Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 16 No. 5 • May 2013


A Key Enzyme in Your Choice Between a Reward Now or a Bigger Reward Later is Part of the Dopamine Reward Seeking System

COMT—catechol-O-methyltransferase—if you haven’t heard of it before, then here is a bit of an introduction to an important part of your dopamine reward seeking system that is appearing in a considerable amount of recent research. It is important because it is the enzyme that degrades dopamine, thus having a major impact on the dopamine level in the brain, especially in the prefrontal cortex, a major site of higher cognitive processes.1 You make a lot of decisions in the prefrontal cortex, including assessing the tradeoffs between getting a reward now or waiting a while and possibly getting a larger reward later. Some researchers call COMT a factor in impatient choice (impulsivity).1

A specific variant (allele) of the COMT gene has been identified as associated with having a steep delay discounting, “the tendency to strongly discount future rewards as a function of their delay and thus choose tempting SSs [sooner-smaller rewards] over even substantially larger LLs [later-larger rewards].” Researchers in one paper1 cite papers that show suboptimal life outcomes in financial, academic, and health domain and in different psychiatric or behavioral disorders such as substance abuse, overeating, relationship infidelity, and pathological gambling in people who have the steep delay discounting. The Val allele (compared to the Met Allele) of COMT is associated with a higher level of enzymatic activity and, as it degrades dopamine, lowers prefrontal cortex dopamine levels.1 COMT has a big effect on your life.

Using a sophisticated noninvasive EEG measurement system, the researchers exposed participants to a choice paradigm between SSs (sooner-smaller rewards) and LLs (later-larger rewards) and were able to calculate the intracortical electrical sources that generated the scalp-recorded activity of each of seven frequency bands. They were able, for example, to identify brain regions whose baseline activation correlates with DD (delay discounting), separately for each EEG frequency band.

The researchers concluded that: “Our research suggests that the Val allele predisposes individuals to a low level of baseline activation in the left DPFC [left dorsal prefrontal cortex] which then biases them toward impatient choice.”

There was another study, however, that found the Met allele to be associated with significantly steeper discounting rates, i.e., more impulsive choices, as compared with the Val allele (reported in #4). It was suggested that the discrepancy may be due to the fact that this study1 had adults as participants whereas the other study’s participants were adolescents. “Numerous aspects of PFC [prefrontal cortex] function, including the expression and activity of COMT, change over the course of adolescence.”4

But that isn’t the end of the story because there are natural products, such as EGCG, that can inhibit COMT, thus decreasing the degradation of dopamine, leading to higher levels of dopamine and, hence, potentially avoiding the disadvantage of impatient choice.

Inhibiting COMT To Decrease Dopamine Degradation in the Brain

EGCG ((-)-epigallocatechin-3-O-gallate, the major catechin found in green (or white) tea), has been recently identified as a high-potency inhibitor of the ubiquitous human enzyme catechol-O-methyltransferase (COMT).2 As of 2010 when another paper was published on EGCG’s effects on COMT,3 there were two drugs approved as COMT inhibitors: tolcapone and entacapone. “However, the use of tolcapone is only limited to fluctuating [Parkinson’s disease] patients who are refractory to other therapies, and requires heightened monitoring for the occurrence of hepatotoxicity [liver damage]. Although entacapone is relatively safer, it appears less efficacious than tolcapone.”3

The detailed molecular analysis of the mechanism by which EGCG inhibits COMT shows it to be a potent non-competitive inhibitor that, while able to interfere with the molecular mechanism by which COMT binds to dopamine, renders EGCG itself a poor substrate for COMT methylation.

In one of the papers,3 researchers studied the effect of EGCG both in vitro (human liver samples) and in vivo (modulation of L-Dopa methylation in rats). “When normal rats (treated with L-DOPA + carbidopa) were given an oral administration of EGCG (at 400 mg/kg), their 3-OMD levels [L-Dopa product after interaction with COMT] in circulation and striatum were reduced by approximately 30%, clearly reflecting an in vivo inhibition of L-DOPA methylation.” The breakdown of L-Dopa was reduced, but L-Dopa plasma concentration was increased only slightly (not statistically significant). This was similar to the results of treatment with L-Dopa + carbidopa plus tolcapone or entacapone in rats or humans.3

The authors3 concluded that: “The significant reduction of 3-OMD by EGCG may increase L-DOPA bioavailability in the central nervous system and particularly, reduce potential cytotoxicity associated with elevated levels of 3-OMD.”

Dopamine and Reward Processing

Another recent paper4 provided an overview of dopamine and reward processing that included COMT and a lot more, noting (for example) that reward processing takes place in multiple brain regions, including the VStr, midbrain, orbitofrontal cortex, anterior cingulate cortex, prefrontal cortex, ventral pallidum, and the medial dorsal nucleus of the thalamus. No wonder, then, that understanding the entire dopamine-reward system is far from complete and is very complex. One oddity, for example, is that “systemic administration of dopamine antagonists selectively reduces the motivation of animals to pursue rewards, without affecting their preferences for such rewards when they can be obtained without effort.”4 (Makes those who prefer getting rewards via the government’s freebies—rewards without effort—sound like they’re on dopamine antagonists.)

EGCG Increases Neurogenesis in the Sub-granular Zone of the Dentate Gyrus in Adult Mice

EGCG does a great deal more than just inhibit COMT, of course. In the area of cognition alone, EGCG also promotes neurogenesis, thus increasing the availability of new youthful adult-born neurons in those areas of the brain where neurogenesis takes place throughout life. One of those areas is the subgranular zone of the dentate gyrus in the hippocampus.

In one study of EGCG and neurogenesis, mice were divided into two groups of 7 mice each, one group of which received vehicle (controls) and one of which was treated with 25 mg/kg of EGCG for four weeks.5 Animals were treated with BrdU (5-bromo-2’-deoxyuridine) by injection and the neurons marked by Ki67 and DCX determined (these are markers of neuronal proliferation). “In the EGCG-treated groups, the number of Ki67+-positive cells were increased by 221.3% (p=0.01) compared to that in the vehicle-treated group (11.7 ± 0.17/section).”5

Hence, the authors conclude, EGCG enhances the survival of immature neuroblasts in the subgranular zone of the dentate gyrus in adult mice.

EGCG Increases the Number of Neural Stem Cells Around a Damaged Area After Rat Traumatic Brain Injury

EGCG is also potently neuroprotective in the injured brain. In one study,6 for example, male Wistar rats were subjected to acute brain trauma while under anesthesia after receiving either water or water with EGCG added to it at 0.1% w/v from 6 to 10 weeks of age. Excitotoxicity elicited under ischemia, such as that occurring during acute brain trauma, is known to cause excessive glutamate release from the injured neurons, with the subsequent influx of increased Ca2+ via glutamate receptors. The increased Ca2+ leads to a substantial increase in free radical generation, with cell degeneration and death following.

The researchers report that, following the initial mechanical insult, damage resulted from blood-brain barrier disruption, excitotoxic damage and free radical production. The scientists then looked for nestin (a marker of neural stem cells) in the cells around the damaged area. They found that the number of nestin-positive cells in the EGCG treatment group showed a significant increase when compared with the number in the water group. There was also a significant increase in the nestin-positive cells at days 3 and 7 following the brain trauma in the EGCG treatment group as compared with the number in the water group (73.0 ±25.8 and 12.4 ±3.3, respectively).6

“Therefore, we speculate that EGCG crosses the BBB [blood-brain barrier] and inhibits neuronal and NSC [neural stem cells] death by free radicals in the damaged area following TBI [traumatic brain injury].”6


  1. Gianotti et al. Why some people discount more than others; baseline activation in the dorsal PFC mediates the link between COMT genotype and impatient choice. Front Neurosci. 6:54 (May 2012).
  2. Zhu et al. Molecular modelling study of the mechanism of high-potency inhibition of human catechol-O-methyltransferase by (-)-epigallocatechin-3-O-gallate. Xenobiotica. 38(2):130-46 (2008).
  3. Kang et al. Dual beneficial effects of (-)-epigallocatechin-3-gallate on levodopa methylation and hippocampal neurodegeneration: in vitro and in vivo studies. PLoS One. 5(8):e11951 (Aug. 2010).
  4. Tunbridge et al. The role of catechol-O-methyltransferase in reward processing and addiction. CNS Neurol Disord Drug Targets. 11:306-23 (2012).
  5. Yoo et al. (-)-epigallocatechin-3-gallate increases cell proliferation and neuroblasts in the subgranular zone of the dentate gyrus in adult mice. Phytother Res. 24:1065-70 (2010).
  6. Itoh et al. (-)-epigallocatechin-3-gallate increases the number of neural stem cells around the damaged area after rat traumatic brain injury. J Neural Transm. 119:877-90 (2012).

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