In plant biology laboratories, researchers treat Nicotiana benthamiana much like a lab rat. This tobacco relative grows fast, is low maintenance, and readily accepts foreign DNA. But now, researchers have pushed this botanical workhorse into strange new territory.
By splicing in genetic instructions borrowed from magic mushrooms, desert toads, and an Amazonian shrub, scientists have engineered the plant’s leaves to simultaneously pump out five powerful psychedelic compounds.
The engineered plant brews a complex cocktail of psilocybin, psilocin, DMT, 5-methoxy-DMT, and bufotenin. These compounds hold immense medical promise for treating severe depression, anxiety, and trauma. Consolidating their production into a single, fast-growing crop could solve a critical supply bottleneck for medical researchers while offering a sustainable alternative to harvesting vulnerable wild species.
A Cross-Kingdom Masterpiece
Psychedelics belong to a class of chemical compounds called tryptamines. For millennia, Indigenous cultures have harvested these substances for spiritual and healing rituals. Today, modern psychiatry views them as powerful tools to rewire the brain and alleviate intractable mental health conditions.
Paula Berman, a postdoctoral researcher at the Weizmann Institute of Science, recognized the growing tension between soaring medical demand and fragile ecosystems.
“We are interested in this, not because of the recreational effects, but because of the medicinal potential,” Berman told 404 Media.
Berman and her colleagues set out to identify the biosynthetic pathways within these organisms. They first cracked the unwritten genetic code of the Psychotria viridis bush and the Acacia acuminata tree to understand how plants build DMT.
Next, they borrowed genetic instructions from the Psilocybe cubensis mushroom and the cane toad (Rhinella marina). They added supportive enzymes from rice and the cress plant to complete the recipe and ensure that the plants can grow healthy. Lastly, they inserted this customized genetic toolkit into the tobacco plant. The result was unprecedented.
“This combination of five psychedelics—I don’t think anyone has ever tried something like it,” senior author Asaph Aharoni told 404 Media. “In one leaf, we get five different psychedelics from three different kingdoms.”
Tinkering With the Assembly Line
While modern studies have shown great promise for psychedelics, it’s not easy to extract such substances. Scientists traditionally rely on complex, often wasteful synthetic chemistry to produce these drugs in the lab. Alternatively, they extract them directly from nature. The researchers caution that over-harvesting for such substances now threatens the Sonoran Desert toad, while habitat loss endangers the Amazonian vines crucial for ayahuasca.
“Over-harvesting endangers the natural availability of these species for native peoples and Indigenous groups,” Berman said. “We have so much respect for the knowledge that they provide us, and we just want to add to this knowledge and to be able to produce these in a more sustainable way.”
But the team faced a major hurdle in their quest for sustainability. While the tobacco plant successfully produced the drugs, the internal pathways competed for the same biological resources. Some compounds emerged only as a tiny trickle.
To fix this, the researchers deployed AlphaFold3, an advanced artificial intelligence tool capable of predicting the three-dimensional shapes of proteins. The AI revealed a structural clash inside an enzyme borrowed from the cress plant.
By swapping a single amino acid, the scientists widened the enzyme’s active site. This microscopic surgical edit boosted the plant’s production of 5-methoxy-DMT by a staggering 40-fold.
A Temporary Factory
Safety was a priority. The researchers didn’t permanently change the tobacco’s genome to ensure that there won’t be any contamination of natural plants. If the tobacco’s DNA were permanently altered, its seeds or pollen could spread to wild relatives or accidentally contaminate the agricultural supply, creating unregulated patches of plants that pump out controlled substances.
The team used “agroinfiltration,” essentially deploying a specialized bacterium to temporarily ferry the genes into the leaves. The plant pumps out the drugs for a short window, but it can’t pass those traits to its seeds.
“One reason that we did that is we are still not sure if we want to make plants where everybody can grab seeds from us and grow a plant with five different compounds” Aharoni explained. “We have to make sure that it stays in research.”
The long-term payoff of this research extends far beyond a single genetically modified leaf. Roughly 25% of prescription drugs are derived wholly or partially from plants. By proving that complex hallucinogenic pathways can be completely rebuilt from scratch, scientists have unlocked what plant biologists view as massive opportunities to create “green factories” that grow new compounds in greenhouses.
Ultimately, this research points toward a fundamental shift in how we manufacture psychiatric medicine. The next breakthrough treatment might not be synthesized using complicated processing steps and hazardous reactants that generate chemical waste. Instead, it could be simply watered, nurtured, and grown right out of the soil.
The study is published in the journal Science Advances.