Why do stimulants help hyperactivity in ADHD?

Background

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, disorganization, hyperactivity, and impulsivity. It is considered a neurodevelopmental disorder because the onset is typically before grade school during the developmental years.

To receive a formal diagnosis of ADHD, there must be six symptoms of inattention and/or six symptoms of hyperactivity. Some symptoms must be present before 12 years of age, and the symptoms must occur in at least two different settings (ex. school and home). Finally, the symptoms must be severe enough to interfere with functioning.¹

The history of ADHD is quite interesting. The American Psychiatric Association released the first manual for diagnosing mental illness in 1952. This manual, called the DSM, did not include ADHD. In 1968, an updated version was released that contained a condition called, “hyperkinetic reaction of childhood”. Hyperkinetic reaction of childhood was characterized by overactivity, restlessness and short attention span, especially in children. The third edition was released in 1980 and contained attention deficit disorder (ADD). ADD had two subtypes, ADD with hyperactivity and ADD without hyperactivity. In 1987, things were simplified when an update was released that changed the name to attention-deficit/hyperactivity disorder. Interestingly, many people still call the condition ADD even though the formal name was changed to ADHD (which accounts for either/both inattention and hyperactivity) over 30 years ago.

What are the treatments for ADHD?

The recommended treatment for ADHD depends on the age of the patient.

• Age 5-6: behavioral therapy and parental training is recommended
• Age 6-12: FDA approved medication along with behavioral therapy
• Age 12+: FDA approved medication along with a recommendation for behavioral therapy
• Adults: psychostimulant such as a methylphenidate or amphetamine product, unless the patient has a history of a substance use disorder

Many stimulants products are available. Most are either a methylphenidate product (or a methylphenidate derivative like dexmethylphenidate) or an amphetamine product (or an amphetamine derivative like dextroamphetamine or lisdexamfetamine).

Additional treatments include norepinephrine reuptake inhibitors like atomoxetine and alpha 2 agonists like clonidine and guanfacine. The benefits of these medications are that they are not controlled substances or addicting like stimulants have the potential to be.

Class	Generic Name	Brand Name
Stimulant	Methylphenidate	Ritalin, Methylin, Ritalin SR, Metadate ER, Methylin ER, Quillichew ER, Metadate CD, Ritalin LA, Cotempla XR ODT, Aptensio XR, Concerta, Daytrana, Quillivant XR, Jornay PM, Adhansia XR
	Dexmethylphenidate	Focalin, Focalin XR
	Amphetamine Mixed Salts	Evekeo, Adderall, Adderall XR, Adzenys ER and XR ODT, Dynavel XR, Mydayis
	Dextroamphetamine	Zenzedi Procentra, Dexedrine Spansule ER
	Lisdexamfetamine	Vyvanse
Norepinephrine reuptake inhibitor	Atomoxetine	Strattera
Alpha 2 Agonist	Clonidine ER	Kapvay
	Guanfacine ER	Intuniv

Why are stimulants used to treat hyperactivity? Woudn’t this make it worse?

Stimulant medications block the reuptake of dopamine and norepinephrine. So once these neurotransmitters are released, they stay in the synapse for longer and have a better chance to exert their effects. Too much dopamine and norepinephrine can cause excessive energy, heart rate changes, anxiety, and overall stimulation, but the cause of hyperactivity in people with ADHD is not too much dopamine and norepinephrine, it is the dysregulation of dopamine and norepinephrine.

At baseline, your brain is releasing small amounts of dopamine and norepinephrine all the time. This is called the tonic release. In someone with ADHD, the tonic amount is decreased, so very little is released. This can lead to inattention because you need parts of your brain to be stimulated to pay attention. Since very little is released at baseline, this leads to a buildup of the neurotransmitters, so when the phasic release finally occurs, it leads to a flood of neurotransmitters, which causes impulsivity and hyperactivity.

When a stimulant medication is given to someone with ADHD, it prevents the reuptake of dopamine and norepinephrine or increases the release of dopamine and norepinephrine, so the tonic release is effectively larger, which treats inattention, and the phasic release is effectively smaller, which treats impulsivity and hyperactivity.^2,3

Substance use disorder considerations:

Many fear stimulants because of there abuse potential. While these medications can be abused, when they are used properly, they decrease substance use disorders. For example, low-dose methylphenidate increases dopamine more in the prefrontal cortex, which helps with ADHD symptoms as compared to the nucleus accumbens, which is a part of the pleasure pathway and can cause substance use disorders.⁴

When used properly in patients with ADHD, stimulants decrease the risk of substance use disorders. In fact, untreated ADHD is a risk factor for substance use disorders. In individuals with ADHD, stimulant medication use was associated with a 31% decreased risk of developing a substance use disorder.⁵ A study in adolescents found that early treatment with stimulants and a longer duration of treatment with stimulants were associated with fewer substance use behaviors in late adolescence.⁶

References:

1. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). https://doi.org/10.1176/appi.books.9780890425596. Text citation: (American Psychiatric Association, 2013).
2. Badgaiyan RD, Sinha S, Sajjad M, Wack DS. Attenuated Tonic and Enhanced Phasic Release of Dopamine in Attention Deficit Hyperactivity Disorder. PLoS One. 2015;10(9):e0137326. Published 2015 Sep 30. doi:10.1371/journal.pone.0137326.
3. Howells FM, Stein DJ, Russell VA. Synergistic tonic and phasic activity of the locus coeruleus norepinephrine (LC-NE) arousal system is required for optimal attentional performance. Metab Brain Dis. 2012 Sep;27(3):267-74. doi: 10.1007/s11011-012-9287-9. Epub 2012 Mar 8. PMID: 22399276.
4. Arnsten, A. Stimulants: Therapeutic Actions in ADHD. Neuropsychopharmacol 31, 2376–2383 (2006). https://doi.org/10.1038/sj.npp.1301164.
5. Chang Z, Lichtenstein P, Halldner L, D’Onofrio B, Serlachius E, Fazel S, Långström N, Larsson H. Stimulant ADHD medication and risk for substance abuse. J Child Psychol Psychiatry. 2014 Aug;55(8):878-85. doi: 10.1111/jcpp.12164. Epub 2013 Oct 25. PMID: 25158998; PMCID: PMC4147667.
6. McCabe SE, Dickinson K, West BT, Wilens TE, Age of Onset, Duration, and Type of Medication Therapy for Attention-Deficit/Hyperactivity Disorder (ADHD) and Substance Use During Adolescence: A Multi-Cohort National Study, Journal of the American Academy of Child & Adolescent Psychiatry (2016), doi: 10.1016/j.jaac.2016.03.011.