Pseudoephedrine—Benefits and Risks

Abstract

Pseudoephedrine (PSE) is a drug with a long history of medical use; it is helpful in treating symptoms of the common cold and flu, sinusitis, asthma, and bronchitis. Due to its central nervous system (CNS) stimulant properties and structural similarity to amphetamine, it is also used for non-medical purposes. The substance is taken as an appetite reducer, an agent which eliminates drowsiness and fatigue, to improve concentration and as a doping agent. Due to its easier availability, it is sometimes used as a substitute for amphetamine or methamphetamine. Pseudoephedrine is also a substrate (precursor) used in the production of these drugs. Time will tell whether legal restrictions on the sale of this drug will reduce the scale of the problem associated with its misuse.

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International Journal of
Molecular Sciences
Review
Pseudoephedrine—Benefits and Risks
Krystyna Głowacka * and Anna Wiela-Hoje´nska


Citation: Głowacka, K.;
Wiela-Hoje´nska, A.
Pseudoephedrine—Benefits and
Risks. Int. J. Mol. Sci. 2021,22, 5146.
https://doi.org/10.3390/
ijms22105146
Academic Editors:
Slavko Komarnytsky and
Adam Matkowski
Received: 27 April 2021
Accepted: 11 May 2021
Published: 13 May 2021
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Copyright: © 2021 by the authors.
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Attribution (CC BY) license (https://
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4.0/).
Department of Clinical Pharmacology, Wroclaw Medical University, Borowska 211a St., 50-556 Wroclaw, Poland;
anna.wiela-hojenska@umed.wroc.pl
*Correspondence: krystyna.glowacka@umed.wroc.pl; Tel.: +48-71-784-05-93
Abstract:
Pseudoephedrine (PSE) is a drug with a long history of medical use; it is helpful in treating
symptoms of the common cold and flu, sinusitis, asthma, and bronchitis. Due to its central nervous
system (CNS) stimulant properties and structural similarity to amphetamine, it is also used for
non-medical purposes. The substance is taken as an appetite reducer, an agent which eliminates
drowsiness and fatigue, to improve concentration and as a doping agent. Due to its easier availability,
it is sometimes used as a substitute for amphetamine or methamphetamine. Pseudoephedrine is also
a substrate (precursor) used in the production of these drugs. Time will tell whether legal restrictions
on the sale of this drug will reduce the scale of the problem associated with its misuse.
Keywords: pseudoephedrine; sympathomimetic; adverse reactions; non-medical use
1. Introduction
Pseudoephedrine (PSE) and ephedrine (E) are alkaloids derived from various species
of Ephedra spp. of the Ephedraceae family. The most common source of their extraction is
Ephedra sinica, also known as Ma Huang. The history of the use of Ephedra products in
medicine is very long; they have been used in China for over 5000 years and in the Middle
East for over 2000 years in the treatment of bronchial asthma, fever, coughs and colds, hay
fever, oedema, bronchitis, urticaria, chronic hypotension, and rheumatism. Nowadays,
they are also used as stimulants, the so-called energisers, and as agents reducing appetite,
body weight and increasing energy consumption. They are popular with bodybuilders,
athletes, schoolchildren and students [1–6].
Although PSE is an E stereoisomer, it has weaker vasoconstrictive effects and smaller
effects on the central nervous system (CNS) compared to ephedrine. Pseudoephedrine is
one of the four stereoisomers of ephedrine (from the natural alkaloid Ephedra from China
or India), because, due to having two stereogenic carbon atoms, it exists as four different
diastereoisomers. Synthetically obtained compounds of PSE occur in the form of a racemate
of diastereoisomers, whose action is twice as weak compared to compounds of natural
origin. This is easily explained, because PSE contains only one active diastereoisomer,
while the second one is as a ballast [2,7–10].
2. Mechanism of Action
Pseudoephedrine is a sympathomimetic with a mixed mechanism of action, direct
and indirect. It indirectly stimulates alpha-adrenergic receptors, causing the release of en-
dogenous norepinephrine (NE) from the granularity of neurons, while it directly stimulates
beta-adrenergic receptors [11–13].
It has an effect similar to ephedrine, but slightly weaker, and has a lower ability to
induce tachycardia and increase systolic blood pressure. Its central effect is weaker than
that of amphetamine, and its peripheral effect is similar to that of epinephrine [
9
]. The
mechanism of pseudoephedrine action is shown graphically in Figure 1.
Int. J. Mol. Sci. 2021,22, 5146. https://doi.org/10.3390/ijms22105146 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2021,22, 5146 2 of 11
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 10
Figure 1. The mechanism of pseudoephedrine action. The principal mechanism by which
pseudoephedrine achieves its effects is by displacing the norepinephrine (noradrenaline) from the
storage vesicles in the presynaptic neurons; then, it is released into the neuronal synapse and be-
comes available to activate the alpha and beta postsynaptic adrenergic receptors.
3. Pharmacokinetics
Unlike epinephrine and norepinephrine, pseudoephedrine is active after oral admin-
istration and is easily absorbed from the gastrointestinal tract. The onset of action occurs
after 30 min and after 1–4 h the drug reaches its maximum concentration in the blood.
When using the extended-release formulation, this time is twice as long. PSE is mainly
excreted unchanged in the urine (43–96%); only a small amount, approximately 1–6%, is
metabolised in the liver by N-demethylation to the active metabolite norpseudoephedrine
(cathine). The time the drug remains in the body depends on the pH of the urine; the value
of the biological half-life (t0.5) decreases when the urine is acidic, and increases when the
urine is alkaline [8,14–19]. Selected pharmacokinetic properties of pseudoephedrine are
presented in Table 1.
Table 1. Pseudoephedrine pharmacokinetics.
Pharmacokinetic Parameters of Pseudoephedrine
Onset of action 30 min
Time to reach Cmax 1–4 h
Time to reach Cmax after administration of
the extended-release formulation 2–6 h
Duration of action 4–12 h
Distribution coefficient 2.64–3.51 l/kg
Biological half-life 3–16 h
Renal clearance 0.44–0.46 l/h/kg,
7.3–7.7 mL/min/kg
Figure 1.
The mechanism of pseudoephedrine action. The principal mechanism by which pseu-
doephedrine achieves its effects is by displacing the norepinephrine (noradrenaline) from the storage
vesicles in the presynaptic neurons; then, it is released into the neuronal synapse and becomes
available to activate the alpha and beta postsynaptic adrenergic receptors.
3. Pharmacokinetics
Unlike epinephrine and norepinephrine, pseudoephedrine is active after oral adminis-
tration and is easily absorbed from the gastrointestinal tract. The onset of action occurs
after 30 min and after 1–4 h the drug reaches its maximum concentration in the blood.
When using the extended-release formulation, this time is twice as long. PSE is mainly
excreted unchanged in the urine (43–96%); only a small amount, approximately 1–6%, is
metabolised in the liver by N-demethylation to the active metabolite norpseudoephedrine
(cathine). The time the drug remains in the body depends on the pH of the urine; the value
of the biological half-life (t
0.5
) decreases when the urine is acidic, and increases when the
urine is alkaline [
8
,
14
–
19
]. Selected pharmacokinetic properties of pseudoephedrine are
presented in Table 1.

Int. J. Mol. Sci. 2021,22, 5146 3 of 11
Table 1. Pseudoephedrine pharmacokinetics.
Pharmacokinetic Parameters of Pseudoephedrine
Onset of action 30 min
Time to reach Cmax 1–4 h
Time to reach Cmax after administration of the
extended-release formulation 2–6 h
Duration of action 4–12 h
Distribution coefficient 2.64–3.51 l/kg
Biological half-life 3–16 h
Renal clearance 0.44–0.46 l/h/kg,
7.3–7.7 mL/min/kg
4. Special Risk Populations
PSE is present in numerous over-the-counter preparations and is taken by pregnant
women. According to the US Food and Drug Administration (FDA), the drug belongs to
category C, which means that animal studies have shown adverse effects on the foetus,
although there are no controlled studies in pregnant women. It can therefore only be used
in cases where the benefit to the mother outweighs the potential risk to the foetus [
18
].
Although there is insufficient evidence of a teratogenic effect of pseudoephedrine, the
results of some studies suggest that it should be used with caution. It has been found
that the use of preparations containing this compound in the first trimester of pregnancy
may increase—almost twice (1.8 times) compared to the control group—the risk of con-
genital evisceration (a developmental defect of the abdominal wall with displacement of
the intestines outside the abdominal cavity). However, these observations were made in
women using mainly combined preparations, so the effect of other ingredients cannot be
excluded. In the third trimester of pregnancy, PSE may cause reduced blood flow in the
uteroplacental circulation, especially in women who smoke [
20
]. Another randomised
population-based study conducted in Massachusetts, USA, involving 3271 live-born chil-
dren without malformations, assessed the risk of preterm birth in relation to the use of
decongestants in the upper respiratory tract. The population-based retrospective cohort
study was conducted between 1998 and 2008 on the basis of an interview. It was found
that the use of pseudoephedrine in the second and third trimester of pregnancy for asthma,
rhinitis, colds, nasal and sinus congestion, reduces the risk of preterm birth compared to
women who have not used these drugs. These observations, however, had many limita-
tions because the women participating in the study constituted a highly heterogeneous
group in terms of age, race, education, social position, economic conditions, health status,
and use of stimulants [21].
During lactation only small amounts, about 0.5% of a single oral daily dose, pass into
breast milk. However, even a single dose of 60 mg reduces daily milk production by 24%.
There are no conclusive results of studies on the efficacy and safety of PSE preparations
in children. Most reports warn against their use in the therapy of children under 12 years of
age, although a multicentre, double-blind, placebo-controlled randomised study by Gelotte
et al. has shown the efficacy and safety of pseudoephedrine hydrochloride 30-mg tablets in
children from 6 to 11 years of age in order to temporarily relieve nasal congestion caused
by colds [22].
The effects of PSE in elderly patients have not been specifically investigated. It is
recommended to follow the adult dosage regimen, with special attention to kidney and
liver function. If these organs are severely impaired, the drug should be used with caution.
Overdosing in people over 60 years of age may cause hallucinations, CNS depression,
seizures and death [18,19].

Int. J. Mol. Sci. 2021,22, 5146 4 of 11
5. Consequences of Pseudoephedrine Use
The drug reduces congestion of the upper respiratory tract mucosa, especially in
the nose and paranasal sinuses (after oral administration), which in turn reduces the
swelling, the amount of secretions and clears the nose. The sympathomimetic effect of
pseudoephedrine may also improve the patency of the Eustachian tube and equalise the
pressure in the middle ear during changes in atmospheric pressure while diving or flying by
plane. The administration of 120 mg of pseudoephedrine to an adult at least 30 min before
a flight may reduce earache. However, no similar effect has been observed in children.
Pseudoephedrine is also effective in cases of urinary incontinence [9,23].
Similarly to other sympathomimetics, PSE stimulates the sympathetic system to fight-
or-flight reactions—speeds up breathing, increases blood pressure, accelerates heart rate,
narrows peripheral blood vessels, causes bronchodilatation, increases blood glucose levels,
stimulates the CNS, as well as giving a sense of an energy surge and improving mood [
9
,
24
].
6. Clinical Use and Contraindications
Pseudoephedrine is recommended for the symptomatic treatment of obstruction in
the nasal cavity, paranasal sinuses and the Eustachian tube. Other indications include
vasomotor rhinitis and adjunctive therapy in allergic rhinitis and otitis media [9,18,19].
Contraindications to pseudoephedrine use are hypersensitivity to the drug, cardio-
vascular diseases (hypertension and coronary artery disease), impaired function of organs
responsible for elimination of the drug (severe liver dysfunction, moderate or severe renal
dysfunction), hyperthyroidism, narrow-angle glaucoma, benign prostatic hyperplasia, dia-
betes mellitus, mental agitation and treatment with monoamine oxidase inhibitors (MAO
inhibitors) currently or in the last two weeks. Contraindications also include physiological
conditions such as pregnancy and lactation, and age under 2 years. The extended-release
form of the drug should not be used until the age of 12 years [18,19].
Although there are no reports of pseudoephedrine disturbing psychophysical perfor-
mance, people driving motor vehicles should exercise caution and not use doses higher
than recommended.
Studies evaluating the effect of this drug on daytime sleepiness and fatigue in patients
suffering from perennial allergic rhinitis showed no positive or negative effect compared
to placebo [25].
7. Dosage
Pseudoephedrine is found as a hydrochloride or sulphate in doses ranging from 30
to 120 mg in about 30 medicinal products. In combined preparations, it is most often
compounded with antihistamines, analgesics and antitussive drugs; it comes in the form
of plain, coated or extended-release tablets, capsules, syrup, powder or granules for oral
fluid preparation. The recommended dosage for adults is 60 mg 3–4 times a day or in the
extended-release form—120 mg every 12 h. In children the dose is 1 mg/kg body weight
4 times a day. In Poland, there are many products containing pseudoephedrine with its
content varying from 30 to 120 mg [15,18,19].
8. Overdose
The maximum permissible daily dose of pseudoephedrine is 240 mg for an adult,
120 mg for children aged 6–12 years and 60 mg for children aged 2–5 years [
18
,
19
]. Toxic
effects may appear not only during the use of increased doses of the drug, but also in
people who are particularly sensitive to the effects of sympathomimetics. Prolonged use of
PSE, especially at short intervals, may reduce the effectiveness of the drug (tachyphylaxis)
and increase the risk of toxic effects. As the result of an overdose, the symptoms of a sym-
pathomimetic effect may vary. Sometimes there is a depressive effect on the CNS (sedative
effect, apnoea, decreased ability to concentrate, cyanosis, coma and circulatory collapse),
other times a stimulating effect (insomnia, hallucinations, tremors and convulsions). In
extreme cases, death may occur. Symptoms of overdose also include headache, dizziness,

Int. J. Mol. Sci. 2021,22, 5146 5 of 11
anxiety, euphoria, tinnitus, blurred vision, ataxia, chest pain, tachycardia, palpitations,
increased or decreased blood pressure, increased thirst, sweating, difficulty urinating,
nausea and vomiting. In children, more frequently observed symptoms are dry mouth,
wide and rigid pupils, hot flushes, fever, and digestive tract dysfunctions [9,18,19].
9. Adverse Reactions
Pharmacotherapy is inevitably associated with the risk of drug-related complications;
the most controversial is the effect of pseudoephedrine on blood pressure and its conse-
quences. Some literature data suggest that oral sympathomimetic drugs may dangerously
increase blood pressure, while others reassure that the danger is exaggerated. One meta-
analysis of randomised controlled trials showed that PSE at the recommended doses had
no effect on systolic and diastolic blood pressure in healthy or controlled hypertensive
patients. Systolic blood pressure increases by an average of 1 mm Hg and the heart rate
increases by three beats per minute. Only about 3% of the analysed patients had pressures
above 140/90 mm Hg [
26
]. During the use of pseudoephedrine preparations, reported
cases include an acute coronary syndrome in a patient who performed hard physical work
and smoked for 30 years; a myocardial infarction, hypertensive crisis and NSTEMI (Non-
ST-Segment Elevation Myocardial Infarction) without ST segment elevation after taking the
drug in the extended-release form by an 87-year-old man with history of mild dementia,
glaucoma and atrial fibrillation; as well as an increased blood pressure of 220/140 mm
Hg, hyperglycaemia, haemorrhagic stroke, strong, reversible spasm of blood vessels and
tachycardia in a driver working at night, a nicotine addict and concomitant drug user for
more than 20 years [
15
,
26
–
29
]. The effect of pseudoephedrine may induce non-convulsive
epileptic states in predisposed individuals with pre-existing neurological disorders [
15
,
30
].
The risk of complications increases in patients with impaired renal and hepatic function.
Unusual behaviour and myoclonic convulsions were observed in a 64-year-old man suffer-
ing from renal failure, who took 240 mg of PSE daily to treat rhinitis [
15
]. Severe agitation
and disorientation can be expected in patients with phenylketonuria due to a disturbed
metabolism of catecholamines [
9
]. Adverse effects of PSE can occur with both oral and
intranasal administration after a single dose or after prolonged (5 days) treatment, without
affecting the dose and irrespective of the vascular condition and age. A 2003 French study
analysed adverse events with intranasal decongestants reported to regional pharmacovigi-
lance centres by healthcare professionals. There were 22 episodes of arterial hypertension,
15 cases of convulsions and 4 cases of stroke after oral administration of drugs containing
pseudoephedrine [
6
]. It can also induce ischemic colitis when used for as little as 3 days or
up to 2 years, in a dose range of 60 to 900 mg/day [
31
]. Less common adverse effects are
skin reactions—cases of scarlet fever-like rash, erythematous spots, skin exfoliation of the
palms and soles of the feet, and Baboon syndrome, clinically manifested by a rash mainly
on the buttocks and within the larger folds of skin, have been reported [
32
,
33
]. When used
in therapeutic doses, PSE may be responsible, especially in children, for the occurrence
of pain and dizziness, increased heart rate, excessive agitation, insomnia and hallucina-
tions [
9
]. “Parasitic” hallucinoses (attacking spiders and insects) have been observed in
children after taking an OTC (over-the-counter) drug containing pseudoephedrine and
triprolidine to treat inflammation of the nasal mucosa [
9
,
15
]. In 2007 Wingert et al. detected
pseudoephedrine in a postmortem analysis of 13 unexpected deaths of children under
2 years of age taking cold medications in the Philadelphia region. Similar observations
were made in 2008 by Rimsza and Newberry, who reviewed case files of unexpected deaths
of children taking cold medications. PSE preparations should not be used in patients before
the age of 12, and according to the French Society of Otorhinolaryngology, until the age
of 15 [
6
]. On the pharmaceutical market, however, there are preparations allowing their
administration to younger patients, e.g., from 7 years of age. The addictive potential of
PSE is confirmed by the case of a 37-year-old woman who abused it for its euphoric effect,
increasing the doses over five years, using 3000–4500 mg daily. Sudden discontinuation of
the drug resulted in depressed mood, visual hallucinations and a feeling of fatigue [
15
].

Int. J. Mol. Sci. 2021,22, 5146 6 of 11
Table 2presents the adverse effects of pseudoephedrine and the incidence of some of
them [18,19,34,35].
Table 2. Complications after the use of pseudoephedrine.
Pseudoephedrine Adverse Effects
CNS stimulation—sleep disturbances (>30%), anxiety, headache, muscle tremor, confusion
Dryness of mucous membranes of the mouth, nose and throat (>15%)
Digestive tract dysfunction—indigestion, nausea, vomiting, decreased appetite, irritation of the
gastric mucosa (5%)
Cardiac arrhythmias, tachycardia, increased blood pressure
Excessive sweating, hyperglycemia, urination disorders
Allergic reactions—redness, rashes
Psychological dependence
10. Interactions
When several drugs are used concomitantly, an interaction may occur between them,
as a result of which the final effect of some drugs changes. The combination of pseu-
doephedrine with other sympathomimetic drugs and monoamine oxidase inhibitors (MAO)
should be avoided. Inhibition of intra-neuronal NE breakdown in sympathetic nerves by
MAO inhibitors leads to an increase in the amount of neuromediator released by pseu-
doephedrine, which may lead to hypertensive crisis and bradycardia. Due to the long
duration of action of MAO inhibitors, a 14-day interval between taking the drugs should
be maintained. Due to the possibility of vasoconstriction and an increase in blood pressure,
especially in patients at risk of ischemic stroke, the concomitant use of pseudoephedrine
with vasoconstrictor drugs such as ergotamine, dihydroergotamine, linezolid, oxytocin,
ephedrine, phenylephrine and bromocriptine is not recommended. Pseudoephedrine may
also increase myocardial excitability and affect ventricular rhythm, especially in patients
with cardiac diseases who are hypersensitive to the cardiac effects of sympathomimetics.
Combination with caffeine present in many OTC medications, dietary supplements and
energy drinks may cause hyperglycaemia and an increase in body temperature. Pseu-
doephedrine used concomitantly with the drugs listed in Table 3may cause undesirable
interactions, resulting in the weakening or potentiation of the drug effects [18,19,36].
Pseudoephedrine may also be responsible for a false-positive urine test for am-
phetamine and methamphetamine. The structural similarity to these drugs means that they
may cross-react in a test using the immunological method. Figure 2shows the similarity in
chemical structure of pseudoephedrine, amphetamine and methamphetamine [3,37,38].
Table 3. Adverse drug interactions of pseudoephedrine.
Pseudoephedrine Interactions
Other Concomitantly Used Medicines and Substances Type and Consequence of Interaction
Antacids (e.g., aluminium hydroxide),
proton pump inhibitors Increase in PSE absorption rate
Kaolin clay Decreased rate of absorption of PSE due to its adsorption on the
surface of kaolin clay
Digitalis glycosides Increased ectopic activity of the heart’s conducting
system, arrhythmia
MAO inhibitors (phenelzine, selegiline, tranylcypromine,
procarbazine)
Synergistic sympathomimetic effect,
significant increase in blood pressure,
hypertensive crisis, bradycardia—
14-day interval between drugs is required

Int. J. Mol. Sci. 2021,22, 5146 7 of 11
Table 3. Cont.
Pseudoephedrine Interactions
Tricyclic antidepressants
Increased effect of PSE, increased risk of
hypertension and cardiac arrhythmias—concomitant use is
not recommended
Methyldopa, guanethidine, reserpine PSE reduces the antihypertensive effect in addition to the
drugs—concomitant use is not recommended
Appetite suppressants Risk of increased blood pressure, increased heart rate—concomitant
use is not recommended
Ergotamine, dihydroergotamine, linezolid, oxytocin,
ephedrine, phenylephrine, bromocriptine
Risk of vasoconstriction and increase in blood pressure—concomitant
use is not recommended
Urine alkalinisation
(e.g., sodium bicarbonate)
Urine alkalinisation increases the reabsorption of PSE, the risk of
seizures, anxiety, restlessness, insomnia, tachycardia
Inhalation agents for general anaesthesia
Acute hypertensive reaction in the perioperative
period—discontinuation of PSE is recommended 24 h before the
planned general anaesthesia
Caffeine
Elevated body temperature, hyperglycaemia, insulinaemia, increased
C-peptide levels
Ethyl alcohol Acute psychosis
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 7 of 10
Urine alkalinisation
(e.g., sodium bicarbonate)
Urine alkalinisation increases the reabsorp-
tion of PSE, the risk of seizures, anxiety,
restlessness, insomnia, tachycardia
Inhalation agents for general anaesthesia
Acute hypertensive reaction in the perioper-
ative period—discontinuation of PSE is rec-
ommended 24 h before the planned general
anaesthesia
Caffeine
Elevated body temperature, hyperglycae-
mia, insulinaemia, increased
C-peptide levels
Ethyl alcohol Acute psychosis
Pseudoephedrine may also be responsible for a false-positive urine test for amphet-
amine and methamphetamine. The structural similarity to these drugs means that they
may cross-react in a test using the immunological method. Figure 2 shows the similarity
in chemical structure of pseudoephedrine, amphetamine and methamphetamine [3,37,38].
Figure 2. Chemical structure of pseudoephedrine and optical isomers of amphetamine and meth-
amphetamine.
11. Self-Medication
The widespread availability of drugs, especially those sold over the counter, and
their advertising encourages many people to self-medicate, also with products containing
pseudoephedrine. Simultaneously using several products under different names for rhi-
nitis, sinusitis, cold or allergic rhinitis—the patient, unaware, exposes himself to overdose.
Moreover, as shown by the study by Pawlaczyk et al., a large percentage of people use
PSE preparations without consulting a doctor. The most frequently reported adverse re-
actions by patients included CNS disturbances—agitation, insomnia, sedation, headache.
It should be noted that currently 720 mg of the active substance can be purchased at a time
at a pharmacy open to the public—1 package containing 12 tablets of 60 mg. The legislator
justified the above regulation with the statement that such an amount will allow for an
effective and safe self-treatment. A patient who purchases a drug at a pharmacy has the
opportunity to consult a pharmacist [15]. Unfortunately, as demonstrated by the study by
Gołda et al., the quality of a pharmaceutical consultation regarding the expedition of
pseudoephedrine at a dose of 60 mg does not always ensure safety. It is therefore neces-
sary to develop and implement specific procedures in this regard [39].
Figure 2.
Chemical structure of pseudoephedrine and optical isomers of amphetamine
and methamphetamine.
11. Self-Medication
The widespread availability of drugs, especially those sold over the counter, and
their advertising encourages many people to self-medicate, also with products containing
pseudoephedrine. Simultaneously using several products under different names for rhinitis,
sinusitis, cold or allergic rhinitis—the patient, unaware, exposes himself to overdose.
Moreover, as shown by the study by Pawlaczyk et al., a large percentage of people use PSE
preparations without consulting a doctor. The most frequently reported adverse reactions

Int. J. Mol. Sci. 2021,22, 5146 8 of 11
by patients included CNS disturbances—agitation, insomnia, sedation, headache. It should
be noted that currently 720 mg of the active substance can be purchased at a time at a
pharmacy open to the public—1 package containing 12 tablets of 60 mg. The legislator
justified the above regulation with the statement that such an amount will allow for an
effective and safe self-treatment. A patient who purchases a drug at a pharmacy has the
opportunity to consult a pharmacist [
15
]. Unfortunately, as demonstrated by the study
by Gołda et al., the quality of a pharmaceutical consultation regarding the expedition of
pseudoephedrine at a dose of 60 mg does not always ensure safety. It is therefore necessary
to develop and implement specific procedures in this regard [39].
12. Non-Medical Use
Medicinal products are not always used as intended. Pseudoephedrine—due to its
properties including increased muscle contractility, increased blood flow to skeletal muscles,
stimulation of glycogenesis, bronchodilatation, increased cardiac tropisms, activation of the
central nervous system, suppression of appetite—is also used as a slimming agent and in
sport—as an ergogenic agent, i.e., improving efficiency, allowing for faster regeneration and
better performance. The influence of PSE on sporting performance has long been a subject
of debate, and observations do not always confirm this effect; however, it is on the list of
substances prohibited for use by athletes during competitions. Due to its wide availability,
it is considered an anti-doping rule violation when its concentration in urine exceeds
150
µ
g/mL. This list is a mandatory international standard and is updated annually by the
World Anti-Doping Agency (WADA), which is part of the World Anti-Doping Programme.
The current list has been in effect since 1 January 2021 [12,13,40,41].
Increased interest in preparations containing pseudoephedrine is related to its use
for recreational purposes, especially by adolescents and young adults, as well as for the
production of psychoactive substances—the synthesis of methamphetamine and methcathi-
none (ephedrone), used as designer drugs [
42
,
43
]. Until recently, publicly available drugs
with PSE were sold on the Polish market without restrictions; this demand was exploited
by some pharmacies. It happened despite the alarm of pharmaceutical inspectors. The
territorial-quantitative analysis of sales data, prepared by US Pharmacia in cooperation
with the Main Pharmaceutical Inspector and the National Bureau for Drug Prevention
in 2009 and 2010, allowed for an indirect assessment of the scale of the phenomenon of
non-medical use of medicines containing pseudoephedrine. These data show that above-
average sales of preparations containing PSE were territorially diversified. A total of
29 areas with intensified sales and 3 medicinal products (Cirrus, Acatar AT, Sudafed) were
identified. The main Polish regions with intensified sales of these products were the four
south-western border provinces. High intensification of the problem was observed in
Lower Silesia (757,000 packages in 2009 and 1332,000 packages in the period from January
to September 2010). Most of the pseudoephedrine available in medicinal products ended
up in the Czech Republic, where it was used as a precursor to synthesise a very popular in
the country local methamphetamine called Pervitin [44].
For many years, the Institute of Forensic Expertise in Kraków (Poland) has been
conducting studies on manufacturing psychoactive substances from medicines. People
experimenting with home drug production often use PSE preparations for this purpose,
in Poland most frequently Sudafed and Acatar. The method is based on the oxidation
of PSE with large amounts of potassium permanganate in an acidified environment; the
resulting ephedrone solution also contains large amounts of manganese. After intravenous
injection, it quickly enters the CNS, accumulating in subcortical structures, and has a strong
neurotoxic effect. Frequently underestimated postural and speech disorders as symptoms
of manganese encephalopathy are observed after only 5–9 months. They manifest as
difficulties in maintaining balance with a tendency to fall backwards, problems with
standing up without support or assistance and moving backwards. Typical is the so-
called “cock gait” caused by dystonic contraction of the foot and calf muscles. Speech
disturbances, sometimes making contact with the environment difficult or impossible, occur

Int. J. Mol. Sci. 2021,22, 5146 9 of 11
in the form of muffled speech and palilalia; they take the form of dysarthria. Compulsive
laughter is not uncommon. Some people develop an extrapyramidal syndrome, including
symptoms such as slowness of movement, bradykinesia, muscle stiffness, hypomimia,
micrography (reduced handwriting), and difficulty with fine movements. Rest tremor
observed in Parkinson’s disease is rare. The diagnosis of manganese encephalopathy
requires confirmation of intravenous use of home-prepared ephedrone with potassium
permanganate; this is followed by a typical magnetic resonance imaging of the brain, which
shows hyperintense lesions in the globus pallidus, shells and thalamic nuclei in the T1
sequence. The differential diagnosis with Parkinson’s disease highlights insensitivity or
minimal sensitivity to anti-Parkinsonian drugs, including L-dopa preparations [
45
–
48
].
Atypical pneumonia, phlebitis, limb necrosis, hepatic and pancreatic disorders have also
occurred in people taking Sudafed products [9,44].
The Regulation of the Minister of Health in Poland on the list of substances with
psychoactive effects and the maximum level of their content in a medicinal product, in force
since 1 January 2017, constituting a restriction on the dispensing of medicinal products
as part of a single sale, has not solved the problem of abuse of medicines containing
psychoactive substances, including the purchase of medicinal products in bulk by some
people for non-medical use of pseudoephedrine as a precursor or a psychoactive substance.
This has made access to medicines with pseudoephedrine somewhat more difficult, but not
impossible. Perhaps changing the availability category of medicinal products containing
pseudoephedrine from ‘OTC’ to ‘Rx’ and selling them on medical prescription would be a
more effective solution.
Author Contributions:
Conceptualisation, A.W.-H. and K.G.; making the table, A.W.-H.; drawing
the figures, K.G.; writing—review and editing, A.W.-H. and K.G.; supervision, A.W.-H. All authors
have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study did not involve humans or animals.
Conflicts of Interest: The authors declare no conflict of interest.
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