If you were an American scientist interested in hallucinogens, the 1950s and 1960s were a great time to be working. Drugs like LSD and psilocybin—the active ingredient in magic mushrooms—were legal and researchers could acquire them easily. With federal funding, they ran more than a hundred studies to see if these chemicals could treat psychiatric disorders.
That heyday ended in 1970, when Richard Nixon signed the Controlled Substances Act. It completely banned the use, sale, and transport of psychedelics—and stifled research into them. “There was an expectation that you could potentially derail your career if you were found to be a psychedelics researcher,” says Jason Slot from Ohio State University.
For Slot, that was a shame. He tried magic mushrooms as a young adult, and credits them with pushing him into science. “It helped me to think more fluidly, with fewer assumptions or acquired constraints,” he says. “And I developed a greater sensitivity to natural patterns.” That ability inspired him to return to graduate school and study evolution, after drifting through several post-college jobs. (“They are not for everyone, they entail risks, they’re prohibited by law in many countries, and only supervised use by informed adults would be advisable,” he adds.)
Ironically, he became a mycologist—an aficionado of fungi. And he eventually came to study the very mushrooms that he had once experienced, precisely because so few others had. “I realized how pitifully little we still knew about the genetics and ecology of such a historically significant substance,” he says.
Why, for example, do mushrooms make a hallucinogen at all? It’s certainly not for our benefit: These mushrooms have been around since long before people existed. So why did they evolve the ability to make psilocybin in the first place?
And why do such distantly related fungi make psilocybin? Around 200 species do so, but they aren’t nestled within the same part of the fungal family tree. Instead, they’re scattered around it, and each one has close relatives that aren’t hallucinogenic. “You have some little brown mushrooms, little white mushrooms ... you even have a lichen,” Slot says. “And you’re talking tens of millions of years of divergence between those groups.”
It’s possible that these mushrooms evolved the ability to make psilocybin independently. It could be that all mushrooms once did so, and most of them have lost that skill. But Slot thought that neither explanation was likely. Instead, he suspected that the genes for making psilocybin had jumped between different species.
These kinds of horizontal gene transfers, where genes shortcut the usual passage from parent to offspring and instead move directly between individuals, are rare in animals, but common among bacteria. They happen in fungi, too. In the last decade, Slot has found a couple of cases where different fungi have exchanged clusters of genes that allow the recipients to produce toxins and assimilate nutrients. Could a similar mobile cluster bestow the ability to make psilocybin?
To find out, Slot’s team first had to discover the genes responsible for making the drug. His postdoc Hannah Reynolds searched for genes that were present in various hallucinogenic mushrooms, but not in their closest non-trippy relatives. A cluster of five genes fit the bill, and they seem to produce all the enzymes necessary to make psilocybin from its chemical predecessors.
After mapping the presence of these five genes in the fungal family tree, Slot’s team confirmed that they most likely spread by jumping around as a unit. That’s why they’re in the same order relative to each other across the various hallucinogenic mushrooms.
These genes seem to have originated in fungi that specialize in breaking down decaying wood or animal dung. Both materials are rich in hungry insects that compete with fungi, either by eating them directly or by going after the same nutrients. So perhaps, Slot suggests, fungi first evolved psilocybin to drug these competitors.
His idea makes sense. Psilocybin affects us humans because it fits into receptor molecules that typically respond to serotonin—a brain-signaling chemical. Those receptors are ancient ones that insects also share, so it’s likely that psilocybin interferes with their nervous system, too. “We don’t have a way to know the subjective experience of an insect,” says Slot, and it’s hard to say if they trip. But one thing is clear from past experiments: Psilocybin reduces insect appetites.
By evolving the ability to make this chemical, which prevents the munchies in insects, perhaps some fungi triumphed over their competitors, and dominated the delicious worlds of dung and rotting wood. And perhaps other species gained the same powers by taking up the genes for those hallucinogens. It’s not clear how they did so. Some scientists think that fungi can occasionally fuse together, giving them a chance to share their DNA, while Slot prefers the idea that in times of stress, fungi can soak up DNA from their environment. Either way, the genes for psilocybin have spread.
Much of this is speculation, based on circumstantial evidence. Since psilocybin is still a controlled substance, Slot can’t legally make it in his lab, which means he can’t prove that the gene cluster he identified actually produces psilocybin in mushrooms. Still, his team have done as much as they can, says Jennifer Wisecaver, an evolutionary biologist from Purdue University who studies fungal genes. “Given the other evidence they provide, I'd say the hypothesis is very compelling,” she says.
This work is part of a resurgence of psilobycin research. Just last week, a German team led by Dirk Hoffmeister identified four enzymes that can produce the drug, paving the way to manufacture it without growing shrooms. Other scientists have shown that psilocybin could have potential for treating depression, helping smokers to quit, and relieving the anxiety felt by cancer patients. “The science that’s being done on [magic mushrooms] has taken on more of an air of respectability,” says Slot.
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