What's in that supplement?

I heard a news story on NPR that inspired this week's blog post. The story was about dietary supplements containing prescription drugs, banned (illegal) substances, and otherwise unlisted and inappropriate ingredients.

Michael J. Ermath by FDA graphic. "Miracle Cure!" Health Fraud Scams (8528312890) 

In the course of the story, reporter Allison Aubrey interviewed Dr. Pieter Cohen. He is a physician, researcher and one of the authors of a paper that recently appeared in The Journal of the American Medical Association (JAMA) about the continued presence of adulterated ingredients in dietary supplements. I decided to do some more reading about this topic, read Dr. Cohen's paper, and see what more I could learn about the ingredients lurking in supplements, particularly those claiming to promote weight loss or enhance performance.

Resources

NPR - Allison Aubrey news story about adulterated dietary supplements (aired 10/22/2014, accessed 10/23/2014)

Michael J. Ermath by FDA graphic. "Miracle Cure!" Health Fraud Scams (8528312890). Licensed under Public domain via Wikimedia Commons - http://commons.wikimedia.org.

A little background

• Billions of dollars a year are spent on dietary supplements. 

• Manufacturers of dietary supplements are not subjected to the same type of pre-market approval process that pharmaceuticals go through. The Food and Drug Administration (FDA) does not evaluate dietary supplements for safety and efficacy before they go out into market. 

• There are regulations regarding dietary supplements and new ingredients. "If the dietary ingredient has not been present in the food supply as an article used for food in the same chemical form that you plan to use in your dietary supplement, you must show why you consider that the new dietary ingredient will reasonably be expected to be safe under the conditions recommended or suggested in the labeling."  FDA - Dietary Supplement Labeling

• Dietary supplement manufacturers are required to make sure that their products are safe and that they only make truthful claims about their products.  

• Because of high rates of dietary supplement use by the people in the armed forces and health risks associated with certain types of dietary supplements, the Department of Defense (DoD) is actively involved in facilitating awareness and research about dietary supplements. Below is an informative video about dietary supplements created by DoD. It provides some general information and focuses on weight-loss and performance enhancing supplement use. It is targeted to members of the armed forces, but it is largely applicable to anyone who is interested.

http://hprc-online.org/blog/stay-informed-about-dietary-supplements

Banned ingredients  

Dietary supplements containing illegal substances are identified through random and targeted sampling of products. Testing may be the result of research, or it may be the result of an investigation by the FDA in response to a number of serious consumer health concerns.

Weight-loss, performance enhancing, and sexual performance dietary supplements are among the main targets for supplement adulteration. These supplements may include (banned) prescription weight loss drugs, amphetamine-like drugs, anabolic steroids, prescription antidepressants and erectile dysfunction medications. This article, FDA Q&A, describes some of the most commonly encountered drugs in weight-loss supplements and the risks associated with them. The FDA also provides a list of some of the products that have tested positive for illegal substances. 

"These products are not legal dietary supplements. They are actually very powerful drugs masquerading as 'all-natural' or 'herbal' supplements, and they carry significant risks to unsuspecting consumers." -- Michael Levy, director of FDA's Division of New Drugs and Labeling Compliance

Why do illegal ingredients end up in dietary supplements? 

• Some of these ingredients were once legal and are now not. 
• It is possible for an ingredient to be unsafe but effective. So, consumers will want more of your specific product because they get the best results. 
• This a health and safety risk because consumers keep coming for more therefore increasing their exposure.  

• It is possible there is a surplus of a drug for some reason. Perhaps it was discontinued or did not get approved.  

• Some drugs are considered experimental in the U.S. because the FDA has not approved them but they are approved in other countries. This is an illegal drug and is not okay to have in the supplement.

• The ingredient may be easy and inexpensive to manufacture.  Including it in the supplement may be cost effective. 

It is important to recognize that not all supplement companies engage in the unscrupulous and illegal practice of product adulteration. Unfortunately, it is difficult to figure out from the label which manufacturers/distributors are okay and which are awful.

Resources

Food and Drug Administration. (March 23, 2011) Questions and Answers on Tainted Products Marketed as Dietary Supplements.  http://www.fda.gov/drugs/resourcesforyou/consumers/buyingusingmedicinesafely/medicationhealthfraud/ucm247094.htm. Accessed November 3, 2014.

Food and Drug Administration. (May 13, 2014) Beware of Fraudulent Weight-Loss 'Dietary Supplements'. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm246742.htm. Accessed October 23, 2014.



In the literature

Cohen P, Maller G, DeSouza A, Neal-Kababick J. (2014) Presence of banned drugs in dietary supplements following FDA recalls. JAMA 32:16. 

From January 2009 through December 2012 the FDA recalled 274 dietary supplements because they contained adulterated ingredients. After the recalls were issued some companies quit selling and manufacturing the recalled product all together and others continued with the assurance that it had been reformulated in some way. Cohen and colleagues wanted to find out if the illegal ingredients were still in the products or if other illegal ingredients had been added to the products.

What they did

• The researchers looked for the following types of products to be included in the study:
• products that were recalled between 1/2009 and 12/31/2012 specifically because of the presence of pharmaceutical ingredients;
• they had to be able to purchase the products during July or August 2013 directly from the manufacturer's website or directly from a retailer (they did not use third party vendors).

• Twenty-seven of the 274 recalled supplements met the inclusion criteria (9.9%). These supplements were sent to a laboratory for analysis.

• All of the samples were analyzed by one laboratory.
• They sent the lab samples labeled only by the claim the manufacturers made (weight loss, sports enhancement, sexual enhancement).
• The lab technicians did not know who made the supplement, what the supplement was, or what the FDA had previously found in the supplement.
• The lab followed all of the procedures and protocols that the FDA uses to screen dietary supplements for adulterated ingredients. 

What they found when they analyzed the 27 recalled supplements

• The majority were produced in the U.S. (74%, 20/27)

• The majority contained at least one prescription drug (66.7%, 18/27)
• Weight loss: 67% (6/9)
• Sports enhancement: 85% (11/13)
• Sexual enhancement: 20% (1/5)

• When they looked at the 20 supplements produced in the U.S., they found that 65% (13/20) contained at least one illegal ingredient.

• The majority of supplements (63%, 17/27) contained the same ingredient initially identified by the FDA that lead to the recall.

• Some products contained more than one illegal ingredient (22.2%, 6/27) that had not been identified by the FDA.

• Here is a summary of ingredients still found in the products they tested:
• Sibutramine and sibutramine analogues (weight loss drug, banned in 2010)
• Sildenafil (prescription drug for erectile dysfunction and pulmonary arterial hypertension)
• Fluoxetine (prescription antidepressant, Prozac)
• Phenolphthalein (prescription laxative, banned)
• Aromatase inhibitors (prescription drugs, breast cancer treatment)
• Various anabolic steroids

Limitations in their research:

• small sample size of 27/274 recalled samples;
• researchers recognize that they may have missed some of the adulterated ingredients because they tested for substances based on how the manufacturers marketed the products. In other words, they specifically looked for certain drugs they might find in products promoted for weight loss and performance enhancement (sports and sexual) but they could have missed out on other ingredients. 
• New ingredients and analogues of existing ones are developed all the time and they have missed some of those. That is always a limitation.
• They assumed that waiting six months from the time of the recall would provide enough of a "wash-out" period to remove the adulterated products from the marketplace and replace them with the (allegedly) reformulated ones. In reality, retailers still may have had recalled products on their shelves. 

Cohen P, Travis J, Venhuic B. (2014). A synthetic stimulant never tested in humans, 1,3-dimethylbutylamine (DBMA), is identified in multiple dietary supplements. Drug Test. Analysis. DOI 101.1002/dta.1735.

1,3-dimethylbutylamine (DMBA) is an analogue of 1,3-dimethylamylamine (DMAA) that is showing up in dietary supplements. DMBA is a stimulant like DMAA. To better understand why it is concerning that DMBA recently started to appear in dietary supplements, we should first look at DMAA. 

DMAA is a synthetic chemical known by names including methylhexanamine or 1,3-dimethylamylamine. It was developed by Eli Lilly in the 1940s and was used as prescription nasal decongestant for many years. The chemical structure of DMAA strongly resembles the chemical structure of amphetamines and this is the the problem with DMAA. While it works to alleviate nasal congestion, it also stimulates the central nervous system like an amphetamine does. It increases blood pressure and the risk of cerebral hemorrhage, stroke, heart attack, and sudden death FDA-Dietary Supplements-DMAA.

In 2006, DMAA started appearing in dietary supplements that promoted weight-loss or enhanced sports performance. DMAA can have severe to deadly effects on blood pressure and cardiovascular health. These effects can be rapid and irreversible. It can happen to otherwise healthy people who take DMAA containing supplements before exercising. Please check out this video from NBC: NBC - Jack3d (DMAA) - Deadly Workout - Video (~9.5 min). 

As of July 2013, USPLabs agreed to voluntarily destroy its remaining stock of Jack3d. There may still be original supplies out there (FDA-Dietary Supplements-DMAA).

DMAA is a stimulant with dangerous and potentially deadly side effects. DMBA is an analogue of DMAA. It has never been studied in humans and it is showing up in dietary supplements. It is not illegal because it is not technically DMAA. It is listed on some product labels in a variety of ways including

• AMP citrate
• 4-amino-2-methylpentane citrate
• 1,3-dimethylbutylamine citrate
• 4-amino-2-pentanamine
• Pentergy
• 4-AMP

What they did

• The researchers looked for the following types of products to be included in the study:
• had to be on the market in April 2014
• had to carry one of the following DMBA market names 
• AMP citrate; 4-amino-2-methylpentane citrate; 1,3-dimethylbutylamine citrate; 4-amino-2-pentanamine; Pentergy; 4-AMP.

What they found

• They found 14 supplements met their inclusion criteria
• Sports related: 38.5% (5/13)
• Weight-loss related: 38.5% (5/13)
• Brain-enhancer: 23.0% (3/13)
• Unclear: (7.7%)

• DMBA present in products tested
• Twelve supplements contained 13-120 mg DMBA
• Based on maximum intake instructions on packaging, will get between 26-320 mg/day DMBA
• Two supplements contained 0 mg DMBA

• Two labels indicated DMBA was extracted from Pouchong tea.
• DMBA is a synthetic product. 
• Cohen and colleagues discuss that if DMBA is in fact an actual degradation product, as one study suggests is possible, then the manufacturers of the dietary supplement would have needed a minimum of 1,000 kg (2,200 lbs) of tea to be able to extract 12 mg of DMBA. That is unrealistic, not cost effective, and highly unlikely. 
• As discussed in the paper, the amount of DMBA in the supplement far exceeds any degradation product that one might be exposed to through drinking tea.

Implications

DMBA appears to be inexpensive and easy to make based on how much of it they detected in supplements. If it were rare or being extracted from plants, it is reasonable to expect it to be used with more discretion. According to Cohen and collegaues, there is no evidence to support that DMBA comes from plants. 

There is a no data available regarding how DMBA impacts the body. It is a chemical analogue of DMAA, which means it is very similar but in some way different. That difference will sometimes alter the way a chemical functions. The effect can be to dull the function, accelerate it, neutralize it, or have no effect at all. With DMBA, no data is available regarding what the effect is.  Considering the devastating effect that DMAA can have it seems like an unnecessary risk to take. DoD recommends military personnel avoid DMBA containing products DoD - DMBA -FAQ.

Reliable Resources

http://www.fda.gov/aboutfda/transparency/basics/ucm193949.htm

http://hprc-online.org/dietary-supplements

http://ods.od.nih.gov/

https://www.consumerlab.com/

http://www.nlm.nih.gov/medlineplus/druginfo/herb_All.html

http://www.quackwatch.com/

http://www.cspinet.org/index.html




Final Thoughts

It is a dangerous world out there when it comes to dietary supplements. It is difficult to know which manufacturers to trust and which , if any, products are worthy of your money. Weight loss and performance enhancement supplement revelations and promotions scroll across our computer screens every day. There are no shortcuts or magic pills.
Changing body weight and improving physical performance requires work. 

If you are considering a supplement of any kind for any purpose, please consider whether or not the the following words, ideas or marketing tools are used. If any of these are a part of the promotion, it may be a red-flag that the product is coming from a less than reputable company.

• Too good to be true
• Use of words like "guaranteed" or "scientific breakthrough"
• Marketing by mass e-mail
• Marketed as an herbal alternative to an FDA approved prescription treatment but promises to provide similar results

Remember that celebrity endorsements are advertisements, even when they come dressed up in lab coats with MD after their name. For me, Dr. Oz is the classic example of someone who has indiscriminately abused his power as a celebrity endorser of health products. Because of his status as a physician, I have long since found his behavior to be the most abhorrent of all. I'll leave you with this John Oliver video clip. It's about 16 minutes long.

"We have seen deaths associated with these weight-loss products. Make no mistake - they can kill you." --Michael Levy, director of the FDA's Division of New Drugs and Labeling Compliance