Methylphenidate and amphetamine or its derivatives are first-line treatments for ADHD as they are considered the most effective pharmaceutical treatments. About 70 percent respond to the first stimulant tried and as few as 10 percent respond to neither amphetamines nor methylphenidate. Stimulants may also reduce the risk of unintentional injuries in children with ADHD. Magnetic resonance imaging studies suggest that long-term treatment with amphetamine or methylphenidate decreases abnormalities in brain structure and function found in subjects with ADHD. A 2018 review found the greatest short-term benefit with methylphenidate in children, and amphetamines in adults.

The likelihood of developing insomnia for ADHD patients taking stimulants has been measured at between 11 and 45 percent for different medications, and may be a main reason for discontinuation. Other side effects, such as tics, decreased appetite and weight loss, or emotional lability, may also lead to discontinuation. Stimulant psychosis and mania are rare at therapeutic doses, appearing to occur in approximately 0.1% of individuals, within the first several weeks after starting amphetamine therapy. The safety of these medications in pregnancy is unclear. Symptom improvement is not sustained if medication is ceased.

The long-term effects of ADHD medication have yet to be fully determined, although stimulants are generally beneficial and safe for up to two years for children and adolescents. Regular monitoring has been recommended in those on long-term treatment. There are indications suggesting that stimulant therapy for children and adolescents should be stopped periodically to assess continuing need for medication, decrease possible growth delay, and reduce tolerance. Although potentially addictive at high doses, stimulants used to treat ADHD have low potential for abuse. Treatment with stimulants is either protective against substance abuse or has no effect.

The majority of studies on nicotine and other nicotinic agonists as treatments for ADHD have shown favorable results; however, no nicotinic drug has been approved for ADHD treatment. Caffeine was formerly used as a second-line treatment for ADHD. It is considered less effective than methylphenidate or amphetamine but more so than placebo for children with ADHD. Pseudoephedrine and ephedrine do not affect ADHD symptoms.

Modafinil has shown some efficacy in reducing the severity of ADHD in children and adolescents.[205] It may be prescribed off-label to treat ADHD.