Psychedelic toad venom chemical could cure depression

In 2022, the US National Park Service urged people to please stop licking Sonoran desert toads. The warning came about because the amphibian - which is frequently called a Colorado River toad - secretes a venom from glands on its back that can provoke an hallucinogenic experience. Biologists think the toads make the chemical to ward off predators. But now a new study published in Nature suggests that a modified version of the venom may prove effective for treatment-resistant depression and anxiety symptoms that don’t respond to traditional antidepressant medicines. Up to one person in three meets this definition. But not everyone can tolerate the hallucinogenic effects. The researchers suspect that the toad chemical is activating two brain pathways: one that produces those hallucinatory experiences, while the other is the depression buster. They’ve modified the molecule to lock onto just the desirable one. David Nutt, a professor of neuropsychopharmacology and the chair of Drug Science at Imperial College London, works on very similar research in his lab, so we asked him to take us through the new results…

David - There's a great need for new treatments in psychiatry. There's been very little innovation from pharma companies over the last 20 years. The biggest and most exciting development has come from academics like my own group using psychedelics. There's really good evidence now that these can lift depression where other treatments have failed. Now, there are different sorts of psychedelics. There are classic ones that people have heard of, like LSD, but there are others popular with aficionados but not so well known. One of them is a molecule called 5-MeO-DMT which comes from, amongst other sources, the Sonoran Desert toad. The toad secretes this molecule, probably as a deterrent to other animals eating it because they get quite powerful hallucinations. Now, 5 MeO-DMT has been known for some time to be a powerful hallucinogen in humans and, like other serotonergic psychedelics - LSD, psilocybin, DMT - it has a potential utility for the treatment of depression. But there is a lot of concern amongst investors and to some extent amongst some patients that a psychedelic trip might be challenging, particularly in depressed people. In fact, it is, there's no question. So there is a feeling that if we could get the therapeutic benefit of psychedelics without the trip, that would be a major advance, which of course it would.

Chris - Do you think it would be possible to divorce the two? Do you have to have the psychedelic element to get the therapeutic depression busting element, or are they mediated through two different routes in the brain and it's just because the molecules activate both you end up with both, but you don't need both?

David - Well, that's the hope. My own personal view, and certainly our own research supports this, is that the magnitude of the psychedelic experience is predictive of the outcome, but I cannot prove that. One thing that is clear is the pharmacology of psychedelic drugs is not just at the serotonin 2A receptor, the psychedelic receptor. There's also an activity through another serotonin receptor called the 5-HT1A receptor. We've long known that this receptor is involved in the brain circuits relating particularly to stress and in fact it's very likely that the antidepressant effects of classic antidepressants like the SSRIs are mediated through enhancing activity at the serotonin 1A receptor. It is a different kind of antidepressant effect with some unwanted deleterious actions like some blunting of emotions, but it's unquestionably a target for antidepressants.

Chris - So what did they do here to try to shed a bit more light on this?

David - What they're trying to do, as many groups are, is to try to get an antidepressant effect through these current hallucinogens, psychedelics, without having hallucinatory effects. They have taken this five methoxy dimethyltryptamine molecule and they have put it through a very sophisticated, very beautiful, series of in silico receptor interactions, looking at how the molecule and predicted chemical variance of the molecule will interact with the protein structure of the receptor. It's extremely high quality, which you might call molecular chemical pharmacology. From that they've come up with a couple of molecules which have specific activity at the 1A receptor, but without activity at the 5-HT1A receptor. So, they have taken the toad venom and turned it into something that is not hallucinogenic, but they believe may still be an antidepressant.

Chris - And is this purely still in the mind's eye of a computer, or have they actually got the molecule and have they put it into a brain yet?

David - Well, they've definitely got the molecules and they've definitely put them into mice and they've definitely shown some impact on tests of depression and anxiety. They have shown that.

Chris - The next step I suppose then is to go the sort of route that you and others have gone, which is to start physically testing this in real life patients to see if you still get this therapeutic effect without the scary hallucinogenic effects?

David - That is the next step. The problem is the compound they have invented is very similar to a compound that was made by Duphar, a drug company that's no longer with us, with exactly the same theory 30 years ago. It didn't work very well in depression, had quite a lot of side effects. So I think it's pretty implausible, frankly, that their new molecules are going to have any real clinical benefit. But of course, it has to be tested, and I may be wrong.

Chris - And of course there are people who don't rely on pharmaceutical companies. They go to the source itself because there is a trend of people licking toads and have done for centuries possibly to get these effects. That's true, isn't it?

David - That is true. But I want to say please don't ever use 5-MeO-DMT from a toad. People seeking out '5 MeO' as we call it, should not source it from the toad. It can be sourced from plants. Please do not use the toad, otherwise the toads will be extinct. The second thing is, people using 5-MeO-DMT are doing so because it produces a very powerful, rather strange, slightly different hallucinatory effects to psilocybin and LSD. We are currently studying that. No one's actually ever done a brain imaging study of the 5-MeO yet. We are starting that at Imperial literally this week. We'll find out whether it does have the same signatures in the brain as other 5-HC2 agonists. You can't get, from a toad or anything else, any other living species, the molecule that they're testing. This is a fluorinated molecule. It's not made in nature. It has to be made in the lab.