"While LLMs offer immediate convenience, our findings highlight potential cognitive costs. Over four months, LLM users consistently underperformed at neural, linguistic, and behavioral levels."

https://www.media.mit.edu/projects/your-brain-on-chatgpt/overview/

Paper: https://arxiv.org/pdf/2506.08872v1

Image source

Approved July 24th, 2026. DEA scheduling is pending. The label's Initial U.S. Approval field is blank. Nothing can be dispensed yet until the DEA officially schedules the drug.

Simtriyo is classified as a CNS stimulant and carries a boxed warning for abuse, misuse, and addiction. The human abuse-potential data are not reassuring.

Adult placebo-subtracted effects were 2.7 to 4.4 points on an 18-item scale, with a flat dose-response.

Binding values

(IC50) (Lower is stronger) In Vitro & Plasma

NET (norepinephrine) 6 nM Plasma 132 ng/mL

DAT (dopamine) 38 nM Plasma 1,580 ng/mL

SERT (serotonin) 83 nM Plasma 1,760 ng/ml

#DAT and SERT are essentially equipotent...

to each other (1.1 ± 0.2). High NET occupancy and only moderate DAT and SERT occupancy were seen at peak concentrations after 400 mg/day. IC50 values are preclinical in vitro figures3; ratios and occupancy are from the phase 1 PET.

This is a NET-preferring agent...

with meaningful secondary dopamine and serotonin engagement, not a balanced triple blocker. That single fact reconciles two things that otherwise look contradictory: efficacy in the atomoxetine range, and an abuse signal that behaved like a stimulant's. The norepinephrine dominance explains the first; the residual dopamine engagement explains the second."

Centanafadine is primarily metabolized by monoamine oxidase A, but is NOT an MAOI itself. That is why the MAOI contraindication and 14-day washout are absolute rather than precautionary, you are blocking the drug's primary clearance pathway while simultaneously stacking monoamine load.

"In the two adult Phase 3 studies, abrupt discontinuation after chronic administration produced a very low degree of withdrawal symptoms, indistinguishable from placebo. The label states directly that even though Simtriyo is a CNS stimulant, it does not produce physical dependence. So: real abuse liability, minimal withdrawal. "

Article Conclusions:

1. The low dose failed in both pediatric trials. That is why the pediatric label has no titration and no low-dose option — the approved pediatric dose is the high dose from the start. If an adolescent is not responding to 280 mg, there is nowhere to go.

2. The adult effect is small. A 2.7- to 4.4-point advantage on an 18-item scale, with confidence intervals reaching −0.14 in one arm. That is in atomoxetine and viloxazine territory, not stimulant territory. And in Study 3 the high dose did numerically worse than the low dose — a flat, arguably non-monotonic dose-response that should temper any assumption that pushing to 280 mg buys much.

3. The pediatric effect is larger than the adult effect. −5.6 in children and −4.4 in adolescents versus −2.7 to −4.4 in adults. If you practice child psychiatry, this is a more interesting drug than if you treat adults — which is the reverse of the marketing emphasis.

4. There are no head-to-head trials — but there is one indirect comparison, and it agrees. A matching-adjusted indirect comparison pooled patient-level data from the two adult trials and propensity-weighted it against published trials of comparators. Centanafadine produced a 6.58-point smaller reduction in AISRS/ADHD-RS than lisdexamfetamine (p < 0.05), and was not statistically different from atomoxetine (2.02 points, p = 0.38). It did show significantly lower rates of several adverse events than all three comparators.9

Read it with the caveats it deserves: a MAIC is not randomization, the analysis was industry-funded, and its own authors note that short-term trials favor faster-onset agents. But it is the best comparative evidence in existence, and it lands exactly where the placebo-subtracted numbers pointed atomoxetine territory, not stimulant territory.

Full Source, read for full information with references. https://psychiatryeducationforum.com/centanafadine/

CYP1A2 inhibition Doubling caffeine AUC is the headline, and it matters for a population that self-medicates with caffeine. But the same pathway carries clozapine, olanzapine, duloxetine, theophylline, tizanidine, and melatonin. Adding centanafadine to a patient on clozapine is not a neutral act. Check every co-prescribed 1A2 substrate before you start.

Alcohol dose dumping. "Don't drink for two hours after your morning dose" is an easy instruction that will be ignored by exactly the adult patients who need it heard. Say it explicitly, and note the mechanism: it is not an additive-sedation warning, it is the slow release capsule releasing its whole payload at once in 2 hours versus 12 hours because someone decided to take two shots of Whiskey with their medicine. Less concentrated alcohol like beer is less worse, but not ideal nor recommended.

I'm not recommending it, it's not a nootropic either, just another tool in the tool box for psychiatrists treating patients. Worth talking about what's on a horizon, however this has not been distributed/released, there are no online individual anecdotes on this.

Participation of Dopamine D1 and D2 Receptors in the Rapid-Onset Behavioral Sensitization to Modafinil

Studies on the abuse potential of modafinil, a psychostimulant-like drug used to treat narcolepsy, are still controversial. While some studies claim no potential for abuse, increasing evidence suggests that modafinil induces abuse-related effects, including rapid-onset behavioral sensitization (i.e., a type of sensitization that develops within hours from the drug priming administration).

The rapid-onset sensitization paradigm is a valuable tool to study the neuroplastic changes that occur quickly after drug administration, and shares neuroadaptations with drug abuse in humans. However, the mechanisms involved in the rapid-onset behavioral sensitization induced by modafinil are uncertain.

Our aim was to investigate the possible involvement of dopamine D1 and D2 receptors on acute modafinil-induced hyperlocomotion and on the induction and expression of rapid-onset behavioral sensitization induced by modafinil in male Swiss mice.

Treatment with the D1 receptor antagonist SCH 23390 or the D2 receptor antagonist sulpiride attenuated the acute modafinil-induced hyperlocomotion in a dose-dependent manner.

Pretreatment with either antagonist before the priming injection of modafinil prevented the development of sensitization in response to a modafinil challenge 4 h later. However, only SCH 23390 decreased the expression of modafinil-induced rapid-onset behavioral sensitization.

Taken together, the present findings provide evidence of the participation of D1 and D2 receptors on the development of rapid-onset behavioral sensitization to modafinil, and point to a prominent role of D1 receptors on the expression of this phenomenon. (repost)

Full study here: https://www.frontiersin.org/articles/10.3389/fphar.2019.00211/full