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.

Evekeo
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)

Instant-release methylphenidate acts quickly and leaves just as fast. Its onset is 15–30 minutes, compared to 1 hour for Adderall, and its duration is 1–2 hours shorter than Adderall’s. A series of formulations have appeared to extend its effects, beginning with wax-coated tablets in 1987. Today, there’s little reason to use the wax tabs like Ritalin SR and Metadate ER, which are notorious for their inconsistent effects. For patients paying out of pocket, wax capsules (eg, Metadate CD) work better for a similar price ($60–$70/month, see: www.goodrx.com) (Elia J, Psychiatry (Edgmont) 2005;2(1):27–35).

Newer extended-release technologies started hitting the market in 2000, and two stand out among the ones that have gone generic: Ritalin LA and Concerta. Ritalin LA is preferred by patients who need a higher dose in the morning, as it contains more fast-acting instant-release methylphenidate within its beaded delivery system. Concerta’s osmotic delivery has a slower onset (1–2 hrs) but a longer duration. It helps to specify the generic manufacturer “Activis” on Concerta scripts, as other generic substitutions are not considered bioequivalent by the FDA (an exception is the 72 mg capsule from Trigen, the only manufacturer of this dose, which is also bioequivalent and has coupons at: https://methylphenidateer72.com).

It’s difficult to imagine how the new methylphenidates could improve on Concerta’s 12 hours of smooth drug delivery, but bear with me. The new brands hope to ease the early mornings when kids are getting ready for school, through preparations that are quick to act or easy to swallow.

Quick to act. Aptensio XR’s onset is 2–3 times faster than Concerta’s and lasts about as long. Jornay PM, which is due out in 2019, offers a novel solution to the morning problem. Taken at night, it starts to work upon awakening 8–10 hours later. Jornay PM is a methylphenidate, and the company is working on an amphetamine version.

Easy to swallow. The remaining new methylphenidates have pharmaco­kinetics that are similar to Concerta but offer different routes of delivery (patch: Daytrana, liquid: Quillivant, chewable: QuilliChew, and orally disintegrating: Cotempla XR-ODT). Do these alternative routes have a role in adults? Swallowing problems do lead to nonadherence in 15% of adults, but the extra cost of these throat-friendly forms can lead to nonadherence as well (Mattingly GW et al, Postgrad Med 2017;129:657–666).

One form, the Daytrana transdermal patch, is probably worth avoiding—it can cause permanent loss of skin pigmentation, called leukoderma, around the application site. The patch is intended to allow easy on-off effects, but it is slow to start (1–2 hours) and lingers for 2–3 hours, or even up to 5 hours in some, after its removal. The patch is also prone to falling off, and can lead to mild overdoses with excess heat.

Focalin
Isomer mix: 100% dex-methylphenidate
Duration: instant release: Focalin (3–5 hr)
long-acting: Focalin XR (8–12 hr)
Although Focalin isolates the dex- isomer that’s responsible for the beneficial effects of methylphenidate, there is little evidence that it is any better than methylphenidate. It’s rumored to cause less insomnia and appetite suppression than methylphenidate, but head-to-head studies to prove that claim are lacking.

Selecting a stimulant
With so many versions available, it’s hard to know where to start. Clinical lore is that children respond better to methylphenidate varieties while adults respond better to amphetamine varieties, and a new meta-analysis backs that up (Cortese S et al, Lancet Psychiatry 2018;5(9):727–738). However, it’s hard to tell which will work best for any given patient, so a 1–2 month trial of each is a reasonable approach. I’ll have both the patient and a family member complete a rating scale at the start and end of each trial; 50% improvement is considered a good response (see ASRS scale at: www.moodtreatmentcenter.com/measurement).

For the amphetamine trial, I’ll generally start with Vyvanse or, if cost is an issue, Adderall XR. For methylphenidate, I tend to chose Concerta for its long, reliable duration. However, there’s little reason to start with one over the other, so my preferences are more a product of habit than science. Another common strategy is to start with instant release and convert to a long-acting form once the dosage is established.

Once I know which class works better, I’ll stick with the original agent that the patient improved on unless there are reasons to explore the different isomeric mixtures within that class. Those reasons are usually cost, efficacy, side effects, and duration. Side effects are the most difficult to predict, though cardiac issues would steer me away from Evekeo.

Converting the dose
Most of the methylphenidate versions have interchangeable dosing; exceptions are listed in the following conversion table.

Converting among the amphetamines is trickier because people differ in their sensitivities to each isomer. The conversion table gives some rough approximations, based on head-to-head comparisons and the potency of their dopaminergic effects (Biederman J et al, Biol Psychiatry 2007;62(9):970–976). Switching between Mydayis, Dyanavel, and Adderall does not require dose conversion.

What about changing from amphetamine to methylphenidate? A rule of thumb is that Adderall is about twice as potent as Ritalin (Adderall 10 mg ≈ Ritalin 20 mg). For more information, there is a useful conversion tool at: www.psychopharmacopeia.com/stimulant_conversion.php.

TCPR Verdict: We have two stimulants, five isomeric mixtures, and 30 formulations, but are patients with ADHD really better off than they were 10 years ago? Probably not; however, some of the reliable long-acting agents like Adderall XR and Concerta have gone generic, adding a needed boost of accessibility to this highly priced and poorly covered line of medications.

Ed note: Additional sources for this article include Physicians’ Desk Reference (71st ed. Montvale, NJ: Thomson PDR; 2017); The Pharmacist’s Letter (https://pharmacist.therapeuticresearch.com/Home/PL), and The Medical Letter (https://secure.medicalletter.org).