Centanafadine Is a Schedule III Stimulant

November 2, 2026 | The Psychiatric Record | Prescribing

On October 30, DEA placed centanafadine, branded Simtriyo, in Schedule III. The same day, FDA's July approval of the drug took effect.

FDA approved Otsuka's new drug application for Simtriyo on July 24, 2026, for ADHD in adults and in children 6 years and older who weigh at least 20 kg. The approval letter attached a condition. The approval date "shall be the date on which the Drug Enforcement Administration (DEA) publishes a notice in the Federal Register announcing the interim final scheduling of centanafadine," and the drug "may be marketed only after" that notice and after Otsuka submits a supplement revising its labeling to show the schedule.

That condition comes from the statute. For a drug that FDA recommends controlling, approval "shall not take effect until the interim final rule controlling the drug is issued." So the July date is when FDA acted, and the approval took effect when DEA's rule did, on October 30. In July, Otsuka said it expected the drug to be available "later this year following scheduling"; we found no launch, availability, or price announcement from the company between October 30 and November 2.

DEA received HHS's Schedule III recommendation on July 18. Its interim final rule, issued under the Controlled Substances Act's expedited process for newly approved drugs, adds centanafadine to the stimulants paragraph of Schedule III, 21 CFR 1308.13(b)(3). Comments are due November 30 (DEA-1743, posted on regulations.gov as docket DEA-2026-1783). The rule is in effect now, and DEA could change the placement in a final rule.

The prescribing information describes centanafadine as "a norepinephrine-dopamine-serotonin reuptake inhibitor and central nervous system stimulant," and calls its mechanism in ADHD "unclear." Otsuka's July release also calls it an NDSRI and CNS stimulant. Neither document calls it a non-stimulant.

A boxed warning covers two risks. The first is suicidal ideation and behavior in children. In the 6-week controlled study in children aged 6 to 12, suicide attempt was reported in 0.7% of centanafadine-treated patients (2 of 304) and in none of 153 on placebo. Separately, in a long-term open-label trial in patients aged 6 to 17, which had no comparison group, suicidal ideation was reported in 5 of 620 (0.8%), and 4 stopped the drug because of it. The counts are small, and zero events on placebo do not show zero risk. The label says all pediatric patients 6 and older should be "monitored closely," especially in the first months. The second boxed risk is abuse, misuse, and addiction; the label tells prescribers to assess each patient's risk before prescribing and to reassess it throughout treatment.

Other warnings cover blood pressure and heart rate, serious cardiac disease, psychiatric adverse reactions, growth suppression in children, peripheral vasculopathy, tics, and serotonin syndrome. The label asks for heart rate and blood pressure before starting, after each dose increase, and periodically. Use with an MAOI, or within 14 days of stopping one, is contraindicated. Centanafadine is not recommended in severe hepatic impairment, and as a moderate CYP1A2 inhibitor it can raise exposure to drugs cleared by that enzyme.

Simtriyo comes as extended-release capsules of 140, 210, and 280 mg, taken once daily in the morning. Adults start at 210 mg and may go to 280 mg. Adolescents 13 to 17 weighing at least 20 kg take 280 mg. Children 6 to 12 are dosed by weight: 140 mg from 20 to under 35 kg, 210 mg from 35 to 50 kg, and 280 mg above 50 kg, each the weight-based equivalent of the 280 mg dose.

Efficacy rests on four 6-week placebo-controlled trials. In children 6 to 12, the 280 mg-equivalent regimen reduced ADHD-RS-5 scores by 16.3 points against 10.8 with placebo, an estimated difference of 5.6; in adolescents the 280 mg difference was 4.4. In both pediatric trials the lower-exposure regimen (140 mg or its weight-based equivalent) did not separate from placebo, and the label states that its effectiveness was not established. The two adult trials used "another formulation of centanafadine," with placebo-subtracted differences of 2.7 to 4.4 points on the AISRS; the label states no expected difference in effectiveness from Simtriyo at 210 and 280 mg. The label's efficacy section reports no head-to-head trial against another ADHD medication.

DEA's rule lays out evidence pointing both ways. In rats, centanafadine fully substituted for amphetamine in drug discrimination and maintained self-administration above saline, though below cocaine.

Two human abuse potential studies, in recreational stimulant users, used single doses of an immediate-release formulation, not the marketed extended-release capsule. In the first (36 participants), Drug Liking scores at 400 and 800 mg were not statistically significantly less than with amphetamine 40 mg; that does not establish equivalence. In the second (61 participants), liking scores at 200 to 800 mg were lower than with amphetamine 15 and 30 mg, significantly so except for 800 mg against amphetamine 15 mg, and on Overall Drug Liking the higher doses shifted toward disliking. The rule concludes that negative subjective effects and adverse events at high doses likely limit abuse relative to amphetamine and lisdexamfetamine.

In two adult phase 3 studies, withdrawal symptoms after abrupt discontinuation were indistinguishable from placebo. The label says this "suggests" centanafadine does not produce physical dependence, and notes it may produce tolerance. In a 52-week open-label adult safety trial with 662 participants, 3 were removed for medication-handling irregularities involving suspected or documented abuse or diversion. DEA also cites in vitro testing showing a risk of alcohol-induced dose-dumping, and the label says to avoid alcohol with a dose and for at least two hours after.

Schedule III reflects DEA's findings that centanafadine has less abuse potential than Schedule I and II drugs and that its abuse may lead to moderate or low physical dependence or high psychological dependence. It is not a finding of no abuse potential.

Prescribing requires a DEA registration covering Schedule III, and registrants who keep the drug on hand must include it in their controlled-substance inventories. The practical difference from Schedule II stimulants is refills. Schedule II prescriptions cannot be refilled, although separate prescriptions totaling up to a 90-day supply are allowed under conditions. A Schedule III prescription may authorize up to five refills, and no fill or refill may occur more than six months after it was issued; beyond either limit, a new prescription is required. These are federal limits; state prescribing and e-prescribing rules may be stricter.

For telemedicine, Schedule III placement changes nothing this year. Under DEA's fourth extension, a DEA-registered practitioner may prescribe Schedule II through V drugs by telemedicine without a prior in-person evaluation, if the rule's conditions are met, through December 31, 2026. The separate pathway for buprenorphine is limited to treatment of opioid use disorder and does not reach an ADHD drug. OIRA lists DEA's special registration final rule as pending review, received August 25. If December 31 passes with no final rule or further extension, this general temporary pathway ends; prescribing after an in-person evaluation, and the narrower statutory telemedicine exceptions, remain available. Our August 17 issue, "Telehealth Is Allowed Right Now Is Not an Authority," set out those authorities and their clocks.

The publicly posted label is behind the schedule. As of November 2, the Simtriyo label on FDA's site and the version on DailyMed still read "controlled substance schedule pending," and section 9.1 says the schedule is "to be determined." The approval letter requires Otsuka to submit revised prescribing information, a Medication Guide, and cartons showing the schedule; the sources we checked did not establish whether that supplement has been filed. Until a revision posts, these publicly posted copies will not show what the federal rule now says.

Price and payer coverage were not available in the sources we reviewed, and the schedule remains interim and open to comment.

A Schedule III listing is not a non-stimulant label, and the boxed warning applies from the first prescription.

Source note: This commentary relies on DEA's interim final rule, FDA's label and approval letter for Simtriyo, federal statutes and prescription regulations, DEA's telemedicine extension, the OIRA review record, and Otsuka's release. Abuse potential findings are as summarized by DEA and HHS in the rule and by FDA in the label; the DEA and FDA eight-factor analyses posted to the docket could not be downloaded in our checks, and we did not review FDA's review documents. Both human abuse potential studies used an immediate-release formulation, and the adult efficacy trials used a different centanafadine formulation. The pediatric suicide-attempt counts come from one 6-week controlled study; the ideation counts come from an uncontrolled open-label trial. Label and announcement checks reflect November 2, 2026. State controlled-substance rules may add requirements not discussed.

Educational Disclaimer: The Psychiatric Record provides general educational information for psychiatric and mental-health professionals. Content does not constitute medical, legal, regulatory, compliance, billing, or other professional advice; does not establish a standard of care; and is not a substitute for independent professional judgment. Prescribing obligations depend on federal and state law and on the current FDA labeling. Clinicians should confirm the current label and applicable state rules before prescribing.