When assessing dopamine and adrenaline function in a patient’s genetic profile, the main genes are COMT, ANKK1, and ADRB2.
COMT: COMT (catecholamine methyltransferase) shares a pathway with MAO-A and is the gene for dopamine, estrogen, and adrenaline.
ANKK1: ANKK1 modulates the density of dopamine receptors in the brain.
ADRB2: Beta-2 adrenergic receptor (ADRB2) is abundantly expressed in cardiac cells, and bronchial smooth muscle cells and is connected to stress levels and heart health.
COMT, Dopamine and Adrenaline
If your patients have heterozygous or homozygous variants in COMT V158M and COMT H62H, they may be more sensitive to chronic stress, low magnesium levels, low vitamin C levels, low or high copper levels, plastic, high calcium supplementation, mercury toxicity (mercury amalgams and too much large fish) IPA beers, and dietary catechol’s including chocolate, green tea, black tea, coffee and wine.
Studies have found that the A allele in V158M results in a 40% decrease in COMT enzyme activity. This can lead to anxiety, impulsiveness, obsessive behavior, irritability (especially under stress), ADHD and abnormal behavior. The positive side of the AA genotype is that there is a higher IQ, high creativity, better memory, drive, reading comprehension and overall cognitive function. The downside of the AA genotype is that the body overreacts to stress.
Constipation can cause the COMT enzyme to move slower, creating high estrogen/anxiety levels. Higher levels of magnesium and vitamin C are needed to help break down and modulate elevated levels of dopamine and adrenaline, while copper levels are also important.
While the homozygous genotype for COMT V158M is associated with slower enzymatic function and naturally higher dopamine and adrenaline levels, the wild-type COMT V158M gene (GG rs4633) is associated with faster enzymatic function, leading to lower prefrontal dopamine, adrenaline and norepinephrine levels.
The benefits to the GG genotype may be a better response to high-pressure situations and the ability to be more emotionally resistant and calm in a crisis. Those with the GG genotype may even thrive more in response to certain stressors and have enhanced cognitive performance due to the elevation of dopamine and adrenaline to more normal levels.
The downside of the GG genotype is that it can affect executive function and problem-solving abilities compared to the AC and AA genotypes of COMT V158M if dopamine remains low. Individuals who had the GG genotype of COMT and variants in ANKK1 showed the lowest cognitive performance, however, both genes can be improved by increasing catecholamine intake, meditation, balanced blood sugar, vitamin D, omega-3 fatty acids, fiber, high-intensity exercise and lower media exposure.
Connecting COMT and ADRB2
In the cardiovascular section, you will see a gene called ADRB2. Since ADRB2 is connected to the catecholamine epinephrine, it is also important to look at the patients COMT function. If your patient has homozygous variants in ADRB2 and variants in COMT, then he or she may be more prone to stress-induced anxiety, high blood pressure and arterial damage from stress.
Magnesium, vitamin C, and adaptogens should be considered highly relevant to this patient while making lifestyle changes and strategies if chronic stress is present. Relaxation techniques that involve slow, deep breathing have been found to be an effective therapeutic intervention that counteracts the adverse clinical effects of stress in disorders including hypertension, anxiety, insomnia, and aging.
COMT, Coffee, Wine and Beer
COMT is a much better indicator than CYP1A2 on how someone will react to coffee. Typically, people with heterozygous or homozygous variants in COMT experience more anxiety and jitteriness with coffee because of the catechols slowing down COMT too much, increasing dopamine and adrenaline levels combined with the effect of caffeine on the adrenal glands.
Like coffee, wine also contains caffeic acid and chlorogenic acid. Red wine will produce a higher dopamine response than white wine, and champagne will produce a higher response than white wine. It is believed that red grapes inhibit the SULT1A enzyme more, and may also explain more headaches/migraines from red wine and champagne. Therefore, people with slow COMT function who like to drink wine may do best with white wine, or limit red wine to 1 glass early in the evening.
You may have wondered why I also listed IPA beers for slowing down COMT. One one hand, hops improve fat metabolism and contain a flavonoid called xanthohumol that strongly suppresses CYP1A2 (suppressing is good), a liver enzyme previously discussed that metabolizes various environmental procarcinogens such as heterocyclic amines (created during high heat cooking of meat or fish), nitrosamines (pesticides, cosmetics), and aflatoxin B1 (mold) that can lead to cancer when overexpressed.
On the other hand, hops are also considered a potent phytoestrogen, and IPA’s use a very high amount of hops. This may be beneficial for post-menopausal women for bone density and hot flashes, but may not be beneficial for men with a slower COMT pathway. It has been my experience that people who don’t do well with coffee due to reduced COMT activity, also do not do well with IPA beers. So if you have patients that like to drink beer, tell them to choose low hop beers like lagers, porters, and stouts.
ANKK1 and Reduced Dopamine Receptors
Dopamine is involved in trial-and-error learning. Variants in genes related to dopamine signaling may also affect a person’s ability to learn. The heterozygous AG and homozygous AA genotypes of ANKK1 have been correlated with up to a 30% reduction in dopamine receptors in a region of the brain known as the striatum. One small study found that people with the normal GG genotype learned from their mistakes easily, while people with the AG or AA genotypes were more likely not to learn from their mistakes and repeat behavior with negative consequences. Another research experiment found that people with generalized social phobia tended to have lower dopamine levels than healthy subjects.
Researchers found that individuals with Internet addiction showed reduced levels of dopamine D2 receptor availability in subdivisions of the striatum. This helps explain the universal iPhone phenomenon of addictive-reward behavior, with excessive use decreasing dopamine receptors and increasing the craving for more.
ANKK1 and Obesity
Poor dopamine uptake may contribute to the development of obesity. This relationship was significantly stronger in women with a heterozygous or homozygous A1 variant in rs1800497. The “A” corresponds to the A1 allele and the “G” is called the A2 allele. A1 heterozygous or homozygous women had lower dopamine activation in response to food, and therefore gained more weight potentially due to their diminished pleasure response from dopamine.
Those with sugar addictions, compulsive eating and obesity may have systems that need much more stimulation to feel pleasure caused by fewer D2 dopamine receptors and the need for extra stimulation to make the receptors “turn on.” Functional MRI studies of teenagers, both lean and obese, found that the teenagers whose brains didn’t light up as much in the dopamine reward centers were more likely to be obese and gain weight later. They also were more likely to have fewer dopamine receptors.
The Connection to Dopamine Receptors and ADHD
The global statistics show that about 10 percent of the world’s population has ADHD. When researchers looked specifically at teenagers in the US, they found the diagnoses had risen 52 percent since 2003. ADHD has been associated with decreased dopamine activity. A meta-analysis of 11 studies with 1645 cases and 1641 controls found that variants in rs1800497 may be associated with ADHD.
Studies have also found that children and adults with ADHD are significantly more likely to be overweight, showing the shared connection to decreased dopamine levels. The heavy metal lead disrupts the dopamine pathway, and 16 out of 18 studies found a significant association between blood lead levels and one of the types of ADHD (Combined / Inattentive / Hyperactive-Impulsive). This is where vitamin C is essential because it reduces blood lead levels while modulating dopamine. Other research has shown that iron deficiency causes a reduced number of dopamine receptors, and a recent study from the Annals of Medical and Health Sciences Research found that low serum iron, ferritin levels, and vitamin D deficiency may be associated with ADHD.
Low blood sugar, refined sugar, high fructose corn syrup, elevated lead levels, elevated copper levels, iron deficiency, omega-3 deficiency, low vitamin D levels and excessive media exposure all have been found to reduce dopamine receptor density. Addressing all of these in your patients will help increase dopamine receptors.
How Are Copper and Lead Levels Connected to Dopamine and Adrenaline?
As you can see in the diagram below, copper is a co-factor for the conversion of dopamine to norepinephrine. Zinc lowers excess copper levels, and vitamin C chelates excess copper. Lead affects the conversion of dopamine to norepinephrine and norepinephrine to epinephrine. When calcium and vitamin C levels are low, lead levels rise.
There has been a lot of discussion regarding copper levels in patients. Copper can affect numerous pathways, including the dopamine pathway, the histamine pathway, and the glutamate pathway.
High copper levels have become more common due to the ubiquitous use of the copper IUD, estrogen dominance (estrogen retains and accumulates copper, and a sensitivity to both oral contraceptives and the copper IUD can be a clue for high copper levels), low zinc intake, copper fungicides, copper pipes, a vegetarian diet, poor gut health (copper elevates in response to infections) and other sources. When copper levels are high, there is a very long list of things that can go wrong related to the immune system, the endocrine system, and the nervous system. High copper speeds up the conversion of dopamine to norepinephrine and epinephrine, creating a low dopamine and high adrenaline state. You may see copper toxicity manifest as ADHD, anger, agitation, autism, anxiety, panic, racing thoughts, insomnia, oxidative stress, severe cramps, endometriosis, and fibroids.
The Neurotransmitter and Mental Health section of the report gives you one of the most valuable insights into your patient’s biochemistry. Connecting the genes in the serotonin, dopamine, adrenaline and estrogen pathway can give you tremendous information into how and why certain disorders are manifesting in your patients.