To the Editor:
Punja et al. [
[1]
] recently published a meta-analysis which found that amphetamines and psychostimulants, such as methylphenidate, are effective in the treatment of pediatric attention-deficit hyperactivity disorder (ADHD). Part of the therapeutic benefit of these medications may lie in their role facilitating sympathetic mechanisms, including increasing heart rate and blood pressure [2
, 3
] or reducing parasympathetic influences. In rat, amphetamines mydriasis was mediated at least in part by the inhibition of parasympathetic outflow [[4]
]. If the pharmacologic benefit of psychostimulants in ADHD rests on the resuscitation of sympathetic mechanisms, these studies, therefore, imply that parasympathetic dominance may be an innate feature of medication-naïve ADHD.Negrao et al. [
[5]
] studied autonomic correlates at rest in a sample of ADHD children, both medicated and nonmedicated, and reported that stimulant-free children experienced a parasympathetic overarousal in comparison to control subjects. Consistent with Punja's findings, methylphenidate use appears to correct this autonomic imbalance at rest. Kim et al. [[6]
] also recently investigated the role of methylphenidate on heart rate variability in ADHD subjects. Heart rate variability parameters indicative of parasympathetic tone showed significant decreases after a 12-week treatment with methylphenidate. The authors suggested that parasympathetic dominance in ADHD was corrected with the use of methylphenidate.It has been proposed elsewhere that exposure to the environmental pollutant, nitrous oxide (N2O), may the principal etiological factor in the development of ADHD and related neuropathologies [
7
, - Fluegge K.
Do toxic synergies of underlying etiologies predispose the positive association between traumatic brain injury and ADHD?.
J Atten Disord. 2016; ([Epub ahead of print])https://doi.org/10.1177/1087054716633858
8
]. The pollutant is mostly associated with agricultural soil management and the increasing use of nitrogen fertilizers [- Fluegge K.
- Fluegge K.
Glyphosate use predicts healthcare utilization for ADHD in the Healthcare Cost and Utilization Project net (HCUPnet): A two-way fixed-effects analysis.
Pol J Environ Stud. 2016; 25https://doi.org/10.15244/pjoes/61742
[9]
], and significant underestimations in pollutant burden have been reported [[10]
]. Inhalational 30% exposure to N2O in healthy humans was shown to impart a parasympathetic dominance via inhibition of sympathetic activity [[11]
]. Chronic exposure to environmentally relevant concentrations (50, 500, 5000 ppm) of the compound has also been previously shown to significantly alter central neurotransmission in CD-1 mice [[12]
]. Trace amounts (500 ppm) of N2O in healthy adult men elicits cognitive impairment on the digit span test, a test of verbal working memory [[13]
]. These studies suggest that trace levels of exposure to N2O in humans may promote both cognitive deficits and autonomic imbalance in healthy humans. The role of psychostimulants in reversing these specific physiological changes may underlie their clinical benefit. Therefore, additional research is needed in understanding the role of environmental pollutants, specifically N2O, in contributing to neurodevelopmental impairment in humans.References
- Amphetamines and methylphenidate for pediatric ADHD: a systematic review and meta-analysis of n-of-1 evidence.J Clin Epidemiol. 2016; 76: 65-75
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- Autonomic mechanisms for morphine and amphetamine mydriasis in the rat.J Pharmacol Exp Ther. 1986; 238: 788-793
- Autonomic correlates at rest and during evoked attention in children with attention-deficit/hyperactivity disorder and effects of methylphenidate.Neuropsychobiology. 2011; 63: 82-91
- Changes of heart rate variability during methylphenidate treatment in attention-deficit hyperactivity disorder children: a 12-week prospective study.Yonsei Med J. 2015; 56: 1365-1371
- Do toxic synergies of underlying etiologies predispose the positive association between traumatic brain injury and ADHD?.J Atten Disord. 2016; ([Epub ahead of print])https://doi.org/10.1177/1087054716633858
- Glyphosate use predicts healthcare utilization for ADHD in the Healthcare Cost and Utilization Project net (HCUPnet): A two-way fixed-effects analysis.Pol J Environ Stud. 2016; 25https://doi.org/10.15244/pjoes/61742
- Nitrogen-use efficiency, nitrous oxide emissions, and cereal production in Brazil: current trends and forecasts.PLoS One. 2015; 10: e0135234
- Indirect nitrous oxide emissions from streams within the US Corn Belt scale with stream order.Proc Natl Acad Sci U S A. 2015; 112: 9839-9843
- Inhalational conscious sedation with nitrous oxide enhances the cardiac parasympathetic component of heart rate variability.Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2008; 106: e1-e5
- Effects of repeated intermittent exposures to nitrous oxide on central neurotransmitters and hepatic methionine synthetase activity in CD-1 mice.Toxicol Ind Health. 1991; 7: 97-108
- Trace anesthetic effects on perceptual, cognitive, and motor skills.Anesthesiology. 1974; 40: 453-458
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Published online: June 29, 2016
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- N-of-1 trials can be aggregated to generate group mean treatment effects: a systematic review and meta-analysisJournal of Clinical EpidemiologyVol. 76
