ADHD medications explained — why stimulants help one person and not another

How ADHD medications work

ADHD medication affects dopamine and norepinephrine signaling in the prefrontal networks of the brain that govern attention, impulsivity, and executive function. Importantly: more dopamine or norepinephrine is not automatically better — too little signal worsens focus, but excessive stimulation can cause anxiety, rigidity, irritability, insomnia, or repetitive behavior.

There are several drug classes: amphetamine-based stimulants, methylphenidate-based stimulants (mechanistically slightly different), atomoxetine (a non-selective norepinephrine reuptake inhibitor with a gradual onset), and alpha-2 agonists (guanfacine, clonidine) — these reduce hyperactivity and emotional reactivity but cause sedation.

Why a stimulant calms one person and unsettles another

Improvement with ADHD medication isn't about "revving up" the brain — it's about a better signal-to-noise ratio that allows better executive control: better inhibition, task initiation, working memory, and less sensation-seeking. Behavior calms down because regulation improves, not because the medication "sedates."

Poor tolerability can have several causes: too high a dose, an ill-suited release duration for the medication form, underlying anxiety, a tendency toward bipolar disorder, inadequate nutrition, or a sleep debt. Sleep debt can override even a positive medication effect — an exhausted child or adult on a stimulant appears more irritable, not more focused.

The Walsh view — five biochemical patterns

Alongside standard psychiatric assessment, the Walsh approach also looks at biochemical context that can affect stimulant tolerability:

• Undermethylation — tends to be associated with obsessive traits, perfectionism, seasonal allergies.
• Overmethylation — tends to be associated with distractibility, racing thoughts, heightened sensitivity, and poorer tolerability of activating treatment.
• Copper overload — contributes to anxiety, irritability, insomnia, and excessive norepinephrine activation — precisely what a stimulant can amplify further.
• Pyroluria — zinc and B6 deficiency contributes to stress intolerance, emotional reactivity, and variable stimulant tolerability.
• Elevated SAH or toxic burden — inhibition of methylation and mitochondrial stress reduce neurological resilience.

No lab test diagnoses ADHD or guarantees which medication will work — a biochemical finding complements the clinical picture, it doesn't replace it.

Short-acting vs. long-acting forms

The same active substance is manufactured in both short-acting and long-acting forms, and the choice between them changes the whole tolerability profile. Short-acting (immediate-release) forms take effect quickly but also wear off quickly — with a risk of a mood or attention dip as the effect fades ("rebound"). Long-acting (extended-release) forms (e.g. OROS technology for methylphenidate, or the prodrug form of lisdexamfetamine) have a smoother onset and offset, which usually means fewer swings, but also less room to fine-tune the dose during the day.

The choice of form matters as much as the choice of active substance — two people on the same molecule but a different form can have a markedly different experience.

Appetite, growth, and sleep

Appetite suppression is a common side effect. What helps: a protein-rich breakfast before the medication takes effect, nutrient-dense meals, tracking growth curves (not just individual measurements), and an evening "catch-up" meal once the medication wears off.

Insomnia is linked to too high a dose, late dosing, or an effect lasting longer than expected. With a well-tuned regimen, sleep usually improves thanks to a better-organized evening routine — if it doesn't improve, it's also worth considering iron deficiency (restless legs), caffeine, or screen time.

With long-term use in children, regular measurement of height, weight, and blood pressure is a standard part of monitoring — not an alarming step, but a standard precaution so that any slowdown in growth is caught early and can be addressed (e.g. "drug holidays" on weekends or school breaks, decided by the doctor).

When a medication stops working as well

Besides tolerance, consider: worsening sleep, a nutritional decline (from appetite suppression), changed daily demands, a change in the medication's form or dosing, the onset of another co-occurring condition, or a need to reconsider the original diagnosis. A reduced response doesn't automatically mean the dose needs to be increased.

Cardiovascular safety and when to call the doctor

Stimulants mildly raise heart rate and blood pressure, which carries no risk for most people, but personal and family cardiovascular history is usually reviewed before starting. Chest pain, fainting, heart pounding beyond the usual degree, or significant shortness of breath during treatment require contacting a doctor immediately — not waiting for the next scheduled check-up.

A practical first step

Never suddenly change or stop a medication that is currently working — any change is always made by the treating doctor.

1. Fill out the free screening — especially if pyroluria or copper overload is suspected alongside ADHD.

2. Consider a pyroluria test (€99) — low zinc and B6 are a common, but easily overlooked, factor in ADHD.

3. Once you have the result, book a 45-minute consultation (€75) — to see what's worth discussing with the treating doctor.

More on how pyroluria typically presents in both adults and children can be found in the article Pyroluria, anxiety, and insomnia.