Inside the Quest to Make “Plant-Based” MDMA

Plant-based MDMA. If this sounds like something dreamed up in a stoned haze by a couple of psychedelic enthusiasts, that’s because… it is. After all, MDMA is a synthetic substance invented in 1912 by German pharmaceutical company Merck, and even as the drug jumped from psychotherapy offices to rave dancefloors, it has remained squarely in the public consciousness as a pill or powder concocted by chemists in a lab, rather than something natural that’s grown in a field. 

But MDMA is a relatively simple molecule that can be synthesized in a variety of ways. Most methods begin with safrole, an organic compound used to make cosmetics, pesticides — and until it was banned in 1960 by the FDA — even food flavoring like root beer. “It’s basically a two-step synthesis if you start with safrole,” said David E. Nichols, a longtime psychedelic chemist who supplied the MDMA used for the Multidisciplinary Association for Psychedelic Studies’ (MAPS) Phase I and II clinical trials. When Nichols made a batch of MDMA in 1985, he was able to order a big bottle of safrole from a chemical supply company without any legal restrictions. But safrole oil is now a tightly controlled List I Chemical under federal law precisely because of its use in the illegal manufacturing of MDMA. 

Still, safrole is found in the sassafras tree and many other plant species that grow abundantly around the world. So if someone with enough capital and ingenuity felt up to the task, they could work with (and around) existing laws to figure out a way to make MDMA from plants — which is exactly what venture capitalist Ford Smith decided he wanted to do. In 2021, Smith was sitting on a couch at his home in Austin, Texas, getting stoned with Rick Doblin, founder of MAPS and leader of the movement to legalize MDMA. Smith had recently learned that MDMA could be derived from plants, and this surprising discovery played into his longtime passion for regenerative and organic plant medicine supply chains. Through his VC firm Ultranative, Smith has invested in several psychedelic and cannabis companies, including a non-profit called ECCO for pesticide-free cannabis. 

The MDMA that MAPS used for its latest, Phase III clinical trials used 5-bromo-1,3-benzodioxole as its starting material, according to a spring 2020 MAPS Bulletin. “Its precursor, 1,2-methylenedioxybenzene, is likely synthesized in one step from catechol, a bulk commodity chemical made in thousands of tons per year from crude oil,” the bulletin stated. This process makes the synthesis of MDMA more complicated, adding several more steps than if you were to begin with safrole. “It’s all the same bus route,” Nichols explained. “[MAPS’ current method] just goes back to the beginning of the bus route; they’re making it from scratch.” Nichols speculated that this commercial chemical method using catechol, which can be bought in bulk as an industrial chemical, is both a scalable and patentable system and, therefore, more desirable if MDMA is legalized one day. 

Knowing that MDMA can be made from nature, Smith decided to pitch Doblin an idea he’d been sitting on: A version of MDMA derived from organic plants harvested by fair-trade farmers. “Would you be interested in that?” Smith asked Doblin. Smith says Doblin chuckled and encouraged him to figure it out, suggesting that he might even one day be able to sell his “plant-based MDMA” to Lykos Therapeutics, the for-profit pharmaceutical arm of MAPS that is currently vying for the FDA approval of MDMA. “So I started spending money,” Smith said. 

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