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 alertness. They are used for various purposes, such as enhancing attention, motivation, cognition, mood, and physical performance. Some stimulants occur naturally, while others are exclusively synthetic. Common stimulants include caffeine, nicotine, amphetamines, cocaine, methylphenidate, and modafinil. Stimulants may be subject to varying forms of regulation, or outright prohibition, depending on jurisdiction.

Stimulants increase activity in the sympathetic nervous system, either directly or indirectly. Prototypical stimulants increase synaptic concentrations of excitatory neurotransmitters, particularly norepinephrine and dopamine (e.g., methylphenidate). Other stimulants work by binding to the receptors of excitatory neurotransmitters (e.g., nicotine) or by blocking the activity of endogenous agents that promote sleep (e.g., caffeine). Stimulants can affect various functions, including arousal, attention, the reward system, learning, memory, and emotion. Effects range from mild stimulation to euphoria, depending on the specific drug, dose, route of administration, and inter-individual characteristics.

Stimulants have a long history of use, both for medical and non-medical purposes. Archeological evidence from Peru shows that cocaine use dates back as far as 8000 B.C.E.<ref>Template:Cite journal</ref> Stimulants have been used to treat various conditions, such as narcolepsy, attention deficit hyperactivity disorder (ADHD), obesity, depression, and fatigue. They have also been used as recreational drugs, performance-enhancing substances, and cognitive enhancers, by various groups of people, such as students, athletes, artists, and workers. They have also been used to promote aggression of combatants in wartime, both historically and in the present day.<ref>Template:Cite news</ref><ref>Template:Citation</ref><ref>Template:Cite journal</ref>

Stimulants have potential risks and side effects, such as addiction, tolerance, withdrawal, psychosis, anxiety, insomnia, cardiovascular problems, and neurotoxicity. The misuse and abuse of stimulants can lead to serious health and social consequences, 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,<ref name="Oxford-stimulant-def">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects.<ref name=NBK64328>Template:Cite book</ref> 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 (namely epinephrine and norepinephrine) and cause similar effects.<ref name="pmid36551221">Template:Cite journal</ref>

Effects

Acute

Stimulants in therapeutic doses, such as those given to patients with attention deficit hyperactivity disorder (ADHD), increase ability to focus, vigor, sociability, libido and may elevate mood. However, in higher doses, stimulants may actually decrease the ability to focus, a principle of the Yerkes-Dodson Law.<ref name="pmid32597132">Template:Cite journal</ref> In higher doses, stimulants may also produce euphoria, vigor, and a decreased need for sleep.

Many, but not all, stimulants have ergogenic effects; that is, they enhance physical performance. Drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while cocaine has the opposite effect.<ref name="pmid16799095">Template:Cite journal</ref>

Neurocognitive enhancing effects of stimulants, specifically modafinil, amphetamine and methylphenidate have been reported in healthy adolescents by some studies,<ref name="pmid24749160"/> and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying.<ref name="pmid24749160">Template:Cite journal</ref> 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.<ref name="pmid24749160"/> 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.<ref name="pmid36056861">Template:Cite journal</ref><ref name="pmid32341841">Template:Cite journal</ref><ref name="Meulen-2017">Template:Cite book</ref>

In some cases, psychiatric phenomena may emerge such as stimulant psychosis, paranoia, and suicidal ideation. Acute toxicity has been reportedly associated with hyperhydrosis, panic attacks, severe anxiety, mydriasis, paranoia, aggressive behavior, excessive motor activity, psychosis, rhabdomyolysis, and punding. The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia.<ref name="pmid15014637">Template:Cite journal</ref> Most drugs classified as stimulants are sympathomimetic, meaning that they stimulate the sympathetic branch of the autonomic nervous system. This leads to effects such as mydriasis (dilation of the pupils), increased heart rate, blood pressure, respiratory rate and body temperature.<ref name=NBK64328/> When these changes become pathological, they are called arrhythmia, hypertension, and hyperthermia, and may lead to rhabdomyolysis, stroke, cardiac arrest, or 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.<ref name="US-1999">Template:Cite book</ref>

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 ischemic heart attacks.<ref name="pmid22682429">Template:Cite journal</ref> 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.<ref name="pmid22917983">Template:Cite journal</ref> 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.<ref name="pmid25648243">Template:Cite journal</ref> However, a 2024 systematic review of the evidence found that stimulants overall improve ADHD symptoms and broadband behavioral measures in children and adolescents, though they carry risks of side effects like appetite suppression and other adverse events.<ref>Template:Cite journal</ref> 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.<ref name="pmid14658920">Template:Cite journal</ref>

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.<ref name=Sor2014>Template:Cite journal</ref> 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,<ref name="pmid16682239">Template:Cite journal</ref> while inhalation may be associated with increased lower respiratory tract infection, lung cancer, and pathological restricting of lung tissue.<ref name="pmid11224724">Template:Cite journal</ref> Cocaine may also increase risk for autoimmune disease<ref name="pmid6725666">Template:Cite journal</ref><ref name="pmid10095180">Template:Cite journal</ref><ref name="pmid9667555">Template:Cite journal</ref> 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.<ref name="pmid22392347">Template:Cite journal</ref><ref name="Thrash-">Template:Cite journal</ref><ref name="Autoxidation1">Template:Cite journal</ref><ref name="Autoxidation2">Template:Cite journal</ref>

Medical uses

Stimulants are widely used throughout the world as prescription medicines as well as without a prescription (either legally or illicitly) as performance-enhancing or recreational drugs. Among narcotics, stimulants produce a noticeable crash or comedown at the end of their effects. In the US, the most frequently prescribed stimulants as of 2013 were lisdexamfetamine (Vyvanse), methylphenidate (Ritalin), and amphetamine (Adderall).<ref name="www.drugs.com-top-100-2013">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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%.<ref name="World-Drug-Report-2015">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Stimulants have been used in medicine for many conditions including obesity, sleep disorders, mood disorders, impulse control disorders, asthma, nasal congestion and, in case of cocaine, as local anesthetics.<ref name="pmid16848922">Template:Cite journal</ref> Drugs used to treat obesity are called anorectics and generally include drugs that follow the general definition of a stimulant, but other drugs such as cannabinoid receptor antagonists also belong to this group.<ref name="pmid15823441">Template:Cite journal</ref><ref name="pmid16924165">Template:Cite journal</ref> Eugeroics are used in management of sleep disorders characterized by excessive daytime sleepiness, such as narcolepsy, and include stimulants such as modafinil and pitolisant.<ref name="FDA-2017">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid23539642">Template:Cite journal</ref> Stimulants are used in impulse control disorders such as ADHD<ref name="Research-Cf-2019">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> and off-label in mood disorders such as major depressive disorder to increase energy, focus and elevate mood.<ref name="pmid22034135">Template:Cite journal</ref> Stimulants such as epinephrine,<ref name="pmid18733372">Template:Cite journal</ref> theophylline and salbutamol<ref name="pmid15778490">Template:Cite journal</ref> orally have been used to treat asthma, but inhaled 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.<ref name="Bicopoulos">Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.</ref><ref name="PubMed Health">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="pmid18321627">Template:Cite journal</ref><ref name="Moncrieff2016">Template:Cite book</ref><ref name="pmid34000249">Template:Cite journal</ref> However, they were largely abandoned for treatment of depression following the introduction of conventional antidepressants in the 1950s.<ref name="pmid18321627"/><ref name="Moncrieff2016"/> Subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years.<ref name="pmid26906078">Template:Cite journal</ref><ref name="pmid17338594">Template:Cite journal</ref>

Stimulants produce a fast-acting and pronounced but transient and short-lived mood lift.<ref name="pmid36009115">Template:Cite journal</ref><ref name="pmid35431828">Template:Cite journal</ref><ref name="pmid26906078" /><ref name="Moncrieff2016" /> In relation to this, they are minimally effective in the treatment of depression when administered continuously.<ref name="pmid36009115" /><ref name="pmid35431828" /> In addition, tolerance to the mood-lifting effects of amphetamine has led to dose escalation and dependence.<ref name="pmid17338594"/> 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.<ref name="pmid29028590">Template:Cite journal</ref><ref name="pmid28590365">Template:Cite journal</ref><ref name="pmid34144366">Template:Cite journal</ref><ref name="pmid34986373">Template:Cite journal</ref> The reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapid tolerance.<ref name="pmid36009115" /><ref name="pmid35431828" /><ref name="Moncrieff2016" /><ref name="pmid15893821" /> Tolerance to the effects of stimulants has been studied and characterized both in animals<ref name="pmid15893821" /><ref name="pmid30768951">Template:Cite journal</ref><ref name="pmid30733244">Template:Cite journal</ref><ref name="pmid30733244-2">Template:Cite journal</ref> and humans.<ref name="pmid27021968">Template:Cite journal</ref><ref name="pmid28936175">Template:Cite journal</ref><ref name="pmid8834422">Template:Cite journal</ref><ref name="pmid11441429">Template:Cite journal</ref> Stimulant withdrawal is remarkably similar in its symptoms to those of major depressive disorder.<ref name="pmid12368072">Template:Cite journal</ref><ref name="pmid15893821">Template:Cite journal</ref><ref name="pmid21161752">Template:Cite book</ref><ref name="pmid16140055">Template:Cite journal</ref>

Chemistry

File:Methamphetamines.PNG

A chart comparing the chemical structures of different 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.Template:Citation needed

Major stimulant classes include phenethylamines and their daughter class substituted amphetamines.<ref name="pmid15801832">Template:Cite journal</ref><ref name="pmid38154512">Template:Cite journal</ref>

Amphetamines (class)

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Substituted amphetamines are a class of compounds based upon the amphetamine structure;<ref name="Amphetamine - a substituted amphetamine" /> it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents.<ref name="Amphetamine - a substituted amphetamine">Template:Cite journal</ref><ref name="Substituted amphetamines">Template:Cite book</ref><ref name="pmid1855720">Template:Cite journal</ref> Examples of substituted amphetamines are amphetamine (itself),<ref name="Amphetamine - a substituted amphetamine" /><ref name="Substituted amphetamines" /> methamphetamine,<ref name="Amphetamine - a substituted amphetamine" /> ephedrine,<ref name="Amphetamine - a substituted amphetamine" /> cathinone,<ref name="Amphetamine - a substituted amphetamine" /> phentermine,<ref name="Amphetamine - a substituted amphetamine" /> mephentermine,<ref name="Amphetamine - a substituted amphetamine" /> bupropion,<ref name="Amphetamine - a substituted amphetamine" /> methoxyphenamine,<ref name="Amphetamine - a substituted amphetamine" /> selegiline,<ref name="Amphetamine - a substituted amphetamine" /> amfepramone,<ref name="Amphetamine - a substituted amphetamine" /> pyrovalerone,<ref name="Amphetamine - a substituted amphetamine" /> MDMA (ecstasy), and DOM (STP). Many drugs in this class work primarily by activating trace amine-associated receptor 1 (TAAR1);<ref name="Miller" /> in turn, this causes reuptake inhibition and effluxion, or release, of dopamine, norepinephrine, and serotonin.<ref name="Miller" /> An additional mechanism of some substituted amphetamines is the release of vesicular stores of monoamine neurotransmitters through VMAT2, thereby increasing the concentration of these neurotransmitters in the cytosol, or intracellular fluid, of the presynaptic neuron.<ref name="E Weihe">Template:Cite journal</ref>

Amphetamine-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treat major depressive disorder, where subjects do not respond well to traditional selective serotonin reuptake inhibitor (SSRI) medications,Template:Citation needed but evidence supporting this use is mixed.<ref name="pmid17338594"/> Two large phase III studies of lisdexamfetamine (a prodrug to amphetamine) as an adjunct to an SSRI or serotonin–norepinephrine reuptake inhibitor (SNRI) in the treatment of major depressive disorder showed no further benefit relative to placebo in effectiveness.<ref name="DaleBang-Andersen2015">Template:Cite journal</ref> Numerous studies have demonstrated the effectiveness of drugs like Adderall (a mixture of salts of amphetamine and dextroamphetamine) in controlling symptoms associated with ADHD. Non-stimulants such as atomoxetine have also found to be effective.<ref>Template:Cite report</ref> Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse.<ref name="www.drugabuse.gov">Efforts of the National Institute on Drug Abuse to Prevent and Treat Prescription Drug Abuse Template:Webarchive, Testimony Before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources Committee on Government Reform, United States House of Representatives, 26 July 2006</ref>

Cocaine analogs

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Hundreds of cocaine analogs have been created, all of them usually maintaining a benzyloxy connected to the 3 carbon of a tropane. Various modifications include substitutions on the 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 catecholamine neurotransmission. Catecholamine neurotransmitters are employed in regulatory pathways implicated in attention, arousal, motivation, task salience and reward anticipation. Classical stimulants either block the reuptake or stimulate the efflux of these catecholamines, resulting in increased activity of their circuits. Some stimulants, specifically those with empathogenic and hallucinogenic effects, also affect serotonergic transmission. Some stimulants, such as some amphetamine derivativesTemplate:Which and, notably, yohimbine, can decrease negative feedback by antagonizing regulatory autoreceptors.<ref name="pmid18500382">Template:Cite journal</ref> Adrenergic agonists, such as, in part, ephedrine, act by directly binding to and activating adrenergic receptors, producing sympathomimetic effects.Template:Citation needed

There are also more indirect mechanisms of action by which a drug can elicit activating effects. Caffeine is an adenosine receptor antagonist, and only indirectly increases catecholamine transmission in the brain.<ref name="National Academies Press (US)-2001">Template:Cite book</ref> 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.<ref name="DrugsMonographForProfessionals">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid32032921">Template:Cite journal</ref><ref name="Stahl-2017">Template:Cite book</ref><ref name="pmid19300566">Template:Cite journal</ref><ref name="pmid28646346">Template:Cite journal</ref>

Notable stimulants

Amphetamine

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Amphetamine is a potent central nervous system (CNS) stimulant of the phenethylamine class that is approved for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.<ref name="FDA Abuse & OD">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Amphetamine is also used off-label as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant.<ref name="Ergogenics" /><ref name="Malenka_2009">Template:Cite book</ref><ref name="Libido">Template:Cite journal</ref><ref name="Nonmedical">Template:Cite journal</ref> Although it is a prescription medication in many countries, unauthorized possession and distribution of amphetamine is often tightly controlled due to the significant health risks associated with uncontrolled or heavy use.<ref name="UN Convention">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="drugpolicy">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> As a consequence, amphetamine is illegally manufactured in clandestine labs to be trafficked and sold to users.<ref name="Chawla-2006" /> Based upon drug and drug precursor seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of methamphetamine.<ref name="Chawla-2006">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions.<ref name="Amph Uses">Template:Cite journal</ref><ref name="Benzedrine">Template:Cite journal</ref> 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.<ref name="Amph Uses" /><ref name="Adderall IR">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Amphetamine is a norepinephrine-dopamine releasing agent (NDRA). It enters neurons through dopamine and norepinephrine transporters and facilitates neurotransmitter efflux by activating TAAR1 and inhibiting VMAT2.<ref name="Miller">Template:Cite journal</ref> At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control.<ref name="Malenka_2009" /><ref name="Libido" /><ref name="FDA Effects">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.<ref name="Ergogenics">Template:Cite journal</ref> In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown.<ref name="FDA Abuse & OD" /><ref name="Malenka_2009" /><ref name="Westfall-2010">Template:Cite book</ref> Very high doses can result in psychosis (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.<ref name="Cochrane">Template:Cite journal</ref><ref name="Stimulant Misuse">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="FDA Abuse & OD" /><ref name="Westfall-2010" /><ref name="Cochrane" />

Caffeine

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File:Roasted coffee beans.jpg

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.<ref name="demon drink">Template:Cite journal Template:Subscription required</ref>

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.<ref name="fda-caffeine">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="australia-interim-decision-ref-canada">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="australia-caffeine">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="australia-interim-decision-ref-canada"/>

Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient,<ref name="pmid29067618">Template:Cite journal</ref> or reducing one of its side-effects (especially drowsiness).<ref name="caffeine-drowsiness">Template:Cite journal</ref> Tablets containing standardized doses of caffeine are also widely available.<ref name="pmid29757951">Template:Cite journal</ref>

Caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors.<ref name="pmid1356551">Template:Cite journal</ref> Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness.<ref name="pmid20190965">Template:Cite journal</ref> Caffeine has been found to increase striatal dopamine in animal models,<ref name="pmid12151508">Template:Cite journal</ref> as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors,<ref name="pmid12804599">Template:Cite journal</ref> 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.<ref name="Fishchman-2016">Template:Cite book</ref> 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.<ref name="pmid19428492">Template:Cite journal</ref>

Coffee consumption is associated with a lower overall risk of cancer.<ref name="pmid18834663">Template:Cite journal</ref> This is primarily due to a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest effect on colorectal cancer.<ref name=Cancer10/> There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of bladder cancer.<ref name=Cancer10>Template:Cite journal</ref> A protective effect of caffeine against Alzheimer's disease is possible, but the evidence is inconclusive.<ref name="pmid20182026">Template:Cite journal</ref><ref name="pmid21427489">Template:Cite journal</ref><ref name="pmid20182037">Template:Cite journal</ref> Moderate coffee consumption may decrease the risk of cardiovascular disease,<ref name=Ding2014>Template:Cite journal</ref> and it may somewhat reduce the risk of type 2 diabetes.<ref name=Dam08>Template:Cite journal</ref> Drinking 1-3 cups of coffee per day does not affect the risk of hypertension compared to drinking little or no coffee. However those who drink 2–4 cups per day may be at a slightly increased risk.<ref name="pmid21450934">Template:Cite journal</ref> Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.<ref name="pmid20706731">Template:Cite journal</ref> It may protect people from liver cirrhosis.<ref name="pmid19825397">Template:Cite journal</ref> There is no evidence that coffee stunts a child's growth.<ref name="Times-Books-2007">Template:Cite book</ref> Caffeine may increase the effectiveness of some medications including ones used to treat headaches.<ref name="pmid21302868">Template:Cite journal</ref> Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.<ref name="pmid20367483">Template:Cite journal</ref>

Ephedrine

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Ephedrine is a sympathomimetic amine similar in molecular structure to the well-known drugs phenylpropanolamine and methamphetamine, as well as to the important neurotransmitter epinephrine (adrenaline). Ephedrine is commonly used as a stimulant, appetite suppressant, concentration aid, and decongestant, and to treat hypotension associated with anesthesia.Template:Citation needed

In chemical terms, it is an alkaloid with a phenethylamine skeleton found in various plants in the genus Ephedra (family Ephedraceae). It works mainly by increasing the activity of norepinephrine (noradrenaline) on adrenergic receptors.<ref name=merck>Merck Manuals EPHEDrine Template:Webarchive Last full review/revision January 2010</ref> 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

File:Ecstasy monogram.jpg

Tablets containing MDMA

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3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly) is a euphoriant, empathogen, and stimulant of the amphetamine class.<ref name="pmid24648791">Template:Cite journal</ref> Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and the DEA listed MDMA as a Schedule I controlled substance, prohibiting most medical studies and applications. MDMA is known for its 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.<ref name="pmid17382831">Template:Cite journal</ref>

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".<ref name="Telegraph.co.uk-2009">Template:Cite news</ref>

MDPV

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Methylenedioxypyrovalerone (MDPV) is a psychoactive drug with stimulant properties that acts as a norepinephrine-dopamine reuptake inhibitor (NDRI).<ref name="SimmlerBuser2012">Template:Cite journal</ref> It was first developed in the 1960s by a team at Boehringer Ingelheim.<ref name="US-Patent-3478050">US Patent 3478050 – 1-(3,4-methylenedioxy-phenyl)-2-pyrrolidino-alkanones</ref> MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as a designer drug. Products labeled as bath salts containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing for Spice and K2 as incense.<ref name="KMBC.com-2010">Template:Cite news</ref><ref name="MDPV Bath Salts Drug Over The Counter">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Incidents of psychological and physical harm have been attributed to MDPV use.<ref name="www.nbc33tv.com-2010">Template:Cite news</ref><ref name="www.nbc33tv.com-2011">Template:Cite news</ref>

Mephedrone

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Mephedrone is a synthetic stimulant drug of the amphetamine and cathinone classes. Slang names include drone<ref name=Cumming>Template:Cite news</ref> and MCAT.<ref name=bbc0803>Template:Cite news</ref> It is reported to be manufactured in China and is chemically similar to the cathinone compounds found in the khat plant of 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 analog of other illegal drugs and can be controlled by laws similar to the 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.<ref name="pmid26074741">Template:Cite journal</ref><ref name="pmid27908258">Template:Cite journal</ref><ref name="pmid32087112">Template:Cite journal</ref>

Methamphetamine

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Methamphetamine (contracted from Template:Nowrap) is a potent psychostimulant of the phenethylamine and amphetamine classes that is used to treat attention deficit hyperactivity disorder (ADHD) and obesity.<ref name = "Malenka">Template:Cite book</ref><ref name="Desoxyn">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid19328213">Template:Cite journal</ref> Methamphetamine exists as two enantiomers, dextrorotary and levorotary.<ref name="Kuczenski">Template:Cite journal</ref><ref name="Mendelson">Template:Cite journal</ref> Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine;<ref name="Westfall-2010" /><ref name="Kuczenski" /><ref name="Mendelson" /> however, both are addictive and produce the same toxicity symptoms at high doses.<ref name="Mendelson" /> Although rarely prescribed due to the potential risks, methamphetamine hydrochloride is approved by the United States Food and Drug Administration (USFDA) under the trade name Desoxyn.<ref name="Desoxyn" /> Recreationally, methamphetamine is used to increase sexual desire, lift the mood, and increase energy, allowing some users to engage in sexual activity continuously for several days straight.<ref name="Desoxyn" />Template:Failed verification<ref name="SF Meth" />Template:Unreliable source?

Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in an equal parts mixture of the right- and left-handed molecules (i.e., 50% levomethamphetamine and 50% dextromethamphetamine).<ref name="SF Meth">Template:Cite episode</ref> Both dextromethamphetamine and racemic methamphetamine are schedule II controlled substances in the United States.<ref name="Desoxyn" /> 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.<ref name="United Nations-2007">Template:Cite book</ref><ref name="incb">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In contrast, levomethamphetamine is an over-the-counter drug in the United States.<ref name="OTC levmetamfetamine" group="note">The active ingredient in some OTC inhalers in the United States is listed as levmetamfetamine, the INN and USAN of levomethamphetamine.<ref name="FDA levmetamfetamine">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="National Center for Biotechnology Information">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref></ref>

In low doses, methamphetamine can cause an elevated mood and increase alertness, concentration, and energy in fatigued individuals.<ref name="Westfall-2010" /><ref name="Desoxyn" /> At higher doses, it can induce psychosis, rhabdomyolysis, and cerebral hemorrhage.<ref name="Westfall-2010" /><ref name="Desoxyn" /> Methamphetamine is known to have a high potential for abuse and addiction.<ref name="Westfall-2010" /><ref name="Desoxyn" /> Recreational use of methamphetamine may result in psychosis or lead to post-withdrawal syndrome, a withdrawal syndrome that can persist for months beyond the typical withdrawal period.<ref name="Cruickshank-2009">Template:Cite journal</ref> Unlike amphetamine and cocaine, methamphetamine is neurotoxic to humans, damaging both dopamine and serotonin neurons in the central nervous system (CNS).<ref name = "Malenka" /><ref name="pmid19328213" /> Unlike the long-term use of amphetamine in prescription doses, which may improve certain brain regions in individuals with ADHD, there is evidence that methamphetamine causes brain damage from long-term use in humans;<ref name = "Malenka" /><ref name="pmid19328213" /> this damage includes adverse changes in brain structure and function, such as reductions in gray matter volume in several brain regions and adverse changes in markers of metabolic integrity.<ref name="Neuroplasticity 1">Template:Cite journal</ref><ref name="Neuroplasticity 2">Template:Cite journal</ref><ref name="pmid19328213" /> However, recreational amphetamine doses may also be neurotoxic.<ref name="pmid6320247">Template:Cite journal</ref>

Methylphenidate

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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 (NDRI), 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

File:Cocaine lines 2.jpg

Lines of cocaine, a popular stimulant

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.<ref name="Avance Psicólogos-2020">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="American Family Physician-1986">Template:Cite journal</ref>

Nicotine

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Nicotine is the active chemical constituent in tobacco, which is available in many forms, including cigarettes, cigars, chewing tobacco, and smoking cessation aids such as nicotine patches, nicotine gum, and electronic cigarettes. Nicotine is used widely throughout the world for its stimulating and relaxing effects. Nicotine exerts its effects through the agonism of 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.<ref name="pmid17382522">Template:Cite journal</ref> 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.<ref name="pmid21036393">Template:Cite journal</ref>

Phenylpropanolamine

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Phenylpropanolamine (PPA; Accutrim; β-hydroxyamphetamine), also known as the stereoisomers norephedrine and norpseudoephedrine, is a psychoactive drug of the phenethylamine and amphetamine chemical classes that is used as a stimulant, decongestant, and anorectic agent.<ref name="pmid15608085">Template:Cite journal</ref> It is commonly used in prescription and over-the-counter 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.<ref name="Health Canada-2009">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In India, human use of PPA and its formulations were banned on 10 February 2011.<ref name="Drugs-banned-India-2013">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Lisdexamfetamine

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Lisdexamfetamine (Vyvanse, etc.) is an amphetamine-type medication, sold for use in treating ADHD.<ref name="medlineplus-gov-2013">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Its effects typically last around 14 hours.<ref name="AHFS20192">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Lisdexamfetamine is inactive on its own and is metabolized into dextroamphetamine in the body.<ref name="pmid28936175"/> Consequently, it has a lower abuse potential.<ref name="pmid28936175"/>

Pseudoephedrine

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Pseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant,<ref name="pmid9018513">Template:Cite journal</ref> or as a wakefulness-promoting agent.<ref name="pmid16531903">Template:Cite journal</ref>

The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations, either as a single ingredient or (more commonly) in combination with antihistamines, guaifenesin, dextromethorphan, and/or paracetamol (acetaminophen) or another NSAID (such as aspirin or ibuprofen). It is also used as a precursor chemical in the illegal production of methamphetamine.

Catha edulis (Khat)

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File:Catha edulis.jpg

Catha edulis

Khat is a flowering plant native to the Horn of Africa and the Arabian Peninsula.<ref name="Tooea">Template:Cite book Template:Open access Template:Link note</ref><ref name="Kciy">Template:Cite news</ref>

Khat contains a monoamine alkaloid called cathinone, a "keto-amphetamine". This alkaloid causes excitement, loss of appetite, and euphoria. In 1980, the World Health Organization (WHO) classified it as a drug of abuse that can produce mild to moderate psychological dependence (less than tobacco or alcohol),<ref name="King">Template:Cite journal</ref> although the WHO does not consider khat to be seriously addictive.<ref name="Kciy" /> 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.<ref name="Hafmc">Haight-Ashbury Free Medical Clinic, Journal of psychoactive drugs, Volume 41, (Haight-Ashbury Publications: 2009), p.3.</ref>

Modafinil

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Modafinil is an eugeroic medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treat excessive daytime sleepiness due to narcolepsy, shift work sleep disorder, or obstructive sleep apnea. While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive.<ref name="pmid31433334">Template:Cite journal</ref> Despite being a CNS stimulant, the addiction and dependence liabilities of modafinil are considered very low.<ref name="pmid23065655">Template:Cite journal</ref><ref name="FDA-2015-Provigil-Prescribing">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="pmid33435717">Template:Cite journal</ref> Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to have mood-elevating properties.<ref name="FDA-2015-Provigil-Prescribing"/> The similarities in effects with caffeine are not clearly established.<ref name="pmid22375280">Template:Cite journal</ref><ref name="Warot-1993">Template:Cite journal</ref> 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.<ref name="pmid16741217">Template:Cite journal</ref><ref name="pmid30285371">Template:Cite book</ref>

Pitolisant

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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.<ref name="www.ncbi.nlm.nih.gov">Template:Cite book</ref><ref name="pmid31644012">Template:Cite book</ref><ref name="Drugs.com-pitolisant-side">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Drugs.com-pitolisant-list-of CNS">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Pitolisant is also considered a medication of eugeroic class, which means that it promotes wakefulness and alertness. Pitolisant is the first wakefulness-promoting agent that acts by blocking the H₃ autoreceptor.<ref name="pmid31997137"/><ref name="pmid28449891"/><ref name="pmid34546302"/>

Pitolisant has been shown to be effective and well-tolerated for the treatment of narcolepsy with or without cataplexy.<ref name="pmid34546302">Template:Cite journal</ref><ref name="pmid28449891">Template:Cite journal</ref><ref name="pmid31997137"/>

Pitolisant is the only non-controlled anti-narcoleptic drug in the US.<ref name="pmid31997137">Template:Cite journal</ref> It has shown minimal abuse risk in studies.<ref name="pmid31997137" /><ref name="pmid32941089">Template:Cite journal</ref>

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.<ref name="pmid2172771">Template:Cite journal</ref> 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.<ref name="pmid35774905">Template:Cite journal</ref>

Recreational use and issues of abuse

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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.

Abuse of central nervous system (CNS) stimulants is common. Addiction to some CNS stimulants can quickly lead to medical, psychiatric, and psychosocial deterioration. Drug tolerance, dependence, and sensitization as well as a withdrawal syndrome can occur.<ref name="pmid1974121">Template:Cite journal</ref> Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity.<ref name="pmid24662599">Template:Cite journal</ref> 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.<ref name="pmid19086771">Template:Cite journal</ref> 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.<ref name="pmid19086771"/>

Dependence potentials of common stimulants<ref name="King" />
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.<ref name="pmid27684277">Template:Cite journal</ref>

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.<ref name="Gian-1999">AJ Giannini. Drug Abuse. Los Angeles, Health Information Press, 1999, pp.203–208</ref>

See also

• Antidepressants
• Depressants
• Hallucinogens
• Nootropics
• Psychoanaleptics

External links

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