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'''Loperamide''' (also known as '''Imodium ''') is an [[opioid]] [[agonist]] that is sold as an anti-diarrheal agent.
'''Loperamide''', commonly branded as '''Imodium''', is a synthetic [[Psychoactive class::opioid]] of the [[Chemical class::phenylpiperidine]] chemical class that is sold as an anti-diarrheal agent. But has off label uses as a pain relief medication, usually effective at 8mg-16mg (this method of using loperamide is not FDA approved, and can be very dangerous depending on your body, medications your taking, and how you administer this substance)


Loperamide crosses the blood-brain barrier in very small amounts, but traditionally these amounts have been considered insignificant. However, loperamide in high doses, has the potential for a significant analgesic or even [[euphoric]] effect.<ref>Poor Man's Methadone: A Case Report of Loperamide Toxicity. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/26355852</ref> Loperamide produces both QRS and QT prolongation at supra-therapeutic dosing.
Loperamide crosses the blood-brain barrier in very small amounts, but traditionally these amounts have been considered insignificant. However, loperamide in high doses, has the potential for a significant [[analgesic]] or even [[euphoric]] effect.<ref>Poor Man's Methadone: A Case Report of Loperamide Toxicity. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/26355852</ref> Use of higher-than-recommended levels of loperamide has been associated with cardiotoxicity. Large doses taken at once can cause arrhythmia and cardiac arrest in some cases, raising serious questions about the safety of recreational loperamide.<ref name="Loperamide Toxicity">Clinical Review: Loperamide Toxicity. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/28506439</ref><ref>Ventricular Tachycardia Storm Induced by Loperamide Abuse. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/30967981</ref>
 
Use of higher-than-recommended levels of loperamide has been associated with cardiotoxicity. Large doses taken at once can cause arrhythmia and cardiac arrest in some cases, raising serious questions about the safety of recreational loperamide.<ref name="Loperamide Toxicity">Clinical Review: Loperamide Toxicity. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/28506439</ref><ref>Ventricular Tachycardia Storm Induced by Loperamide Abuse. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/30967981</ref>


==History and culture==
==History and culture==
Loperamide is a phenylpiperidine derivative, [[opioid]] [[agonist]] thought to have a low potential for central nervous effects. It was launched by Janssen Pharmaceutica in 1973. On release loperamide was classified in the US as a schedule II narcotic, before transfer to to schedule V in 1977. In November 1982 loperamide was removed from schedule V or 'decontrolled'.
Loperamide is a phenylpiperidine derivative, [[opioid]] [[agonist]] thought to have a low potential for central nervous effects. It was launched by Janssen Pharmaceutica in 1973. On release loperamide was classified in the US as a schedule II narcotic, before transfer to to schedule V in 1977. In November 1982 loperamide was removed from schedule V or 'decontrolled' and made available over-the-counter.


This appears to have been based on initial, preclinical studies indicative of dependence and [[withdrawal]] in animal studies. The consensus of later studies was that loperamide has a low potential for abuse, based on an apparent lack of central nervous effects.
This appears to have been based on initial, preclinical studies indicative of dependence and [[withdrawal]] in animal studies. The consensus of later studies was that loperamide has a low potential for abuse, based on an apparent lack of central nervous effects.


Web and internet forum based discussion of loperamide seems to be focused on two topics related to [[opioid]] use; its application in the management of [[withdrawal]] and its potential for central nervous effects. Appearing in threads or posts on various forums as early as 2005, there appears to have been a sustained increase in interest in loperamide.
Web and internet forum based discussion of loperamide seems to be focused on two topics related to [[opioid]] use; its application in the management of [[withdrawal]] and its potential for central nervous effects. Appearing in threads or posts on various forums as early as 2005, there appears to have been a sustained increase in interest in loperamide.
According to the report, between 2010 and 2011, there was a 10-fold increase in web forum postings about [[oral]] loperamide abuse. Most (70 percent) of the postings discussed using the drug to self-treat a discomforting [[opioid]] withdrawal, while 25 percent focused on using loperamide to simply get high.
According to the report, between 2010 and 2011, there was a 10-fold increase in web forum postings about [[oral]] loperamide abuse. Most (70 percent) of the postings discussed using the drug to self-treat a discomforting opioid withdrawal, while 25 percent focused on using loperamide to simply get high.
All of this may be having tragic consequences. According to the researchers, there was a 71 percent jump in loperamide abuse/misuse-related calls to poison control centers across the United States between 2011 and 2014.<ref>Addicts Using Diarrhea Drug Imodium to Get High | https://www.webmd.com/mental-health/addiction/news/20160505/addicts-using-diarrhea-drug-imodium-to-get-high</ref><ref>"I just wanted to tell you that loperamide WILL WORK": a web-based study of extra-medical use of loperamide. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/23201175</ref><ref>Loperamide misuse and abuse. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/28189538</ref>
All of this may be having tragic consequences. According to the researchers, there was a 71 percent jump in loperamide abuse/misuse-related calls to poison control centers across the United States between 2011 and 2014.<ref>Addicts Using Diarrhea Drug Imodium to Get High | https://www.webmd.com/mental-health/addiction/news/20160505/addicts-using-diarrhea-drug-imodium-to-get-high</ref><ref>"I just wanted to tell you that loperamide WILL WORK": a web-based study of extra-medical use of loperamide. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/23201175</ref><ref>Loperamide misuse and abuse. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/28189538</ref>


==Chemistry==
==Chemistry==
Loperamide is a phenylpiperidine derivative with a chemical structure similar to [[opioid]] [[receptor]] [[agonists]] such as diphenoxylate and bezitramide. Like diphenoxylate, it has a [[methadone]]-like structure and a piperdine moiety.<ref>An Introduction to Medicinal Chemistry. | https://books.google.com/books?id=Pj7xJRuhZxUC&pg=PA644#v=onepage&q&f=false</ref>
{{chemistry}}
Loperamide is a phenylpiperidine derivative with a chemical structure similar to [[opioid]] [[receptor]] [[agonists]] such as [[wikipedia:diphenoxylate|diphenoxylate]] and [[wikipedia:bezitramide|bezitramide]]. Like diphenoxylate, it has a [[methadone]]-like structure and a [[piperidine]] moiety.<ref>An Introduction to Medicinal Chemistry. | https://books.google.com/books?id=Pj7xJRuhZxUC&pg=PA644#v=onepage&q&f=false</ref>


==Pharmacology==
==Pharmacology==
{{pharmacology}}
{{pharmacology}}
Loperamide is an [[opioid]]-[[receptor]] [[agonist]] and acts on the μ-[[opioid]] [[receptors]] in the myenteric plexus of the large intestine. Loperamide works like [[morphine]], decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall. It is considered to have a low abuse potential because of substantial first-pass metabolism and P-glycoprotein-mediated efflux at the level of the blood-brain barrier. Central nervous system [[opioid]] effects are not observed after therapeutic [[oral]] dosing because of poor bioavailability and minimal central nervous system penetration. However, central nervous system [[opioid]] effects do occur after supratherapeutic [[oral]] doses.<ref name="Loperamide Death">Loperamide Abuse Associated With Cardiac Dysrhythmia and Death. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/27140747</ref>
Loperamide is an [[opioid]]-[[receptor]] [[agonist]] and acts on the μ-opioid receptors in the myenteric plexus of the large intestine. Loperamide works like [[morphine]], decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular smooth muscles of the intestinal wall. It is considered to have a low abuse potential because of substantial first-pass metabolism and P-glycoprotein-mediated efflux at the level of the blood-brain barrier. Central nervous system opioid effects are not observed after therapeutic [[oral]] dosing because of poor bioavailability and minimal central nervous system penetration. However, central nervous system opioid effects do occur after supratherapeutic oral doses.<ref name="Loperamide Death">Loperamide Abuse Associated With Cardiac Dysrhythmia and Death. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/27140747</ref>


Concurrent administration of P-glycoprotein inhibitors such as quinidine potentially allows loperamide to cross the blood–brain barrier and produce central [[morphine]]-like effects. Loperamide taken with quinidine was found to produce respiratory depression, indicative of central [[opioid]] action.<ref>Increased drug delivery to the brain by P-glycoprotein inhibition. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/11014404</ref>
Concurrent administration of P-glycoprotein inhibitors such as quinidine potentially allows loperamide to cross the blood–brain barrier and produce central [[morphine]]-like effects. Loperamide taken with quinidine was found to produce respiratory depression, indicative of central [[opioid]] action.<ref>Increased drug delivery to the brain by P-glycoprotein inhibition. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/11014404</ref>


Loperamide is metabolized by the cytochrome P450 (CYP) system and is a substrate for the CYP3A4 isoenzyme. Concurrent administration with CYP3A4 inhibitors may elevate loperamide concentrations.<ref>Loperamide: a pharmacological review. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/18192961</ref>
Loperamide is metabolized by the cytochrome P450 (CYP) system and is a substrate for the CYP3A4 isoenzyme. Concurrent administration with [[Template:List CYP450 inhibitors|CYP3A4 inhibitors]] may elevate loperamide concentrations.<ref>Loperamide: a pharmacological review. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/18192961</ref>


==Subjective effects==
==Subjective effects==
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*'''[[Effect::Pupil constriction]]'''
*'''[[Effect::Pupil constriction]]'''
*'''[[Effect::Respiratory depression]]'''
*'''[[Effect::Respiratory depression]]'''
*'''[[Constipation]]'''
*'''[[Effect::Abnormal heartbeat]]'''
*'''[[Abnormal heartbeat]]'''
*'''[[Effect::Increased heart rate]]'''
*'''[[Increased heart rate]]'''
*'''[[Effect::Stomach cramps]]'''
*'''[[Stomach cramps]]'''
*'''[[Effect::Difficulty urinating]]'''
*'''[[Difficulty urinating]]'''
*'''[[Effect::Decreased libido]]'''
*'''[[Effect::Orgasm suppression]]'''
*'''[[Effect::Appetite suppression]]'''
*'''[[Effect::Cough suppression]]'''
*'''[[Effect::Vasodilation]]'''
*'''[[Effect::Motor control loss]]'''
*'''[[Effect::Muscle relaxation]]'''
}}
}}
|{{effects/cognitive|
|{{effects/cognitive|


*'''[[Effect::Cognitive euphoria]]''' - In loperamide, this effect is less pronounced compared to other [[opioids]].
*'''[[Effect::Cognitive euphoria]]''' - This particular substance can be considered as less intense in its cognitive euphoria when compared to other [[opioids]].
*'''[[Effect::Anxiety suppression]]'''
*'''[[Effect::Anxiety suppression]]'''
*'''[[Effect::Dream potentiation]]'''
*'''[[Effect::Dream potentiation]]'''
*'''[[Effect::Sleepiness]]'''
*'''[[Effect::Creativity enhancement]]'''
*'''[[Effect::Thought deceleration]]'''
}}
{{effects/visual|
The visual effects of loperamide are relatively mild across all dosages and mostly present when high doses have been consumed. When compared to other [[opioids]] that are capable of inducing visual effects, the overall visual effects of loperamide are mild. They are most similar to that of [[dissociatives]] with a mild dream-like immersive effect similar to that of [[deliriants]]. The visuals can be greatly enhanced with the addition of hallucinogens and cannabis, but one should be wary as the interactions are not well documented and the chance of cardiovascular shock, serotonin syndrome, or other fatal complications is high.
====Enhancements====
*'''[[Effect::Brightness alterations]]''' - The surroundings can become brighter with a mild high-contrast effect, be slightly darkened/gloomy, or not change at all.
*'''[[Effect::Frame rate enhancement]]''' - At common to high doses, particularly when looking around with only the eyes but keeping the head stationary, or when the view angle changes suddenly, a mild but noticeable sluggishness/latency can be perceived. This effect is similar in feel to certain sedating dissociatives. This is an inconsistently manifested effect with some people never reporting such effects.
*'''[[Effect::Immersion enhancement]]''' - This effect is most similar to that of deliriants.
====Distortions====
*'''[[Effect::Depth perception distortions]]'''
}}
}}
}}
}}
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Since 2015, several reports of sometimes-fatal cardiotoxicity due to high-dose loperamide abuse have been published.<ref name="Loperamide Death"/><ref>Loperamide Induced Torsades de Pointes: A Case Report and Review of the Literature. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/26989420</ref>
Since 2015, several reports of sometimes-fatal cardiotoxicity due to high-dose loperamide abuse have been published.<ref name="Loperamide Death"/><ref>Loperamide Induced Torsades de Pointes: A Case Report and Review of the Literature. (PubMed.gov / NCBI) | https://www.ncbi.nlm.nih.gov/pubmed/26989420</ref>
It is strongly recommended that one use [[responsible drug use|harm reduction practices]], and take extreme caution when using this substance.


===Tolerance and addiction potential===
===Tolerance and addiction potential===
Loperamide is not considered physically and psychologically addictive. However, the development of physical dependence on the drug is potentially possible, since loperamide has been shown to cause a mild physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild [[opiate]] [[withdrawal]] were observed following abrupt discontinuation of long-term treatment of animals with loperamide.<ref>[Physical dependence on loperamide hydrochloride in mice and rats]. | https://www.jstage.jst.go.jp/article/yakushi1947/102/11/102_11_1074/_article/-char/ja/</ref>
Loperamide is not considered physically and psychologically addictive. However, the development of physical dependence on the drug is potentially possible, since loperamide has been shown to cause a mild physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild [[opiate]] [[withdrawal]] were observed following abrupt discontinuation of long-term treatment of animals with loperamide.<ref>[Physical dependence on loperamide hydrochloride in mice and rats]. | https://www.jstage.jst.go.jp/article/yakushi1947/102/11/102_11_1074/_article/-char/ja/</ref> Therefore the chronic use of loperamide can be considered as [[Addiction potential::mildly addictive]] and is capable of causing both physical and psychological dependence. When physical dependence has developed, [[Opioids#Discontinuation|withdrawal symptoms]] may occur if a person suddenly stops their usage.


Tolerance to many of the effects of loperamide develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Loperamide presents cross-tolerance with all other opioids, meaning that after the consumption of loperamide all opioids will have a reduced effect.
Tolerance to many of the effects of loperamide develops with prolonged and repeated use. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption). Loperamide presents cross-tolerance with all other opioids, meaning that after the consumption of loperamide all opioids will have a reduced effect.
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*'''[[Stimulants]]''' - Because loperamide increases BPM and BP and stimulants also do this, cardiac arrest, hypertensive crisis, stroke, and heart attack all become much more likely to occur. Besides it can be dangerous to combine depressants with stimulants due to the risk of accidental excessive intoxication. Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states.
*'''[[Stimulants]]''' - Because loperamide increases BPM and BP and stimulants also do this, cardiac arrest, hypertensive crisis, stroke, and heart attack all become much more likely to occur. Besides it can be dangerous to combine depressants with stimulants due to the risk of accidental excessive intoxication. Stimulants mask the sedative effect of depressants, which is the main factor most people use to gauge their level of intoxication. Once the stimulant effects wear off, the effects of the depressant will significantly increase, leading to intensified disinhibition, motor control loss, and dangerous black-out states.
*'''[[Dissociatives]]''' - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the [[recovery position]] or have a friend move them into it.
*'''[[Dissociatives]]''' - This combination can result in an increased risk of vomiting during unconsciousness and death from the resulting suffocation. If this occurs, users should attempt to fall asleep in the [[recovery position]] or have a friend move them into it.
*'''CYP450 3A4 or 2C8 inhibitors''' -  Coadministration with drugs that enhance the gastrointestinal absorption or inhibit the metabolism of loperamide (e.g., potent CYP450 3A4 or 2C8 inhibitors) may increase the plasma concentrations and adverse effects of loperamide. <ref> https://www.drugs.com/drug-interactions/erythromycin-with-loperamide-simethicone-1009-0-1483-0.html?professional=1 </ref> That includes; erythromycin, ritonavir, grapefruit.


==Legal status==
==Legal status==
{{LegalStub}}
{{LegalStub}}
Loperamide is legal and available in over-the-counter preparations in most parts of the world.  
Loperamide is legal and available in over-the-counter preparations in most parts of the world.  
==Extraction and smoking==
Loperamide can be extracted from the parenting product, usually pills, specifically non gel pills.  Loperamide is extracted with ethyl alcohol, when extracted, the resulting product tends to be a green or teal group of crystals, which is loperamide and coloring from the medications manufacture.  These crystals are often then removed from the container that they were formed in, and put into a smoking device of some sort, usually a pipe designed for crystalline substances.  However according to experience reports from Erowid, extracted loperamide smells very strongly of chemicals, and was compared to the smell that of methamphetamine and crack cocaine.


==See also==
==See also==
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*[https://en.wikipedia.org/wiki/Loperamide Loperamide (Wikipedia)]
*[https://en.wikipedia.org/wiki/Loperamide Loperamide (Wikipedia)]
*[https://www.erowid.org/pharms/loperamide/ Loperamide (Erowid Vault)]
*[https://www.erowid.org/pharms/loperamide/ Loperamide (Erowid Vault)]
*[https://isomerdesign.com/PiHKAL/explore.php?id=8677 Loperamide (TiHKAL / Isomer Design)]
*[https://isomerdesign.com/PiHKAL/explore.php?id=8677 Loperamide (Isomer Design)]


==References==
==References==
{{reflist}}
{{reflist}}
[[Category:Psychoactive substance]]
[[Category:Psychoactive substance]]
[[Category:Depressant]]
[[Category:Opioid]]
[[Category:Opioid]]
[[Category:Piperidine]]
[[Category:Diphenylpropylamine]]
[[Category:Phenylpiperidine]]
[[Category:Approval]]
[[Category:Approval]]
[[Category:Proofread]]
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{{#set:Featured=true}}
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