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. 

First, he hired the pharmaceutical consulting company Pharmazone to scour the Amazon for plant species that could yield commercially viable quantities of safrole. The team came back with an herbaceous plant called Piper hispidum, also known as “Jamaican pepper” or “pimento longa,” that grows natively in Central and South America and is used locally as a traditional medicine to treat diseases, inflammation, and digestive issues. Smith’s team then linked him with a farmer named Leandro Martins, whose family owns land in Acre, a state in northwestern Brazil that borders Peru and Bolivia, where Piper hispidum grows abundantly. 

“Nobody cares about this plant,” Martins told me via a translator from his apartment in Sao Paulo. “In Acre, farmers kill pimento longa because it’s considered undesirable, and they prefer to grow other plant species that are more lucrative.” Until 2014, Martin’s father grew Piper hispidum on his property, he explained, and the family had sold it to pharmaceutical companies interested in using it as an antidepressant. Their research was unsuccessful, however, so the sales were discontinued. Additionally, the plant is challenging to cultivate on a large scale because it must be pruned twice a year and requires costly irrigation throughout the year; growers also need a special license to export pimento longa, as it is controlled by Brazil’s federal police.

In 2015, a major flood in Acre destroyed Martins’ family’s farm. Now, the land continues to flood every year. Instead of reinvesting into their infrastructure, the Martins decided to go around Acre and ask other farmers not to destroy the plant, but sell it to them instead. In this way, they developed a network of small, local farmers — an aspect that was especially appealing to Smith, who wanted to work with a plant that could be farmed or harvested by Indigenous communities.  

“In the Amazon, there’s a history of biopiracy,” Smith said. “Pharmaceutical companies send their chemists on these R&D missions where Indigenous elders tell them what plant species [cure] certain ailments. They take notes, then fly back to a biotech hub where they patent a small molecule. They never tie any of their profits back to the Amazonian Indigenous communities, which actually created the intellectual property.”

Martins is not Indigenous, but Acre is known for its large Indigenous population, including the Shawãdawa, Yawanawá, Yaminawás, and Katukinas people. “Some farmers might have Indigenous features, but they aren’t necessarily living in a tribe,” said Martins, explaining that these farmers were happy to open up their lands in the Amazon forest to sell the plant to Martins because it brings them extra income year-round. After transporting the material back to their property, Martins’ family then distills the plant into safrole oil in an on-site facility and sells the oil to buyers like Smith. 

Next, Smith imported the safrole oil to a lab in Austin with a special DEA license that allows it to manufacture Schedule I substances; eight months of development later, that lab was able to turn the safrole oil into a final product of 99.9% pure MDMA. Smith had thus succeeded in creating a proof of concept for his fair-trade, plant-derived MDMA supply chain. The real question is: What was the point of going through all of this money and effort? A better high? A more environmentally sustainable product? A version of MDMA that might be more appealing to a public that is just starting to warm up to the idea of legal psychedelics? 

“This is actually a really good idea from a branding perspective,” argued Smith. If Lykos is able to push the FDA legalization of MDMA forward, they will have an exclusivity period of about six years, he explained. After that period, Pfizer and other big pharmaceutical companies could make their own competitive, generic versions of MDMA. MAPS and Lykos’ current version of MDMA used in their Phase III trials is likely made from catechol, an industrial chemical that is also naturally derived, but takes several more steps to synthesize than starting from safrole oil. Smith is thus placing his bets on being able to convince Lykos that switching over to his more sustainable, fair trade, and ethical version of MDMA will give them a competitive market advantage over other pharmaceutical companies’ generic versions. 

Compared to psilocybin mushrooms or cannabis, Doblin pointed out, MDMA lacks an “entourage effect,” where different compounds work together to create greater benefits or a different kind of high. “You’re extracting precursors [from a natural source], then chemically modifying them to get MDMA,” Doblin said. Regardless of which precursors the chemists are starting with, the end product made in these labs is still the same compound: high-purity MDMA. “It’s the placebo effect,” said Doblin. “Plant-based MDMA is no different in any way at all, but people think ‘natural’ is better.” 

“Generally, the public has been fearful of chemicals, and there’s a resurgence of people wanting to get back to nature,” agreed Sue Sisley, a researcher who is conducting the first human trials using whole natural mushrooms. (Research up to date has relied on synthetic versions of the psilocybin molecule.) But, Sisley pointed out that the placebo effect is an influential variable and, in some cases, might even be helpful for therapeutic outcomes. “If people believe that natural is better than synthetic, it might also increase the efficacy and longevity of the medicine,” she said. 

Smith and his allies also hope that another possible advantage of rebranding MDMA as a “natural” medicine is that achieving reform might be easier. In recent years, Oregon and Colorado have established legal frameworks for plant-based-assisted therapies and decriminalized the possession of mushrooms and natural psychedelics at the state level. Meanwhile, city councils in places like Oakland, Santa Cruz, and Ann Arbor have passed resolutions to make natural psychedelics the lowest priority of local law enforcement. This effectively prevents police from using funds to pursue people for possessing or using them.

“We’ve learned from polling like we did in Oregon [and]Colorado that we can pass plant-based medicines, but synthetics are a bridge too far,” said David Bronner, CEO of Dr. Bronner’s soap and a major advocate in the psychedelic movement. “MDMA derived from natural sources just sounds a lot better, even though it’s not anything different from a safety perspective,” he said. “But just for electoral voting reasons, that’s a way better framework.” 

Still, there’s a long way to go before Ford’s dream of fair-trade, sustainably-grown MDMA can become a reality. According to Martins, he would need to go back to planting the Piper hispidum plant himself to reach the global scale that Smith is promising, which would require buying more land, hiring specialists, and investing heavily in irrigation and transport. In 2020, Martins quoted Smith 1.5 million reais (USD $256,764.37), which is probably much higher after adjustments for inflation. The hope that Lykos will buy the fair-trade version and psychedelic activists will get measures on future ballots or get resolutions passed by city councils also remains purely within the realm of speculation. 

Yet Martins says that the piper plant can benefit the environment. It flourishes in cattle lands that have been deforested by Brazil’s powerful agriculture industry and thus has great potential for reforestation. Given that the black market ecstasy trade has also decimated forests in Cambodia, where the rare safrole-producing Mreah Prew Phnom tree grows, threatening one of the last rainforests in Southeast Asia and polluting its rivers, Martins’ sustainable approach also offers a more environmentally conscious method of cultivating safrole-producing plants for MDMA.

More important than the marketing language used to rebrand MDMA, however, is how much this process is going to cost compared to current ways of manufacturing the drug legally on a mass scale. “That’s going to be the real driving force,” Doblin said. Furthermore, what will really drive sales if and when MDMA is legalized is the data and stories of people who’ve been through the therapy and benefited from it, Doblin continued. “If you’re trying to help people feel more comfortable with MDMA, the preparation, the integration, and all that is way more important than this idea.” 

For now, the notion of plant-based and fair-trade MDMA is just a conversation by psychedelic movement insiders that paints a rosy picture of what a sustainable plant medicine supply chain could be. “Right now,” said Bronner, “it’s just a fantasy.” 

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