Stimulants (also known ascentral nervous system stimulants, orpsychostimulants, or colloquially asuppers) are a class of drugs that increasealertness. They are used for various purposes, such as enhancingattention,motivation,cognition,mood, andphysical performance. Some stimulants occur naturally, while others are exclusively synthetic. Common stimulants includecaffeine,nicotine,amphetamines,cocaine,methylphenidate, andmodafinil. Stimulants may be subject to varying forms of regulation, or outright prohibition, depending on jurisdiction.
Stimulants increase activity in thesympathetic nervous system, either directly or indirectly. Prototypical stimulants increase synaptic concentrations ofexcitatory neurotransmitters, particularlynorepinephrine anddopamine (e.g., methylphenidate). Other stimulants work by binding to thereceptors 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, includingarousal,attention, thereward system,learning,memory, andemotion. Effects range from mild stimulation toeuphoria, 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.[1] Stimulants have been used to treat various conditions, such asnarcolepsy,attention deficit hyperactivity disorder (ADHD),obesity,depression, andfatigue. They have also been used asrecreational drugs,performance-enhancing substances, andcognitive 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.[2][3][4]
Stimulants have potential risks and side effects, such asaddiction,tolerance,withdrawal,psychosis,anxiety,insomnia,cardiovascular problems, andneurotoxicity. The misuse and abuse of stimulants can lead to serious health and social consequences, such asoverdose,dependence,crime, andviolence. Therefore, the use of stimulants is regulated by laws and policies in most countries, and requires medical supervision and prescription in some cases.
Astimulant is an overarching term that covers manydrugs including those that increase the activity of thecentral nervous system and the body,[5] drugs that are pleasurable and invigorating, or drugs that havesympathomimetic effects.[6] Sympathomimetic effects are those effects that mimic or copy the actions of thesympathetic 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 (namelyepinephrine andnorepinephrine) and cause similar effects.[7]
Stimulants in therapeutic doses, such as those given to patients withattention 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 theYerkes-Dodson Law.[8] In higher doses, stimulants may also produce euphoria, vigor, and a decreased need for sleep.
Many, but not all, stimulants haveergogenic 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.[9]
Neurocognitive enhancing effects of stimulants, specificallymodafinil, amphetamine and methylphenidate have been reported in healthy adolescents by some studies,[10] and is a commonly cited reason among illicit drug users for use, particularly among college students in the context of studying.[10] 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.[10] 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.[11][12][13]
In some cases, psychiatric phenomena may emerge such asstimulant psychosis,paranoia, andsuicidal ideation. Acute toxicity has been reportedly associated with hyperhydrosis, panic attacks, severe anxiety, mydriasis, paranoia, aggressive behavior, excessive motor activity, psychosis, rhabdomyolysis, andpunding. The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia.[14] Most drugs classified as stimulants aresympathomimetic, meaning that they stimulate the sympathetic branch of the autonomic nervous system. This leads to effects such asmydriasis (dilation of the pupils), increased heart rate, blood pressure, respiratory rate and body temperature.[6] When these changes become pathological, they are calledarrhythmia,hypertension, andhyperthermia, and may lead torhabdomyolysis,stroke,cardiac arrest, orseizures. 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.[15]
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 andischemicheart attacks.[16] 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.[17] A review of a year long period of prescription stimulant use in those withADHD found that cardiovascular side effects were limited to transient increases in blood pressure only.[18] 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.[19] 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.[20]
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, andsepsis.[21] Some effects are dependent upon the route of administration, with intravenous use associated with the transmission of many disease such asHepatitis C,HIV/AIDS and potential medical emergencies such asinfection,thrombosis orpseudoaneurysm,[22] while inhalation may be associated with increasedlower respiratory tract infection,lung cancer, and pathological restricting of lung tissue.[23] Cocaine may also increase risk for autoimmune disease[24][25][26] and damage nasal cartilage. Abuse of methamphetamine produces similar effects as well as marked degeneration of dopaminergic neurons, resulting in an increased risk forParkinson's disease.[27][28][29][30]
Stimulants are widely used throughout the world asprescription medicines as well as without a prescription (either legally orillicitly) asperformance-enhancing orrecreational drugs. Among narcotics, stimulants produce a noticeable crash orcomedown at the end of their effects. In the US, the most frequently prescribed stimulants as of 2013 werelisdexamfetamine (Vyvanse),methylphenidate (Ritalin), andamphetamine (Adderall).[31] It was estimated in 2015 that the percentage of the world population that had usedcocaine during a year was 0.4%. For the category "amphetamines and prescription stimulants" (with "amphetamines" includingamphetamine andmethamphetamine) the value was 0.7%, and forMDMA 0.4%.[32]
Stimulants have been used in medicine for many conditions includingobesity,sleep disorders,mood disorders,impulse control disorders,asthma,nasal congestion and, in case of cocaine, aslocal anesthetics.[33] Drugs used to treat obesity are calledanorectics and generally include drugs that follow the general definition of a stimulant, but other drugs such ascannabinoid receptor antagonists also belong to this group.[34][35]Eugeroics are used in management of sleep disorders characterized byexcessive daytime sleepiness, such asnarcolepsy, and include stimulants such asmodafinil andpitolisant.[36][37] Stimulants are used in impulse control disorders such asADHD[38] andoff-label inmood disorders such asmajor depressive disorder to increaseenergy, focus and elevate mood.[39] Stimulants such asepinephrine,[40]theophylline andsalbutamol[41] orally have been used to treat asthma, but inhaledadrenergic 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.[42][43]
Stimulants were one of the first classes of drugs to be used in the treatment ofdepression, beginning after the introduction of the amphetamines in the 1930s.[44][45][46] However, they were largely abandoned for treatment of depression following the introduction of conventionalantidepressants in the 1950s.[44][45] Subsequent to this, there has been a resurgence in interest in stimulants for depression in recent years.[47][48]
Stimulants produce a fast-acting and pronounced but transient and short-livedmood lift.[49][50][47][45] In relation to this, they are minimally effective in the treatment of depression when administered continuously.[49][50] In addition, tolerance to the mood-lifting effects of amphetamine has led to dose escalation anddependence.[48] Although the efficacy for depression with continuous administration is modest, it may still reachstatistical significance overplacebo and provide benefits similar in magnitude to those of conventional antidepressants.[51][52][53][54] The reasons for the short-term mood-improving effects of stimulants are unclear, but may relate to rapidtolerance.[49][50][45][55] Tolerance to the effects of stimulants has been studied and characterized both in animals[55][56][57][58] and humans.[59][60][61][62] Stimulantwithdrawal is remarkably similar in its symptoms to those ofmajor depressive disorder.[63][55][64][65]
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 asubstituted methylenedioxyphenethylamine, asubstituted amphetamine and consequently, asubstituted phenethylamine.[citation needed]
Major stimulant classes includephenethylamines and their daughter classsubstituted amphetamines.[66][67]
Substituted amphetamines are aclass of compounds based upon theamphetamine structure;[68] it includes allderivative compounds which are formed by replacing, orsubstituting, one or morehydrogen atoms in the amphetamine core structure withsubstituents.[68][69][70] Examples of substituted amphetamines are amphetamine (itself),[68][69]methamphetamine,[68]ephedrine,[68]cathinone,[68]phentermine,[68]mephentermine,[68]bupropion,[68]methoxyphenamine,[68]selegiline,[68]amfepramone,[68]pyrovalerone,[68]MDMA (ecstasy), andDOM (STP). Many drugs in this class work primarily by activatingtrace amine-associated receptor 1 (TAAR1);[71] in turn, this causesreuptake inhibition and effluxion, or release, ofdopamine,norepinephrine, andserotonin.[71] An additional mechanism of some substituted amphetamines is the release ofvesicular stores ofmonoamine neurotransmitters throughVMAT2, thereby increasing the concentration of these neurotransmitters in thecytosol, or intracellular fluid, of thepresynaptic neuron.[72]
Amphetamine-type stimulants are often used for their therapeutic effects. Physicians sometimes prescribe amphetamine to treatmajor depressive disorder, where subjects do not respond well to traditionalselective serotonin reuptake inhibitor (SSRI) medications,[citation needed] but evidence supporting this use is mixed.[48] Two largephase III studies oflisdexamfetamine (aprodrug to amphetamine) as an adjunct to an SSRI orserotonin–norepinephrine reuptake inhibitor (SNRI) in the treatment of major depressive disorder showed no further benefit relative to placebo in effectiveness.[73] Numerous studies have demonstrated the effectiveness of drugs likeAdderall (a mixture ofsalts of amphetamine anddextroamphetamine) in controlling symptoms associated withADHD. Non-stimulants such asatomoxetine have also found to be effective.[74] Due to their availability and fast-acting effects, substituted amphetamines are prime candidates for abuse.[75]
Hundreds of cocaine analogs have been created, all of them usually maintaining a benzyloxy connected to the 3 carbon of atropane. Various modifications include substitutions on thebenzene 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.
Most stimulants exert their activating effects by enhancingcatecholamine neurotransmission. Catecholamine neurotransmitters are employed in regulatory pathways implicated in attention, arousal, motivation, task salience and reward anticipation. Classical stimulants eitherblock the reuptake orstimulate the efflux of these catecholamines, resulting in increased activity of their circuits. Some stimulants, specifically those withempathogenic andhallucinogenic effects, also affectserotonergic transmission. Some stimulants, such as some amphetamine derivatives[which?] and, notably,yohimbine, can decreasenegative feedback by antagonizing regulatoryautoreceptors.[76]Adrenergic agonists, such as, in part,ephedrine, act by directly binding to and activatingadrenergic receptors, producing sympathomimetic effects.[citation needed]
There are also more indirectmechanisms of action by which a drug can elicit activating effects. Caffeine is anadenosine receptor antagonist, and only indirectly increases catecholamine transmission in the brain.[77]Pitolisant is anhistamine 3 (H3)-receptor inverse agonist. Ashistamine 3 (H3) receptors mainly act asautoreceptors, pitolisant decreases negative feedback tohistaminergic neurons, enhancing histaminergic transmission.
The precisemechanism of action of some stimulants, such as modafinil, for treating symptoms of narcolepsy and other sleep disorders, remains unknown.[78][79][80][81][82]
Amphetamine is a potentcentral nervous system (CNS) stimulant of thephenethylamine class that is approved for the treatment ofattention deficit hyperactivity disorder (ADHD) andnarcolepsy.[83] Amphetamine is also used off-label as aperformance andcognitive enhancer, and recreationally as anaphrodisiac andeuphoriant.[84][85][86][87] 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.[88][89] As a consequence, amphetamine is illegally manufactured inclandestine labs to be trafficked and sold to users.[90] Based upon drug anddrug precursor seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that ofmethamphetamine.[90]
The first pharmaceutical amphetamine wasBenzedrine, a brand of inhalers used to treat a variety of conditions.[91][92] 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 asmixed amphetamine salts,dextroamphetamine, andlisdexamfetamine.[91][93]
Amphetamine is anorepinephrine-dopamine releasing agent (NDRA). It enters neurons throughdopamine andnorepinephrine transporters and facilitates neurotransmitter efflux by activatingTAAR1 and inhibitingVMAT2.[71] At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improvedcognitive control.[85][86][94] Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[84] In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapidmuscle breakdown.[83][85][95] Very high doses can result inpsychosis (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.[96][97] 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.[83][95][96]
Caffeine is a stimulant compound belonging to thexanthine class of chemicals naturally found incoffee,tea, and (to a lesser degree)cocoa orchocolate. It is included in manysoft drinks, as well as a larger amount inenergy drinks. Caffeine is the world's most widely used psychoactive drug and by far the most common stimulant. InNorth America, 90% of adults consume caffeine daily.[98]
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.[99] 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.[100][101] 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.[100]
Caffeine is also included in some medications, usually for the purpose of enhancing the effect of the primary ingredient,[102] or reducing one of its side-effects (especially drowsiness).[103] Tablets containing standardized doses of caffeine are also widely available.[104]
Caffeine's mechanism of action differs from many stimulants, as it produces stimulant effects by inhibiting adenosine receptors.[105] Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness.[106] Caffeine has been found to increase striatal dopamine in animal models,[107] as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors,[108] 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.[109] 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.[110]
Coffee consumption is associated with a lower overall risk ofcancer.[111] This is primarily due to a decrease in the risks ofhepatocellular andendometrial cancer, but it may also have a modest effect on colorectal cancer.[112] There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk ofbladder cancer.[112] A protective effect of caffeine againstAlzheimer's disease is possible, but the evidence is inconclusive.[113][114][115] Moderate coffee consumption may decrease the risk ofcardiovascular disease,[116] and it may somewhat reduce the risk oftype 2 diabetes.[117] Drinking 1-3 cups of coffee per day does not affect the risk ofhypertension compared to drinking little or no coffee. However those who drink 2–4 cups per day may be at a slightly increased risk.[118] Caffeine increasesintraocular pressure in those withglaucoma but does not appear to affect normal individuals.[119] It may protect people fromliver cirrhosis.[120] There is no evidence that coffee stunts a child's growth.[121] Caffeine may increase the effectiveness of some medications including ones used to treatheadaches.[122] Caffeine may lessen the severity ofacute mountain sickness if taken a few hours prior to attaining a high altitude.[123]
Ephedrine is asympathomimeticamine similar in molecular structure to the well-known drugsphenylpropanolamine andmethamphetamine, as well as to the importantneurotransmitterepinephrine (adrenaline). Ephedrine is commonly used as a stimulant,appetite suppressant, concentration aid, anddecongestant, and to treathypotension associated with anesthesia.[citation needed]
In chemical terms, it is analkaloid with aphenethylamine skeleton found in various plants in the genusEphedra (familyEphedraceae). It works mainly by increasing the activity ofnorepinephrine (noradrenaline) onadrenergic receptors.[124] It is most usually marketed as thehydrochloride orsulfate salt.
The herbmá huáng (Ephedra sinica), used intraditional Chinese medicine (TCM), contains ephedrine andpseudoephedrine as its principal active constituents. The same may be true of other herbal products containing extracts from otherEphedra species.
3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly) is a euphoriant,empathogen, and stimulant of the amphetamine class.[125] Briefly used by some psychotherapists as an adjunct to therapy, the drug became popular recreationally and theDEA listed MDMA as aSchedule I controlled substance, prohibiting most medical studies and applications. MDMA is known for itsentactogenic properties. The stimulant effects of MDMA includehypertension,anorexia (appetite loss),euphoria, social disinhibition,insomnia (enhanced wakefulness/inability to sleep), improvedenergy, increased arousal, and increasedperspiration, 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.[126]
Due to the relative safety of MDMA, some researchers such asDavid 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".[127]
Methylenedioxypyrovalerone (MDPV) is apsychoactive drug with stimulant properties that acts as anorepinephrine-dopamine reuptake inhibitor (NDRI).[128] It was first developed in the 1960s by a team at Boehringer Ingelheim.[129] MDPV remained an obscure stimulant until around 2004, when it was reported to be sold as adesigner drug. Products labeled asbath salts containing MDPV were previously sold as recreational drugs in gas stations and convenience stores in the United States, similar to the marketing forSpice andK2 as incense.[130][131]
Incidents of psychological and physical harm have been attributed to MDPV use.[132][133]
Mephedrone is asynthetic stimulant drug of theamphetamine andcathinone classes. Slang names include drone[134] and MCAT.[135] It is reported to be manufactured in China and is chemically similar to the cathinone compounds found in thekhat plant ofeastern Africa. It comes in the form of tablets or a powder, which users can swallow, snort, or inject, producing similar effects toMDMA,amphetamines, andcocaine.
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 ananalog of other illegal drugs and can be controlled by laws similar to theFederal 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.[136][137][138]
Methamphetamine (contracted fromN-methyl-alpha-methylphenethylamine) is a potent psychostimulant of thephenethylamine andamphetamineclasses that is used to treatattention deficit hyperactivity disorder (ADHD) andobesity.[139][140][141] Methamphetamine exists as twoenantiomers,dextrorotary andlevorotary.[142][143] Dextromethamphetamine is a stronger CNS stimulant thanlevomethamphetamine;[95][142][143] however, both are addictive and produce the same toxicity symptoms at high doses.[143] Although rarely prescribed due to the potential risks, methamphetamine hydrochloride is approved by theUnited States Food and Drug Administration (USFDA) under the trade nameDesoxyn.[140] Recreationally, methamphetamine is used toincrease sexual desire,lift the mood, and increaseenergy, allowing some users to engage in sexual activity continuously for several days straight.[140][failed verification][144][unreliable source?]
Methamphetamine may be sold illicitly, either as pure dextromethamphetamine or in anequal parts mixture of the right- and left-handed molecules (i.e., 50% levomethamphetamine and 50% dextromethamphetamine).[144] Both dextromethamphetamine and racemic methamphetamine areschedule II controlled substances in the United States.[140] 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 theUnited Nations Convention on Psychotropic Substances treaty.[145][146] In contrast,levomethamphetamine is anover-the-counter drug in the United States.[note 1]
In low doses, methamphetamine can cause anelevated mood and increase alertness, concentration, and energy in fatigued individuals.[95][140] At higher doses, it can inducepsychosis,rhabdomyolysis, andcerebral hemorrhage.[95][140] Methamphetamine is known to have a high potential forabuse andaddiction.[95][140] Recreational use of methamphetamine may result in psychosis or lead topost-withdrawal syndrome, a withdrawal syndrome that can persist for months beyond the typical withdrawal period.[149] Unlikeamphetamine andcocaine, methamphetamine isneurotoxic to humans, damaging bothdopamine andserotonin neurons in thecentral nervous system (CNS).[139][141] 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;[139][141] this damage includes adverse changes in brain structure and function, such as reductions ingray matter volume in several brain regions and adverse changes in markers of metabolic integrity.[150][151][141] However, recreational amphetamine doses may also be neurotoxic.[152]
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 anorepinephrine-dopamine reuptake inhibitor (NDRI), by blocking thenorepinephrine transporter (NET) and thedopamine 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 is anSNDRI. Cocaine is made from the leaves of thecoca shrub, which grows in the mountain regions of South American countries such asBolivia,Colombia, andPeru, regions in which it was cultivated and used for centuries mainly by theAymara 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 inophthalmology.[153] 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. Othertropane derivative drugs related to cocaine are also known such astroparil andlometopane but have not been widely sold or used recreationally.[154]
Nicotine is the active chemical constituent intobacco, which is available in many forms, includingcigarettes,cigars,chewing tobacco, andsmoking cessation aids such asnicotine patches,nicotine gum, andelectronic cigarettes. Nicotine is used widely throughout the world for its stimulating and relaxing effects. Nicotine exerts its effects through the agonism ofnicotinic acetylcholine receptors, resulting in multiple downstream effects such as increase in activity of dopaminergic neurons in the midbrainreward system, and acetaldehyde one of the tobacco constituent decreased the expression ofmonoamine oxidase in the brain.[155] 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.[156]
Phenylpropanolamine (PPA; Accutrim; β-hydroxyamphetamine), also known as thestereoisomers norephedrine and norpseudoephedrine, is apsychoactive drug of thephenethylamine andamphetaminechemical classes that is used as a stimulant,decongestant, andanorectic agent.[157] It is commonly used inprescription andover-the-countercough and cold preparations. Inveterinary medicine, it is used to controlurinary incontinence in dogs undertrade names Propalin and Proin.
In the United States, PPA is no longer sold without a prescription due to a possible increased risk ofstroke 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.[158] In India, human use of PPA and its formulations were banned on 10 February 2011.[159]
Lisdexamfetamine (Vyvanse, etc.) is an amphetamine-type medication, sold for use in treatingADHD.[160] Its effects typically last around 14 hours.[161] Lisdexamfetamine is inactive on its own and is metabolized intodextroamphetamine in the body.[60] Consequently, it has a lower abuse potential.[60]
Pseudoephedrine is asympathomimeticdrug of thephenethylamine andamphetaminechemical classes. It may be used as anasal/sinus decongestant, as a stimulant,[162] or as awakefulness-promoting agent.[163]
Thesalts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in manyover-the-counterpreparations, either as a single ingredient or (more commonly) in combination withantihistamines,guaifenesin,dextromethorphan, and/orparacetamol (acetaminophen) or anotherNSAID (such asaspirin oribuprofen). It is also used as a precursor chemical in the illegal production of methamphetamine.
Khat is aflowering plant native to theHorn of Africa and theArabian Peninsula.[164][165]
Khat contains amonoaminealkaloid calledcathinone, a "keto-amphetamine". This alkaloid causes excitement,loss of appetite, andeuphoria. In 1980, theWorld Health Organization (WHO) classified it as adrug of abuse that can produce mild to moderatepsychological dependence (less than tobacco oralcohol),[166] although the WHO does not consider khat to be seriously addictive.[165] 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, includingDjibouti,Ethiopia,Somalia, Kenya andYemen.[167]
Modafinil is aneugeroic medication, which means that it promotes wakefulness and alertness. Modafinil is sold under the brand name Provigil among others. Modafinil is used to treatexcessive daytime sleepiness due tonarcolepsy,shift work sleep disorder, orobstructive 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.[168] Despite being a CNS stimulant, the addiction anddependence liabilities of modafinil are considered very low.[169][170][171] Although modafinil shares biochemical mechanisms with stimulant drugs, it is less likely to havemood-elevating properties.[170] The similarities in effects withcaffeine are not clearly established.[172][173] Unlike other stimulants, modafinil does not induce a subjectivefeeling of pleasure or reward, which is commonly associated witheuphoria, an intense feeling of well-being. Euphoria is a potential indicator ofdrug 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.[174][175]
Pitolisant is aninverse agonist (antagonist) of thehistamine 3 (H3) autoreceptor. As such, pitolisant is anantihistamine medication that also belongs to the class of CNS stimulants.[176][177][178][179] Pitolisant is also considered a medication ofeugeroic class, which means that it promotes wakefulness and alertness. Pitolisant is the firstwakefulness-promoting agent that acts by blocking theH3 autoreceptor.[180][181][182]
Pitolisant has been shown to be effective and well-tolerated for the treatment ofnarcolepsy with or without cataplexy.[182][181][180]
Pitolisant is the only non-controlled anti-narcoleptic drug in theUS.[180] It has shown minimal abuse risk in studies.[180][183]
Blocking thehistamine 3 (H3) autoreceptor increases the activity of histamineneurons in the brain. The H3 autoreceptors regulatehistaminergic activity in the central nervous system (and to a lesser extent, the peripheral nervous system) by inhibitinghistamine biosynthesis and release upon binding to endogenous histamine.[184] 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.[185]
Stimulants enhance the activity of thecentral andperipheral nervous systems. Common effects may include increasedalertness,awareness,wakefulness,endurance,productivity, andmotivation,arousal,locomotion,heart rate, andblood pressure, and a diminished desire forfood andsleep. 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 ofcentral nervous system (CNS) stimulants is common.Addiction to some CNS stimulants can quickly lead tomedical,psychiatric, andpsychosocial deterioration.Drug tolerance,dependence, andsensitization as well as awithdrawal syndrome can occur.[186] Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity.[187] Research on a progressive ratioself-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.[188] 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.[188]
| Dependence potentials of common stimulants[166] | ||||
|---|---|---|---|---|
| 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 |
Psychosocial treatments, such ascontingency 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.[189]
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.[190]
A well-known textbook of physical treatments described stimulants as having 'limited value in depression' because the euphoria they induce quickly wears off and 'the patient slips back' (Sargant & Slater 1944).
{{cite book}}: CS1 maint: location missing publisher (link)Substituted amphetamines, which are also called phenylpropylamino alkaloids, are a diverse group of nitrogen-containing compounds that feature a phenethylamine backbone with a methyl group at the α-position relative to the nitrogen (Figure 1). Countless variation in functional group substitutions has yielded a collection of synthetic drugs with diverse pharmacological properties as stimulants, empathogens and hallucinogens [3]. ... Beyond (1R,2S)-ephedrine and (1S,2S)-pseudoephedrine, myriad other substituted amphetamines have important pharmaceutical applications. The stereochemistry at the α-carbon is often a key determinant of pharmacological activity, with (S)-enantiomers being more potent. For example, (S)-amphetamine, commonly known as d-amphetamine or dextroamphetamine, displays five times greater psychostimulant activity compared with its (R)-isomer [78]. Most such molecules are produced exclusively through chemical syntheses and many are prescribed widely in modern medicine. For example, (S)-amphetamine (Figure 4b), a key ingredient in Adderall and Dexedrine, is used to treat attention deficit hyperactivity disorder (ADHD) [79]. ...
[Figure 4](b) Examples of synthetic, pharmaceutically important substituted amphetamines.
The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39).
Amphetamines and caffeine are stimulants that increase alertness, improve focus, decrease reaction time, and delay fatigue, allowing for an increased intensity and duration of training...
Physiologic and performance effects
• Amphetamines increase dopamine/norepinephrine release and inhibit their reuptake, leading to central nervous system (CNS) stimulation
• Amphetamines seem to enhance athletic performance in anaerobic conditions 39 40
• Improved reaction time
• Increased muscle strength and delayed muscle fatigue
• Increased acceleration
• Increased alertness and attention to task
Therapeutic (relatively low) doses of psychostimulants, such as methylphenidate and amphetamine, improve performance on working memory tasks both in individuals with ADHD and in normal subjects...it is now believed that dopamine and norepinephrine, but not serotonin, produce the beneficial effects of stimulants on working memory. At abused (relatively high) doses, stimulants can interfere with working memory and cognitive control, as will be discussed below. It is important to recognize, however, that stimulants act not only on working memory function, but also on general levels of arousal and, within the nucleus accumbens, improve the saliency of tasks. Thus, stimulants improve performance on effortful but tedious tasks...through indirect stimulation of dopamine and norepinephrine receptors.
Stimulant misuse appears to occur both for performance enhancement and their euphorogenic effects, the latter being related to the intrinsic properties of the stimulants (e.g., IR versus ER profile)...
Although useful in the treatment of ADHD, stimulants are controlled II substances with a history of preclinical and human studies showing potential abuse liability.
Unlike cocaine and amphetamine, methamphetamine is directly toxic to midbrain dopamine neurons.
Neuroimaging studies have revealed that METH can indeed cause neurodegenerative changes in the brains of human addicts (Aron and Paulus, 2007; Chang et al., 2007). These abnormalities include persistent decreases in the levels of dopamine transporters (DAT) in the orbitofrontal cortex, dorsolateral prefrontal cortex, and the caudate-putamen (McCann et al., 1998, 2008; Sekine et al., 2003; Volkow et al., 2001a, 2001c). The density of serotonin transporters (5-HTT) is also decreased in the midbrain, caudate, putamen, hypothalamus, thalamus, the orbitofrontal, temporal, and cingulate cortices of METH-dependent individuals (Sekine et al., 2006) ...
Neuropsychological studies have detected deficits in attention, working memory, and decision-making in chronic METH addicts ...
There is compelling evidence that the negative neuropsychiatric consequences of METH abuse are due, at least in part, to drug-induced neuropathological changes in the brains of these METH-exposed individuals ...
Structural magnetic resonance imaging (MRI) studies in METH addicts have revealed substantial morphological changes in their brains. These include loss of gray matter in the cingulate, limbic, and paralimbic cortices, significant shrinkage of hippocampi, and hypertrophy of white matter (Thompson et al., 2004). In addition, the brains of METH abusers show evidence of hyperintensities in white matter (Bae et al., 2006; Ernst et al., 2000), decreases in the neuronal marker, N-acetylaspartate (Ernst et al., 2000; Sung et al., 2007), reductions in a marker of metabolic integrity, creatine (Sekine et al., 2002) and increases in a marker of glial activation, myoinositol (Chang et al., 2002; Ernst et al., 2000; Sung et al., 2007; Yen et al., 1994). Elevated choline levels, which are indicative of increased cellular membrane synthesis and turnover are also evident in the frontal gray matter of METH abusers (Ernst et al., 2000; Salo et al., 2007; Taylor et al., 2007).
Topical nasal decongestants --(i) For products containing levmetamfetamine identified in 341.20(b)(1) when used in an inhalant dosage form. The product delivers in each 800 milliliters of air 0.04 to 0.150 milligrams of levmetamfetamine.
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