Long-Term Safety of Stimulant Use for ADHD: Findings from Nonhuman Primates

Volkow, Nora D.

doi:10.1038/npp.2012.127

Cited by 23 publications

(9 citation statements)

References 9 publications

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“…Possible explanations include: (1) treatment with psychostimulants may enhance the mechanism(s) responsible for the linkage between earlier-onset ADHD and BG&C diseases expression, (2) a history of ADHD with psychostimulant use may accelerate the temporal related degeneration of the relevant neuronal pathways primarily in those patients who eventually, with age, will manifest this disorder regardless of an ADHD history, or (3) psychostimulant treatment is a marker for a more severe ADHD phenotype, which in turn increases the risk of earlier BG&C diseases expression. Due to a general lack of evidence in either animals [46,47] or humans [48] that methylphenidate per se damages nigrostriatal dopaminergic neurons, the latter explanation may be the most plausible (however see also ref. [49]).…”

Section: Discussionmentioning

confidence: 99%

Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of attention-deficit/hyperactivity disorder

Curtin

Fleckenstein

Keeshin

et al. 2018

Neuropsychopharmacol

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Attention-deficit/hyperactivity disorder (ADHD) is marked by an ongoing pattern of inattention and/or hyperactivity and involves dysregulated dopaminergic pathways. Dopaminergic agents (i.e., amphetamine and methylphenidate) are thus prescribed to treat ADHD. As little is known regarding long-term consequences of either ADHD or its treatment, the objective of this study was to determine if either alters the risk of diseases of the basal ganglia and cerebellum, including Parkinson's disease. Statewide medical records from 1996 to 2016 were retrieved from the Utah Population Database to conduct a retrospective cohort study. Participants included ADHD patients (International Classification of Diseases, 9th revision (ICD-9) diagnosis codes 314.0-314.2, 314.8, 314.9) and 5:1 random sex-matched and age-matched subjects with no ADHD diagnosis history. Both patients and non-ADHD subjects met the following eligibility criteria: (1) no prior diagnosis of Parkinson's disease, secondary parkinsonism, basal ganglia disease, or essential tremor (ICD-9 codes 332.0, 332.1, 333.0, 333.1), (2) born in 1950 or later and age ≥20 years at last follow-up, and (3) no history of substance abuse (illicit drugs or alcohol). Outcomes were measured as time to diagnosis of diseases of the basal ganglia and cerebellum, death, or study-end. A Cox model incorporating a competing risk of death was used to provide hazard ratio estimates. Patients with ADHD (N = 31,769) had a 2.4-fold increased risk of basal ganglia and cerebellum diseases (95% confidence interval (CI): 2.0-3.0; P < 0.0001) compared with 158,790 non-ADHD persons, after controlling for sex and age and adjusting for tobacco use and psychotic conditions. In 4960 ADHD patients prescribed psychostimulants, risk of basal ganglia and cerebellum diseases between ages 21 and 49 years was especially pronounced, at 8.6-fold (95% CI: 4.8-15.6; P < 0001). The association of ADHD patients prescribed psychostimulants with higher risk of diseases of the basal ganglia and cerebellum may reflect a more severe ADHD phenotype rather than a direct association between prescribed stimulant use and basal ganglia or cerebellum disorders. Future studies to assess and stratify patient risk so as to inform treatment are warranted.

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Section: Discussionmentioning

confidence: 99%

Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of attention-deficit/hyperactivity disorder

Curtin

Fleckenstein

Keeshin

et al. 2018

Neuropsychopharmacol

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“…Moreover, medication status was controlled for in all repeated measures ANOVAs. There is a lack of clarity regarding chronic effects of ADHD medication, with different studies reporting contradicting results with regard to its impact on dopaminergic markers ( Gill et al , 2012 ; Volkow et al , 2012 ). Further research and suitable study designs are needed to fully characterize the consequences of long-term pharmacological ADHD treatment both at the behavioural and at the neurobiological levels.…”

Section: Discussionmentioning

confidence: 99%

A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment

Campo

Fryer

Hong

et al. 2013

Brain

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Through the combined use of 18F-fallypride positron emission tomography and magnetic resonance imaging this study examined the neural mechanisms underlying the attentional deficits associated with attention deficit/hyperactivity disorder and their potential reversal with a single therapeutic dose of methylphenidate. Sixteen adult patients with attention deficit/hyperactivity disorder and 16 matched healthy control subjects were positron emission tomography and magnetic resonance imaging scanned and tested on a computerized sustained attention task after oral methylphenidate (0.5 mg/kg) and placebo administration in a within-subject, double-blind, cross-over design. Although patients with attention deficit/hyperactivity disorder as a group showed significant attentional deficits and reduced grey matter volume in fronto-striato-cerebellar and limbic networks, they had equivalent D2/D3 receptor availability and equivalent increases in endogenous dopamine after methylphenidate treatment to that observed in healthy control subjects. However, poor attentional performers drawn from both the attention deficit/hyperactivity disorder and the control groups had significantly reduced left caudate dopamine activity. Methylphenidate significantly increased dopamine levels in all nigro-striatal regions, thereby normalizing dopamine levels in the left caudate in low performers. Behaviourally, methylphenidate improved sustained attention in a baseline performance-dependent manner, irrespective of diagnosis. This finding was accompanied by an equally performance-dependent effect of the drug on dopamine release in the midbrain, whereby low performers showed reduced dopamine release in this region. Collectively, these findings support a dimensional model of attentional deficits and underlying nigro-striatal dopaminergic mechanisms of attention deficit/hyperactivity disorder that extends into the healthy population. Moreover, they confer midbrain dopamine autoreceptors a hitherto neglected role in the therapeutic effects of oral methylphenidate in attention deficit/hyperactivity disorder. The absence of significant case–control differences in D2/D3 receptor availability (despite the observed relationships between dopamine activity and attention) suggests that dopamine dysregulation per se is unlikely to be the primary cause underlying attention deficit/hyperactivity disorder pathology in adults. This conclusion is reinforced by evidence of neuroanatomical changes in the same set of patients with attention deficit/hyperactivity disorder.

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“…23 These risks may be compounded by outcomes if individuals are unaware of the correct doses and medical contraindications; 24 risks might also be compounded by factors that have not yet been studied or documented. 25 Current studies and medical literature have not captured outcomes such as "being more efficient in work or school" or "getting better grades," which are real-world enhancement goals outside of the laboratory environment. How physicians might reconcile such nonstandardized goals with medical indications and whether the ability or inability to meet these types of goals might eventually be turned into a medical condition by enhancement practices remain impending questions.…”

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confidence: 99%