Not long ago, sandwiched between a story on toast and the five-second rule, and a selfie of Zac Efron eating a worm, was this journalistic pearl:
Painting made by individual with Parkinson’s Disease taking L-Dopa.
It prompted me to recall another Daily Mail gem:
Creativity and rat casinos. What could these possibly have in common? Dopamine, of course, and the impact of high levels of it in the brain.
If we look at CNS dopamine in a vacuum, that is, if we put down for a minute the complex neurological interconnections between dopamine and other CNS neurotransmitters (including serotonin, GABA, epinephrine, norepinephrine, glutamate), we might think of dopamine as being the stuff of life, good and bad. And indeed, much data corroborates this notion: Pleasure and reward, concentration, creativity, anxiety, PTSD, obsession, addiction, pain, sleep, sexual arousal, fine motor coordination, restless legs. Dopamine, too much or too little, seems to be involved in all of these states and more.
Figure 1: Dopaminergic neurons interact closely with serotonergic neurons in the brain influencing a number of behaviors and functions.
The Parkinson/Creativity story describes a small but compelling study published last month in the Annals of Neurology. The results showed that patients with Parkinson’s Disease (PD) treated with dopaminergic drugs demonstrated significantly enhanced verbal and visual creativity, as compared to a neurologically healthy control group. Faust-Socher, et al., speculated that this creative burst was due to the reduction of latent inhibition, leading to a widening of the associative network and increased divergent thinking.
Give PD patients dopamine, they get creative…
In this study, increasing dopamine availability (in the form of a D2 agonist quinpirole) enhanced the expectation of rewards (gambling behavior); whereas decreasing dopamine activity (by inhibition of dopamine receptor D4) decreased the ‘slot machine’ play of the rats. The authors concluded that inhibition of dopamine availability (by blocking D4 receptors) could be a way to treat compulsive gamblers.
Rats plus dopamine equals gambling.
But what about in humans?
Increased CNS dopamine in some PD patients has been linked not just to creativity, but also to addictive behaviors, including compulsive gambling, shopping, sexual behaviors and others.
And what about a whole family with a genetic mutation that causes high brain dopamine?
In some patients, I look for mutations in genes involved in producing the enzymes (COMT and MAO) that metabolize dopamine, epinephrine and norepinephrine (Figure 2).
Figure 2. Count the times COMT is involved in metabolizing not just dopamine, but epinephrine and norepinephrine.
COMT (membrane-bound catechol-o-methyltransferase) is the enzyme that metabolizes dopamine, epinephrine and norepinephrine (Figure 2). The soluble form of COMT, which outside of the brain is found in liver, kidneys and gut, metabolizes estrogen.
The COMT Val158Met genetic mutation significantly slows down the rate of dopamine, epinephrine and norepinephrine clearance in the frontal cortex of the brain. Of note, this mutation slows prefrontal metabolism of dopamine by up to 50% (Figure 3). This means there is a lot more dopamine around stimulating the post synaptic neurons. While the prefrontal cortex COMT enzyme has a higher affinity for dopamine metabolism, epinephrine and norepinephrine are also metabolized more slowly and therefore around longer.
Figure 3. In this figure, we see that in post mortem prefrontal cortex tissue COMT activity in homozygous COMT V158M (listed here as met/met) as 35%-50% lower than the wild type COMT val/val. Full text here.
A rather remarkable family…
I have worked with members of this family of five — mom, dad, and three children, two adult females and an adult male — for a number of years now. Over the course of time, we’ve amassed a good deal of laboratory data, and most recently, quite a bit of genetic data.
This family is homozygous for the COMT Val158Met mutation. Myriad conditions associated with the mutation have been found, including:
- Creativity: Four musicians, a graphic artist, a potter, three published writers.
- Focus: A PhD, an engineer, a physician.
- Addiction: Strong family history of addiction, including alcoholism, smoking, pathological gambling, food addiction.
- Mental health: Including PTSD, anxiety disorder, depression.
- Estrogen excess: Both daughters have uterine fibroids and fibrocystic breast disease. The maternal grandmother had breast cancer. (Remember that COMT is also needed for estrogen metabolism, and in some studies the mutation has been associated with increased risk for breast cancer and fibroids.)
- Relevant family history includes a maternal cousin with schizophrenia.
- Methylation defects: Elevated homocysteine. The four members who were tested were found to have significantly elevated levels*
*The COMT enzyme requires the methylation cofactor s-adenosylmethionine (SAM). If the slow COMT mutation is consuming increased quantities of SAM to push the enzyme to work (my hypothesis) perhaps this is why methylation is seen as compromised, causing higher homocysteine. This is discussed in an earlier blog I wrote on Parkinson’s Disease and Lead Toxicity.
What’s fascinating about this isn’t any one single issue in the family, but that the collective familial pattern does point to some kind of dopamine imbalance, and not all of it negative!
Thoughts on treatment
Goals include preserving the beneficial attributes associated with the COMT Val158Met, while tweaking the negative effects of it. Major priorities have included supporting a reduction in epinephrine- that is, nudging toward a parasympathetic, calming responses rather than living in the epinephrine-charged fight-or-flight tendency that the COMT Val158Met mutation may encourage.
Beyond reducing epinephrine, HPA balance is important with adrenal supportive therapies.
We also need to reduce the estrogen burden and support appropriate metabolism. This is readily done through an anti-inflammatory, lower sugar diet, and supplements that reduce estrogen production and improve estrogen metabolism. I just blogged on this topic in relation to men – but I used the same general ideas with the two daughters.
Finally, behavioral modifications have been particularly important with this family. In one study, those with the COMT Val158Met mutation were apt to choose high risk, addictive behaviors under stress, whereas receiving calming support during stress reduced the behaviors.
My good friend Dr. Tom Sult will be challenging me on this blog, no doubt. And his feedback is always welcome. Is this case as simple as one genetic mutation, one set of inevitable outcomes? The answer is a resounding no. A single genetic mutation doesn’t an addict or brilliant musician make. Rather, there is a complex interplay between environmental exposures, including diet and lifestyle habits, parental influence, ethnicity, toxin exposures, exercise, sleep, play, age and on and on. All coalesce to make the whole person, or in this case, the whole family.
Note that everything I’ve stated is backed up by a peer-reviewed publication. Indeed, The COMT Val158Met research is extensive and fascinating. And NOT all findings agree. For instance: COMT Val158Met has been associated with uterine fibroids in certain ethnic groups, but not all. I reviewed many, many papers, links and citations for this piece. Rather than listing them all here, I invite you to start your COMT exploration here: http://www.snpedia.com/index.php/Rs4680