Ethylphenidate (EPH) is a
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS)
stimulant
Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, ...
and a close
analog of
methylphenidate
Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
.
Ethylphenidate acts as a
norepinephrine–dopamine reuptake inhibitor
A norepinephrine–dopamine reuptake inhibitor (NDRI) is a type of drug that inhibits the reuptake of the monoamine neurotransmitters norepinephrine and dopamine and thereby increases extracellular levels of these neurotransmitters and nor ...
, meaning it effectively boosts the levels of the
norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
and
dopamine
Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.
Neurotra ...
s in the brain, by binding to, and partially blocking the transporter
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s that normally remove those
monoamine
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.
All monoamines are ...
s from the
synaptic cleft
Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in neuromuscular junction, muscles or glands. Chemical synapses allow neurons to form biological neural ...
.
Ethylphenidate, being almost identical to methylphenidate in both structure and pharmacodynamics, likely also doesn't solely act as a "classical" reuptake inhibitor but primarily as an
inverse agonist
In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist.
A neutral antagonist has no activity in the absence of an agonist or inverse agon ...
at the
dopamine transporter
The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...
(DAT), inducing dopamine
transporter reversal Reverse transport, or transporter reversal, is a phenomenon in which the substrate (biochemistry), substrates of a membrane transport protein are moved in the opposite direction to that of their typical movement by the transporter. Transporter rever ...
and subsequent dopamine release from the
axon terminal
Axon terminals (also called terminal boutons, synaptic boutons, end-feet, or presynaptic terminals) are distal terminations of the branches of an axon. An axon, also called a nerve fiber, is a long, slender projection of a Neuron, nerve cell tha ...
into the synaptic cleft in a manner similar to but distinct from amphetamines.
Pharmacology
Pharmacokinetics
Ethylphenidate metabolizes into methylphenidate and
ritalinic acid
Ritalinic acid is a substituted phenethylamine and an inactive major metabolite of the psychostimulant drugs methylphenidate, dexmethylphenidate and ethylphenidate. When administered orally, methylphenidate is extensively metabolized in the liv ...
.
Tiny amounts of ethylphenidate can be formed ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
'' when
ethanol
Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
and
methylphenidate
Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
are coingested, via
hepatic
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
transesterification
Transesterification is the process of exchanging the organic functional group R″ of an ester with the organic group R' of an alcohol. These reactions are often catalyzed by the addition of an acid or base catalyst. Strong acids catalyze the r ...
.
Ethylphenidate formation appears to be more common when large quantities of methylphenidate and
alcohol
Alcohol may refer to:
Common uses
* Alcohol (chemistry), a class of compounds
* Ethanol, one of several alcohols, commonly known as alcohol in everyday life
** Alcohol (drug), intoxicant found in alcoholic beverages
** Alcoholic beverage, an alco ...
are consumed at the same time, such as in non-medical use or
overdose
A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014. scenarios. However, the transesterfication process of methylphenidate to ethylphenidate, as tested in mice liver, was dominant in the inactive (−)-enantiomer but showed a prolonged and increased maximal plasma concentration of the active (+)-enantiomer of methylphenidate.
Additionally, only a small percentage of the consumed methylphenidate is converted to ethylphenidate.
This
carboxylesterase
The enzyme carboxylesterase (or carboxylic-ester hydrolase, EC 3.1.1.1; systematic name carboxylic-ester hydrolase) catalysis, catalyzes reactions of the following form:
:a Ester, carboxylic ester + H2O \rightleftharpoons an Alcohol (chemistry), ...
-dependent transesterification process is also known to occur when
cocaine
Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...
and alcohol are consumed together, forming
cocaethylene
Cocaethylene (ethylbenzoylecgonine) is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed by the liver in small amounts when cocaine and ethanol coexi ...
.
Pharmacodynamics
All available data on ethylphenidate's pharmacodynamics are drawn from studies conducted on rodents. Ethylphenidate is more selective to the
dopamine transporter
The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...
(DAT) than methylphenidate, having approximately the same efficacy as the parent compound,
but has significantly less activity on the
norepinephrine transporter
The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene.
NET is a monoamine transporter and is responsible for the sodium ...
(NET).
Its
dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
Dopaminergic pathways, Dopaminergic brain pathways facil ...
pharmacodynamic
Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...
profile is nearly identical to methylphenidate, and is primarily responsible for its
euphoric
Euphoria ( ) is the experience (or affect) of pleasure or excitement and intense feelings of well-being and happiness. Certain natural rewards and social activities, such as aerobic exercise, laughter, listening to or making music and danci ...
and reinforcing effects.
The
eudysmic ratio for ethylphenidate is superior to that of methylphenidate.
[
The following is ethylphenidate's binding profile in the mouse, alongside methylphenidate's. Figures for both the ]racemic
In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...
and the dextrorotary enantiomer
In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
s are given:[
]
Legality
* Ethylphenidate is a schedule II drug under the Convention on Psychotropic Substances
The Convention on Psychotropic Substances of 1971 is a United Nations treaty designed to control psychoactive drugs such as amphetamine-type stimulants, barbiturates, benzodiazepines, and psychedelics signed in Vienna, Austria on 21 February ...
.
* Ethylphenidate is illegal in the Netherlands
, Terminology of the Low Countries, informally Holland, is a country in Northwestern Europe, with Caribbean Netherlands, overseas territories in the Caribbean. It is the largest of the four constituent countries of the Kingdom of the Nether ...
, as the Opium Law List I covers it, as of April 27, 2018
* In the United States, effective November 21, 2024, Etheylphenidate was placed in Schedule I of the Controlled Substances Act
The Controlled Substances Act (CSA) is the statute establishing federal government of the United States, federal drug policy of the United States, U.S. drug policy under which the manufacture, importation, possession, use, and distribution of ...
.
** On September 22, 2023, the DEA filed a proposed rule for placement of Ethylphenidate into Schedule I status. Public commenting opened on September 22, 2023, and closed on November 21, 2023.
* Ethylphenidate was made schedule I at the state level in Alabama
Alabama ( ) is a U.S. state, state in the Southeastern United States, Southeastern and Deep South, Deep Southern regions of the United States. It borders Tennessee to the north, Georgia (U.S. state), Georgia to the east, Florida and the Gu ...
on March 18th, 2014.
* Ethylphenidate is illegal in Sweden as of December 15, 2012.
* Ethylphenidate is illegal to manufacture, distribute or import in the UK, as of 10 April 2015 it has been placed under a Temporary Class Drug
A temporary class drug is a relatively new status for controlled drugs, which has been adopted in some jurisdictions, notably New Zealand and the United Kingdom, to attempt to bring newly synthesised designer drugs under legal control. The contro ...
Order which automatically places it in a Class-B-like category. Though ordinarily the TCDO would only last 1 year, the ACMD reported that since its invocation prevalence of MPA had significantly decreased, and that it had been challenging to collect information about the drug. As a result of this, they requested that the TCDO be extended a further year from 26 June 2016.
* Ethylphenidate is illegal in Jersey
Jersey ( ; ), officially the Bailiwick of Jersey, is an autonomous and self-governing island territory of the British Islands. Although as a British Crown Dependency it is not a sovereign state, it has its own distinguishing civil and gov ...
under the Misuse of Drugs (Jersey) Law 1978.
* Australian state and federal legislation contains provisions that mean that analogues of controlled drugs are also covered by the legislation. Ethylphenidate would be an analogue of methylphenidate
Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
under this legislation.
* Ethylphenidate is controlled in Canada under the Controlled Drugs and Substances Act
Control may refer to:
Basic meanings Economics and business
* Control (management), an element of management
* Control, an element of management accounting
* Comptroller (or controller), a senior financial officer in an organization
* Controll ...
under Schedule III as of May 5, 2017.
* Ethylphenidate is illegal in Germany as of May 7, 2013.
* Ethylphenidate is illegal in Austria by the "Neue Psychoaktive Substanzen Gesetz" (New Psychoactive Substances Act) NPSG since 1 January 2012
* Ethylphenidate is illegal in Denmark as of February 1, 2013.
* Ethylphenidate is illegal in Poland by "the Act on Counteracting Drug Addiction" since July 1, 2015.
* It is illegal in Lithuania to use, buy, possess, transport, sell or import Ethylphenidate from 2015
* As of October 2015, ethylphenidate is a controlled substance in China.
* In Finland ethylphenidate is scheduled in government decree on substances, preparations and plants considered to be narcotic drugs.
See also
* Alcohol (drug)
Alcohol, sometimes referred to by the chemical name ethanol, is the active ingredient in alcoholic drinks such as beer, wine, and distilled spirits (hard liquor). Alcohol is a central nervous system (CNS) depressant, decreasing Action potent ...
* Ethanol
Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
* HDEP-28
* HDMP-28
* Naphthylisopropylamine
* Naphyrone
* 2β-Propanoyl-3β-(2-naphthyl)-tropane (WF-23)
* Isopropylphenidate
* Methylphenidate
Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
* Propylphenidate
* 3,4-Dichloromethylphenidate
* 4-Fluoroethylphenidate
* Cocaethylene
Cocaethylene (ethylbenzoylecgonine) is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed by the liver in small amounts when cocaine and ethanol coexi ...
(compound formed when cocaine
Cocaine is a tropane alkaloid and central nervous system stimulant, derived primarily from the leaves of two South American coca plants, ''Erythroxylum coca'' and ''Erythroxylum novogranatense, E. novogranatense'', which are cultivated a ...
and ethanol
Ethanol (also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound with the chemical formula . It is an Alcohol (chemistry), alcohol, with its formula also written as , or EtOH, where Et is the ps ...
are taken together)
References
{{Monoamine reuptake inhibitors
Alcohol
Drug culture
Ethyl esters
2-Benzylpiperidines
Sympathomimetic amines
Norepinephrine–dopamine reuptake inhibitors
Stimulants
Designer drugs
Euphoriants
2-Piperidinyl compounds