Table 3. Selected drugs that modify catechol-O-methyltransferase effects.

Condition	Drug/treatment	Findings	Ref.
Psychiatric disorders
Attention deficit hyperactivity disorder	Methylphenidate is a norepinephrine–dopamine reuptake inhibitor	A recent review of COMT-stimulant pharmacogenetic effects suggested the strongest benefit of methylphenidate for ADHD was observed among val/val patients	[81]
Substance-use disorder	Nicotine replacement therapy and bupropion a norepinephrine–dopamine reuptake inhibitor	In a large RCT in smokers of European ancestry, compared with placebo, met/met homozygotes were more likely to abstain from smoking than val-allele carriers. In a trial of bupropion, COMT haplotypes predicted the response to drug versus placebo	[82,83]
Major depressive disorder	Antidepressants milnacipran, fluoxetine, paroxetine, fluvoxamine, mirtazapine, venlafaxine, duloxetine and electroconvulsive therapy	Many studies report significant COMT rs4680 associations with antidepressant treatment response, for example, milnacipran, fluoxetine, paroxetine, fluvoxamine, mirtazapine, venlafaxine and duloxetine. Notably, many of these studies did not include a placebo control. An RCT of duloxetine for MDD did not find a genome-wide association between COMT in placebo or drug treatment arms. The val-allele was also found to be influence treatment response to electroconvulsive therapy	[84–85]
Generalized Anxiety disorder	Venlafaxine, a serotonin-norepinephrine reuptake inhibitor	A nominally significant association with response to venlafaxine was reported for the secondary treatment outcome	[86]
Bipolar disorder	Lamotrigine (an anticonvulsant) plus folic acid (vitamin B9)	There was a negative impact of randomized lamotrigine plus folic acid on met-allele carrier	[87]
Schizophrenia	Antipsychotic medications including olanzapine, clozapine and risperidone	In a recent meta-analysis (N = 10 studies), response to antipsychotic treatment was significantly associated with the COMT met/met genotype	[88]
Chronic fatigue syndrome	Clonidine, an α-2 adrenergic agonist	In an RCT of clonidine for treating chronic fatigue syndrome, COMT modified effects of clonidine in the primary outcome, steps taken per day	[89]
Working memory	Tetrahydrocannabinol (THC) a cannabinoid receptor agonist	Val/Val individuals in two studies were impaired on cognitive tests when randomized to THC compared with placebo	[90,91]
Neurological disease and conditions
Parkinson disease	Vitamin C (ascorbic acid) is an anti-oxidant	Vitamin C was one of the first drugs evaluated as a possible adjunct therapy to levodopa because of its COMT inhibitory effects. More recently, in the human blood metabolite GWAS, O-methylascorbate a metabolite of vitamin C was significantly associated with rs4680 (p = 5e-178)	[92,93]
	Nitrocatechols for example, entacapone and tolcapone are selective and reversible inhibitors of COMT [94]	Entacapone acts peripherally and is only slightly able to penetrate the blood brain barrier. Tolcapone can penetrate the blood brain barrier and an RCT is underway in patients with relapsed or refractory neuroblastoma	[45,95]
Pain	Morphine and fentanyl are exogenous opioids	COMT genetic variation has been associated with variability in opioid requirement for postoperative and cancer pain	[96,97]
Cardiometabolic disease
Bradycardia	Isoproterenol is an analog of epinephrine and a β adrenoreceptor agonist	An epinephrine analog is used to treat bradycardia	[98]
Diabetes	Insulin detemir	In an RCT of recombinant insulin, reduction of HbA1c was significantly better among met-allele carriers compared with val-allele homozygotes	[99]
Pre-eclampsia	Hydralazine and verapamil	Hydralazine, a widely accepted drug for the treatment of pre-eclampsia, was shown to inhibit placental COMT activity. Verapamil was explored as a potential drug to treat pre-eclampsia. COMT activity was suppressed in term placental explants after 6-hour exposure to verapamil or hydralazine	[100]
Hypertension	Calcium-channel blockers, angiotensin-receptor blockers and diuretics	The val-allele was associated with lower systolic blood pressure in participants treated with Calcium-channel blockers. This effect was even stronger among elderly individuals. Similar effects were seen among participants treated with angiotensin-receptor blockers and there was a significant association with another COMT SNP rs737865 and diuretics	[101]
Cardiovascular disease prevention	Aspirin, an antiplatelet, analgesic and anti-inflammatory drug and vitamin E an anti-oxidant	Significant COMT-by-aspirin and COMT-by-vitamin E effect modification were reported in a randomized trial of cardiovascular disease prevention	[52]
Cancer prevention
Prostate cancer prevention	Finasteride, inhibits dihydrotestosterone production	In the PCPT RCT, the val-allele was associated with increased risk of prostate cancer among patients randomized to finasteride	[102]
Prevention of all invasive cancers	Vitamin E (α-tocopherol) is an anti-oxidant	In two large RCTs, COMT-by-vitamin E effect modification was reported in cancer prevention such that met-allele homozygotes benefited from vitamin E therapy but val-allele homozygotes did not	[52,103]
Prevention of chronic disease	Quercetin and fisetin are flavonoids used as supplements in chronic disease prevention	These phytochemicals are found in onions, apples and red wine. They have antioxidant and anti-inflammatory effects and inhibit COMT function. They are sold as supplements to prevent cancer and other chronic diseases
Cancer prevention	Green tea catechins include catechin, epicatechin and epigallocatechin-3-O-gallate [104]	In a population-based case–control study, risk of breast cancer was significantly lower among tea drinkers who were met-allele carriers. The combination of quercetin and green tea was found to enhance inhibition of prostate cancer xenograft tumor growth. Higher energy expenditure and fat oxidation were observed among met/met participants randomized to placebo in an RCT of the cardiometabolic effects of green tea. Differential effects were also observed in the green tea treatment arm	[105–106]

ADHD: Attention-deficit hyperactivity disorder; MDD: Major depressive disorder; RCT: Randomized controlled trial.