Synthetic cannabinoid kidney damage speculation

[serotonin2A]

I'm glad that my counterarguments have helped to refine your thinking....

One thing to note is that NSAID nephrotoxicity is pretty rare given how widely they are used. Phenacetin and acetaminophen are obviously very toxic in overdose, but that is because they happen to be converted to a particularly toxic metabolite. Is there reason to think that the cannabinoids would be substantially more nephrotoxic then the NSAIDS?

Quoting your post above "Having done some further research, I can now describe the entire mechanism for the production of a potent ht3 antagonist from PB-22."

The problem with that statement, of course, is that it is impossible to do what you are claiming because there is no evidence that the metabolites are potent 5-HT3 antagonists. No one can say with any confidence that the metabolites are capable of interacting with 5-HT3, especially with high affinity. One easy test would be to try to dock the metabolites into a 5-HT3 model...

I think it is perfectly reasonable to speculate about these interactions, but here you have built up an argument that is based on several assumptions, and if one of the assumptions is incorrect then the entire story collapses. First there is the matter of whether the proposed metabolites bind to 5-HT3. This is a very big hill to climb because there are not a lot of conjugated metabolites that are capable of binding to serotonin receptors. Second, it's not clear that the conjugated metabolites are actually generated in humans in vivo. Third, the in vitro work suggested that these would be minor metabolites, so they may not be produced at high enough concentration to bind to 5-HT3. Fourth, if the metabolites are 5-HT3 antagonists and are generated at high levels, would that actually have any clinical significance? As I noted earlier, morphine is a 5-HT3 antagonist, but I'm not aware of any evidence that the effect is toxicologically relevant. Fifth, most cannabinoids lack an ester linkage, so they would be metabolized differently than PB-22. It seems extremely unlikely that more than one metabolic route would exist that could convert cannabinoids to 5-HT3 antagonists. As the expression goes, lightning doesn't strike twice.

 

[BallsStapledToLeg]

This seems relevant
http://www.bluelight.org/vb/threads/743668-KIDNEY-DAMAGE-from-AB-APINACA

Its interesting to note that this compound isn't closely related to XLR-11 so it likely produces its nephrotoxic effects via some sort of non-metabolic process. Also, upon reviewing the CDC report it appears 11/12 cases reported severe vomiting which could perhaps decrease the threshold for kidney damage via severe dehydration.

What are your thoughts?

 

[niflheim]

Balls - The AB-cannabinoids have a valyl group. Some medications can be conjugated with valine to increase oral bio-availability, one example being valacyclovir, the valyl ester of the antiviral drug acyclovir. Interestingly enough there's some recent research suggesting that interactions between valacyclovir and NSAIDs can cause acute kidney injury (Acute kidney injury during concomitant use of valacyclovir and loxoprofen: detecting drug-drug interactions in a spontaneous reporting system). One marker for chronic kidney disease is the metabolic production of valine hydantoin as a result of reactive urea breakdown products reacting with the n-terminal valine residues of heamoglobin (see the introduction of this paper for a better description: A colorimetric method for measurement of carbamylated haemoglobin in patients with chronic kidney disease using a spectrophotometer). As mentioned previously valproic acid (a valine derivative) inhibits glucuronidation ,Apparently so does the hydantoin derivative phenytoin (Phenobarbital and phenytoin increased acetaminophen hepatotoxicity due to inhibition of UDP-glucuronosyltransferases in cultured human hepatocytes). I have no idea if valine hydantoin has the same effect, but it doesn't seem unreasonable to think it might.

I haven't heard any reports of AB-FUBINACA causing kidney issues. It turns out that the limited metabolic studies that have veen done show a difference in how AB-FUBINACA is metabolised vs AB-PINACA (UPLC/ESI-MS/MS-based determination of metabolism of several new illicit drugs, ADB-FUBINACA, AB-FUBINACA, AB-PINACA, QUPIC, 5F-QUPIC and α-PVT, by human liver microsome.) "The oxidation of ADB-FUBINACA and AB-FUBINACA mainly occurred on the N-(1-amino-alkyl-1-oxobutan) moiety. However, the oxidation of AB-PINACA seemed to occur on the 1-pentyl moiety." I'm not sure what the result of that is, but it seems plausible that the modification of the valine group could prevent the carbamylation reaction. Obviously that's an in vitro study using only a small part of the metabolic machinery present in vivo, so it may not reflect actual metabolism in humans, but it's suggestive.

So this actually appears consistent with my original hypothesis for XLR-11, but with a different route towards inhibition of glucuronidation For XLR-11 I suggest that the tetramethylcyclopropyl group acts as a potent analogue of valproic acid, which inhibits glucuronidation, for AB-PINACA this seems to be due to the carbamylation reaction with urea-breakdown products and consequent production of valine hydantoin. From that point onwards, the outcomes are the same - higher production of reactive cysteine conjugates and resulting oxidative damage. Although another possibility is that the cysteine conjugates or their metabolic successors form insoluble crystals within the renal tubules (which was new to me, but it's apparently a mechanism of nephrotoxicity for acyclovir). Any other drugs that are metabolised by the inhibited glucuronosyltransferases could also contribute. Either way, NSAIDs are likely to make things worse via reduced blood flow to the kidneys (and cannabinoids probably act as NSAIDs anyway).

 

[niflheim]

serotonin - Sorry for the lack of response - those were good questions. I got sidetracked while looking at possible answers, and I came to the conclusion that some of the metabolites are likely to act as analogues of lipoic acid, which is a more interesting thing than the 5-ht3 question by a long way. There's not a lot of research on short-chain fatty acid analogues, though, so it's even more supposition than before and not something I can construct a good argument around.

 

[niflheim]

Also looking at the original post about AB-PINACA kidney injury (the post says AB-APINACA, but I'm assuming AB-PINACA was the drug involved as the initial A in APINACA is the same positional group that the AB in AB-PINACA refers to), the poster mentions taking promethazine codeine a couple of days prior to the AB-PINACA. Looking at this useful table, many NSAIDs as well as codeine are substrates for UGT2B7 (one of the glucuronosyltransferase enzyme). which is inhibited by valproic acid. Depletion of this enzyme in the kidney fits with the cysteine conjugate theory above. (In terms of harm reduction, avoiding combinations of cannabinoids and the drugs listed under that enzyme in the table would be a good idea for users, especially with any cannabinoids associated with kidney damage).

 

[serotonin2A]

This mechanism has become very non-specific. Gluconuration is one of main pathways that the body uses to excrete things that contain a hydroxy group (i.e., many drugs or drug metabolites), so it is extremely common for compounds to interact with it. You could propose this mechanism to explain almost any type of kidney injury. I'm sure you could explain the bladder toxicity produced by ketamine the same way.

One thing that would be helpful is if you could propose a clear, falsifiable hypothesis.

 

[BallsStapledToLeg]

It appears that there is some controversy over CB2 expression in human kidneys, Larrinaga et al. (2010) reported negative CB2 protein and mRNA in human kidneys. However, Barutta et al. (2011) reported CB2 receptors in human glomeruli predominantly in podocytes.

Below is some random findings I made before I had to cut this post short:

CB1 receptors appear to function in the kidney as regulators of Na++/K+ ATPase in a rather complicated manner, so it would seem it has several signalling pathways in human kidney cells. CB2 receptors (the bulk of the newer literature supports their presence in human kidneys) appear be negatively regulated by proximal tubule albumin concentrations, which perhaps could partially explain the albuminuria seen in the CDC cases if they were desensitized or otherwise functionally inhibited by exposure to the synthetic cannabinoids?

I'll do some more research on possible pharmacodynamic reasons later, my lunch is over

 

[niflheim]

serotonin- Sorry, but no. This has got to the point where it's really dull - probably for you as well as me. Clearly some cannabinoids cause kidney damage under some set of conditions and there must be a mechanism by which this occurs. I find it interesting to think about that and find plausible explanations for it. I'm well aware that I'm not operating within clearly defined scientific principles - and how could I be? I don't have the time, resources and I'm not embedded within the kind of academic context that makes science work like science and not like this. You are not a peer reviewer and this isn't a paper I need to publish so that I can improve some specious influence score that might maybe one day mean tenure.

An interesting conversation would involve the exchange of ideas - I'd be genuinely happy to hear why I'm wrong and (this is the important bit) what explanation fits the known facts and evidence better. And if you want to engage with the argument rather than shutting down discussion, a good starting place might be explaining why you think that synthetic cannabinoids that have structural and functional similarities with various NSAIDs known to cause kidney damage via production of reactive metabolites (carboxylates get metabolised into reactive acyl-glucuronides; ketoprofen covalently binds with UGT enzymes depleting the pool of glucuronidative enzymes, naproxen forms CoA thioesters) are unlikely to share similar toxicity profiles? (And maybe the culprit is via one of those mechanisms rather than cysteine conjugation?) Or - and it's entirely possible - if these ideas aren't any use to you and provide nothing of interest, don't.

 

[serotonin2A]

An interesting conversation would involve the exchange of ideas - I'd be genuinely happy to hear why I'm wrong and (this is the important bit) what explanation fits the known facts and evidence better. And if you want to engage with the argument rather than shutting down discussion, a good starting place might be explaining why you think that synthetic cannabinoids that have structural and functional similarities with various NSAIDs known to cause kidney damage via production of reactive metabolites (carboxylates get metabolised into reactive acyl-glucuronides; ketoprofen covalently binds with UGT enzymes depleting the pool of glucuronidative enzymes, naproxen forms CoA thioesters) are unlikely to share similar toxicity profiles? (And maybe the culprit is via one of those mechanisms rather than cysteine conjugation?) Or - and it's entirely possible - if these ideas aren't any use to you and provide nothing of interest, don't.

The problem that I have been trying to point out (although maybe not clearly) is that many of the structural and functional similarities you are citing are not specific enough to be meaningful. There is very little evidence that acyl gluconurides as a class have toxicological effects in vivo. NSAIDS are actually very safe substances given how common their use is (we can only hope that synthetic cannabinoids will prove to be that safe), and I can't think of any reason to assume that synthetic CB1 agonists would produce toxicity via the same route as ketoprofen. Although there may be some carboxylates that are toxic, there are many others that are not, so the presence of that one structural element does not really prove anything. It is well known that THC is metabolized to 11-COOH-THC. So it seems to me that you are cherry picking evidence. Unfortunately, it isn't easy to predict whether a molecule will display toxicity in vivo based solely on its structure. I'm not saying what you are proposing is impossible, but there are many other explanations that are just as likely. I think idle speculation is OK, but in some of your posts you have been recommending certain actions based on harm reduction, and I think most people here would agree that you shouldn't make those type of statements unless you actually have some evidence to back up your recommendations.

 

[niflheim]

Cherry-picking would be to ignore data that does not fit in preference of data that does. I'm not ignoring data that doesn't fit, and you haven't presented any. What I'm doing here is another thing. which is usually called 'research'.

NSAID's in wide use have a good safety profile precisely because they are the ones least associated with adverse side effects. Even so, each year a handful of acute kidney injury cases still occur with no other known cause. The NSAIDs that have more frequent renal side-effects either never reach market or are used in the context of ongoing monitoring of kidney function. The current synthetic cannabinoids derive from the indometacin derivative pravadoline, which was the starting point for the WIN series cannabinoids, which were the starting point for the JWH series, from which most of the currently marketed derivatives are derived. i.e. the synthetic cannabinoids we're talking about derive directly from the NSAIDs. Which, incidentally, was pointed out earlier in the thread, by the way, so I may have made the mistake of thinking that it didn't need to be repeated every time I make connections between the two.

Here's APICA and indometacin side by side:

You may find it interesting to look at a 3d overlay of these two and compare the cannabinoid structures to the various proposed COX-1 and COX-2 SARs. (The different position of the nitrogen in the indole of indometacin is an issue for cannabinoid activity, but the reverse isn't true).

The speculative conclusions I've reached suggest some harm-reduction strategies. I assume that people who are concerned and want to minimise their risk can read my posts and decide whether to act on the information themselves. I'm not sure that suggesting that people may wish to avoid potential cannabinoid/medication interactions is really all that controversial. It's not like I'm presenting this as undeniable truth. But if there's a consensus that this is not allowed, then I'll avoid doing that in future. I don't see how the random internet guy suggesting that smoking spice and taking advil might not be a good idea is going to cause people problems, but if it's really disapproved of, then I have no problem keeping my mouth shut about ways people can reduce their risk (risks being, by their nature, uncertain) of serious kidney damage.

Edit: The bulkiness of the adamantyl group on APICA may or may not be an issue for COX activity, but that's not shared by the majority of synthetic cannabinoids.

 

[serotonin2A]

Cherry-picking would be to ignore data that does not fit in preference of data that does. I'm not ignoring data that doesn't fit, and you haven't presented any. What I'm doing here is another thing. which is usually called 'research'.

Listing a few examples that agree with your hypothesis without acknowledging all the other inconsistent evidence is cherry picking data. There are many examples of drugs/metabolites with carboxylic moieties that are perfectly safe.

NSAID's in wide use have a good safety profile precisely because they are the ones least associated with adverse side effects. Even so, each year a handful of acute kidney injury cases still occur with no other known cause. The NSAIDs that have more frequent renal side-effects either never reach market or are used in the context of ongoing monitoring of kidney function. The current synthetic cannabinoids derive from the indometacin derivative pravadoline, which was the starting point for the WIN series cannabinoids, which were the starting point for the JWH series, from which most of the currently marketed derivatives are derived. i.e. the synthetic cannabinoids we're talking about derive directly from the NSAIDs. Which, incidentally, was pointed out earlier in the thread, by the way, so I may have made the mistake of thinking that it didn't need to be repeated every time I make connections between the two.

Pravadoline may have been derived from NSAIDS, but one of the goals of moving from pravadoline to the WIN series to the JWH series was to make selective cannabinoids that lacked NSAID activity. The synthetic cannabinoids we are discussing are not NSAIDs. WIN 55,212-2 was designed as an analog of pravadoline that did not alter prostaglandin synthesis. And the later generations of cannabinoid agonists were developed to be even more selective. So I don't see this as a good argument.

Here's APICA and indometacin side by side:

You may find it interesting to look at a 3d overlay of these two and compare the cannabinoid structures to the various proposed COX-1 and COX-2 SARs. (The different position of the nitrogen in the indole of indometacin is an issue for cannabinoid activity, but the reverse isn't true).

There may be some similar structural elements present in these two chemicals, but so what? Those two compounds are competely different pharmacologically. The cannabinoid on the left is not a NSAID, and indomethacin isn't a cannabinoid. This is why I am saying that the similarities you are pointing out are too general. The fact that their pharmacological properties are completely different shows that these superficial similarities are meaningless in terms of predicting how drugs will act in the body.

To quote from the book Gout: Basic Science and Clinical Practice, "The single most significant side-effect other than gastrointestinal bleeding is the different nephrotoxic responses that may be observed with indomethacin and other NSAIDs...The clinical syndromes associated with these nephrotoxic responses primary result from the inhibition of renal prostaglandin synthesis by NSAIDs." Inhibiting prostaglandin synthesis reduces renal blood flow, which impairs renal function. Since the cannabinoids are not NSAIDs and do not inhibit COX enzymes, it is really a moot point to try to link cannabinoid and NSAID toxicity.

The speculative conclusions I've reached suggest some harm-reduction strategies. I assume that people who are concerned and want to minimise their risk can read my posts and decide whether to act on the information themselves. I'm not sure that suggesting that people may wish to avoid potential cannabinoid/medication interactions is really all that controversial. It's not like I'm presenting this as undeniable truth. But if there's a consensus that this is not allowed, then I'll avoid doing that in future. I don't see how the random internet guy suggesting that smoking spice and taking advil might not be a good idea is going to cause people problems, but if it's really disapproved of, then I have no problem keeping my mouth shut about ways people can reduce their risk (risks being, by their nature, uncertain) of serious kidney damage.

The chart you listed includes drugs for epilepsy, bipolar disorder, congestive heart failure, breast cancer, etc. There may be some people who need to take those drugs tp treat serious medical conditions. For someone who is prescribed one of those drugs and is also dependent on a synthetic cannabinoid, it may not be easy to stop using the cannabinoid, so they might decide to keep taking the cannabinoid and stop the other drug based on your advice. That is one reason why I think overstating this issue is a poor harm reduction strategy.

 

[niflheim]

Like I said, this is dull. I will not be replying further in this thread.

 

[niflheim]

Actually, one more post before I go.

Just to be clear, I am in no way advocating that people stop taking medications that are managing serious medical conditions on the basis of some random person's haphazard pubmed searches. People should come to their own conclusions about how much additional risk the things I've suggested here actually represent. There is obviously a diverse range of opinions on the likelihood of the mechanisms I've suggested and there's no statistical data that could provide any idea of the incidence of kidney injury in association with synthetic cannabinoids with or without any other substances. Even if I'm entirely correct about everything I've suggested, the risks may well be low enough that it has no meaningful consequence.

Speaking only for myself, if I were a user of synthetic cannabinoids (I'm not and consider them unsafe for reasons outside of the discussion here), then all other things being equal I would avoid the combinations that I've suggested may be problematic. Obviously all other things are not equal if that choice has its own risks. If I were under the care of a medical professional and felt I could not discontinue my use, I would disclose this and discuss possible interactions with the people qualified to and responsible for making medical decisions affecting my health. (That's easy for me to say - medical treatment is free where I live and I'm a middle-class professional who used to work in a related, though non-clinical field, which means I'm used to treating doctors as expert service providers instead of gatekeepers of treatment). There are essentially no circumstances that would lead me to discontinue or avoid the use of a prescribed medication based on an unknown and possibly non-existant risk of interactions with a chemical I bought from the internet.

 

[fatstep]

The -setron thing is extremely interesting, as I as well as others' WDs have been completely stopped with IV ondansetron and I've always wondered how Zofran could completely stop my WDs

 

[swimmingencouraged]

Dealkylation of the amine chain has been found in metabolic studies of JWH-018 and 5F-AKB-48 (and probably others).

serotonin2A - since the most potent 5-ht3 antagonists have doses as low as 10ug, and cannabinoid doses of 1mg or upwards aren't uncommon (especially with tolerant users), even a decrease in potency of a couple of magnitudes could still produce significant ht3 antagonism. I've looked for ht3 binding data for synthetic cannabinoids and it doesn't seem to be out there, but if it does exist I'd be happy to be pointed in the right direction.

I'm not sure what to make of this but 5f-akb-48 landed me in the hospital. Definitely felt toxic, but that's not exactly a scientific projection now is it.