes with self-medication practices apart from dependence and abuse abound including: incorrect use, delay in care, adverse reactions, drug interactions, masking of another physical or mental health issue … [105]. When talking to patients about prescriptions or supplements I believe the initial mantra should be “less is more” and patients appear to appreciate that philosophy because it saves money and sets a philosophy from baseline that you are objective when it comes to pill ingestion (aka “not in the back pocket of the pharmaceutical or supplement industry”).

Arsenic, tobacco, mercury, … are all natural but I do not recommend them. Pills contain all kinds of obscure compounds such as fillers and binders and compounds that are not natural at all and the body must metabolize and excrete them. And the longest-lived populations in the world from Andorra to Mediterranean to Singapore are not massive pill consumers (quite the contrary) [1]. There is also nothing natural about indoor pipes, heating and cooling systems, airplanes, highways …, but I am grateful they exist. The “natural” is better debate is one that I find is often used to create some kind of debate advantage that is usually tied into something financial or profitable in the industry. I often explain to the public and patients that I have no idea if something natural is better, worse or the same for you unless it is tested. For example, I have heard for years that natural vitamin E supplements are better compared to synthetic but in reality in major clinical trials the benefit and toxicity have been similar or with slight differences neither advantageous or disadvantageous. In fact, it could be argued that from eye disease to other medical conditions such as Alzheimer disease that synthetic vitamin E actually has slightly better efficacy data now [13, 14, 20–22], but in reality I treat them the same. It could also be argued that Centrum Silver is the most tested synthetic multivitamin in the history of medicine from the 11-year and over 14,000 individuals tested versus placebo in the Physicians Health Study II. Regardless of the modest reduction in cancer and cataracts the percentage of patients experiencing or reporting rash with the placebo or multivitamin was 27–29 %. In other words, ingesting any pill including a placebo has the potential to create some minor to major side effects. There is nothing “natural” about taking a pill unless one actually needs a pill.

Many, if not most drugs have patients that experience “tachyphylaxis ” (Greek, meaning “rapid” and “protection”) or desensitization to a medication after it has been utilized for a short or long period of time. For example, histamine 2-receptor antagonists, antidepressants, statins, nitrates, and most classes of drugs have some patients that experience this phenomenon [106–109]. Yet there is little to no research on tachyphylaxis with dietary supplements. However, it is evident that in multiple past studies utilizing a well-known supplement a form of tachyphylaxis can easily occur, for example when larger doses of l-arginine are administered in patients with essential hypertension to increase nitric oxide levels [110]. It is also known that saturation kinetics does not allow some supplements to exceed a certain concentration without excessive displacement in the urine or other physiologic spaces or as another metabolic by-product. This is another form of tolerance, but whether or not tachyphylaxis is encouraged under these circumstances is not well known and does not matter simply because toxicity eventually surfaces because of this phenomenon. Ingesting too much of a compound eventually causes saturation of the blood or tissue and the rest of the compound is discarded or increases to unhealthy levels [25]. For example, overexposure to calcium and vitamin C supplements could increase the risk of kidney stones [111, 112]. Selenium can get deposited in soft tissues and increase the risk of nail or hair loss, and perhaps even diabetes, skin cancer recurrence, and other cancers in excessive amounts [1, 25]. Thus, the concept of tachyphylaxis and/or saturation kinetics needs to be explained to patients as another reason why a supplement should not be ingested without extensive analysis of the benefit-to-risk scenario. Folic acid has a metabolic by-product known as “UMFA” or unmetabolized serum folic acid that could be a future concern in those that ingest mega-quantities of this dietary supplement. Vitamin A can cause excessive damage to the liver in large amounts. Vitamin B6 can cause a sensory neuropathy at excessive intakes. And the list goes on and on …. The idea that “water-soluble” vitamins like the B-vitamins or vitamin C are harmless in excess if you take excess amounts that just get excreted in urine is obviously an antiquated thought process and designation, as is “fat-soluble” essentially (although fat in diet may increase their absorption). In other words, all of these compounds or supplements display toxicity in excess and this has already been known for some supplements and for the rest it is starting to reveal itself via good research.

• Pill esophagitis? Ulcers? Kidney stones made of sand (silicon dioxide) oh my? The ongoing list of side effects from dietary supplements or pills. Another reason that pill ingestion is not “natural” unless needed.

Pills come with unique side effects, and although life saving in many cases, another reason not to ingest a pill unless needed is due to “pill esophagitis .” This is known in the pharmaceutical industry for example and often it is due to patients not drinking enough water or standing up when ingesting a pill [113]. The symptoms of pill esophagitis include difficulty swallowing, pain on swallowing, and retrosternal pain. Yet dietary supplements can also cause pill esophagitis and esophageal ulcers [114], so the concern or at least recognition over this side effect in the supplement industry should immediately match that of the pharmaceutical industry. Increasing awareness of dietary supplement side effects allows for the identification of pill side effects unique to the industry itself, especially when compounds such as “silicon dioxide ” (aka “sand”) are utilized in some products to a large extent (improve flow or anti-caking agent). Recently, recognition of an increased risk of 100 % silicate based kidney stones can occur in products that contain ample amounts of this compound [115]. And this is just one of many compounds uniquely utilized in pills, especially supplements that were believed to be inert in humans.

Grand Rapids, Michigan became the world’s first city to add fluoride to its drinking water in 1945 and within 6 years of this landmark change a study showed dramatic reductions in tooth decay among children living in this area [116]. Next, the US surgeon general and others began to endorse it. Fast forward to now, and approximately 75 % of Americans receive fluoridated water . However, recently federal officials (aka Department of Health and Human Services) released a statement that they are lowering the recommended amount of fluoride in drinking water because some kids are getting too much, which could cause white splotches on their teeth (also known as “fluorosis ”). This overexposure to fluoride appears to be permanent in many cases unless of course an individual receives some kind of tooth whitening procedure to correct it. In fact, in one study 40 % of adolescents had tooth spottiness or streaking. Thus, this recent announcement to lower fluoride is a smart move. Since 1962, the government has recommended a range of 0.7 mg/L for warmer areas where individuals consume more water to 1.2 mg in cooler areas. Now, the new government standard is simply 0.7 everywhere. Not dramatic, but a small significant step in the right direction. The CDC’s advice for small children is to not use fluoride toothpaste for children under 2 unless recommended by a dentist and use only a pea-sized amount of toothpaste for children 2–6 and avoid fluoride mouthwash.

And regardless of what side of the fence you are when it comes to fluoridating water, the bigger implications of this latest government recommendation has even far broader implications when it comes to future nutrition and supplement recommendations! What? What is Dr. Moyad talking about? How is that related to the whole fluoride controversy—seems like an obvious non-sequitur Moyad, right? Nope!

Several years ago during my lectures I decided to review clinical studies with health care professionals that showed why getting more of something that is perceived to be healthy, if you are already healthy, has in general never been shown to be better. And the reason I added this to my teachings and regular lectures is due to the disturbing trend I began to see in countless situations, where a plethora of compounds were being added to the food or beverage supply in large amounts from so many directions including fluoride. You see, one of the biggest frustrations I was experiencing was antiquated nutritional lectures being given to health care professionals as if we were living in the year 1750 and mentioning for example that if you do not get enough vitamin C you can get scurvy. If you do not get enough vitamin B6, you can get nerve damage, not enough beta-carotene or vitamin A then night blindness, or if you do not get enough niacin you can get the disease “pellagra ” [25]! Our clinics are not satiated by these medical conditions anymore.

Today the issue is not getting too little vitamin C, but some individuals are getting too much supplemental vitamin C , which is increasing their risk of kidney stones [25]. Too much supplemental B6 actually can increase the risk of nerve damage, too much supplemental beta-carotene in former and current smokers could increase the risk of lung cancer, too much supplemental vitamin A can increase the risk of liver toxicity, and consuming too much supplemental niacin is now linked to liver toxicity and potentially heart unhealthy changes. Physicians in the USA hardly ever see these nutritional deficiency diseases anymore unless they volunteer in third world countries. In fact, most of the nutritional deficiencies I see today are from the overuse of many medications, which is now “first world” country. For example, chronic use of acid reflux drugs can result in a deficiency of vitamin B12 and/or magnesium, which the FDA recognizes along with multiple other issues [117]. My point is that nutritional education needs to change to spend more time addressing what I call in medical publications the “over-antioxidation of our population” or “the over-antioxidation of the US population” [118].

We now live in a time where nutrition and supplements are a billion dollar industry where folks compete to add the latest and greatest nutrient to the food supply, which in some cases can result in an overexposure to many things. For example, selenium deficiency use to be a serious problem in some countries, and it is still can rarely cause a serious medical condition known as “Keshan disease ” but today an overexposure of selenium is more common and could lead to problems [12, 25]. I remember only a few years ago attending multiple medical lectures where Keshan disease was mentioned as a reason for some individuals to supplement with selenium?!

In one of the largest dietary supplement studies ever completed in the world (SELECT Trial) in healthy individuals, researchers recently found the potential for an increased aggressive prostate cancer risk in men getting large amounts of selenium from food and then taking a higher dose of selenium as a supplement [43]. In other words, if you were already receiving sufficient selenium from the diet and then you added more in terms of a supplement (200 μg a day), then more was not better. However, it was not that long ago selenium was difficult to find in our food supply but in the 1990s when preliminary research showed a potential anticancer and overall health benefit of selenium it took only a few years before it started getting added to many nutritional products from protein powders to almost every basic multivitamin. So, by the time this landmark SELECT study started the minimal deficiency once seen in the USA with selenium was no longer an issue, and sufficiency or overexposure quickly became the problem [25]. There is also the concern that an overexposure to selenium can increase the risk of skin cancer returning after treatment. This is also somewhat similar to the story with calcium supplements in this country. Some US restaurants have now enriched their breads with calcium, and calcium is fortified in many foods and beverages from numerous almond milks that contain over 450 mg of calcium in just 8 ounces, to some multivitamins replete with calcium. Now, in most major clinical trials women are getting enough calcium from food and beverages to match or exceed the RDA so that by the time a clinical trial of calcium supplements and bone health is initiated, many of the participants are replete with calcium before the study even starts. This was observed not long ago in one of the largest clinical trials in the world to prevent bone loss and fractures known as “WHI” or the Women’s Health Initiative [119]. The end result … more kidney stones in the group taking calcium and recent concerns that more calcium is not better for women and men. Calcium and vitamin D deficiency used to be such a problem in the USA that the disease rickets (a bad bone disease ) occurred, but now this has become rare, and it was only a few decades ago that not getting enough calcium caused an increase risk of kidney stones [25].

Now, think about the number 1 cause of acute liver failure in the USA. It is due to overexposure to the over-the-counter pain reliever acetaminophen, generally (not always) in combination with alcohol. However, acetaminophen has been around a long time and so has alcohol, so why only more recently did this become a problem? In my opinion it is due to the overexposure of a drug that use to be just sold as a pain reliever and during my lifetime it got added to almost everything you can imagine, from as many as 50 % of the cold and flu therapies, to many of other targets discomfort relievers [25]. We woke up one day and it was everywhere and it is now so easy to be overexposed to this drug. Acetaminophen is a good drug but the overexposure to it has led to devastating consequences.

And fluoride use to be fairly difficult to ingest in the USA and during my lifetime it got added to almost all the dental products such as toothpaste and mouthwashes and the drinking water supply [116]. Thus, the call for the reduction of fluoride by the US government (a first in over 50 years) in my opinion is a harbinger of things to come where sudden overexposure to certain compounds and ingredients and eventually the risk will exceed the benefit, and more government or simply personalized regulation will reduce the overexposure of what not to long ago was a “deficiency.” It is not 1700 or 1850 and part of our challenge is accepting the benefits and limitations of past dietary and medical advice, and how it really pertains to the modern world. We need to be vigilant and be willing to admit when we have reached the point where more does not mean better, and at least with fluoride that moment has arrived. The question now is “What is next?”

Is there really anything the US population and other industrialized countries have an overt “deficiency” of today that might still exist 50 years from now in the population? There are a small number of subtle exceptions or true subtle “deficiencies” today and for objectivity and completeness of this discussion they are mentioned in the next section.

This will be reviewed in the next chapter, especially fiber but these two “deficiencies” I often lecture on are simply part of eating more heart healthy and primarily pertain to chronic disease prevention.

Low potassium is a problem for arguably 98–99 % of the population. Why? Few people realize that the suggested intake or arguably the recommended daily allowance (RDA) or recommended daily intake for adults is 4700 mg/day (only 1–2 % of the population) [1]. This is how much is needed to keep the body functioning normally in terms of disease prevention, for example stroke and hypertension, kidney stones … [120]. Say you eat a banana every day, but that only gives you 450 mg or less so where are you going to get another 4000+ mg during your day? Another 8+ or so bananas daily?