Synthetic Psychedelics May Soon Replace Your Shrooms

Scientists are engineering microbes that can produce the hallucinogen psilocybin

TThe 1976 book Psilocybin: Magic Mushroom Grower’s Guide is a classic manual for raising the illegal hallucinogen. But while its whimsical gardening tips — “mushrooms are fully dried when hard to the touch, like crackers” — are still relevant today, they may not be for long. That’s because earlier this month researchers announced they had genetically engineered a strain of a ubiquitous bacterium that can pump out the potent psychedelic compound in magic mushrooms, called psilocybin, without using the fungus at all.

The team took genes related to psilocybin synthesis, plucked from the genome of one psychedelic mushroom species, and inserted them into the DNA of Escherichia coli, a common bacteria that lives in the human body. The new recombinant strain produced psilocybin as it grew. Already medical compounds like insulin and human growth hormone are made through similar synthetic biology methods, and the new findings open the possibility that psilocybin could also be produced en masse without relying on farms of whole mushrooms or costly chemical synthesis.

There’s good reason to try. Psilocybin has proven its worth in early clinical trials as a powerful treatment for anxiety, depression, addiction, and post-traumatic stress disorder, slowly shedding its association with the unruly counterculture of the 1960s. If its success in psychological studies continues, psilocybin could potentially treat millions of people who don’t respond to traditional pharmaceuticals.

Industrial production of psilocybin is already in the works. Startups like Silicon Valley venture capitalist Peter Thiel’s COMPASS Pathways have begun synthesizing the compound according to the U.S. Food and Drug Administration’s stringent Good Manufacturing Practice (GMP) regulations. The chemically synthesized psilocybin can qualify for Phase 3 clinical trials in the U.S. and EU, but following those rules is prohibitively expensive, hampering research efforts.

While the main focus is the pharmaceutical market — meaning for use treating mental illness — Jones notes that there’s interest from “players in potential future recreational market” as well.

However, if J. Andrew Jones and his team at Miami University in Ohio can show that their recombinant strain of psilocybin-producing Escherichia coli can cheaply scale up production, it could change the face of psilocybin research and pharmaceuticals. In their recent Metabolic Engineering paper, Jones and his colleagues called their work a “significant step towards demonstrating the feasibility of industrial production of biologically-derived psilocybin.”

Jones tells OneZero that his team is “currently in talks with several potential investors that are looking to push this technology into industrial-scale production for a variety of markets.” While the main focus is the pharmaceutical market — meaning for use treating mental illness — Jones notes that there’s interest from “players in potential future recreational market” as well.

To produce psilocybin, E. coli needs something to start with. Because of the particular enzyme pathway they inserted into their strain, Jones’ team began with 4-hydroxyindole, which is relatively expensive at about $218 for a gram. (A team that genetically modified the fungus Aspergillus fumigatus to make psilocybin in 2017 began with tryptophan, a natural amino acid that’s much cheaper at roughly $15 per gram.)

The culturing process is akin to brewing beer. The engineered E. coli are put into a large vat called a bioreactor that maintains the temperature, pH, nutrient supply, and oxygenation needed for the culture to grow and thrive, all the while pumping out the psilocybin.

Despite its higher costs, Jones’ team produced 10 times as much psilocybin as the Aspergillus group. And if research and pharmaceutical demand for the magic in magic mushrooms does increase, as experts suggest, that ability to scale up will prove vital.

The emerging psilocybin industry’s fate rests on the success of the ongoing clinical trials and, of course, the future legal status of the drug. Sudhakar Selvaraj, MD, PhD, and an assistant professor of psychiatry at UTHealth in Houston who is working on a global Phase 2 trial of psilocybin’s ability to relieve treatment-resistant depression, admits it’s early days for the research, but believes it’s worth investigating how the hallucinogen can complement therapy.

“I’m not sure how beneficial [industrial production] is going to be for us until we know that it works in the regular clinical trial,” Selvaraj tells OneZero.

The clinical trial Selvaraj is working on, which received an FDA Breakthrough Therapy designation this year, was funded by Thiel’s COMPASS Pathways. Chief communications officer Tracy Cheung tells OneZero that the company was interested in new methods of psilocybin production, but notes “they don’t have an impact on what we do as we already have access to GMP psilocybin for our trials.”

Right now a bigger issue than how psilocybin can be produced is whether it can be legally used at all. The FDA considers psilocybin a Schedule I drug, which means it has no currently accepted medical use and a high potential for abuse, and cultivation, sale, or possession are considered grounds for arrest. But that could soon change. Last year, researchers at Johns Hopkins and the University of Alabama called for the drug’s rescheduling in a piece in the journal Neuropharmacology, arguing that it belonged in Schedule IV along with most other pharmaceuticals.

“You know, it’s probably easier to go on the black market and buy mushrooms.”

As synthetic biology makes psilocybin easier to produce, however, it may become harder to control access to the chemical — or for that matter, other scheduled drugs. In 2015, Tania Bubela, a biotech policy expert who serves as a faculty dean at Simon Fraser University in British Columbia, co-authored a statement in Nature demanding regulations on such “home-brew opiates” in response to work by researchers who successfully engineered yeast to produce the highly addictive painkiller morphine without opium poppies. “In principle,” Bubela and her co-authors wrote, “anyone with access to the yeast strain and basic skills in fermentation would be able to grow morphine-producing yeast using a home-brew kit for beer-making.”

Bubela admits there’s a better case to be made for biomanufacturing psilocybin because it’s so expensive to synthesize chemically or derive from mushrooms, at least compared to the biosynthesis of opiates from poppies. “If [psilocybin] does eventually get market authorization for any number of conditions,” she continues, “then having the ability to manufacture at a rate that isn’t cost-prohibitive is important for everyone.”

Psilocybin production has come a long way since it was homegrown in Mason jars, tucked away in dark rooms. As the new field of synthetic biology develops, the same could someday be said of many drugs, illicit or not. “I like to think that metabolic engineering can, in theory, produce any chemical/drug,” says Jones. “We just need to first identify an enzymatic pathway capable of the biosynthesis, [which is] easier said than done.”

But for now, rigorous regulations and steep costs remain obstacles that only well-funded companies like COMPASS can overcome — along with perhaps the most ambitious home chemists. David Nichols, Ph.D., a retired Purdue University medical chemist who pioneered early psilocybin synthesis techniques, doesn’t recommend that they try.

“They’d really have to get sterile technique developed, probably have to get some special equipment, then they’d have to figure out how to get these organisms,” he says. “They are not going to be something you can just probably order off the shelf.”

“You know, it’s probably easier to go on the black market and buy mushrooms.”

Editor, Medium Coronavirus Blog. Senior editor at Future Human by OneZero. Previously: science at Inverse, genetics at NYU.

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