Eg melatonin could maybe decrease it (though also make one more sleepy too). That said, past a certain dose higher doses of melatonin don’t seem to increase sleepiness, and vyvanse may just overcome this
Tbf, I know that some of the “cool people” [eg one is noted EA/AI Safety person] just take it 1x-2x per week - usually this is enough to get people to do the “high activation energy” things they need to do while not making them tolerant/dependent and it most likely drastically reduces increased risk of Parkinson’s that could happen from taking it every day as prescribed. It’s also not 100% clear if occasional cycling (esp with co-administration of melatonin) causes any damage at all, since b/c hormetic effects.
It’s also important to note that these things have appetite suppressant effects that can be pro-longevity on the rest of the body (esp if they are used to induce 48+ hour long fasts). Also it’s said by one person that using a lot of Vyvanse/Adderall seems to normalize the brain development of young kids with ADHD (at least the ones who are a mess without meds and whose brains then become ADAPTED to the condition where they’re constantly a mess - which screws up self-confidence and many many other things that are downstream)
I’m currently taking adderall but have not been doing it long term, just in the past few months. The only things i know to do to are basic health practices, like making exercise a priority, sleeping, and keeping my blood sugar stable. I supplement with Fish oil. Occasionally I will take melatonin before bed for potential protective effects but I do worry about regular use screwing with my hormones.
In one of the links you mentioned cannabis may have protective benifits. do you have any specific insights there that might be applied?
I would really do anything that could mitigate any damage being caused by adderall use. Ritalin and Modafinil just don’t work well.
Hi Alex, thanks for this post. I am curious if you have moved onto Vyvanse from Adderall? And if you view has changed on the use of stimulant. Also I read some people use it with L-Theanine / Gabe to counter the potential jittery.
And what about this: “Chronic use of amphetamines may increase the risk of developing Parkinson’s”.
Synaptic Specializations at Dopamine Release Sites Orchestrate Efficient and Precise Neuromodulatory Signaling
Abstract: Dopamine is a key chemical neuromodulator that plays vital roles in various brain functions. Traditionally, neuromodulators like dopamine are believed to be released in a diffuse manner and are not commonly associated with synaptic structures where pre- and postsynaptic processes are closely aligned. Our findings challenge this conventional view. Using single- bouton optical measurements of dopamine release, we discovered that dopamine is predominantly released from varicosities that are juxtaposed against the processes of their target neurons. Dopamine axons specifically target neurons expressing dopamine receptors, forming synapses to release dopamine. Interestingly, varicosities that were not directly apposed to dopamine receptor-expressing processes or associated with neurons lacking dopamine receptors did not release dopamine, regardless of their vesicle content. The ultrastructure of dopamine release sites share common features of classical synapses. We further show that the dopamine released at these contact sites induces a precise, dopamine-gated biochemical response in the target processes. Our results indicate that dopamine release sites share key characteristics of conventional synapses that enable relatively precise and efficient neuromodulation of their targets.
High-dose or chronic amphetamine/methamphetamine floods the cytosol with dopamine, which auto-oxidises to quinones and generates H₂O₂ via monoamine oxidase-B (MAO-B); hyperthermia and glutamate release amplify the insult. Loss of dopamine transporter (DAT), tyrosine-hydroxylase and vesicular monoamine transporter signalling is the usual read-out of this “terminal” damage.
How selegiline
could
help … and why the story is complicated
Pharmacological action
Theoretical impact on amphetamine toxicity
Counter-points
Irreversible MAO-B inhibition at ≤10 mg/day (humans) blocks dopamine deamination → less H₂O₂, less 6-OHDA formation
Reduces one major ROS source; explains lower HVA/DOPAC levels in selegiline-treated brains
MAO-A (still active) and non-enzymatic oxidation keep producing ROS; amphetamine toxicity also involves glutamate and mitochondrial stress that MAO-B inhibition alone can’t stop
Co-treatment 0.5–2 mg kg⁻¹ for 21 days with 10 mg kg⁻¹ meth
Oxidative markers, hippocampal BDNF/Akt
Significant protection and better mood/cognition scores in rats
Post-treatment (starting 24 h after meth binge) 0.02–2 mg kg⁻¹ for 18 days
Striatal DA, HVA
No rescue of dopamine depletion; high dose worsened mortality
Older mouse studies (1990s)
TH-positive fibre counts
Mixed—some no effect, some modest protection; differences traceable to temperature control and selegiline stereoisomer
Meta-pattern:
Protection is inconsistent, heavily dose- and timing-dependent, and disappears if selegiline is given after damage is underway.
Human evidence: almost a blank page
No controlled trials have examined selegiline as a neuroprotectant in therapeutic amphetamine (Adderall, Vyvanse) users or in stimulant-use disorder.
Imaging of Parkinson patients on 10 mg/day selegiline patch for years shows no obvious DAT loss, but this is confounded by disease-related degeneration and concurrent levodopa.
Epidemiology of MAO-B inhibitor users does not show lower Parkinson risk from prescribed amphetamine, but datasets are too small for a firm conclusion.
Practical implications if you are taking prescription stimulants
Question
Evidence-based answer
Will a MAO-B-selective 5–10 mg/day dose reliably prevent long-term dopaminergic wear-and-tear?
Unproven. Animal data look promising for pre-treatment, but protection is partial and has not been translated to humans.
Could it back-fire?
At clinical doses selegiline’s l-amphetamine metabolite is weak (∼1/20 the potency of d-amphetamine) but still adds catecholaminergic load. Higher doses (>10 mg oral or ≥15 mg transdermal) lose MAO-B selectivity and increase blood-pressure and serotonin-toxicity risks if combined with SSRIs or bupropion.
Is rasagiline or safinamide safer?
They lack amphetamine metabolites and have similar propargyl antioxidant signalling; very limited amphetamine–interaction data, but theoretically cleaner.
Could lowering peripheral dopamine metabolism (↓ HVA) reduce oxidative stress?
Possibly, but most stimulant oxidative burden arises inside axons, not in the periphery; MAO-B inhibition only addresses part of the pathway.
Other proven strategies
Keep core temperature down, avoid sleep deprivation, use the lowest effective stimulant dose, maintain antioxidant status (N-acetyl-cysteine, vitamin C/E), and monitor DAT density or HVA if clinically justified.
Bottom line
Selegiline has several mechanisms that could dampen amphetamine-induced oxidative injury—MAO-B blockade, propargyl neurotrophic signalling, and (at low doses) reduced dopamine efflux. Rodent data are split: some studies show 30–60 % protection, others none, and a few report worse outcomes at high doses. No human study has yet asked the question directly. Therefore, while low-dose selegiline is biologically plausible as a partial safeguard, it should not be relied on as a stand-alone antidote to amphetamine neurotoxicity. Until clinical trials arrive, the best defence remains responsible stimulant dosing, temperature and sleep control, and general antioxidant support—selegiline can be an adjunct, not a guarantee.
