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DARK Classics in Chemical Neuroscience: Loperamide

Cori A. Malinky, Craig W. Lindsley, and Changho Han*

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ABSTRACT: Loperamide, a popular and inexpensive over-the-counter

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antidiarrheal medicine, is a potent μ-opioid receptor agonist approved by

the U.S. Food and Drug Administration (FDA). It has been on the market
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since 1976 and is relatively safe with no central nervous system-related side
effects when used for a short period of time at the recommended
therapeutic dose (2−8 mg/day). In recent years, loperamide has become
notoriously known as the “poor man’s methadone” for people with
substance dependence due to the increase in loperamide overdoses from
self-administered medication to treat opioid withdrawal symptoms. As a
result, in 2018, the FDA decided to limit the available packaged dose of
loperamide to stop prominent abuse. This review provides the synthesis
and chemical properties of loperamide as well as the pharmacology and
adverse effects of its use and the social effects of such abuse.
KEYWORDS: Loperamide, Imodium, μ-Opioid receptor agonist, Abuse, Cardiotoxicity

■ BACKGROUND
Loperamide, also known as Imodium, is a readily available
bind to opioid receptors in the CNS and show strong analgesic
and sedative effects.25−28 Because of their therapeutic value,
antidiarrheal medicine.1,2 It was first discovered in 1969 by opioid analgesics have been widely used for various medical
purposes in patients.28−32 The role of opioid receptors in the
Paul Janssen from Janssen Pharmaceutica.3 Initially, it was
GI tract are quite different from those localized within the
introduced as a schedule V drug by following a study that
CNS.33−36 In general, these inhibitory receptors in the GI tract
showed a potential risk of opioid physical dependence at
contribute to increase gut transit time by stimulating
supratherapeutic doses.4−6 However, loperamide exhibited
nonpropulsive contractions and increase the rectal tone (see
outstanding efficacy as well as a favorable safety margin at
ref 18 for additional information).35,37,38 Among those three
the therapeutic dose (2−8 mg/day) in subsequent studies
receptors, the MOR shows the highest expression level in the
conducted on human volunteers. This resulted in its removal
enteric nerve cells and therefore is considered as a major
from the FDA’s controlled substance list in 1982.6−10
contributor for the GI tract-related effects of loperamide.2,33,39
Loperamide has since become a nonprescription, over-the-
As an inexpensive MOR agonist, substance-dependent
counter (OTC) antidiarrheal medicine.11 In addition, it has
people began to take loperamide far more (70−100 mg/day)
been used as a first-line treatment of chemotherapy-induced
than the recommended dose (2−8 mg/day) to induce a mild
diarrhea (CID), a side effect associated with a gastrointestinal
high for the self-treatment of opioid withdrawal symp-
toxicity of chemotherapy agents.12 It also showed therapeutic
toms.9,40−43 Loperamide is significantly more affordable for
potential as a peripheral analgesic to treat inflammatory pain,13
people with substance dependence because it only costs
neuropathic pain,14−16 and cancer pain.17 Loperamide can $36.75−52.5/week for the self-treatment (35−50 caplets × 7
inhibit voltage-gated L-type calcium channels and trigger days) in comparison to typical methadone treatment, which
autophagy-dependent cell death as well.18,19 It currently costs around $126/week (medication and supplemental
remains an OTC drug with an affordable price (∼$0.15/ medical services costs).44 Moreover, people have shared their
caplet) which can be purchased online or at a local store.20,21 experiences on social media, and the Internet community
Loperamide is a peripherally restricted potent μ-opioid
receptor (MOR) agonist, and its importance has recently been
showcased by the World Health Organization (WHO) by its Received: June 8, 2021
inclusion in the model list of essential medicines.22 μ, κ, and δ Accepted: July 22, 2021
opioid receptors (MOR, KOR, and DOR) are inhibitory G
protein-coupled opioid receptors found in the central nervous
system (CNS) as well as in the gastrointestinal (GI) tract.23−25
Blood−brain barrier (BBB) permeable opioids and opiates

© XXXX American Chemical Society https://doi.org/10.1021/acschemneuro.1c00382

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Figure 1. X-ray crystal structure of loperamide (HCl salt)1 and its chemical properties.
Figure 2. Synthesis of loperamide (1).3,60
began calling it a “poor man’s methadone” or “Lope”.45 The
number of Internet posts with loperamide mentions has
exponentially increased since 2005, and the social media
attention has triggered a huge increase in documented cases of
loperamide misuse.5,9,42,46−49 As expected, there are an
increasing number of reports on patients with fatal
cardiotoxicity due to this abuse.9,41,43,49−53 The FDA reported
15 761 total loperamide-related adverse cases with 7204 being
considered serious instances, including 403 total fatalities.54 A
total of 63% of these reported cases have occurred since
2015.54 Between 2010 and 2015, intentional loperamide
exposure nearly doubled from 201 cases to 383 cases.55
Surveys conducted in the third quarter of 2017 of ∼40 000 US
and UK participants actively taking loperamide revealed that
4.9% (US) and 22.5% (UK) of users take loperamide to treat
or prevent withdrawal symptoms. In addition, 4.2−6.8% (US)
and 14.3−41.5% (UK) of users take loperamide recreation-
ally.56 As consequence, since 2018, the FDA has limited the
packaged dose of loperamide to prevent its abuse and to
encourage safe use as an antidiarrheal medication.57
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■ CHEMICAL PROPERTIES AND SYNTHESIS
Loperamide is a phenylpiperidine derivative which was first
synthesized and discovered in 1969 from a synthetic opioid
antidiarrheal agent discovery effort.3 While in development,
loperamide was known as R 18553. Its IUPAC name is 4-[4-
(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-N,N-dimethyl-2,2-
diphenylbutanamide.3 As reported in Figure 1, its molecular
weight is 476.2 g/mol. Loperamide is shelf stable in the
absence of light and relatively lipophilic (logP = 5.5).3,58
Loperamide hydrochloride exists in the crystalline state as two
distinct polymorphs and a tetrahydrate.3 It is usually
distributed in the form of polymorph I which is recrystallized
in cold isopropanol while being stirred.3 This form of
loperamide has a melting point of ∼224 °C, is soluble in
polar organic solvents such as methanol (28.6 g/100 mL) and
methylene chloride (35.1 g/100 mL), and is considerably less
soluble in neutral water (pH = 7, 0.4 g/100 mL) as well as
acidic water (pH = 1.7, 0.14 g/100 mL).3,58 Loperamide
hydrochloride can be formulated with various glycerols to
improve its aqueous solubility.59
The original synthesis of loperamide hydrochloride is the
main synthetic route used in production since 1969.3,60
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Figure 3. Metabolism of loperamide (1). (A) Major human phase I metabolites of loperamide and relative ion chromatogram peak intensities of
metabolites.68 Loperamide (20 μM) was incubated in NADPH-supplemented human liver microsomes. (B) Other reported minor metabolites.

Loperamide hydrochloride is synthesized convergently over six
linear steps.3,60 As shown in Figure 1, 2 is subjected to a
sequence of ring closing and ring opening steps to form
lactaminium bromide salt 8. This is accomplished over four
synthetic steps, and the first transformation can be achieved via
two different approaches. In the original disclosure, 2 is
hydrolyzed and subsequently cyclized in the presence of acetic
acid and water to afford 5. Alternatively, more stable starting
material 3 can be reacted with 4 in the presence of sodium
reagent 10 is reacted with 9 to form 11, which then undergoes
catalytic hydrogenation to afford the desired piperidine core
12. Intermediates 8 and 12 are then condensed to afford the
loperamide free base 1. 1 is then transformed into a salt in the
presence of hydrochloric acid and crystallized in isopropanol to
afford loperamide hydrochloride.3,60 Each distinct polymorph
as well as the tetrahedral crystalline form can be preferentially
formed depending on the recrystallization conditions.3
Loperamide hydrochloride is currently synthesized and
manufactured on an industrial scale.59

■
hydroxide to provide 5. The resulting lactone 5 is then opened
with HBr to give the alkyl halide 6. 6 is then cyclized over two
steps to produce the lactaminium bromide salt 8. The DRUG METABOLISM AND PHARMACOKINETICS
piperidine core of loperamide (Figure 2; 12) is synthesized Loperamide (Figure 3; 1) can be well absorbed in the GI tract;
over two steps starting from benzylpiperidone 9. Aryl Grignard however, its plasma concentration is usually very low due to
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rapid metabolism (Figure 3) and, as a result, poor
pharmacokinetic properties (Table 4).3,7,61,62 Upon being
administered, loperamide is extensively metabolized in the liver
where it undergoes N-demethylation, hydroxylation, and/or
oxidative N-dealkylation (Figure 3).3,62−66 These metabolites
have been confirmed by independent groups using different
methods such as high-performance liquid chromatography-
atmospheric pressure ionization mass spectrometry analysis of
human excretion,63 in vivo radiolabeled studies in rat
models,3,64,66 and in vivo/in vitro LC-MS analysis of human
and rat hepatocytes.62 A study consisting of in vivo and in vitro
analysis of human and rat hepatocytes suggests the most
abundant loperamide metabolite is M3 (Figure 3A) and
continued demethylation affords M7 (Figure 3B).62 It is
unclear if both M3 and M7 are formed during first-pass
metabolism or if M7 is formed during subsequent metabolism.
CYP3A4 and CYP2C8 have been implicated in playing a key
role in the demethylation process, whereas CYP2B6 and
CYP2D6 appear to only play a minor role.43 An in vivo analysis
of human plasma and urine showed that M3 was the major
metabolite and was detected in higher concentrations than
both M1 and M7 within urine samples.63 A study consisting of
in vivo and in vitro analysis of human and rat hepatocytes
suggests another major metabolite of loperamide as being
hydroxylated metabolite M2.62 Other hydroxylated metabolites
of loperamide were also identified (Figure 3; M1 and M6). M1
is believed to be converted into glucuronides.3,64,66 Approx-
imately 15% of the administered dose is later metabolized into
glucuronides which are excreted in the bile.3,64,66 It is
noteworthy that minor metabolite M5 contains a potentially
neurotoxic pyridinium cation moiety.3,64,66 Additionally,
oxidative N-dealkylation of loperamide generates fragmented
metabolites M8 and M9, which are then excreted in both the
urine and bile without any other effects.3,62−66
Within an aqueous environment, loperamide hydrochloride
begins to degrade through hydrolytic cleavage of the piperidine
connection to form M8 and M9, and/or is dehydrated to form
pyridinium cation, M5.3 In vitro and in vivo DMPK studies
have identified similar loperamide metabolites which are
detailed in Figure 3A,B.3,62−67
The pharmacokinetics of loperamide has been studied in
detail, but reports have varied significantly based on the dosage
and subject variability.61,62,65 A simplified PK profile of
loperamide is discussed here (Table 4), and a more thorough
discussion can be found in the research conducted by Zamek-
Gliszczynski et al.61 Loperamide has an oral bioavailability (F)
of 4% with a clearance (CL) of 30 mL·min−1·kg−1 in Han
Wistar rat.61,62 In humans, oral bioavailability is much lower
(%F = 0.3%).61 The free fraction of loperamide in rat plasma
(f ur) was reported to be 5.8% with a recovery rate of 95%,
which signifies loperamide’s stability within plasma.3,64,66 As
discussed above, the hepatic first-pass metabolism is the
primary source of major metabolites of loperamide.3,63−66,69
The total plasma concentration (Cmax) after oral administration
was reported to be 0.02 μΜ, resulting in a total plasma
concentration unbound (Cu,max) of 1.2 nΜ.3,64,66 Although
loperamide has a high volume of distribution (Vdss= 4 L/kg),
studies conducted with tritiated loperamide have shown that
loperamide and its metabolites are scarcely found within
tissue.3,61,62,64,66 The half-life (t1/2) varies depending on the
dose, 2 and 11.5 h for 5.1 μmol/kg and 10.1 μmol/kg,
respectively.62 The prolonged t1/2 of supratherapeutic doses of
loperamide is of the utmost concern when considering its
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ability to penetrate the BBB and induce morphine-like
euphoria that has led to its ongoing abuse.70
■
PHARMACOLOGY
Within in vitro binding assays, loperamide displays a potent
affinity for the human MOR (Ki = 3.3 nM), 50-fold more
potent than morphine with a longer duration of action.71−73 It
exhibits 15-fold selectivity over DOR (Ki = 48 nM) and 350-
fold selectivity over KOR (Ki = 1156 nM).71 [35S]GTPγS
binding studies indicate the agonist character of loperamide on
human MOR (EC50 = 56 nM).71 Moreover, loperamide
inhibited forskolin-stimulated cAMP accumulation (IC50 = 25
nM) in human MOR transfected cells.71
Because of its poor systemic bioavailability, loperamide
mainly stimulates MORs at the large intestinal myenteric and
submucosal plexi of the enteric wall at recommended
therapeutic doses (2−8 mg/day).40,61,62 This stimulation
inhibits the release of acetylcholine and prostaglandins and
results in decreased peristaltic activity, antisecretory activity,
and increased intestinal transit time.40,73 As a result, more
fluids and electrolytes can be absorbed.40,61,62,73 Loperamide
has also been shown to affect many other receptors and signal
transmission pathways. For example, it modulates serotonin
release and enteric 5-hydroxy-tryptamine (5-HT) release.73
Loperamide is a known antagonist of various calcium channels,
the NK2 receptors, and calmodulin as well.73 In recent years,
there have been a variety of reports on the analgesic effects of
loperamide.15,17,42,74,75 Considering its lack of CNS pene-
tration potential at the therapeutic dose, the use of loperamide
to manage pain could be beneficial compared to other
analgesics because of a lower potential of abuse while
displaying a higher MOR potency and longer duration of
action.13,15,16,71−74,76,77 The studies conducted have adminis-
tered loperamide in a plethora of different methods, including,
orally, intravenously, intrathecally, via spinal tap, and as a
topical ointment.13,15,74,78 When delivered intravenously to
mice, loperamide was shown to inhibit sodium channels to
alleviate inflammatory hyperalgesia.13 On the other hand,
inflammation became more severe and accelerated arthritis
progression when applied as a topical ointment to Lewis rats.79
■
BEHAVIORAL PHARMACOLOGY
Loperamide lacks CNS activity at prescribed doses (2−8 mg/
day) due to its poor systemic bioavailability, rapid metabolism,
and P-gp liability.3,7,61,62 However, at supratherapeutic doses
(70−400 mg/day) or in combination with P-glycoprotein
inhibitors, it can also cause opioid-like behavioral effects.9,40−43
There are multiple reports that show the analgesic effects of
loperamide in animal models.13,15,16,71−74,76,77 A recent study
from Bartus and colleagues used the tight junction relaxing
agent, Cereport, to increase brain levels of loperamide.75 In
their studies, loperamide produced a significant analgesic effect
when animals were tested on a hot plate apparatus.75 However,
it is noteworthy that analgesic effects were only observed under
extremely rigorous study conditions. People have also tried to
overdose on loperamide to achieve euphoric effects, but
successful cases are very rare.9,41,67,80,81 This may be because
the loperamide misusers experienced dangerous side effects,
such as respiratory depression and paralytic ileus, before
reaching sufficiently high levels of loperamide in the
brain.51,80,82
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ADVERSE EFFECTS AND DOSAGE Loperamide misuse at supratherapeutic doses (e.g., 50−300
The OTC antidiarrheal loperamide is readily available with or mg/day) can cause severe opioid poisoning symptoms such as
without a prescription in many different formulation types: respiratory depression as well as catastrophic cardiac
tablets, capsules, liquid forms, and orodispersible tablets.40 The abnormalities, including the QTc prolongation (≥500 ms)
recommended maximal dose does not exceed 8 mg/day and the QRS interval widening (≥120 ms).51 The American
without prescription or 16 mg/day with prescription.40,65,83 Association of Poison Control Centers (AAPCC) data indicate
The healthcare professional recommends 4 mg as a starting about a 7-fold increase in poison center calls related to
dose for acute diarrhea, followed by 2 mg dosing after each loperamide misuse from 2011 to 2015.86 Therefore, the FDA
unformed stool while keeping maximal daily dose (8 mg/day issued a safety alert about loperamide misuse on June 7,
or 16 mg/kg with prescription).83 However, loperamide is not 2016.11
recommended for children less than 2 years old, and the Table 2 shows an exemplary demographic profile of
suggested dose for chronic use is much lower (2 mg, twice a loperamide as well as other antidiarrheals reported in the
day).84 At the recommended therapeutic dose (2−8 mg/day), 2019 AAPCC report.52 In 2019, 1310 loperamide-related cases
effects of loperamide are restricted to periphery, especially the were mentioned. Among them, 902 cases were related to
gut (due to its P-gp liability (efflux ratio = 10.4)85 and low oral loperamide single exposure, and 56 reported cases were related
bioavailability (%F = 0.3%)86). At a therapeutic dose, the to either major medical issues or death. As shown in Table 2,
plasma concentration of loperamide remains <2 ng/mL.40 the potential risk from the abuse of loperamide could be higher
Thus, loperamide generally shows a wide margin of safety and compared to other antidiarrheals, and healthcare providers
a less potential for abuse at the recommended dose. should educate their patients of its potential risk at
Commonly reported adverse effects of loperamide both at supratherapeutic doses. Juurlink et al. studied 24 reported
therapeutic doses and supratherapeutic doses are listed in cases (published between 2014 and 2017) of loperamide-
Table 1.5,11,51,84,87 Minor adverse effects at therapeutic doses associated cardiac toxicity.41 Their case study showed that
patients came to the clinic with various symptoms (e.g.,
Table 1. Reported Side Effectsa of Loperamide presyncope, palpitations, loss of consciousness, recurrent
(1)5,11,51,84,87 syncope, dyspnea, presyncope, seizurelike activity, generalized
weakness, cardiac arrest, dyspnea, meiosis, vomiting, anxiety,
therapeutic doses supratherapeutic doses and chest tightness).41 Loperamide plasma concentration was
common minor serious side effects short-term very high (22−210 μg/L) in most of the cases. In some
side effects with long-term use overdoes long-term overdoes extreme cases, patients were reported to have taken 800 mg/
• constipation • toxic megacolon • stomach • severe day of loperamide for 18 months.7 Four of the twenty-four
discomfort cardiotoxicity patients died from overdosing.41
• dry mouth • paralytic ileus • vomiting • cardiac Interaction between loperamide and CYPs (especially,
arrhythmias
CYP2C8, CYP3A4), or P-gp inhibitors is well studied,41,67,70
• dizziness • angioedema • drowsiness • respiratory
depression and selected brand names of therapeutic agents that can
• tiredness • Stevens− • abdominal • central nervous interact with loperamide are listed in Table 3.53 As expected,
Johnsons pain system
syndrome depression Table 3. Potential Loperamide Interactors53
• headache • allergic reactions
• nausea brand name of potential interactors
a
The most commonly discussed side effects from publicly accessible • Tagamet HB • Eryc
Web sites are highlighted in bold. • Prevpac • Eryped
• Biaxin • Lopid
• Ery-Tab • Onmel
include constipation, dizziness, tiredness, headache, nausea,
• Sporanox • Nuedexta
and dry mouth. Patients can develop more severe side effects
• Zantac • Qualaquin
with long-term usage. These include toxic megacolon, paralytic
• Kaletra • Technivie
ileus, angioedema, Stevens-Johnsons syndrome, and allergic
• Norvir • Viekira Pak
reactions. Additionally, accidental overdose can cause vomit-
ing, drowsiness, abdominal pain, and stomach discomfort.

Table 2. Exposure Cases of Antidiarrheals Listed in the 2019 AAPCC Report52

reason for exposure medical outcome of human exposurec
no. of case no. of single treated in health
antidiarrheals mentionsa exposuresb care facility unintentional intentional none minor moderate major death
loperamide 1310 902 395 574 261 276 91 78 50 6
diphenoxylate and atropine 192 101 54 74 17 32 8 8 5 0
containing
non-narcotic containing 31 25 3 21 0 10 1 0 0 0
(excluding salicyl containing)
other narcotic containing 2 1 0 1 0 0 0 0 0 0
paregoric containing 3 3 3 2 1 0 0 0 1 0

a
The number of times the specific substance generic code was reported in any human exposure case. bThe number of human exposure cases that
identified only one substance. cThe rests are not counted due to no follow-ups and other reasons.

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Figure 4. SAR overview of loperamide in relation to MOR.

the aforementioned side effects of loperamide can also occur Table 4. In Vivo Pharmacokinetic Profile Comparison of
when users took loperamide with its interactors. Bowman et al. Loperamide (1) and Sila-loperamide (13) in Rat (Han
studied trends in the potential for loperamide misuse using Wistar Rats)62
available case studies.40 67% of reported loperamide misuse
cases examined are related to coadministration; yet, loper-
amide was a primary source of adverse effects. Studies have
shown that coadministration of loperamide interactors can
increase plasma concentration of loperamide up to 4.2 fold and
increase its t1/2 up to 36.9 h.88 Case reports published after
2014 indicate loperamide users are using other OTC
medications (such as antihistamines and/or cimetidine) to
elevate the exposure and effect of loperamide.40,52

■ STRUCTURE−ACTIVITY RELATIONSHIPS
Nearly 50 years after the discovery of loperamide, Sakamoto
and co-workers reported structure−activity relationship (SAR)
studies on the piperidine core of loperamide.3,89 To expedite
the SAR exploration process, the piperidine core was replaced
with a piperazine (Figure 4).89 Although this modification
resulted in a 10-fold loss in potency, they were able to quickly
generate various analogues using rather simple chemistry, such
as an SN2 reaction. Another study replaced the C4 carbon
atom with a silicon atom to generate a sila-loperamide
analogue that was shown to exhibit enhanced metabolic
stability and exhibited diminished BBB permeability (Table 4;
13).62 The resulting sila-loperamide analogue exhibited similar
PK properties yet was less prone to metabolism.62 Moreover,
the sila-loperamide (13) exhibited lower BBB permeability,
suggesting that a carbon/silicon switch may be a viable option
for manipulating pharmacological properties and preventing
abuse (Table 4).62
A computational docking study of loperamide suggests that
the basic nitrogen of the piperidine core (N1) may participate
in a charge−charge interaction with the Asp128 residue within
the binding pocket of hMOR.90 An in vitro study result with
loperamide N-oxide seems to support the claims of the docking
study; the loperamide N-oxide was not as active as
loperamide.3,91 Deletion of the C4-OH is tolerated, resulting
in potency similar to loperamide.89,91,92 The original patent for
loperamide contained various structural alterations of the
piperidine core, including methyl substitutions, as well as
replacement of the C4-OH with a methyl group, all of which
resulted in a dramatic loss of potency.60
The most studied structural feature of loperamide is the right
side of loperamide (chlorophenyl moiety), which has been
shown to tolerate many structural alterations (Figure 4).89,91,92
Such structural alterations include fused aromatic and pyridyl
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ring systems. Various substituents on the aryl group (Me-,
MeO-, OH-, F-, and Cl-) are well tolerated and reported to
exhibit equivalent or better potency.89,91,92 In nearly every
instance, substitution at the 6-position provided more potent
analogues than substitutions at the 7- or 8-positions (Figure
4).89,92 In some cases, substitution at the 6-position provided a
20-fold increase in potency with good selectivity.92
Reported SAR studies of the left side of loperamide (N,N-
dimethyl-3,3-diphenylbutanamide component) are limited
(Figure 4). Changing the amide group into 1° or 2° amides
resulted in a slight loss of potency.91 Replacing the amide with
a carboxylic acid was 1000-fold less active, and complete
deletion of the amide group resulted in a 100-fold loss in
potency.91 Interestingly, replacement of the amide with a
methyl ester retained potency in some cases.91 SAR studies of
the gem-diphenyl moiety have not been reported to our
knowledge.90 However, a docking study suggests the spatial
orientation of the diphenyl groups in relation to the amide
group is responsible for the different binding modes of the
MOR and DOR binding pockets.90 Follow-up SAR studies
around this moiety are warranted.
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HISTORY AND IMPORTANCE IN NEUROSCIENCE
Loperamide was discovered in 1969 at Janssen Pharmaceutica
as a potent MOR agonist and has gained a certain notoriety
over the years. It has come to be known by many names:
commercially available as Imodium, referenced in literature as
the “Poor man’s methadone”, and termed as “Lope” on social
media.5,9,42,46−49 The use of loperamide as a means to
attenuate opioid withdrawal remains a topic of debate due to
its cardiovascular toxicity and potential of physical dependence
through repeated administrations.41,80,81,93,94 It was first
approved by the FDA as a schedule V narcotic drug but was
later removed from the controlled substance list and has since
become an OTC available antidiarrheal medication.4−10 In
2016, loperamide was the single best-selling OTC drug in
Great Britain, and the WHO recently included loperamide in
the model list of essential medicines, showcasing the
importance of the drug.22,95
At recommended doses for a limited length of time,
loperamide is an effective medication for the treatment of
diarrhea.9,40−44,46,65 Additionally, it has increasingly been used
for the treatment of opioid withdrawal symptoms.44,65,67,96
Internet forum users insist loperamide may show a methadone-
like effect for the treatment of substance use disorders at
supratherapeutic doses. Some users even experienced a
euphoric effect.46,65 Since 2005, there has been a significant
increase in documented cases of loperamide misuse as well as
an increasing number of patients with fatal cardiotoxicity
related to the overdosed loperamide mediated inhibition of the
hERG channels.9,41,43,49−53 The FDA has warned that taking
loperamide at a higher than recommended dose, either for its
antidiarrheal effect or for its euphoric effect, may cause serious
heart problems including the potential of inducing cardiac
arrest leading to death.9,41,43,49−53 What qualifies loperamide as
a DARK CLASSIC substance of abuse is that successful cases
of achieving an euphoric effect are very rare because misusers
typically succumb to dangerous side effects (respiratory
depression, paralytic ileus, cardiac arrest, etc.) before reaching
sufficiently high levels of loperamide in the brain.5,9,42,46−49
Healthcare workers should continue to emphasize the DARK
SIDE of loperamide misuse to prevent future abuse.
■
AUTHOR INFORMATION
Corresponding Author
Changho Han − Warren Center for Neuroscience Drug
Discovery, Vanderbilt University School of Medicine,
Nashville, Tennessee 37232, United States; orcid.org/
0000-0002-0832-7070; Email: changho.han@
vanderbilt.edu
Authors
Cori A. Malinky − Warren Center for Neuroscience Drug
Discovery, Vanderbilt University School of Medicine,
Nashville, Tennessee 37232, United States
Craig W. Lindsley − Warren Center for Neuroscience Drug
Discovery, Department of Pharmacology, and Department of
Biochemistry, Vanderbilt University School of Medicine,
Nashville, Tennessee 37232, United States; Department of
Chemistry, Vanderbilt Institute of Chemical Biology,
Vanderbilt University, Nashville, Tennessee 37232, United
States; orcid.org/0000-0003-0168-1445
Complete contact information is available at:
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Review
Author Contributions
C.A.M., C.W.L, and C.H. all researched and wrote sections of
this review manuscript.
Funding
We thank William K. Warren, Jr., and the William K. Warren
Foundation who funded the William K. Warren, Jr. Chair in
Medicine (to C.W.L).
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
We thank Dr. Darren Engers, Dr. Aaron M. Bender, and Dr.
Julie Engers for their help in the review process.
■
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