You may have noticed that a confusing array of new stimulants has been approved in the last few years. Since 2012, there have been five new amphetamines and two new methylphenidates. What are these preparations? Are any of them worth prescribing to your patients? To prepare you for the promotional downpour that’s likely to accompany all this repackaging, we’ve pulled together a just-the-facts comparison.
The three faces of amphetamine
For many years, amphetamine was only available in two preparations: Dexedrine and Adderall. Now there is a third, Evekeo, and to understand how these three differ, we’ll need to review the amphetamine isomers.
Amphetamine comes in two isomeric forms: dextro- and levo-amphetamine. These two molecules are mirror images of one another. Of the two, dextro-amphetamine is more potent, with a higher abuse potential and greater appetite suppressant effects. Levo-amphetamine is longer-lasting and causes more cardiac side effects. Adderall mixes the dextro- and levo-isomers in a 3:1 ratio (with more dextro-), while Dexedrine and Vyvanse are pure dextro-. In Evekeo the ratio is even, 1:1.
Isomer mix: 1:1 dextro-:levo-amphetamine
Duration: instant release: Evekeo$ (9.25 hr)
($ indicates available as brand only)
Few people know that Evekeo is identical to an older drug, Benzedrine. Released in 1935, Benzedrine was the first stimulant to enter the U.S. market. Better known on the streets as “Bennie,” Benzedrine developed a reputation as a drug of abuse that was memorialized in Elton John’s song “Bennie and the Jets.” It was a favorite of the Beat generation, whose founder, Jack Kerouac, reportedly wrote all of On the Road over the course of three Benzedrine-fueled days. Benzedrine’s reputation for abuse was part of what led to its decline, but its actual abuse potential is less than Dexedrine’s and more than Ritalin’s.
The other reason Benzedrine fell out of use was efficacy. In 1976, a placebo-controlled crossover study concluded that Benzedrine was less effective for ADHD than the two other stimulants in use at the time: Ritalin and Dexedrine (Gross MD, Dis Nerv Syst 1976;37:14–16). However, a subset (15%) in that study actually fared better with Benzedrine, suggesting that Evekeo may have a role in a minority of patients with ADHD.
Evekeo is not the only stimulant to undergo this type of resurrection. Adderall had been available for years as the weight loss medication Obetrol. By the 1990s, amphetamines had fallen out of favor as anorexics, so Obetrol was renamed to the equally evocative “ADDerall” and repackaged for ADHD.
Adderall & co.
Isomer mix: 3:1 dextro-:levo-amphetamine
Duration: instant release: Adderall IR (4–6 hr)
long-acting: Adderall XR (10–12 hr), Adzenys XR-ODT$ and ER liquid$ (10–12 hr), Dyanavel XR liquid$ (12 hr), Mydayis$ (16 hr)
Most of the new long-acting versions of Adderall offer little advantages over the original XR outside of an easier-to-swallow delivery. Mydayis is an exception. With a 16-hour duration, Mydayis offers a unique advantage for patients whose “day is” longer than the 12 hours of coverage that the other extended-release formulations provide (Markowitz JS et al, J Child Adolesc Psychopharmacol 2017;27(8):678–689). However, a generic equivalent of that effect can be achieved with Adderall XR in the morning and an additional IR in the late afternoon.
Dexedrine & co.
Isomer mix: 100% dextro-amphetamine
Duration: instant release: Zenzedi$ (4–6 hr), ProCentra liquid$ (4–6 hr) long-acting: Dexedrine ER spansules (6–10 hr), Vyvanse$ (9–14 hr)
The more potent of the two isomers, dextro-amphetamine, is available in instant- and extended-release versions. Zenzedi is a branded form of the instant-release version, and its main advantage is dose customization (it comes in 7 sizes: 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, and 30 mg, while the generic instant-release version only comes in 5 mg and 10 mg). The original instant-release brand, Dexedrine, is no longer manufactured, but an ER form is available as Dexedrine spansules—a common cause for confusion at the pharmacy.
One drawback of the dextro- form is its greater abuse liability. To get around that, Vyvanse was created in 2007 by tacking an amino acid (L-lysine) onto dextro-amphetamine to create lisdexamfetamine. The stimulant becomes activated as the amino acid is removed in the bloodstream. This activation process imparts a unique advantage to Vyvanse that patients who’ve never thought of snorting it will appreciate. Compared to Dexedrine, Vyvanse’s metabolism is more steady and consistent, which translates to a longer duration of action and smoother effects throughout the day (Mattingly GW et al, Postgrad Med 2017;129:657–666). Vyvanse also capitalizes on the unique anorexic effects of the dextro- isomer and is the only stimulant with FDA approval for binge eating disorder, where it works best in the higher dose range (50–70 mg).
The new methylphenidates
Methylphenidate arrived in the 1960s as Ritalin, just as concern about stimulant abuse was rising. This was good timing, as methylphenidate’s potential for abuse is lower than that of the amphetamines. Like the amphetamines, methylphenidate is also available in dex- and levo- isomeric forms, but in this case the levo- form is not just less effective, it is practically inert. There is no 3:1 mixture of these isomers, which are available as 1:1 methylphenidate (Ritalin, etc) or pure dex-methylphenidate (Focalin).
Methylphenidate & co.
Isomer mix: 1:1 dex:levo methylphenidate
Duration: instant release: Ritalin, Methylin chewable, Ritalin liquid (3–5 hr) intermediate-acting: Methylphenidate SR wax tabs (aka Ritalin SR, Metadate ER) (4–8 hr), Ritalin LA (6–9 hr), Metadate CD (8–10 hr), QuilliChew ER$ (8 hr) long-acting: Concerta (12 hr), Cotempla XR-ODT$ (12 hr), Daytrana transdermal patch$ (12 hr), Aptensio XR$ (12 hr), Quillivant/QuilliChew XR$ (12 hr), Jornay PM$ (8–11 hr)