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Thread: Loperamide the OTC fentanyl (reason for no CNS activity)

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    Loperamide the OTC fentanyl (reason for no CNS activity) 
    #1
    I have read several threads on this site from people like me that dream about buying Immodium from the store and eating a fraction of a pill to get smacked. I was very surprised with all you drug experts, that no one has mentioned the fact that the biggest reason that Loperamide will never cross the Blood Brain Berrior is because they formulate the tablets with magnesium stearate. All of the experiments that showed that Loperamide can suppress morphine withdrawal, involved Loperamide without any Magnesium Stearate. They then did an experiment that showed that Loperamide formulated with Magnesium Stearate was very insoluble in the intestines and showed no potential for addiction. In this way the Loperamide can be very efficient with releiving diarhea where next to none of it gets into the blood stream. Perhaps this is the only Opioid that can be made insoluble with a chemical like MS and that is why the government uses it. Perhaps without the MS, Loperamide would be very euphoric. It just doesnt make sense that a chemical by itself could penetrate the intestines but not the BBB. If Loperamide with Magnesium is insoluble to the intestines, you would think there is no way someone could do a cold water extraction to Isolate just the loperamide. Before even mentioning the taking of other chemicals like Doxepin to make Loperamide cross the BBB, one should know how to take the magnesium stearate out. If this is the novel opioid, the only thing I could think of would be to buy the pure chemical from a chemical manufacturer. Is there a way to isolate the Loperamide?
     

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    #2
    I assume the paper you're talking about is

    Clin Pharmacol Ther. 1980 Dec;28(6):812-9.
    Abuse potential of loperamide.

    Jaffe JH, Kanzler M, Green J.

    Effects of the currently marketed form of loperamide (Imodium capsules) that might relate to abuse potential were examined. Study I was a double-blind "dose run-up" in adult male subjects with a history of illicit drug use but no history of opioid addiction. Subjective responses to doses of loperamide ranging from 12 to 60 mg were compared with responses to 120 mg codeine sulfate (96 mg base) and to placebo. Based on study I, loperamide (60 mg) was used in study II and its effects were compared with those of codeine (96 mg base) and placebo in an exaddict subject group. Study II subjects had had extensive opioid experience but were not actively addicted at the time of this double-blind, inpatient study. In study II, as in study I, unlike loperamide and placebo, codeine induced pupillary constriction. Loperamide (60 mg) induced a detectable subjective effect in somewhat over half the subjects, was "liked" little or not at all, and was identified as "dope" at a frequency less than that for a threshold dose of oral codeine. It was concluded that in its present form, i.e., capsules containing loperamide mixed with magnesium stearate, loperamide poses little threat of potential abuse.
    I'm interested, I'm going to have a look.
    Last edited by BilZ0r; 23-08-2005 at 23:16.
     

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    #3
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    Ooooooooooooooh that sounds VERY interesting. got a shitload of loperamide in my drawer lol.
     

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    #4
    A google search shows that magnesium stearate is insoluble in water.
     

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    #5
    I was under the impression the main reason loperamide lacked CNS activity was due to it being a p-glycoprotein substrate. There are two different studies evincing CNS activity of loperamide when quinidine is coadministered. One tested miosis, the other respiratory depression.
    I have found many commonly available items (herbal extracts, supplements or food items) which are p-glycoprotein inhibitors, but inhibition at the BBB is probably trickier.
    Also, any successful technique which gains currency will rapidly lead to loperamide being scheduled (it originally was).
     

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    #6
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    I had a bit of an idea, I would bet, that if a lipophillic clathrate-type or cage structure molecule could be used to encapsulate the loperamide, and that would pass the BBB, we might be onto something.

    http://www.eurekalert.org/pub_releas...cs-c012805.php

    Thats something that would fit the general concept of what I am trying to get at.
     

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    #8
    "CONCLUSIONS: P-gp-mediated efflux of loperamide is supplemented under pH gradient conditions. Hence, drugs used to decrease acid secretion in the stomach could result in higher plasma loperamide levels based on our in vitro system reflecting the in vivo environment."

    A note about that: proglumide could therefore serve multiple functions in enhancing the CNS effects of loperamide.
     

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    #9
    So how is the ABC gene product (multidrug resistance transporter) related to P-glycoprotein, or is it just another multidrug eflux pump?
     

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    #10
    ABC (ATP Binding Cassette) genes code for various active transporters. P-glycoprotein is an MDR, belonging to that family.

    Many people believe grapefruit juice potentiates opiates such as morphine by inhibiting CYP3A4. This is incongruent with the fact that morphine's main metabolite, M6G, is a much more powerful agonist. The real reason might actually be its inhibition of P-gp.
    Last edited by stvip; 23-08-2005 at 06:58.
     

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    #11
    I think ABCB1 is the classic MDR1 transporter. And I think this is at least in the same family as PGP, if not actually the same molecule or a slight variant thereof. This is interesting. A friend told me a while ago that he had been using loperamide to ease his withdrawals, and that it actually helped with the mental side of it and not just the gut pains. He also mentioned using a lot of grapefruit juice around that perioid. I'm wondering if the two might be connected. I don't have time right now, but maybe someone could look up grapefruit juice and ABCB1/MDR1.. The Clin Pharm Ther article (2000) sounds promising. Maybe also look up some other PGP/ABCB1/MDR1 inhibitors.
     

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    #12
    "One of the main reasons for its lack of central nervous system (CNS) activity is a combination first-pass metabolism and P-gp-mediated efflux preventing brain penetration."

    plug?
     

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    #13
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    The P-glycoproteins are present both in the gut, and in the blood-bain barrier, anything taken orally, would first need to swamp those in the gut, and then those in the BBB, plugging, I was thining of the same thing the other day, plugging, combined with a P-gp inhibitor, would at least make it somewhat easier to get loperamide into the CNS.
     

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    #14
    I think ABCB1 is the classic MDR1 transporter. And I think this is at least in the same family as PGP, if not actually the same molecule or a slight variant thereof.
    That is correct.

    I've scoured the journals - commonly available P-gp inhibitors include: black pepper (piperine), turmeric (curcumin), resveratrol (is not present in all red wines, extracts are available), citrus juices (grapefruit, pomello, orange and lemon, especially the latter). Quinidine is actually proven to work, specifically with loperamide. The others may not have sufficient potency or bioavailability to affect the almighty BBB.
    I should note that animal studies have demonstrated the dangers of lacking P-gp functionality, though quinidine is considered quite safe.

    So what exactly is to 'plug', how would that allow you to play?
     

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    #15
    plug=putting drugs up your ass

    that way it would avoid first pass metabolism and possibly make its way to the CNS....

    although, in all honesty, if simply plugging loperamide up the ass and drinking grapefruit juice is the solution, i'd think someone would have already done it.

    but i am just a dumb ass with no real knowledge, so who knows...i certainly don't discourage some experiments(safe ones, atleast)....
     

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    #16
    there's still the problem of magnesium stearate...
    but this is probably worth a try.
     

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    #17
    I don't currently have access to Clin Pharmacol Ther. 1980 (early issues don't exist in electronic format). Could anyone post an excerpt from there or otherwise discussing the role of magensium stearate in hindering loperamide absorption? Never heard of that before. Anyhow, I doubt that's intractable - couldn't nearly any stable alkaloid be converted to freebase, then resalted as needed (say, with HCl)?

    As for the rectal route - bon voyage. Beyond first-pass metabolism, it also circumvents the issue of acidic enviornmet (see my comment about proglumide). However, I'm not certain whether these P-gp inhibitors enact a local surface effect. If they do, adding one to the loperamide mix might be helpful. Perhaps quercetin which inhibits P-gp, CYP3A, may prevent withdrawal symptoms, and is readily available.
     

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    #18
    I'll get the reference tommorow. But back it up:

    Many people believe grapefruit juice potentiates opiates such as morphine by inhibiting CYP3A4. This is incongruent with the fact that morphine's main metabolite, M6G, is a much more powerful agonist. The real reason might actually be its inhibition of P-gp.
    You can find studies which show that M6G is anywhere from 800x to 0.3 times as analgesic as morphine, but radioligand wise, M6G has been consistantly shown to have a lower affinity for the Mu-opioid receptor subtypes (as reviewed by [1]). Meanwhile, even if we ignore that, only ~10% of morphine is metabolized to M6G, with a peak concentration some 20x less than morphine.

    While M6G might be an active metabolite, saying that it is has a bigger role in morphine induced subjective feelings that morphine is a pretty big call.

    ...Or have I read you wrong?
     

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    #19
    I have tried grapefruit juice with poppy seed tea. I am reasonably satisfied that I absorb more of the morphine/alkaloids if I drink the grapefruit juice beforehand. I believe the AUC is raised by the grapefruit. I have seen a similar effect in graphs of methadone concentrations and the effects of grapefruit. I'd be interested to find out whether its local inhibition of intestine 3A4, or whether local (or neural..) inhibition of PGP is a significant factor too.
    I'm going to look up the Mg Stearate thing if I can and maybe the mdone thing
     

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    PGP inhibition markedly increases opiate analgesia 
    #20
    Lightbulb
    OK OK check this out. I could imagine that a PGP inhibitor could be combined with intravenous doses of opioids to reduce the quantity required and increase the rush.

    The several PGP inhibitors ive seen look potentially dangerous. eg propranolol

    "Opiate-induced Analgesia Is Increased and Prolonged in Mice Lacking P-glycoprotein.
    Anesthesiology. 92(5):1392-1399, May 2000.
    Thompson, Susan J. M.D., Ph.D. *; Koszdin, Kari D.V.M. +; Bernards, Christopher M. M.D. ++

    Abstract:
    Background: P-glycoprotein is a transmembrane protein expressed by multiple mammalian cell types, including the endothelial cells that comprise the blood-brain-barrier. P-glycoprotein functions to actively pump a diverse array of xenobiotics out of the cells in which it is expressed. The purpose of this study was to determine if P-glycoprotein alters the analgesic efficacy of clinically useful opioids.

    Methods: Using a standard hot-plate method, the magnitude and duration of analgesia from morphine, morphine-6-glucuronide, methadone, meperidine, and fentanyl were assessed in wild-type Friends virus B (FVB) mice and in FVB mice lacking P-glycoprotein [mdr1a/b (-/-)]. Analgesia was expressed as the percent maximal possible effect (%MPE) over time, and these data were used to calculate the area under the analgesia versus time curves (AUC) for all opioids studied. In addition, the effect of a P-glycoprotein inhibitor (cyclosporine, 100 mg/kg) on morphine analgesia in both wild-type and mdr knockout mice was also determined.

    Results: Morphine induced greater analgesia in knockout mice compared with wild-type mice (AUC 6,450 %MPE min vs. 1,610 %MPE min at 3 mg/kg), and morphine brain concentrations were greater in knockout mice. Analgesia was also greater in knockout mice treated with methadone and fentanyl but not meperidine or morphine-6-glucuronide. Cyclosporine pretreatment markedly increased morphine analgesia in wild-type mice but had no effect in knockout mice.

    Conclusions: These results suggest that P-glycoprotein acts to limit the entry of some opiates into the brain and that acute administration of P-glycoprotein inhibitors can increase the sensitivity to these opiates.
     

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    #21
    It was a very useless paper, it had no references on the fact that sterate retarded intestinal absorption, just that sterate was insoluble so that it made parenteral use difficult (again no citation). The bulk of the paper was simpley bitching about the retiredment of the Lexington addiction facility where they could do drug dependecy trials on prison inmates.

    And in reply to ^ Yeah, I had no doubt that P-glycoprotein reduces plasma and brain concentrations of opiates, I think there is a lot of evidence out there in the liturature.
     

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    #22
    Your post prompted me to review what is currently known about M6G. Recently, the applied potenital role of M6G has been advanced by human clinical trials comparing it with morphine. Generally, it has been found to be equipotent with morphine, with somewhat slower onset, and significantly reduced sife effects (nausea, emesis, respiratory depression), which agrees with animal studies. We might very well see it in clinical use soon.
    As for the receptor binding assays, there is some good evidence M6G may affect a different receptor subtype (though I should mention that the nature of opioid receptor subtypes isn't at all well understood).

    So I agree with your point that there isn't evidence that the CYP3A4 inhibition is actually incongruent with perceived greater potency, though I still believe P-gp inhibition is probably the more important function of grapefruit juice (since otherwise I would expect rather altered perceived pharmacokinetics).

    Anyhow, could the original poster provide a reference to the putative role of magnesium stearate in inhibiting loperamide's absorption?

    The several PGP inhibitors ive seen look potentially dangerous. eg propranolol
    There are plenty of inhibitors which should be quite harmless, such as those from dietary sources. Of course, it's not clear they are sufficiently potent. I have thus far found three studies in human subjects confirming the ability of quinidine to allow supraspinal activity of oral loperamide (though one of the studies predicted 16 mg loperamide + 600 mg quinidine would be inferior potency to 30 mg morphine (all oral) based on miosis measurements), so there's no need to worry about the basic feasibility of this.
     

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    #23
    Are any of you guys in the medical or chemical profession?

    Coz... wowza...

    "The restrigated sublinexed C487 correlates extangilly to the GPG receptors; in a double beer-bound survey results were found to be inconclusive."
     

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    #24
    cimitidine as an acid reducer and pgp inhibitor?
     

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    #25
    I have found many commonly available items (herbal extracts, supplements or food items) which are p-glycoprotein inhibitors, but inhibition at the BBB is probably trickier.
    Last edited by sekio; 10-04-2012 at 19:06. Reason: snip url
     

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