08/02/2026
• Fast COMT (Val/Val) clears dopamine quickly from the prefrontal cortex, leaving lower baseline dopamine tone there
• Lower PFC dopamine is more classically linked to attention regulation problems and low motivation — this genotype has been studied more consistently (though still with mixed/modest results) in relation to executive function and sustained attention than slow COMT has
• “Wired but tired” could show up here too, but through a different route: some people with fast COMT compensate by chasing stimulation (caffeine, sugar, novelty, stress) to boost dopamine, which can produce a jittery, overstimulated feeling layered on top of underlying fatigue and low drive
• Fast metabolizers may also feel effects of stimulants (like caffeine) more intensely and burn through them faster, which can produce a spike-crash pattern that feels like wired-but-tired.
Other factors may come into:
• Caffeine — especially late-day use or high tolerance requiring escalating doses
• Alcohol, which fragments sleep even if it helps you fall asleep
• Ni****ne
• Irregular meal timing or poor nutrition
• Sedentary patterns or, conversely, overtraining without recovery
Other biological factors
• Iron deficiency/anemia (low ferritin causes fatigue and attention issues even without full anemia)
• Vitamin D, B12, magnesium deficiencies
• Inflammation (chronic low-grade inflammation is increasingly linked to fatigue and cognitive symptoms).
If you want to learn about the impact of epigenetic, gut and micronutrient deficiencies on your symptoms, contact us to schedule your free 15 min introductory call to get started with our functional medicine program today!
