Dearest Humble Voyager,
Thank you for sparking this discussion, you argue some very good points; I support your excellent observations. It is not surprising that amphibians produce the pharmacological cocktail they do inside their granular glands.
The generalized occurrence of granular glands in the anurans (amphibians without tails) suggests that they represent a primitive character in the order. Again, if we think about it in terms of geological time and adaptive function, amphibians evolved from fish 400 million years ago, and gradually Tiktaalik Roseae (see “Your inner fish” by Neil Shubin) replaced fins with rays reminiscent of fingers to be able to prop itself out of the water, developed spiracles as the foundation for a respiratory system to breathe air that eventually gave way to lungs. Scales, protective cutaneous structures found in the fish and in the earliest amphibians, became unnecessary in the terrestrial environment. What amphibians developed instead of scales were the glands that have played the role of protection of the organism against a number of adverse factors in their new terrestrial environment. (See “Cutaneous granular glands and amphibian venoms” by R.C. Toledo and C. Jared).
These glands, in so far as they allowed these animals to spend longer periods of time on land rather than water, represented an evolutionary advance and a nifty adaptive strategy for dealing with whatever terrestrial adversary they were likely to encounter in a most efficient manner. Being barely adapted to land life and in transition mode from water to land critters, early amphibians were at the whim of anything that might have come across them on the shores of the Earth at the end of the Devonian period, so to exude and if necessary forcibly excrete transdermally the bufogenins and bufotoxins inside their glands most definitely conferred to them a protective factor and advantage in the midst of their extreme vulnerability as they adapted to their new ecological niche.
It is interesting to note that amphibians use their toxins for protection and NOT for attack. According to G.G. Habermehl, in his book “Venomous animals and their toxins”, until recently it was commonly held that these secretions are used only against predators. However, his research showed that is not the case, as he observed that these toxins primarily protect against microorganisms. The skin of amphibians would be the perfect substrate for bacteria and fungi in the new terrestrial environment since it must be continuously moist to allow for the exchange oxygen and carbon dioxide, so it makes perfect sense that these vertebrates took it upon themselves to generate a whole gamut of bioactive chemicals to protect their viability and livelihood.
Amphibian secretions may contain cardiotoxic, neurotoxic, haemotoxic, myotoxic, hallucinogenic, hypotensive, hypertensive, antibiotic and anesthetic components. You better believe the early amphibians devised the perfect pharmacopeia to match any adversary microorganism that could prevent it from successfully adapting to the ecological niche it may have newly found itself in.
“I would also argue that these types of toxins are actually evolutionarily advantageous because they are such simple compounds that are ubiquitous in nature.” … This is a beautifully elegant point you make Humble Voyager, I agree with you fully. I think it is safe to say that serotonin is a signaling molecule, and given that nature follows the principle of parsimony, it makes sense that rather than invent new compounds, with altogether different molecular structures, it would rather just tweak an atom or two to create analogues and slight variations of other compounds that are already being manufactured and don’t take too much effort to produce, but nevertheless meet the organism's signaling needs and otherwise.
So, I agree with you that 5-MeO-DMT is a byproduct of the same metabolic process that produces bufotenine (5-HO-DMT). It is still interesting to ponder what adaptive function may the fact that the Incilius Alvarius toad, a species with a very geographically restricted area of distribution, possesses the enzyme 5-hydroxyindole-O-Methyl-transferase that converts 5-HO-DMT into 5-MeO-DMT in the parotid and tibial glands, whereas other amphibians don’t. What about the very unique environment, the harsh conditions of the Sonoran desert region made it evolutionary advantageous for this amphibian to take that extra biochemical step of expressing this particular enzyme that renders it able to produce enormous quantities of 5-MeO-DMT? There has to be a logical biological advantageous reason for it, wouldn’t you think?
Vittorio Erspamer, an Italian pharmacologist whose research led to the isolation, identification, synthesis and pharmacological study of more than sixty new chemical compounds, including serotonin itself and octopamine (
https://en.wikipedia.org/wiki/Vittorio_Erspamer ) did some research with the Incilius Alvarius toad. In his 1976 paper titled “5-Methoxy-and 5-hydroxyindoles in the skin of Bufo Alvarius”, he states that Serotonin (5-HT), which is the parent substance of all indolealkylamines present in the Incilius Alvarius skin is present only in traces. This means, he explains, that 5-HT once formed is immediately submitted to the combined action of N-methyl-transferase and 5-hydroxy-O-methyl-transferace; the final result being the formation and accumulation of enormous amounts of 5-MeO-DMT.
The amphibians that made it to our time date back 200 million years. That is a lot of time for nature to craft and refine its concoction, you would think that perhaps other amphibian species, particularly the Bufo Marinus toad for example as mentioned in the original comment by Flux, that also has these large glands and produces bufotenine, would have started also expressing this enzyme 5-hydroxyindole-O-Methyl-transferase and consequently producing 5-MeO-DMT as well. Why not? Why only Incilius Alvarius? 5-MeO-DMT does not necessarily contribute towards the capacity of the toad to ward off predators, (we know it only works if vaporized) it is the bufogenins and other bufotoxins that successfully scare away skunks, raccoons and anything else that tries to mess with them. (See Defensive Behavior and Effects of Toxins in Bufo Alvarius by Joe A. Hanson and James L. Vial).
Two things make the Incilius Alvarius toad unique... it is only found in the Sonoran desert region and it is the only bufo species that expresses this particular enzyme 5-hydroxyindole-O-Methyl-transferase … so I feel its fair to argue that somehow those two elements have something to do with the fact that this toad is a generous 5-MeO-DMT making machine, whereas others are not.
That humans were nowhere near being around when the Incilius Alvarius species was evolving in the Sonoran desert is a great point that clearly invalidates the speculative idea I had expressed regarding the possibility of “interspecies altruistic behavior”. I just thought it would be fun to entertain that possibility from a merely philosophical standpoint.
“Psychoactive compounds represent keys to the locks of neural receptors, and what better deterrent than a key which fits the locks on all animals? “…. Absolutely, another beautiful example of nature’s inclination for sticking to the principle of parsimony to get things done.
“It is not until recent times of modern man that one constituent compound, 5-MeO-DMT has become valuable. To the untrained mind, the experience would be absolutely terrifying and would essentially result in the same end game as the venom did with other animals. However, mankind has an interesting brain.”
This is an important point you make, and one that warrants further exploration as this lines up with the cultural phenomenon we are currently experiencing with the sudden (past 5 years) explosive popularity of toad venom as an “ancestral” practice. But let’s save that discussion for another post and for now keep this on the biological, rather than the cultural track we have been discussing.
I could not agree more with you when you say that mankind has an interesting brain. I think the reason why we have the type of experience we have when these simple molecules bind to our receptors is because of the nature of our own hardware and our capacity for consciousness, symmetry, reason, etc. Our typical mammalian-primate perceptual system is enhanced with an elaborate conceptual system added on top and intertwined like everything else in our triune brain.
Which again, brings me back to the idea of “Ontogeny recapitulates phylogeny” and presents me with the invitation to philosophize around the idea of how does our current phylogeny may recapitulate our future ontogeny? "Anything that can evolve may eventually evolve"…
It is conceptually challenging for us to think in terms of geological time, given our average lifespan is what? 80 years if lucky? We are nevertheless made of the same star stuff that everything else that exists in the universe is and everything is ever-evolving. We don’t tend to think about these things mainly because we are born into a culturally and socially constructed world that has been handed down to us through the institutions of ritual, symbol and myth that indoctrinate us into a particularly narrow religious/political/economical worldview.
If we go back to the idea of thinking of simple, ubiquitous compounds throughout nature as signaling molecules, it makes me curious so as to inquire what might nature be trying to signal back to itself by making these systems available? I guess I write this as an animist that sees nature itself as a dynamic energetic flow that is ever-fluctuating, expanding and exploring new realms of being and self-awareness.
“And now we are in a stage of human-molecule relationship where the information being gained could potentially unify the species as an agent for natural survival” …. What a bold statement to make, I am with you. I think we have a shot, let’s not miss the point by way of our individual and collective blindspots.
Whatever the reason why 5-MeO-DMT may be present in the Incilius Alvarius toad, and however the mechanism for developing the human perceptual system that has endowed us with the ability to tap into these “altered states of awareness” evolved, here we are, cognizant and aware that there is a simple molecule present throughout the plant and animal kingdom that happens to fit our receptor locks in ways that lead us to “unity consciousness states” that may result in the opportunity for enhanced self-awareness, which ultimately places the responsibility for positive change in each and every one of us. What are we going to do with this?
“These molecules are incredible agents of change. They can shift a perception wildly. But I would argue that they are worthless on their own.”
Yes, not only worthless, they are incredibly dangerous if used in a less than ideal situation. I feel that as we move along the trajectory we find ourselves in with the research being done to legitimize the use of these compounds, it is very important that we keep a level-headed approach and are careful with the claims we make about them. The last thing we need is people’s enthusiasm to make it sound like this is a panacea that can cure all ailments; that is simply not the case. The inner work required for personal transformation will never come from a molecule…the molecules are merely catalysts that kindly show us where our work lies, but then it is up to each individual’s agency and volition to actually do anything with the insight they may have been able to download from the experience.
Will the human mind be able to integrate the concepts elicited by such a molecule into discernible change?”
This is a very important question and one that the individuals at the forefront of utilizing this molecule both for scientific and therapeutic purposes ought to strive toward living a positive answer to by holding each other accountable, using the compounds responsibly and sustainably, being congruent, doing our own work, being humble and open for growth and learning. Keeping in check the profit model that seems to be emerging, being extra sensitive to our own blindspots and having the willingness to bring those blindspots into focus to work with.
“It is not until a human being takes responsibility for its own operating system and makes the change in behavior, however hard it may be, that evolution can occur. And that process is very slow indeed.”
I absolutely agree with you… and yes the process for taking responsibility of our own operating system and hardware is very slow indeed, but I do feel strongly that through concerted effort vested into practices like mindfulness, self-compassion, loving-kindness and through the responsible use of psychedelics as catalyzing agents for stabilizing long-term positive change, we can initiate a process of self-directed neuroplasticity that may indeed help us over-write our primitive-mammalian brain and perhaps little by little add another layer to our triune brain, or at least, for the time being, little by little further exert an inhibiting executive top down control on our limbic emotional brain and our primitive reptilian brain so we may learn how to get out of, and stay out of “fight-flight” and figure out how to turn on the “play and engage” mode as we connect our neocortex in new and unprecedented ways.
Just a couple of days ago I was reading about this 40 year old genetic study in Russia where they were doing selective breeding for the behavioral trait of “tameness” among the silver fox. In just 40 years they were able to induce some powerful genetic changes, scientists report:
“As our breeding program has progressed, we have indeed observed changes in some of the animals’ neurochemical and neurohormonal mechanisms. For example, we have measured a steady drop in the hormone-producing activity of the foxes’ adrenal glands. Among several other roles in the body, the adrenal cortex comes into play when an animal has to adapt to stress. It releases hormones such as corticosteroids, which stimulate the body to extract energy from its reserves of fats and proteins. After 12 generations of selective breeding, the basal levels of corticosteroids in the blood plasma of our domesticated foxes had dropped to slightly more than half the level in a control group. After 28 to 30 generations of selection, the level had halved again. The adrenal cortex in our foxes also responds less sharply when the foxes are subjected to emotional stress. Selection has even affected the neurochemistry of our foxes’ brains. Changes have taken place in the serotonin system, thought to be the leading mediator inhibiting animals’ aggressive behavior. Compared with a control group, the brains of our domesticated foxes contain higher levels of serotonin; of its major metabolite, 5-oxyindolacetic acid; and of tryptophan hydroxylase, the key enzyme of serotonin synthesis. Serotonin, like other neurotransmitters, is critically involved in shaping an animal’s development from its earliest stages.”
So, while it is not viable to think that humans are going to start a selective breeding program, we can nevertheless use our higher cognition to try to find ways to affect our neurochemistry and neurohormones in ways that can lead to a similar outcome as the one found with the foxes. If we could find a way to downregulate our corticosteroid output and increase our serotonin production and its enzymes over the next 40 years…we may be able to experience a most powerful example of what Thomas Kuhn referred to as a “paradigm shift”.
