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| Pronunciation | /ˌsuːdoʊ.ɪˈfɛdrɪn,-ˈɛfɪdriːn/ ⓘ |
| Trade names | Afrinol, Sudafed, Sinutab, others |
| Other names | PSE; PDE; (+)-ψ-Ephedrine; ψ-Ephedrine; d-Isoephedrine; (1S,2S)-Pseudoephedrine; d-Pseudoephedrine; (+)-Pseudoephedrine;L(+)-Pseudoephedrine; Isoephedrine; (1S,2S)-α,N-Dimethyl-β-hydroxyphenethylamine; (1S,2S)-N-Methyl-β-hydroxyamphetamine |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682619 |
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| Routes of administration | By mouth[1][2] |
| Drug class | Norepinephrine releasing agent;Nasal decongestant;Stimulant |
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| Bioavailability | ~100%[9] |
| Protein binding | 21–29% (AGPTooltip alpha-1-acid glycoprotein,HSATooltip Human serum albumin)[10][11] |
| Metabolism | Not extensivelymetabolized[12][1][2] |
| Metabolites | •Norpseudoephedrine[1] |
| Onset of action | 30 minutes[1] |
| Eliminationhalf-life | 5.4 hours (range 3–16 hours dependent onurinepH)[2][1][12] |
| Duration of action | 4–12 hours[1][13] |
| Excretion | Urine: 43–96% (unchanged)[1][12][2][9] |
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| ECHA InfoCard | 100.001.835 |
| Chemical and physical data | |
| Formula | C10H15NO |
| Molar mass | 165.236 g·mol−1 |
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Pseudoephedrine, sold under the brand nameSudafed among others, is asympathomimetic medication which is used as adecongestant to treatnasal congestion.[1][14][2] It has also been usedoff-label for certain other indications, like treatment oflow blood pressure.[15][16][17] At higher doses, it may produce various additional effects includingstimulant,[18][1]appetite suppressant,[19] andperformance-enhancing effects.[20][21] In relation to this, non-medical use of pseudoephedrine has been encountered.[18][1][19][20][21] The medication is takenby mouth.[1][2]
Side effects of pseudoephedrine includeinsomnia, elevatedheart rate, increasedblood pressure,restlessness,dizziness,anxiety, anddry mouth, among others.[22][2][1][23] Rarely, pseudoephedrine has been associated with seriouscardiovascular complications likeheart attack andhemorrhagic stroke.[19][24][16] Some people may be more sensitive to itscardiovascular effects.[23][1] Pseudoephedrine acts as anorepinephrine releasing agent, thereby indirectly activatingadrenergic receptors.[25][2][26][1] As such, it is an indirectly actingsympathomimetic.[25][2][26][1] Pseudoephedrine significantly crosses into thebrain, but has someperipheral selectivity due to itshydrophilicity.[26][27] Chemically, pseudoephedrine is asubstituted amphetamine and is closely related toephedrine,phenylpropanolamine, andamphetamine.[1][14][2] It is the (1S,2S)-enantiomer ofβ-hydroxy-N-methylamphetamine.[28]
Along with ephedrine, pseudoephedrine occursnaturally inephedra, which has been used for thousands of years intraditional Chinese medicine.[14][29] It was firstisolated from ephedra in 1889.[29][14][30] Subsequent to itssynthesis in the 1920s, pseudoephedrine was introduced for medical use as a decongestant.[14] Pseudoephedrine is widely availableover-the-counter (OTC) in both single-drug andcombinationpreparations.[31][23][14][2] Availability of pseudoephedrine has been restricted starting in 2005 as it can be used to synthesizemethamphetamine.[14][2]Phenylephrine has replaced pseudoephedrine in many over-the-counteroral decongestant products.[2] However, oral phenylephrine appears to be ineffective as a decongestant.[32][33] In 2023, pseudoephedrine was the 292nd most commonly prescribed medication in the United States, with more than 400,000 prescriptions.[34][35] In 2023, the combination withbrompheniramine anddextromethorphan was the 281st most commonly prescribed medication in the United States, with more than 700,000 prescriptions.[34][36] In 2023, the combination withloratadine was the 300th most commonly prescribed medication in the United States, with more than 400,000 prescriptions.[37][38]
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Pseudoephedrine is asympathomimetic and is well-known for shrinking swollen nasal mucous membranes, so it is often used as adecongestant. It reduces tissuehyperemia,edema, andnasal congestion commonly associated withcolds orallergies. Other beneficial effects may include increasing the drainage ofsinus secretions, and opening of obstructedEustachian tubes. The samevasoconstriction action can also result inhypertension, which is a noted side effect of pseudoephedrine.
Pseudoephedrine can be used either as oral or astopical decongestant. Due to itsstimulating qualities, however, the oral preparation is more likely to cause adverse effects, includingurinary retention.[39][40] According to one study, pseudoephedrine may show effectiveness as anantitussive drug (suppression ofcough).[41]
Pseudoephedrine isindicated for the treatment of nasal congestion, sinus congestion, and Eustachian tube congestion.[42] Pseudoephedrine is also indicated forvasomotor rhinitis and as an adjunct to other agents in the optimum treatment ofallergic rhinitis,croup,sinusitis,otitis media, andtracheobronchitis.[42]
Amphetamine-type stimulants and othercatecholaminergic agents are known to havewakefulness-promoting effects and are used in the treatment ofhypersomnia andnarcolepsy.[43][44][45] Pseudoephedrine at therapeutic doses does not appear to improve or worsen daytimesleepiness, daytimefatigue, orsleep quality in people withallergic rhinitis.[1][46] Likewise,somnolence was not lower in children with thecommon cold treated with pseudoephedrine for nasal congestion.[47] In any case,insomnia is a knownside effect of pseudoephedrine, although the incidence is low.[22] In addition, doses of pseudoephedrine above the normal therapeutic range have been reported to producestimulant effects including insomnia and fatigue resistance.[18]
There has been interest in pseudoephedrine as anappetite suppressant for the treatment ofobesity.[19] However, due to lack of clinical data and potential cardiovascular side effects, this use is not recommended.[19] Only a singleplacebo-controlled study of pseudoephedrine forweight loss exists (120 mg/dayslow-release for 12 weeks) and found no significant difference in weight lost compared to placebo (-4.6 kg vs. -4.5 kg).[19][48] This was in contrast tophenylpropanolamine, which has been found to be more effective at promoting weight loss compared to placebo and has been more widely studied and used in the treatment of obesity.[49][50][48]
Pseudoephedrine has been used limitedly in the treatment oforthostatic intolerance includingorthostatic hypotension[15] andpostural orthostatic tachycardia syndrome (POTS).[17][51][52] However, its effectiveness in the treatment of POTS is controversial.[17][51] Pseudoephedrine has also been used limitedly in the treatment of refractoryhypotension inintensive care units.[16] However, data on this use are limited tocase reports andcase series.[16]
Pseudoephedrine is also used as a first-line prophylactic for recurrentpriapism.[53]Erection is largely aparasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition. Data for this use are howeveranecdotal and effectiveness has been described as variable.[53]
Treatment ofurinary incontinence is anoff-label use for pseudoephedrine and related medications.[54][55]
Pseudoephedrine is available by itselfover-the-counter in the form of 30 and 60 mgimmediate-release and 120 and 240 mgextended-releaseoraltablets in theUnited States.[31][56][57][58]
Pseudoephedrine is also available over-the-counter andprescription-onlyin combination with numerous other drugs, includingantihistamines (acrivastine,azatadine,brompheniramine,cetirizine,chlorpheniramine,clemastine,desloratadine,dexbrompheniramine,diphenhydramine,fexofenadine,loratadine,triprolidine),analgesics (acetaminophen,codeine,hydrocodone,ibuprofen,naproxen),cough suppressants (dextromethorphan), andexpectorants (guaifenesin).[31][56]
Pseudoephedrine has been used in the form of thehydrochloride andsulfatesalts and in a polistirex form.[31] The drug has been used in more than 135 over-the-counter and prescription formulations.[23] Many prescription formulations containing pseudoephedrine have been discontinued over time.[31]
Pseudoephedrine iscontraindicated in patients withdiabetes mellitus,cardiovascular disease, severe or uncontrolledhypertension, severecoronary artery disease,prostatic hypertrophy,hyperthyroidism,closed-angle glaucoma, or bypregnant women.[59] The safety and effectiveness of nasal decongestant use in children is unclear.[60]
Common side effects with pseudoephedrine therapy may includecentral nervous system (CNS)stimulation,insomnia,restlessness,excitability,dizziness, andanxiety.[19][16][61] Infrequent side effects includetachycardia orpalpitations.[19] Rarely, pseudoephedrine therapy may be associated withmydriasis (dilated pupils),hallucinations,arrhythmias,hypertension,seizures, andischemic colitis; as well as severeskin reactions known as recurrent pseudo-scarlatina,systemic contact dermatitis, and non-pigmentingfixed drug eruption.[19][62][59] Pseudoephedrine, particularly when combined with other drugs includingnarcotics, may also play a role in the precipitation of episodes ofpsychosis.[19][63] It has also been reported that pseudoephedrine, among othersympathomimetic agents, may be associated with the occurrence ofhemorrhagic stroke and othercardiovascular complications.[19][24][16]
Due to its sympathomimetic effects, pseudoephedrine is avasoconstrictor andpressor agent (increasesblood pressure), apositive chronotrope (increasesheart rate), and apositive inotrope (increasesforce of heart contractions).[19][1][23][20][21] The influence of pseudoephedrine on blood pressure at clinical doses is controversial.[1][23] A closely related sympathomimetic and decongestant,phenylpropanolamine, waswithdrawn due to associations with markedly increased blood pressure and incidence of hemorrhagic stroke.[23] There has been concern that pseudoephedrine may likewise dangerously increase blood pressure and thereby increase the risk of stroke, whereas others have contended that the risks are exaggerated.[1][23] Besides hemorrhagic stroke,myocardial infarction,coronary vasospasm, andsudden death have also rarely been reported with sympathomimeticephedra compounds like pseudoephedrine andephedrine.[19][16]
A 2005meta-analysis found that pseudoephedrine at recommended doses had no meaningful effect onsystolic ordiastolic blood pressure in healthy individuals or people with controlledhypertension.[1][23] Systolic blood pressure was found to slightly increase by 0.99 mm Hg on average and heart rate was found to slightly increase by 2.83 bpm on average.[1][23] Conversely, there was no significant influence on diastolic blood pressure, which increased by 0.63 mg Hg.[23] In people with controlled hypertension, systolic hypertension increased by a similar degree of 1.20 mm Hg.[23]Immediate-release preparations, higher doses, being male, and shorter duration of use were all associated with greater cardiovascular effects.[23] A small subset of individuals withautonomic instability, perhaps in turn resulting in greater adrenergic receptor sensitivity, may be substantially more sensitive to the cardiovascular effects of sympathomimetics.[23] Subsequent to the 2005 meta-analysis, a 2015systematic review and a 2018 meta-analysis found that pseudoephedrine at high doses (>170 mg) could increase heart rate and physical performance with largereffect sizes than lower doses.[20][21]
A 2007Cochrane review assessed the side effects of short-term use of pseudoephedrine at recommended doses as a nasal decongestant.[22] It found that pseudoephedrine had a small risk ofinsomnia and this was the only side effect that occurred at rates significantly different from placebo.[22] Insomnia occurred at a rate of 5% and had anodds ratio (OR) of 6.18.[22] Other side effects, includingheadache andhypertension, occurred at rates of less than 4% and were not different from placebo.[22]
Tachyphylaxis is known to develop with prolonged use of pseudoephedrine, especially when it is re-administered at short intervals.[1][19]
There is a case report of temporarydepressive symptoms upondiscontinuation andwithdrawal from pseudoephedrine.[19][64] The withdrawal symptoms included worsenedmood andsadness, profoundly decreasedenergy, a worsened view of oneself, decreased concentration,psychomotor retardation, increasedappetite, and increased need forsleep.[19][64]
Pseudoephedrine has psychostimulant effects at high doses and is apositive reinforcer withamphetamine-like effects in animals including rats and monkeys.[65][66][67][68] However, it is substantially lesspotent thanmethamphetamine orcocaine.[65][66][67]
The maximum total daily dose of pseudoephedrine is 240 mg.[1] Symptoms ofoverdose may includesedation,apnea, impaired concentration,cyanosis,coma,circulatory collapse,insomnia,hallucinations,tremors,convulsions,headache,dizziness,anxiety,euphoria,tinnitus,blurred vision,ataxia,chest pain,tachycardia,palpitations,increased blood pressure,decreased blood pressure,thirstiness,sweating, difficulty withurination,nausea, andvomiting.[1] In children, symptoms have more often includeddry mouth,pupil dilation,hot flashes,fever, andgastrointestinal dysfunction.[1] Pseudoephedrine may producetoxic effects both with use of supratherapeutic doses but also in people who are more sensitive to the effects of sympathomimetics.[1]Misuse of the drug has been reported in one case at massive doses of 3,000 to 4,500 mg (100–150 × 30-mg tablets) per day, with the doses gradually increased over time by this individual.[1][69] No fatalities due to pseudoephedrine misuse have been reported as of 2021.[18] However, death with pseudoephedrine has been reported generally.[1][14][19]
Concomitant or recent (previous 14 days)monoamine oxidase inhibitor (MAOI) use can lead tohypertensive reactions, includinghypertensive crisis, and should be avoided.[1][59] Clinical studies have found minimal or no influence of certain MAOIs like the weak non-selective MAOIlinezolid and the potent selective MAO-B inhibitorselegiline (as atransdermal patch) on thepharmacokinetics of pseudoephedrine.[70][71][72][73] This is in accordance with the fact that pseudoephedrine is notmetabolized bymonoamine oxidase (MAO).[26][12][74] However, pseudoephedrineinduces the release of norepinephrine, which MAOIs inhibit the metabolism of, and as such, MAOIs can still potentiate the effects of pseudoephedrine.[75][1][71] No significant pharmacodynamic interactions have been found with selegiline,[71][73] but linezolid potentiatedblood pressure increases with pseudoephedrine.[70][72] However, this was deemed to be without clinical significance in the case of linezolid, though it was noted that some individuals may be more sensitive to thesympathomimetic effects of pseudoephedrine and related agents.[70][72] Pseudoephedrine iscontraindicated with MAOIs likephenelzine,tranylcypromine,isocarboxazid, andmoclobemide due to the potential for synergistic sympathomimetic effects and hypertensive crisis.[1][19] It is also considered to be contraindicated with linezolid and selegiline as some individuals may react more sensitively to coadministration.[70][72][71][73]
Concomitant use of pseudoephedrine with othervasoconstrictors, includingergot alkaloids likeergotamine anddihydroergotamine,linezolid,oxytocin,ephedrine,phenylephrine, andbromocriptine, among others, is not recommended due to the possibility of greater increases in blood pressure and risk ofhemorrhagic stroke.[1] Sympathomimetic effects and cardiovascular risks of pseudoephedrine may also be increased withdigitalis glycosides,tricyclic antidepressants,appetite suppressants, andinhalational anesthetics.[1] Likewise, greater sympathomimetic effects of pseudoephedrine may occur when it is combined with other sympathomimetic agents.[19] Rare but serious cardiovascular complications have been reported with the combination of pseudoephedrine andbupropion.[14][76][77] Increase ofectopic pacemaker activity can occur when pseudoephedrine is used concomitantly withdigitalis.[1] Theantihypertensive effects ofmethyldopa,guanethidine,mecamylamine,reserpine, andveratrum alkaloids may be reduced by sympathomimetics like pseudoepehdrine.[1]Beta blockers likelabetalol may reduce the effects of pseudoephedrine.[78][79]
Urinary acidifying agents likeascorbic acid andammonium chloride can increase theexcretion of and thereby reduce exposure toamphetamines including pseudoephedrine, whereasurinary alkalinizing agents includingantacids likesodium bicarbonate as well asacetazolamide can reduce the excretion of these agents and thereby increase exposure to them.[1][12][80]
Pseudoephedrine is asympathomimetic agent which acts primarily or exclusively byinducing the release of norepinephrine.[81][26][2][25] Hence, it is an indirectly acting sympathomimetic.[81][26][2] Some sources state that pseudoephedrine has a mixedmechanism of action consisting of both indirect and direct effects by binding to and acting as anagonist ofadrenergic receptors.[1][16] However, theaffinity of pseudoephedrine for adrenergic receptors is described as very low or negligible.[81]Animal studies suggest that the sympathomimetic effects of pseudoephedrine are exclusively due to norepinephrine release.[82][83]
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref | ||
|---|---|---|---|---|---|---|
| Dextroamphetamine (S(+)-amphetamine) | 6.6–7.2 | 5.8–24.8 | 698–1765 | [86][87] | ||
| S(–)-Cathinone | 12.4 | 18.5 | 2366 | [25] | ||
| Ephedrine ((–)-ephedrine) | 43.1–72.4 | 236–1350 | >10000 | [86] | ||
| (+)-Ephedrine | 218 | 2104 | >10000 | [86][25] | ||
| Dextromethamphetamine (S(+)-methamphetamine) | 12.3–13.8 | 8.5–24.5 | 736–1291.7 | [86][88] | ||
| Levomethamphetamine (R(–)-methamphetamine) | 28.5 | 416 | 4640 | [86] | ||
| (+)-Phenylpropanolamine ((+)-norephedrine) | 42.1 | 302 | >10000 | [25] | ||
| (–)-Phenylpropanolamine ((–)-norephedrine) | 137 | 1371 | >10000 | [25] | ||
| Cathine ((+)-norpseudoephedrine) | 15.0 | 68.3 | >10000 | [25] | ||
| (–)-Norpseudoephedrine | 30.1 | 294 | >10000 | [25] | ||
| (–)-Pseudoephedrine | 4092 | 9125 | >10000 | [25] | ||
| Pseudoephedrine ((+)-pseudoephedrine) | 224 | 1988 | >10000 | [25] | ||
| Notes: The smaller the value, the more strongly the substance releases the neurotransmitter. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds. | ||||||
Pseudoephedrineinduces monoamine releasein vitro with anEC50Tooltip half maximal effective concentration of 224 nM fornorepinephrine and 1,988 nM fordopamine, whereas it is inactive forserotonin.[25][89][85] As such, it is about 9-foldselective for induction of norepinephrine release over dopamine release.[25][89][85] The drug has negligible agonistic activity at theα1- andα2-adrenergic receptors (Kact >10,000 nM).[25] At theβ1- andβ2-adrenergic receptors, it acts as apartial agonist with relatively lowaffinity (β1 = Kact = 309 μM,IATooltip intrinsic activity = 53%; β2 = 10 μM;IA = 47%).[90] It was anantagonist or very weak partial agonist of theβ3-adrenergic receptor (Kact =ND;IA = 7%).[90] It is about 30,000 to 40,000 times less potent as a β-adrenergic receptor agonist than(–)-isoproterenol.[90]
Pseudoephedrine's principal mechanism of action relies on its action on the adrenergic system.[91][92] Thevasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response.[93] Pseudoephedrine acts on α- and β2-adrenergic receptors, to cause vasoconstriction and relaxation of smooth muscle in the bronchi, respectively.[91][92] α-Adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated, the muscles contract, causing the blood vessels to constrict (vasoconstriction). The constricted blood vessels now allow less fluid to leave the blood vessels and enter the nose, throat, and sinus linings, which results in decreased inflammation of nasal membranes, as well as decreased mucus production. Thus, by constriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion.[2] Activation of β2-adrenergic receptors produces relaxation of the smooth muscle of the bronchi,[91] causing bronchial dilation and in turn decreasing congestion (although not fluid) and difficulty breathing.
Pseudoephedrine is lesspotent as a sympathomimetic andpsychostimulant thanephedrine.[1][61] Clinical studies have found that pseudoephedrine is about 3.5- to 4-fold less potent than ephedrine as a sympathomimetic agent in terms ofblood pressure increases and 3.5- to 7.2-fold or more less potent as abronchodilator.[61] Pseudoephedrine is also said to have much less central effect than ephedrine and to be only a weak psychostimulant.[26][61][2][81][68]Blood vessels in the nose are around five times more sensitive than theheart to the actions of circulatingepinephrine (adrenaline), which may help to explain how pseudoephedrine at the low doses used in over-the-counter products can produce nasal decongestion with minimal effects on the heart.[2] Compared todextroamphetamine, pseudoephedrine is about 30 to 35 times less potent as a norepinephrine releasing agent and 80 to 350 times less potent as adopamine releasing agentin vitro.[25][86][87]
Pseudoephedrine is a very weakreversible inhibitor ofmonoamine oxidase (MAO)in vitro, including bothMAO-A andMAO-B (Ki = 1,000–5,800 μM).[94] It is far less potent in this action than other agents like dextroamphetamine andmoclobemide.[94]
Pseudoephedrine isorally active and is readilyabsorbed from thegastrointestinal tract.[1][2] Its oralbioavailability is approximately 100%.[9] The drug reachespeak concentrations after 1 to 4 hours (mean 1.9 hours) in the case of theimmediate-release formulation and after 2 to 6 hours in the case of theextended-release formulation.[1][2] Theonset of action of pseudoephedrine is 30 minutes.[1]
Pseudoephedrine, due to its lack ofpolarphenolicgroups, is relativelylipophilic.[12] This is a property it shares with related sympathomimetic and decongestant agents likeephedrine andphenylpropanolamine.[12] These agents are widelydistributed throughout the body and cross theblood–brain barrier.[12] However, it is said that pseudoephedrine and phenylpropanolamine cross the blood-brain barrier only to some extent and that pseudoephedrine has limitedcentral nervous system activity, suggesting that it is partiallyperipherally selective.[26][27] The blood-brain barrier permeability of pseudoephedrine, ephedrine, and phenylpropanolamine is reduced compared to otheramphetamines due to the presence of ahydroxyl group at the β carbon which decreases theirlipophilicity.[27] As such, they have a greater ratio of peripheral cardiovascular to central psychostimulant effect.[27] Besides entering the brain, these substances also cross theplacenta and enterbreast milk.[12]
Theplasma protein binding of pseudoephedrine has been reported to be approximately 21 to 29%.[10][11] It is bound toα1-acid glycoprotein (AGP) andalbumin (HSA).[10][11]
Pseudoephedrine is not extensivelymetabolized and is subjected to minimalfirst-pass metabolism with oral administration.[12][1][2] Due to itsmethyl group at the αcarbon (i.e., it is anamphetamine), pseudoephedrine is not asubstrate formonoamine oxidase (MAO) and is not metabolized by thisenzyme.[26][12][74][75] It is also not metabolized bycatecholO-methyltransferase (COMT).[26] Pseudoephedrine isdemethylated into themetabolitenorpseudoephedrine to a small extent.[1][12] Similarly to pseudoephedrine, this metabolite isactive and showsamphetamine-like effects.[12] Approximately 1 to 6% of pseudoephedrine is metabolized in theliver viaN-demethylation to form norpseudoephedrine.[1]
Pseudoephedrine isexcreted primarily via thekidneys inurine.[1][12] Its urinary excretion is highly influenced by urinarypH and is increased when the urine isacidic and is decreased when it isalkaline.[1][12][61]
Theelimination half-life of pseudoephedrine on average is 5.4 hours[2] and ranges from 3 to 16 hours depending on urinary pH.[1][12] At a pH of 5.6 to 6.0, theelimination half-life of pseudoephedrine was 5.2 to 8.0 hours.[12] In one study, a more acidic pH of 5.0 resulted in a half-life of 3.0 to 6.4 hours, whereas a more alkaline pH of 8.0 resulted in a half-life of 9.2 to 16.0 hours.[12] Substances that influence urinary acidity and are known to affect the excretion of amphetamine derivatives includeurinary acidifying agents likeascorbic acid andammonium chloride as well asurinary alkalinizing agents likeacetazolamide.[80]
A majority of anoral dose of pseudoephedrine is excreted unchanged in urine within 24 hours of administration.[12] This has been found to range from 43 to 96%.[1][12][2] The amount excreted unchanged is dependent on urinary pH similarly to the drug's half-life, as a longer half-life and duration in the body allows more time for the drug to be metabolized.[12]
Theduration of action of pseudoephedrine, which is dependent on itselimination, is 4 to 12 hours.[1][13]
Pseudoephedrine has been reported to accumulate in people withrenal impairment.[95][96][97]
Pseudoephedrine, also known structurally as (1S,2S)-α,N-dimethyl-β-hydroxyphenethylamine or as (1S,2S)-N-methyl-β-hydroxyamphetamine, is asubstituted phenethylamine,amphetamine, andβ-hydroxyamphetaminederivative.[1][14][2] It is adiastereomer ofephedrine.[29]
Pseudoephedrine is asmall-moleculecompound with themolecular formula C10H15NO and amolecular weight of 165.23 g/mol.[28][98] It has an experimentallog P of 0.89, while its predicted log P values range from 0.9 to 1.32.[28][98][99] The compound is relativelylipophilic,[12] but is also morehydrophilic than other amphetamines.[27] The lipophilicity of amphetamines is closely related to their brain permeability.[100] For comparison to pseudoephedrine, the experimental log P ofmethamphetamine is 2.1,[101] ofamphetamine is 1.8,[102][101] ofephedrine is 1.1,[103] ofphenylpropanolamine is 0.7,[104] ofphenylephrine is -0.3,[105] and ofnorepinephrine is -1.2.[106] Methamphetamine has high brain permeability,[101] whereas phenylephrine and norepinephrine areperipherally selective drugs.[2][107] The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).[108]
Pseudoephedrine is readilyreduced intomethamphetamine oroxidized intomethcathinone.[1]
ephedrine_enantiomers.svg)
Thedextrorotary (+)- or d-enantiomer is (1S,2S)-pseudoephedrine, whereas the levorotating (−)- or l- form is (1R,2R)-pseudoephedrine.
In the outdatedD/L system (+)-pseudoephedrine is also referred to asL-pseudoephedrine and (−)-pseudoephedrine asD-pseudoephedrine (in theFischer projection then the phenyl ring is drawn at bottom).[109][110]
Often theD/L system (withsmall caps) and thed/l system (withlower-case) are confused. The result is that the dextrorotary d-pseudoephedrine is wrongly namedD-pseudoephedrine and the levorotary l-ephedrine (the diastereomer) wronglyL-ephedrine.
The IUPAC names of the two enantiomers are (1S,2S)- respectively (1R,2R)-2-methylamino-1-phenylpropan-1-ol. Synonyms for both arepsi-ephedrine andthreo-ephedrine.
Pseudoephedrine is theINNTooltip International Nonproprietary Name of the (+)-form, when used as pharmaceutical substance.[111]
Pseudoephedrine may be quantified in blood, plasma, or urine to monitor any possible performance-enhancing use by athletes, confirm a diagnosis of poisoning, or to assist in a medicolegal death investigation. Some commercialimmunoassay screening tests directed at the amphetamines cross-react appreciably with pseudoephedrine, butchromatographic techniques can easily distinguish pseudoephedrine from other phenethylamine derivatives. Blood or plasma pseudoephedrine concentrations are typically in the 50 to 300 μg/L range in persons taking the drug therapeutically, 500 to 3,000 μg/L in people with substance use disorder involving pseudoephedrine or poisoned patients, and 10 to 70 mg/L in cases of acute fataloverdose.[112][113]
Although pseudoephedrine occurs naturally as analkaloid in certain plant species (for example, as a constituent of extracts from theEphedra species, also known asma huang, in which it occurs together with other isomers ofephedrine), the majority of pseudoephedrine produced for commercial use is derived fromyeastfermentation ofdextrose in the presence ofbenzaldehyde. In this process, specialized strains of yeast (typically a variety ofCandida utilis orSaccharomyces cerevisiae) are added to large vats containing water, dextrose and the enzymepyruvate decarboxylase (such as found inbeets and other plants). After the yeast has begun fermenting the dextrose, the benzaldehyde is added to the vats, and in this environment, the yeast converts the ingredients to the precursorl-phenylacetylcarbinol (L-PAC). L-PAC is then chemically converted to pseudoephedrine viareductive amination.[114]
The bulk of pseudoephedrine is produced by commercialpharmaceutical manufacturers in India and China, where economic and industrial conditions favor its mass production for export.[115]
Pseudoephedrine, along withephedrine, occursnaturally inephedra.[14][29][116] This herb has been used for thousands of years intraditional Chinese medicine.[14][29][116] Pseudoephedrine was firstisolated and characterized in 1889 by the German chemistsLadenburg and Oelschlägel, who used a sample that had been isolated fromEphedra vulgaris by theMerck pharmaceutical corporation ofDarmstadt, Germany.[29][30][117] It was firstsynthesized in the 1920s inJapan.[14] Subsequently, pseudoephedrine was introduced for medical use as a decongestant.[14]
Pseudoephedrine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name, whilepseudoéphédrine is itsDCFTooltip Dénomination Commune Française andpseudoefedrina is itsDCITTooltip Denominazione Comune Italiana.[118][119][120][121]Pseudoephedrine hydrochloride is itsUSANTooltip United States Adopted Name andBANMTooltip British Approved Name in the case of thehydrochloridesalt;pseudoephedrine sulfate is itsUSAN in the case of thesulfate salt;pseudoephedrine polistirex itsUSAN in the case of the polistirex form; andd-isoephedrine sulfate is itsJANTooltip Japanese Accepted Name in the case of the sulfate salt.[118][119][120][121] Pseudoephedrine is also known asΨ-ephedrine andisoephedrine.[118][120]
 | Theinclusion or exclusion of items from this list orlength of this list is disputed. Please discuss this issue on thetalk page. |
The following is a list of consumer medicines that either contain pseudoephedrine or have switched to a less-regulated alternative such asphenylephrine.
Over-the-counter pseudoephedrine has beenmisused as apsychostimulant.[18] Sixcase reports and onecase series of pseudoephedrine misuse have been published as of 2021.[18] There is a case report ofself-medication with pseudoephedrine in massive doses for treatment ofdepression.[18][69]
Pseudoephedrine has been used as aperformance-enhancing drug inexercise andsports due to its sympathomimetic and stimulant effects.[20][21] Because of these effects, pseudoephedrine can increaseheart rate, elevateblood pressure, improvemental energy, and reducefatigue, among other performance-enhancing effects.[20][21][23]
A 2015systematic review found that pseudoephedrine lacked performance-enhancing effects at therapeutic doses (60–120 mg) but significantly enhanced athletic performance at supratherapeutic doses (≥180 mg).[20] A subsequent 2018meta-analysis, which included seven additional studies, found that pseudoephedrine had a small positive effect on heart rate (SMDTooltip standardized mean difference = 0.43) but insignificant effects on time trials, perceived exertion ratings, bloodglucose levels, and bloodlactate levels.[21] However, subgroup analyses revealed thateffect sizes were larger for heart rate increases and quicker time trials in well-trained athletes and younger participants, for shorter exercise sessions with pseudoephedrine administered within 90 minutes beforehand, and with higher doses of pseudoephedrine.[21] Adose–response relationship was established, with larger doses (>170 mg) showing greater increases in heart rate and faster time trials than with smaller doses (≤170 mg) (SMD = 0.85 for heart rate andSMD = -0.24 for time trials, respectively).[21] In any case, the meta-analysis concluded that the performance-enhancing effects of pseudoephedrine were marginal to small and likely to be lower in magnitude than withcaffeine.[21] It is relevant in this regard that caffeine is a permitted stimulant in competitive sports.[21]
Pseudoephedrine was on theInternational Olympic Committee's (IOC) banned substances list until 2004 when theWorld Anti-Doping Agency (WADA) list replaced the IOC list. Although WADA initially onlymonitored pseudoephedrine, it went back onto the "banned" list on 1 January 2010.[125]
Pseudoephedrine is excreted through urine, and the concentration in urine of this drug shows a large inter-individual spread; that is, the same dose can give a vast difference in urine concentration for different individuals.[126] Pseudoephedrine is approved to be taken up to 240 mg per day. In seven healthy male subjects, this dose yielded a urine concentration range of 62.8 to 294.4 microgram per milliliter (μg/mL) with mean ± standard deviation 149 ± 72 μg/mL.[127] Thus, normal dosage of 240 mg pseudoephedrine per day can result in urine concentration levels exceeding the limit of 150 μg/mL set by WADA for about half of all users.[128] Furthermore, hydration status does not affect the urinary concentration of pseudoephedrine.[129]
Its membership in theamphetamine class has made pseudoephedrine a sought-afterchemical precursor in theillicit manufacture ofmethamphetamine andmethcathinone.[1] As a result of the increasing regulatory restrictions on the sale and distribution of pseudoephedrine, pharmaceutical firms have reformulated medications to use alternative compounds, particularlyphenylephrine, even though its efficacy as an oral decongestant has been demonstrated to be indistinguishable from placebo.[139]
In the United States, federal laws control the sale of pseudoephedrine-containing products.[140][141][142] Retailers in the US have created corporate policies restricting the sale of pseudoephedrine-containing products.[143][144] Their policies restrict sales by limiting purchase quantities and requiring a minimum age and government issued photographic identification.[141][142] These requirements are similar to and sometimes more stringent than existing law. Internationally, pseudoephedrine is listed as aTable I precursor under theUnited Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[145]
Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way the products are regulated. As of 2006[update], all products containing pseudoephedrine have been rescheduled as either "Pharmacist Only Medicines" (Schedule 3) or "Prescription Only Medicines" (Schedule 4), depending on the amount of pseudoephedrine in the product. A Pharmacist Only Medicine may only be sold to the public if a pharmacist is directly involved in the transaction. These medicines must be kept behind the counter, away from public access.
Pharmacists are also encouraged (and in some states required) to log purchases with the online database Project STOP.[146]
As a result, some pharmacies no longer stock Sudafed, the common brand of pseudoephedrine cold/sinus tablets, opting instead to sell Sudafed PE, aphenylephrine product that has not been proven effective in clinical trials.[139][147][2]
Until 2024, several formulations of pseudoephedrine were available over-the-counter in Belgium.[148] However, new legislation came into effect in November 2024, banning the over-the-counter sale of all medicines containing pseudoephedrine.[149][150]
Health Canada has investigated the risks and benefits of pseudoephedrine andephedrine/Ephedra. Near the end of the study, Health Canada issued a warning on their website stating that those who are under the age of 12, or who have heart disease and may have strokes, should avoid taking pseudoephedrine and ephedrine. Also, they warned that everyone should avoid taking ephedrine or pseudoephedrine with other stimulants likecaffeine. They also banned all products that contain both ephedrine (or pseudoephedrine) and caffeine.[151]
Products whose only medicinal ingredient is pseudoephedrine must be kept behind the pharmacy counter. Products containing pseudoephedrine along with other medicinal ingredients may be displayed on store shelves but may be sold only in a pharmacy when a pharmacist is present.[152][153]
The Colombian government prohibited the trade of pseudoephedrine in 2010.[154]
Pseudoephedrine is an over-the-counter drug in Estonia.[155]
Pseudoephedrine medicines can only be obtained with a prescription in Finland.[156][failed verification]
Pseudoephedrine-containing combination products were available over-the-counter from pharmacies, most commonly with paracetamol, under the brand names "Dolirhume","Actifed Rhyme Jour et Nuit" et al. Products combining pseudoephedrine and ibuprofen or certain antihistamines were also available (e.g. "Rhinadvil"). However, products containing pseudoephedrine as a single ingredient are not sold.[citation needed] In October 2023, the French health department officially warned against the usage of pseudoephedrine for patients with a cold. It also suggested the substance's availability could be restricted in the future, pending its pharmaceutical re-evaluation onEU level.[157][158]In December 2024, the government announced pseudoephedrine medicines would henceforth only be obtainable with a prescription.[159]
Various pseudoephedrine-containing products in combination with ibuprofen,aspirin, or antihistamines can be obtained without a prescription upon request at a pharmacy. Common names include Aspirin Complex, Reactine Duo, and RhinoPront. Products containing pseudoephedrine as a single ingredient are not available.[citation needed]
Medications that contain more than 10% pseudoephedrine are prohibited under the Stimulants Control Law in Japan.[160]
On 23 November 2007, the use and trade of pseudoephedrine in Mexico was made illegal as it was argued that it was extremely popular as a precursor in the synthesis of methamphetamine.[161]
Pseudoephedrine was withdrawn from sale in 1989 due to concerns about adverse cardiac side effects.[162]
Since April 2024, pseudoephedrine has been classified as a restricted (pharmacist-only) drug in theMisuse of Drugs Act 1975 which allows the purchase of medicines containing pseudoephedrine from a pharmacist without a prescription.[163]
Pseudoephedrine, ephedrine, and any product containing these substances, e.g. cold and flu medicines, were first classified in October 2004 as Class C Part III (partially exempted) controlled drugs, due to being the principal ingredient in methamphetamine.[164] New Zealand Customs and police officers continued to make large interceptions of precursor substances believed to be destined formethamphetamine production. On 9 October 2009, Prime MinisterJohn Key announced pseudoephedrine-based cold and flu tablets would become prescription-only drugs and reclassified as a class B2 drug.[165] The law was amended by The Misuse of Drugs Amendment Bill 2010, which passed in August 2011.[166]
In November 2023, theNational-led coalition government announced that the sale of cold medication containing pseudoephedrine would be allowed (as part of the coalition agreement between the National and ACT parties).[167]
Pseudoephedrine is available without a prescription in combination (withaspirin) under the brand name "Aspirin Complex." There is also a preparation consisting of a single ingredient 120 mg extended-release tablet that can be obtained at pharmacies with a prescription or after consultation with a pharmacist.[citation needed]
In Turkey, medications containing pseudoephedrine are available by prescription only.[168]
In the UK, pseudoephedrine is available over-the-counter under the supervision of a qualified pharmacist, or on prescription. In 2007, theMHRA reacted to concerns over the diversion of ephedrine and pseudoephedrine for the illicit manufacture of methamphetamine by introducing voluntary restrictions limiting over-the-counter sales to one box containing no more than 720 mg of pseudoephedrine in total per transaction. These restrictions became law in April 2008.[169] No form of ID is required.
TheUnited States Congress has recognized that pseudoephedrine is used in the illegal manufacture of methamphetamine. In 2005, theCommittee on Education and the Workforce heard testimony concerning education programs and state legislation designed to curb this illegal practice.[citation needed]
Attempts to control the sale of the drug date back to 1986, when federal officials at theDrug Enforcement Administration (DEA) first drafted legislation, later proposed by SenatorBob Dole, that would have placed several chemicals used in the manufacture of illicit drugs under theControlled Substances Act. The bill would have required each transaction involving pseudoephedrine to be reported to the government, and federal approval of all imports and exports. Fearing this would limit legitimate use of the drug, lobbyists from over-the-counter drug manufacturing associations sought to stop this legislation from moving forward and were successful in exempting from the regulations all chemicals that had been turned into a legal final product, such as Sudafed.[170]
Before the passage of theCombat Methamphetamine Epidemic Act of 2005, sales of the drug became increasingly regulated, as DEA regulators and pharmaceutical companies continued to fight for their respective positions. The DEA continued to make greater progress in its attempts to control pseudoephedrine as methamphetamine production skyrocketed, becoming a serious problem in the western United States. When purity dropped, so did the number of people in rehab and people admitted to emergency rooms with methamphetamine in their systems. This reduction in purity was usually short-lived, however, as methamphetamine producers eventually found a way around the new regulations.[171]
Congress passed the Combat Methamphetamine Epidemic Act of 2005 (CMEA) as an amendment to the renewal of theUSA Patriot Act.[141] Signed into law by PresidentGeorge W. Bush on 6 March 2006,[140] the act amended21 U.S.C. § 830, concerning the sale of pseudoephedrine-containing products. The law mandated two phases, the first needing to be implemented by 8 April 2006, and the second to be completed by 30 September 2006. The first phase dealt primarily with implementing the new buying restrictions based on the amount, while the second phase encompassed the requirements of storage, employee training, and record keeping.[172] Though the law was mainly directed at pseudoephedrine products it also applies to all over-the-counter products containing ephedrine, pseudoephedrine, and phenylpropanolamine, their salts, optical isomers, and salts of optical isomers.[172]Pseudoephedrine was defined as a "scheduled listed chemical product" under21 U.S.C. § 802(45(A)). The act included the following requirements for merchants ("regulated sellers") who sell such products:
The requirements were revised in the Methamphetamine Production Prevention Act of 2008 to require that a regulated seller of scheduled listed chemical products may not sell such a product unless the purchaser:[142]
Most states also have laws regulating pseudoephedrine.[173][174][175]
The states of Alabama, Arizona, Arkansas, California, Colorado, Delaware, Florida, Georgia, Hawaii (as of May 1, 2009[update]) Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana (as of August 15, 2009[update]), Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska,[176] Nevada, New Jersey, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter." Though the drug can be purchased without a prescription, states can limit the number of units sold and can collect personal information from purchasers.[177]
The states of Oregon and Mississippi previously required a prescription for the purchase of products containing pseudoephedrine. However, as of 1 January 2022, these restrictions have been repealed.[178][179] The state of Oregon reduced the number of methamphetamine lab seizures from 448 in 2004 (the final full year before implementation of the prescription only law)[180] to a new low of 13 in 2009.[181] The decrease inmeth lab incidents in Oregon occurred largely before the prescription-only law took effect, according to a NAMSDL report titledPseudoephedrine Prescription Laws in Oregon and Mississippi.[177] The report posits that the decline in meth lab incidents in both states may be due to other factors: "Mexican traffickers may have contributed to the decline in meth labs in Mississippi and Oregon (and surrounding states) as they were able to provide ample supply of equal or greater quality meth at competitive prices." Additionally, similar decreases in meth lab incidents were seen in surrounding states, according to the report, and meth-related deaths in Oregon have dramatically risen since 2007. Some municipalities in Missouri have enacted similar ordinances, includingWashington,[182]Union,[183]New Haven,[184]Cape Girardeau[185] andOzark.[186] Certain pharmacies inTerre Haute, Indiana do so as well.[187]
Another approach to controlling the drug on the state level mandated by some state governments to control the purchases of their citizens is the use of electronic tracking systems, which require the electronic submission of specified purchaser information by all retailers who sell pseudoephedrine. Thirty-two states now require theNational Precursor Log Exchange (NPLEx) to be used for every pseudoephedrine and ephedrine OTC purchase, and ten of the eleven largest pharmacy chains in the US voluntarily contribute all of their similar transactions to NPLEx. These states have seen dramatic results in reducing the number of methamphetamine laboratory seizures. Before the implementation of the system in Tennessee in 2005, methamphetamine laboratory seizures totaled 1,497 in 2004 but were reduced to 955 in 2005, and 589 in 2009.[181] Kentucky's program was implemented statewide in 2008, and since statewide implementation, the number of laboratory seizures has significantly decreased.[181] Oklahoma initially experienced success with its tracking system after implementation in 2006, as the number of seizures dropped in that year and again in 2007. In 2008, however, seizures began rising again, and have continued to rise in 2009.[181]
NPLEx appears to be successful by requiring the real-time submission of transactions, thereby enabling the relevant laws to be enforced at the point of sale. By creating a multi-state database and the ability to compare all transactions quickly, NPLEx enables pharmacies to deny purchases that would be illegal based on gram limits, age, or even to convicted meth offenders in some states. NPLEx also enforces the federal gram limits across state lines, which was impossible with state-operated systems. Access to the records is by law enforcement agencies only, through an online secure portal.[188]
Pseudoephedrine has been studied in the treatment ofsnoring.[189] However, data are inadequate to support this use.[189]
A study has found that pseudoephedrine can reducemilk production inbreastfeeding women.[190][191] This might have been due to suppression ofprolactinsecretion.[191] Pseudoephedrine might be useful forlactation suppression.[190][191]
{{cite thesis}}: CS1 maint: DOI inactive as of October 2025 (link)It is also relevant to other sympathomimetic amines contained in over-the-counter cough and cold remedies as decongestants, such as phenylpropanolamine and pseudoephedrine. Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines. It is not often realized, however, that this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut. However, MAO inhibition in sympathetic neurones allows the cytoplasmic pool of noradrenaline to increase. It is this pool that is released by indirectly acting sympathomimetic amines and their responses are therefore potentiated irrespective of whether they are deaminated by MAO (Youdim & Finberg, 1991).
Metamfetamine acts in a manner similar to amfetamine, but with the addition of the methyl group to the chemical structure. It is more lipophilic (Log p value 2.07, compared with 1.76 for amfetamine),4 thereby enabling rapid and extensive transport across the blood–brain barrier.19
Lipophilicity was the first of the descriptors to be identified as important for CNS penetration. Hansch and Leo54 reasoned that highly lipophilic molecules will partitioned into the lipid interior of membranes and will be retained there. However, ClogP correlates nicely with LogBBB with increasing lipophilicity increasing brain penetration. For several classes of CNS active substances, Hansch and Leo54 found that blood-brain barrier penetration is optimal when the LogP values are in the range of 1.5-2.7, with the mean value of 2.1. An analysis of small drug-like molecules suggested that for better brain permeation46 and for good intestinal permeability55 the LogD values need to be greater than 0 and less than 3. In comparison, the mean value for ClogP for the marketed CNS drugs is 2.5, which is in good agreement with the range found by Hansch et al.22
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