Amphetamine type stimulants (ATS) are a group of synthetic drugs that are chemical derivatives of the parent compound alpha-methylphenethylamine, also known as
amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
. Common ATS includes amphetamine,
methamphetamine
Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...
,
ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
,
pseudoephedrine
Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.
It was first characteri ...
,
3,4-methylenedioxymethamphetamine
3,4-Methylenedioxymethamphetamine (MDMA), commonly seen in tablet form (ecstasy) and crystal form (molly or mandy), is a potent empathogen–entactogen with stimulant properties primarily used for recreational purposes. The desired ...
(MDMA),
3,4-methylenedioxyamphetamine
3,4-Methylenedioxyamphetamine (also known as MDA and sass) is an empathogen-entactogen, psychostimulant, and psychedelic drug of the amphetamine family that is encountered mainly as a recreational drug. In terms of pharmacology, MDA acts mo ...
(MDA) and
3,4-methylenedioxyethylamphetamine (MDEA).
ATS when used illicitly has street names including ice, meth, crystal, crank, bennies, and speed. Within the group of amphetamine-type stimulants, there are also prescription drugs including
mixed amphetamine salts
Adderall and Mydayis are trade names for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio bet ...
,
dextroamphetamine
Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and ...
, and
lisdexamfetamine
Lisdexamfetamine, sold under the brand name Vyvanse among others, is a stimulant medication that is mainly used to treat attention deficit hyperactivity disorder (ADHD) in people over the age of five as well as moderate-to-severe binge eating ...
.
Amphetamine was first synthesized in 1887 by the Romanian chemist
Lazar Edeleano.
It has since been used to treat a range of disorders from
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
to
ADHD
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
and illicitly for
recreational purposes. Amphetamine-type stimulants contain chemical groups including unsubstituted
phenyl ring
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
, a methyl group at the alpha-position, and primary amino group, which accounts for its
psychostimulant
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
activities. ATS with multiple substitutions on the phenyl ring has a
hallucinogenic effect on top of the
psychostimulant effect, and are categorised as the ecstasy-class drugs.
Amphetamine
Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
-type stimulants in general are
sympathomimetic
Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in hea ...
amine that stimulates the
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
, also proven to cause insomnia, arousal, and reduced hunger. Due to its physiological and psychological effects, ATS has been used to suppress appetite, improve cognitive performance, as well as treating
ADHD
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
,
depression, and
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affec ...
. Amphetamine type stimulants are also known for their addictive property and widespread problem of
substance abuse
Substance abuse, also known as drug abuse, is the use of a drug in amounts or by methods which are harmful to the individual or others. It is a form of substance-related disorder. Differing definitions of drug abuse are used in public health, ...
. The adverse effects of ATS, especially when chronically used, include
obsessive–compulsive tendencies,
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
,
paranoia
Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy concer ...
,
hallucination
A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinatio ...
s,
aggression
Aggression is overt or covert, often harmful, social interaction with the intention of inflicting damage or other harm upon another individual; although it can be channeled into creative and practical outlets for some. It may occur either reacti ...
,
mania
Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wit ...
and in extreme cases,
amphetamine psychosis
Stimulant psychosis is a mental disorder characterized by psychotic symptoms (such as hallucinations, paranoid ideation, delusions, disorganized thinking, grossly disorganized behaviour) which involves and typically occurs following an overdose or ...
.
History
__FORCETOC__
Amphetamine, the parent compound of amphetamine-type stimulants was first synthesized by Romanian chemists Lazar Edeleano in 1887. Around the same time, amphetamine's precursor
ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
was also abstracted from a Chinese herbal medicine
ephedra Ephedra may refer to:
* Ephedra (medicine), a medicinal preparation from the plant ''Ephedra sinica''
* ''Ephedra'' (plant), genus of gymnosperm shrubs
See also
* Ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is of ...
by a Japanese Chemist.
After its discovery, amphetamine was purified and put into medical use in the 1900s.
Amphetamine was originally sold as a
decongestant
A decongestant, or nasal decongestant, is a type of pharmaceutical drug that is used to relieve nasal congestion in the upper respiratory tract. The active ingredient in most decongestants is either pseudoephedrine or phenylephrine (the latter of ...
inhaler in the United States in 1933 and led to widespread ATS abuse in military forces and civilians later on.
The details of history of amphetamine can be found
here
Here is an adverb that means "in, on, or at this place". It may also refer to:
Software
* Here Technologies, a mapping company
* Here WeGo (formerly Here Maps), a mobile app and map website by Here
Television
* Here TV (formerly "here!"), a TV ...
.
Chemistry
Ephedrine is the precursor of synthetic amphetamines. The
diastereomer
In stereochemistry, diastereomers (sometimes called diastereoisomers) are a type of stereoisomer. Diastereomers are defined as non-mirror image, non-identical stereoisomers. Hence, they occur when two or more stereoisomers of a compound have dif ...
of ephedrine,
pseudoephedrine
Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses.
It was first characteri ...
is found in
Ephedra sinica
''Ephedra sinica'' (also known as Chinese ephedra or Ma Huang) is a species of ''Ephedra'' native to Mongolia, Russia (Buryatiya, Chita, Primorye), and northeastern China ( Gansu, Hebei, Heilongjiang, Jilin, Liaoning, Nei Mongol, Ni ...
together along with
ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
. Ephedrine and pseudoephedrine are both generally used for weight reduction and performance enhancement. They are also precursors of
methamphetamine
Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamph ...
synthesis.
The activity of amphetamine-type stimulants depends on their unsubstituted phenyl ring, alphy methyl group, primary amino group and two-carbon side-chain that connects the primary amino group and the phenyl ring.
Hallucinogenic activity of ATS are often caused by multiple substitutions on the phenyl ring, examples include 4-bromo-2,5-dimethoxyamphetamine and 2,5-dimethoxy-4-methylamphetamine. When the methoxy group is substituted in the para position of the ATS molecule, the hallucinogenic potency will become significantly high.
Pharmacology
Amphetamine type stimulants can be subdivided based on their activity on the central nervous system, compounds with hallucinogenic properties are the MDMA-related compounds. All ATS acts as
psychostimulants
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
, which produce stimulatory effects and leads to hyperarousal and increased movement. While MDMA-related compounds possess a structure similar to
mescaline
Mescaline or mescalin (3,4,5-trimethoxyphenethylamine) is a naturally occurring psychedelic protoalkaloid of the substituted phenethylamine class, known for its hallucinogenic effects comparable to those of LSD and psilocybin.
Biological sou ...
and has hallucinogenic properties on top of psychostimulant properties.
ATS facilitates
monoamine neurotransmission by blocking membrane monoamine transporters, which results in inhibited clearance of monoamine. Examples of monoamine transporters include
dopamine transporter
The dopamine transporter (also dopamine active transporter, DAT, SLC6A3) is a membrane-spanning protein that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopam ...
s, norepinephrine transporters and serotonin transporters.
ATS are also competitive antagonists that compete with the monoamine neurotransmitters due to their similar structures. ATS then enter the presynaptic neuron and inhibit the
vesicular monoamine transporter 2
The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the ''SLC18A2'' gene. SLC18A2 is an integral membrane protein that transports monoamines—particul ...
(VMAT2) to reduce the reuptake of monoamine neurotransmitters.
ATS inhibits monoamine oxidase and hence inhibits monoamine degradation and some of them may have interaction with presynaptic intracellular receptors that promote monoamine neurotransmission.
For instance, methamphetamine acts as an agonist of sigma-1 receptor.
Pharmacodynamics
ATS use disorders are related to the
GABA system. Research shows that ATS use would affect normal function of the
GABAA receptor
The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Upon opening, the GABAA receptor on ...
s.
Clonazepam
Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine clas ...
, which is a
GABAA receptor agonist, is shown to prevent the acquisition of
behavioural sensitization to methamphetamine. GABAA receptor antagonist is shown to aggravate ATS use disorders. Hence, a possible mechanism could be that activating GABAA receptor reduces
dopaminergic
Dopaminergic means "related to dopamine" (literally, "working on dopamine"), dopamine being a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain. Dopaminergic brain pathways facilitate d ...
neurotransmission and GABAA receptors may have an inhibitory role in ATS-induced disorders.
ATS also inhibit GABAB receptors,
glutamic acid decarboxylase
Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) and carbon dioxide (). GAD uses pyridoxal-phosphate (PLP) as a cofactor. The reaction p ...
(GAD),
GABA transporter GABA transporters ( Gamma-Aminobutyric acid transporters) belong to the family of neurotransmitters known as sodium symporters, also known as solute carrier 6 ( SLC6). These are large family of neurotransmitter which are Na+ concentration dependen ...
s (GAT) and promote GABA metabolism. This leads to the reduced expression of extracellular GABA expression, inhibited biosynthesis of GABA-nergic neurotransmitter and depressed function of GABAB receptors-GIRK channels.
Pharmacokinetics
ATS can be administered via oral (swallowing),
intranasal
Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivered ...
(inhaling vapour or snorting), and
intravenous routes. Taking ATS orally is the most common route of administration. The response time and other
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
profile of ATS varies for different routes of administration.
ATS are metabolised by liver enzymes especially
cytochrome P450 2D6, producing metabolites including 4-hydroxyamphetamine, 4 hydroxynorephedrine, hippuric acid, benzoic acid and benzyl methyl ketone.
The metabolism of ATS may vary from person to person due to
genetic polymorphism
A gene is said to be polymorphic if more than one allele occupies that gene's locus within a population. In addition to having more than one allele at a specific locus, each allele must also occur in the population at a rate of at least 1% to gen ...
of the enzyme CYP450 2D6.
Under normal conditions, around 5 to 30% of amphetamine is excreted unchanged in the urine.
However, the urinary excretion of amphetamine and other ATS is highly dependent on the pH. A small amount of amphetamine is also produced from metabolism of methamphetamine, but does not cause any significant clinical effect.
Uses
Treatment of Attention Deficit Hyperactivity Disorder
Dextroamphetamine
Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and ...
and
Lisdexamfetamine
Lisdexamfetamine, sold under the brand name Vyvanse among others, is a stimulant medication that is mainly used to treat attention deficit hyperactivity disorder (ADHD) in people over the age of five as well as moderate-to-severe binge eating ...
are widely used for
Attention Deficit Hyperactivity Disorder (ADHD). These two drugs are first-line drugs for children, adolescents and adults.
Antidepressant
Amphetamine has been used in the past to treat
anhedonia
Anhedonia is a diverse array of deficits in hedonic function, including reduced motivation or ability to experience pleasure. While earlier definitions emphasized the inability to experience pleasure, anhedonia is currently used by researchers t ...
, a major phenomenon of
depression. The use of ATS as an
antidepressant
Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
was no longer common after the production of the more effective
tricyclic antidepressant
Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...
s and
monoamine oxidase inhibitors (MAOI). ATS were established as a detriment to public health.
Appetite suppressant
A study conducted by the pharmaceutical company
Smith, Kline & French (SKF) in 1947 showed that amphetamine can affect the
brain center for appetite and help to reduce weight. In the late 1960s, weight reduction was the most common indication for ATS.
Nowadays, to suppress appetite, the combination of
fenfluramine
Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome.https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212102s003lb ...
and
phentermine
Phentermine ( phenyl- tertiary-butyl amine), with several brand names including Ionamin and Sentis, is a medication used together with diet and exercise to treat obesity. It is taken by mouth for up to a few weeks at a time, after which the ben ...
is still used.
Treatment for narcolepsy
Amphetamine type stimulants can be used in the treatment of narcolepsy, a rare neurological disorder where the brain is unable to regulate the sleep-wake mechanism. Amphetamines causes an increase in dopamine release, which is the proposed mechanism for its wake-promoting effect. ATS such as
dextroamphetamine
Dextroamphetamine is a central nervous system (CNS) stimulant and an amphetamine enantiomer that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and ...
are used in the treatment of narcolepsy when another
CNS stimulant
Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
,
modafinil
Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant medication used to treat sleepiness due to narcolepsy, shift work sleep disorder, and obstructive sleep apnea. While it has seen off-label ...
is not effective.
Cognitive performance
Early users of amphetamine-type stimulants may report that their cognitive performance and working abilities are improved . Low-to-moderate doses of ATS improves psychomotor output without significantly affecting memory, verbal task performance and intelligence measures. ATS may boost the school performance of some students through emotional mechanisms that increase their confidence.
However, amphetamine-type stimulants is not prescribed for this use legally.
Abuse
Amphetamine is frequently used for pleasure and
abused
Abuse is the improper usage or treatment of a thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, crimes, or other t ...
because of the addictive properties. The definition of ATS abuse is ''a maladaptive pattern of substance use manifested by recurrent and significant adverse consequences related to the repeated use of substances''. While
dependence refers to the use of amphetamine 'accompanied by evidence of tolerance, withdrawal, or compulsive behaviour".
Abuse of ATS is a threat to global public health. The United Nations World Drug Report states that about 0.3-1.3% of the global population has ATS abuse problems, where methamphetamine accounts for 71% of global ATS seizures.
Adverse effects
The adverse effect of ATS may be caused by many factors, including
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. of prescribed drugs, or use of illicit substance that are not safe in any pharmacological relevant dose.
ATS-related fatality and toxicity usually arises from abuse of ATS, rather than
adverse drug reaction
An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...
s. ATS may lead to serious health issues with dose-dependent severity.
Psychosis
Substantial evidence shows that psychotic patients, especially patients with schizophrenia, are more likely to engage in ATS abuse. ATS abuse inhibits dopamine transporter (DAT) and increases dopamine level in the synaptic cleft. The extent of DAT inhibition is associated with the symptoms.
Amphetamine-type stimulants-induced psychosis has been reported ever since 1938. Symptoms mainly include delusions and hallucinations. Different kinds of hallucinations are also seen, like auditory, visual, olfactory and tactile hallucinations.
Less common symptoms are bizarre behaviour and thought disorder. Though some believed that the ATS-induced psychosis cannot be distinguished from schizophrenia, delusions of persecution are often reported as a characteristic of ATS-induced psychosis.
The duration of ATS-induced psychosis has substantial variations, from weeks to months. Based on their durations, psychosis can be divided into two types. One type has a shorter psychotic state that shows improvement as the central action of ATS changes. The other type has a longer duration.
Toxicity
The toxic dose of ATS varies between person due to development of drug tolerance and genetic polymorphism of the CYP450 2D6 gene.
Different ATS also have different toxic dose. Methamphetamine fatality from ATS have been reported after ingestion of a minimal dose of 1.3 mg/kg, while the estimated minimum lethal dose in a non-addicted adult is 200 mg.
Generally, children are more likely to develop toxicity and have lower chances of developing tolerance.
Treatment
Studies suggest treatment of ATS-induced psychosis by
risperidone
Risperidone, sold under the brand name Risperdal among others, is an atypical antipsychotic used to treat schizophrenia and bipolar disorder. It is taken either by mouth or by injection (subcutaneous or intramuscular). The injectable versions ...
and
olanzapine
Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is ta ...
.
While some suggest the usage of low-dose antipsychotic medications to alleviate the symptoms by preventing sensitisation.
Studies show that antidepressants like fluoxetine,
imipramine
Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. The drug is also used to treat bedwetting. ...
and
desipramine
Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression. It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activiti ...
have very limited effects for ATS abuse since they may reduce craving or increase period of adherence to short-to-medium-term treatments.
A variety of psychosocial interventions have been shown to be effective in reducing substance abuse and risk behaviours associated with ATS.
There is a strong recommendation that intensive psychosocial interventions be implemented, developed, and adapted to the social context in which they are implemented
References
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Designer drugs