The compound was first synthesized in 1944 by chemist Leandro Panizzon and marketed as “Ritalin” by Swiss company CIBA (now Novartis) in 1954. The name “Ritalin” derives from the first name of Panizzon’s wife, i.e. Marguerite, nicknamed Rita, who used Ritalin to compensate for low blood pressure.
Methylphenidate was not reported to be a stimulant until 1954. The drug was introduced for medical use in the United States in 1957. Although it was first used to allay barbiturate-induced coma, narcolepsy, and depression. It was later used to treat memory deficits in the elderly. Production and prescription only rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.
In 2000, Alza Corporation received US FDA approval to market Concerta, an extended-release form of methylphenidate.
It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012. In 2022, it was the 32nd most commonly prescribed medication in the United States, with more than 17 million prescriptions. It is available as a generic medication.
Methylphenidate is a synthetic molecule of the substituted phenethylamine and substituted phenidate classes. It contains a phenethylamine core featuring a phenyl ring bound to an amino (-NH2) group through an ethyl chain.
It is structurally similar to amphetamine, featuring a substitution at Rα which is incorporated into a piperidine ring ending at the terminal amine of the phenethylamine chain. Additionally, it contains a methyl carboxylate bound to Rβ of its structure.
Methylphenidate is a chiral compound, presumably produced as a racemic mixture. It has an enantiopure also sold as a pharmaceutical; the dextrorotary enantiopure is known as "dexmethylphenidate" and is commonly sold asFocalin andFocalin XR.
Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects.
The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers.
The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2R,2'R)-(+)-threo-methylphenidate hydrochloride has been published.
Methylphenidate primarily acts as a norepinephrine-dopamine reuptake inhibitor (NDRI). It is most active at modulating levels of dopamine and, to a lesser extent, norepinephrine. Methylphenidate binds to and blocks dopamine transporters and norepinephrine transporters.
While both amphetamine and methylphenidate are dopaminergic, it should be noted that their methods of action are somewhat distinct. Specifically, methylphenidate is a dopamine reuptake inhibitor while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine. Each of these drugs have a corresponding effect on norepinephrine which are weaker than their effects on dopamine.
Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from most other phenethylamine derivatives as methylphenidate is thought to increase general firing rate, whereas amphetamine reduces firing rate and reverses the flow of the monoamines via TAAR1 activation.
A toxic dose of methylphenidate is considered to be more than 2 mg/kg or 60 mg of an immediate-release formulation, or more than 4 mg/kg or 120 mg of an intact extended-release formulation. In the majority of cases in one study, methylphenidate overdose was asymptomatic or characterized by minor symptoms even in children under age 6.
However, a significant amount of patients (31%) in the study developed symptoms typical of stimulant overdose, most commonly tachycardia, agitation, and paradoxically lethargy. In the 2012 National Poison Data System report, methylphenidate exposure was reported 9,787 times, with 1,609 reporting no adverse effects, 1,009 reporting mild effects, 662 reporting moderate effects, 33 reporting major symptoms, and no cases resulting in death.
It is strongly advised to use harm reduction practices if using this substance.
In terms of its tolerance, methylphenidate can be used multiple days in a row for extended periods of time and is often prescribed to be used in this way. Tolerance to many of the effects of methyphenidate develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects.
In the case of acute (i.e. one-off) exposure, it generally takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Methylphenidate presents cross-tolerance with all dopaminergic stimulants, meaning that after the consumption of methyphenidate all stimulants will have a reduced effect."
As with other stimulants,moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal effects may occur if a person suddenly stops their usage.
Methylphenidate has some potential for abuse due to its action on dopamine transporters. Methylphenidate, like other stimulants, increases dopamine levels in the brain. However, at therapeutic doses this increase is slow and thus euphoria only rarely occurs even when it is administered intravenously. The abuse and addiction potential of methylphenidate is therefore significantly lower than other dopaminergic stimulants.
The abuse potential is increased when methylphenidate is crushed and insufflated (snorted) or injected.. It should be noted that due to the fillers in the pill, however, that this can be harmful to the nasal cavities, and intravenous use can cause emphysema (a lower respiratory tract disease, aka ritalin lung when caused by Ritalin tablets). The intravenous use of methylphenidate, commonly marketed as Ritalin and widely used as a stimulant drug in the treatment of attention deficit hyperactivity disorder, can lead to emphysematous changes known as Ritalin lung.
. The primary source of methylphenidate for abuse is the diversion from legitimate prescriptions rather than illicit synthesis. Those who use methylphenidate medicinally generally take it orally as instructed while intranasal and intravenous are the preferred means for recreational use.
Chronic use (i.e. high dose, repeat dosing) may increase the risk of psychosis. The safety profile of short-term methylphenidate therapy has been well-established, with short-term clinical trials revealing a very low incidence (0.1%) of methylphenidate-induced psychosis at therapeutic dose levels.
Psychotic symptoms from methylphenidate can include hearing voices, visual hallucinations, urges to harm oneself, severe anxiety, mania, disinhibition, paranoid and grandiose delusions, confusion, emotional suppression, increased aggression, and irritability.
Methylphenidate (when taken orally) has a low bioavailability around 30%. If taken with alcohol (ethanol), blood plasma levels of dexmethylphenidate are increased by up to 40%. A metabolite called ethylphenidate is also formed.
- Alcohol induced dose dumping (AIDD)
In vitro data suggest that some extended-release stimulants may experience dose dumping in the presence of alcohol. This is a concern because the ADHD patient population is at risk for alcohol abuse. The potential for dose dumping when taking extended-release stimulants with alcohol could lead to unintended and dangerous side effects for those with ADHD.
An example of an extended-release formula includes the methylphenidate medication brand Concerta.
- MDMA** - The neurotoxic effects of MDMA may be increased when combined with other stimulants.
Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.
- Australia: Methylphenidate is a 'Schedule 8' controlled substance. Such drugs must be kept in a lockable safe before being handed out and possession without prescription carries hefty fines and even imprisonment.
- Austria: Methylphenidate is legal for medical use under the AMG (Arzneimittelgesetz Österreich) and illegal when sold or possessed without a prescription under the SMG (Suchtmittelgesetz Österreich).
- Canada: Methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act (along with LSD, psychedelic mushrooms, and mescaline). It is illegal to possess without a prescription pursuant to Part G (section G.01.002) of the Food and Drug Regulations under the Food and Drugs Act.
- France: Methylphenidate is scheduled as a "stupéfiant", i.e. a recognized drug of abuse. It can only be prescribed on a narcotic prescription form.
- Germany: Methylphenidate is a controlled substance under Anlage III of the BtMG. It can only be prescribed on a narcotic prescription form.
- New Zealand: Methylphenidate is a 'Class B2 controlled substance'. Unlawful possession is punishable by six-month prison sentence and the distribution of it is punishable by a 14-year sentence.
- Sweden: Methylphenidate is a List II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison.
- Switzerland: Methylphenidate is a controlled substance specifically named under Verzeichnis A. Medicinal use is permitted.
- Turkey: Methylphenidate is a 'red prescription' only substance and illegal when sold or possessed without a prescription.
- United Kingdom: Methylphenidate is a controlled 'Class B' substance. Possession without a prescription carries with it a sentence of up to 5 years and/or an unlimited fine and supplying it is 14 years and/or an unlimited fine.
- United States: Methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high potential for abuse.
It is a widespread myth that methylphenidate could lead to false-positives for amphetamine in drug screenings. However, there was found no immunoassay cross reactivity in laboratory study.
Responsible use
Stimulants
Amphetamine
Methylphenidate (Wikipedia)
Methylphenidate (Erowid Vault)
Methylphenidate (Isomer Design)
Methylphenidate (DrugBank)
Dexmethylphenidate (DrugBank)
Methylphenidate (Drugs-Forum)
Leonard, B. E., McCartan, D., White, J., & King, D. J. (2004). Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects. Human Psychopharmacology: Clinical and Experimental, 19(3), 151-180. https://doi.org/10.1002/hup.579
