Methylphenidate

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is the most widely prescribed central nervous system (CNS) stimulant medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect, commonly ranging from 2–4 hours. Though there is little to no evidence, and in some cases contradictory evidence, to support its use as an athletic performance enhancer, cognitive enhancer, aphrodisiac or euphoriant, claims persist that it can be used for these purposes.

Common adverse reactions of methylphenidate include: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain. Withdrawal symptoms may include: chills, depression, drowsiness, dysphoria, exhaustion, headaches, irritability, lethargy, nightmares, restlessness, suicidal thoughts, and weakness.

Methylphenidate is believed to work by blocking the reuptake of dopamine and norepinephrine by neurons. It is a central nervous system (CNS) stimulant of the phenethylamine and piperidine classes. Despite the claim made by some urban legends, it is not a cocaine derivative nor analog; cocaine is a local anesthetic and ligand channel blocker with SNDRI action, while methylphenidate is an NDRI with 2–3 fold selectivity for the dopamine transporter (DAT) over the norepinephrine transporter (NET). Cocaine is also more potent in serotonin transporters (SERTs) than NDRI sites.

Methylphenidate was first synthesized in 1944 and was approved for medical use in the United States in 1955. It was originally sold by Swiss company CIBA (now Novartis). It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012. In 2020, it was the 41st most commonly prescribed medication in the United States, with more than 15million prescriptions. It is available as a generic medication.

In the United Kingdom, through the National Health Service, the drug is first-line medication for the treatment of attention deficit hyperactivity disorder (ADHD).

Uses

Methylphenidate is most commonly used to treat ADHD and narcolepsy.

Attention deficit hyperactivity disorder

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder. The addition of behavioural modification therapy can have additional benefits on treatment outcome. The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose. Immediate release methylphenidate is used daily along with the longer-acting form to achieve full-day control of symptoms. Methylphenidate is not approved for children under six years of age.

In children over age 6 and adolescents, the short-term benefits and cost effectiveness of methylphenidate are well established. A number of reviews have established the safety and effectiveness for individuals with ADHD over several years.

Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans. There is evidence to suggest that children diagnosed with ADHD who do not receive treatment will have an increased risk of substance use disorders as adults.

The precise magnitude of improvement in ADHD symptoms and quality of life that are produced by methylphenidate treatment remains uncertain as of November 2015. Methylphenidate is not included in the World Health Organization Essential Medicines List, as findings by the World Health Organization indicate that evidence of benefit versus harm to be unclear in the treatment of ADHD. A 2021 systematic review concluded that there is no clear evidence for using IR Methylphenidate (immediate-release) for adults.

Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a "study drug" by some populations, which may be harmful. This also applies to people who may be experiencing a different issue and are misdiagnosed with ADHD. People in this category can then experience negative side-effects of the drug which worsen their condition.

Narcolepsy

Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and uncontrollable sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance. Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test (MSLT), but performance does not improve to levels comparable to healthy people.

Other medical uses

Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. There is weak evidence in favor of methylphenidate's effectiveness for depression, including providing additional benefit in combination with antidepressants. In individuals with terminal cancer, methylphenidate can be used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function. A 2021 systematic review and meta-analysis found that all studies on geriatric depression reported positive results of methylphenidate use; the review recommended short-term use in combination with citalopram. A 2018 review found low quality evidence supporting its use to treat apathy as seen in Alzheimer's Disease in addition to slight benefits for cognition and cognitive performance.

Enhancing performance

A 2015 review found that therapeutic doses of amphetamine and methylphenidate result in modest improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults;
the cognition-enhancing effects of these drugs are known to occur through the indirect activation of both dopamine receptor D₁ and adrenoceptor α₂ in the prefrontal cortex. Methylphenidate and other ADHD stimulants also improve task saliency and increase arousal. Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks, and are used by some students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use, performance-enhancing use rather than use as a recreational drug, is the primary reason that students use stimulants.

Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and cognitive control. Like amphetamine and bupropion, methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system. Similar to the loss of cognitive enhancement when using large amounts, large doses of methylphenidate can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia. While literature suggests it might improve cognition, most authors agree that using the drug as a study aid when ADHD diagnosis is not present does not actually improve GPA. Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.

Contraindications

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine, and tranylcypromine), or individuals with agitation, tics, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks. Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it "is not a major human teratogen".

Adverse effects

Overall, adverse events associated with long-acting MPH formulations are similar with the most common adverse effects including appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), oromandibular dystonia, lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure, and heart rate (typically mild), and tachycardia (rapid heart rate). Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3  cigarettes per day. Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.

There is some evidence of mild reductions in height with prolonged treatment in children. This has been estimated at or less per year during the first three years with a total decrease of over 10 years.

Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.

Methylphenidate can worsen psychosis in people who are psychotic, and in very rare cases it has been associated with the emergence of new psychotic symptoms. It should be used with extreme caution in people with bipolar disorder due to the potential induction of mania or hypomania. There have been very rare reports of suicidal ideation, but some authors claim that evidence does not support a link. Logorrhea is occasionally reported. Libido disorders, disorientation, and visual hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.

U.S. Food and Drug Administration-commissioned studies in 2011, indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events ( sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death. The certainty of the evidence was stated as very low.

A 2018 review found tentative evidence that it may cause both serious and non-serious adverse effects in children.

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, agitation, tremors, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache, tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rhabdomyolysis, coma, and circulatory collapse.
A methylphenidate overdose is rarely fatal with appropriate care. Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.

Treatment of a methylphenidate overdose typically involves the administration of benzodiazepines, with antipsychotics, α-adrenoceptor agonists and propofol serving as second-line therapies.

Addiction and dependence

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has moderate liability among addictive drugs; accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug. When used above the medical dose range, stimulants are associated with the development of stimulant psychosis. As with all addictive drugs, the overexpression of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in methylphenidate addiction.

Biomolecular mechanisms

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain's reward system. At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system, or the reward pathway in particular, to the extent necessary to cause persistent increases in ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens; consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction. However, when methylphenidate is used at sufficiently high recreational doses through a bioavailable route of administration (e.g., insufflation or intravenous administration), particularly for use of the drug as a euphoriant, ΔFosB accumulates in the nucleus accumbens. Hence, like any other addictive drug, regular recreational use of methylphenidate at high doses eventually gives rise to ΔFosB overexpression in D1-type neurons which subsequently triggers a series of gene transcription-mediated signaling cascades that induce an addiction.

Interactions

Methylphenidate may inhibit the metabolism of vitamin K anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants, and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations. There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification, not unlike the hepatic formation of cocaethylene from cocaine and ethanol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.

Pharmacology

Pharmacodynamics

Methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It is a benzylpiperidine

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