what is caffeine

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,[1] drugs that are pleasurable and invigorating, or drugs that have sympathomimetic effects.[2] 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. The most frequently prescribed stimulants as of 2013 were lisdexamfetamine, methylphenidate, and amphetamine.[3] 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 Ecstasy 0.4%.[4]

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 decrease 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.[5] 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.[6]

In some cases psychiatric phenomenon may emerge such as stimulant psychosis, paranoia, and suicidal ideation. Acute toxicity has been reportedly associated with a homicide, paranoia, aggressive behavior, motor dysfunction, and punding. The violent and aggressive behavior associated with acute stimulant toxicity may partially be driven by paranoia.[7] 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.[8] 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.[9]

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.[10] 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.[11] 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.[12] 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.[13]

what is caffeine

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.[14] 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,[15] while inhalation may be associated with increased lower respiratory tract infection, lung cancer, and pathological restricting of lung tissue.[16] Cocaine may also increase risk for autoimmune disease[17][18][19] 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.[20][21][22][23]

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.[24] 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.[25][26]Eugeroics are used in management of sleep disorders characterized by excessive daytime sleepiness, such as narcolepsy, and include stimulants such as modafinil.[27][28] Stimulants are used in impulse control disorders such as ADHD[29] and off-label in mood disorders such as major depressive disorder to increase energy, focus and elevate mood.[30] Stimulants such as epinephrine,[31]theophylline and salbutamol[32] 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.[33][34]

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

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

Major stimulant classes include phenethylamines and their daughter class substituted amphetamines.[according to whom?]

Substituted amphetamines are a class of compounds based upon the amphetamine structure;[35] it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with substituents.[35][36][37] Examples of substituted amphetamines are amphetamine (itself),[35][36]methamphetamine,[35]ephedrine,[35]cathinone,[35]phentermine,[35]mephentermine,[35]bupropion,[35]methoxyphenamine,[35]selegiline,[35]amfepramone,[35]pyrovalerone,[35]MDMA (ecstasy), and DOM (STP). Many drugs in this class work primarily by activating trace amine-associated receptor 1 (TAAR1);[38] in turn, this causes reuptake inhibition and effluxion, or release, of dopamine, norepinephrine, and serotonin.[38] 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.[39]

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,[citation needed] but evidence supporting this use is poor/mixed.[40] 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.[41] 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.[42]

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.

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.[43]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.[44]Pitolisant is an H3-receptor inverse agonist. As H3 receptors mainly act as autoreceptors, pitolisant decreases negative feedback to histaminergic neurons, enhancing histaminergic transmission.

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.[45] Amphetamine is also used off-label as a performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant.[46][47][48][49] 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.[50][51] As a consequence, amphetamine is illegally manufactured in clandestine labs to be trafficked and sold to users.[52] Based upon drug and drug precursor seizures worldwide, illicit amphetamine production and trafficking is much less prevalent than that of methamphetamine.[52]

The first pharmaceutical amphetamine was Benzedrine, a brand of inhalers used to treat a variety of conditions.[53][54] 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.[53][55]

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.[38] At therapeutic doses, this causes emotional and cognitive effects such as euphoria, change in libido, increased arousal, and improved cognitive control.[47][48][56] Likewise, it induces physical effects such as decreased reaction time, fatigue resistance, and increased muscle strength.[46] In contrast, supratherapeutic doses of amphetamine are likely to impair cognitive function and induce rapid muscle breakdown.[45][47][57] Very high doses can result in psychosis (e.g., delusions and paranoia), which very rarely occurs at therapeutic doses even during long-term use.[58][59] 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.[45][57][58]

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.[60] A few jurisdictions restrict its sale and use.[citation needed] 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.[61] Adenosine receptors are thought to be a large driver of drowsiness and sleep, and their action increases with extended wakefulness.[62] Caffeine has been found to increase striatal dopamine in animal models,[63] as well as inhibit the inhibitory effect of adenosine receptors on dopamine receptors,[64] 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, which people preferring placebo over caffeine in a study on drug abuse liability published in an NIDA research monograph.[65] 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.[66]

Coffee consumption is associated with a lower overall risk of cancer.[67] 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.[68] 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.[68] A protective effect of caffeine against Alzheimer’s disease is possible, but the evidence is inconclusive.[69][70][71] Moderate coffee consumption may decrease the risk of cardiovascular disease,[72] and it may somewhat reduce the risk of type 2 diabetes.[73] 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.[74] Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals.[75] It may protect people from liver cirrhosis.[76] There is no evidence that coffee stunts a child’s growth.[77] Caffeine may increase the effectiveness of some medications including ones used to treat headaches.[78] Caffeine may lessen the severity of acute mountain sickness if taken a few hours prior to attaining a high altitude.[79]

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 anaesthesia.

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.[80] 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.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, or molly) is a euphoriant, empathogen, and stimulant of the amphetamine class.[81] 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.[82]

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”.[83]

Methylenedioxypyrovalerone (MDPV) is a psychoactive drug with stimulant properties that acts as a norepinephrine-dopamine reuptake inhibitor (NDRI).[84] It was first developed in the 1960s by a team at Boehringer Ingelheim.[85] 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.[86][87]

Incidents of psychological and physical harm have been attributed to MDPV use.[88][89]

Mephedrone is a synthetic stimulant drug of the amphetamine and cathinone classes. Slang names include drone[90] and MCAT.[91] 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.

Methamphetamine (contracted from N-methyl-alpha-methylphenethylamine) is a potent psychostimulant of the phenethylamine and amphetamine classes that is used to treat attention deficit hyperactivity disorder (ADHD) and obesity.[92][93][94] Methamphetamine exists as two enantiomers, dextrorotary and levorotary.[95][96] Dextromethamphetamine is a stronger CNS stimulant than levomethamphetamine;[57][95][96] however, both are addictive and produce the same toxicity symptoms at high doses.[96] 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.[93] 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.[93][97]

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).[97] Both dextromethamphetamine and racemic methamphetamine are schedule II controlled substances in the United States.[93] 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.[98][99] In contrast, levomethamphetamine is an over-the-counter drug in the United States.[note 1]

In low doses, methamphetamine can cause an elevated mood and increase alertness, concentration, and energy in fatigued individuals.[57][93] At higher doses, it can induce psychosis, rhabdomyolysis, and cerebral hemorrhage.[57][93] Methamphetamine is known to have a high potential for abuse and addiction.[57][93] 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.[102] Unlike amphetamine and cocaine, methamphetamine is neurotoxic to humans, damaging both dopamine and serotonin neurons in the central nervous system (CNS).[92][94] Entirely opposite to the long-term use of amphetamine, there is evidence that methamphetamine causes brain damage from long-term use in humans;[92][94] 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.[103][104][94]

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

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

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

Cocaine 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.[105] 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.[106]

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 receptor, 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.[107] 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.[108]

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.[109] 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 proposed 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.[110] In India, human use of PPA and its formulations were banned on 10 February 2011.[111]

what is caffeine

Propylhexedrine (Hexahydromethamphetamine, Obesin) is a stimulant medication, sold over-the-counter in the United States as the cold medication Benzedrex.[112] The drug has also been used as an appetite suppressant in Europe. Propylhexedrine is not an amphetamine, though it is structurally similar; it is instead a cycloalkylamine, and thus has stimulant effects that are less potent than similarly structured amphetamines, such as methamphetamine.

The abuse potential of propylhexedrine is fairly limited, due its limited routes of administration: in the United States, Benzedrex is only available as an inhalant, mixed with lavender oil and menthol. These ingredients cause unpleasant tastes, and abusers of the drug have reported unpleasant “menthol burps”. Injection of the drug has been found to cause transient diplopia and brain stem dysfunction.[113][114][115]

Pseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant,[116] or as a wakefulness-promoting agent.[117]

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.

Khat is a flowering plant native to the Horn of Africa and the Arabian Peninsula.[118][119]

Khat contains a monoamine alkaloid called cathinone, a “keto-amphetamine”, that is said to cause 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),[120] although the WHO does not consider khat to be seriously addictive.[119] It is banned in some countries, such as the United States, Canada, and Germany, while its production, sale, and consumption are legal in other nations, including Djibouti, Ethiopia, Somalia, and Yemen.[121]

Modafinil, sold under the brand name Provigil among others, is a CNS stimulant and a medication to treat sleepiness due to narcolepsy, shift work sleep disorder, or obstructive sleep apnea.[1][7] While it has seen off-label use as a purported cognitive enhancer, the research on its effectiveness for this use is not conclusive.[8][9] It is taken by mouth

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.[122] Stimulants may be screened for in animal discrimination and self-administration models which have high sensitivity albeit low specificity.[123] 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.[124]

Psychosocial treatments, such as contingency management, have demonstrated improved effectiveness when added to treatment as usual consisting of counselling and/or case-management. This is demonstrated with a decrease in dropout rates and a lengthening of periods of abstinence.[126]

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.[127]

“World Drug Report 2015”

Archived

“Methamphetamine-induced neurotoxicity: the road to Parkinson’s disease”

Archived

“The Voice of the Patient A series of reports from the U.S. Food and Drug Administration’s (FDA’s) Patient-Focused Drug Development Initiative”

Archived

“Adderall XR Prescribing Information”

Archived

“World Drug Report 2006”

Archived

“Adderall IR Prescribing Information”

Archived

“Adderall XR Prescribing Information”

Archived

“Stimulant Misuse: Strategies to Manage a Growing Problem”

the original

Testing for Abuse Liability of Drugs in Humans

the original

“Desoxyn Prescribing Information”

Archived

Preventing Amphetamine-type Stimulant Use Among Young People: A Policy and Programming Guide

Archived

“List of psychotropic substances under international control”

the original

2HI4

1544

13077

ENSG00000140505

ENSMUSG00000032310

what is caffeine

P05177

P00186

NM_000761

NM_009993

NP_000752

NP_034123

Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body.[5] In humans, the CYP1A2 enzyme is encoded by the CYP1A2 gene.[6]

CYP1A2 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. CYP1A2 localizes to the endoplasmic reticulum and its expression is induced by some polycyclic aromatic hydrocarbons (PAHs), some of which are found in cigarette smoke. The enzyme’s endogenous substrate is unknown; however, it is able to metabolize some PAHs to carcinogenic intermediates. Other xenobiotic substrates for this enzyme include caffeine, aflatoxin B1, and paracetamol (acetaminophen). The transcript from this gene contains four Alu sequences flanked by direct repeats in the 3′ untranslated region.[7]

CYP1A2 also metabolizes polyunsaturated fatty acids into signaling molecules that have physiological as well as pathological activities. It has monoxygenase activity for certain of these fatty acids in that it metabolizes arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid) but also has epoxygenase activity in that it metabolizes docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and similarly metabolizes eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenic acid and 17S,18R-eicosatetraenic acid isomers (termed 17,18-EEQ).[8]

19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts arterioles, elevates blood pressure, promotes inflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated (see 20-Hydroxyeicosatetraenoic acid). The EDP (see Epoxydocosapentaenoic acid) and EEQ (see epoxyeicosatetraenoic acid) metabolites have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit angiogenesis, endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines.[9][10][11][12] It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids.[9][12][13] EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by epoxide hydrolases, particularly soluble epoxide hydrolase, and therefore act locally.

CYP1A2 is not regarded as being a major contributor to forming the cited epoxides[12] but could act locally in certain tissues to do so.

The authoratitive list of star allele nomenclature for CYP1A2 along with activity scores is kept by PharmVar[14]

Expression of CYP1A2 appears to be induced by various dietary constituents.[15] Vegetables such as cabbages, cauliflower and broccoli are known to increase levels of CYP1A2. Lower activity of CYP1A2 in South Asians appears to be due to cooking these vegetables in curries using ingredients such as cumin and turmeric, ingredients known to inhibit the enzyme.[16]

Following is a table of selected substrates, inducers and inhibitors of CYP1A2.

Inhibitors of CYP1A2 can be classified by their potency, such as:

Moderate

Weak

Unspecified potency:

Moderate inducers:[19]

Unspecified potency:

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

2hi4: Crystal Structure of Human Microsomal P450 1A2 in complex with alpha-naphthoflavone

3E4E, 3E6I, 3GPH, 3KOH, 3LC4, 3T3Z

1571

13106

ENSG00000130649

ENSMUSG00000025479

what is caffeine

P05181

Q05421

NM_000773

NM_021282

NP_000764

NP_067257

Cytochrome P450 2E1 (abbreviated CYP2E1, EC 1.14.13.n7) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.[5]

While CYP2E1 itself carries out a relatively low number of these reactions (~4% of known P450-mediated drug oxidations), it and related enzymes CYP1A2 and CYP3A4 are responsible for the breakdown of many toxic environmental chemicals and carcinogens that enter the body, in addition to basic metabolic reactions such as fatty acid oxidations.[6]

CYP2E1 is a membrane protein expressed in high levels in the liver, where it composes nearly 50% of the total hepatic cytochrome P450 mRNA[7] and 7% of the hepatic cytochrome P450 protein.[8] The liver is therefore where most drugs undergo deactivation by CYP2E1, either directly or by facilitated excretion from the body.

CYP2E1 metabolizes mostly small, polar molecules, including toxic laboratory chemicals such as dimethylformamide, aniline, and halogenated hydrocarbons (see table below). While these oxidations are often of benefit to the body, certain carcinogens and toxins are bioactivated by CYP2E1, implicating the enzyme in the onset of hepatotoxicity caused by certain classes of drugs (see disease relevance section below).

CYP2E1 also plays a role in several important metabolic reactions, including the conversion of ethanol to acetaldehyde and to acetate in humans,[9] where it works alongside alcohol dehydrogenase and aldehyde dehydrogenase. In the conversion sequence of acetyl-CoA to glucose, CYP2E1 transforms acetone via hydroxyacetone (acetol) into propylene glycol and methylglyoxal, the precursors of pyruvate, acetate and lactate.[10][11][12]

CYP2E1 also carries out the metabolism of endogenous fatty acids such as the ω-1 hydroxylation of fatty acids such as arachidonic acid, involving it in important signaling pathways that may link it to diabetes and obesity.[13] Thus, it acts as a monooxygenase to metabolize arachidonic acid to 19-hydroxyeicosatetraenoic acid (19-HETE) (see 20-Hydroxyeicosatetraenoic acid). However, it also acts as an epoxygenase activity to metabolize docosahexaenoic acid to epoxides, primarily 19R,20S-epoxyeicosapentaenoic acid and 19S,20R-epoxyeicosapentaenoic acid isomers (termed 19,20-EDP) and eicosapentaenoic acid to epoxides, primarily 17R,18S-eicosatetraenic acid and 17S,18R-eicosatetraenic acid isomers (termed 17,18-EEQ).[14] 19-HETE is an inhibitor of 20-HETE, a broadly active signaling molecule, e.g. it constricts arterioles, elevates blood pressure, promotes inflammation responses, and stimulates the growth of various types of tumor cells; however the in vivo ability and significance of 19-HETE in inhibiting 20-HETE has not been demonstrated (see 20-Hydroxyeicosatetraenoic acid). The EDP (see Epoxydocosapentaenoic acid) and EEQ (see epoxyeicosatetraenoic acid) metabolites have a broad range of activities. In various animal models and in vitro studies on animal and human tissues, they decrease hypertension and pain perception; suppress inflammation; inhibit angiogenesis, endothelial cell migration and endothelial cell proliferation; and inhibit the growth and metastasis of human breast and prostate cancer cell lines.[15][16][17][18] It is suggested that the EDP and EEQ metabolites function in humans as they do in animal models and that, as products of the omega-3 fatty acids, docosahexaenoic acid and eicosapentaenoic acid, the EDP and EEQ metabolites contribute to many of the beneficial effects attributed to dietary omega-3 fatty acids.[15][18][19] EDP and EEQ metabolites are short-lived, being inactivated within seconds or minutes of formation by epoxide hydrolases, particularly soluble epoxide hydrolase, and therefore act locally. CYP2E1 is not regarded as being a major contributor to forming the cited epoxides[18] but could act locally in certain tissues to do so.

Following is a table of selected substrates of CYP2E1. Where classes of agents are listed, there may be exceptions within the class.

CYP2E1 exhibits structural motifs common to other human membrane-bound cytochrome P450 enzymes, and is composed of 12 major α-helices and 4 β-sheets with short intervening helices interspersed between the two.[13] Like other enzymes of this class, the active site of CYP2E1 contains an iron atom bound by a heme center which mediates the electron transfer steps necessary to carry out oxidation of its substrates. The active site of CYP2E1 is the smallest observed in human P450 enzymes, with its small capacity attributed in part to the introduction of an isoleucine at position 115. The side-chain of this residue protrudes out above the heme center, restricting active site volume compared to related enzymes that have less bulky residues at this position.[13] T303, which also protrudes into the active site, is particularly important for substrate positioning above the reactive iron center and is hence highly conserved by many cytochrome P450 enzymes.[13] Its hydroxyl group is well-positioned to donate a hydrogen bond to potential acceptors on the substrate, and its methyl group has also been implicated in the positioning of fatty acids within the active site.[24],[25] A number of residues proximal to the active site including L368 help make up a constricted, hydrophobic access channel which may also be important for determining the enzyme’s specificity towards small molecules and ω-1 hydroxylation of fatty acids.[13]

.

In humans, the CYP2E1 enzyme is encoded by the CYP2E1 gene.[26] The enzyme has been identified in fetal liver, where it is posited to be the predominant ethanol-metabolizing enzyme, and may be connected to ethanol-mediated teratogenesis.[27] In rats, within one day of birth the hepatic CYP2E1 gene is activated transcriptionally.

CYP2E1 expression is easily inducible, and can occur in the presence of a number of its substrates, including ethanol,[21]isoniazid,[21]tobacco,[28]isopropanol,[6]benzene,[6]toluene,[6] and acetone.[6] For ethanol specifically, it seems that there exist two stages of induction, a post-translational mechanism for increased protein stability at low levels of ethanol and an additional transcriptional induction at high levels of ethanol.[29]

CYP2E1 is inhibited by a variety of small molecules, many of which act competitively. Two such inhibitors, indazole and 4-methylpyrazole, coordinate with the active site’s iron atom and were crystallized with recombinant human CYP2E1 in 2008 to give the first true crystal structures of the enzyme.[13] Other inhibitors include diethyldithiocarbamate[20] (in cancer), and disulfiram[21] (in alcoholism).

CYP2E1 is expressed in high levels in the liver, where it works to clear toxins from the body.[7][8] In doing so, CYP2E1 bioactivates a variety of common anesthetics, including acetaminophen, halothane, enflurane, and isoflurane.[6] The oxidation of these molecules by CYP2E1 can produce harmful substances such as trifluoroacetic acid chloride from halothane [30] or NAPQI from paracetamol (acetaminophen) and is a major reason for their observed hepatotoxicity in patients.

CYP2E1 and other cytochrome P450 enzymes can inadvertently produce reactive oxygen species (ROS) in their active site when catalysis is not coordinated correctly, resulting in potential lipid peroxidation as well as protein and DNA oxidation.[13] CYP2E1 is particularly susceptible to this phenomenon compared to other P450 enzymes, suggesting that its expression levels may be important for negative physiological effects observed in a number of disease states.[13]

CYP2E1 expression levels have been correlated with a variety of dietary and physiological factors, such as ethanol consumption,[31] diabetes,[32] fasting,[33] and obesity.[34] It appears that cellular levels of the enzyme may be controlled by the molecular chaperone HSP90, which upon association with CYP2E1 allows for transport to the proteasome and subsequent degradation. Ethanol and other substrates may disrupt this association, leading to the higher expression levels observed in their presence.[35] The increased expression of CYP2E1 accompanying these health conditions may therefore contribute to their pathogenesis by increasing the rate of production of ROS in the body.[13]

According to a 1995 publication by Y Hu et al, a study in rats revealed a 8- to 9-fold elevation of CYP2E1 with fasting alone, compared to a 20-fold increase in enzyme level accompanied by a 16-fold increase in total catalytic capacity in rats who were both fasted and given large quantities of ethanol for 3 consecutive days. Starvation appears to upregulate CYP2E1 mRNA production in liver cells while alcohol seems to stabilize the enzyme itself post-translation and thus protect it from degradation by normal cellular proteolytic processes, giving the two an independent synergistic effect.

Trees have been genetically engineered to overexpress the CYP2E1 enzyme. These transgenic trees have been used to remove pollutants from groundwater, a process known as phytoremediation.[36]

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“Assessment of Zopiclone”

1TQN, 1W0E, 1W0F, 1W0G, 2J0D, 2V0M, 3NXU, 3TJS, 3UA1, 4I3Q, 4I4G, 4I4H, 4K9T, 4K9U, 4K9V, 4K9W, 4K9X, 4NY4, 5A1P, 5A1R, 4D6Z, 4D75, 4D78, 4D7D

1576

n/a

ENSG00000160868

n/a

what is caffeine

P08684

n/a

NM_001202855NM_001202856NM_001202857NM_017460

n/a

NP_001189784NP_059488

n/a

Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1.14.13.97) is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.

While many drugs are deactivated by CYP3A4, there are also some drugs which are activated by the enzyme. Some substances, such as grapefruit juice and some drugs, interfere with the action of CYP3A4. These substances will therefore either amplify or weaken the action of those drugs that are modified by CYP3A4.

CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes. Several other members of this family are also involved in drug metabolism, but CYP3A4 is the most common and the most versatile one. Like all members of this family, it is a hemoprotein, i.e. a protein containing a heme group with an iron atom. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene.[3] This gene is part of a cluster of cytochrome P450 genes on chromosome 7q22.1.[4]

CYP3A4 is a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids, and other lipids components.

The CYP3A4 protein localizes to the endoplasmic reticulum, and its expression is induced by glucocorticoids and some pharmacological agents. Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism;[5] substrates include acetaminophen, codeine, ciclosporin (cyclosporin), diazepam, and erythromycin. The enzyme also metabolizes some steroids and carcinogens.[6] Most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from the body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, and many protoxins being toxicated into their toxic forms (for examples – see table below).

CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), i.e. (±)-8,9-, (±)-11,12-, and (±)-14,15-epoxyeicosatrienoic acids.[7] The EETs have a wide range of activities including the promotion of certain types of cancers (see epoxyeicosatetraenoic acid). CYP3A4 promotes the growth of various types of human cancer cell lines in culture by producing (±)-14,15-epoxyeicosatrienoic acids which stimulate these cells to grow.[8] The cytochrome P450 is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE).[9] 20-HETE has a wide range of activities that also include growth stimulation in breast and other types of cancers (see 12-hydroxyeicosatetraenoic acid).

The CYP3A4 gene exhibits a much more complicated upstream regulatory region in comparison with its paralogs.[10] This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands, instead of relying on gene variants for wider specificity.[10]Chimpanzee and human CYP3A4 are highly conserved in metabolism of many ligands, although four amino acids positively selected in humans led to a 5-fold benzylation of 7-BFC in the presence of the hepatotoxic secondary bile acid lithocholic acid.[11] This change in consequence contributes to an increased human defense against cholestasis.[11]

Fetuses tend to not express CYP3A4 in their liver tissue,[clarification needed] but rather CYP3A7 (EC 1.14.14.1), which acts on a similar range of substrates. CYP3A4 is absent in fetal liver but increases to approximately 40% of adult levels in the fourth month of life and 72% at 12 months.[12][13]

Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body, where it may play an important role in metabolism. CYP3A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows prodrugs to be activated and absorbed – as in the case of the histamine H1-receptor antagonist terfenadine.

Recently CYP3A4 has also been identified in the brain, however its role in the central nervous system is still unknown.[14]

Cytochrome P450 enzymes perform an assortment of modifications on a variety of ligands, utilizing its large active site and its ability to bind more than one substrate at a time to perform complicated chemical alterations in the metabolism of endogenous and exogenous compounds. These include hydroxylation, epoxidation of olefins, aromatic oxidation, heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, dehydrogenation reactions, and aromatase activity.[15][16]

Hydroxylation of an sp3 C-H bond is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand.[17] In fact, hydroxylation is sometimes followed by dehydrogenation, leading to more complex metabolites.[16] An example of a molecule that undergoes more than one reaction due to CYP3A4 includes tamoxifen, which is hydroxylated to 4-hydroxy-tamoxifen and then dehydrated to 4-hydroxy-tamoxifen quinone methide.[16] Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes.

The first pathway suggested is a cage-controlled radical method (“oxygen rebound”), and the second involves a concerted mechanism that does not utilize a radical intermediate but instead acts very quickly via a “radical clock”.[17]

In 1998, various researchers showed that grapefruit juice, and grapefruit in general, is a potent inhibitor of CYP3A4, which can affect the metabolism of a variety of drugs, increasing their bioavailability.[18][19][20][21][22] In some cases, this can lead to a fatal interaction with drugs like astemizole or terfenadine.[19] The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the Lancet entitled “Interactions of Citrus Juices with Felodipine and Nifedipine”, and was the first reported food-drug interaction clinically. The effects of grapefruit last from 3–7 days, with the greatest effects when juice is taken an hour previous to administration of the drug.[23]

In addition to grapefruit, other fruits have similar effects. Noni (M. citrifolia), for example, is a dietary supplement typically consumed as a juice and also inhibits CYP3A4;[24]pomegranate juice has this effect as well.[25]

While over 28 single nucleotide polymorphisms (SNPs) have been identified in the CYP3A4 gene, it has been found that this does not translate into significant interindividual variability in vivo. It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates.

CYP3A4 alleles which have been reported to have minimal function compared to wild-type include CYP3A4*6 (an A17776 insertion) and CYP3A4*17 (F189S). Both of these SNPs led to decreased catalytic activity with certain ligands, including testosterone and nifedipine in comparison to wild-type metabolism.[26]

Variability in CYP3A4 function can be determined noninvasively by the erythromycin breath test (ERMBT). The ERMBT estimates in vivo CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (14C-N-methyl)-erythromycin.[27]

CYP3A4 is induced by a wide variety of ligands. These ligands bind to the pregnane X receptor (PXR). The activated PXR complex forms a heterodimer with the retinoid X receptor (RXR), which binds to the XREM region of the CYP3A4 gene. XREM is a regulatory region of the CYP3A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4. Activation of the PXR/RXR heterodimer initiates transcription of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in the presence of aflatoxin B1, M1, and G1. Indeed, due to the enzyme’s large and malleable active site, it is possible for the enzyme to bind multiple ligands at once, leading to potentially detrimental side effects.[28]

Induction of CYP3A4 has been shown to vary in humans depending on sex. Evidence shows an increased drug clearance by CYP3A4 in women, even when accounting for differences in body weight. A study by Wolbold et al. (2003) found that the median CYP3A4 levels measured from surgically removed liver samples of a random sample of women exceeded CYP3A4 levels in the livers of men by 129%. CYP3A4 mRNA transcripts were found in similar proportions, suggesting a pre-translational mechanism for the up-regulation of CYP3A4 in women. The exact cause of this elevated level of enzyme in women is still under speculation, however studies have elucidated other mechanisms (such as CYP3A5 or CYP3A7 compensation for lowered levels of CYP3A4) that affect drug clearance in both men and women.[29]

CYP3A4 substrate activation varies amongst different animal species. Certain ligands activate human PXR, which promotes CYP3A4 transcription, while showing no activation in other species. For instance, mouse PXR is not activated by rifampicin and human PXR is not activated by pregnenalone 16α-carbonitrile[30] In order to facilitate study of CYP3A4 functional pathways in vivo, mouse strains have been developed using transgenes in order to produce null/human CYP3A4 and PXR crosses. Although humanized hCYP3A4 mice successfully expressed the enzyme in their intestinal tract, low levels of hCYP3A4 were found in the liver.[30] This effect has been attributed to CYP3A4 regulation by the growth hormone signal transduction pathway.[30] In addition to providing an in vivo model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity.[30]

CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances.[31] Due to the enzyme’s extensive presence in the intestinal mucosa, the enzyme has shown sensitivity to starvation symptoms and is upregulated in defense of adverse effects. Indeed, in fatheaded minnows, unfed female fish were shown to have increased PXR and CYP3A4 expression, and displayed a more pronounced response to xenobiotic factors after exposure after several days of starvation.[31] By studying animal models and keeping in mind the innate differences in CYP3A4 activation, investigators can better predict drug metabolism and side effects in human CYP3A4 pathways.

Estimates of the turnover rate of human CYP3A4 vary widely. For hepatic CYP3A4, in vivo methods yield estimates of enzyme half-life mainly in the range of 70 to 140 hours, whereas in vitro methods give estimates from 26 to 79 hours.[32] Turnover of gut CYP3A4 is likely to be a function of the rate of enterocyte renewal; an indirect approach based on recovery of activity following exposure to grapefruit juice yields measurements in the 12- to 33-hour range.[32]

Due to membrane-bound CYP3A4’s natural propensity to conglomerate, it has historically been difficult to study drug binding in both solution and on surfaces. Co-crystallization is difficult since the substrates tend to have a low Kd (between 5-150 μM) and low solubility in aqueous solutions.[33] A successful strategy in isolating the bound enzyme is the functional stabilization of monomeric CYP3A4 on silver nanoparticles produced from nanosphere lithography and analyzed via localized surface plasmon resonance spectroscopy (LSPR).[34] These analyses can be used as a high-sensitivity assay of drug binding, and may become integral in further high-throughput assays utilized in initial drug discovery testing. In addition to LSPR, CYP3A4-Nanodisc complexes have been found helpful in other applications including solid-state NMR, redox potentiometry, and steady-state enzyme kinetics.[34]

Following is a table of selected substrates, inducers and inhibitors of CYP3A4. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP3A4 can be classified by their potency, such as:

Strong

Moderate

Weak

what is caffeine

Unspecified potency

Strong potency

Unspecified potency

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

1tqn: Crystal Structure of Human Microsomal P450 3A4

1w0e: CRYSTAL STRUCTURE OF HUMAN CYTOCHROME P450 3A4

1w0f: CRYSTAL STRUCTURE OF HUMAN CYTOCHROME P450 3A4

1w0g: CRYSTAL STRUCTURE OF HUMAN CYTOCHROME P450 3A4

2j0d: CRYSTAL STRUCTURE OF HUMAN P450 3A4 IN COMPLEX WITH ERYTHROMYCIN

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[1]

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https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf

2VN0, 1PQ2, 2NNH, 2NNI, 2NNJ

1558

13098

ENSG00000138115

ENSMUSG00000025003

what is caffeine

P10632

P56656

NM_000770NM_001198853NM_001198854NM_001198855NM_030878

NM_010003NM_001373937

NP_000761NP_001185782NP_001185783NP_001185784

NP_034133NP_001360866

Cytochrome P4502C8 (abbreviated CYP2C8), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. Cytochrome P4502C8 also possesses epoxygenase activity, i.e. it metabolizes long-chain polyunsaturated fatty acids, e.g. arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and Linoleic acid to their biologically active epoxides.[5]

Following is a table of selected substrates, inducers and inhibitors of 2C8.

Inhibitors of CYP2C8 can be classified by their potency, such as:

Strong

Moderate

Unspecified potency

Unspecified potency

Where classes of agents are listed, there may be exceptions within the class.

CYP2C8 also possesses epoxygenase activity: it is one of the principal enzymes responsible for attacking various long-chain polyunsaturated fatty acids at their double (i.e. alkene) bonds to form epoxide products that act as signaling agents. It metabolizes: 1) arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs); 2) linoleic acid to 9,10-epoxy octadecaenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecaenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); 3) docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and 4) eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).[8][9][10]

Along with CYP2C8, CYP2C9, CYP2C19, CYP2J2, and possibly CYP2S1 are the main producers of EETs and, very likely, EEQs, EDPs, and the epoxides of linoleic acid.[11][12]

1pq2: Crystal Structure of Human Drug Metabolizing Cytochrome P450 2C8

1OG2, 1OG5, 1R9O, 4NZ2

1559

72303

ENSG00000138109

ENSMUSG00000067231

what is caffeine

P11712

n/a

NM_000771

NM_028191

NP_000762

n/a

Cytochrome P450 2C9 (abbreviated CYP2C9) is an enzyme that in humans is encoded by the CYP2C9 gene.[5][6]

CYP2C9 is an important cytochrome P450 enzyme, which plays a major role in the oxidation of both xenobiotic and endogenous compounds. CYP2C9 makes up about 18% of the cytochrome P450 protein in liver microsomes. About 100 therapeutic drugs are metabolized by CYP2C9, including drugs with a narrow therapeutic index such as warfarin and phenytoin, and other routinely prescribed drugs such as acenocoumarol, tolbutamide, losartan, glipizide, and some nonsteroidal anti-inflammatory drugs. By contrast, the known extrahepatic CYP2C9 often metabolizes important endogenous compounds such as serotonin and, owing to its epoxygenase activity, various polyunsaturated fatty acids, converting these fatty acids to a wide range of biological active products.[7][8]

In particular, CYP2C9 metabolizes arachidonic acid to the following eicosatrienoic acid epoxide (EETs) stereoisomer sets: 5R,6S-epoxy-8Z,11Z,14Z-eicosatetrienoic and 5S,6R-epoxy-8Z,11Z,14Z-eicosatetrienoic acids; 11R,12S-epoxy-8Z,11Z,14Z-eicosatetrienoic and 11S,12R-epoxy-5Z,8Z,14Z-eicosatetrienoic acids; and 14R,15S-epoxy-5Z,8Z,11Z-eicosatetrainoic and 14S,15R-epoxy-5Z,8Z,11Z-eicosatetrainoic acids. It likewise metabolizes docosahexaenoic acid to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]) and eicosapentaenoic acid to epoxyeicosatetraenoic acids (EEQs, primarily 17,18-EEQ and 14,15-EEQ isomers).[9] Animal models and a limited number of human studies implicate these epoxides in reducing hypertension; protecting against myocardial infarction and other insults to the heart; promoting the growth and metastasis of certain cancers; inhibiting inflammation; stimulating blood vessel formation; and possessing a variety of actions on neural tissues including modulating neurohormone release and blocking pain perception (see epoxyeicosatrienoic acid and epoxygenase).[8]

In vitro studies on human and animal cells and tissues and in vivo animal model studies indicate that certain EDPs and EEQs (16,17-EDPs, 19,20-EDPs, 17,18-EEQs have been most often examined) have actions which often oppose those of another product of CYP450 enzymes (e.g. CYP4A1, CYP4A11, CYP4F2, CYP4F3A, and CYP4F3B) viz., 20-Hydroxyeicosatetraenoic acid (20-HETE), principally in the areas of blood pressure regulation, blood vessel thrombosis, and cancer growth (see 20-Hydroxyeicosatetraenoic acid, epoxyeicosatetraenoic acid, and epoxydocosapentaenoic acid sections on activities and clinical significance). Such studies also indicate that the eicosapentaenoic acids and EEQs are: 1) more potent than EETs in decreasing hypertension and pain perception; 2) more potent than or equal in potency to the EETs in suppressing inflammation; and 3) act oppositely from the EETs in that they inhibit angiogenesis, endothelial cell migration, endothelial cell proliferation, and the growth and metastasis of human breast and prostate cancer cell lines whereas EETs have stimulatory effects in each of these systems.[10][11][12][13] Consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of EDPs and EEQs in animals as well as humans, and in humans is by far the most prominent change in the profile of polyunsaturated fatty acids metabolites caused by dietary omega-3 fatty acids.[10][13][14]

CYP2C9 may also metabolize linoleic acid to the potentially very toxic products, vernolic acid (also termed leukotoxin) and coronaric acid (also termed isoleukotoxin); these linoleic acid epoxides cause multiple organ failure and acute respiratory distress in animal models and may contribute to these syndromes in humans.[8]

The CYP2C9 gene is highly polymorphic.[15] At least 20 single nucleotide polymorphisms (SNPs) have been reported to have functional evidence of altered enzyme activity.[15] In fact, adverse drug reactions (ADRs) often result from unanticipated changes in CYP2C9 enzyme activity secondary to genetic polymorphisms. Especially for CYP2C9 substrates such as warfarin and phenytoin, diminished metabolic capacity because of genetic polymorphisms or drug-drug interactions can lead to toxicity at normal therapeutic doses.[16][17]

The label CYP2C9*1 is assigned by the Pharmacogene Variation Consortium (PharmVar) to the most commonly observed human gene variant.[18] Other relevant variants are cataloged by PharmVar under consecutive numbers, which are written after an asterisk (star) character to form an allele label.[19][20] The two most well-characterized variant alleles are CYP2C9*2 (NM_000771.3:c.430C>T, p.Arg144Cys, rs1799853) and CYP2C9*3 (NM_000771.3:c.1075A>C, p.Ile359Leu, rs1057910),[21] causing reductions in enzyme activity of 30% and 80%, respectively.[15]

On the basis of their ability to metabolize CYP2C9 substrates, individuals can be categorized by groups. The carriers of homozygous CYP2C9*1 variant, i.e. of the *1/*1 genotype, are designated extensive metabolizers (EM), or normal metabolizers.[22] The carriers of the CYP2C9*2 or CYP2C9*3 alleles in a heterozygous state, i.e. just one of these alleles (*1/*2, *1/*3) are designated intermediate metabolizers (IM), and those carrying two of these alleles, i.e. homozygous (*2/*3, *2/*2 or *3/*3) — poor metabolizers (PM).[23][24] As a result, the metabolic ratio – the ratio of unchanged drug to metabolite – is higher in PMs.

A study of the ability to metabolize warfarin among the carriers of the most well-characterized CYP2C9 genotypes (*1, *2 and *3), expressed as percentage of the mean dose in patients with wild-type alleles (*1/*1), concluded that the mean warfarin maintenance dose was 92% in *1/*2, 74% in *1/*3, 63% in *2/*3, 61% in *2/*2 and 34% in 3/*3.[25]

The Association for Molecular Pathology Pharmacogenomics (PGx) Working Group in 2019 has recommended a minimum panel of variant alleles (Tier 1) and an extended panel of variant alleles (Tier 2) to be included in assays for CYP2C9 testing.

CYP2C9 variant alleles recommended as Tier 1 by the PGx Working Group include CYP2C9 *2, *3, *5, *6, *8, and *11. This recommendation was based on their well-established functional effects on CYP2C9 activity and drug response availability of reference materials, and their appreciable allele frequencies in major ethnic groups.

The following CYP2C9 alleles are recommended for inclusion in tier 2: CYP2C9*12, *13, and *15.[15]

CYP2C9*13 is defined by a missense variant in exon 2 (NM_000771.3:c.269T>C, p.Leu90Pro, rs72558187).[15] CYP2C9*13 prevalence is approximately 1% in the Asian population,[26] but in Caucasians this variant prevalence is almost zero.[27] This variant is caused by a T269C mutation in the CYP2C9 gene which in turn results in the substitution of leucine at position-90 with proline (L90P) at the product enzyme protein. This residue is near the access point for substrates and the L90P mutation causes lower affinity and hence slower metabolism of several drugs that are metabolized CYP2C9 by such as diclofenac and flurbiprofen.[26] However, this variant is not included in the tier 1 recommendations of the PGx Working Group because of its very low multiethnic minor allele frequency and a lack of currently available reference materials.[15] As of 2020, the evidence level for CYP2C9*13 in the PharmVar database is limited, comparing to the tier 1 alleles, for which the evidence level is definitive.[18]

Not all clinically-significant genetic variant alleles have been registered by PharmVar. For example, in a 2017 study, the variant rs2860905 showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3.[28] Allele A (23% global frequency) is associated with decreased dose of warfarin as compared to the allele G (77% global frequency). Another variant, rs4917639, according to a 2009 study, has strong effect on warfarin sensitivity, almost the same as if CYP2C9*2 and CYP2C9*3 were combined into a single allele.[29] The C allele at rs4917639 has 19% global frequency. Patients with the CC or CA genotype may require decreased dose of warfarin as compared to patients with the wild-type AA genotype.[30] Another variant, rs7089580 with T allele having 14% global frequency, is associated with increased CYP2C9 gene expression. Carriers of AT and TT genotypes at rs7089580 had increased CYP2C9 expression levels comparing to wild-type AA genotype. Increased gene expression due to rs7089580 T allele leads to increased rate of warfarin metabolism and increased warfarin dose requirements. In a study published in 2014, the AT genotype showed slightly higher expression than TT, but both much higher than AA.[31] Another variant, rs1934969 (in studies of 2012 and 2014) have been shown to affect the ability to metabolize losartan: carriers of TT genotype have increased CYP2C9 hydroxylation capacity for losartan comparing to AA genotype, and, as a result, lower metabolic ratio of losartan, i.e. faster losartan metabolism.[32][33]

Most inhibitors of CYP2C9 are competitive inhibitors. Noncompetitive inhibitors of CYP2C9 include nifedipine,[34][35]phenethyl isothiocyanate,[36]medroxyprogesterone acetate[37] and 6-hydroxyflavone. It was indicated that the noncompetitive binding site of 6-hydroxyflavone is the reported allosteric binding site of the CYP2C9 enzyme.[38]

Following is a table of selected substrates, inducers and inhibitors of CYP2C9. Where classes of agents are listed, there may be exceptions within the class.

Inhibitors of CYP2C9 can be classified by their potency, such as:

Strong

Moderate

Unspecified potency

Strong

Weak

CYP2C9 attacks various long-chain polyunsaturated fatty acids at their double (i.e. alkene) bonds to form epoxide products that act as signaling molecules. It along with CYP2C8, CYP2C19, CYP2J2, and possibly CYP2S1 are the principle enzymes which metabolizes 1) arachidonic acid to various epoxyeicosatrienoic acids (also termed EETs); 2) linoleic acid to 9,10-epoxy octadecaenoic acids (also termed vernolic acid, linoleic acid 9:10-oxide, or leukotoxin) and 12,13-epoxy-octadecaenoic (also termed coronaric acid, linoleic acid 12,13-oxide, or isoleukotoxin); 3) docosahexaenoic acid to various epoxydocosapentaenoic acids (also termed EDPs); and 4) eicosapentaenoic acid to various epoxyeicosatetraenoic acids (also termed EEQs).[8] Animal model studies implicate these epoxides in regulating: hypertension, Myocardial infarction and other insults to the heart, the growth of various cancers, inflammation, blood vessel formation, and pain perception; limited studies suggest but have not proven that these epoxides may function similarly in humans (see epoxyeicosatrienoic acid and epoxygenase pages).[8] Since the consumption of omega-3 fatty acid-rich diets dramatically raises the serum and tissue levels of the EDP and EEQ metabolites of the omega-3 fatty acid, i.e. docosahexaenoic and eicosapentaenoic acids, in animals and humans and in humans is the most prominent change in the profile of polyunsaturated fatty acids metabolites caused by dietary omega-3 fatty acids, eicosapentaenoic acids and EEQs may be responsible for at least some of the beneficial effects ascribed to dietary omega-3 fatty acids.[62][63][64]

1og2: STRUCTURE OF HUMAN CYTOCHROME P450 CYP2C9

1og5: STRUCTURE OF HUMAN CYTOCHROME P450 CYP2C9

1r9o: Crystal Structure of P4502C9 with Flurbiprofen bound

Last published: December 16, 2020

Caffeine is a stimulant drug, which means it speeds up the messages travelling between the brain and the body.

It’s found in the seeds, nuts and leaves of a number of different plants, including:

Caffeine is used in a number of different products. The amount of caffeine in products can vary dramatically, so it’s always best to check the label. The average amounts are listed below.

Average amounts 3

what is caffeine

Caffeine

Fact sheet

353.3 KB

pdf

Adapted from Food Standards Australia & New Zealand (2019).

There is no safe level of drug use. Use of any drug always carries some risk. It’s important to be careful when taking any type of drug.

Caffeine affects everyone differently, based on:

The following effects may be experienced within 30 minutes after consuming caffeine, and may continue for up to 6 hours:

Children and young people who consume energy drinks containing caffeine may also suffer from sleep problems and anxiety.5-7

If a large amount of caffeine is consumed it can also cause an overdose.

Call an ambulance straight away by dialling triple zero (000) if you experience any of the following effects.

It is unlikely that a toxic amount of caffeine can be consumed from caffeinated beverages alone.8 However, large doses of caffeine are dangerous and there have been deaths from people consuming caffeine in tablet or powder form.9

People who use caffeinated products, such as weight loss products or powdered caffeine for performance and image enhancing aids, should ensure they are aware of the recommended reasonable amount of caffeine to consume per serving.

Regular, heavy use of caffeine (such as more than 4 cups of coffee a day) may eventually cause:

The effects of taking caffeine with other drugs – including over-the-counter or prescribed medications – can be unpredictable and dangerous, and could cause:

Giving up caffeine after using it for a long time is challenging because the body has to get used to functioning without it. Withdrawal symptoms usually start within 12-24 hours after the last dose. The symptoms can last for around 2-7 days, or even longer for people who consume a lot.2

These symptoms can include:

Pure and highly concentrated caffeine food products are prohibited in Australia.3 Since December 2019, the retail sale of foods where caffeine is present in a concentration of 5% or more for foods that are solid or semi-solid, or 1% or more for foods that are liquid, has been prohibited.3

Psychology, Deakin University, National Drug and Alcohol Research Centre, Institute of Culture and Society, University of Western Sydney, NSW Poisons Information Centre; 2013.

dehydration,

dizziness,

excitability,

fast breathing,

fast heart rate,

feeling active,

feeling alert,

headache,

higher body temperature,

restlessness,

stomach pains

Last updated: 16 Dec 2020

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It’s almost midnight and Aaron has already had a full day of school, work,
and after-school activities. He’s tired and knows he could use some sleep. But he
still hasn’t finished his homework. So he reaches for his headphones — and some caffeine.

Caffeine is a drug that is naturally produced in the leaves and seeds of many plants.
It’s also produced artificially and added to certain foods. Caffeine is defined as
a drug because it stimulates the central nervous system, causing increased alertness.
Caffeine gives most people a temporary energy boost and elevates mood.

Caffeine is in tea, coffee, chocolate, many soft drinks, and pain relievers and
other over-the-counter medications. In its natural form, caffeine tastes very bitter.
But most caffeinated drinks have gone through enough processing to camouflage the
bitter taste.

Teens usually get most of their caffeine from soft drinks and energy drinks. (In
addition to caffeine, these also can have added sugar and artificial flavors.) Caffeine
is not stored in the body, but you may feel its effects for up to 6 hours.

Many people feel that caffeine increases their mental alertness. Higher doses of
caffeine can cause anxiety, dizziness, headaches, and the jitters. Caffeine can also
interfere with normal sleep.

what is caffeine

Caffeine sensitivity (the amount of caffeine that will produce
an effect in someone) varies from person to person. On average, the smaller the person,
the less caffeine needed to produce side effects. Caffeine sensitivity is most affected
by the amount of caffeine a person has daily. People who regularly take in a lot of
caffeine soon develop less sensitivity to it. This means they may need more caffeine
to achieve the same effects.

Caffeine is a mild diuretic, meaning it causes a person to urinate (pee) more.
Drinking a moderate amount of caffeine isn’t likely to cause dehydration, but
it’s probably a good idea to stay away from too much caffeine in hot weather, during
long workouts, or in other situations where you might sweat a lot.

Caffeine also may cause the body to lose calcium, and that can lead to bone loss
over time. Drinking caffeine-containing soft drinks and coffee instead of milk can
have an even greater impact on bone density and the risk of developing document.write(def_osteoporosis_T);

Caffeine can aggravate certain heart problems. It also may interact with some medicines
or supplements. If you are stressed or anxious, caffeine can make these feelings worse.
Although caffeine is sometimes used to treat migraine headaches, it can make headaches
worse for some people.

Caffeine is usually thought to be safe in moderate amounts. Experts consider 200–300
mg of caffeine a day to be a moderate amount for adults. But consuming as little as
100 mg of caffeine a day can lead a person to become “dependent” on caffeine.
This means that someone may develop withdrawal symptoms (like tiredness, irritability,
and headaches) if he or she quits caffeine suddenly.

Teens should try to limit caffeine consumption to no more than 100 mg of caffeine
daily, and kids should get even less. The following chart includes common caffeinated
products and the amounts of caffeine they contain:

Drink/Food/ Supplement

Amt. of Drink/Food

Amt. of Caffeine

SoBe No Fear

8 ounces

83 mg

Monster energy drink

16 ounces

160 mg

Rockstar energy drink

8 ounces

80 mg

Red Bull energy drink

8.3 ounces

80 mg

Jolt cola

12 ounces

72 mg

Mountain Dew

12 ounces

55 mg

Coca-Cola

12 ounces

34 mg

Diet Coke

12 ounces

45 mg

Pepsi

12 ounces

what is caffeine

38 mg

7-Up

12 ounces

0 mg

Brewed coffee (drip method)

5 ounces

115 mg*

Iced tea

12 ounces

70 mg*

Cocoa beverage

5 ounces

4 mg*

Chocolate milk beverage

8 ounces

5 mg*

Dark chocolate

1 ounce

20 mg*

Milk chocolate

1 ounce

6 mg*

Jolt gum

1 stick

33 mg

Cold relief medication

1 tablet

30 mg*

Vivarin

1 tablet

200 mg

Excedrin extra strength

2 tablets

130 mg

*denotes average amount
of caffeine

Source: U.S. Food and Drug Administration, National Soft Drink Association, Center
for Science in the Public Interest.

If you’re taking in too much caffeine, you may want to cut back. The best way is
to cut back slowly. Otherwise, you could get headaches and feel tired, irritable,
or just plain lousy.

Try cutting your intake by replacing caffeinated sodas and coffee with noncaffeinated
drinks, like water, decaffeinated coffee, caffeine-free sodas, and caffeine-free teas.
Start by keeping track of how many caffeinated drinks you have each day, then substitute
one of these daily drinks with a caffeine-free alternative. Continue this for a week.
Then, if you are still drinking too much caffeine, substitute another of your daily
drinks, again, keeping it up for a week. Do this for as many weeks as it takes to
bring your daily caffeine intake below the 100-milligram mark. Taking a gradual approach
like this can help you wean yourself from caffeine without unwanted side effects like
headaches.

As you cut back on the amount of caffeine you consume, you may find yourself feeling
tired. Be sure you’re getting enough sleep and boost your energy by exercising. As
your body adjusts to less caffeine, your energy levels should return to normal in
a few days.

Note: All information on TeensHealth® is for educational purposes only. For specific medical advice, diagnoses, and treatment,
consult your doctor.

© 1995-document.write(KHcopyDate); The Nemours Foundation. All rights reserved.

Images provided by The Nemours Foundation, iStock, Getty Images, Veer, Shutterstock,
and Clipart.com.

Caffeine is a bitter substance that occurs naturally in more than 60 plants including

There is also synthetic (man-made) caffeine, which is added to some medicines, foods, and drinks. For example, some pain relievers, cold medicines, and over-the-counter medicines for alertness contain synthetic caffeine. So do energy drinks and “energy-boosting” gums and snacks.

what is caffeine

Most people consume caffeine from drinks. The amounts of caffeine in different drinks can vary a lot, but it is generally

Caffeine has many effects on your body’s metabolism. It

Within one hour of eating or drinking caffeine, it reaches its peak level in your blood. You may continue to feel the effects of caffeine for four to six hours.

For most people, it is not harmful to consume up to 400mg of caffeine a day. If you do eat or drink too much caffeine, it can cause health problems, such as

Some people are more sensitive to the effects of caffeine than others.

Energy drinks are beverages that have added caffeine. The amount of caffeine in energy drinks can vary widely, and sometimes the labels on the drinks do not give you the actual amount of caffeine in them. Energy drinks may also contain sugars, vitamins, herbs, and supplements.

Companies that make energy drinks claim that the drinks can increase alertness and improve physical and mental performance. This has helped make the drinks popular with American teens and young adults. There’s limited data showing that energy drinks might temporarily improve alertness and physical endurance. There is not enough evidence to show that they enhance strength or power. But what we do know is that energy drinks can be dangerous because they have large amounts of caffeine. And since they have lots of sugar, they can contribute to weight gain and worsen diabetes.

Sometimes young people mix their energy drinks with alcohol. It is dangerous to combine alcohol and caffeine. Caffeine can interfere with your ability to recognize how drunk you are, which can lead you to drink more. This also makes you more likely to make bad decisions.

You should check with your health care provider about whether you should limit or avoid caffeine if you

If you have been consuming caffeine on a regular basis and then suddenly stop, you may have caffeine withdrawal. Symptoms can include

These symptoms usually go away after a couple of days.

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Update on Emergency Department Visits Involving Energy Drinks: A Continuing Public Health Concern

Caffeine is a naturally occurring substance found in the leaves, seeds and/or fruit of more than 60 plants.

Whether derived from natural or artificial sources, “caffeine is caffeine,” and all sources have the same basic properties.

Caffeine is used to flavor some beverages, contributing to the taste profile of products to which it is added.

Many of us enjoy a daily pick-me-up such as a freshly brewed cup of coffee, an ice cold soft drink, a hot cup of tea or an energy drink—all of which share a common ingredient: caffeine. It comes from a variety of natural sources but also can be synthesized.

Research has shown that beverages are the leading dietary source of caffeine. Not only is caffeine consumed on a daily basis by a major part of the population, it’s also one of the most studied food ingredients on Earth.

what is caffeine

Moderate caffeine consumption is considered to be in the range of 300 to 400 milligrams per day (mg/day), or about three to four 8-ounce cups of home-brewed coffee per day. According to FDA, the European Food Safety Authority and Health Canada, caffeine consumption of up to 400 mg daily is not associated with adverse health effects in the general healthy population of adults.

 

Let’s assume you’re one of the 85 percent of Americans who consume caffeine every day. Whether you like coffee, tea, cola, or energy drinks, once you’ve armed yourself with some basic facts, it isn’t difficult to make sure that your daily buzz is part of a balanced diet.

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Think you’re a caffeine expert? Try our quiz and find your “Caffeine IQ”.

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what is caffeine

Caffeine has its perks, but it can pose problems too. Find out how much is too much and if you need to curb your consumption.

If you rely on caffeine to wake you up and keep you going, you aren’t alone. Millions of people rely on caffeine every day to stay alert and improve concentration.

Up to 400 milligrams (mg) of caffeine a day appears to be safe for most healthy adults. That’s roughly the amount of caffeine in four cups of brewed coffee, 10 cans of cola or two “energy shot” drinks. Keep in mind that the actual caffeine content in beverages varies widely, especially among energy drinks.

Caffeine in powder or liquid form can provide toxic levels of caffeine, the U.S. Food and Drug Administration has cautioned. Just one teaspoon of powdered caffeine is equivalent to about 28 cups of coffee. Such high levels of caffeine can cause serious health problems and possibly death.

Although caffeine use may be safe for adults, it’s not a good idea for children. Adolescents and young adults need to be cautioned about excessive caffeine intake and mixing caffeine with alcohol and other drugs.

Women who are pregnant or who are trying to become pregnant and those who are breast-feeding should talk with their doctors about limiting caffeine use to less than 200 mg daily.

Even among adults, heavy caffeine use can cause unpleasant side effects. And caffeine may not be a good choice for people who are highly sensitive to its effects or who take certain medications.

Read on to see if you may need to curb your caffeine routine.

You may want to cut back if you’re drinking more than 4 cups of caffeinated coffee a day (or the equivalent) and you have side effects such as:

Some people are more sensitive to caffeine than are others. If you’re susceptible to the effects of caffeine, even small amounts may prompt unwanted effects, such as restlessness and sleep problems.

How you react to caffeine may be determined in part by how much caffeine you’re used to drinking. People who don’t regularly drink caffeine tend to be more sensitive to its effects.

Caffeine, even in the afternoon, can interfere with your sleep. Even small amounts of sleep loss can add up and disturb your daytime alertness and performance.

Using caffeine to mask sleep deprivation can create an unwelcome cycle. For example, you may drink caffeinated beverages because you have trouble staying awake during the day. But the caffeine keeps you from falling asleep at night, shortening the length of time you sleep.

Some medications and herbal supplements may interact with caffeine. Examples include:

Talk to your doctor or pharmacist about whether caffeine might affect your medications.

Whether it’s for one of the reasons above or because you want to trim your spending on coffee drinks, cutting back on caffeine can be challenging. An abrupt decrease in caffeine may cause withdrawal symptoms, such as headaches, fatigue, irritability and difficulty focusing on tasks. Fortunately, these symptoms are usually mild and get better after a few days.

To change your caffeine habit, try these tips:

If you’re like most adults, caffeine is a part of your daily routine. Usually, it won’t pose a health problem. But be mindful of caffeine’s possible side effects and be ready to cut back if necessary.

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Caffeine is naturally found in the leaves and fruits of some plants. It is in coffee, black and green tea, cocoa, cola soft drinks and energy drinks. It may also be in chocolate bars, energy bars and some non-prescription medications, such as cough syrup and slimming tablets. Guarana (a popular additive in energy drinks) is also a natural source of caffeine.

Caffeine is a stimulant, which means it increases activity in your brain and nervous system. It also increases the circulation of chemicals such as cortisol and adrenaline in the body. 

In small doses, caffeine can make you feel refreshed and focused. In large doses, caffeine can make you feel anxious and have difficulty sleeping.

Like many other drugs, it’s possible to develop a tolerance to caffeine, which means you need bigger and bigger doses to achieve the same effect. 

Caffeine is well absorbed by the body, and the short-term effects are usually experienced between 5 and 30 minutes after having it. These effects can include increased breathing and heart rate, and increased mental alertness and physical energy. Depending on the individual, these effects can last up to 12 hours.

what is caffeine

Some of the signs and symptoms of having too much caffeine include:

How you react to caffeine depends on your body mass, health and metabolism. It also depends on whether your body is used to getting regular doses of caffeine and how much you have in one serving. Research suggests that 400mg per day or less is an acceptable dose of caffeine for the general population.

Approximate caffeine levels per serve include:

Energy drinks contain caffeine, as well as ingredients such as taurine and guarana (a natural source of caffeine). Energy drinks do not hydrate and should not be confused with sports drinks. 

The caffeine and sugar content of energy drinks is high. In fact it is often higher than in soft drinks. The levels of caffeine in energy drinks vary between brands, so it is important to read the label before having them.

Children and pregnant women should avoid drinking energy drinks. 

Like many other drugs, it’s possible to build up a tolerance to caffeine. This means you become used to its effects on your body and need to take larger amounts to achieve the same results. Over time, you may become physically and psychologically dependent on caffeine to function effectively. 

If you are dependent on caffeine and you stop having it, you may experience withdrawal symptoms. These may include:

Symptoms of caffeine withdrawal may begin within 12 to 24 hours and can last about seven days. 

The easiest way for you to break caffeine dependence is to reduce the amount you’re having gradually. This gives your nervous system time to adapt to functioning without the drug.

Some people who need to take special care with caffeine include:

However, check the anti-doping rules of your particular sporting code to make sure caffeine is not a restricted drug for the sport you play.

This page has been produced in consultation with and approved
by:

This page has been produced in consultation with and approved
by:

The size of a standard drink can vary according to the type of alcohol.

Amphetamines are psychostimulant drugs that speed up the workings of the brain.

Prolonged misuse of steroids can cause liver damage and severe mood swings.

Benzodiazepines (tranquillisers) are highly addictive and should only be used for certain conditions in a short-term or emergency situation.

This page has been produced in consultation with and approved
by:

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Content on this website is provided for information purposes only. Information about a therapy, service, product or treatment does not in any way endorse or support such therapy, service, product or treatment and is not intended to replace advice from your doctor or other registered health professional. The information and materials contained on this website are not intended to constitute a comprehensive guide concerning all aspects of the therapy, product or treatment described on the website. All users are urged to always seek advice from a registered health care professional for diagnosis and answers to their medical questions and to ascertain whether the particular therapy, service, product or treatment described on the website is suitable in their circumstances. The State of Victoria and the Department of Health & Human Services shall not bear any liability for reliance by any user on the materials contained on this website.

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acceptable dose of caffeine

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