Edited by Allie Logerfo (Georgetown University)

Herbal supplements are really popular. Some of my crunchier friends swear by them. My Mother is constantly asking me to eat strange Bengali roots and pills claiming that my liver, kidney, ear. . . needs a good cleansing. But there is danger in the supplement world and I thought I would take the time to explain it.

Herbal Supplements Have Changed The World

Herbal supplements get a bad rap. Many of them have grown out of century old remedies. Willow bark for headaches gave rise to Aspirin, arguably one of the best medicines of all time. Very potent therapies for diseases like cancer and diabetes have also grown out of the Pacific Yew Tree and chinese remedies respectively. (Just a reminder, hemlock and heroine also have natural origins; not all things natural are good.)

It’s Extremely Difficult to Figure Out What an Herbal

Supplement Does

But controversy surrounds the herbal supplement business. 1, 2, 3 GNC, Target and Walmart all carry an arsenal of herbal supplements, and we are inundated by advertising for these supplements. For example, “Natural Cures They Don’t Want You to Know About!” Then, you run in to a headlines like this: ”Herbal Supplements Are Often Not What They Seem” and “New York Attorney General Targets Supplements at Major Retailers.”

Recently the NY Attorney general set up a little experiment to see if Herbal Supplement suppliers were being honest about what they were selling. 4,5

The Experiment: A Simple Experiment Reveals Major Problems with Herbal Supplements

The Attorney General selected 4 popular stores as their source of these supplements: Walmart, Walgreens, Target, and GNC. The AG, Attorney General, went to multiples of each stores: Three NY Target stores, 4 NY GNC stores, 3 Walgreens, and 3 Walmarts. The AG’s office selected GInkoa, Echinacea, Saw Palmetto, and St. John’s Wort off the shelf purchased them and then analyzed them.5

I was unable to find the actual lab results, but according to the AG the samples were then sent to a lab which then DNA Barcoded the samples to see if they carried the plant they claimed to carry. DNA Barcoding is essentially just PCR and sequencing of a segment of DNA. The sequence of that segment is then compared to a database which will identify the code as a certain organism. (It’s been used to show that tuna in NYC isn’t always tuna)

Each of the samples was tested 5 times. I was unable to determine whether the samples were sent to different labs or if the barcoding results were similar across all 5 trials. (Cease and Desist Documents)

The Results5

What does this mean?

DNA Matched Product: If the tablet contained the plant it was supposed to contain then you would find that the DNA matched the product label.

Tested Positive For Biological Contaminants: DNA of other plants was found in the tablet. These plants were not listed in the ingredients. People can be allergic to these plant contaminants making the product unsafe. 6, 7, 8, 9

No Plant DNA: This does not mean that the plant was not added to the pill. For example, this does not mean that there was no garlic in the garlic pill. It is possible the pill-making-process destroyed the DNA of the ingredients in that filling, or the ingredients were never added.

DNA is an extremely robust compound. A quick search revealed that scientists at Max Planck have used DNA that is over 100,000 years old.10 You can freeze DNA, dry it, chew it, boil it, or stick it in your pocket and go for a walk on the beach. Heck, my freshman students manage to extract their own DNA all the time, and they are GREAT at destroying things. The point is simply that in order to complete destroy DNA, one has to work pretty hard or use chemicals/enzymes which specifically destroy DNA.

This is CRAZY: Why Doesn’t Anybody Do Anything About This?

You, my friend, are correct. This does seem crazy. Below is the law.

1. The FDA is a federal regulatory agency that evaluates drugs and medicines. A medicine is a compound that is used to treat a medical condition.

2. The IDC determines what negative health states are considered a medical condition.

3. If somebody claims that a compound or procedure can treat a medical condition, the FDA will evaluate that statement. Meaning they can test the product and hold the producers to a high standard.

4. If a natural product claims to have health benefits, without saying that it treats a medical condition, it does not require FDA approval

5. The supplement manufacturer is responsible for making sure that their OWN products and statements are truthful and not-misleading (Not the FDA)

6. Supplement manufacturers are not responsible for batch to batch consistency.

The Future

To be clear, the FDA is not dropping the ball. These supplements, which are regulated in a similar manner as fruit, are simply not under their purview. If the FDA suddenly began testing all supplements, it would be a gargantuan (not just massive) undertaking. Forbes says that this industry is generating at least 32 Billion dollars a year.11 The FDA already has an incredibly difficult task of balancing the need to get health restoring products out to the public as quickly as possible with the caution it must show while testing these products to make sure they are safe.

Decision Time: How Relates to You

From this evidence I am extrapolating that not all dietary supplements are safe, some are outright dangerous. However, it would be unfair to say that all dietary supplements are unsafe. The question is HOW DO YOU TELL THE GOOD SUPPLEMENTS FROM THE BAD SUPPLEMENTS? The answer, unfortunately, is that you can’t. Not unless you can do some barcoding of your own. Please be moderate when you are using these supplements and make sure that you tell your doctor about the fact that you are using them.

As of March 2015, GNC has agreed to exceed FDA safety guidelines. THEY are promising that their supplements are safe and verifying this by testing their products in-house and by external companies.

My question is simply, what will everyone else do? . . . and perhaps more importantly, what should they do?

Citations

1. Nytimes.com,. Retailers Are Warned Over Herbal Supplements. (2015). at

2. O’CONNOR, A. Herbal Supplements Are Often Not What They Seem. Nytimes.com (2013). at

3. Schneiderman, A. A.G. Schneiderman Asks Major Retailers To Halt Sales Of Certain Herbal Supplements As DNA Tests Fail To Detect Plant Materials Listed On Majority Of Products Tested | www.ag.ny.gov. Ag.ny.gov (2015). at

4. Ag.ny.gov (Attorney General of NY),. A.G. Schneiderman Announces Agreement With GNC To Implement Landmark Reforms For Herbal Supplements | www.ag.ny.gov. (2015). at

5. Documentcloud.org,. NY Attorney General Cease and Desist Documents. (2015). at

6. Fda.gov (Food and Drug Administration),. Dietary Supplements: FDA Consumer Advice on Products Containing Ground Cumin with Undeclared Peanuts. (2015). at

7. Fda.gov (FOOD AND DRUG ADMINISTRATION),. Energy "Drinks" and Supplements: Investigations of Adverse Event Reports. (2015). at

8. Food and Drug Administration,. Voluntary and Mandatory Reports on 5-Hour Energy, Monster Energy, and Rockstar. (U.S. Department of Health and Human Services, 2012). at

9. Fda.gov (FOOD AND DRUG ADMINISTRATION),. FDA Consumer Advice on Products Containing Ground Cumin with Undeclared Peanuts. (2015). at

10. Dabney, J. et al. Complete mitochondrial genome sequence of a Middle Pleistocene cave bear reconstructed from ultrashort DNA fragments. Proceedings of the National Academy of Sciences110, 15758-15763 (2013).

11. Forbes,. Nutritional Supplements Flexing Muscles As Growth Industry. (2013). at

Edited by Alexandra Logerfo1

^{Based on an article published in Frontiers in Behavioral Neuroscience in May of 2014 (Link to the article)}

The Comical Introduction:

The ability to forget and the ability to remember are two seemingly opposing processes. Ask anybody about the two and they will generally say that they would like to forget less and remember more. The strength of a memory is sometimes coupled to the strength of the emotions tied to it: stronger emotion, stronger memory. This concept is what led me to write about an article discussing the relationship between memory and emotion.²

Memory	Emotion
What if you were unable to forget every single bad thing that your best friend did to you? Though you tried to forgive, every time you see his face you remember that time he puked Mudslides all over the floor of a certain Washington University residence hall because he decided funneling them would be a good idea, and left you to clean it up	The memory itself wouldn’t be that horrible if it didn’t come with emotion, the fear that you were going to get caught, the irritation that he couldn’t help you, and of course the stomach turning that accompanies a task like that.

Background and the Real Problem:

While the situation above is completely made up³, and somewhat comical, it highlights the relationship between memory and emotion. Traumatic experiences such as rape, abuse, or shell shock result in what is called “aversive learning.” This aversive learning can result in cue or context based expression of fear. This means that items and/or sounds associated with the event (cues) or similar situations (contexts) can trigger the expression of fear. It can be debilitating, forcing people to experience the terror of an already horrible incident over and over again. This is one of the key aspects of post-traumatic stress disorder (PTSD). People experience intense fear/anxiety when exposed to cues and contexts.

The hippocampus is a part of the brain that is often associated with memory, and the amygdala is a part of the brain that is associated with the emotion of anxiety. Neuroscience is all about finding the connections between parts of the brain and that is what Dennis Sparta and Jim Smithuis set out to do in an article titled

“

Before I can get into the heart of the article and the research findings, I need to explain two things: the process of experiencing a traumatic memory and the technique of optogenetics.

The process of experiencing a traumatic memory involves two basic parts. Let’s use the example of a mugging. You first have to gain the information; that is termed acquisition. Seeing a masked man, experiencing fear, and then storing the experience and the paired emotion of fear in your brain is acquisition. The second part, expression, might involve you seeing a completely different masked man and then stopping in your tracks because of that fear.

Optogenetics has been around for a little while now, but its usage is permeating more and more of neuroscience. This technique allows a scientist to put a light sensitive switch in a specific subset of neurons. By shining light on these specific neurons, scientists can stimulate the neuron or shut it down. It is a step forward in solving one of the toughest problems in neuroscience: resolution. Before optogenetics, shutting down neurons involved using direct injections or lesioning parts of the brain. Neither of these are terribly accurate and affect neurons in the magnitude of thousands - a large section of neurons is damaged and the role of specific neurons cannot be established. Metaphorically, this would be like knocking out a school, seeing that graffiti in an area decreased and then concluding that schools are responsible for graffiti, when in reality, only a couple of kids are responsible for the graffiti.

The Experiment

This experiment attempts to identify a specific connection between fear/anxiety (Basolateral amygdala, BLA) and memory (hippocampal formation) through a brain region called the entorhinal cortex (EC). Specifically, the authors, Sparta and Smithius, inhibit the BLA-EC pathway to look at its role in both the acquisition and the expression of contextual fear.

They start by virally “installing” the optogenetic channels into the BLA. This will allow them to control neurons. The two channels they installed, halorhodopsin and channelrhodopsin-2, were attached to a yellow fluorescent protein (YFP). Halorhodopsin allowed the scientists to shut the neurons down and

Once placement was verified, they ran a fairly standard contextual fear acquisition paradigm. On Day 1, two groups of mice were placed in a room and then shocked. The first group had the BLA-EC pathway inhibited, and the second had the pathway activated. The mice were placed in the room for a short amount of time on Day 2 and then again on Day 3, which was a week later. On Day 2, scientists looked to see if the mice froze when placed in the room without being shocked. Freezing indicated that the mice remembered the context, the room, and associated it with fear. They did the same thing on Day 3.

Mice with inactive BLA-EC pathways on Day 1 did not freeze as much as mice with active BLA-EC pathways. This indicated that the non-freezing mice, with inhibited BLA-EC pathways, weren’t associating the room with fear even though they had been shocked.

I am glad that Sparta and Smithius went a step further. They repeated the experiment but only inhibited the BLA-EC pathway in one of two groups when the mice were RE-EXPOSED to the room on Day 2. Shutting down the BLA-EC at this time would mean that the BLA-EC was removed during the expression of contextual fear and not acquisition of it. To clarify, the BLA-EC was not shut down on Day 1, as it was in the previous experiment.

Both groups of mice froze equally when re-exposed to the room. That means that even mice with inactive BLA-EC froze, which indicates they were experiencing fear to the same degree as mice with the active BLA-EC.

Let’s summarize everything here. If the BLA-EC pathway was blocked when mice were learning to associate the room with shocks (Day 1), then the mice did not express fear when re-exposed to the room (Day 2 and 3). If the BLA-EC pathway was unblocked when the mice were learning to associate the room with shocks, then the mice did express fear when re-exposed to the room. When the BLA-EC pathway was unblocked during learning, but blocked during re-exposure the mice did express fear.

Discussion

Sparta and Smithius demonstrated in their experiment that the hippocampus and the BLA communicate while a subject is learning about or experiencing painful stimuli. This means that fear and visual memory are linked during the storage process. I’m interested to know if the mice with the blocked BLA-EC pathway remembered the room. It is possible that they did not freeze simply because they did not remember the room?

As of right now, I haven’t been able to find any optogenetic studies done on humans. I think the FDA would currently frown on injecting viruses into a person’s head and attaching flashlights that shine into the brain. But this type of technology, in which we voluntarily manipulate very specific neurons, is coming.

PTSD isn’t the only disease involving memory that could benefit from this technology and additional research using optogenentics. Aspects of addiction also involve very powerful learning. Could there be a soldier in whom we could inhibit PTSD? Could there be criminals who could erase memories of their crimes? I have no clue, but certain things are for sure: Our understanding of the brain is changing with new technologies, and our evolved understanding is going to force us to reconsider how we deal with human behavior.

Footnotes

[1] Logerfo can be contacted at aclogerfo02@gmail.com, if you need help with science writing.

[2] The other reason is that one of my 12th graders presented this article in Journal Club, and I was confused by it. Thanks Elizabeth Krauetler for explaining it to me.

[3] By completely made up I mean that it is a completely true story.