Circadian Rhythm Connections: Part 1 – Mood Disorders

Roosters crowing at the first crack of daylight. Morning glories unfurling their blooms as the sun rises in the sky. Lightning bugs flickering just as dusk falls.

Most people intuitively understand that plants respond to sunlight, using photosynthesis to produce energy and store sugar during daylight.  It is easy to also apply the thought of daily rhythms to animals, with nocturnal mice scurrying around at night and diurnal birds chirping in the morning.

What is often more difficult to understand is how deeply circadian rhythms are hardwired into us, humans. While evolutionary biologist may argue exactly how the circadian clocks evolved through different species, there is no argument that all animals and plants are governed by circadian rhythms, from blue-green algae preparing for sunrise to much more complex organisms with nocturnal and diurnal patterns.[ref]

Why is it so hard for us to understand that humans also are affected by light and dark?

Human hubris?  We are superior, beyond the animal rhythms of nature.  We craft tools for extending light into the night, and our society now functions 24 hours a day. Take back the night. Light it up; party all night.

But it seems that our chickens have come home to roost (pun intended).  This human determination to conquer the night, a 24-hour society of hustling and bustling, is probably at the root of so many diseases including mood disorders, cancers, heart disease, dementia, and diabetes.  In fact, over the course of this multi-part series of articles, I will make the case that research studies are showing that circadian disruption is at the heart of most of our chronic health problems.

Before you mentally check out and decide that this article doesn’t apply to you, I challenge you to read to the end and check out the overwhelming evidence for yourself.

This isn’t hippie-dippie, crackpot, wacko stuff. There is a true abundance of evidence that ignoring our circadian rhythm is fundamentally detrimental to our health.

This goes much deeper than just the standard, oft-repeated advice that you should sleep well. Everyone knows that they should sleep well – and most ignore it.  Sleep is involved, but I think I can make the case that good sleep is a byproduct of good circadian function.

The flow of science usually starts with observing a phenomenon. It is talked about, poked-and-prodded, and theories fly. But a true understanding of a phenomenon or a disease comes with understanding the mechanisms that cause it, reverse-engineering it. One way of reverse-engineering chronic diseases is to look at the genes that cause an increased risk for a disease. Modeling the disease state can then happen in an animal model using genetic manipulation, or knocking out a gene to see the effect.  It isn’t as neat and straightforward in biology as it is in engineering, but the principle remains the same.

My path into investigating the impact of circadian rhythms started with diving into genetics and a fascination with the genes that control our core circadian clocks. Humans (like all animals) have a few core genes that regulate our internal rhythms such as the rise and fall of our hormones, enzymes level fluctuation, cellular repair, body temperature, and the sleep/wake cycle.

Our core circadian rhythm is set by the rising levels of two proteins, CLOCK and BMAL1, that join together each day. Levels of CLOCK and BMAL1 rise over the daylight hours, eventually getting to a high enough level that they inhibit themselves, thus allowing the subsequent increase of the other half of our circadian genes: PER (period) and CRY (cryptochrome).  This feedback loop runs on approximately a 24-hour rhythm.

Notice the word approximately. Circadian comes from the Latin words circa (about) and dia (day). About a day. The daily fluctuations of our circadian rhythms usually take a little over 24 hours for humans kept in total darkness, and other animals may have slightly shorter than 24 hour periods. The CLOCK and BMAL1 timing needs to be regularly set and adjusted.

So what sets the beginning of our daily rhythm: morning sunlight.

The shorter wavelengths of sunlight in the 450-480nm wavelengths, what we perceive as blue light, are exciting a non-image forming photoreceptor in the retina of the eye that signals the beginning of the day. Like a lock and key, the specific wavelength of blue light causes the excitation of the molecule, triggering the signal for our circadian clock. (If you think back to plant biology, this same mechanism is at  work in photosynthesis with a specific wavelength of light exciting the chlorophyll pigment inside the chloroplast.)

If you are thinking back to high school biology and only rods and cones in the retina that form images, you may be surprised to find that there is a third type of photoreceptor in the eye known as intrinsically photosensitive retinal ganglion cells (ipRGC’s). The blue light-sensitive pigment in these cells is known as melanopsin, and it has only been known for less than 20 years.[ref]

So if our eyes are not supposed to be exposed to light at night, what about the fact that we have had light at night ever since our caveman ancestors first lit up a fire to keep their caves toasty at night? Good question. Firelight (and light from candles, oil lamps, etc) gives a nice warm glow; it is mainly light in the yellow and red end of the visible light spectrum without any of the shorter, blue wavelengths.

Over 100 years ago we conquered the night with electric lights, but these incandescent bulbs also cast a warm, yellowish light with only a little in the blue wavelength spectrum. Black and white TV’s came into living rooms in the ‘50’s, and by the 1980’s everyone had color TV’s pouring blue flickering light out into the night as we sat glued to the Duke of Hazard and The A-Team.

Fast forward thirty more years to our current era of ubiquitous devices such as cell phones, tablets, and laptops, all glowing with light in the shorter, blue wavelengths.  Add in the effects of LED and compact fluorescent light bulbs, which both have sharp peaks of blue wavelengths in their spectrum – the pure white light includes a lot of blue light in it. (Anyone else here see the irony of the government banning incandescent light bulb production in favor of the lights that are increasing our chronic health problems?)

We are now bombarding the receptors in our retinas at night with light in the exact wavelength (480nm) that signals to our brain that it is daytime.

All of this core circadian oscillation is taking place in a region of the brain called the suprachiasmatic nucleus (SCN).  Located in the hypothalamus the SCN is connected to the retina and receives the signal from the ipRGC’s. One interesting fact about the SCN is that when it is isolated from the rest of the brain, the cells still maintain electrical and molecular rhythms – the clock keeps on ticking.[ref]

It helps to visualize the rise and fall of the circadian genes like a sine wave, with the amplitude (height) of the wave being important as well as the phase (length of time) affecting us.

Let’s get into some of the scientific studies that investigate the importance of our circadian rhythm.

Mood Disorders:
In 2005, the NIH estimated that 9.5% of the adult population suffered from mood disorders.[ref] The 2016 statistics show that 18.3% of US adults suffer from a mental illness (which is a bit broader of a category than just mood disorder).[ref]  This topic is relevant to so many of us, and the science linking mood disorders to circadian dysfunction leads us to new solutions and alternatives to the psychiatric medications that so often come with side effects.

Seasonal Affective Disorder:
Let’s start with an easy and obvious example:  Seasonal Affective Disorder (SAD) is a well-known disorder that involves the onset of depressive symptoms with the changing amount of daylight in the fall or winter. SAD affects between 2 – 9% of the population, depending on the latitude. It is now thought that the decreased intensity or brightness of the light is what triggers SAD rather than a shorter period of daylight. One effective therapy for seasonal affective disorder is bright light therapy.[ref]  More to read: Genetics of Seasonal Affective Disorder

A study of diurnal (active during daylight) rats found that decreasing the intensity of light could effectively cause anxiety-like behavior. In other words, dim light was causal for mood disturbance. The researchers also found that the decreased light intensity caused a disruption to the HPA axis with increased corticosterone production.[ref]  Corticosterone in rodents is equivalent to cortisol production in humans.

Bipolar disorder:
The link between circadian disruption and bipolar disorder has been known since before the 1970’s. Bipolar patients with a shortened circadian period are the ones who respond to lithium carbonate[ref], which has recently been shown to inhibit GSK3beta, directly impacting the core clock genes. Lithium also causes an increase in the amplitude of the production core circadian protein PER2[ref]

The worldwide lifetime risk of bipolar disorder is a little over 2%, with onset most likely occurring between the ages of 17-27.  One mutation in the gene, CLOCK, causes people to be more likely to stay up a little later in the evenings (evening chronotype); it is also linked to a doubling of the risk of bipolar disease.  [ref]

Major depressive disorder (MDD) has also been linked to circadian disruption. Our neurotransmitter levels of serotonin, norepinephrine, and dopamine all fluctuate with a circadian rhythm over the day. Moreover, MAOA (monoamine oxidase A), which terminates dopamine signaling, is a transcriptional target of the core circadian genes, BMAL1 and PER2.[ref]

It is interesting to look at how antidepressants work. Studies show that SSRI’s shorten or advanced the circadian period, and fluoxetine (Prozac) also causes phase advances.[ref] It is thought that SSRI’s are increasing serotonin in the SCN (suprachiasmatic nucleus), and part of the reason that it takes a little time for them to be effective is that they are changing the body’s circadian rhythm which takes a little while to adjust.[ref]

This brings us back to the chicken or the egg argument. Are mood disorders causing the changes in circadian rhythms or are alter circadian rhythms causing mood disorders?[ref] There seem to be arguments on both sides, and it could be that both sides are correct in that the interrelated feedback loops could keep driving the dysfunction.[ref]

One strong argument for circadian dysfunction causing mood disorders is that genetic variants in the core circadian genes are linked to increased risk of major depressive disorder, bipolar disorder, and anxiety. Another strong link is that altering the CLOCK gene in mice can produce a mouse model of depression. One specific strain, called CLOCKdelta19 mice, causes a longer circadian period with mania and anxiety during daylight and euthymia in darkness[ref] Knockdown of BMAL1 in the SCN of mice induced helplessness, behavioral despair, anxiety and weight gain.[ref]

But not all circadian gene mutations cause mood disorders. Per1 and Per2 mouse mutant strains have altered circadian rhythms without mood alterations. This has led some to hypothesize that light, rather than circadian rhythm, plays a causal role in mood disorders.[ref] While a genetic variant of the CLOCK gene may double the risk of bipolar disorder, obviously not everyone with the variant will become bipolar.[ref]

Looking at animal models of depression adds more fuel to both sides of the argument.  Chronic mild stress causes a dampening in the amplitude of circadian rhythms in mice. It also causes a damping of amplitudes of daily temperature variations and of corticosterone production.[ref]

What do human studies show?
Shift workers who alter their schedules for work are at an increased risk for depression.[ref] While the numbers vary depending on the study, a 2017 meta-analysis came up with a conservative estimate of a 43% increase in the risk of depression for those who work the night shift.[ref]

A number of human core clock genes are associated with the risk for MDD and seasonal affective disorder. Again, finding that circadian gene variants can cause mood disorders is a strong indicator that circadian disruption drives mood disorders.  Recently, it was shown that a PER3 mutation that causes Familial Advanced Sleep Phase Disorder (people who have this naturally want to go to sleep very early in the evening and get up extremely early in the morning) also is causal for seasonal affective disorder. The same study created a mouse model that decreased PER3 expression, which showed that not only were the mice depressed, but the severity of depression was worse with a shorter photoperiod. [ref]

A study of patients with depression looked at the gene expression at the time of death (you can’t do a lot of in vivo studies on gene expression in the brain with people who are living). The study found that compared to non-depressed, people with depression controls who had died at the same time of day showed a phase delay in gene expression, strongly linking circadian rhythm changes to depression.  [ref]

Sleep disturbance goes along with altered circadian rhythms, and sleep disturbances are a hallmark of both bipolar disorder and depression. It is theorized that dampened and shifted circadian rhythms can explain the sleep disturbances in mood disorders. Indeed, dampened temperature fluctuations (our body temperature is supposed to drop at night) and dampened hormonal rhythms are a big part of depression. In bipolar patients, it has been shown that circadian gene expression is phase advanced in manic states and delayed during periods of depression. [ref]

A recent study of blue-blocking glasses for bipolar patients had very positive results.  The study used two groups of patients, one group wearing blue-blocking glasses from 6 pm to 8 am for seven days, while the other group wore clear lenses. After seven days, the group wearing blue-blocking glasses had a drop in the Young Mania Rating Scale of 14.1 compared to the placebo group which had a drop of 1.7.[ref]  Simple, inexpensive, and effective – blocking blue light in the evenings had a significant impact after only a week.

Let me wrap this up by pointing out some things that may seem obvious now:

  • We are a society that is chronically somewhat stressed.
  • Most of us spend the majority of our day inside with low amounts of light (compared to sunlight).
  • We are constantly telling our body that it is morning instead of night by our use of electronic devices with blue light hitting our eyes at night.
  • All of this is having a deleterious effect on our circadian rhythm.


Block the Blue Light at Night:  
Blue-blocking glasses (amber or orange colored lenses) in the evening for a couple of hours before bedtime.  This means wearing them constantly since less than a minute of blue light can delay melatonin onset for quite a while. One study found a 50% increase in melatonin production after just two weeks of wearing blue-blocking glasses. [ref] Be sure to look for ones that block 100% of the blue light wavelengths.

Alternatively, you could stop watching TV in the evenings, avoid reading from a lighted eReader, and refrain from looking at your cell phones, tablets, and laptops. Couple the avoidance of all electronics with low lighting in your house from bulbs that have a red hue and you are on the right track to resetting your circadian clock.

Bright Light During the Day:
Sunlight during the daytime is really important. There is just no way to get enough brightness from normal light bulbs during the day. Try eating your breakfast and lunch outside, or park farther from work and walk in the sunshine for a bit before your day begins. Just make it a priority to get some sunlight. A study shows that even sitting next to a window in your office can help. [ref]  Another study found that increasing morning light decreased depression and increased sleep quality. [ref]

Light therapy devices are becoming more and more prevalent, and the studies on them are showing efficacy for more than just seasonal affective disorder. One recent clinical trial found light therapy effective for postpartum depression [ref], and another in dementia patients also found bright light therapy effective.[ref] There are literally a couple thousand studies available on light therapy for depression, so I would encourage you to research the topic. Note that for most studies on depressed patients, the participants continue their current depression medication during the trial. If you are currently on medication, please don’t just throw out your bottle of pills and turn on a bright light—talk with your doctor and come up with a plan.

Darkness at Night:
Dark Therapy has been tried for some bipolar patients, with forced darkness for 10 hours per night leading to stabilization in mood.[ref] Along those same lines, all of us can benefit from blocking out all light sources in our bedrooms while we sleep. Get some blackout curtains (inexpensive on Amazon), and cover up all the little LED lights on chargers, etc.

Final thoughts:
Read and learn more,  pay attention to your circadian rhythm, and realize that the inconvenience of staying on a normal sleep/wake routine more than pays off in benefits for your long-term mental and physical health.


Serotonin: How your genes affect this neurotransmitter

serotoninSerotonin… most of us think of the commercials with happy brain neurons bouncing the serotonin molecule between them. Turns out that there is a lot more to this molecule than most of us realize.

About 90% of serotonin is made in the gut and regulates motility there.[ref] Serotonin is also involved in various other bodily functions such as in bone mass regulation, cardiovascular health, the endocrine system, and appetite.

In the brain, serotonin is involved in many different functions. It acts as a neurotransmitter, sending a chemical message between neurons. It is also the precursor molecule for melatonin, which is vital to our circadian rhythm and sleep.[ref]

Some researchers believe that imbalances in serotonin may play a role in depression or anxiety. Common anti-depressants include SSRI’s which are thought to increase serotonin levels in the brain, although the method through which they work is still not completely understood.[ref]

Balance seems to be a key word with serotonin. Too much serotonin is known as serotonin syndrome. Symptoms include restlessness, confusion, shivering, diarrhea, and more.[ref]

Genetic Variants that Could Change Serotonin Levels:
Serotonin, also known as 5-hydroxytryptamine or 5-HT, is synthesized from the amino acid tryptophan using tryptophan hydroxylase (TPH1 and TPH2 gene).  It is transported by SLC6A4, and there are several receptors for serotonin, HTR1A, HTR1B, and HTR2A.

All of these work in concert: from the creation of serotonin from amino acids to the transport of serotonin to the receptors that are necessary to receive this chemical messenger.

Below is a compilation of studies on genetic variants that affect serotonin.  It is not an exhaustive list, but, perhaps, a starting point for you to find out more about your genes.

1.) Serotonin Synthesis: Tryptophan Hydroxylase (TPH1 and TPH2)
Tryptophan hydroxylase is an enzyme that acts as a catalyst for the reaction that produces serotonin from the amino acid tryptophan. Iron is a co-factor, and BH4 is also used in the reaction. There are two genes that code for tryptophan hydroxylase: TPH1 is mainly in the gut, skin, and pineal gland, while TPH2 is in the central nervous system. A good overview of TPH2 can be found in the introduction of this study which also explains the link with GABA levels as well.

TPH2 has several polymorphisms that have been linked to psychiatric issues such as obsessive-compulsive disorder, depression, and bipolar disorder. These polymorphisms may be affecting the rate at which serotonin is being produced in the brain.

Check your 23andMe results for rs4570625 (v4, v5):

  • GG: most common form
  • GT: decreased risk of depression[ref], less anxiety and aggression[ref][ref]
  • TT: decreased risk of depression, less anxiety and aggression, more likely to be honest [ref]

There are a couple of interesting studies that combined the rs4570625 genotypes with the BNDF Val66Met (rs6265) genotypes. Those with rs4570625 GG and rs6265 Val/Val (TT on 23andMe) were more likely to have “impaired inhibition of negative emotional content”.[ref] This is a very good reminder that none of our genetic variants are acting alone, and, especially when it comes to psychiatric and brain-related issues, genes interact with other genes and the environment.

2.) Serotonin Transporter:  5-HTTLPR Short and Long
SLC6A4 is the gene that encodes the serotonin transporter. It is also called SERT or 5-HTT in some of the research. One variant that has been studied extensively is the 5-HTTLPR variant which is a variable number tandem repeat. This just means that there is a short version of the gene and a long version.  There have been quite a few studies done on the short/short vs. long/long forms of this variant.  Studies in the ’90’s and early 2000’s found that those with the short version of the gene were more prone to depression due to stressful events.  Here is a nice article summarizing the research that has been done on this gene:  Controversial Gene-Depression Link Confirmed in New Study.

Variable number tandem repeats are not included in 23andMe or AncestryDNA data, but there are SNPs that usually go along with the serotonin transporter repeats. So you can get a pretty good idea of whether you carry the long or short version, but the linkage here isn’t 100% accurate.

A couple of studies have found that two SNPs predict the long or short version of 5-HTTPLPR fairly well – around 95+% of the time. [ref][ref][ref]  These are found in both v4 and v5 for 23andMe.

5HTTLPR rs2129785 rs11867581
 Probably Long  T  G
 Probably Long  C  A
 Probably Short  T  A

So why do we care about the long or short version of this serotonin transporter? There have been hundreds of studies done on this gene looking at the relationship between the long or short version and a variety of personality traits. The most replicated link seems to be between those carrying the short/short version and risk of anxiety disorders.[ref][ref]  [ref] Additional studies have shown that the short allele also increases the risk for major depressive disorder.[ref]

The short form of this gene is associated with lower 5-HTT activity. [ref]

Perhaps more interestingly, the long and short forms of this gene have been studied to see the interaction with prescription medications:

  • Escitalopram (Lexapro) was studied in a clinical trial of adults aged 60+ with generalized anxiety disorder. The study found that escitalopram had “no efficacy” for those with the low activity haplotype.[ref]
  • In a study of citalopram for depression after TBI, the results showed that those patients carrying the short/short genotype were more likely to have adverse events. (But honestly, with 84% of patients having adverse events, it doesn’t look like genotype plays a huge role here.)[ref]
  • In an analysis of studies on Caucasian populations, those with the long/long genotype had a better response rate to SSRI’s.  This didn’t hold true for Asian populations, though.[ref]

One more interesting correlation for this gene is found in irritable bowel syndrome.  Serotonin plays a major role in the gut, and IBS patients with a short allele had worse symptoms than those with a long/long version of this gene.[ref]

The short/short genotype is also tied to an increased risk of gastrointestinal intolerance of metformin.[ref]

3.) Serotonin Receptors: HTR1A, HTR1B, HTR2A

While there is still debate among researchers on this topic, one recent paper explains that the function of the brain serotonin receptors is to moderate stress and anxiety through patience and coping.  The HTR1 receptors are thought to mediate the ability to tolerate a source of stress, ‘passive coping’, while the HTR2 receptors mediate the ability to actively cope and improve one’s ability to change due to adversity.

On the serotonin receptor gene HTR1A, the polymorphism rs6295 is also known as C(-1019)G.  In the plus (23andMe) orientation, C is the minor allele, but most studies use the minus orientation and will note G as the minor allele. Note that this is a very common variant with almost half of most populations carrying the minor allele.

Check your 23andMe results for rs6295 (v4, v5)

  • CC: higher impulsiveness, increased risk for depression[ref][ref]
  • GG: normal

The HTR1B gene that codes for another serotonin receptor. One well studied genetic variant is rs6296.  Again, in the 23andMe orientation, G would be the risk allele, but when you read through the studies, it will refer to C as the minor allele.

Check your  23andMe results for rs6296 (v4, v5):

  • GG: increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD[ref][ref]
  • CG: somewhat increased risk of depression, anxiety after stressful life events, increased risk of childhood aggressive behavior, ADHD
  • CC: normal (most common type)

The serotonin 2A receptor (HTR2A) also has several well-studied variants including rs6314, also known as C1354T.  In the 23andMe orientation, A is the minor allele.

Check your 23andMe results for rs6314 (v4, v5):

  • AA: reduced serotonin 2A receptors in prefrontal cortex, increased risk of social withdrawal[ref][ref]
  • AG: reduced serotonin 2A receptors in prefrontal cortex, increased risk of social withdrawal
  • GG: normal (most common)

Here are a few other studies on rs6314:

  • In a study, paroxetine (Paxil) therapy response was tied to rs6314 polymorphism.  Those with the minor allele  (A) had a 7.5 times greater chance of response than those with GG. [ref]
  • An interesting 2013 study looked at serotonin receptor polymorphisms in association with a food reward.  The study found that there was an association between rs6314 A allele and susceptibility towards food reinforcement.  [ref]
  • A study found that those with the minor allele may not improve as much on olanzapine (an antipsychotic). [ref]

Another HTR2A very common variant has also been well studied. The variant rs6311 (C allele) has been found to be associated with increased risk of aggression in adults. [ref]

Check your 23andMe results for rs6311 (v4, v5):

  • CC:  more empathy for happiness, more speed-dating success for women[ref], increased risk of sexual dysfunction with SSRI[ref][ref]
  • CT: more empathy for happiness,
  • TT: normal



Get outside: While your genes have an effect on serotonin levels in the body, there are also several environmental factors that also influence serotonin production.  Exposure to bright light or sunlight is correlated to higher serotonin levels.[ref] Physical activity may also increase serotonin levels. Eating foods high in tryptophan may also increase serotonin levels, but it is hard to know how much of an effect it has on serotonin in the brain.[ref]

Gut health: Don’t forget in all this talk about neurotransmitters that serotonin plays a big role in the gut. Here is a great research article on serotonin and the gut microbiome: Serotonin, tryptophan metabolism and the brain-gut-microbiome axis

There are quite a few studies (mostly animal studies) showing the effect of Lactobacillus species on serotonin production in the gut. This not only seems to have an effect on gut mobility and gut issues, but it also has an effect, perhaps through the gut-brain axis, on anxiety and depression.[ref][ref][ref][ref]

A good overview of the gut-brain axis and the recent research on the effect of gut microbes on mood and anxiety can be found in the March 2018 journal article “Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders“.

There are quite a few clinical trials showing that specific probiotics are effective for depression and anxiety (whether due to serotonin problems or other reasons). One clinical trial for postpartum depression found that Lactobacillus rhamnosus was effective. [ref] another clinical trial in IBS patients with depression found that Bifidobacterium longum reduced depression but not anxiety.[ref] A clinical trial using Lactobacillus casei, acidophilus, and Bifidobacterium bifidum found a significant decrease in depression scores. [ref]  One probiotic that has worked well for me is the Renew Life Ultimate Flora that combines several strains of Lactobacillus and Bifidobacterium.

Meditation: Considering the intersection of so many studies between trauma, stress, serotonin and depression/anxiety, mindfulness meditation may be something to explore. [ref]

5-HTP: There is a supplemental form of the precursor to serotonin, 5-HTP that is readily available. There are many studies showing the effect of supplementing with 5-HTP, but I would say that caution is always advised when taking supplements that can affect your neurotransmitters. If you are under a doctor’s care or on other medications, be sure to check with your doctor.  A case report shows that mixing MAOI prescription with over the counter 5-HTP supplement caused an adverse reaction (manic episode).[ref] [ref][ref]




Is the nootropic drug modafinil likely to work for you?

Modafinil is being used as a nootropic drug that increases alertness and gives a sense of well being — to some users. Like most drugs, individual results seem to vary.  One reason for the variation is a common genetic variation in the COMT gene.

Modafinil is a prescription medication (in the US) for decreasing daytime drowsiness in narcolepsy patients.  Off-label, it is a popular drug for neuroenhancement. Does it work? Clinical trials have shown that it is effective for cognitive enhancement, but the trials didn’t differentiate between genotypes and show a range of effectiveness.

Modafinil is thought to work by increasing dopaminergic neurotransmission, which depends on the activity of the gene, COMT (catechol-O-methyltransferase).  COMT is the enzyme that breaks down neurotransmitters (including dopamine, epinephrine, and norepinephrine), and the rate at which it metabolizes the neurotransmitters affects their levels in the brain.

When investigating modafinil’s effectiveness in people with different genotypes, research results showed that those with the COMT Val/Val genotype had a much better response than those with the Met/Met genotype in terms of sustained vigilant attention. In fact, the study says that modafinil “was hardly effective in subjects with the Met/Met genotype”. For both genotypes, modafinil worked in keeping the subjects from feeling sleepy, so the difference in genotype was on the cognitive benefits rather than wakefulness.

Check your 23andMe results for rs4680 (v.4 and v.5):

  • GG: (Val/Val) higher COMT activity, better response to modafinil
  • AG: intermediate COMT activity
  • AA: (Met/Met) lower COMT activity, not as much response to modafinil


Another study looked at the effects of modafinil on REM and non-REM sleep and found that it varied by COMT genotype. This sleep deprivation study found that modafinil increased specific EEG activity in those with the Val/Val genotype during sleep recovery (after modafinil and sleep deprivation for 40 hours).  The study concludes: ” in NREM sleep, the drug increased EEG activity in 3.0-6.75 and > 16.75 Hz frequencies exclusively in Val/Val allele carriers. Taken together, the data show that the promotion of wakefulness by pharmacological interference with dopaminergic and adenosinergic mechanisms differently affects sleep EEG markers of sleep homeostasis.”


If you’ve ever tried modafinil and wonder why it didn’t have much of an effect on you, perhaps the reason is in your genes.

I’m not going to weigh in on whether or not you should take modafinil… or where to buy it. You can go read about it on Reddit for that type of info.

If you have histamine intolerance, mast cell problems, or anorexia, please note that modafinil may increase histamine levels in the brain.

If you are interested in other effects of the COMT gene, check out my article: COMT – Genetic Connections to Neurotransmitter Levels

If you are wondering about the metabolism of other drugs, I suggest starting with checking your phase I detoxification genes (CYP450’s) through my  Phase I Detox report or by reading about it here.


Choline – An Essential Nutrient

Choline-An Essential NutrientI just finished listening to an interesting podcast featuring Dr. Zeisel, a researcher at the NC Nutrition Research Institute.  The interview discussed the body’s need for choline and the impact of some genetic variants on our ability to produce it in the body.  So I decided to dig into this a little more and look at some of the SNPs covered by 23andMe data related to choline.

A little background information…

Choline is involved in several critical roles in the body including:

  • supporting methylation reactions through donating a methyl group (TMG/betaine)
  • formation of acetylcholine, a neurotransmitter and cell-signaling molecule
  • formation of phosphatidylcholine which makes up cell membranes[ref]
  • muscle function [ref]
  • deficiency in choline contributes to non-alcoholic fatty liver disease

Recent studies of choline levels show:

  • academic achievement in 15-year olds is significantly associated with plasma choline levels [ref]
  • choline plus B-vitamins may increase neuroplasticity and speed recovery after a stroke [ref]
  • crocodile choline may be a treatment of gastric cancer [ref]
  • choline deficiency is correlated to lower bone mineral density [ref]
  • high serum choline concentrations may increase the risk of colon cancer [ref]
Role of Choline in Methylation Cycle. Wikimedia Commons, Public Domain

Generally, people can make some choline in their liver; a percentage of people have genetic variants that reduce their ability to make choline and need to ensure adequate intake through food or supplements.

Choline is the precursor to acetylcholine, which is a neurotransmitter.  Acetylcholine controls muscles, heart rhythm, and other function.

The FDA gives a recommended adequate intake for adults as 425-550 mg/day.   [ref]

Genetic Variants Related to Choline

PEMT – phosphatidylethanolamine N-methyltransferase

The PEMT pathway is responsible for the body’s production of phosphatidylcholine which is part of the phospholipid bilayer making up the membranes surrounding our cells.  Note that 23andMe does not cover all of the SNPs in PEMT that are relevant to choline levels.

rs7946: (v.4 and v.5) CT and TT variants have somewhat decreased PEMT enzyme activity [ref]

CHKA – Choline kinase alpha

The first step of the CDP-PC pathway.

rs10791957: (v.4 and v.5) AA and AC variants have a lower turnover of methionine to PC
“Specifically, the variant appears to decrease the use of dietary choline for PEMT-PC synthesis relative to CDP-PC synthesis. Variant individuals displayed decreased turnover of choline-derived methionine → PEMT-PC over the study period, indicating decreased activity of PEMT relative to women without the variant, and also tended to exhibit lower relative PEMT-PC/CDP-PC enrichment as compared to non-variants.”[ref]
In another study, those with CC were found to be “less likely to have clinical symptoms after consuming a low-choline diet.” [ref]

BHMT – Betaine-homocysteine S-methyltransferase

rs3733890: (v.4 and v.5)   AA and GA variants have lower conversion of choline to betaine and more conversion of choline to CDP-PC
“Together, these results indicate that the variant favors the use of dietary choline for CDP-PC synthesis at the expense of betaine synthesis.” [ref]

FMO3 – Flavin-containing monooxygenase

rs2266782:  (v.4 and v.5) GA and AA variants have greater turnover of betaine to methionine and greater turnover of choline-derived methionine to PEMT-PC
“While a previous study from our group suggested that the variant might be associated with increased use of choline as a methyl donor in men (based on increased DMG pool size) [43], results from the present study, indicate that women with the variant actually use choline less as methyl donor. Variant women tended to have a lower turnover of betaine → methionine over the study period. In addition, variant women exhibited a greater turnover of choline-derived methionine → PEMT-PC over the study period, which is consistent with previous findings from our lab that have identified lower methionine excretion among variant individuals (i.e., a greater use of methionine may reduce excretion)” [ref]

MTHFD1 – methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1

rs2236225 (G1958A): (v.4 and v.5) Carriers of the A allele are more likely to have choline deficiency on a low choline diet (modified by folate intake) [ref] [ref]  In one study with premenopausal women, those with an A-allele were 15 times more likely to show choline deficiency symptoms on a diet low in choline.

Food and supplements:

Excellent (egg-cellent :-) sources of choline in foods include:  eggs, liver, shitake mushrooms, milk, and various meats.  [ref]  Raw egg yolks are a better source of choline than cooked, but there are drawbacks, especially if you don’t know the source of your eggs.

Choline supplement options include CDP-choline, phosphatidylcholine, alpha-GPC, and choline citrate. is a good source of information on the different types of choline.

More to read:

Dr. Amy Yasko also has a lot of information about the role of choline in the methylation cycle.  Her view is that MTHFR variants can be bypassed using choline if a person doesn’t have BHMT or PEMT variants. Her free book Companion Guide: Feel Good Nutrigenomics is a good place to start, and her full book Feel Good Nutrigenomics as well as videos, etc can be found on her website.

Linus Pauling Institute (University of Oregon) – Choline

Genetics of Grinding Your Teeth

The Genetic Polymorphisms involved in Teeth Grinding (Bruxism)
The Genetic Polymorphisms involved in Teeth Grinding (Bruxism)

It never fails to amaze me how many of our quirks and traits have a genetic basis.  A study that came out last week caught my eye. Bruxism, teeth grinding, is linked to a genetic variant.

The study, Genetic polymorphisms in the serotoninergic system are associated with circadian manifestations of Bruxism, looked into several polymorphisms in neurotransmitters such as serotonin.  For some people, SSRI’s are effective in helping  control teeth grinding.

The September 2016 study found that a variant in the HTR2A gene, which codes for a 5-HT2 serotonin receptor, is associated with bruxism.  Those with a C allele in rs2770304  were found to have twice the normal risk for bruxism.[ref]

Another study from 2012 of bruxism in a Japanese population found a different variant in HTR2A to be significant.  In that study, a G allele for rs6313 gave a 4 times greater risk for grinding your teeth in your sleep.  [ref]

Both variants are very common and have many other studies associated with them. [ref]

Check your 23andMe results for rs2770304

  • CC: 2X increased risk of bruxism (teeth grinding)
  • CT: increased risk of bruxism
  • TT: wildtype/normal


Check your 23andMe results for rs6313

  • GG: 4X increased risk of bruxism
  • AG: increased risk of bruxism
  • AA: wildtype/normal


So what can you do with this information? Logically, if you are grinding your teeth and have these variants, you could look into the serotonin system.   Be cautious and read up on serotonin before starting supplements that could affect your neurotransmitter levels.  Honestly, it is not clear to me whether it would be better to try to stimulate more serotonin or to try to decrease serotonin for bruxism.  Tryptophan is an amino acid that may increase serotonin, as well as 5-HTP. [ref]  So talk with your doctor and get your serotonin levels checked.

A little lithium and B-12 makes the world a happier place – for some.

A Little Lithium + B12 may make the world a happier place - depending on your #genetic snps.

A Little Lithium + B12 may make the world a happier place - depending on your #genetic snps. It is funny sometimes, looking back on the journey you take to discover something new and personal to your health. Of all the lessons that I’ve learned from reading through thousands of research studies on genes, the most important lessons sometimes come from stumbling across a nugget of information that hits a chord. For me, seeing first hand the power of supplementing with a little mineral (lithium orotate) was eye-opening as to the power of combining genetics with nutrients.  

Let me cut to the chase (since no one reads to the end of the article): for some people, supplementing with lithium orotate helps with anxiety, mood, and anger issues, while for other people, lithium orotate supplements will have little or no noticeable effect on mood. Genes play a role in this.

Before going any further into this, I want to clarify that I’m referring to supplementing with an over-the-counter mineral supplement of lithium orotate or lithium aspartate. This is different than the large, prescription doses of lithium carbonate used for bipolar disorder. Lithium is actually a naturally occurring mineral that is found in foods at concentrations dependent upon the mineral content of the soil. We naturally get about 3 -4 mg in our food each day.  Supplemental lithium orotate comes in 5mg and 10 mg dosages.

Dr. Amy Yasko explains on her website why she thinks some of us need and use more of the mineral lithium than others. She recommends checking lithium levels for all autistic children and suggests supplementing with low levels of lithium for MTR/MTRR mutations. Dr. Yasko states that “Lithium not only plays a role in mood, glutamate control and limiting aggression but also has been shown to be involved in B12 transport.”[ref]  She recommends making sure your lithium level is in balance before adding in B12.

In addition to Dr. Yasko’s clinical work associating B12 and lithium, there are several studies showing this as well.[ref] [ref] Why is vitamin B12 so darn important to your mood?  Vitamin B12, along with folate, is essential for the production of tetrahydrobiopterin (BH4) which, in turn, is involved in the production of the neurotransmitters serotonin, melatonin, dopamine, norepinephrine, and epinephrine.[ref]

On a personal note, one family member (who is homozygous for several of the snps below) found that supplementing with lithium orotate and B12 was extremely helpful and is no longer irritated by, well, everyone and everything. The rest of the family, without the homozygous SNPs, doesn’t really notice any difference when taking lithium orotate, showing once again that everyone is different. It is truly amazing, though, the difference it makes when you hit on the right food or supplement for your body and your genes.

Genes involved:
Here is a list of the MTR and MTRR SNPs involved and the allele to look for:

Check your 23andMe results: (v.4 and v.5)

Dr. Yasko also has an excellent video of a seminar where she lays out her research on the effects of lithium. She makes the case that lithium, through the inhibition of thioredoxin, can increase COMT, which is an enzyme that regulates and degrades dopamine, epinephrine, and norepinephrine. She now also checks the COMT status in regards to lithium supplementation.

Check your 23andMe results: (v.4 and v.5)


Lithium Supplements

Lithium orotate and lithium aspartate are both available in health food stores and online in 5 mg doses. Amazon carries several brands including Seeking Health’s Lithium Orotate (5mg) and Weyland’s Lithium Orotate (5mg or 10mg)*.

Natural Sources of Lithium:
Lithium occurs naturally in spring water in certain areas and can range from less than 1 mcg/l to well over 100 mcg/l.  It is also found in the soil and can be taken up by plants depending on the concentration in the soil. Here is a map of a few places in the US showing lithium levels in the well water.

A study in 1989 looked at the lithium levels in the water in 27 counties in Texas.  The study showed that counties that had water with higher lithium levels had significantly lower violent crime rates and suicide rates.  There have been several more studies completed more recently in other countries that show the same decrease in suicide and homicide with higher levels of naturally occurring lithium.

Studies on lithium levels found naturally in drinking water:

  • Lithium in the Public Water Supply and Suicide Mortality in Greece 2013 – “The purpose of the present study was to evaluate the association between lithium levels in the public water supply and prefecture-based suicide rates in Greece. Analyses were conducted with respect to lithium levels in 149 samples from 34 prefectures of Greece. The average lithium level was 11.10 [mu]g/l (range 0.1 to 121 [mu]g/l). The results indicate that there is a tendency for lower suicide rates in the prefectures with high levels of lithium in drinking water.”
  • A Negative Association Between Lithium in Drinking Water and the Incidences of Homicides, in Greece, 2015 – “total of 149 samples of drinking water were collected from 34 out of 52 prefectures, and data for homicides were taken from National Statistic Service of Greece (Hellenic Statistical Authority – EL.STAT). The average lithium level was 11.10 [mu]g/l (SD=21.16). The results indicate that there is a tendency for a lower mean number of homicides in the prefectures with high levels of lithium in drinking water (R ^sup 2^=0.054, [beta]=-0.38, p=.004).”

Lithium and Polyunsaturated Fatty Acids (PUFA):
Several studies have found that lithium reduces arachidonic acid (inflammatory polyunsaturated fatty acid) production in the brain.  One theory is that this reduction of neuroinflammation is a reason that prescription strength lithium chloride works for bipolar disorder.  For more information about genetics and variants that affect fatty acid composition, check out the article on Omega-3 vs. Omega-6 fats and your genes.

These two studies are worth reading if you are interested in the link between lithium and neuroinflammation:

Lithium in the News:
There have been a couple of really good articles recently explaining the benefits of a little lithium.

Uses for high dosage lithium:
For well over a century, lithium has been used in high pharmacological doses (typically 300-1200+ mg per day) to treat bipolar disorder and other mood disorders.  It is also being investigated and used to slow the progress of ALS, dementia, and Alzheimer’s disease.

Studies on lithium (pharmacological doses for mood disorders) and genetic polymorphisms:

Safety of taking lithium:
Prescription levels of lithium do come with long-term side effects including higher risks of hypothyroidism and kidney problems.

  • Lithium toxicity from an internet dietary supplement, 2007 — case study of an 18-year-old who took 18 tablets of Find Serenity Now, each of which contained 120mg of lithium orotate.  She went to the emergency department with nausea and was discharged after a few hours to a psychiatric hospital.
  • Lithium toxicity profile: a systematic review and meta-analysis, 2012 — A meta-study on side effects from prescription dosages of lithium carbonate used for mood disorders showed that lithium increased the risk for hypothyroidism and weight gain. It also showed an increased risk of renal failure, with overall risk being 0.5%.

Updated on 2/4/2017