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Loperamide can cause life-threatening heart complications and death.[1][2] It is strongly discouraged to use this substance in high doses. Please see this section for more details. Fatal overdose may occur when opiates are combined with other depressants such as benzodiazepines, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.[3] It is strongly discouraged to combine these substances, particularly in common to heavy doses.



Loperamide, commonly branded as Imodium, is a synthetic opioid of the phenylpiperidine chemical class that is sold as an anti-diarrheal agent.

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.[4] 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.[5][6]

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'.

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. 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.[7][8][9]

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 piperidine moiety.[10]

Pharmacology

This pharmacology section is incomplete. You can help by adding to it.

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.[11]

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.[12]

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.[13]

Subjective effects

This subjective effects section is a stub. As such, it is still in progress and may contain incomplete or wrong information. You can help by expanding or correcting it.

In comparison to the effects of other opioids, this compound can be described as less euphoric. Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), a literature which relies on collected anecdotal reports and the personal experiences of PsychonautWiki contributors. As a result, they should be taken with a healthy amount of skepticism. It is worth noting that these effects will not necessarily occur in a consistent or reliable manner, although higher doses (common+) are more likely to induce the full spectrum of reported effects. Likewise, adverse effects become much more likely with higher doses and may include serious injury or death.

Experience reports

There are currently no anecdotal reports which describe the effects of this compound within our experience index. Additional experience reports can be found here:

Toxicity and harm potential

This toxicity and harm potential section is a stub. As such, it may contain incomplete or even dangerously wrong information. You can help by expanding or correcting it.

We also recommend that you conduct independent research and use harm reduction practices when using this substance.

Toxicity

Although it is relatively safe at therapeutic doses, increasing reports describe its misuse and abuse at very high doses either for euphoric effects or to attenuate symptoms of opioid withdrawal. The most common presentation of loperamide intoxication is syncope which is caused by serious cardiac dysrhythmia and can lead to death.[14] Loperamide produces both QRS and QT prolongation at supra-therapeutic dosing.[15] Features of conventional opioid toxicity may also be present.[5][11]

The majority of patients had loperamide toxicity due to misuse/abuse, in-line with national trends. In patients avoiding withdrawal, doses >100 mg were observed. When taken in large doses (>200 mg), loperamide may cause significant cardiovascular effects, including QTc-prolongation and ventricular dysrhythmias.[16]

Since 2015, several reports of sometimes-fatal cardiotoxicity due to high-dose loperamide abuse have been published.[11][17]

It is strongly recommended that one use harm reduction practices, and take extreme caution when using this substance.

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.[18] Therefore the chronic use of loperamide can be considered as mildly addictive and is capable of causing both physical and psychological dependence. When physical dependence has developed, 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.

Dangerous interactions

Although many psychoactive substances are reasonably safe to use on their own, they can quickly become dangerous or even life-threatening when combined with other substances. The list below includes some known dangerous combinations (although it cannot be guaranteed to include all of them). Independent research (e.g. Google, DuckDuckGo) should always be conducted to ensure that a combination of two or more substances is safe to consume. Some interactions listed have been sourced from TripSit.

Depressants ( 1,4-Butanediol, 2M2B, alcohol, barbiturates, gabapentinoids, GHB/GBL, methaqualone, opioids ) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation and sedation caused by each other and can lead to unexpected loss of consciousness at high doses. There is also 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.

( ) - This combination can result in dangerous or even fatal levels of respiratory depression. These substances potentiate the muscle relaxation and sedation caused by each other and can lead to unexpected loss of consciousness at high doses. There is also 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. 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.

- 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.

Legal status

This legality section is a stub. As such, it may contain incomplete or wrong information. You can help by expanding it.

Loperamide is legal and available in over-the-counter preparations in most parts of the world.

See also

References