Past, Present, and Future of “Biological Aging” with Dr. Fitzgerald
I admit it. I’ve harvested a scientific nugget or two from the Daily Mail.
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:
Do Parkinson’s drugs make people more creative?
Painting made by individual with Parkinson’s Disease taking L-Dopa.
It prompted me to recall another Daily Mail gem:
Casino for RATS — complete with ‘slot machines’
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…
But what about rats and casinos?
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.
The Caveats…..
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.
The research…
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
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I googled exactly about this – to see where there are other such behavioural patterns running in families. And I am quite shocked to say that it sounds quite similar to my experience in my family… And I just discovered yesterday that I have the COMT V158M (MM) polymorphism. For years I have been trying to figure out that there has to be some common explanation for the various strange and destructive behaviours and some amazingly brilliant & resilient characteristic that run in my family. Simple things like OCD in day to day activities, insomnia and inability to sleep on time…. and bigger things like success in certain occupations. fibroids and estrogenic issues and even manifestation of a FPP (fantasy prone personality). It makes so much sense now… Its strange but most individuals in my family are so self-involved and dealing with so much themselves that they wouldn’t care to listen to this!!
Thanks, RB– I appreciate your comment. Yes, high brain dopamine can result in some interesting stuff, eh? DrKF
Hi there, I found this very interesting. I apparently have low COMT via the SNP rs4860 AA. I can relate to this article also. I have had a lot of creative alcoholics in the family (including myself). Alcohol gives me a feeling of euphoria and relief that I believe far exceeds the effect on a “normal” person. I am interested in optimizing my diet to raise my COMT levels so my moods can be stabilized and also so alcohol is not a big a problem for me. Doing some digging I found that Methlcobalamin (B12) doses help in the synthesis of COMT. Also that Quercetin (an anto-oxidant) deactivates COMPT, the second one could be a problem removing from my diet because I’m a vegan who focuses on eating whole foods. Do you have anymore detailed advice on an optimal diet to raise COMT levels? Keep in mind a paleo style low sugar diet isn’t really an option for me.
Thanks a lot.
Matt, connect with our awesome nutrition team— reach out to Rhonda at frontdesk@drkarafitzgerald.com
thanks!
Having just received my 23andMe results and finding out that I have the A/ A variant of the 4680 gene, coupled with the C677T (T/T) AND an APOE3/E4 is a kick in the jimmies!
My family has always been highly successful on one end and highly unsuccessful on the other end. Thankfully I am in the latter group. I’m a physician (ER doc), highly anxious, a worriet and also a warrior and a bit of a risk taker as well. I used to abuse nicotine and alcohol but gave that up 20 years ago . All in all, I guess this has served me quite well through the years but now going into middle age the excessive stress has fnally caught up with me and I am Reinventing myself in order to reduce my stress and hopefully increase my longevity.
Like most Physicians in traditional medicine I did not receive any training in nutritional medicine or polymorphism related nuances other than how it relates to extreme forms of dysfunction such as inborn errors of metabolism etc.
I find all of this extremely confusing even for someone who has had extensive training in science. There are so many different interpretations to what specific polymorphisms actually mean. Some places dismiss all of this as rubbish and other places seem to place and unneeded emphasis on genetic polymorphisms. Obviously there has to be some sort of balance somewhere in the middle.
After finding out this information yesterday I have an overwhelming urge to run to the health food store and by large stacks of methylated folate, B12, B6, DIM, SAMe, adrenal support, detox formulas, and more. Also based on the APOE4 status I should probably buy myself some long-term care insurance and begin taking supplements to support my brain! I’m not sure how I am supposed to inform my four children of the wonderful genes that they have been blessed with!
But alas, I am reminded that all life is precious and each of us have been blessed with special talents and gifts. I am so thankful that God has given me what he has given me! Life is more then focusing on my disease States, genetic predispositions, weaknesses and failures. I am reminded to not think too highly of myself, not to worry about tomorrow, to be good to my neighbors. I am to live life to the fullest, pray without ceasing, run the race with endurance but not run with scissors!
Speaking of running, I’m thinking now would be a good time for a peaceful run on the beach! After that, I may run to the store and get some SAMe and some methylfolate and another big sack of broccoli! Oops, maybe I’d better find out what my genes say about my sulfur detoxification Pathways first! Haha! Eric
Eric,
Thank you for that well-said capsule summary on what is likely going on in many folks minds after obtaining their 23&Me! It’s overwhelming, to say the least. Genes are-thank God- not ones destiny, especially with regard to SNPs. I know that particular study I cite in the blog you’ve read on COMT is compelling, but even there, the data on the impact of lower COMT functionality is pretty limited and conflicted. I wholeheartedly agree with your approach: a run on the beach, a good diet, reducing stress, balance, balance and more balance…and gratitude.
Of course, if you are inclined to do a bit of a “drill down” into making some sense of your 23&Me, I wouldn’t go it alone. Find a good FxMed clinician to review the data and make a couple of suggestions. Consider looking at– with said clinician– associated metabolomic biomarkers, too (organic acids, etc). Check out our methylation diet and lifestyle book– you can get the preface for free, just go to that page (under professionals tab). You’ll see I’m in agreement with the lifestyle approach…
Kara
should I avoid buspironee. the anxiety medication, if I have that two compt ++, vdr tag++, and Mao++, and mtrr++
Trey – Buspar interacts with dopamine, adrenalin and serotonin receptor binding and probably others. Therefore, your SNP pattern could impact how you respond to the medication. We recommend that you make your prescribing physician aware of your SNPs, particularly COMT and MAO. They can either prescribe another medication or start you at a very low dose.
Best wishes,
DrKF
I’ve spent a lot of time first reading about the highly sensitive person and it fit me perfectly. I then got more curious about the brain and what might be going on, so I got started with 23andme. I have this polymorphism (AA) which got me reading more about. I was at first discouraged but then learned that many of the cool things that I feel are benefits to me may be due to this polymorphism (and I see a connection between it and some HSP traits). It’s funny that I’m now feeling pretty thankful for it…it’s not something that I would trade.
I have this gene mutation, COMT G472A…158Met. I also have had uterine fibroids and endometriosis. I’ve had 4 miscarriages. I’m vegan, don’t drink alcohol and am fit. I am very sensitive to stress and work at hiding this every day. It’s hard to be brave. I now have peripheral neuropathy issues. No diagnosis on that yet. IDK…just adding this to your data as well.
I would love to speak with you regarding my family (including immediate) history with COMT Met/Met and how it’s ruining some lives. I recently discovered our youngest son has COMT Met Met and I’m finally feeling like I’m getting the answers I needed a long time ago for myself and my oldest son. My oldest has been diagnosed schizoaffective. I could use help understanding treatment and which type of doctor can help treat our family.
Thank you for reaching out. Please contact the office here: https://www.drkarafitzgerald.com/contact-2/ or call (203) 304-9502 to make an appointment.
I can’t agree with you more! Your article was sorely welcomed and easier to read than the countless medical journals of which many use specific jargon/pomp in order to exceed/impress their peers, or more plainly; to appear more intelligible/credible to the medical community.
As for the family, did they have any MTHFR mutations? MAO-R297R?
Interestingly, Joy- NO MTHFR– all wild type. I am not sure about MAO- if I get that info, I’ll let you know. So glad you enjoyed. DrKF
I am homozygous for both V158M, rs4680 AA and H62H, rs4633 TT. Everything you mentioned in your article is true for myself and other members in my family. I have had to learn how to positively channel the OCD and perfectionism I have. I also have ADHD. On the other hand, I have a professional degree and have always been able to succeed at anything that interests me.
I happened upon your blog while researching Comt & MTHFR. Finding out this has answered a lot of question. I have both & my birth mom has Parkinson now. I suspect my maternal line carry’s the mutation but being adopted makes it difficult to confirm. I not only struggled in school but I’m not sure I’m very creative either. I did however grow up (adopted) in a very emotionally volitive environment & wonder just how much that effected me. Both my kids excelled academically, top 5 in high school & top 3 % in college & continue to be successful & HAPPY! whereas I struggled my entire life making basic decisions, feeling ok in my own skin etc. Enter antidepressants & I navigated motherhood & a bad marriage.
Anyway, I’m recently off antidepressants after 20 years & struggling but don’t want to go back on. Do you know anyone having success with CBD oil?
Eileen,
If you can, do give yourself the gift of working with a functional medicine doc. You could do that through us, or if you would like to consult with an functional med-trained psychiatrist, the very best doctor I know is Bob Hedaya, MD at wholepsychiatry.com …. keep us posted. My best to you— DrKF
I do agree with all the ideas you have introduced on your post. They are very convincing and will definitely work. Still, the posts are very short for newbies. May just you please prolong them a little from subsequent time? Thank you for the post.
Your hard work is evident.
This is such an interesting read. Thanks a bunch for sharing!
This blog post is packed with great content!