Medication approval journey
amphetamine (Adderall XR)
Approved for ADHD in children, adolescents and adults
Before changing anything
Stopping abruptly causes withdrawal effects that can be severe
Stopping a stimulant abruptly after regular use commonly causes a crash — fatigue, low mood, heavy sleep. It is not usually dangerous, but it is worth planning rather than improvising.
How long the trials actually ran
The longest trial behind the amphetamine approval ran 4 weeks.
The gap between how long the trials ran and how long people actually take these medications is the single most important thing on this page. It is not evidence that longer use is unsafe or ineffective. It is evidence that longer use was not what got tested.
The approval, step by step
Step 1
What the approval was actually based on
Which studies did the FDA rely on, how long did they run, and who was in them?
A double-blind, randomized, placebo-controlled, parallel-group study was conducted in children aged 6 to 12 (N=584)... for three weeks... A double-blind, randomized, placebo-controlled, parallel-group study was conducted in adults (N=255) who met DSM-IV criteria for ADHD... or placebo once daily in the morning for four weeks.
FDA-approved labelling, 14 CLINICAL STUDIES — read the label on DailyMed
Our reading
Three weeks in 584 children, four weeks in 327 adolescents, four weeks in 255 adults. Large trials, short trials. One finding on this label deserves more attention than it gets: in both the adolescent and the adult trials the label states there was not adequate evidence that doses above 20 mg/day conferred additional benefit. A great many people are prescribed more than that. This entry is anchored on Adderall XR, not on the 1960 immediate-release application, because the two are different NDAs with different labels.
Step 2
The approval
When was it approved, under what application, and by whose review?
- Approved
- October 11, 2001
- Application
- NDA021303
- Review
- STANDARD
- Original sponsor
- Shire (now Takeda)
- Holds it now
- Takeda Pharmaceuticals USA
- Label submissions since
- 25
Source: openFDA Drugs@FDA, original application ORIG-1
Step 3
What was added after it was on the market
Which warnings arrived only after millions of people were already taking it?
The stimulant boxed warning was rewritten in 2023
22 years after approval
In May 2023 the FDA required the boxed warning on the entire prescription stimulant class — amphetamines and methylphenidates both — to be updated. The specific gap it was closing is unusual and worth knowing: the old labels did not adequately say that most people who misuse these medications get them from a family member or a peer, and that sharing them can cause a substance use disorder in the person you share them with.
This was an update to a warning that already existed, not a new alarm about the medication working. Stimulants remain first-line treatment for ADHD.
Worth asking
How should I be storing this, how do we dispose of what I do not use, and how will we monitor whether my dose is still right over time.
Step 4
What independent research has found since
What has been learned by people who were not selling it?
Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children,…
17 years after approval
Across 133 randomized trials, amphetamines were the most effective ADHD medication in adults and showed the largest symptom reduction in children (clinician-rated SMD -1.02), but they were also the least well-tolerated option, with roughly 2 to 3 times the odds of dropping out for side effects compared with placebo.
Worth asking
Amphetamines look most effective for adults but hardest to tolerate — which side effects would make us switch, and what would we switch to?
Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults
17 years after approval
Pooling 19 randomized trials with 2,521 adults, amphetamines reduced clinician-rated ADHD symptom severity (SMD -0.90) over an average of about 5 weeks, including mixed amphetamine salts (SMD -0.80), but nearly tripled withdrawals due to adverse events and showed no evidence of better treatment retention.
Worth asking
Most amphetamine trials in adults lasted only a few weeks — how will we judge whether Adderall is still helping me months from now?
Psychosis with Methylphenidate or Amphetamine in Patients with ADHD
18 years after approval
In 221,846 insured adolescents and young adults starting a stimulant for ADHD, new-onset psychosis occurred in about 1 in 660 patients, and amphetamine starters had a 65% higher risk than methylphenidate starters (0.21% vs 0.10%).
Worth asking
Given amphetamines carry a somewhat higher psychosis risk than methylphenidate, does my personal or family mental-health history change which stimulant we should choose?
Psychosis with Methylphenidate or Amphetamine in Patients with ADHD — Moran LV, et al. (2019)
ADHD Pharmacotherapy and Mortality in Individuals With ADHD
23 years after approval
Among 148,578 Swedish people newly diagnosed with ADHD, starting medication was associated with 21% lower all-cause mortality over 2 years — about 9 fewer deaths per 10,000 people — driven mainly by fewer deaths from unnatural causes such as accidents and overdoses.
Worth asking
Beyond day-to-day symptom control, what does staying on treatment change about the bigger risks — accidents, substance use, driving — in my situation?
ADHD Pharmacotherapy and Mortality in Individuals With ADHD — Li L, et al. (2024)
ADHD medications and risk of serious cardiovascular events in young and middle-aged adults
10 years after approval
Among 443,198 adults aged 25-64 (150,359 users of amphetamines, methylphenidate, or atomoxetine), current medication use was not associated with more heart attacks, sudden cardiac deaths, or strokes than nonuse (adjusted rate ratio 0.83).
Worth asking
I've heard mixed things about stimulants and heart risk — what does my own blood pressure and cardiovascular history mean for taking Adderall?
Step 5
What still is not known
Which questions you might reasonably have has nobody answered yet?
- The label says doses above 20 mg/day showed no additional benefit in two of the three trials. What is your dose, and what was the reason for it?
- Four weeks at the longest. This is often taken every day for decades.
- The stimulant boxed warning was rewritten in 2023 to address misuse and dependence, twenty-two years after approval.
Deciding about amphetamine?
- 12 questions to ask before starting a psychiatric medication — each with the study behind it
- Already on it? The 10-question annual review — including the honest case for staying
- How long every drug here was tested before approval — one chart, all medications
Open amphetamine (Adderall XR) in Resolv
The app has the full approval journey, the resources behind it, and people working through the same questions.
