Conantokin peptides / Conopeptides from Cone Snail venom as novel dissociative drugs

[Vastness]

Wasn't sure whether to post this in the Psychedelics forum or here, I figure that this is highly likely to be a purely theoretical topic at the moment though so am posting it here.

Anyway I recently noticed that PsychonautWiki has the "Conantokin Peptides" listed as a pharmacological class of dissociative drugs - a little research and it seems these compounds are peptides derived from the venom of certain species of marine "Cone snails".

From the Wikipedia page on Conantokins:

Conantokins are a small family of helical peptides that are derived from the venom of predatory marine snails of the genus Conus. Conantokins act as potent and specific antagonists of the N-methyl-D-aspartate receptor (NMDAR).[1] They are the only naturally-derived peptides to do so.[2] The subtypes of conantokins exhibit a surprising variability of selectivity across the NMDAR subunits, and are therefore uniquely useful in developing subunit-specific pharmacological probes.

A little more research, and it seems that there are some "marine derived" drugs under investigation for various conditions - this Researchgate publication lists a few of them, such as Ziconotide, as well as one derived from (the venom of?) a "Nemertine worm". Ziconotide itself is only approved for intrathecal use, ie, injection directly into the cerebrospinal fluid, and seems to have a list of some potentially quite serious side effects so is unlikely to have much recreational potential. As far as I can tell, the effects of being stung by a Cone snail are also pretty serious, potentially fatal, and, therefore, likely not recreational.

However, I am curious, does anyone know of any research into the likely effects of these interesting and unusual substances in humans? Or, if not, would anyone like to speculate as to their potential subjective effects, toxicity, and recreational potential when compared to currently well known dissociatives / NMDA antagonists, ie, ketamine and those from the arylcyclohexylamine class?

Given that humans have found ways to try getting high on a whole bunch of other venomous animals, ie, cane toads, tree frogs, and that there is even that guy who injects himself with small amounts of snake venom, it's kind of surprising to me that no-one has tried to harvest this venom before for self-administration, or that some culture in human history hasn't tried to utilise it in this way, although I guess this is maybe because these Cone snails do not come into contact with humans that often, and/or that the venom in it's natural, unrefined form is just too toxic and dangerous for anyone to bother with. Perhaps also it would just be too difficult to harvest this venom, at least in any kind of humane way. Anyway, I'd be interested to hear anyone's thoughts on this.

 

[Cotcha Yankinov]

I'm not aware of this genre of compound being used recreationally but I will say there was some investigation into similar snail compounds for addiction, some of the snail toxins block nicotinic acetylcholine receptors quite potently and high throughput screening identified some compounds that were highly selective for blocking nicotinic alpha3beta4 receptors. Blockade of a3b4 receptors is probably responsible for a large portion of ibogaine's anti addiction effects.

https://www.ncbi.nlm.nih.gov/pubmed/24649848

 

[JacksinPA]

I got interested in the cone snails while watching a video during a course on evolution. There are at least 700+ species of snail in the family Conidae & each makes a cocktail of 100+ peptide toxins suited for its particular environment. They can be separated into those who eat worms, other snails & even fish. One set of peptide toxins can stun a fish by putting it to sleep. Another set is a unique insulin that the snail's immune to but puts the target fish into hypoglycemic shock. The fish eaters are the larger species. Conus geographus, for instance, is a large fish eater known as the 'cigarette snail' because if your stung by one you only have time to smoke one before you stop breathing and die.

Peptide chemistry requires specialized equipment & expensive, hard-to-source amino acids & reagents.

The other downside to peptides is the RA is IV or injection into the cerebrospinal fluid.

 

[JacksinPA]

Those pages were all blank.

 

[Limpet_Chicken]

Yeah there is no way in hell crude cone snail venom could be used, if at all it would have to be the individual active compounds, and without modification (sometimes derivatives such as altering an N-terminus to an amide etc. can stabilize some peptides against metabolic destruction) are likely to be of poor bioavailability.

And you definitely don't want to go try getting yourself stung by a cone snail. As stated about especially the fish-eating ones, the venom is very fast acting indeed. I've seen how rapid the onset can be in fish, and it can be so fast that the snail slyly, slowly extends its proboscis, and fires a tethered dart, in reality a highly modified radular tooth, connected to a venom gland, and the fish is paralyzed or dead INSTANTLY. Just stops moving the moment its hit, as if it had been taken out by a shotgun blast to the head.

And the fish-eating ones such as C.geographus, C.textile and C.marmoreus especially, tend to be both large (and as such capable of delivering more venom), and eating fish, they need the venom to be effective to prevent either prey escaping, or the prey fighting back and injuring or killing the otherwise slow moving snail. These things are like wheelchair-bound navy seals snipers. Slow, and compared to a fish, crippled in terms of mobility, but deadly stealthy, and packing the marine molluscan equivalent of a barrett light .50 anti-materiel rifle and multipurpose raufoss shell loadout.

And they are quite capable of stinging through a wetsuit, dry-suit etc. And even some of the non-fish-eaters, snail eating species like C.textile have been fingered for a fair few human deaths. Got an old shell somewhere actually, a small cone snail, I think C.textile, brought back from turkey when I went on holiday (making absolutely certain that it was dead before picking it up or even touching it, in this case, the shell was completely hollow and it was utterly dessicated, from lying on the dry sand, and I knew there to be no animal inside it), very beautiful creatures, but potentially as deadly as they are pretty.

Very interesting about the insulin-mimetic, sending fish into hypoglycaemic shock.

 

[ClarityPSY]

Funnily enough, I noticed that these substances were listed on that page while I was making an unrelated edit to it. Something seemed a bit off, so I did a Google search only to find this place as the only result! Pretty much the last thing I was hoping to see Upon review, I think it's fair to say that this addition is extremely speculative and over-eager at best. I have removed them from the article on the basis that there does not appear to be any documentation whatsoever that confirms actual dissociative properties when administered to humans. If anyone has any evidence to the contrary, feel free to send it to me

 

[Limpet_Chicken]

Thats likely because of the ROA requirements. Would these peptides (inc. things like prialt) be active via intravenous route? or is it solely via intrathecal route? obviously it seems more likely that a peripherally active agent like an insulin mimetic or something blocking the neuromuscular junction doesn't need to pass the BBB to be active, hence the potentially lethal effects of a large fish-eating cone snail sting.