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Author: Stephen J. Klemawesch, MD

Melatonin: Medicine, Myth or Mischief

Melatonin: Medicine, Myth or Mischief

The sale of melatonin is a two billion dollar a year business which must mean that a lot of people have trouble sleeping. 

Sleep is an intricately choreographed neurologic process.  Critical to good sleep is the circadian variation of the reticular activating system.  Melatonin produced in our brains has a mild modulating effect on our sleep cycle.  However, people who have had their pineal gland (a major source of melatonin) removed are able to sleep just fine. 

Because melatonin sales are not regulated by the FDA, scientists decided to do controlled studies to determine its potential benefit.  Multiple studies comparing melatonin to placebo found the same results.  Sleep latency (the time required to fall asleep) was decreased by 7 minutes and total sleep duration was increased by 8 minutes.  So, there is a measurable benefit, albeit very modest. 

The flip side of the coin is safety.  Accidental or purposeful overdoses with melatonin occur in one out of 20 ER visits for overdose.  Some children have died or

required ventilator support to recover. The other issue is content of the product.  Chemical assays of melatonin products have shown that the actual content can vary from 83% lower to 478% higher than what was claimed on the label.  One chewable tablet for children contained 9 mg rather than the 1.5 mg noted on the label.  Moreover, a quarter of the products sampled contained serotonin (not on the label) in addition to melatonin. 

Twenty-five years ago, the science journal “Cell” cautioned about melatonin madness.  They advised ignoring the hyperbole and histrionics of advertising and instead to focus on sound science.    

 Dear Dr. K; Is it just me or is there a

 Dear Dr. K; Is it just me or is there a

he- –  of a lot of cold and flu this winter?

It’s not just you.  Covid-19 is adding to its historical legacy by this resurgence of other respiratory infections.  According to epidemiologists (scientists who study the incidence and distribution of diseases) this is unprecedented.   For instance, hospitalization rates for both adults and children for influenza are the highest in over twenty-five years. 

The simple explanation is that the cumulative load of infections that would have occurred over the past three years, but didn’t due to mask wearing and social isolation, are now making up for lost time. 

Another factor that markedly attenuated influenza was the decrease in global travel.  The influenza virus has always relied on our “small global community created by travel” to infect the maximum number of humans.  Now with global travel returning to pre-Covid frequency the flu virus has hitched a ride. 

RSV (respiratory syncytial virus) has used a different strategy.  Normally RSV infects a small portion of young children each season.  The small numbers have kept it from being epidemic or pandemic.  Also, once infected the child develops resistance.  But for three years many children have “missed the illness” leading to a very large population of susceptible hosts.  With more children all getting sick at once, the trickle-down effect has been a spread to older adults whose immunity has waned over the years.  So once again hospitalization rates for children but now also older adults are unprecedented.   Then add on all the other “cold viruses” such as Rhinovirus and Coronavirus into the “catch-up” mix and you have a lot of sick people out there. 

Respiratory bacteria also follow the Darwinian mantra of survive and propagate.  Some of the leaders in the bacterial pack are Pneumococcus, Streptococcus, Hemophilus, Moraxella and Mycoplasma.  The relaxing of social isolation and mask use have allowed them to play “catch up”.

A few practical strategies to lessen your chance of illness include the usual hand washing advice.  But, nasal saline rinses at the end of the school day or work day can provide an additional mechanism of protection.  Finally, getting a flu vaccine has value.  Many Americans are fed up with all of the Covid vaccines and have consequently avoided their usual annual flu shot.

EBV and MS

EBV and MS

The cause of MS (multiple sclerosis) has long been sought.  Although many factors are felt to predispose to it, genetics and environment top the lists.  For instance, the illness is much more common in Europe and North America than in the rest of the world. 

Viral infections have long been suspects.  Now there is mounting evidence that the Epstein Barr Virus (EBV) may be the culprit.  Two recently published research studies lend credence to this possibility. 

The first study was done on service members on active duty who came down with MS.  Over the study period 801 patients developed MS and all but one of them had evidence of active EBV infection.  Now, don’t over interpret this finding.  Evidence for prior EBV infection (the main cause for Mono, although CMV can also cause Mono) can be found in 90 plus percent of young adults and MS is a comparatively rare disease. 

But the other recent study done by immunologists at Stanford University found that 25% of the MS patients they studied had a blood antibody that reacted to both EBNA1 protein and GlialCAM (glial cell adhesion molecule) protein.   These two proteins are very similar in their chemical structure even though one is a viral protein and the other is a protein found in myelin sheaths.  This is a phenomenon called molecular mimicry.  Long story short what seems to be happening is the immune systems attempt to irradicate the virus via the anti-EBNA1 antibody ends up attacking the GlialCAM protein in the myelin sheath of nerves.  The myelin sheath can be thought of as the plastic or rubber insulation on an electric wire.  Damage to the sheath leads to altered nerve conduction and hence the numbness and muscle weakness found in MS. 

The Stanford scientists extended their research in a mouse model.  In one group of mice they injected EBNA-1 protein into their brains and in the control group a non-viral protein of similar size.  A handful of the EBNA-1 injected mice developed neurologic disorders whereas none of the control group did.  

Gut-Brain Axis

Gut-Brain Axis

Up until recently, scientists had minimal understanding of how our GI tract and brain are connected.  Until this new research I naively figured the only connection was my tummy telling my brain when I was hungry.  As it turns out there is a very strong bidirectional interplay between the brain and the GI tract and a major fulcrum is the gut microbiome.  The ENS (enteric (GI) nervous system) interacts with the intestinal membrane and its immune cells.  Changes in the membrane and immune cells are mediated by local hormones and neuroactive molecules.  These, in turn, affect the local nerves which send messages to the brain.  And the brain sends messages back. 

The importance of these connections has led to better understanding of both GI problems and neurologic disorders.   For instance, these is mounting evidence that altered GI microbiome plays a role in anxiety, depression, OCD behavior, autism, Parkinson’s disease, Alzheimer’s disease, and others.  On the other side of the equation is greater understanding of how the brain contributes to irritable bowel syndrome and inflammatory bowel disease. 

The ENS is often referred to as the second brain because of its size (100 million neurons and 400 million glial cells), its complexity and the similarity of neurotransmitters with the central nervous system (CNS).

One mechanism whereby the gut microbiome can contribute to neurologic disorders is via these neurotransmitters.  For instance, some “bad” gut flora lead to low levels of amino valeric acid and taurine, both of which are essential to making to making the neurotransmitter called GABA.  Patients with OCD and autism have low levels of GABA. 

On the other side of the equation, proper brain signaling to the ENS is important for producing a protein essential to a healthy intact epithelial barrier in the intestines: GDNF (glial derived neurotrophic factor).  Reduced barrier function is one of the main flaws that causes inflammatory bowel disease.  So, if the patient is suffering from stress, the brain in turn sends “distress” signals to the gut with the resultant worsening symptoms. 

Germ free mice have been the surrogate for humans in researching modifications in gut flora.  Since these specialized mice are germ sterile, researchers can establish any gut flora desired and measure its outcome.  These experiments are remarkable in that by establishing a “bad” flora researchers can make young, playful and social mice become withdrawn, and “depressed” and can also create mice who exhibit Parkinsonian movements and mice who suffer memory loss.

As exciting as this research is there are as yet no proven clinical applications for humans. 

Hypnotherapy for IBS

Hypnotherapy for IBS

Scientists at Monash University in Melbourne, Australia have developed a hypnotherapy-based computer app to help people with IBS (irritable bowel syndrome). 

The program called Nerva guides users through a ten-minute hypnotherapy session every day for six weeks.  The neural therapy is designed to correct the disordered signaling from brain to gut.  Patients who complete the six-week program report a reduction in symptom severity from 67 (on a scale of 100) to 39.  Adding a low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet has additional benefit. 

Alpha Fold

Alpha Fold

An AI called Alpha Fold developed by London based company Deep Mind is a computer-based program trained to predict protein shapes by recognizing patterns in structures already solved by years of tedious experimental work using electron microscopes and other methods.  So far, it has predicted 400,000 protein structures including most of known human proteins. 

Now you might ask: “OK, what is the big deal and why is this in your newsletter?”  Well as it turns out many biologic processes work based on the shape of molecules.  For instance, as the Corona virus has mutated over the past three years its 3-dimensional structure has changed dramatically.  This is one reason that the original vaccines and the original nasal swab tests have become less efficient as doing their jobs; prevention and recognition. 

Another example is insulin allergy.  Years ago, the only available insulin for diabetics was from beef or swine.  Insulin allergy was fairly common back then.  But once the “human insulin” was developed (which uses a human gene transferred into test tube bacteria) it was mistakenly thought that there would no longer be insulin allergy.  Beef insulin has a four amino acid difference from human insulin.  Pig insulin has a three amino acid difference.  But “human insulin” from tissue culture has an identical amino acid sequence; however, the 3-D structure produced by the bacteria is different than that produced by the human pancreas. 

In some cases, this 3-D difference can lead to the development of allergy. The other foible that can occur is the development of anti-insulin antibodies which lead to insulin resistance.  Again, the antibodies are in response to the 3-D structural difference from nascent insulin. 

The efficiency and therefore the benefit of many medications is related to how well they fit into cellular receptors in the body.  This too comes down to 3-D structure.  Long story short, this new research has the potential to revolutionize medicine.  

House Plant Police

House Plant Police

Researchers at the University of Washington have developed a “souped-up” house plant to “police” indoor pollutants. 

Indoor air pollution is a reality.  A myriad of chemicals from cooking to cleaning materials to increasing outdoor pollutants can adversely affect human health. 

Benzene and Formaldehyde are known carcinogens and certain states have strict rules limiting their use (notably California and Minnesota). 

It has been known that indoor plants can remove these pollutants but their impact is very minor.  The scientists in Seattle modified the common house plant pothos by adding a rabbit gene for an enzyme that breaks down pollutants.  These “souped-up” golden pothos have a remarkable ability to remove and detoxify pollutants. 

In Canada, Oirgen Air is selling the new pothos plants and in the US Neoplants will begin sales this month. NASA scientists are conducting experiments with these plants to help reduce pollutants in the re-circulated air in the orbiting space station. 

Dear Dr. K- 

Dear Dr. K- 

I recently read that monkey pox vaccine can be given ID.  Is that true?

Yes, it is true.  In fact, early research indicates that it is the preferred route of administration in terms of getting the best immunologic protection. 

At this point the only other vaccines approved for ID (intradermal) dosing are the flu vaccines and the polio vaccine.  The advantages of ID vaccination are several.  It can generate an immune response as good or better than an intramuscular vaccine but with as little as one fifth the dose.  Owing to its superficial administration it avoids the rare risk of nerve, blood vessel or muscle injury that can occur with IM dosing.  The Gates Foundation has spent 5 billion dollars to help eradicate global polio and have used the dosing efficiency to great advantage.

A Shift in Asthma Strategy

A Shift in Asthma Strategy

They say “nothing stays the same” and as I keep aging, I couldn’t agree more! Change is always occurring in medical guidelines as well.  What I’d like to address here is how this applies to asthma therapy. 

For quite some time now, the standard of care for asthmatics has been to have both a rescue inhaler and a maintenance inhaler.  The majority of rescue inhalers use albuterol, a bronchodilator, which relaxes airway smooth muscles that are constricted.  The benefit is brief, lasting 3 to 6 hours, and the medication does not address the underlying inflammation which is the cause of the muscle constriction, that’s where a maintenance inhaler comes in.  Most maintenance inhalers are either single entity topical steroid or a combination steroid and long-acting bronchodilator. 

Overuse of albuterol is associated with excess risk for severe asthma exacerbations and even death.  Globally the majority of asthma related deaths are due to this scenario.  And a contributing cause is the cost of different inhalers: albuterol being relatively inexpensive while maintenance inhalers being expensive. 

This has led the Global Initiative for Asthma (GINA) to a new guideline that adds a topical steroid to all albuterol inhalers.  So far, the United States has not adopted this strategy.  Multiple international studies have documented a major improvement in patient outcomes with this approach:  marked reduction in the need for systemic steroids (oral or injected), reduced visits to emergency departments, reduced hospitalizations and reduced death. 

Tardigrade Research

Tardigrade Research

Tardigrades are microscopic organisms about the size of a dust mite but are really cute as they look like a baby manatee.  For being so tiny they have some really special properties that scientists hope to adapt to human health. 

Tardigrades are incredibly tough.  They can survive being frozen down to minus 272° Celsius, being exposed to a vacuum in outer space, being completely dried out and being exposed to 500 times the dose of x-rays that would kill a human. 

Tardigrade indestructibility stems from its ability to adapt.  Cold, dryness, vacuum, and x-radiation all cause damage to cell walls and to DNA within cells.  A tardigrade can abrogate these damages by synthesizing special “repair proteins”.  These special proteins support the cell’s membranes, essential proteins, and DNA.  One of these “repair proteins” Dsup has only been found in tardigrades and no other living organism.  Dsup binds to DNA and physically shields it from oxidative damage. 

In human cells our DNA has built in spare repair parts called telomeres.  As we live and are exposed to oxidative/inflammatory stresses our cells use the telomeres to repair damage.  But once the telomere resource is used up the cell will misfunction and even potentially become cancerous. 

And so, there is very active research into finding a way to protect human cells with Dsup.  Already scientists have inserted the gene to produce Dsup in experimental animals and it is working beautifully.  As a side-bar NASA scientists are looking at the possibilities of using Dsup to help long term space flight (with its attendant exposure to ionizing radiation for astronauts).