Cannabinoid Inverse Agonists To Reduce Tolerance.

[8L4YN3]

Alrighty i'm no pharmacologist, and my knowledge about such issues is resticted to what i learn during my daily reading of random bullshit.

But upon learning about a chemical called Rimonabant, which is an inverse cannabinoid agonist, which apprently means it has to exact opposite action as agonist cannabinoids that hit the same receptors, THC for example.

Now i know of a study which is http://jpet.aspetjournals.org/content/300/2/588.full , which seems to demonstrate that ultra low doses of the opioid antagonist, naltrexone, actually reverse tolerance, and make the morphines action much stronger. The study is a fair read, but if you can be bothered to read it you will see where i'm coming from.

One could speculate that ultra low doses of rimonabant could prevent cannabis tolerance and make cannabis highs more intense, pure speculation of course. And i'm aware that we arent comparing two identical types of drug actions here. For example naltrexone is an antagonist, while rimonabant is an inverse agonist. I cant honestly say i know the difference between an antagonist and an inverse agonist, but they seem to do the basic thing of having the opposite action than full agonists at the same receptor sites. And then theres the fact that morphine is a full agonist where as THC is only a partial agonist, so we're not comparing the exact same situations here once you lok at things a little closer.

But still i think it is obvious that a compound exists that could reverse cannabis tolerance, prevent its build up if used over long periods, and potentiate cannabinoids that get us high. I'm not saying Rimonabant does this but it's trippy to think about.

And reminds us just how amazing chemistry and the field of drugs are. Literally endless possibilities.

 

[Vader]

Using it to reduce tolerance doesn't sound that attractive to me for the following reasons:
Cannabis tolerance isn't generally that much of an issue unless you're smoking everyday. In that case, you're unlikely to want to take a day off, much less take a drug that is going to take you to a new nadir of un-stonedness. Rimonabant sounds pretty unpleasant:
http://www.viceland.com/int/v16n8/htdocs/new-frontiers-of-sobriety-984.php
Not something I'd volunteer for.

Another problem with the analogy to opioids is the ceiling to cannabis tolerance. You hear plenty of stories of the crazy doses hardcore junkies can tolerate, nay, require; you don't really get the same with cannabis. An eighth a day is pretty impressive toking, and the cost of that pales compared to a smack habit.

However, in light of the study you posted to (interesting read btw), it might be interesting to see what effects an "ultra-low" dose of rimonabant had in terms of cannabis potentiation. We'd have to establish what exactly an "ultra-low" dose is, but I might consider being a guinea pig for that. I can lay my hands on rimonabant, so it's not a pipe dream...

And reminds us just how amazing chemistry and the field of drugs are.

Oh yes.

 

[MoeMadness]

So does naltrexone actually reverse tolerance or is potentiating to make euphoria seem stronger? I remember reading something about folks dosing DXM prior to intake of any opioids to help slow tolerance levels, but I can't find the one in particular I'm looking for....

 

[georgy]

Using it to reduce tolerance doesn't sound that attractive to me for the following reasons:
Cannabis tolerance isn't generally that much of an issue unless you're smoking everyday. In that case, you're unlikely to want to take a day off, much less take a drug that is going to take you to a new nadir of un-stonedness. Rimonabant sounds pretty unpleasant:
http://www.viceland.com/int/v16n8/htdocs/new-frontiers-of-sobriety-984.php
Not something I'd volunteer for.

Another problem with the analogy to opioids is the ceiling to cannabis tolerance. You hear plenty of stories of the crazy doses hardcore junkies can tolerate, nay, require; you don't really get the same with cannabis. An eighth a day is pretty impressive toking, and the cost of that pales compared to a smack habit.

However, in light of the study you posted to (interesting read btw), it might be interesting to see what effects an "ultra-low" dose of rimonabant had in terms of cannabis potentiation. We'd have to establish what exactly an "ultra-low" dose is, but I might consider being a guinea pig for that. I can lay my hands on rimonabant, so it's not a pipe dream...


Oh yes.

Lol, I'm reading the rimonabant experience report. Jesus Christ it sounds terrible. There are some things that people should not tamper with... "Anti-weed" drugs seems like one of those things.

 

[Vader]

I disagree wholeheartedly, I think that any psychoactive drug that offers a reasonable margin of safety can produce a worthwhile (if not enjoyable) experience, and I think that experimentation with Rimonabant could well be interesting.

 

[HeavilySedated]

Wikipedia: "Rimonabant blocks the psychoactive and some of the cardiovascular effects of Δ9-tetrahydrocannabinol (THC) in humans without affecting the pharmacokinetics."

It sounds like it's not going to reduce tolerance, just kill the high.

However, there is an interesting point here. It also says on Wikipedia that Rimonabant has much of the opposite effects of THC. For instance, it causes short term memory enhancement. It was taken off the market though, so good luck for anyone trying to get it.

 

[Vader]

^AMT was taken off the market, doesn't mean it's unavailable. Obviously it is generally going to nullify the effects of cannabis, but in light of the study that blane posted, I think that it might be interesting to see if there is paradoxical potentiation at very low doses.

 

[HeavilySedated]

This drug was around for a long time now. If it had the magical effects you are talking about, people would have figured it a long time ago. I'm not saying anything conclusive, I'm just saying that I'm very skeptic about the whole idea. The referenced paper about morphine (not that I've read it) has absolutely no bearing here at all, because the idea that effects observed with mu-opioid receptors are replicable with CB1 receptors is just preposterous.

But again, I'm no scientist. If you're willing, go and get the stuff. I would be most interested to hear about what the stuff actually feels like in general.

 

[Vader]

This drug was around for a long time now. If it had the magical effects you are talking about, people would have figured it a long time ago.

Naltrexone has been around for a long time, and the paradoxical potentiation at low doses has just been discovered. Aspirin was found to protect against cancer just last year. New effects of old drugs are discovered all the time.

The referenced paper about morphine (not that I've read it) has absolutely no bearing here at all, because the idea that effects observed with mu-opioid receptors are replicable with CB1 receptors is just preposterous.

Why is it preposterous? "Like causes have like effects" is a pretty well-accepted axiom. Opioid antagonists have opposite actions to opioid agonists; if from this, I was to infer from this that cannabinoid antagonists have opposite actions to agonists, would you dismiss it as preposterous that the effect might be replicated with those receptors? I have an abstract that says that low doses of antipsychotics potentiate LSD, paradoxically. Coincidence? Or could this actually be a relatively common action over many kinds of receptor?

 

[HeavilySedated]

Naltrexone has been around for a long time, and the paradoxical potentiation at low doses has just been discovered. Aspirin was found to protect against cancer just last year. New effects of old drugs are discovered all the time.

Why is it preposterous? "Like causes have like effects" is a pretty well-accepted axiom. Opioid antagonists have opposite actions to opioid agonists; if from this, I was to infer from this that cannabinoid antagonists have opposite actions to agonists, would you dismiss it as preposterous that the effect might be replicated with those receptors? I have an abstract that says that low doses of antipsychotics potentiate LSD, paradoxically. Coincidence? Or could this actually be a relatively common action over many kinds of receptor?

1. As you can infer from the Wikipedia page, the effects of Rimonabant on cannabis have been studied in humans. The issue of tolerance (let alone potentiating) is not even mentioned.

2. Naltrexone is an opioid antagonist. Rimonabant is a reversed agonist. That's two different things. "Like causes have like effects" doesn't apply. Every receptor tolerance is formed differently. Morphine tolerance is highly physiological, while cannabis tolerance is more psychological. go read a little about phosphorylation processes in the brain.

3. We are talking about tolerance here. Potentiating means increasing the effect threshold with another substance. Your LSD example is irrelevant, because nobody would usually even go to the lengths of building tolerance with it. Potentiating in the literal sense is synergizing different drugs together, and I don't think that's what the thread here is about.

Again, I'm not making any statements, just giving my two cents here. There is no real theoretical basis to make the assumptions the OP has in mind, but science is essentially a field of trial and error after all. Rimonabant is not a safe drug, so I'm definitely not encouraging you to go and do it, but in the name of science I am kind of appreciating what you are trying to do here.

 

[Vader]

1. And the studies of naltrexone on opioids have not? All I'm saying is that even well-studied drugs sometimes reveal interesting things.

2. Point taken. However, "similar causes have similar effects" might come into play.

3. I think there are two separate issues here, potentiation and tolerance. I suppose you could say that if the potentiation is really a "reverse tolerance" then they're one and the same. What we're talking about is a low dose of one drug making the subjective effects another drug stronger than they would otherwise be. If that's not potentiation then IDK what is. My LSD example is indeed about potentiation; volunteers trained to recognise LSD could do so at a lower threshold dose when it was co-administered with chlopromazine.

I understand where you're coming from, and I appreciate your input. I think that Rimonabant could serve as a tool to better understand the endocannabinoid system. I have very little interest in potentiating cannabis for practical reasons, I have only idle curiosity. As you say, Rimonabant would be interesting to experiment with, and this is a "while I'm at it, why not..." kind of thing rather than a hypothesis that I'm particularly wedded to. I'm also reasonably skeptical with regards to the study Blayne linked to; I've not heard of many junkies co-administering naltrexone to get more bang for their buck.

 

[8L4YN3]

Using it to reduce tolerance doesn't sound that attractive to me for the following reasons:
Cannabis tolerance isn't generally that much of an issue unless you're smoking everyday. In that case, you're unlikely to want to take a day off, much less take a drug that is going to take you to a new nadir of un-stonedness. Rimonabant sounds pretty unpleasant:
http://www.viceland.com/int/v16n8/htdocs/new-frontiers-of-sobriety-984.php
Not something I'd volunteer for.

Another problem with the analogy to opioids is the ceiling to cannabis tolerance. You hear plenty of stories of the crazy doses hardcore junkies can tolerate, nay, require; you don't really get the same with cannabis. An eighth a day is pretty impressive toking, and the cost of that pales compared to a smack habit.

However, in light of the study you posted to (interesting read btw), it might be interesting to see what effects an "ultra-low" dose of rimonabant had in terms of cannabis potentiation. We'd have to establish what exactly an "ultra-low" dose is, but I might consider being a guinea pig for that. I can lay my hands on rimonabant, so it's not a pipe dream...


Oh yes.

Hey dude, pretty much agree with you. And definitely get what you mean, and kinda what i said in the opening post that like i know it's a pretty rough comparison, more of a food for thought type thing.

I was more thinking like of the possibilities, and with drugs it just seems to be this infinitely amazing field of exploration where by you tinker with some atoms in a molecule, and bam you have a brand new drug with new properties ect.

And i agree, inverse cannabinoid agonist is going to feel very crap. The opposite to how being stoned feels. I even think used to market Rimonabant as like an anti-obesity drug because it has the opposite effect on appetite to THC and the other partial agonists.

I'm no chemist(lol probably evident from reading my posts) though.

What an amazing field of exploration. Sometimes i think to myself how satisfying it would have been to be shulgin himself, tinkering with this and that, making brand new drugs with new properties, it's just amazing when you think of it like the whole field of drugs.

And i dont mean this from a purely psychoactive chemical, getting high, drug abuse perspective, like drugs dont just have to be things that effects our mind, it amazes me to think what drugs are waiting to be synthed or what have you that could have unimaginable benefits to people.

---
And yerg, of course no junkie is going to knowingly administer an antagonist to themselves are they, just because no junkie had worked out for themselves that ultra low doses of naltrexone can potentiate or whatever and you have never heard of it from users, dosn't mean it cant be true dude. Makes total sense why no one had worked this out for themselves, because honestly, if you were addicted to opioids(maybe you are like me lol), you're not going to even try any dose of naltrexone, and why would you, why would anyone randomly get this idea that gee maybe ultra low dose of naltrexone could help my tolerance, so why dont i risk throwing myself into sickness so i can explore this... It's never going to happen man. And i very much doubt any junkie would derive from the study i linked, NALTREXONE LOWERS TOLERANCE, like it's a fair read, so it makes total sense to me that no users had stumbled upon this themselves.

 

[Captain.Heroin]

A drug which is an antagonist will block a receptor from being activated by an agonist. It won't activate the receptor.

An antagonist would bring the activity of the receptor to the baseline.

An inverse agonist is going to be different from an antagonist.

 

[Vader]

Well, at least if this thread accomplishes nothing else it can be something of a pharmacology 101 for CD. Thanks Cap'n.

 

[Coolio]

This drug was around for a long time now. If it had the magical effects you are talking about, people would have figured it a long time ago. I'm not saying anything conclusive, I'm just saying that I'm very skeptic about the whole idea. The referenced paper about morphine (not that I've read it) has absolutely no bearing here at all, because the idea that effects observed with mu-opioid receptors are replicable with CB1 receptors is just preposterous.

You do know that the CB1 receptor and mu opioid receptor are actually physically close and allosterically interact, right? One theory posits that CB1 and MOR (mu opioid receptor) are 'G-protein coupled heterodimeric receptor complexes'.

http://www.springerlink.com/content/e270651374680601/
http://www.ionchannels.org/showabstract.php?pmid=16806307
http://onlinelibrary.wiley.com/doi/10.1038/sj.bjp.0706757/full

 

[Coolio]

Naloxone and naltrexone only work to prevent the development of tolerance to mu opioid receptor agonists at "Ultra Low Doses." I think taking ultra low doses of CB1 antagonists between doses of exogenous CB1 agonists or combined with could very well also reduce the development of tolerance to CB1 agonists. This would explain why cannabis users do not develop tolerance fast and the tolerance plateaus, as compared to users of JWH-018 or CP 55,940 or many other synthetic cannabinoids. Cannabis contains many natural CB1 antagonists at low concentrations.