stimulant 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 invigorating, or drugs that have sympathomimetic effects. 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. the most frequently prescribed stimulants as of 2013 were lisdexamfetamine (vyvanse), methylphenidate (ritalin), and amphetamine (adderall). 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%. ritalin: 20 mg sustained-release (sr) tablets effects acute stimulants in therapeutic doses, such as those given to patients with adhd, increases 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. in higher doses, stimulants may also produce euphoria, vigor, and a decreased need for sleep. many, but not all, stimulants have ergogenic effects. drugs such as ephedrine, pseudoephedrine, amphetamine and methylphenidate have well documented ergogenic effects, while cocaine has the opposite effect. neurocognitive enhancing effects of stimulants, specifically modafinil, amphetamine and methylphenidate have been documented in healthy adolescents, and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying. in some cases, psychiatric phenomena may emerge such as stimulant psychosis, paranoia, and suicidal ideation. acute toxicity has been reportedly associated with homicide, paranoia, aggressive behavior, motor dysfunction, and punding. the violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia. most drugs classified as stimulants are sympathomimetics, that is they stimulate the sympathetic branch of the autonomic nervous system. this leads to effects such as mydriasis, increased heart rate, blood pressure, respiratory rate and body temperature. 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. 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. 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. 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. 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. 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. 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, while inhalation may be associated with increased lower respiratory tract infection, lung cancer, and pathological restricting of lung tissue. cocaine may also increase risk for autoimmune disease 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. medical uses 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. 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. eugeroics are used in management of sleep disorders characterized by excessive daytime sleepiness, such as narcolepsy, and include stimulants such as modafinil. stimulants are used in impulse control disorders such as adhd and off-label in mood disorders such as major depressive disorder to increase energy, focus and elevate mood. stimulants such as epinephrine, theophylline and salbutamol 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. 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. however, they were largely abandoned for treatment of depression following the introduction of conventional antidepressants in the 1950s. subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years. stimulants produce a fast-acting and pronounced but transient and short-lived mood lift. in relation to this, they are minimally effective in the treatment of depression when administered continuously. in addition, tolerance to the mood-lifting effects of amphetamine has led to dose escalation and dependence. 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. the reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapid tolerance. tolerance to the effects of stimulants has been studied and characterized both in animals and humans. stimulant withdrawal is remarkably similar in its symptoms to those of major depressive disorder. chemistry for details on stimulant classes, see substituted phenethylamine and substituted amphetamine. 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. when referring to stimulants, the parent drug (e.g., amphetamine) will always be expressed in the singular; with the word "substituted" placed before the parent drug (substituted amphetamines). major stimulant classes include phenethylamines and their daughter class substituted amphetamines. amphetamines (class) main article: substituted amphetamines substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents. examples of substituted amphetamines are amphetamine (itself), methamphetamine, ephedrine, cathinone, phentermine, mephentermine, bupropion, methoxyphenamine, selegiline, amfepramone, pyrovalerone, mdma (ecstasy), and dom (stp). many drugs in this class work primarily by activating trace amine-associated receptor 1 (taar1); in turn, this causes reuptake inhibition and effluxion, or release, of dopamine, norepinephrine, and serotonin. 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. amphetamines-type stimulants are often used for their therapeutic effects. physicians sometimes prescribe amphetamine to treat major depression, where subjects do not respond well to traditional ssri medications, but evidence supporting this use is poor/mixed. notably, two recent large phase iii studies of lisdexamfetamine (a prodrug to amphetamine) as an adjunct to an ssri or snri in the treatment of major depressive disorder showed no further benefit relative to placebo in effectiveness. numerous studies have demonstrated the effectiveness of drugs such as adderall (a mixture of salts of amphetamine and dextroamphetamine) in controlling symptoms associated with adhd. due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse. cocaine analogues main article: list of cocaine analogues hundreds of cocaine analogues 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 analogues 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 derivatives and, notably, yohimbine, can decrease negative feedback by antagonizing regulatory autoreceptors. 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 a drug can elicit activating effects. caffeine is an adenosine receptor antagonist, and only indirectly increases catecholamine transmission in the brain. pitolisant is an h3-receptor inverse agonist. as h3 receptors mainly act as autoreceptors, pitolisant decreases negative feedback to histaminergic neurons, enhancing histaminergic transmission. notable stimulants amphetamine main article: amphetamine 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. amphetamine is also used off-label as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. 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. as a consequence, amphetamine is illegally manufactured in clandestine labs to be trafficked and sold to users. based upon drug and drug precursor seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of methamphetamine. the first pharmaceutical amphetamine was benzedrine, a brand of inhalers used to treat a variety of conditions. 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. 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. at therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control. likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength. in contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown. very high doses can result in psychosis (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use. 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. caffeine main article: 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. a few jurisdictions restrict its sale and use. caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient, or reducing one of its side-effects (especially drowsiness). tablets containing standardized doses of caffeine are also widely available. caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors. adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness. caffeine has been found to increase striatal dopamine in animal models, as well as inhibit the