“Poor man’s methadone” can kill the poor man. Extra-medical uses of loperamide: a review

DARK Classics in Chemical Neuroscience: Loperamide

“…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%).…”

“…3,64,66 As discussed above, the hepatic first-pass metabolism is the primary source of major metabolites of loperamide. 3,[63][64][65][66]69 The total plasma concentration (C max ) after oral administration was reported to be 0.02 μΜ, resulting in a total plasma concentration unbound (C u,max ) of 1.2 nΜ. 3,64,66 Although loperamide has a high volume of distribution (Vd ss = 4 L/kg), studies conducted with tritiated loperamide have shown that loperamide and its metabolites are scarcely found within tissue.…”

“…22,95 At recommended doses for a limited length of time, loperamide is an effective medication for the treatment of diarrhea. 9,[40][41][42][43][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 methadonelike effect for the treatment of substance use disorders at supratherapeutic doses.…”

Loperamide as a Potential Drug of Abuse and Misuse: Fatal Overdoses at the Medical University of South Carolina

“…It was first marketed in the United States of America in 1977 and classified as Schedule II. It was later transferred to Schedule V before being removed from the controlled substance list in 1982 and placed on nonprescription status in 1988 because it was believed to have a low abuse potential due to low bioavailability, a wide margin of safety, and a minimal side effect profile. It has since been found to cause cardiotoxicity in supratherapeutic doses through modulation of potassium channels and sodium channels, resulting in a prolonged QT‐interval and QRS widening .…”

“…Often, these posts suggest using a combination of other substances to enhance the opioid effects, including P‐gp inhibitors to help overcome the blood–brain barrier and CYP450 inhibitors to further increase plasma concentration and length of effect by decreasing loperamide metabolism . Supratherapeutic loperamide dosages necessary to achieve euphoria are often stated to be above 200 mg per day (a normal therapeutic dose is listed as no more than 16 mg in 24 h) . P‐gp may already be inhibited due to effects of high concentrations of desmethylloperamide, explaining reports of CNS effects using only high dose loperamide .…”