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Amphetamine type stimulants (ATS) are a group of synthetic drugs that are chemical derivatives of the parent compound alpha-methylphenethylamine, also known as amphetamine. Common ATS includes amphetamine, methamphetamine, ephedrine, pseudoephedrine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDEA).

Amphetamine is a sympathomimetic amine that stimulates the central nervous system, but may cause anorexic. Other ATS have the same physiological effect as amphetamine, except MDMA, MDA, MDEA, and MDBD. These are also known as the ‘ecstasy’-group substance, that causes hallucination.

ATS are central nervous system stimulants that are proven to cause insomnia, arousal and reduced hunger. High doses of ATS can cause manic syndrome, increased libido and euphoria. The adverse effects, especially when chronically used, include depression, hallucination, aggressive behaviors and in extreme cases, methamphetamine-induced psychosis.

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.

Treatment of Attention Deficit Hyperactivity Disorder
Dextroamphetamine and Lisdexamfetamine are widely used for Attention Deficit Hyperactivity Disorder (ADHD). These two drugs are first-line drugs for children, adolescents and adults according to the CADDRA (Canadian ADHD Resource Alliance).

Antidepressant
Amphetamine was an antidepressant because anhedonia was considered a major phenomenon of depression. The use of ATS as an antidepressant was no longer common after the production of tricyclic antidepressants and monoamine inhibitors (MAOI) and ATS were established as a detriment to public health.

Appetite suppression
A pharmaceutical company named Smith, Kline & French (SKF) conducted a study in 1947, showing that amphetamine affect the brain center for appetite to reduced weight. In the late 1960s, weight reduction was the most common indication for ATS. Fenfluramine is used with phentermine to achieve appetite suppression.

Cognitive performance
Early users 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.

Non-medical use
Amphetamine is frequently used for pleasure and abused because of the addictive properties. Amphetamine was originally sold as a decongestant inhaler in the United States in 1933 and led to widespread ATS abuse in military forces and civilians.

Abuse
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”.

Physical
ATS may lead to multiple detrimental health issues and the severity of them may increase with doses. Physical problems such as cardio-vascular problems, abdominal pain, sweating, pupil dilation, parasitosis can be observed from using ATS.

Other adverse effects include blood-borne viruses, sleep disorders, fatigue, poor eating habits,etc. Blood-borne viruses like HIV can occur because of sharing syringes to inject ATS.

Psychosis
Substantial evidence shows that psychotic patients, especially schizophrenic patients, 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.

Treatment
Studies suggest treatment of ATS-induced psychosis by risperidone and olanzapine. While some suggest the usage of low-dose antipsychotic medications to alleviate the symptoms by preventing sensitisation.

Studies show that antidepressants like fluoxetine, imipramine and desipramine have very limited effects for ATS abuse since they may reduce craving or increase period of adherence to short-to-medium-term treatments.

A study suggests that no medication is effective for treatment of amphetamine withdrawal and the benefits of using mirtazapine in ATS abuse are not clear.

Chemistry
Ephedrine is the precursor of synthetic amphetamines.The diastereomer of ephedrine, pseudoephedrine is found in Ephedra sinica together along with ephedrine. Ephedrine and pseudoephedrine are both generally used for weight reduction and performance enhancement. They are also precursors of methamphetamine 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.

= Toxicity =

= Pharmacology = Amphetamine type stimulants can be divided into two groups based on their activity on the central nervous system. One group acts as psychostimulants, which produce stimulatory effects and leads to hyperarousal and increased movement. While the other group possess a structure similar to mescaline, a hallucinogenic substance.

ATS facilitates monoamine neurotransmission by blocking membrane monoamine transporters, which results in inhibited clearance of monoamine. Examples of monoamine transporters include dopamine transporters, 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 (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 receptors. Clonazepam, 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 neurotransmission and GABAA receptors may have an inhibitory role in ATS-induced disorders.

ATS also inhibit GABAB receptors, glutamic acid decarboxylase (GAD), GABA transporters (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), nasal (inhaling vapour or snorting), and intravenous routes. Taking ATS orally is the most common route of administration. The response time and other pharmacokinetics profile of ATS varies for different routes of administration. For oral route, the concentration of the drug will peak approximately 3 hours after administration. The peak concentration time for intravenous routes is around 15 minutes.

ATS are metabolised by liver enzymes including cytochrome P460 2D6,

= History = Amphetamine was discovered in the 1887 by the Romanian chemist Lazar Edeleano.