ADHD is the most common pediatric neurobehavioral disorder, and among adults who are seeking treatment for mental health, about 16% have ADHD. Unfortunately, only 1 in 5 adults with ADHD receive treatment due to substantial barriers to care and adequate assessment.
Medicine has utilized stimulant medications for over 130 years with good results for a number of different medical conditions. We have an even longer history with stimulant medications than we do with antibiotics. The history of stimulant medications for ADHD is an example of the complex interplay between clinical needs, technological innovation, societal attitudes, and regulatory framework. As we deepen our understanding of ADHD and its treatment, the chronicle of stimulant medications can provide context to current barriers to care.
Amphetamine was first synthesized in 1887, and the racemic mixture was marketed in the form of the Benzedrine inhaler for the treatment of asthma and nasal congestion. Amphetamine was made available in tablet form in 1930 when it was used as a treatment for narcolepsy and also by the military to increase wakefulness in World War II soldiers.
Benzedrine was the first stimulant to enter the U.S. market in 1933 as a decongestant inhaler. In 1935 Benzedrine sulfate pills were introduced as a treatment for a wide variety of medical conditions, including narcolepsy, obesity, low blood pressure, low libido, and chronic pain.
In 1932, German doctors Franz Kramer and Hans Pollnow described a condition they called hyperkinetic disease. This condition described children who were more impulsive, had difficulty staying still in class, and had problems with attention and self-control.
In 1937, the effects of Benzedrine were studied in children with behavior and neurological disorders and improved their behavior and ability to pay attention. Ritalin was first marketed in 1954 as a treatment for chronic fatigue and depression, but doctors began using it off-label to treat hyperkinetic disease. In 1968, American Psychiatric Association (APA) finally included the condition, then known as “hyperkinetic reaction of childhood,” in the second edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). Later in 1980, the APA renamed the condition as attention deficit disorder (ADD), and in 1987 adjusted the name again to attention deficit hyperactivity disorder (ADHD).
In 1942 Benzedrine was supplied to British and American combat troops in World War II for use in exceptional circumstances (e.g., to keep escort ship officers awake and alert in continuous pursuit of submarines for 24 hours or more, for fighter pilots to keep alert in the air despite multiple daily missions and for paratroopers to stay fighting longer).
In the 1950s, reports began to emerge about the recreational use of Benzedrine inhalers, and in 1959, the United States Food and Drug Administration (FDA) made it a prescription drug. After its removal from open sale, a black market continued in many large cities.
From 1950 through 1980, Benzedrine was better known on the streets as “Bennies” and developed a reputation as a drug of abuse memorialized in Elton John’s song “Bennie and the Jets.” It was a favorite of the Beat generation, with Jack Kerouac reportedly writing all of ”On the Road” over the course of three Benzedrine-fueled days. Paul Erdős, who is said to have defined a mathematician as "a device for turning coffee into theorems," neglected in that aphorism to mention that he relied heavily on Benzedrine as well. Norbert Wiener, in his autobiographical I Am a Mathematician: The Later Life of a Prodigy, wrote ruefully, "I tried to work against time. More than once, I computed all through the night to meet some imaginary deadline which wasn't there." Benzedrine’s reputation for abuse was part of what led to its decline, but its actual abuse potential is less than Methamphetamine’s and more than Ritalin’s. Benzedrine also fell out of favor due to its lack of efficacy. In 1976, a study found it less effective for ADHD than Ritalin and Dexedrine. However, it was noted that a small proportion (15%) of participants responded better to Benzedrine. This is why Benzedrine was resurrected in 2019 under a new name, “Evekeo.” This formulation might be beneficial for a select minority of ADHD patients.
Evekeo is not the only stimulant to undergo this type of resurrection and rebranding. Adderall has been available since 1960 as the weight loss medication Obetrol. By the 1990s, immediate-release amphetamines had fallen out of favor for weight loss due to side effects from crashes after the short-acting medications wore off, so Obetrol was renamed to “Adderall” and repackaged for ADHD in 1996.
By the late 1990s, both awareness of ADHD and diagnoses of ADHD had significantly increased. The Americans with Disabilities Act included ADHD as a protected disability, and adults that were diagnosed as children with ADHD began to express that they felt different from their peers. A 1994 cover of Time magazine read, “Disorganized? Distracted? Discombobulated? Doctors Say You Might Have ATTENTION DEFICIT DISORDER. It’s not just kids who have it.” Almost 20 years later, in 2013 the APA changed the diagnostic criteria to include more adults with ADHD whose diagnoses were missed when they were children.
The late 1990s and early 2000s also brought a significant trend in the media asserting that ADHD was overdiagnosed and a convenient excuse for adolescents who seemed lazy or impulsive. Concerns of overprescribing and stimulant abuse followed this trend and are often at the forefront of many people’s minds who are less familiar with more up-to-date ADHD literature.
This contributes to attitudes from primary care and psychiatric prescribers who are influenced by these past accusations of overprescribing or overdiagnosis and contribute to one of the major roadblocks undiagnosed ADHDers face, gatekeeping by the very same medical providers who have taken an oath to help them.
To this day, the criteria and screening for ADHD continue to be outdated and cause a significant diagnostic struggle for both people of color and those assigned female at birth. Compared to white children, the odds of being diagnosed with ADHD are almost 70% lower for Black children, 50% lower for Latino children, and 46% lower for children of other non-caucasian races. In addition, boys are 2–3 times more likely to receive treatment for ADHD than those who identify as girls.
Although all of the psychostimulant class medications are in the highly restricted Schedule II classification of medications due to the abuse potential of a similar drug, meth-amphetamine. Most people with ADHD do not experience stimulants in the same way that other people do. It is more difficult (although not impossible) for someone with ADHD to feel the euphoric effects of a high dose of stimulant. Many people with ADHD report they sometimes feel like taking a nap after drinking coffee. This is because stimulants are increasing dopamine, which for people with ADHD is correcting an Consequently, there is a low potential for abuse of these medications by people who have confirmed they have ADHD with objective testing. These medications are notorious for having a short half-life, and they are eliminated from the body without causing withdrawal each evening and during sleep. In fact, we have a hard time making these medications last long enough for people with ADHD, and an entire industry has been devoted to creating effective long-acting delivery systems that lengthen their duration of action.
There are only two stimulant-class medications that are considered first-line treatments for ADHD: Amphetamines and methylphenidates. All of the 30 or so FDA-approved stimulant medications on the market are just different ways of delivering these two molecules consistently over an extended period of time.