The clinical utility of prescription stimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD) is well characterized and robust.1 ADHD is a persistent and pervasive neurodevelopmental disorder with an etiology influenced by the interplay of environmental and genetic factors.2 The cardinal symptoms of ADHD—hyperactivity, impulsivity, and/or inattention—are usually noticed by parents, teachers, and/or other caregivers in mid- to late childhood. Symptoms may cause noticeable impairments in social interaction and limit effective communication, social cooperation, and academic success.3,4 Early diagnosis by qualified mental health professionals (eg, psychotherapists, psychiatrists, behavioral neurologists) is associated with greater long-term symptom management.5 Interestingly, up to 85% of patients diagnosed with ADHD early in life continue to have symptoms into adulthood, meaning long-term treatment consideration is likely necessary.69 Amphetamine (AMP) salts and methylphenidate (MPH), both prescription stimulants with many formulations (Table 1), have been recommended as first-line treatments for ADHD in both pediatric and adult populations in the United States for decades, although adjunctive behavioral therapy may produce even better outcomes in adults.1,57,1014

Table 1.

FDA-Approved Formulations for the Treatment of ADHD

Trade name Dosage Maximum recommended
Focalin XR 5–40 mg capsules 1 mg/kg or 30 mg/day
Concerta 18–54 mg tablets 2 mg/kg or 72 mg/day
Ritalin LA 10–40 mg capsules 2 mg/kg or 60 mg/day
Metadate CD 10–60 mg capsules 2 mg/kg or 60 mg/day
Daytrana 10–30 mg patches 30 mg/day
Ritalin SR 20 mg tablets 2 mg/kg or 60 mg/day
Methylin ER 10–20 mg tablets 2 mg/kg or 60 mg/day
Quillivant 25 mg/5 mL suspension 60 mg QAM
Focalin 2.5–10 mg tablets 2 mg/kg or 60 mg/day
Ritalin 5–20 mg tablets 2 mg/kg or 60 mg/day
Methylin 5–20 mg tablets or 5–10 mg/5 mL solution 2 mg/kg or 60 mg/day
Vyvanse 10–70 mg capsules 1 mg/kg or 70 mg/day
Adderall XR 5–30 mg capsules 1 mg/kg or 30 mg/day
Dexedrine 5–15 mg capsules 1 mg/kg or 30 mg/day
Adderall 5, 7.5, 10, 12.5, 15, 20, 30 mg tablets 1 mg/kg or 30 mg/day
Dextroamphetamine 5–10 mg tablets 1 mg/kg or 30 mg/day
ProCentra 5 mg/5 mL solution 1 mg/kg or 30 mg/day

Although the employment of stimulants in the treatment of nosologic predecessors to ADHD has been commonplace since the mid-20th century,8,15 adequate comprehensive consideration of the potential neurological sequelae of long-term stimulant use, prescribed or otherwise, is noticeably lacking in the literature. Alarmingly, the Schedule II status of stimulant medications indicates their abuse and dependency potential is similar to the medications implicated in the current opioid epidemic. These factors should be of great importance to the interested clinical, toxicological, and epidemiological communities given the popular ease of access to, high prevalence of, and largely unknown long-term neurological sequelae of prescription stimulant use and misuse that I consider in this article. Importantly, the prevalence of ADHD is estimated to be between 5% and 10% in American children and 2.8% and 5.2% in adults, yet the prevalence of non-medical use (NMU) of stimulants is estimated to exceed that of the very condition(s) for which they are indicated.10,11,1620 If prescription stimulants are more prevalent among the population than the condition(s) they are prescribed for, clinicians and epidemiologists should know what to look for when future patients without documented ADHD present with symptoms of dopaminergic and noradrenergic pathology. The same is true for those with a history of ADHD treatment, although historical stimulant use would hopefully be documented. Similar to medications approved for any variety of condition, NMU of stimulants indicated for ADHD is associated with a variety of adverse effects, and the potential for serious harm in the long term remains poorly characterized.21 This article includes a brief primer on ADHD etiology and pathophysiology; considers the current state of NMU epidemiology; reviews the mechanisms of action of AMP and MPH; and, finally, summarizes known molecular and clinical manifestations of AMP and MPH neurotoxicity.

Primer on ADHD Etiology and Pathophysiology

ADHD (previously called attention-deficit disorder) is characterized by pervasive cognitive, behavioral, and emotional dysfunction.4,22 There are three clinical presentations of ADHD classified in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; Table 2), with the combined presentation being the most prevalent (62%).23 Although roughly 75% of the risk for ADHD is attributed to genetics, large genome-wide association studies have been mostly unsuccessful in convincingly detecting DNA polymorphisms specifically associated with ADHD.2,20,24 Thankfully, this may be changing as recent work has found variants on FOXP2, SORCS3, and DUSP6, among other genes, to be associated with a 1.077 to 1.198 increased odds of ADHD development.25 Variants of genes involved in dopamine transmission, DRD4, DRD5, COMT, and DAT1, among others, have been shown to be associated with ADHD, providing evidence for the catecholamine dysregulation hypothesis of ADHD.2,24,2631 Norepinephrine (NE) signaling is believed to be attenuated alongside dopamine (DA) in ADHD, which is likely the reason the NE reuptake inhibitor atomoxetine alleviates ADHD symptoms in some with the condition.27,3234 Inhibition of neurotransmitter transporters, a mechanism of action of both AMP and MPH, prevents presynaptic reuptake of DA and NE molecules, thus allowing post-synaptic receptors greater access to their respective ligands.3537 The greater effectiveness of AMP and MPH compared to atomoxetine in individuals with ADHD is likely due to the frequent functional and anatomical changes seen in dopamine transport (DAT) in dopaminergic regions such as the frontal cortex, striatum, and basal ganglia compared to noradrenergic regions.1,3842 Serotonergic, acetylcholinergic, opioid, and glutamatergic signaling pathways are implicated in the pathophysiology of ADHD, as well, but current pharmacotherapeutic options target mainly NE and DA.43,44 As the etiology of ADHD is not unitary, it is likely that causal pathways will be interactive and dynamic; genetic, structural, functional, environmental, and social factors each appear to contribute to ADHD pathophysiology.45 Importantly, though the mechanisms of action of stimulants are identical in those with and without ADHD, their known outcomes are not.18,42,46

Table 2.

DSM-5 Diagnostic Criteria for ADHD by Presentation

Presentation DSM-5 diagnostic criteria
(≥ 5 of the following for at least 6 months in adults)
Predominantly inattentive • Frequent failure to pay attention to detail in work, academic, or social settings
• Difficulty sustaining attention in tasks or play activities
• Frequently fails to listen when spoken to directly
• Difficulty managing and organizing tasks and activities
• Tends to avoid tasks requiring sustained mental effort
• Frequently loses materials necessary for daily tasks
• Easily distracted by extraneous stimuli
• Often forgetful of daily activities
Combined • Shows characteristics of inattentive and hyperactive/impulsive presentations
Predominantly hyperactive/ impulsive • Frequent fidgeting, tapping, or squirming
• Often leaves task at hand when attention is expected
• Often restless
• Struggles to play or engage in restful activities
• Seems to be constantly moving or unable to sit still for extended periods of time
• Talks more than expected
• Tends to blurt out answers before question is finished
• Often interrupts others
Has trouble waiting in line


PubMed was used to search the literature for English-language articles published between 2005 and April 2020. The cutoff year of 2005 was selected as the novel Adult ADHD Self-Report Scale, version 1.1, the first adequate instrument used in the assessment of adult ADHD symptomatology, entered use in the World Health Organization’s World Mental Health Survey Initiative that year.47 Search terms including ADHD, attention deficit hyperactivity disorder, amphetamine, and methylphenidate were used alone and in combination with toxicity, epidemiology, adverse effects, etiology, pharmacology, and/or misuse. The additional filters of journal article and review were used to identify peer-reviewed articles addressing amphetamine and/or methylphenidate toxicology, misuse, and pharmacology, as well as ADHD treatment, etiology, pathophysiology, and epidemiology. The reference lists of retrieved articles were regularly hand-searched for other relevant reviews, trials, or original research to identify additional records for use. Titles, abstracts, and full texts that resulted from keyword searches were reviewed briefly to determine topical relevance, and the journal an article was published in was checked for quality using InCites Journal Citation Reports and/or Google Scholar Metrics. Individual articles were rated for quality using the McMaster University Effective Public Health Practice Project tool when deemed appropriate.48 To reduce the number of publications to review, the most up-to-date review papers were used whenever possible. Publications were selected according to professional judgment of quality, relevance to MPH/AMP toxicology or pharmacology, and whether findings had clinical relevance. Older publications, such as a 1981 report on MPH hallucinosis, were included when necessary.49

Exclusion of an article occurred if (1) it pertained to ADHD comorbid with a diagnosed psychiatric or developmental disorder (eg, autism spectrum disorder, obsessive-compulsive disorder, mood disorder), (2) concerned the effectiveness of ADHD interventions used outside mainstream medicine (eg, fish oil, ginger), (3) pertained to toxicity profiles beside neurological, (4) focused on psychosocial management of ADHD, or (5) concerned ADHD secondary to some other medical condition. The PRISMA flow diagram for this review’s selection procedure is presented in Figure 1.50 After applying inclusion and exclusion criteria and hand-searching reference lists from important articles in the literature, a total of 488 articles were considered for review. Of the 5006 articles initially yielded during the search, 114 were used in authoring this article.

Figure 1.
Figure 1. Flow Diagram of Records Identified, Screened, and Included.

*Excluded due to topical irrelevance, low publication quality, or publication type

Non-Medical Use Epidemiology

Recognition by the psychiatric and behavioral medicine communities that ADHD persists into adulthood in at least a large proportion of cases has increased subsequent availability of stimulant medications in the adult population.51 Given the strong motivation by young adults (aged 18 to 25 years)—many of whom are in college—to perform well academically, the positive effects on cognitive functioning in those who use stimulants for ADHD are plausibly expected to produce similar effects in anyone who uses them. As stimulant medications are known to boost working memory, processing speed, sociability, attention, etc in patients with ADHD, the average individual engaging in NMU simply (and erroneously) expects those clinical benefits to translate into improved test scores, more hours spent studying, and cognitive stamina.26

Misuse of stimulants, defined as the NMU of prescription medications used to treat ADHD and other conditions, is especially prevalent on American college campuses.52 American young adults misuse prescription stimulants significantly more frequently each year compared to the general adult population.19,5355 Prescription stimulants are reported to be easily accessible on college campuses, and, as neural networks underlying decision-making and risk assessment are not fully mature until the mid-twenties, so is the tendency to experiment with stimulants or other substances for perceived benefit.5658 Young adulthood is the period wherein addiction and neuropsychiatric conditions are most likely to become symptomatic, making experimentation with powerful prescription medications and psychotropic substances rife with potential danger.56 Alarmingly, the results of the 2018 National Survey on Drug Use and Health (NSDUH) showed that stimulant misuse eclipsed opioid misuse for the second year in a row, with 6.5% and 5.5% of young adults between 18 and 25 years of age misusing stimulants and opioids, respectively.59

Most non-medical users of stimulants report obtaining the medication from their family, friends, or peers.18,19,60 Interestingly, though effective long-term pharmacological management of ADHD is associated with overall decreased odds of developing a substance use disorder,6163 between 4% and 35% of college students diagnosed with ADHD report previous NMU of their medication.18 Using data published between 2005 and 2019, I calculated the pooled prevalence of NMU among Americans aged 18 to 25 years, regardless of their educational status (Table 3). Although estimates ranged from 2% to 31%,60,85 the estimated mean pooled prevalence of NMU among American young adults, including college students, is 9.21% (Table 3). The 2018 NSDUH found that compared to adults aged 26 years and older, young adults reported NMU between 3 times and 4 times more frequently.59 Furthermore, Compton, the deputy director of the NIDA, and colleagues recently found young adults to have roughly 5 times the odds of initiating NMU than older adults.19,59 Whether there is a statistically significant trend toward higher prevalence of NMU among the young adult population is difficult to ascertain given the wide range of estimates in the literature and lack of uniform measurement method. Although the NSDUH found a relatively stable 4-year prevalence of NMU among young adults, peer-reviewed publications almost uniformly vary from the official reports.59 It is unclear why a complete picture of NMU among young adults has remained so elusive. Perhaps this is due to geographical differences or cultural idiosyncrasies among individual college campuses. Furthermore, this variance is multifactorial: definitions (or lack thereof ) of NMU, sample size, classification of drugs, and methodology tend to differ from one study to the next.

Table 3.

NMU Prevalence in Young Adults (including college students) Reported Between 2005 and 2019

Source N Prevalence
Teter et al, 2005 9161 5.4%
Teter et al, 2006 4580 5.9%
Lord et al, 2009 950 5.0%
Weyandt et al, 2009 363 8.9%
Upadhyaya et al, 2010 3307 2.1%
Rabiner et al, 2010 3407 8.9%
Clegg-Kraynok et al, 2011 492 7.0%
Garnier-Dykstra et al 2012 1253 17.7%
Lookatch et al, 2012 206 26.1%
Bavarian et al, 2013 520 25.6%
Hartung et al, 2013 1153 25.9%
Webb et al, 2013 144 15.0%
Wasserman et al, 2014 380 15.2%
Messina et al, 2014 1016 25.4%
Meisel & Goodie, 2015 279 17.2%
Cassidy et al, 2015 2073 11.3%
Gallucci et al, 2015 1020 12%
Weyandt et al, 2016 807 5.9%
Bavarian et al, 2017 554 16.6%
Kinman et al, 2017 988 23%
McCabe et al, 2018 4004 7.3%
Le et al, 2018 939 11.4%
Schulenberg et al, 2019 900 8.3%
Pooled Prevalence 38,496 9.21%

Mechanisms of Action

The therapeutic effect of stimulants provides for greater attention to tasks at hand, access to working memory, planning, reward processing, and other relevant tasks that constitute executive functioning.7 The two neurotransmitters associated with executive functioning, DA and NE, are highly concentrated in the prefrontal cortex (PFC) and act intimately in tandem. AMP and MPH are known to enhance DA and NE neurotransmission in the PFC by increasing synaptic availability of DA and NE.43,45,86 Interestingly, the mechanisms of action of AMP and MPH differ: MPH is a strong inhibitor of presynaptic dopamine transporters (DAT) and weak inhibitor of norepinephrine transporters, whereas AMP competitively inhibits DAT and norepinephrine transporters, increases DA release by inhibiting vesicular monoamine transporter 2, and blocks monoamine oxidase breakdown of DA and NE.43 The product of both drugs, though, is the aforementioned amplified concentration of stimulatory neurotransmitters in the synaptic cleft and availability for use.14 See Figure 2 for a simplified visual depiction of AMP and MPH mechanisms of action.

Figure 2.
Figure 2.

The schematic on the left depicts baseline DA and NE transmission. Much of the DA/NE undergoes reuptake into the presynaptic terminal, where it undergoes break- down by monoamine oxidase (MAO), repackaging, or sequestration. The DA/NE that does make it into the synapse binds its respective receptor. AMP and MPH are the shown on the right. AMP can diffuse through the cell membrane, where it can bind MAO and transporters. It can also bind to DAT’s, MPH, on the other hand, is a strong inhibitor of NET’s.

The therapeutic effect of AMP and MPH is dependent upon the rate of release, the dose, and the duration of activity of the formulation.14,87 This therapeutic effect has an inverted U-shape: up to a point, the increased DA and NE that results from stimulant medications normalizes PFC neuronal activity and dysfunctional executive functioning seen in ADHD, but excessive DA and NE results in neuronal death, impaired inhibitory signaling, and downstream behavioral consequences.8890 Therapeutic formulations of MPH and AMP include extended-release and immediate-release and are designed to act along this U-shaped dose-response curve. Interestingly, the d-isomer of both AMP and MPH has more potent binding potential than the l-isomer for their respective receptors of interest.87 Because d-AMP, the isoform most active in common pharmaceutical AMP, blocks reuptake of DA and increases DA and NE neuronal firing at therapeutic doses,43,87,91,92 clinicians should be aware of AMP’s broad activity across the brain.14 This is especially true in those engaging in NMU, who commonly use supratherapeutic doses.85,93,94 Although meta-analyses have shown MPH and AMP to produce comparable benefits in executive functioning, the two have subtly different mechanisms of action.95,96 Like AMP, the d-isoform of MPH is the most active form, specifically binding PFC and striatal DAT in a dose-dependent relationship.97 This pharmacokinetic similarity explains the shared increases in extracellular DA and NE seen, although MPH also agonizes 5-HT1A.43 Adrenergic receptors are activated, thus encouraging cortical excitability; guanfacine and clonidine, two non-stimulant medications used in ADHD management, have been shown to elicit similar effects.98 MPH, in a fashion analogous to cocaine but not AMP, does not act directly as a DA/NE reuptake inhibitor; rather, MPH acts as an inverse agonist of DAT and NE transporters.99 Lastly, as mentioned previously, MPH inhibits DAT to a greater extent than AMP and thus indirectly increases dopaminergic and noradrenergic transmission.43,97

Molecular and Clinical Manifestations of AMP/MPH Neurotoxicity


Most individuals engaging in NMU of AMP experience rapid sensitization. This is due to upregulation of DAT to accommodate unnatural synaptic DA concentrations, and therefore greater doses of AMP are required to achieve the sought-after euphoric effect with each subsequent dose.100 It is believed that behavioral reinforcement of euphoria, as well as sensitization (necessitating higher doses for effect),101 is regulated by the nucleus accumbens (NAcc), the region of the brain most associated with reward processing, pleasure sensation, and other behavioral processes associated with addiction.43 As dose increases beyond the therapeutic range, neurotoxic effects of greater DA concentrations begin to unfold in dopaminergic regions such as the NAcc, PFC, and the structures along the mesolimbic pathway.102 With chronic high-dose (ie, supratherapeutic) stimulant use comes alterations in dopamine receptors 2 and 3, presynaptic DA release and synthesis, and postsynaptic DAT availability, indicating a general attenuation of dopaminergic circuits.43,88,100,103 In animal models, this is hypothesized to be the result of neuronal death due to oxidative stress.104,105 In order to reach the euphoric effect many individuals seek by NMU, continued dose increases are necessary to break through tolerance, and, as the DA circuitry is already damaged, NMU escalation adds fuel to the fire. The rare psychoses reported among those who use stimulants appropriately, as well as the relatively common ones reported in non-medical users, are thought to arise from uncontrolled excitatory signaling resulting from aforementioned impairments in inhibitory signaling.88 It is hypothesized that to compensate for toxic DA concentrations, affected neurons decrease their DA receptor and transporter availability to prevent subsequent excitatory overstimulation.100 The downstream effect of this protective mechanism—diminished overall DA availability—results in neuropsychological dysfunction.


Unlike AMP, MPH’s effects on DA and NE are due also to disinhibition of dopamine receptor 2 and activation of dopamine receptor 1.43 In a murine model, chronic high-dose MPH exposure (10 mg/kg daily for 12 weeks) has been associated with increased oxidative stress in nigrostriatal dopaminergic neurons, specifically due to heightened sensitivity to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).106 MPTP is a strong substrate for the DA receptor and is tightly linked to the etiology and pathophysiology of Parkinson disease (PD).107 Oakes and colleagues at East Tennessee State University recently described a dose-dependent elevation in striatal dopaminergic neuronal DA-quinone production with chronic MPH exposure in a murine model.108 As the neuroimmune cascade is activated by oxidative stress, glutathione conjugates with the DA-quinone and sequesters it. Unfortunately, as glutathione reserves are depleted by chronic use, greater oxidative stress occurs. Although the majority of the literature regarding stimulant-induced neurotoxicity has focused on AMP, it is likely that the differential mechanisms of MPH-induced boosts in catecholamine concentration require specific investigation. This is salient given the differential effects of MPTP on dopaminergic neurons exposed to MPH compared to AMP. Whether MPH differs from AMP in its proclivity to actually induce Parkinsonism in individuals with ADHD or non-medical users has yet to be assessed. Clinicians should consider available evidence from animal and epidemiological studies of MPH-induced neuropathology when choosing appropriate treatment for ADHD, especially if the patient has a family history of PD.


The most common clinical manifestations of AMP NMU-induced neurotoxicity include stroke, Parkinsonism, seizure, and psychosis.109 As the mechanism of action of methamphetamine is very similar to that of AMP,110 many of the potential adverse effects of methamphetamine use are liable in AMP NMU. The risk for hemorrhagic stroke, but not ischemic stroke, is increased between 5- and 7-fold among stimulant users under 45 years of age compared to those who do not use.109 Acute cerebrovascular effects (eg, hypertension, tachycardia, cerebral vasospasm) and chronic use-induced effects (eg, apoptosis of vascular smooth muscle, atherosclerosis, inflammatory vascular processes) of stimulants have been reported to put users at increased later risk for arrhythmias and resultant thromboembolism.109 PD is thought to result from reduced striatal DA, DAT, and morphological defects in dopaminergic neurons.111 Given AMP NMU is observed to result in what are morphological precursors to PD, the increased risk (1.5–3 times) and earlier onset (median of 6 years) of PD among those who use high-dose stimulants is understandable.109,112 The acutely augmented concentrations of DA associated with AMP NMU are also associated with lower concentrations of gamma-aminobutyric acid—the neurotransmitter involved in regulating excitatory and inhibitory signaling in the brain—and may lower seizure threshold.113

Finally, the occurrence of psychosis in those using AMP (2.4%) and the high prevalence of AMP-induced episodic psychoses’conversion to schizophrenia (~33%) are clinically salient.114,115 Acute psychosis, though dynamic and complex, has long been associated with overactive DA signaling and transport.116 The pathophysiology of ADHD, as mentioned above, also involves dysregulation of DA. Granted, the correlation between DA and ADHD symptomatology is inverted in psychosis, but individual risk factors are not infrequently shared between psychiatric disorders. Supratherapeutic doses common to NMU are able to manifest psychotic symptoms, but the normalizing influence therapeutic AMP has on ADHD-associated DA signaling makes psychosis exceedingly rare in patients with ADHD.117 In the context of specifically AMP-induced psychosis, repeated use of high-dose stimulants in both therapeutic and misuse contexts is associated with greater blood-brain barrier porosity and tight-junction dysfunction.118 Interestingly, AMP is associated with a 4-fold greater DA release compared to MPH, which likely contributes to the greater probability of AMP- than MPH-induced psychosis.119 The treatment of both AMP-induced and organic psychoses involves dopamine receptor 2 blockade with antipsychotics with the intention to decrease overactive dopamine and associated transmission.115,116 Interestingly, many patients who benefit from DA blockade report adverse effects similar to ADHD symptoms: diminished subjective well-being, self-control, and cognitive functioning, as well as lethargy and emotional dysregulation.120,121


MPH and AMP neurotoxicity is quite similar at the molecular level. This similarity can be mapped onto clinical outcomes, as well, with the important exception of psychosis. Moran and colleagues recently reported results from a large cohort study of individuals using MPH and AMP for ADHD.119 They found a 10-year incidence of 1.78 new psychotic episodes per 1000 person-years in those taking MPH compared to 2.83 new episodes per 1000 person-years in those taking AMP. The risk for stimulant-induced psychosis during the study period was also significantly attenuated in MPH-treated compared to AMP-treated patients (0.10% and 0.21%, respectively).119 Interestingly, there also appears to be a greater risk for psychosis in patients treated with AMP by physicians without psychiatric training when compared to those treated by board-certified psychiatrists.119 This highlights potential implications for the management of ADHD by primary care physicians and questions whether primary care should be the setting wherein ADHD is diagnosed, treated, and followed.


The NMU of stimulants by healthy adults leads to mixed results at best and significant decreases in neuropsychological performance at worst.46,122124 Much to the chagrin of healthy college students looking for a leg up, college grade point average and NMU are inversely correlated.71, 123 Attention, inhibitory control, short-term episodic memory, and delayed episodic memory may be slightly positively affected by NMU, but cognitive functions such as working memory are worsened.122 Concerningly, students reporting their NMU in research settings fail to perceive that their use of stimulants carries risk of adverse effects or that NMU fails to produce positive changes that are worth the risk. It is therefore unlikely that deleterious neuropsychological and neurotoxic outcomes are being considered by those who engage in NMU. In contrast to NMU, the employment of prescription stimulants for ADHD is thought to be safe and effective for at least the short term.11 Upregulation of DAT, normalization of structural abnormalities, and increased striatal DA availability are associated with long-term treatment with MPH in individuals with ADHD.7,125 Working memory, response inhibition, and reaction time—domains commonly affected by ADHD—are reported to be positively impacted behavioral responses to the molecular and structural changes associated with treatment.7,126

The prevalence of prescription stimulant misuse in the adult population is deeply concerning at both the public health and clinical levels. This is compounded by the fact that the epidemiologic studies included in this review do not report a uniform estimated NMU prevalence. This may indicate a weak grasp by the public health community on the problem of stimulant NMU. Consideration of the stage of neurodevelopment that many adults reporting NMU are in, as well as the general dearth of literature considering long-term therapeutic use and NMU of prescription stimulants, will likely be of paramount importance to future clinicians treating ADHD and the potential negative sequelae of stimulant use. Future public health and clinical education should be augmented to include stimulant misuse trends and outcomes as practitioners in both arenas will likely encounter its effects as the population ages.127 As clinician societies and government agencies begin requiring drug manufacturers to consider long-term effectiveness in their stimulant medications, it is likely ADHD pharmacotherapy will evolve.

With the exception of just two large-scale studies—the Multimodal Treatment Study of Children With ADHD and the Comparison of Methylphenidate and Psychotherapy in Adult ADHD Study (COMPAS)—the consideration of pharmacotherapy’s potential benefits and risks for patients long term remains wholly inadequate.128130 For better or worse, current guidelines leave the formulation and dose of medication prescribed open to interpretation by clinicians.14 The precarious state of ADHD treatment was recently debated in the Journal of the American Academy of Child and Adolescent Psychiatry.131,132 Swanson,132 a University of California, Irvine professor of pediatrics and a principal investigator on the COMPAS, recently reported that the impressive effect sizes, symptom reduction, and behavioral outcomes associated with short-term pharmacotherapy have not conclusively been demonstrated to be maintained in the long term. In response to Swanson, Coghill,131 a renowned child/adolescent psychiatrist and scientist at the University of Melbourne, wrote that current trials continue to find that long-term pharmacotherapy is indeed effective when used dynamically, pragmatically, and subject to new clinical insights. Coghill’s argument was reinforced by two studies recently published in the American Journal of Psychiatry: one finding sustained MPH effectiveness over 2 years in pediatric ADHD and the other finding inverse associations between long-term treatment and risk for suicide and substance abuse, among other outcomes.133,134

Parallel to substantive change to the ADHD management landscape, long-term, robust exploration of differences in outcomes between individuals who begin treatment in adulthood versus childhood, potential unknown neurological outcomes in the contexts of both NMU and ADHD, and prescription stimulant toxicology is urgently needed. Questions related to long-term, consistent treatment with medication across the life span remain wide open to evidence-based and individualized study and conclusions, although the clinical recommendations in the DSM-5 remain the gold standard given the current state of treatment options. Lastly, though this review of the literature is comprehensive, there are many basic unknowns concerning the relationship between prescription stimulants and neurotoxicity.


This narrative review presented the current understanding of prescription stimulant–induced neurotoxicity in both licit and illicit categories found in the literature. Although the sparse data available suggest long-term treatment of ADHD to be associated with positive outcomes in educational, social, psychological, and emotional domains, it is unclear whether this is due to the medications’ continued action or the development of coping mechanisms over time. Additionally, as much the same for individuals engaged in NMU of MPH and AMP, future work is needed to measure the risks to and outcomes in neurological functioning and safety in those being treated for ADHD. It is also important to note that, though a comprehensive range of publications was considered for use in this review, the sheer number of records available made universal consideration impossible. Finally, beyond the clinical monitoring and treatment of potential sequelae, the public health and clinical communities must play a significantly more engaged role in educating the public about the proper use of stimulants—especially if we aim to prevent increased presentation of prescription stimulant neurotoxicity in the future.


  1. (((amphetamine OR methylphenidate)) AND (ADHD OR attention deficit hyperactivity disorder)) AND (treatment OR epidemiology OR adverse effects OR pathophysiology OR etiology) - 5576

  2. (((amphetamine OR methylphenidate)) AND (ADHD OR attention deficit hyperactivity disorder)) AND (treatment OR epidemiology OR adverse effects OR pathophysiology OR etiology) AND (English[lang]) - 5228

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  8. Search ((((((((amphetamine or methylphenidate)) AND (ADHD or attention deficit hyperactivity disorder)) AND (treatment or epidemiology or adverse effects or pathophysiology or etiology)) AND (( Journal Article[ptyp] OR Review[ptyp]) AND English[lang])) AND ( Journal Article[ptyp] OR Review[ptyp]) AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang]) AND (( Journal Article[ptyp] OR Review[ptyp]) AND hasabstract[text] AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang] AND (jsubsetaim[text] OR medline[sb])))) NOT (infant or trauma or driving or pregnancy or comorbid or autism or natural or adjunct or complementary or supplement or mineral or herbal or vitamin or intellectual or disability) Sort by: Best Match Filters: Journal Article; Review; Full text; Publication date from 2005/01/01; English; Core clinical journals; MEDLINE - 1992

  1. (((amphetamine or methylphenidate or central nervous system stimulant)) AND (toxicology or pharmacology or abuse or misuse)) - 96359

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  3. (((amphetamine or methylphenidate or central nervous system stimulant)) AND (toxicology or pharmacology or abuse or misuse)) AND ( Journal Article[ptyp] OR Review[ptyp]) AND English[lang] - 84789

  4. (((amphetamine or methylphenidate or central nervous system stimulant)) AND (toxicology or pharmacology or abuse or misuse)) AND ( Journal Article[ptyp] OR Review[ptyp]) AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang] - 31575

  5. (((amphetamine or methylphenidate or central nervous system stimulant)) AND (toxicology or pharmacology or abuse or misuse)) AND ( Journal Article[ptyp] OR Review[ptyp]) AND hasabstract[text] AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang] - 30749

  6. (((amphetamine or methylphenidate or central nervous system stimulant)) AND (toxicology or pharmacology or abuse or misuse)) AND ( Journal Article[ptyp] OR Review[ptyp]) AND hasabstract[text] AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang] AND (jsubsetaim[text] OR medline[sb]) – 30117

  7. ((((((amphetamine or methylphenidate or central nervous system stimulant)) AND (toxicology or pharmacology or abuse or misuse))) AND (( Journal Article[ptyp] OR Review[ptyp]) AND hasabstract[text] AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang] AND (jsubsetaim[text] OR medline[sb])))) NOT (infant or trauma or driving or pregnancy or comorbid or autism or natural or adjunct or complementary or supplement or mineral or herbal or vitamin or intellectual or disability) AND ( Journal Article[ptyp] OR Review[ptyp]) AND hasabstract[text] AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang] AND (jsubsetaim[text] OR medline[sb]) - 23279

    Search ((((((((amphetamine or methylphenidate or central nervous system stimulant)) AND (toxicology or pharmacology or abuse or misuse))) AND (( Journal Article[ptyp] OR Review[ptyp]) AND hasabstract[text] AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang] AND (jsubsetaim[text] OR medline[sb])))) NOT (infant or trauma or driving or pregnancy or comorbid or autism or natural or adjunct or complementary or supplement or mineral or herbal or vitamin or intellectual or disability)) AND (( Journal Article[ptyp] OR Review[ptyp]) AND hasabstract[text] AND (“2005/01/01”[PDat]: “3000/12/31”[PDat]) AND English[lang] AND (jsubsetaim[text] OR medline[sb]))) Sort by: Best Match Filters: Journal Article; Review; Full text; Publication date from 2005/01/01; English; Core clinical journals; MEDLINE - 22750


I am deeply grateful for the scholarly guidance and encouragement of Dr. Justin A. Colacino, PhD, MA, MPH (University of Michigan School of Public Health). I also want to thank Dr. Sean E. McCabe, PhD (University of Michigan School of Nursing) for his inspiring intellectual and expert opinion, suggestions, and resourcefulness. I am thankful for the aid of Dr. Matthew S. Zawistowski, PhD (University of Michigan School of Public Health) in data manipulation. Finally, I want to thank Dr. Alfred Franzblau, MD (University of Michigan School of Public Health) for his mentorship.


The author has no conflicts of interest to report.


Heal, DJ, Smith, SL, Gosden, J, Nutt, DJ. Amphetamine, past and present—a pharmacological and clinical perspective. J Psychopharmacol. 2013; 27(6):479–496. doi:10.1177/0269881113482532

Gallo, EF, Posner, J. Moving towards causality in attention-deficit hyperactivity disorder: overview of neural and genetic mechanisms. Lancet Psychiatry. 2016; 3(6):555–567. doi:10.1016/S2215-0366(16)00096-1

Bellani, M, Moretti, A, Perlini, C, Brambilla, P. Language disturbances in ADHD. Epidemiol Psychiatr Sci. 2011; 20(4):311–315. doi:10.1017/S2045796011000527

American Psychiatric Association. DSM-5 diagnostic classification. In: Diagnostic and Statistical Manual of Mental Disorders. 5th ed. American Psychiatric Association; 2013. doi:10.1176/appi.books.9780890425596.x00diagnosticclassification

Wolraich, ML, Hagan, JF, Allan, C, Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2019; 144(4):e20192528. doi:10.1542/peds.2019-2528

Volkow, ND, Swanson, JM. Clinical practice: adult attention deficit-hyperactivity disorder. N Engl J Med. 2013; 369(20):1935–1944. doi:10.1056/NEJMcp1212625

Mahone, EM, Denckla, MB. Attention-deficit/hyperactivity disorder: a historical neuropsychological perspective. J Int Neuropsychol Soc. 2017; 23(9–10 special issue):916–929. doi:10.1017/S1355617717000807

Posner, J, Polanczyk, GV, Sonuga-Barke, E. Attention-deficit hyperactivity disorder. Lancet. 2020; 395(10222):450–462. doi:10.1016/S0140-6736(19)33004-1

Uchida, M, Spencer, TJ, Faraone, SV, Biederman, J. Adult outcome of ADHD: an overview of results from the MGH longitudinal family studies of pediatrically and psychiatrically referred youth with and without ADHD of both sexes. J Atten Disord. 2018; 22(6):523–534. doi:10.1177/1087054715604360

Chan, E, Fogler, JM, Hammerness, PG. Treatment of attention-deficit/hyperactivity disorder in adolescents: a systematic review. JAMA. 2016; 315(18):1997–2008. doi:10.1001/jama.2016.5453

Young, JL, Goodman, DW. Adult attention-deficit/hyperactivity disorder diagnosis, management, and treatment in the DSM-5 era. Prim Care Companion CNS Discord. 2016; 18(6). doi:10.4088/PCC.16r02000

Mattingly, GW, Wilson, J, Rostain, AL. A clinician’s guide to ADHD treatment options. Postgrad Med. 2017; 129(7):657–666. doi:10.1080/00325481.2017.1354648

Briars, L, Todd, T. A review of pharmacological management of attention-deficit/hyperactivity disorder. J Pediatr Pharmacol Ther. 2016; 21(3):192–206. doi:10.5863/1551-6776-21.3.192

Childress, AC, Komolova, M, Sallee, FR. An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations. Expert Opin Drug Metab Toxicol. 2019; 15(11):937–974. doi:10.1080/17425255.2019.1675636

Rasmussen, N. Amphetamine-type stimulants: the early history of their medical and non-medical uses. Int Rev Neurobiol. 2015; 120:9–15. doi:10.1016/bs.irn.2015.02.001

Xu, G, Strathearn, L, Liu, B, Yang, B, Bao, W. Twenty-year trends in diagnosed attention-deficit/hyperactivity disorder among US children and adolescents, 1997–2016. JAMA Netw Open. 2018; 1(4):e181471. doi:10.1001/jamanetworkopen.2018.1471

Thapar, A, Cooper, M. Attention deficit hyperactivity disorder. Lancet. 2015; 387(10024):1240–1250. doi:10.1016/S0140-6736(15)00238-X

Faraone, SV, Rostain, AL, Montano, CB, Mason, O, Antshel, KM, Newcorn, JH. Systematic review: nonmedical use of prescription stimulants: risk factors, outcomes, and risk reduction strategies. J Am Acad Child Adolesc Psychiatry. 2020; 59(1):100–112. doi:10.1016/j.jaac.2019.06.012

Compton, WM, Han, B, Blanco, C, Johnson, K, Jones, CM. Prevalence and correlates of prescription stimulant use, misuse, use disorders, and motivations for misuse among adults in the United States. Am J Psychiatry. 2018; 175(8):741–755. doi:10.1176/appi.ajp.2018.17091048

Wolraich, ML, Chan, E, Froehlich, T, ADHD diagnosis and treatment guidelines: a historical perspective. Pediatrics. 2019; 144(4):e20191682. doi:10.1542/peds.2019-1682

McCabe, SE, Veliz, P, Wilens, TE, Schulenberg, JE. Adolescents’ prescription stimulant use and adult functional outcomes: a national prospective study. J Am Acad Child Adolesc Psychiatry. 2017; 56(3):226–233.e4. doi:10.1016/j.jaac.2016.12.008

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. American Psychiatric Association; 1980.

Wilens, TE, Biederman, J, Faraone, SV, Martelon, M, Westerberg, D, Spencer, TJ. Presenting ADHD symptoms, subtypes, and comorbid disorders in clinically referred adults with ADHD. J Clin Psychiatry. 2009; 70(11):1557–1562. doi:10.4088/JCP.08m04785pur

Bonvicini, C, Faraone, SV, Scassellati, C. Attention-deficit hyperactivity disorder in adults: a systematic review and meta-analysis of genetic, pharmacogenetic and biochemical studies. Mol Psychiatry. 2016; 21(7):872–884. doi:10.1038/mp.2016.74

Demontis, D, Walters, RK, Martin, J, Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder. Nat Genet. 2019; 51(1):63–75. doi:10.1038/s41588-018-0269-7

Faraone, SV, Asherson, P, Banaschewski, T, Attention-deficit/hyperactivity disorder. Nat Rev Dis Primers. 2015; 1:15020. doi:10.1038/nrdp.2015.20

Sharma, A, Couture, J. A review of the pathophysiology, etiology, and treatment of attention-deficit hyperactivity disorder (ADHD). Ann Pharmacother. 2014; 48(2):209–225. doi:10.1177/1060028013510699

Mereu, M, Contarini, G, Buonaguro, EF, Dopamine transporter (DAT) genetic hypofunction in mice produces alterations consistent with ADHD but not schizophrenia or bipolar disorder. Neuropharmacology. 2017; 121:179–194. doi:10.1016/j.neuropharm.2017.04.037

Franke, B, Faraone, SV, Asherson, P, The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry. 2012; 17:960–987. doi:10.1038/mp.2011.138

Faraone, SV, Larsson, H. Genetics of attention deficit hyperactivity disorder. Mol Psychiatry. 2019; 24:562–575. doi:10.1038/s41380-018-0070-0

Montarolo, F, Martire, S, Perga, S, NURR1 deficiency is associated to ADHD-like phenotypes in mice. Transl Psychiatry. 2019; 9(1):207. doi:10.1038/s41398-019-0544-0

Spencer, RC, Devilbiss, DM, Berridge, CW. The cognition-enhancing effects of psychostimulants involve direct action in the prefrontal cortex. Biol Psychiatry. 2015; 77(11):940–950. doi:10.1016/j.biopsych.2014.09.013

Arnsten, AFT, Pliszka, SR. Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/hyperactivity disorder and related disorders. Pharmacol Biochem Behav. 2011; 99(2):211–216. doi:10.1016/j.pbb.2011.01.020

Di Miceli, M, Gronier, B. Psychostimulants and atomoxetine alter the electrophysiological activity of prefrontal cortex neurons, interaction with catecholamine and glutamate NMDA receptors. Psychopharmacology (Berl). 2015; 232(12):2191–2205. doi:10.1007/s00213-014-3849-y

Aggarwal, S, Mortensen, OV. Overview of monoamine transporters. Curr Protoc Pharmacol. 2017; 79 12.16.1–12.16.17. doi:10.1002/cpph.32

Wilens, TE. Mechanism of action of agents used in attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2006; 67(suppl 8):32–38.

Vaughan, RA, Foster, JD. Mechanisms of dopamine transporter regulation in normal and disease states. Trends Pharmacol Sci. 2013; 34(9):489–496. doi:10.1016/

Devilbiss, DM, Berridge, CW. Cognition-enhancing doses of methylphenidate preferentially increase prefrontal cortex neuronal responsiveness. Biol Psychiatry. 2008; 64(7):626–635. doi:10.1016/j.biopsych.2008.04.037

Xing, B, Li, Y-C, Gao, W-J. Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex. Brain Res. 2016; 1641(pt B):217–233. doi:10.1016/j.brainres.2016.01.005

Spencer, RC, Klein, RM, Berridge, CW. Psychostimulants act within the prefrontal cortex to improve cognitive function. Biol Psychiatry. 2012; 72(3):221–227. doi:10.1016/j.biopsych. 2011.12.002

Schmeichel, BE, Berridge, CW. Neurocircuitry underlying the preferential sensitivity of prefrontal catecholamines to low-dose psychostimulants. Neuropsychopharmacology. 2013; 38(6):1078–1084. doi:10.1038/npp.2013.6

Weyandt, LL, Marraccini, ME, Gudmundsdottir, BG, Misuse of prescription stimulants among college students: a review of the literature and implications for morphological and cognitive effects on brain functioning. Exp Clin Psychopharmacol. 2013; 21(5):385–407. doi:10.1037/a0034013

Faraone, SV. The pharmacology of amphetamine and methylphenidate: relevance to the neurobiology of attention-deficit/hyperactivity disorder and other psychiatric comorbidities. Neurosci Biobehav Rev. 2018; 87:255–270. doi:10.1016/j.neubiorev.2018.02.001

Cheng, J, Liu, A, Shi, MY, Yan, Z. Disrupted glutamatergic transmission in prefrontal cortex contributes to behavioral abnormality in an animal model of ADHD. Neuropsychopharmacology. 2017; 42(10):2096–2104. doi:10.1038/npp.2017.30

Brown, KA, Samuel, S, Patel, DR. Pharmacologic management of attention deficit hyperactivity disorder in children and adolescents: a review for practitioners. Transl Pediatr. 2018; 7(1):36–47. doi:10.21037/tp.2017.08.02

Wilens, TE, Carrellas, NW, Martelon, MK, Neuropsychological functioning in college students who misuse prescription stimulants. Am J Addict. 2017; 26(4):379–387. doi:10.1111/ajad.12551

Kessler, RC, Adler, L, Ames, M, The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005; 35(2):245–256. doi:10.1017/S0033291704002892

National Collaborating Centre for Methods and Tools. Quality assessment tool for quantitative studies. Effective Public Health Practice Project. McMaster University, Toronto.

Young, JG. Methylphenidate-induced hallucinosis: case histories and possible mechanisms of action. J Dev Behav Pediatr. 1981; 2(2):35–38. doi:10.1097/00004703-198106000-00003

Moher, D, Liberati, A, Tetzlaff, J, Altman, DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6(7):e1000097. doi:10.1371/journal.pmed.1000097

Lakhan, SE, Kirchgessner, A. Prescription stimulants in individuals with and without attention deficit hyperactivity disorder: misuse, cognitive impact, and adverse effects. Brain Behav. 2012; 2(5):661–677. doi:10.1002/brb3.78

DeSantis, A, Noar, SM, Webb, EM. Speeding through the frat house: a qualitative exploration of nonmedical ADHD stimulant use in fraternities. J Drug Educ. 2010. doi:10.2190/DE.40.2.d

Wilens, TE, Kaminski, TA. Prescription stimulants: from cognitive enhancement to misuse. Pediatr Clin North Am. 2019; 66(6):1109–1120. doi:10.1016/j.pcl.2019.08.006

Robitaille, C, Collin, J. Prescription psychostimulant use among young adults: a narrative review of qualitative studies. Subst Use Misuse. 2016; 51(3):357–369. doi:10.3109/10826084.2015.1110170

Grant, BF, Saha, TD, Ruan, WJ, Epidemiology of DSM-5 drug use disorder: results from the national epidemiologic survey on alcohol and related conditions-III. JAMA Psychiatry. 2016; 73(1):39–47. doi:10.1001/jamapsychiatry.2015.2132

Arain, M, Haque, M, Johal, L, Maturation of the adolescent brain. Neuropsychiatr Dis Treat. 2013; 9:449–461. doi:10.2147/NDT.S39776

Mui, HZ, Sales, P, Murphy, S. Everybody’s doing it: initiation to prescription drug misuse. J Drug Issues. 2014; 44(3):236–253. doi:10.1177/0022042613497935

Phillips, EL, McDaniel, AE. College Prescription Drug Study Key Findings Report. The Ohio State University; 2018.

Substance Abuse and Mental Health Services Administration. Key Substance Use and Mental Health Indicators in the United States: Results from the 2018 National Survey on Drug Use and Health. US Department of Health and Human Services; 2019.

Upadhyaya, HP, Kroutil, LA, Deas, D, Durell, TM, Van Brunt, DL, Novak, SP. Stimulant formulation and motivation for nonmedical use of prescription attention-deficit/hyperactivity disorder medications in a college-aged population. Am J Addict. 2010; 19(6):569–577. doi:10.1111/j.1521-0391.2010.00078.x

Quinn, PD, Chang, Z, Hur, K, ADHD medication and substance-related problems. Am J Psychiatry. 2017; 174(9):877–885. doi:10.1176/appi.ajp.2017.16060686

Upadhyay, N, Chen, H, Mgbere, O, Bhatara, VS, Aparasu, RR. The impact of pharmacotherapy on substance use in adolescents with attention-deficit/hyperactivity disorder: variations across subtypes. Subst Use Misuse. 2017; 52(10):1266–1274. doi:10.1080/10826084.2016.1273955

Asherson, P. Drug treatments for ADHD reduce risk of substance use disorders. Am J Psychiatry. 2017; 174(9):827–828. doi:10.1176/appi.ajp.2017.17070733

Teter, CJ, Esteban, S, Cranford, JA, Prevalence and motives for illicit use of prescription stimulants in an undergraduate student sample. J Am Coll Health. 2005. doi:10.3200/JACH.53.6.253-262

Teter, CJ, McCabe, SE, LaGrange, K, Illicit use of specific prescription stimulants among college students: Prevalence, motives, and routes of administration. Pharmacotherapy. 2006. doi:10.1592/phco.26.10.1501

Lord, S, Downs, G, Furtaw, P, Nonmedical use of prescription opioids and stimulants among student pharmacists. J Am Pharm Assoc. 2009. doi:10.1331/JAPhA.2009.08027

Weyandt, LL, Janusis, G, Wilson, KG, Nonmedical prescription stimulant use among a sample of college students: Relationship with psychological variables. J Atten Disord. 2009. doi:10.1177/1087054709342212

Rabiner, DL, Anastopoulos, AD, Costello, EJ, Predictors of nonmedical ADHD medication use by college students. J Atten Disord. 2010; 13(6):640–648. doi:10.1177/1087054709334505

Clegg-Kraynok, MM, McBean, AL, Montgomery-Downs, HE. Sleep quality and characteristics of college students who use prescription psychostimulants nonmedically. Sleep Med. 2011; 12(6):598–602.

Garnier-Dykstra, LM, Caldeira, KM, Vincent, KB, Nonmedical use of prescription stimulants during college: four-year trends in exposure opportunity, use, motives, and sources. J Am Coll Health. 2012; 60(3):226–234. doi:10.1080/07448481.2011.589876

Lookatch, SJ, Dunne, EM, Katz, EC. Predictors of nonmedical use of prescription stimulants. J Psychoact Drugs. 2012. doi:10.1080/02791072.2012.662083

Bavarian, N, Flay, BR, Ketcham, PL, Illicit use of prescription stimulants in a college student sample: A theory-guided analysis. Drug Alcohol Depend. 2013. doi:10.1016/j. drugalcdep.2013.04.024

Hartung, CM, Canu, WH, Cleveland, CS, Stimulant medication use in college students: Comparison of appropriate users, misusers, and nonusers. Psychol Addict Behav. 2013. doi:10.1037/a0033822

Wasserman, JA, Fitzgerald, JE, Sunny, MA, Nonmedical use of stimulants among medical students. J Osteopathic Med. 2014; 114(8).

Messina, BG, Silvestri, MM, Diulio, AR, Alcohol use, impulsivity, and the non-medical use of prescription stimulants among college students. Addict Behav. 2014;39(12).

Meisel, MK, Goodie, AS. Predicting prescription drug misuse in college students’ social networks. Addict Behav. 2015; 45.

Cassidy, TA, Varughese, S, Russo, L, Nonmedical use and diversion of ADHD stimulants among U.S. adults ages 18–49. J Atten Disord. 2015; 19(7).

Gallucci, AR, Usdan, SL, Martin, RJ, Pill popping problems: The non-medical use of stimulant medications in an undergraduate sample. Drugs Educ Prev Policy. 2014.

Weyandt, LL, Oster, DR, Marraccini, ME, Prescription stimulant medication misuse: Where are we and where do we go from here? Exp Clin Psychopharmacol. 2016. doi:10.1037/pha0000093

Bavarian, N, McMullen, J, Flay, BR, A mixed-methods approach examining illicit prescription stimulant use: Findings from a northern California University. J Prim Prevent. 2017; 38(4).

Kinman, BA, Armstrong, KJ, Hood, KB. Perceptions of risks and benefits among nonprescription stimulant consumers, diverters, and non-users. Subst Use Misuse. 2017; 52(10).

Schepis, TS, Teter, CJ, McCabe, SE. Prescription drug use, misuse and related substance use disorder symptoms vary by educational status and attainment in U.S. adolescents and young adults. Drug Alcohol Depend. 2018; 189.

Le, VT, Norris Turner, A, McDaniel, A, Nonmedical use of over-the-counter medications is significantly associated with nonmedical use of prescription drugs among university students. J Am Coll Health. 2018; 66(1).

Schulenberg, J, Johnston, L, O’Malley, P, Monitoring the Future National Survey Results on Drug Use, 1975–2018: Volume II, College Students and Adults Ages; 2019:19–60.

Rabiner, DL, Anastopoulos, AD, Costello, EJ, Hoyle, RH, McCabe, SE, Swartzwelder, HS. The misuse and diversion of prescribed ADHD medications by college students. J Atten Disord. 2009; 13(2):144–153. doi:10.1177/1087054708320414

Soto, PL, Wilcox, KM, Zhou, Y, Erratum: long-term exposure to oral methylphenidate or dl-amphetamine mixture in peri-adolescent rhesus monkeys: effects on physiology, behavior, and dopamine system development. Neuropsychopharmacology. 2013; 38(6):1141. doi:10.1038/npp.2013.15

Markowitz, JS, Patrick, KS. The clinical pharmacokinetics of amphetamines utilized in the treatment of attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2017; 27(8): 678–689. doi:10.1089/cap.2017.0071

Gonçalves, J, Baptista, S, Silva, AP. Psychostimulants and brain dysfunction: a review of the relevant neurotoxic effects. Neuropharmacology. 2014; 87:135–149. doi:10.1016/j.neuropharm.2014.01.006

Weyandt, LL, Oster, DR, Marraccini, ME, Prescription stimulant medication misuse: where are we and where do we go from here? Exp Clin Psychopharmacol. 2016; 24(5):400–414. doi:10.1037/pha0000093

Arnsten, AFT. Stimulants: therapeutic actions in ADHD. Neuropsychopharmacology. 2006; 31(11):2376–2383. doi:10.1038/sj.npp.1301164

Courtney, KE, Ray, LA. Clinical neuroscience of amphetamine-type stimulants: from basic science to treatment development. Prog Brain Res. 2016; 223:295–310. doi:10.1016/bs.pbr.2015.07.010

Reith, MEA, Gnegy, ME. Molecular mechanisms of amphetamines. Handb Exp Pharmacol. 2020; 258:265–297. doi:10.1007/164_2019_251

Steiner, H, Van Waes, V. Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants. Prog Neurobiol. 2013; 100(1):60–80. doi:10.1016/j.pneurobio.2012.10.001

Urban, KR, Gao, W-J. Psychostimulants as cognitive enhancers in adolescents: more risk than reward? Front Public Health. 2017; 5:260. doi:10.3389/fpubh.2017.00260

Catalá-López, F, Hutton, B, Núñez-Beltrán, A, The pharmacological and non-pharmacological treatment of attention deficit hyperactivity disorder in children and adolescents: protocol for a systematic review and network meta-analysis of randomized controlled trials. Syst Rev. 2015; 4:19. doi:10.1186/s13643-015-0005-7

Faraone, SV, Glatt, SJ. A comparison of the efficacy of medications for adult attention-deficit/hyperactivity disorder using meta-analysis of effect sizes. J Clin Psychiatry. 2010; 71(6):754–763. doi:10.4088/JCP.08m04902pur

Wilens, TE. Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder. J Clin Psychopharmacol. 2008; 28(3 suppl 2):S46–S53. doi:10.1097/JCP.0b013e318173312f

Jain, R, Katic, A. Current and investigational medication delivery systems for treating attention-deficit/hyperactivity disorder. Prim Care Companion CNS Disord. 2016; 18(4). doi:10.4088/PCC.16r01979

Heal, DJ, Gosden, J, Smith, SL. Dopamine reuptake transporter (DAT) “inverse agonism”—a novel hypothesis to explain the enigmatic pharmacology of cocaine. Neuropharmacology. 2014; 87:19–40. doi:10.1016/j.neuropharm.2014.06.012

Schrantee, A, Václavů, L, Heijtel, DFR, Dopaminergic system dysfunction in recreational dexamphetamine users. Neuropsychopharmacology. 2015; 40(5):1172–1180. doi:10.1038/npp.2014.301

Wang, Q, Li, D, Bubula, N, Campioni, MR, McGehee, DS, Vezina, P. Sensitizing exposure to amphetamine increases AMPA receptor phosphorylation without increasing cell surface expression in the rat nucleus accumbens. Neuropharmacology. 2017; 117:328–337. doi:10.1016/j.neuropharm.2017.02.018

Berman, SM, Kuczenski, R, McCracken, JT, London, ED. Potential adverse effects of amphetamine treatment on brain and behavior: a review. Mol Psychiatry. 2009; 14(2):123–142. doi:10.1038/mp.2008.90

Ashok, AH, Mizuno, Y, Volkow, ND, Howes, OD. Association of stimulant use with dopaminergic alterations in users of cocaine, amphetamine, or methamphetamine: a systematic review and meta-analysis. JAMA Psychiatry. 2017; 74(5):511–519. doi:10.1001/jamapsychiatry.2017.0135

Lohr, KM, Masoud, ST, Salahpour, A, Miller, GW. Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease. Eur J Neurosci. 2017; 45(1):20–33. doi:10.1111/ejn.13357

Cadet, JL, Krasnova, IN, Jayanthi, S, Lyles, J. Neurotoxicity of substituted amphetamines: molecular and cellular mechanisms. Neurotox Res. 2007; 11(3–4):183–202. doi:10.1007/BF03033567

Sadasivan, S, Pond, BB, Pani, AK, Qu, C, Jiao, Y, Smeyne, RJ. Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice. PLoS One. 2012; 7(5). doi:10.1371/journal.pone.0033693

Langston, JW. The MPTP story. J Parkinsons Dis. 2017; 7(suppl 1):S11–S19. doi:10.3233/JPD-179006

Oakes, HV, Ketchem, S, Hall, AN, Ensley, T, Archibald, KM, Pond, BB. Chronic methylphenidate induces increased quinone production and subsequent depletion of the antioxidant glutathione in the striatum. Pharmacol Reports. 2019; 71(6):1289–1292. doi:10.1016/j.pharep.2019.08.003

Lappin, JM, Sara, GE. Psychostimulant use and the brain. Addiction. 2019; 114(11):2065–2077. doi:10.1111/add.14708

Nestler, EJ, Hyman, SE, Malenka, RC. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. 2nd ed. McGraw-Hill; 2009.

Kalia, LV, Lang, AE. Parkinson’s disease. Lancet. 2015; 386(9996):896–912. doi:10.1016/S0140-6736(14)61393-3

Dowling, GJ, Weiss, SRB, Condon, TP. Drugs of abuse and the aging brain. Neuropsychopharmacology. 2008; 33:209–218. doi:10.1038/sj.npp.1301412

Childress, A. The safety of extended-release drug formulations for the treatment of ADHD. Expert Opin Drug Saf. 2017; 16(5):603–615. doi:10.1080/14740338.2017.1317344

Medhus, S, Rognli, EB, Gossop, M, Holm, B, Mørland, J, Bramness, JG. Amphetamine-induced psychosis: transition to schizophrenia and mortality in a small prospective sample. Am J Addict. 2015; 24(7):586–589. doi:10.1111/ajad.12274

Lieberman, JA, First, MB. Psychotic disorders. N Engl J Med. 2018; 379(3):270–280. doi:10.1056/NEJMra1801490

Marder, SR, Cannon, TD. Schizophrenia. N Engl J Med. 2019; 381(18):1753–1761. doi:10.1056/NEJMra1808803

Voce, A, McKetin, R, Burns, R, Castle, D, Calabria, B. The relationship between illicit amphetamine use and psychiatric symptom profiles in schizophrenia and affective psychoses. Psychiatry Res. 2018; 265:19–24. doi:10.1016/j.psychres.2018.04.015

Bramness, JG, Gundersen, ØH, Guterstam, J, Amphetamine-induced psychosis—a separate diagnostic entity or primary psychosis triggered in the vulnerable? BMC Psychiatry. 2012; 12:221. doi:10.1186/1471-244X-12-221

Moran, LV, Ongur, D, Hsu, J, Castro, VM, Perlis, RH, Schneeweiss, S. Psychosis with methylphenidate or amphetamine in patients with ADHD. N Engl J Med. 2019; 380(12):1128–1138. doi:10.1056/NEJMoa1813751

Kaar, SJ, Gobjila, C, Butler, E, Henderson, C, Howes, OD. Making decisions about antipsychotics: a qualitative study of patient experience and the development of a decision aid. BMC Psychiatry. 2019; 19(1):309. doi:10.1186/s12888-019-2304-3

Kaar, SJ, Natesan, S, McCutcheon, R, Howes, OD. Antipsychotics: mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology. 2020; 172:107704. doi:10.1016/j.neuropharm.2019.107704

Weyandt, L, White, TL, Gudmundsdottir, BG, Neurocognitive, autonomic, and mood effects of adderall: a pilot study of healthy college students. Pharmacy. 2018; 6(3):58. doi:10.3390/pharmacy6030058

Arria, AM, Caldeira, KM, Vincent, KB, Do college students improve their grades by using prescription stimulants nonmedically? Addict Behav. 2017; 65:245–249. doi:doi:10.1016/j. addbeh.2016.07.016

Berridge, CW, Devilbiss, DM. Psychostimulants as cognitive enhancers: the prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder. Biol Psychiatry. 2011; 69(12):e101–e111. doi:10.1016/j.biopsych.2010.06.023

Lam, AP, Matthies, S, Graf, E, Long-term effects of multimodal treatment on adult attention-deficit/hyperactivity disorder symptoms: follow-up analysis of the COMPAS trial. JAMA Netw Open. 2019; 2(5):e194980. doi:10.1001/jamanetworkopen.2019.4980

Pievsky, MA, McGrath, RE. Neurocognitive effects of methylphenidate in adults with attention-deficit/hyperactivity disorder: a meta-analysis. Neurosci Biobehav Rev. 2018; 90:447–455. doi:10.1016/j.neubiorev.2018.05.012

Loskutova, NY, Waterman, J, Callen, E, Staton, EW, Bullard, E, Shields, J. Knowledge, attitudes, and practice patterns of health professionals toward medical and non-medical stimulant use by young adults. J Am Board Fam Med. 2020; 33(1):59–70. doi:10.3122/jabfm.2020.01.190071

Philipsen, A, Jans, T, Matthies, S, Multimodal treatment of adult ADHD: a randomized controlled multicentre trial (COMPAS). ADHD Atten Deficit Hyperact Disord. 2015; 7:1–119. doi:10.1007/s12402-015-0169-y

MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 1999; 56(12):1073–1086. doi:10.1001/archpsyc.56.12.1073

Cortese, S, Adamo, N, Del Giovane, C, Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis. Lancet Psychiatry. 2018; 5(9):727–738. doi:10.1016/S2215-0366(18)30269-4

Coghill, D. Debate: are stimulant medications for attention-deficit/hyperactivity disorder effective in the long-term? J Am Acad Child Adolesc Psychiatry. 2019; 58(10):938–939. doi:10.1016/j.jaac.2019.07.002

Swanson, JM. Debate: are stimulant medications for attention-deficit/hyperactivity disorder effective in the long term? J Am Acad Child Adolesc Psychiatry. 2019; 58(10):936–938. doi:10.1016/j.jaac.2019.07.001

Matthijssen, A-FM, Dietrich, A, Bierens, M, Continued benefits of methylphenidate in ADHD after 2 years in clinical practice: a randomized placebo-controlled discontinuation study. Am J Psychiatry. 2019; 176(9):754–762. doi:10.1176/appi.ajp.2019.18111296

Pliszka, SR. Is there long-term benefit from stimulant treatment for ADHD? Am J Psychiatry. 2019; 176(9):685–686. doi:10.1176/appi.ajp.2019.19070681