The Drugs and Dietary Supplements Dilemma

How would you like to have a pill that would reduce body fat, increase muscle mass, and improve glucose tolerance?  Well, you do, if you’re a mouse.  Making a similar product available for people and knowing that it will work?  That’s another story.

Wonder Drug? 

Ursolic Acid, a component of apple peels, increases muscle mass and decreases fat mass when 0.14% of ursolic acid was added to the diet of mice.  In addition, it seems to increase the activity of insulin!  Ursolic acid also increases brown fat, a tissue that shares developmental origins with skeletal muscle.

Consistent with increased skeletal muscle and brown fat, ursolic acid increases energy expenditure, leading to reduced obesity, improved glucose tolerance:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379974/

and http://www.eurekalert.org/pub_releases/2015-09/uoih-kom090815.php

Seems like a wonder drug, right?  Except that it isn’t.  And it’s not likely to become one.  Why? Well, there are several reasons:

• These studies were done in mice.  Mice are not people.
• Clinical trials to prove safety and effectiveness in people are expensive, hundreds of millions for a full set of Phase 1, 2, and 3 clinical trials. 
• Most importantly, ursolic acid is not patentable.  The compound exists in nature and its use to increase Body/Mass Index has already been disclosed. So no drug company can make money on it.

Ok, why not just eat apples?  They have 50mg per peel.  You would have to eat the peels of > 60 apples per day in order to get the amount of ursolic acid that the mice got.  Not an impossible task.  But I’m not going to start peeling apples yet.  I’d still need some answers:

• Is the ursolic acid in apple peels bioavailable?  I don’t know. 
• What else is in apple peels that becomes important at 60 per day?  I don’t know.
• Does ursolic acid work in people the way it appears to work in mice?  I don’t know.

The Cost of Clinical Trials

So here’s where we are.  We know that ursolic acid provides significant benefits to mice.  But to my knowledge no one has conducted any clinical trials to demonstrate that it will have the same benefit in humans.  The fact that these trials would cost hundreds of millions of dollars with no possibility of a payback means that no drug company is going to pursue an ursolic acid formulation.  It’s probably not going to happen.

The Dietary Supplement Alternative

There is an alternative, though. You could take ursolic acid dietary supplement pills.  You can get 200mg tablets.  But the same questions apply:

• Is it bioavailable to people in that form?  I don’t know. 
• What is the appropriate dose in humans?  I don’t know. 
• How much is too much in humans?  I don’t know. 
• What is the chronic toxicity in humans at 50mg/day?  I don’t know. 
• Does it even work in humans?  I don’t know. 

But, if ursolic acid is available as a dietary supplement, hasn’t all this work been done in order to get it approved by FDA?  The answer is no.

The Dietary Supplement Health and Education Act (DSHEA)

Here’s what the Dietary Supplement Health and Education Act of 1994 requires in order for the ursolic acid dietary supplement manufacturer to begin selling their product.  The dietary supplement must either:

1. Contain only dietary ingredients which have been present in the food supply as an article used for food in a form in which the food has not been chemically altered; or
2. Demonstrate that there is a history of use or other evidence of safety establishing that the dietary ingredient when used under the conditions recommended or suggested in the labeling of the dietary supplement will reasonably be expected to be safe.  The manufacturer must supply this information to FDA at least 75 days before being introduced or delivered for introduction into interstate commerce.

In either case, it is up to FDA to demonstrate in court that the dietary supplement is not safe.

The Dietary Supplement Ingredient Directory on the FDA website shows actions that FDA has taken on various ingredients that are found in dietary supplements.

In the case of ursolic acid, since it has been present in the food supply since Eve gave the apple to Adam, the manufacturer probably had only to comply with clause #1.

Functionality

There is no efficacy proof required of a new dietary ingredient unless the manufacturer makes health claims.  In this particular case I don’t think the ursolic acid dietary supplement manufacturer needed to make any claims.  Body builders and other people concerned about their health read the headlines, search the internet, and buy the product based on third party information.

The Dilemma

I’ll talk about health claims in a future post.  The central theme I want to focus on here is the fact that it’s not going to be approved as drug in the foreseeable future.  That means that we will not know if, in fact, it works on humans. 

In the meantime people are buying ursolic acid containing dietary supplements.  Their downside risk is not just that they could be throwing away their money.  If a body builder does not get the increased muscle mass he was looking for, it’s not a tragedy.

But what if someone were to use an ursolic acid containing dietary supplement thinking that it might enhance insulin activity?  What if they delayed other known treatments for diabetes that are known to work?

Steve Jobs died of pancreatic cancer, which in most cases has no viable treatment.  His particular type, however, was an islet cell neuroendocrine tumor, which is treatable. Instead of undergoing the conventional treatment, he chose alternatives, including dietary supplements.  Jobs eventually did start conventional treatments, but only after a delay of nine months.

Did this delay shorten his life?  Some experts say yes.  Some say no.  One thing we know for sure.  The alternative treatments did not work.  Am I saying that Jobs didn’t have a right to choose his own treatment?  Of course not.  But I will say that people who are faced with life threatening decisions sometimes don’t make the best decisions.

If one of the smartest people in the world made bad decisions by postponing the standard treatment for his islet cell neuroendocrine tumor, what are normal people doing?

One thing I want to make clear is that dietary supplements are in general very safe.  DSHEA has been in effect for 20 years now and the number of reported adverse events is extremely low.  In addition the FDA regulations that govern how dietary supplements are actually made are quite good.  You might take a look at "How Do You Tell if a Dietary Supplement Will Work?" to investigate further.

My point is that patentability of ursolic acid, the cost of clinical trials, and the ready availability of dietary supplements means that we probably will never know whether ursolic acid actually works in humans.

Do I think we have a problem with the current regulations?  No, especially compared to other issues that FDA is working on, like imported foods.  Do we have the potential to do better?  Yes; I will propose some options in a future post.  In the meantime, I would love to hear your ideas.  Please add a comment to this post!