Another theory on wild dagga pharmacology

[DL-ark]

I've been poking around, and I dont have much time but I found quite a few studies on Wild dagga(leonotus Leonurus) itself, and one if it's diterpenoids: Marrubiin.
So, here we can see that Wild Dagga can block convulsions caused by both NMDA and assorted GABA antagonists: http://www.ncbi.nlm.nih.gov/pubmed/12046862

However, it seems apparent that whatever is binding to GABA does not have a higher affinity than Bicuculine.
Here we see the analgesic properties of Marrubiin: http://www.ncbi.nlm.nih.gov/pubmed/10839213

This study suggests that analgesia is not due to mu-opioid binding, perhaps so, GABA? glutamate antagonist?

Antinociceptive effects of Wild Dagga itself: http://www.ncbi.nlm.nih.gov/pubmed/16082426

This study has a lot of info on the effects of Marrubiin (Warning: PDF download)

I'll post more later, but at this point I am hypothesizing that Wild Dagga's recreational effects are due to GABA-A agonism and NMDA/Glutamate antagonism via Marrubiin

Wild dagga is looking like a very good prospect - vasodilating, anti-nociceptive, anti-convulsant, anti-diabetic. At one point I (stupidly) used wild dagga every day for 3 weeks straight, without withdrawls, so maybe it's effects are not mediated through gaba (or I am just really lucky)

Also, I am wondering if the anti-diabetic effects would help to prevent adult onset diabetes, or actually increase the chances of diabetes in non-diabetics?

It could be a good combination drug with stimulants/vasoconstrictants. I myself love it by itself.

 

[Jonneh]

Interesting thoughts. Perhaps there is more to the effects of this plant than the previously hypothesised adenosine reuptake inhibition, but don't you think this action alone would be sufficient to explain the anti-convulsant effects? It seems a little simpler than positing both GABA and NMDA receptor agonism. Adenosine A1 receptor agonists are good anti-convulsants.

 

[DL-ark]

Interesting thoughts. Perhaps there is more to the effects of this plant than the previously hypothesised adenosine reuptake inhibition, but don't you think this action alone would be sufficient to explain the anti-convulsant effects? It seems a little simpler than positing both GABA and NMDA receptor agonism. Adenosine A1 receptor agonists are good anti-convulsants.

Well, it doesn't much explain the analgesia and euphoria. Additionally, Leonurine is a very strange molecule that is not super water soluble, yet very small amounts of dagga tea can be very potent. I think it is very possible that the compounds both are active, but I am speculative on Leonurine being the sole active compound.

 

[Jonneh]

Well, it doesn't much explain the analgesia and euphoria.

It may well not. Do you know of any purely pro-adenosinergic drug that has been tasted? No doubt I'm missing some.

Additionally, Leonurine is a very strange molecule that is not super water soluble, yet very small amounts of dagga tea can be very potent. I think it is very possible that the compounds both are active, but I am speculative on Leonurine being the sole active compound.

Good point. Plants are very rarely one trick ponies anyway, it's true

 

[DL-ark]

It may well not. Do you know of any purely pro-adenosinergic drug that has been tasted? No doubt I'm missing some.

Nope, I haven't heard of any purely adenosinergic drugs, supposedly acetic acid is a adenosine reuptake inhibitor, so if anyone wants to shotgun some vinegar...

Adenosine 2A is often in heteromer with D2 and/or CB1 receptors. This may explain why leonurine is sometimes described as cannabimimetic. This could also just be Hammilton's rule of cannabis association:

The plants that are borderline placebo active seem to be the ones most likely to be compared to cannabis. People can find cannabis like effects in anything or nothing if they're looking hard enough, it seems.

(From this thread)

 

[DL-ark]

I think I had it all wrong, marrubiin very much resembles the structure of a neurosteroid, which would suggest gabaergic activity. I highly doubt that marrubiin is an NMDA antagonist, as it really doesn't fit the SAR. Leonurine on the other hand could possibly be an NMDA antagonist, it's structure also resembles an AdRI, but greatly resembles the amino "acid" arginine.

EDIT:

WOWOWOW, I found something quite conclusive, here is a paper with a chart of some binding assays for some of the maruubin analogues that can be found in Wild Dagga!

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390464/

It appears to have a high affinity for 5HT1A, 5HT3, D1, H1, M3 (oops - anticholinergic?), and sigma1.

Maybe 5ht1a agonism, 5HT3 antagonism, D1 agonism and im not sure about H1 and M3, it doesn't feel particularly histaminergic (Speculation).

Edit: eureka! The M3 receptor has a great deal to do with diabetes, M3 itself is responsible for regulation of insulin. Antagonists of M3 are known to cause diabetes-like side effects. Wild Dagga is well known for it's antidiabetic properties and therefore I propose that some of the compounds in wild dagga are M3 agonists. Maybe those compounds with affinity for D1 are antagonists? wild dagga is know to treat hypertension.

This must mean that some other class of compounds in wild dagga account for the glutaminergic effects, I'd like to see what other receptors were tested with these chemicals. (I am particularly interested in GABA-A delta) but I can't seem to find anywhere where the full data for this is shown ( for free).

 

[polymath]

I just noticed that the compound marrubiin (upper image) has some features similar to salvinorin A (lower image):

The crude estimate from Swiss target prediction gives mu, delta and kappa opioid receptor as the most likely receptor targets of marrubiin.

Some reports in Erowid seem to imply that the wild dagga plant has some real psychoactive effects, but some others disagree (differing quality or a different part of the plant?).

Edit: Note the risk if this is a weak mu partial agonist and someone with a bad opioid dependence takes some.

 

[sekio]

there have been studies on the activity of marubiin, a good review is [ref]

apparently it does have some activity as an analgesic but its effects are not reversed by naloxone, meaning it is not likely to be a mu- opioid related mechanism [ref]
some derivatives are also active analgesics [ref]

 

[polymath]

If it's mostly a kappa/delta agonist and has only a minor mu effect, then the effect of naloxone on the antinociception doesn't necessarily look statistically significant. In that case dosing with antihistamines could improve it.

Nothing is said anywhere about esterifying that tertiary alcohol (with propionyl, or even cinnamoyl group).