After reading a Yahoo! Big League Stew article titled "MLB players were given 2,500 additional drug tests last season" published on December 1st, I decided that now was the time to finally write an article on prescription stimulant use in Major League Baseball. As many of you already know, I am in my sixth (and final) year of pharmacy school and will graduate with a Pharm.D. from Butler University in May 2015. In previous posts related to the medical field, I have looked at cortisone shots and Tommy John surgery, but this time around, I will be discussing the use of prescription stimulants in baseball—with the main focus being on Adderall, the most-prescribed prescription stimulant in America.

Before delving into the details on Adderall, though, it is necessary to define Therapeutic Use Exemption (TUE) per the MLB/MLBPA Joint Drug Agreement:

A Player authorized to ingest a Prohibited Substance through a valid, medically appropriate prescription provided by a duly licensed physician shall receive a Therapeutic Use Exemption ("TUE"). To be "medically appropriate," the Player must have a documented medical need under the standards accepted in the United States or Canada for the prescription in the prescribed dosage.

Also important is detailing what must be present in order for a physician to diagnose a patient with ADHD:

Criteria needed for the diagnosis of ADHD: Six or more of the following symptoms (in either category) must be present for at least six months before turning 12 years old with significant impairment in at least two settings.

A. Inattention (statistically more common in girls)

Often fails to give close attention to details or makes careless mistakes in school work, occupational, or other activities Often has difficulty sustaining attention in tasks or activities Doesn't seem to listen when spoken to directly Doesn't follow through on instructions and fails to finish duties at work/school/home Difficult organizing tasks and activities Avoids or is reluctant to engage in activities requiring sustained mental focus Often loses things necessary for tasks or activities Easily distracted Is often forgetful in daily activities

B. Hyperactivity (statistically more common in boys)

Fidgets or squirms in seat Leaves seat when remaining seated is expected Runs or climbs in situations where it's inappropriate Unable to play or engage in leisure activities quietly Often "on the go," acting as if "driven by a motor" Talks excessively Blurts out answer before question completed Difficulty waiting his or her turn Interrupts or intrudes others

So, what about Adderall, a first-line ADHD treatment legally taken by 109 MLB players in 2014?

Generic name: dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate (mixed salts)

Chemical structure:

Mechanism of action: Promotes the release and inhibits the reuptake of norepinephrine (NE) and dopamine (DA), thus extending the effects of these two neurotransmitters on receptors in the brain; Some data suggests that high doses affect serotonin levels as well, yet another stimulatory neurotransmitter

Net result: Improvement in attention, hyperactivity, impulsivity, self-control, physical/verbal aggression, and academic performance; Also produces a decreased sense of fatigue, increased motor activity and mental alertness, and leads to brighter spirits

Pharmacodynamics (what drug does to body) & pharmacokinetics (what body does to drug)

Adderall Dosage Form Time Until Effect Duration of Effect Elimination Half-Life Immediate-Release (IR) ~1 hour 4-6 hours ~10-14 hours Extended-Release (XR) ~1 hour 10-12 hours ~10-14 hours

After a patient first proves tolerability to the immediate-release form of Adderall (yes, there are still side effects present in what many seem to believe is a "wonder drug"), a common practice by physicians is to prescribe extended-release Adderall to be taken every morning followed by an immediate-release form to be taken in the afternoon or early evening to serve as a "boost" when the effect of the morning dose is "wearing off." This regimen provides for morning, afternoon, and evening management while not affecting the patient's sleep at night. Thus, based on the information included in the table above, taking IR Adderall one hour before a game should allow for a player to receive the prescription's benefits for at least the full duration of a three-hour game.

Discussion

With 30 teams and 40 players per roster, 112 TUEs for Adderall means that roughly 9% of the "MLB population" has prescription stimulant-managed ADHD. According to the Anxiety and Depression Association of America, 4% of the U.S. adult population has ADHD. Though ADHD is more common in boys (and subsequently continuing into young adult males) than girls (important to note in an all-male MLB population), it is still interesting that its presence in the MLB more than doubles its presence in the general population. Even more notable is that this 9% accounts for those being treated with prescription stimulants specifically. Though prescription stimulants are considered the gold standard of treatment, many patients with ADHD either have never been diagnosed by a physician, are given other options (such as non-stimulant Strattera), or manage it without prescription medications.

There are many things I wish were made public though are clearly and understandably protected by law, such as the symptoms present at diagnosis as well as the age at diagnosis. As noted above, statistics show that hyperactivity symptoms are more common in boys/males, the MLB population. Thus, technically speaking via official diagnosis criteria, the 112 players taking prescription stimulants experienced six or more of the 18 listed symptoms before the age of 12 and were statistically more likely to have experienced hyperactivity symptoms over inattention symptoms.

The next thing I found interesting was that in 2006, only 28 MLB players were granted ADHD-related TUEs. Just one year later, this number jumped significantly to 103, when MLB officials began cracking down on illegal amphetamine use. Seven years later, the number of ADHD-related TUEs has remained relatively steady, but I am still intrigued by the vast increase in 2007 TUEs and by the fact that the MLB population has significantly higher rates of stimulant-managed ADHD than the general population, despite the reasoning given that it is more common in boys/males.

The last thing I would like to know more about is why all of these players seem to be taking Adderall (and presumably its generic equivalent) exclusively. I could not find access to Dr. Jeffrey Anderson's official drug report (if one of my readers somehow has access to this, I'd love to see it), but many major news sites (including the Yahoo! one I linked to in the opening paragraph) seem to be reporting that the 112 TUEs were for Adderall specifically, when in actuality, there are many other viable prescription stimulant options for ADHD such as Vyvanse, Ritalin, Focalin, and Concerta. They all have basically the same mechanism of action, so it does not matter all that much for the average fan, but as a passionate fan of both baseball and pharmacy, I really am interested in knowing the exact details, something that wasn't made available in the MLB.com press release.

Credit to the drug's package insert (at DailyMed) for Adderall's chemical structure as well as drug databases such as Clinical Pharmacology and Micromedex.