Stimulants, most often amphetamine or methylphenidate, have been the mainstay of pharmacotherapy for patients with attention-deficit/hyperactivity disorder (ADHD).1 A meta-analysis of results from 135 clinical trials demonstrated that these drugs are highly effective in children with this disorder.2 Immediate-release stimulant formulations have been replaced in the past decade with longer-duration preparations that overcome the limitations of the drugs' short elimination half-lives. These new long-release drugs no longer require treatment during the school day, which may help eliminate poor adherence and stigmatization among young patients.
The psychostimulants used for treatment of children with ADHD have putative effects on central dopamine (DA) and norepinephrine (NE) pathways.3 They are thought to increase the synaptic concentration of DA by occupying and blocking the dopamine transporter (DAT). Positron emission tomographic (PET) scans of adult volunteers with documented histories of ADHD as children have shown that, when given orally, [11C] methylphenidate occupies the DA transporter in the striatal area of the brain, but at a rate far slower than intravenous cocaine. The benefits of increasing synaptic DA may be the enhancement of executive control processes, overcoming the deficits in inhibitory control and working memory reported in children with ADHD.
Methylphenidate (MPH) has been used extensively in the treatment of ADHD. It exists as four optical isomers: d-threo, lthreo, d-erythro, and l-erythro MPH Stimulant activity of the MPH molecule resides in the threo racemate, and the erythro isomers have been eliminated from current commercial preparations of the drug.3 MPH exerts its therapeutic effect by blocking DAT while altering dopamine signaling. This increases extracellular dopamine, which stimulates dopamine autoreceptors attenuating release of this neurotransmitter in response to activation. D-amphetamine (DEX) is more potent than MPH in promoting release of dopamine from neuronal stores, because it both blocks reuptake and causes presynaptic release of DA from axons.3 MPH has major effects on brain activity, as reflected by glucose use, in the prefrontal cortex, basal ganglia, and cerebellum.
Classic stimulant effects in adults include a prolongation of performance at repetitive tasks before the onset of fatigue, decreased sense of fatigue, mood elevation, euphoria, increased speech rate, and increased initiative. The psychostimulants increase CNS alertness, as shown on tasks requiring vigilance — both on laboratory tasks, such as the continuous performance task, or on the job, such as maintaining the ability to notice new events on a radar screen over periods of hours. These changes have been described as the drug's ability to “increase capacity,” although this phrase has been interpreted incorrectly to mean increasing a person's ability above his or her innate intelligence.
The central nervous system (CNS) psychostimulant effects of MPH and DEX may result in part from their lack of benzene ring substitutents. Prominent central effects include activation of the medullary respiratory center and a lessening of central depression from barbiturates. The role of these compounds in altering the seizure threshold is complex. DEX reduces the maximal seizure discharge following electroconvulsive therapy and prolongs the post-ictal period. It accelerates and desynchronizes the electroencephalogram (EEG) and has been thought to increase the seizure threshold. The MPH package insert, on the other hand, suggests that it may decrease the seizure threshold, but this has never been documented in a controlled study in humans.4
Psychostimulants are amines and occasionally are described as the noncatecholamine sympathomimetics due to their chemical resemblance to those neurotransmitters. Sympathomimetics are alpha-adrenergic and beta-adrenergic receptor agonists that have potent agonist effects at alpha-adrenergic and beta-adrenergic receptors. DEX stimulates cardiac muscle, raising systolic and diastolic blood pressure, with a reflex slowing of heart rate. Psychostimulants also may cause urinary bladder smooth muscle to contract at the sphincter and will increase uterine muscle tone and produce bronchodilatation.
Early neurochemical theories postulated that ADHD symptoms were exacerbated by central dopamine (DA) dysfunction. Post-synaptic dopamine blocking agents, such as neuroleptics, should make ADHD symptoms worse; dopamine agonists, such as L-DOPA, should improve them. However, pure dopamine agonists, such as piribidel and L-DOPA, showed no effect compared with placebo, whereas dopamine blocking agents, such as thioridazine, were beneficial. Single-neurotransmitter-deficit etiological models of ADHD have not been supported by pharmacologic studies.
MPH and DEX have different intra-cellular actions. DEX's DA release can be blocked by alpha-methyl-tyrosine (AMPT) but not reserpine, suggesting DA originates from a cytoplasmic pool of newly synthesized monoamines. The release of DA by MPH, on the other hand, can be blocked by reserpine pre-treatment and has therefore been thought to involve long-term vesicular storage.
Stimulation Medications and Cerebral Metabolism
Psychostimulants have become the medications of choice for the treatment of children with ADHD. Their central mechanisms of action whereby motor activity is reduced, sustained attention is increased, and impulsivity is reduced may be related to their action in blocking the DAT. Studies using positron emission tomography (PET) scanning have demonstrated that adults with a history of ADHD show 8.1% lower levels of cerebral glucose metabolism than controls, with the greatest differences in the superior prefrontal cortex and premotor areas.5
MPH and DEX elevate glucose metabolism in the brains of rats, although patients with schizophrenia given DEX show decreased glucose metabolism. Similarly, no changes in cerebral glucose metabolism were found in PET scans done before and during treatment with medication for 19 MPH-treated and 18 DEX-treated adults with ADHD, even though the adults showed significant changes in behavior.6 In a related study, the midsagital cross-sectional area of the corpus callosum was measured from magnetic resonance images of 18 boys with ADHD and 18 matched boys with no psychiatric disorder, with two of seven anatomical areas being significantly smaller in the boys with ADHD.7 The authors concluded that these findings were in support of abnormal frontal lobe development and function in ADHD.
Behavioral Effects Related to Absorption
Psychostimulant medication effects on ADHD are concentrated within the absorption phase. Monoamine neurotransmitters are released into the synapse in one or more pulses during this period of rapid psychostimulant concentration change. The rate of absorption from psychostimulants follows zero-order kinetics, which has been called a “ramp effect.”
A double-blind, placebo-controlled study of nine boys with ADHD ages 5 to 12 showed that all drug effects on activity level and classroom behavior occurred during MPH absorption time for both standard tablet and long-acting spansule given once in the morning.8 Significant placebo-active drug differences in behavior and activity level occurred in the early part of the absorption phase. Psychostimulants may be most effective when plasma level concentrations are increasing most rapidly. For example, the immediate-release (IR), standard MPH tablet's steeper absorption curve may give it more powerful clinical activity (and adverse effects) than the more slowly absorbed sustained-release MPH formulation.
The structure of the psychostimulants has been related to their CNS activity. Early studies postulated that d-isomers of amphetamine were selectively more effective for norepinephrine release, but both dand l-amphetamine had equal effects on DA. A double-blind crossover study reported that l-amphetamine took longer to act, and was not as effective on measures of attention as the d-isomer.9 Similarly, MPH's d-isomer has a greater effect on locomotor activity and reuptake inhibition of labeled dopamine than its l-isomer.10
The MPH molecule has two asymmetric carbon atoms, resulting in 4 optical isomers: both d- and l-forms of the threo and erythro racemates. The threo isomer appears to have more potency than the erythro, perhaps due to the 60-degree skew relationship between the tertiary amine and the carbomethoxy groups, as they are in cocaine. This key relationship may increase these compounds' ability to block cellular membrane reuptake processes. In the erythro form, these groups are trans-staggered, and therefore no weak bond is formed between the nitrogen and carbonyl atoms.10 The commercial manufacturing process produces the dl-threo-methylphenidate racemate exclusively.
Absorption and Metabolism
Psychostimulants are absorbed rapidly from the gut and act quickly, often within the first 30 minutes following ingestion. Food enhances absorption. Although some pharmacokinetic data has suggested MPH bioavailabilities in the 80% range, more recent studies place the actual figure closer to 30%.11 DEX concentrations in plasma vary from 40 to 120 ng/mL in treated ADHD children. MPH produces lower plasma concentrations — as low as 7 to 10 ng/mL — suggesting a large first-pass effect. Yet these low MPH concentrations can be surprisingly effective. This is explained by MPH's low plasma binding (15%), which makes it highly available to cross the blood-brain barrier. This situation creates a favorable brain-plasma partition, with higher concentration in CNS than in plasma.10 PET scan studies of basal ganglia show almost total occupancy of striatal DAT from an oral 10 mg MPH dose in adults within 1 hour.12 Effects on behavior appear during absorption, beginning 30 minutes after ingestion and lasting 3 to 4 hours. Plasma half-lives range from 3 hours for MPH to 11 hours for d-amphetamine. The concentration-enhancing and activity-reducing effects of MPH can disappear well before the medication leaves the plasma, a phenomenon termed “clockwise hysteresis.”
MPH's metabolism is especially rapid and complete — rapid because it is not highly bound to plasma protein, nor does it disappear into fat stores. MPH peaks in plasma 2 to 2.5 hours (Tmax) after ingestion, later falling to half the peak (half-life) after 3 hours. The parent compound is metabolized by hydrolysis of the ester group to give the equivalent carboxylic acid, ritalinic acid. Approximately 20% is oxidized (to p-hydroxy- and oxomethylphenidate), as well as conjugated derivatives by the liver.
Animal studies have shown a 100:1 margin of safety exists between a single MPH dose approximating a human clinical dose and one that produces lethality in two other animal species.13 As a result, MPH's standard oral dose range of 0.3 to 1.2 mg per kilogram per day is quite safe. In the animal lab, the median lethal dose (LD50) is 48.3 mg/kg by intravenous route and 367 mg/kg by oral route, compared with LD50 for amphetamine in rats of 55 mg/kg.13 Ninety-day subchronic toxicity studies of MPH in rats (with doses up to 120 mg per kilogram per day) showed decreases in body weight but no signs of growth inhibition, reproductive problems or carcinogenicity.13 A 120-day study of beagles treated with 10 mg per kilogram per day (ten times human dose) of MPH produced hyperactivity and hyperexcitability in the dogs, but there was no appetite suppression, growth suppression, convulsion, or change in liver tissue.13
Long-Term Addiction Risk
MPH is a ubiquitous therapeutic agent that has been approved and used to treat ADHD since the late 1960s. As we enter the 21st century, the number of psychostimulant products available for prescription in the United States has tripled within the past 10 years, owning to the approval of a number of long-duration preparations. All of the stimulant medications are classified as schedule II drugs, which mean that unsupervised use can lead to addiction and dependence, based on studies of laboratory animals. This is a serious concern, as the targeted population of patients with ADHD have a threefold risk of addiction compared with those without ADHD when they are adolescents and young adults.
Although pharmacology of all these compounds has been well described, new data show all stimulants are not equal pharmacologically when it comes to the risk of long-term, high-dose addictive use.5 The similarities and differences between MPH, cocaine, methampheta-mine, and amphetamine are important for considerations of risk factors for addiction. While each of these compounds blocks the DA receptor, cocaine has significantly faster clearance from the receptor than does MPH, making it more suitable for binging and repeated doses.
MPH's availability only in pill form makes it less accessible for abuse. Even so, when MPH is given orally in pill form, it eventually binds most of the available dopamine transporter (DAT) in the brain's striatal area. It binds less well in older people, as they have fewer DAT binding sites. People with addictions have discovered that MPH gives more euphoric responses if injected intravenously. However, taking dissolved MPH pills by that route leads to severe difficulties with eyes, lungs, and heart as the talc particles in the tablets become micro-emboli and cause diffuse strokes. If both MPH and cocaine are prepared for intravenous use and then given to adults with ADHD, on the other hand, both drugs cause euphoric responses.
The majority of reports of animals given MPH via intravenous or intra-peritoneal routes show development of classic addiction and tolerance.14 These reports suggest that the route of administration has a great deal to do with MPH's addiction potential. If MPH preparations could be taken only orally, the drug could be far safer. For example, if MPH were prepared in a chemical complex from which it could only be released by stomach enzymes, then the compound would have no activity if snorted or injected.
A variety of factors shape the subjective responses of children and adolescents with ADHD to methylphenidate in pill form. Elation is not seen, but rather calming, reduction of motor activity, and increased interest in tasks. This positive response is not as clearly evident in adolescents who are using marijuana daily, so experts suggest helping such patients stop their marijuana habit before starting stimulant treatment. If MPH is snorted by school-age children, they report that it makes them feel racy and jumpy but not elated. Rapoport15 noted that identical oral doses by weight of DEX produced mild dysphoria in school-age normal children, but increased confidence and more rapid speech in college students, suggesting a developmental effect. In a later study with Elia,16 Rapoport showed very high doses of methylphenidate produce improvement in some children with ADHD who had not been responsive to DEX, but also induced dysphoria and obsessive behaviors (but not elation).
Stimulant medication, though classified by the DEA as controlled with a schedule IIa rating, are ubiquitous in our society because of their popularity as an effective treatment for childhood ADHD. The number of stimulant products available for practitioners has tripled in the last decade. Although stimulants' action on central dopamine systems can be reinforcing, especially when delivered via intraperitoneal or intravenous routes in laboratory animals, they are far less addicting when taken orally by children in the context of a medical treatment. Fortunately, the therapeutic stimulants, available orally, have different pharmacodynamic and pharmacokinetic properties than the illicit stimulants, methamphetamine and cocaine. The lack of intravenous forms of the therapeutic stimulants acts as a natural barrier and tends to prevent addiction. Furthermore, MPH produces dysphoria in school age children, further limiting its reinforcing properties. These pharmacokinetics and pharmaco-dynamics of methylphenidate and amphetamine treatments for ADHD thus are less addicting because of their delivery systems. Future products, employing novel methods that only allow the drug molecule to be available if ingested, should further increase the safety of these important therapeutic agents.
- Ford R, Greenhill L. Stimulant medications. In: Martin A, Scahill L, Charney D, Leckman J, eds. Pediatric Psychopharmacology: Principles and Practice? New York, NY: Oxford University Press; 2003:255–263.
- Jadad AR, Boyle M, Cunningham C, Kim M, Schachar R. Treatment of Attention-Deficit/Hyperactivity Disorder. Agency for Healthcare Research and Quality, US Department of Health and Human Services. November1999. Publication No. 00-E005. Available at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1.chapter.14677. Accessed February 21, 2005.
- Swanson J, Volkow ND, Pharmacokinetic and pharmacodynamic properties of methylphenidate in humans, In: Solanto MV, Arnsten AFT, Castellanos FX, eds. Stimulant Drugs and ADHD: Basic and Clinical Neuroscience. New York, NY: Oxford University Press; 2001:259–283.
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- Greenhill LL, Shockey E, Halperin J, March JS. Stimulants. In: Tasman A, Kay J, Lieberman JA, eds. Psychiatry. 2nd ed. Hoboken, NJ: John Wiley and Sons; 2003:2062–2095.
- Birmaher B, Greenhill LL, Cooper TB, Fried J, Maminski B. Sustained release methylphenidate: pharmacokinetic studies in ADDH males. J Am Acad Child Adolesc Psychiatry. 1989;28(5):768–772. doi:10.1097/00004583-198909000-00020 [CrossRef]2793805
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- Patrick KS, Markowitz JS. Pharmacology of methylphenidate, amphetamine enantiomers and pemoline in attention-deficit/hyperactivity disorder. Human Psychopharmacology. 1997; 12:527–546. doi:10.1002/(SICI)1099-1077(199711/12)12:6<527::AID-HUP932>3.0.CO;2-U [CrossRef]
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