DEA Puts Centanafadine, the ADHD Drug Sold as Simtriyo, in Schedule III. Here Is What Changes for Prescribers.
A DEA rule effective Oct. 30 makes Otsuka's ADHD drug Schedule III, not Schedule II like other stimulants, so refills are allowed. Comments close Nov. 30.
Centanafadine, the attention-deficit/hyperactivity disorder (ADHD) drug Otsuka sells as Simtriyo, became a Schedule III controlled substance on Oct. 30 under a Drug Enforcement Administration (DEA) interim final rule published that day.
The Food and Drug Administration (FDA) approved the once-daily extended-release capsule on July 24 for ADHD in adults and in children 6 and older who weigh at least 20 kg. Otsuka said in its approval announcement that Simtriyo would be commercially available "later this year" following DEA scheduling. The schedule DEA chose, III rather than the Schedule II status of amphetamine, lisdexamfetamine and methylphenidate, sets the prescribing rules clinicians will work under.
Why Schedule III and not Schedule II?
Because the Department of Health and Human Services (HHS) and DEA both concluded that its abuse potential is lower than that of Schedule II stimulants. Centanafadine is a triple reuptake inhibitor of norepinephrine, dopamine and serotonin. The rule calls it a central nervous system stimulant whose mechanism "has some similarities to schedule II stimulants like cocaine."
The animal data pointed toward stimulant-like abuse liability. In rats, centanafadine fully generalized to an amphetamine cue and sustained intravenous self-administration above saline, though at lower rates than cocaine. The human data moved it down a schedule. In two human abuse potential studies in nondependent recreational stimulant users, the rule says, high doses produced drug liking greater than placebo but less than amphetamine, a dose-dependent shift toward disliking and "a clear lack of willingness to take the drug again." HHS concluded that negative effects such as nausea, vomiting, tremor and somnolence limit its abuse potential relative to Schedule II drugs.
What do the abuse study numbers show?
A real stimulant signal that did not climb with dose. The Script Pad's arithmetic from scores reported in the rule, from the second study of 61 participants on the Addiction Research Center Inventory amphetamine subscale (range 0 to 11): placebo scored 2.8. Immediate-release amphetamine 15 mg and 30 mg scored 5.9 and 7.7, or 3.1 and 4.9 points above placebo. Centanafadine 200 mg, 400 mg and 800 mg, roughly the marketed dose up to about four times it, scored 5.1, 4.8 and 4.9, or 2.3, 2.0 and 2.1 points above placebo. Doubling amphetamine raised the score by 1.8 points. Quadrupling centanafadine did not raise it at all.
Across 37 clinical studies, HHS reported no overdoses and suspected diversion at one site. In a 52-week open-label Phase 3 safety study of 662 adults, three participants were removed for medication handling irregularities, including one who used a 30-tablet supply in nine days. In two Phase 3 trials, HHS found no withdrawal syndrome after abrupt discontinuation.
Schedule III is a lower schedule, not a loose one. Simtriyo carries a boxed warning for abuse, misuse and addiction, and the rule notes a risk of alcohol-induced dose dumping in laboratory testing.
What changes at the prescription pad?
Mainly refills and how a prescription can reach the pharmacy. Under DEA's refill rule for Schedule III and IV drugs, a prescription may be refilled no more than five times and not more than six months after the date it was issued. For Schedule II drugs, refills are prohibited. A pharmacist may also dispense a Schedule III drug on a written, faxed, oral or electronic prescription. Anyone who prescribes or dispenses it needs a DEA registration covering Schedule III, and practices that keep stock must meet Schedule III to V security, inventory and recordkeeping rules, the rule says.
The label adds its own limits. Otsuka's announcement lists a second boxed warning: higher rates of suicidal ideation and behaviors than placebo in patients 6 to 12 years old. The drug is not recommended for children under 6 or under 20 kg. Approval rested on four randomized, double-blind, placebo-controlled Phase 3 trials, two in adults and two in children and adolescents. The announcement did not report effect sizes.
Why it matters
For a patient who needs a stimulant-class ADHD drug, a prescription that can carry refills is a practical difference from the Schedule II options. It does not replace the screening the label requires: assess abuse and misuse risk before prescribing, ask about alcohol and watch younger children for suicidal thoughts. The rule took effect on publication. Comments and hearing requests on Docket DEA-1743 are due Nov. 30, after which DEA must issue a final rule.
It is not the only scheduling change this fall. DEA has also moved to place two kratom-derived opioids in Schedule I, and CVS's $315 million settlement keeps pharmacists asking about controlled-substance prescriptions. Add centanafadine to the Schedule III list in your EHR and prescribing protocols now, before the first patient asks for it.
Reported, fact-checked and edited by The Script Pad's editorial staff. See How we use AI.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
