This is a research call, not a recommendation to use methcathinone, mephedrone, or any illicit cathinone as ADHD medication. The near-term ask is: test the pharmacology in human in vitro models before anyone makes confident claims about "less neurotoxic Adderall," especially for NQO1 *2/*2 / P187S homozygous backgrounds.

The motivating split is simple:

• methylphenidate / Concerta / Ritalin: DAT/NET reuptake blockers. They amplify firing-dependent catecholamine tone but do not run transporters backward.
• amphetamine / Adderall: DAT/NET substrate releasers. They can drive dopamine efflux in a more firing-independent way and also disturb vesicular dopamine handling.
• methcathinone / mephedrone-like beta-keto amphetamines: also transporter substrate/releasers, not methylphenidate-like pure blockers, but with weaker VMAT2 interaction in several assay systems.

That creates an uncomfortable but testable hypothesis: for ADHD patients who need releaser-like efficacy and do not respond well enough to methylphenidate-class blockers, can one design a DAT/NET releaser that is slower-onset, less abuse-prone, and less VMAT2-disruptive than amphetamine?

Why NQO1 *2/*2 matters

The NQO1 *2 allele is P187S / rs1800566. The mutant protein has reduced FAD binding and stability and is rapidly degraded; homozygous *2/*2 is often treated experimentally as a severe low-activity NQO1 state. https://pmc.ncbi.nlm.nih.gov/articles/PMC6328894/ https://pmc.ncbi.nlm.nih.gov/articles/PMC8027776/

This matters for dopamine because cytosolic dopamine can oxidize through dopamine o-quinone and aminochrome chemistry. NQO1 / DT-diaphorase can two-electron-reduce aminochrome toward leukoaminochrome and avoid the one-electron semiquinone route. A review on aminochrome neuroprotection notes that DT-diaphorase accounts for about 97% of total quinone reductase activity in substantia nigra. https://pmc.ncbi.nlm.nih.gov/articles/PMC8868244/

My local NQO1 work points in the same direction: P187S looks less like a dead quinone pocket and more like a fragile flavin-supported holo-state under dopamine-quinone stress. The best computational rescue-like states were flavin-state changes and downstream GSTM2/GSH/NAC handling, not a magical direct amphetamine detox route.

So the NQO1-specific question is not "does amphetamine bind NQO1?" The better question is: does a stimulant exposure increase cytosolic/extravesicular dopamine oxidation enough that an NQO1-deficient background has less reserve?

Why cathinones are relevant, but not automatically safe

Mephedrone and methylone have been shown to act as substrate releasers at monoamine transporters in brain tissue. https://pmc.ncbi.nlm.nih.gov/articles/PMC3306880/

At the same time, mephedrone has reduced VMAT2 potency compared with MDMA and other amphetamine-type agents, which is one reason people have proposed that it may be less able to disrupt intracellular monoamine stores. https://pmc.ncbi.nlm.nih.gov/articles/PMC4978154/

That is the pharmacological opening: beta-keto amphetamine structure can preserve transporter-substrate activity while weakening VMAT2 liability.

But there is a major correction: methcathinone itself is not a clean "safe Adderall." A dopamine-neurotoxicity comparison across methamphetamine, mephedrone, methcathinone, and 4-methylmethamphetamine found that mephedrone often shows lower neurotoxic potential than methamphetamine under standard rodent conditions, whereas methcathinone is much less reassuring. https://pmc.ncbi.nlm.nih.gov/articles/PMC6083857/

And the broader synthetic-cathinone literature is mixed: mephedrone neurotoxicity remains controversial and context-dependent, with harsher dosing/environmental conditions producing worse transporter and inflammatory signals in some studies. https://pubmed.ncbi.nlm.nih.gov/27908258/ https://pubmed.ncbi.nlm.nih.gov/24892744/

Legal and development reality

Methcathinone and mephedrone are Schedule I controlled substances in the US. A March 2026 DEA notice still lists methcathinone as Schedule I, while amphetamine, lisdexamfetamine, and methylphenidate are Schedule II. https://public-inspection.federalregister.gov/2026-05359.pdf

So the realistic therapeutic program is not "use methcathinone." It is:

1. Use methcathinone/mephedrone only as controlled research probes.
2. Identify the pharmacological axis worth preserving: DAT/NET release with minimal VMAT2 disruption.
3. Engineer safer versions: slow-onset, prodrug-like, oral-only, lower redosing pressure, lower SERT/5-HT confounding if ADHD is the target, and clear cardiovascular limits.
4. Test them first in human neural models stratified by NQO1 genotype.

What I want tested

The proper first experiment is not a human trial. It is a Maxine.science-style human in vitro screening campaign using dopaminergic neuron cultures, midbrain organoids, or assembloids with electrophysiology and biochemical injury readouts.

The panel should compare:

• methylphenidate / dexmethylphenidate: blocker controls
• d-amphetamine / lisdexamfetamine-derived exposure: clinical releaser controls
• methcathinone and mephedrone: cathinone research probes
• methylone or related substrate releasers: mixed DAT/SERT comparators
• MDPV-like blockers only as "not releasers" controls, not as therapeutic leads
• future slow-onset VMAT2-sparing DAT/NET releaser candidates

The genotype layer should include isogenic NQO1 WT, heterozygous, and P187S/P187S cells. The key readouts should be dopamine efflux, cytosolic dopamine, vesicular dopamine depletion, dopamine o-quinone/aminochrome/adduct markers, mitochondrial stress, oxidative damage, neurite integrity, synaptic activity, hyperexcitability, inflammatory glial response, and recovery after washout.

The hypothesis that would justify a drug-development program:

At matched ADHD-relevant functional catecholamine output, a VMAT2-sparing releaser produces less cytosolic dopamine oxidation, less aminochrome-like burden, and less injury in NQO1 P187S/P187S dopaminergic models than amphetamine.

The hypothesis that would kill it:

The cathinone probe is equally or more injurious than amphetamine after matching for dopamine release, redosing-like exposure, temperature/stress, and washout recovery. Or it wins only because it is weaker, shorter, or more serotonergic rather than genuinely safer.

Bottom line

Concerta/Ritalin not being strong enough for some patients is real clinically, but it does not make old recreational cathinones ready medicines. The useful idea is narrower and better:

Build and test a slow-onset, abuse-resistant, VMAT2-sparing DAT/NET releaser as a possible "less dopamine-quinone-toxic amphetamine" for the subgroup that needs releaser-like ADHD efficacy, with NQO1 *2/*2 as a pre-specified vulnerability model.

Until that is shown in organoids/cell systems, "less neurotoxic Adderall" is a hypothesis, not a conclusion.