In the United States, a national parent survey estimate suggests 7.0 million children aged 3–17 (11.4%) had ever been diagnosed with ADHD in 2022. Among children with current ADHD, about 53.6% were taking ADHD medication in 2022.

Broader prescribing data also show sustained growth: a DEA-commissioned report found dispensed stimulant prescriptions increased by ~34% from 2012 to 2023, and in 2023 the most frequently dispensed stimulants were amphetamine (51%) and methylphenidate (21%).

Despite regularly being prescribed for the treatment of ADHD, stimulants such as Methylphenidate (Ritalin) and Amphetamine (Adderall), appear to come with some considerable risks to long-term brain health. Excessive stimulation of dopamine/norepinephrine systems involves a number of damaging mechanisms:

• damage the brain via oxidative stress (dopamine oxidation and ROS)
• glutamate-driven excitotoxicity (NMDA/calcium overload)
• mitochondrial dysfunction (energy failure and more ROS)
• hyperthermia, further amplifying risk of injury

Therapeutic-range ADHD dosing generally doesn’t show the same toxicity in rodent studies, and methylphenidate may be less risky mechanistically because it blocks reuptake rather than forcing dopamine release.

In humans, a 1-year MRI trial in adults found no brain-volume loss with methylphenidate vs placebo. However, a notable nonhuman primate study using an Adderall-like drug at human-comparable blood levels reported large reductions in striatal dopamine markers (Ricaurte et al., 2005). Four weeks of ADHD-treatment dosing of amphetamine found:

• Caudate nucleus and putamen: 44–47% dopamine depletion
• Nucleus accumbens: ~30% depletion
• Significant reduction in DAT protein and DAT binding sites

Whilst human studies are more limited, they also point to changes in dopaminergic signalling. A 2001 study on 9 children being treated with methylphenidate used SPECT scanning to identify changes in striatal D2 dopamine receptor binding.

They found that after 3 months of treatment, D2 receptor availability was significantly reduced in all regions of the striatum (the reward centre of the brain). This was equivalent to up to a 30% down-regulation.

Are Dopaminergic Changes Permanent?

If prescribed stimulants were causing meaningful dopaminergic neurodegeneration at population scale, you might expect epidemiologic signals (e.g., Parkinson’s disease risk).

Illicit amphetamine exposure has been linked to higher PD risk in several studies, but a more recent study focusing on prescribed stimulants in adults with ADHD found results not consistent with the same increased PD risk seen with illicit stimulants.

Illicit amphetamine users were found to be almost 3 times more likely to develop Parkinson’s disease (Curtin et al. 2014). However, a retrospective cohort study of 59,471 stimulant-treated individuals did not find an increased risk of Parkinson’s disease over a 30 year follow-up (Kindt et al. 2024).

Does recovery just take time?

Recent neuroimaging reviews summarize a consistent pattern: with prolonged abstinence, some brain measures (especially dopaminergic markers and some structural measures) show partial normalization, though not always complete, and not always matched by full cognitive recovery (Wen et al. 2023).

Several sMRI studies reported increases in grey matter measures during abstinence, implying some structural normalisation:

• First four weeks of abstinence: One study (Morales et al., 2012) reported grey matter volume was significantly higher across frontal, temporal, occipital, and insular regions within the first 4 weeks of abstinence (interpreted in the review as consistent with early structural recovery).
• ≥ 6 months abstinence: Another study (Kim et al., 2006) reported that abstinence of six months or more was associated with greater grey matter density in the right middle frontal gyrus, and this increase correlated with improved executive function.
• Possible sex-pattern effects: one study found prolonged abstinence associated with higher grey matter volume in hippocampal, orbitofrontal, and parietal regions in males only.

Whilst the review generally found improvements with sustained abstinence, one study actually found lower cingulate grey matter volume at 12 months that wasn’t present at 6 months compared to control (Ruan et al. 2018). It could mean the structural difference developed or progressed over time during abstinence, rather than being “fixed” at the point of stopping use.

Dopamine & Neurogenesis

Across anatomical, cell-culture, and in vivo studies, there’s evidence that dopamine stimulates Subventricular Zone Neurogenesis neurogenesis, mainly by acting on D2-like receptors on transit-amplifying progenitors (Borta et al. 2006).

The subventricular zone (SVZ) is a thin layer of cells that lines the walls of the lateral ventricles in the brain. It’s notable for being one of the two regions of the brain that sustain neurogenesis into adulthood (the other being the dentate gyrus).

Dopaminergic fibers from the substantia nigra innervate the SVZ, C-cells express D2-like receptors, and dopamine depletion with toxins reduces SVZ proliferation (particularly C-cells), while D2/D3 agonists increase it.

Similar relationships are reported in primates and in postmortem PD brains, where proliferating SVZ precursors are reduced. The functional consequences are uncertain, but it’s been suggest that reduced SVZ/SGZ neurogenesis could plausibly contribute to PD non-motor symptoms such as olfactory deficits, mood changes, and memory impairment.

Is dopaminergic neurogenesis possible?

Dopaminergic neurogenesis is possible in principle. Adult mice continuously generate new olfactory bulb (OB) interneurons from subventricular zone (SVZ) stem cells, including dopaminergic (tyrosine hydroxylase–expressing) interneurons in the glomerular layer (GL) that shape sensory input processing.

In a 2014 study by Lazarini et al, researchers induced local dopaminergic cell loss by injecting the dopamine toxin 6-hydroxydopamine into the dorsal glomerular layer of the olfactory bulb.

Intrabulbar 6-hydroxydopamine caused a spatially restricted, transient reduction (~40%) of tyrosine hydroxylase interneurons near the injection site, accompanied by a brief wave of apoptosis. Mice showed marked deficits in innate olfactory behaviours, notably abnormal responses to aversive predator/spoiled-food odours. Over time, TH+ interneuron numbers in the lesioned GL recovered (complete by ~1 month).

This recovery coincided with a transient increase in immature neuron markers (DCX) locally in the GL, without increased SVZ/RMS proliferation, and with evidence (lentiviral labeling of SVZ-born neuroblasts) that newly generated neurons were preferentially recruited/integrated into glomerular circuits specifically within the damaged region.

Behavioral function recovered later (~2 months), consistent with a lag between replenishing cell numbers and maturation/functional integration.

However, in humans, carbon-14 “birth dating” studies (using bomb-test–derived ¹⁴C in DNA) found little to no detectable addition of new olfactory-bulb neurons in adulthood, implying that the rodent-style ongoing production of new OB dopaminergic interneurons is not a major process in adult humans.

References

https://www.cdc.gov/adhd/data/index.html

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Ricaurte GA, Mechan AO, Yuan J, Hatzidimitriou G, Xie T, Mayne AH, McCann UD. Amphetamine treatment similar to that used in the treatment of adult attention-deficit/hyperactivity disorder damages dopaminergic nerve endings in the striatum of adult nonhuman primates. J Pharmacol Exp Ther. 2005 Oct;315(1):91-8. doi: 10.1124/jpet.105.087916. Epub 2005 Jul 13. PMID: 16014752.

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Curtin K, Fleckenstein AE, Robison RJ, Crookston MJ, Smith KR, Hanson GR. Methamphetamine/amphetamine abuse and risk of Parkinson’s disease in Utah: a population-based assessment. Drug Alcohol Depend. 2015 Jan 1;146:30-8. doi: 10.1016/j.drugalcdep.2014.10.027. Epub 2014 Nov 16. PMID: 25479916; PMCID: PMC4295903.

Kindt HM, Tuan WJ, Bone CW. Do prescription stimulants increase risk of Parkinson’s disease among adults with attention-deficit hyperactivity disorder? A retrospective cohort study. Fam Pract. 2024 Aug 14;41(4):605-609. doi: 10.1093/fampra/cmac153. PMID: 36593727.

Xinwen Wen, Lirong Yue, Zhe Du, Linling Li, Yuanqiang Zhu, Dahua Yu, Kai Yuan, Implications of neuroimaging findings in addiction, Psychoradiology, Volume 3, 2023, kkad006, https://doi.org/10.1093/psyrad/kkad006

Borta, A. and Höglinger, G.U. (2007), Dopamine and adult neurogenesis. Journal of Neurochemistry, 100: 587-595. https://doi.org/10.1111/j.1471-4159.2006.04241.x