Methylphenidates mechanism of action in the release of dopamine and norepinephrine is fundamentally different from most other phenethylamine derivatives, as methylphenidate is thought to increase neuronal firing rate, whereas amphetamine reduces firing rate, but causes monoamine release by reversing the flow of the monoamines through monoamine transporters via a diverse set of mechanisms, including TAAR1 activation and modulation of VMAT2 function, among other mechanisms. The difference in mechanism of action between methylphenidate and amphetamine results in methylphenidate inhibiting amphetamines effects on monoamine transporters when they are co-administered.Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed. A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.Methylphenidate may protect neurons from the neurotoxic effects of Parkinsons disease and methamphetamine use disorder. The hypothesized mechanism of neuroprotection is through inhibition of methamphetamine-DAT interactions, and through reducing cytosolic dopamine, leading to decreased production of dopamine-related reactive oxygen species.The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate. The studied maximized daily dosage of OROS methyphenidate appears to be 144 mg/day. Pharmacokinetics
Methylphenidate taken by mouth has a bioavailability of 11–52% with a duration of action around 2–4 hours for instant release (i.e. Ritalin), 3–8 hours for sustained release (i.e.
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.