Soon after Vyvanse’s patent expired in 2023, applications for generic formulations of lisdexamfetamine dimesylate started flowing into the FDA. There are now 18 approved generic versions of the medication, a relief for patients facing the nationwide stimulant shortage. In this piece, I’ll look at what sets lisdexamfetamine apart from other stimulants. 

The prodrug

Lisdexamfetamine is an inactive prodrug of dextroamphetamine (Dexedrine), a stimulant with a long history of use in children and adults with ADHD or narcolepsy. It remains inactive until the lysine is cleaved off, converting the prodrug to active dextroamphetamine. Originally, this was assumed to occur in the GI tract, but we now know the cleavage takes place in red blood cells. The delay in activation means that snorting or injecting the medication results in much less of a high compared to other amphetamine formulations (Carton L et al, Expert Rev Clin Pharmacol 2022;15(8):921–925). Abuse rates of lisdexamfetamine are lower than those for short-acting stimulants, and people with amphetamine use disorder tend to “like” the euphoria with lisdexamfetamine less than they do with short-acting mixed amphetamine salts like Adderall. 

The D-isomer

Amphetamine comes as two mirror-­image isomers, dextro- (D-) amphetamine and levo- (L-) amphetamine, each with different biological effects. Of the two, D-amphetamine has more potent effects on the central nervous system (two to four times more powerful). L-amphetamine has a longer half-life and causes more side effects like motor tics and cardiovascular effects. Of the pure D-amphetamine medications, lisdexamfetamine is preferred because of its lower abuse potential and longer duration of action.

The clinical difference

Many patients report a “smoother” experience taking lisdexamfetamine compared to mixed amphetamine salts, which may also relate to the prodrug mechanism. Activation in the red blood cells is much more consistent than absorption in the GI tract, which means that lisdexamfetamine’s levels are less affected by food, gut pH, or bariatric surgery (Auiler JF et al, Curr Med Res Opin 2002;18(5):311–316). Extended-release beads of mixed amphetamine salts (Adderall XR), for example, are delayed more by a heavy meal (around two and a half hours) than lisdexamfetamine (around one hour). 

A network meta-analysis of ADHD treatments identified amphetamines as the most effective treatments for ADHD in adults. In this class, lisdexamfetamine was among the most effective amphetamines (it had the highest difference from placebo), but there was no statistically significant evidence of it being superior to other long-acting amphetamines (Cortese S et al, Lancet Psychiatry 2018;5(9):727–738).

Binge eating disorder

In 2015, the FDA approved lisdexamfetamine for binge eating disorder (BED) as part of its priority review program, given limited treatment options. It remains the only approved medication for BED. Amphetamines have long been known to decrease appetite, sometimes causing weight loss (more so than methylphenidates), and lisdexamfetamine’s use in BED is an example of leveraging a side effect as a therapeutic. The number needed to treat for achieving remission (four weeks of no bingeing) was 4 in the pivotal trials (McElroy SL et al, Neuropsychopharmacology 2016;41(5):1251–1260). 

Vyvanse’s manufacturer sought FDA approval in depression augmentation, where it showed early promise in Phase II trials (Trivedi MH et al, J Clin Psychiatry 2013;74(8):802–809; Madhoo M et al, Neuropsychopharmacology 2014;39(6):1388–1398). When it advanced to larger Phase III trials and an additional dose-ranging study, it didn’t work and thus was not granted the indication (Richards C et al, J Psychopharmacol 2017;31(9):1190–1203; Richards C et al, J Affect Disord 2016;206:151–160). 

A single trial in bipolar depression augmentation found no difference in the main depressive scale compared to placebo (McElroy SL et al, Int Clin Psychopharmacol 2015;30(1):6–13). 

Conversion from Adderall to Vyvanse

If you are converting from amphetamine/D-amphetamine mixed salts (Adderall), where there is a 3:1 ratio of D-amphetamine to L-amphetamine, to lisdexamfetamine, you need to adjust for isomers. That’s because D-amphetamine is more potent than L-amphetamine. Ordinarily this would mean a reduction in dose (which is true when converting to pure D-amphetamine), but lisdexamfetamine’s dosing is inflated by the lysine weighing down the active form of the drug. Thus, when converting from Adderall to Vyvanse, the conversion factor is 2.6. If the amphetamine/D-amphetamine mixed salts dose is 20 mg, this would translate to about 50 mg of lisdexamfetamine, and 30 mg would translate to 70 mg (see the table “Lisdexamfetamine Overview”).

Carlat Verdict 

While methylphenidates remain the first choice for ADHD given the favorable side effect profile, we recommend considering generic lisdexamfetamine along- side or even before other long-acting amphetamines as a next step.