Stimulant

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Ritalin: 20 mg sustained-release
(SR) tablets

Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase the activity of the

.

Stimulants work by affecting the levels of certain neurotransmitters, such as dopamine, norepinephrine, serotonin, histamine and acetylcholine, in the synapses between neurons. These neurotransmitters regulate various functions, such as arousal, the reward system, learning, memory, and emotion. By increasing their availability, stimulants can produce a range of effects, from mild stimulation to euphoria, depending on the dose, route of administration, and individual factors.

Stimulants have a long history of use, both for medical and non-medical purposes. They have been used to treat various conditions, such as

cognitive enhancers
, by various groups of people, such as students, athletes, workers, and soldiers.

However, stimulants also have potential risks and side effects, such as

overdose, dependence, crime, and violence
. Therefore, the use of stimulants is regulated by laws and policies in most countries, and requires medical supervision and prescription in some cases.

Definition

A stimulant is an overarching term that covers many drugs including those that increase the activity of the central nervous system and the body,[1] drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects.[2] Sympathomimetic effects are those effects that mimic or copy the actions of the sympathetic nervous system. The sympathetic nervous system is a part of the nervous system that prepares the body for action, such as increasing the heart rate, blood pressure, and breathing rate. Stimulants can activate the same receptors as the natural chemicals released by the sympathetic nervous system and cause similar effects.[3]

Effects

Acute

Stimulants in therapeutic doses, such as those given to patients with

ergogenic effects. The term "ergogenic" means "enhancing physical performance".[5] Ergogenic effects are those effects that improve physical performance or endurance. For example, if a drug makes run faster, lift heavier, or last longer, it is said to have ergogenic effects. Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while cocaine has the opposite effect.[6] Neurocognitive enhancing effects of stimulants, specifically modafinil, amphetamine and methylphenidate have been reported in healthy adolescents by some studies,[7] and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying.[7] Still, results of these studies is inconclusive: assessing the potential overall neurocognitive benefits of stimulants among healthy youth is challenging due to the diversity within the population, the variability in cognitive task characteristics, and the absence of replication of studies.[7] Research on the cognitive enhancement effects of modafinil in healthy non-sleep-deprived individuals has yielded mixed results, with some studies suggesting modest improvements in attention and executive functions while others show no significant benefits or even a decline in cognitive functions.[8][9][10]

In some cases, psychiatric phenomena may emerge such as

seizures. However, given the complexity of the mechanisms that underlie these potentially fatal outcomes of acute stimulant toxicity, it is impossible to determine what dose may be lethal.[12]

Chronic

Assessment of the effects of stimulants is relevant given the large population currently taking stimulants. A systematic review of cardiovascular effects of prescription stimulants found no association in children, but found a correlation between prescription stimulant use and

heart attacks.[13] A review over a four-year period found that there were few negative effects of stimulant treatment, but stressed the need for longer-term studies.[14] A review of a year long period of prescription stimulant use in those with ADHD found that cardiovascular side effects were limited to transient increases in blood pressure only.[15] Initiation of stimulant treatment in those with ADHD in early childhood appears to carry benefits into adulthood with regard to social and cognitive functioning, and appears to be relatively safe.[16]

Abuse of prescription stimulants (not following physician instruction) or of illicit stimulants carries many negative health risks. Abuse of cocaine, depending upon route of administration, increases risk of cardiorespiratory disease, stroke, and sepsis.[17] Some effects are dependent upon the route of administration, with intravenous use associated with the transmission of many disease such as Hepatitis C, HIV/AIDS and potential medical emergencies such as infection, thrombosis or pseudoaneurysm,[18] while inhalation may be associated with increased lower respiratory tract infection, lung cancer, and pathological restricting of lung tissue.[19] Cocaine may also increase risk for autoimmune disease[20][21][22] and damage nasal cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of dopaminergic neurons, resulting in an increased risk for Parkinson's disease.[23][24][25][26]

Medical uses

Stimulants are widely used throughout the world as

illicitly) as performance-enhancing or recreational drugs. Among narcotics, stimulants produce a noticeable crash or comedown at the end of their effects. The most frequently prescribed stimulants as of 2013 were lisdexamfetamine (Vyvanse), methylphenidate (Ritalin), and amphetamine (Adderall).[27] It was estimated in 2015 that the percentage of the world population that had used cocaine during a year was 0.4%. For the category "amphetamines and prescription stimulants" (with "amphetamines" including amphetamine and methamphetamine) the value was 0.7%, and for MDMA 0.4%.[28]

Stimulants have been used in medicine for many conditions including

adrenergic drugs are now preferred due to less systemic side effects. Pseudoephedrine is used to relieve nasal or sinus congestion caused by the common cold, sinusitis, hay fever and other respiratory allergies; it is also used to relieve ear congestion caused by ear inflammation or infection.[38][39]

Depression

Stimulants were one of the first classes of drugs to be used in the treatment of depression, beginning after the introduction of the amphetamines in the 1930s.[40][41][42] However, they were largely abandoned for treatment of depression following the introduction of conventional antidepressants in the 1950s.[40][41] Subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years.[43][44]

Stimulants produce a fast-acting and pronounced but transient and short-lived

dependence.[44] Although the efficacy for depression with continuous administration is modest, it may still reach statistical significance over placebo and provide benefits similar in magnitude to those of conventional antidepressants.[47][48][49][50] The reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapid tolerance.[45][46][41][51] Tolerance to the effects of stimulants has been studied and characterized both in animals[51][52][53][54] and humans.[55][56][57][58] Stimulant withdrawal is remarkably similar in its symptoms to those of major depressive disorder.[59][51][60][61]

Chemistry

amphetamine derivatives

Classifying stimulants is difficult, because of the large number of classes the drugs occupy, and the fact that they may belong to multiple classes; for example, ecstasy can be classified as a substituted methylenedioxyphenethylamine, a substituted amphetamine and consequently, a substituted phenethylamine.[citation needed]

When referring to stimulants, the parent drug (e.g., amphetamine) will always be expressed in the singular[according to whom?]; with the word "substituted" placed before the parent drug (substituted amphetamines).

Major stimulant classes include

substituted amphetamines.[62][63]

Amphetamines (class)

Amphetamines-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat

ADHD. Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse.[70]

Cocaine analogs

Hundreds of cocaine analogs have been created, all of them usually maintaining a benzyloxy connected to the 3 carbon of a

benzene ring
, as well as additions or substitutions in place of the normal carboxylate on the tropane 2 carbon. Various compound with similar structure activity relationships to cocaine that aren't technically analogs have been developed as well.

Mechanisms of action

Most stimulants exert their activating effects by enhancing

empathogenic and hallucinogenic effects, also affect serotonergic transmission. Some stimulants, such as some amphetamine derivatives and, notably, yohimbine, can decrease negative feedback by antagonizing regulatory autoreceptors.[71] Adrenergic agonists, such as, in part, ephedrine, act by directly binding to and activating adrenergic receptors
, producing sympathomimetic effects.

There are also more indirect mechanisms of action a drug can elicit activating effects. Caffeine is an adenosine receptor antagonist, and only indirectly increases catecholamine transmission in the brain.[72] Pitolisant is an histamine 3 (H3)-receptor inverse agonist. As histamine 3 (H3) receptors mainly act as autoreceptors, pitolisant decreases negative feedback to histaminergic neurons, enhancing histaminergic transmission.

The precise mechanism of action of some stimulants, such as modafinil, for treating symptoms of narcolepsy and other sleep disorders, remains unknown.[73][74][75][76][77]

Notable stimulants

Amphetamine

Amphetamine is a potent

drug precursor seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of methamphetamine.[85]

The first pharmaceutical amphetamine was

Benzedrine, a brand of inhalers used to treat a variety of conditions.[86][87] Because the dextrorotary isomer has greater stimulant properties, Benzedrine was gradually discontinued in favor of formulations containing all or mostly dextroamphetamine. Presently, it is typically prescribed as mixed amphetamine salts, dextroamphetamine, and lisdexamfetamine.[86][88]

Amphetamine is a

cognitive control.[80][81][89] Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[79] In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown.[78][80][90] Very high doses can result in psychosis (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.[91][92] As recreational doses are generally much larger than prescribed therapeutic doses, recreational use carries a far greater risk of serious side effects, such as dependence, which only rarely arises with therapeutic amphetamine use.[78][90][91]

Caffeine

Roasted coffee beans, a common source of caffeine.

Caffeine is a stimulant compound belonging to the xanthine class of chemicals naturally found in coffee, tea, and (to a lesser degree) cocoa or chocolate. It is included in many soft drinks, as well as a larger amount in energy drinks. Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. In North America, 90% of adults consume caffeine daily.[93]

A few jurisdictions restrict the sale and use of caffeine. In the United States, the FDA has banned the sale of pure and highly concentrated caffeine products for personal consumption, due to the risk of overdose and death.[94] The Australian Government has announced a ban on the sale of pure and highly concentrated caffeine food products for personal consumption, following the death of a young man from acute caffeine toxicity.[95][96] In Canada, Health Canada has proposed to limit the amount of caffeine in energy drinks to 180 mg per serving, and to require warning labels and other safety measures on these products.[95]

Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient,[97] or reducing one of its side-effects (especially drowsiness).[98] Tablets containing standardized doses of caffeine are also widely available.[99]

Caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors.[100] Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness.[101] Caffeine has been found to increase striatal dopamine in animal models,[102] as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors,[103] however the implications for humans are unknown. Unlike most stimulants, caffeine has no addictive potential. Caffeine does not appear to be a reinforcing stimulus, and some degree of aversion may actually occur, per a study on drug abuse liability published in an NIDA research monograph that described a group preferring placebo over caffeine.[104] In large telephone surveys only 11% reported dependence symptoms. However, when people were tested in labs, only half of those who claim dependence actually experienced it, casting doubt on caffeine's ability to produce dependence and putting societal pressures in the spotlight.[105]

Coffee consumption is associated with a lower overall risk of

acute mountain sickness if taken a few hours prior to attaining a high altitude.[118]

Ephedrine

Ephedrine is a

appetite suppressant, concentration aid, and decongestant, and to treat hypotension
associated with anesthesia.

In chemical terms, it is an

It is most usually marketed as the hydrochloride or sulfate salt.

The herb má huáng (Ephedra sinica), used in traditional Chinese medicine (TCM), contains ephedrine and pseudoephedrine as its principal active constituents. The same may be true of other herbal products containing extracts from other Ephedra species.

MDMA

Tablets containing MDMA

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly) is a euphoriant,

entactogenic properties. The stimulant effects of MDMA include hypertension, anorexia (appetite loss), euphoria, social disinhibition, insomnia (enhanced wakefulness/inability to sleep), improved energy, increased arousal, and increased perspiration, among others. Relative to catecholaminergic transmission, MDMA enhances serotonergic transmission significantly more, when compared to classical stimulants like amphetamine. MDMA does not appear to be significantly addictive or dependence forming.[121]

Due to the relative safety of MDMA, some researchers such as David Nutt have criticized the scheduling level, writing a satirical article finding MDMA to be 28 times less dangerous than horseriding, a condition he termed "equasy" or "Equine Addiction Syndrome".[122]

MDPV

Methylenedioxypyrovalerone (MDPV) is a

K2 as incense.[125][126]

Incidents of psychological and physical harm have been attributed to MDPV use.[127][128]

Mephedrone

Mephedrone is a

eastern Africa. It comes in the form of tablets or a powder, which users can swallow, snort, or inject, producing similar effects to MDMA, amphetamines, and cocaine
.

Mephedrone was first synthesized in 1929, but did not become widely known until it was rediscovered in 2003. By 2007, mephedrone was reported to be available for sale on the Internet; by 2008 law enforcement agencies had become aware of the compound; and, by 2010, it had been reported in most of Europe, becoming particularly prevalent in the United Kingdom. Mephedrone was first made illegal in Israel in 2008, followed by Sweden later that year. In 2010, it was made illegal in many European countries, and, in December 2010, the EU ruled it illegal. In Australia, New Zealand, and the US, it is considered an

Federal Analog Act
. In September 2011, the USA temporarily classified mephedrone as illegal, in effect from October 2011.

Mephedrone is neurotoxic and has abuse potential, predominantly exerted on 5-hydroxytryptamine (5-HT) terminals, mimicking that of MDMA with which it shares the same subjective sensations on abusers.[131][132][133]

Methamphetamine

Methamphetamine (contracted from

lift the mood, and increase energy, allowing some users to engage in sexual activity continuously for several days straight.[135][failed verification][139][unreliable source?
]

Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in an

schedule II controlled substances in the United States.[135] Also, the production, distribution, sale, and possession of methamphetamine is restricted or illegal in many other countries due to its placement in schedule II of the United Nations Convention on Psychotropic Substances treaty.[140][141] In contrast, levomethamphetamine is an over-the-counter drug in the United States.[note 1]

In low doses, methamphetamine can cause an

gray matter volume in several brain regions and adverse changes in markers of metabolic integrity.[145][146][136] However, recreational amphetamine doses may also be neurotoxic.[147]

Methylphenidate

Methylphenidate is a stimulant drug that is often used in the treatment of ADHD and narcolepsy and occasionally to treat obesity in combination with diet restraints and exercise. Its effects at therapeutic doses include increased focus, increased alertness, decreased appetite, decreased need for sleep and decreased impulsivity. Methylphenidate is not usually used recreationally, but when it is used, its effects are very similar to those of amphetamines.

Methylphenidate acts as a norepinephrine-dopamine reuptake inhibitor, by blocking the norepinephrine transporter (NET) and the dopamine transporter (DAT). Methylphenidate has a higher affinity for the dopamine transporter than for the norepinephrine transporter, and so its effects are mainly due to elevated dopamine levels caused by the inhibited reuptake of dopamine, however increased norepinephrine levels also contribute to various of the effects caused by the drug.

Methylphenidate is sold under a number of brand names including Ritalin. Other versions include the long lasting tablet Concerta and the long lasting transdermal patch Daytrana.

Cocaine

recreational
stimulant

Cocaine is an

SNDRI. Cocaine is made from the leaves of the coca shrub, which grows in the mountain regions of South American countries such as Bolivia, Colombia, and Peru, regions in which it was cultivated and used for centuries mainly by the Aymara people. In Europe, North America, and some parts of Asia, the most common form of cocaine is a white crystalline powder. Cocaine is a stimulant but is not normally prescribed therapeutically for its stimulant properties, although it sees clinical use as a local anesthetic, in particular in ophthalmology.[148] Most cocaine use is recreational and its abuse potential is high (higher than amphetamine), and so its sale and possession are strictly controlled in most jurisdictions. Other tropane derivative drugs related to cocaine are also known such as troparil and lometopane but have not been widely sold or used recreationally.[149]

Nicotine

nicotinic acetylcholine receptors, resulting in multiple downstream effects such as increase in activity of dopaminergic neurons in the midbrain reward system, and acetaldehyde one of the tobacco constituent decreased the expression of monoamine oxidase in the brain.[150] Nicotine is addictive and dependence forming. Tobacco, the most common source of nicotine, has an overall harm to user and self score 3 percent below cocaine, and 13 percent above amphetamines, ranking 6th most harmful of the 20 drugs assessed, as determined by a multi-criteria decision analysis.[151]

Phenylpropanolamine

Phenylpropanolamine (PPA; Accutrim; β-hydroxyamphetamine), also known as the

cough and cold preparations. In veterinary medicine, it is used to control urinary incontinence in dogs under trade names
Propalin and Proin.

In the United States, PPA is no longer sold without a prescription due to a possible increased risk of stroke in younger women. In a few countries in Europe, however, it is still available either by prescription or sometimes over-the-counter. In Canada, it was withdrawn from the market on 31 May 2001.[153] In India, human use of PPA and its formulations were banned on 10 February 2011.[154]

Lisdexamfetamine

Lisdexamfetamine (Vyvanse, etc.) is an amphetamine-type medication, sold for use in treating ADHD.[155] Its effects typically last around 14 hours.[156] Lisdexamfetamine is inactive on its own and is metabolized into dextroamphetamine in the body.[56] Consequently, it has a lower abuse potential.[56]

Pseudoephedrine

Pseudoephedrine is a

wakefulness-promoting agent.[158]

The

NSAID (such as aspirin or ibuprofen
). It is also used as a precursor chemical in the illegal production of methamphetamine.

Catha edulis (Khat)

Photograph of the khat plant
Catha edulis

Khat is a flowering plant native to the Horn of Africa and the Arabian Peninsula.[159][160]

Khat contains a

drug of abuse that can produce mild to moderate psychological dependence (less than tobacco or alcohol),[161] although the WHO does not consider khat to be seriously addictive.[160] It is banned in some countries, such as the United States, Canada, and Germany, while its production, sale, and consumption are legal in other countries, including Djibouti, Ethiopia, Somalia, Kenya and Yemen.[162]

Modafinil

mood-elevating properties.[165] The similarities in effects with caffeine are not clearly established.[167][168] Unlike other stimulants, modafinil does not induce a subjective feeling of pleasure or reward, which is commonly associated with euphoria, an intense feeling of well-being. Euphoria is a potential indicator of drug abuse, which is the compulsive and excessive use of a substance despite adverse consequences. In clinical trials, modafinil has shown no evidence of abuse potential, that is why modafinil is considered to have a low risk of addiction and dependence, however, caution is advised.[169][170]

Pitolisant

Pitolisant is an inverse agonist (antagonist) of the histamine 3 (H3) autoreceptor. As such, pitolisant is an antihistamine medication that also belongs to the class of CNS stimulants.[171][172][173][174] Pitolisant is also considered a medication of eugeroic class, which means that it promotes wakefulness and alertness. Pitolisant is the first eugeroic drug that acts by blocking the H3 autoreceptor.[175][176][177]

Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.[177][176][175]

Pitolisant is the only non-controlled anti-narcoleptic drug in the US.[175] It has shown minimal abuse risk in studies.[175][178]

Blocking the histamine 3 (H3) autoreceptor increases the activity of histamine neurons in the brain. The H3 autoreceptors regulate histaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibiting histamine biosynthesis and release upon binding to endogenous histamine.[179] By preventing the binding of endogenous histamine at the H3, as well as producing a response opposite to that of endogenous histamine at the receptor (inverse agonism), pitolisant enhances histaminergic activity in the brain.[180]

Recreational use and issues of abuse

Stimulants enhance the activity of the central and peripheral nervous systems. Common effects may include increased alertness, awareness, wakefulness, endurance, productivity, and motivation, arousal, locomotion, heart rate, and blood pressure, and a diminished desire for food and sleep. Use of stimulants may cause the body to reduce significantly its production of natural body chemicals that fulfill similar functions. Until the body reestablishes its normal state, once the effect of the ingested stimulant has worn off the user may feel depressed, lethargic, confused, and miserable. This is referred to as a "crash", and may provoke reuse of the stimulant.

sensitization as well as a withdrawal syndrome can occur.[181] Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity.[182] Research on a progressive ratio self-administration protocol has found amphetamine, methylphenidate, modafinil, cocaine, and nicotine to all have a higher break point than placebo that scales with dose indicating reinforcing effects.[183] A progressive ratio self-administration protocol is a way of testing how much an animal or a human wants a drug by making them do a certain action (like pressing a lever or poking a nose device) to get the drug. The number of actions needed to get the drug increases every time, so it becomes harder and harder to get the drug. The highest number of actions that the animal or human is willing to do to get the drug is called the break point. The higher the break point, the more the animal or human wants the drug. In contrast to the classical stimulants such as amphetamine, the effects of modafinil depend on what the animals or humans have to do after getting the drug. If they have to do a performance task, like solving a puzzle or remembering something, modafinil makes them work harder for it than placebo, and the subjects wanted to self-administer modafinil. But if they had to do a relaxation task, like listening to music or watching a video, the subjects did not want to self-administer modafinil. This suggests that modafinil is more rewarding when it helps the animals or humans do something better or faster, especially considering that modafinil is not commonly abused or depended on by people, unlike other stimulants.[183]

Dependence potentials of common stimulants[161]
Drug Mean Pleasure Psychological dependence Physical dependence
Cocaine 2.39 3.0 2.8 1.3
Tobacco 2.21 2.3 2.6 1.8
Amphetamine 1.67 2.0 1.9 1.1
Ecstasy
1.13 1.5 1.2 0.7

Treatment for misuse

Psychosocial treatments, such as contingency management, have demonstrated improved effectiveness when added to treatment as usual consisting of counseling and/or case-management. This is demonstrated with a decrease in dropout rates and a lengthening of periods of abstinence.[184]

Testing

The presence of stimulants in the body may be tested by a variety of procedures. Serum and urine are the common sources of testing material although saliva is sometimes used. Commonly used tests include chromatography, immunologic assay, and mass spectrometry.[185]

See also

Notes

  1. INN and USAN of levomethamphetamine.[142][143]

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