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Non-Addictive Opioids

"Loperamide is an opioid, a piperidine similar to fentanyl, yet it is not addictive in the traditional sense, as it does not permeate the blood brain barrier. Loperamide is also known as immodium.... "

It does not permeate the BBB, therefore does not get you high.

Isnt that what I said? I said that it does not go through the BBB, which makes it not addictive in the traditional sense.....


Loperamide, which was once a schedule 5 drug, is READILY available OTC at all drug stores under the brandname Immodium. Most places also sell a generic loperamide tablets, which are the same, and both are manufactured in the same factory. Although it doesnt permeate the BBB, it does significantly help with opioid withdrawal.

And its possible if you made loperamide in a polystirex like form (which are tiny plastic particles binded to the drug that help it cross the BBB, it was used with DXM in the brand name "desylem"), and in doing this it may result in a CNS active substance, a potent opioid agonist.

Also p-glycoprotein inhibitors like quinidine, or its fellow optical isomer quinine, has been used in the following pubmed study to make loperamide a poteny CNS active opioid agonist. The last sentance of the following qoute is particularly alluring ("can be reversed by a drug causing P-glycoprotein inhibition, resulting in serious toxic and abuse potential")......

BACKGROUND: Although the antidiarrheal loperamide is a potent opiate, it does not produce opioid central nervous system effects at usual doses in patients. On the basis of in vitro studies demonstrating that loperamide is a substrate for the adenosine triphosphate-dependent efflux membrane transporter P-glycoprotein, we postulated that inhibition of P-glycoprotein with quinidine would increase entry of loperamide into the central nervous system with resultant respiratory depression. METHODS: To test this hypothesis, a 16-mg dose of loperamide was administered to eight healthy male volunteers in the presence of either 600 mg quinidine, a known inhibitor of P-glycoprotein, or placebo. Central nervous system effects were measured by evaluation of the respiratory response to carbon dioxide rebreathing as a measure of opiate-induced respiratory depression. RESULTS: Loperamide produced no respiratory depression when administered alone, but respiratory depression occurred when loperamide (16 mg) was given with quinidine at a dose of 600 mg (P < .001). These changes were not explained by increased plasma loperamide concentrations.

CONCLUSION: This study therefore demonstrates first the potential for important drug interactions to occur by a new mechanism, namely, inhibition of P-glycoprotein, and second that the lack of respiratory depression produced by loperamide, which allows it to be safely used therapeutically, can be reversed by a drug causing P-glycoprotein inhibition, resulting in serious toxic and abuse potential.

When i read the above, i was quite interested, especially about the "serious toxic and abuse potential". I have used quinine to see if it works, in varying doses, as well as varying doses of loperamide, and though i definately noticed potentiation, there was VERY little CNS activity. But quinidine is a stronger p-glycoprotein inhibitor than quinine, so maybe if i had used quinidine, i would have experienced better results. If we could someone way figure out how to make loperamide cross the blood brainbarrier, we could convert a relatively cheap, legal, easily obtainable OTC medication into a potent opioid. I think the polysterix may be the best solution, or perhaps a stronger p-glycoprotein inhibitor combined with a polisterix verision of loperamide might work. If this did actually materialize and someone figured out the way and it starts circulating as a recreational drug, loperamide would become scheduled once again, or watched like ephedrine/pseudoephedrine.
 
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I took 4mg yesterday and it did very little, if anything. I just dont particularly trust this one.
 
I have the full text of the article, and it isn't as great as it sounds. There is no mention anywhere in it of subjective feelings or euphoria. They measured plasma concentrations of loperamide and monodesmethyl-loperamide and found them to be higher, and then had the subjects use rebreathers and found that the high ones breathed slower even as the other ones hyperventilated. The results are definitely significant, but I doubt you can just take some quinidine and then some loperamide and nod out. You'll get some effects, but not enough to be worth the constipation or damage you could do to your heart.

The problem with loperamide is that it's a P-glycoprotein substrate, and PGP isn't just in the blood-brain barrier. There's tons of it in your intestines as well, so by taken quinidine orally you mostly just inhibit PGP in the intestines, and then a little bit in the BBB. So plasma concentrations of PGP substrates go up, but not much more makes it into the brain.

If you were to IV quinidine, it would have a much greater inhibitory effect on PGP in the BBB, but then you also would have to IV the loperamide. That I bet will get you nice and high. But then you run into some other problems: you don't want to take that much quinidine every day unless you want to fuck up your heart, loperamide hcl is not at all water soluble, and it's who knows the dose. It could be in the microgram range, or it could be a few milligrams. Without knowing how potent loperamide actually is compared to other opioids, or how much is gonna make it into the brain, you could easily OD on it.

So, if anybody ever finds themself with a syringe full of quinidine, and another full of loperamide, tell me how it goes. Until then, there are other drugs, morphine in particular, that are also PGP substrates and could benefit from pre-administration of quinidine. There are however many clinical uses of PGP inhibitors, and so pharmaceutical companies are working on much more effective ones. They won't be on the market for years, maybe decades, and there's a good chance they'll be watched carefully or controlled so that we can't just take Sudafed and Immodium for one kickass speedball.

This study shows that the drug elacridar (GF120918) increases brain concentrations of docetaxel, a PGP substrate, up to 59% of the concentrations in MDR knockout mice (mice who don't have PGP, so loperamide enters the brain freely and gets them really high):
http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=15110893

Even more promising is this study, which claims that with "further optimization of the dose and schedule of GF120918, we could achieve paclitaxel brain levels of about 80-90% of those reached in Pgp knockout mice":
http://www.ncbi.nlm.nih.gov/entrez/...ve&db=pubmed&dopt=Abstract&list_uids=12855665
 
Like i said, ive taken large doses of quinine and quinidine with large doses of loperamide. No euphoria, but there were effects. I definately agree that IV administration would be key in combination with quinidine to get some actual results. But again, who knows the active potency of loperamide once successfully across the barier....
 
There have been studies... they knocked out the enzyme in some rats that blocks the loperamide from crossing. The conclusion was that it got the rats off pretty well.

Anyone have links explaining what factors allow or prevent a given molecule from crossing the blood-brain barrier?
 
The whole concept of turning loperamide into an abusable narcotic is totally of the rails unless you happen to be a chemist that is highly bent on polymerization systems..
 
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