Chemically synthesized psilocybin has a long history, and there has been a lot written and discussed about the differences and similarities between natural psychedelics and synthesized psychedelics, mostly relating to psilocybin.
“I know that the main differences are really political, not pharmacological,” Rick Doblin, founder and executive director of the Multidisciplinary Association for Psychedelic Studies (MAPS), said during a panel at the 2022 Wonderland psychedelics conference held recently in Miami. “So people have this romantic idea about that, if it’s from nature, it’s good. If it’s from a lab, like MDMA or LSD, it’s bad.”
Synthesizing psilocybin for use in clinical trials really is about controlling the amount of the psilocybin content. Mushrooms are living organisms that have a natural variability, even when cultivated in controlled conditions, according to a study of psilocybe cubensis, the most commonly known and used psilocybin mushroom by researchers today.
Benefits of synthetic psilocybin
The study showed that mushrooms grown in a controlled culture had a level of the psilocin that was generally zero in the first fruiting of the mushroom from a given culture. That level of psilocin reached a maximum by the fourth fruiting.
The same study found that samples from outside sources had psilocybin/psilocin levels that varied by a factor of 10 – or more – from one collection to the next.
That means that the handful of natural magic mushrooms you get from the black market may be much stronger than other mushrooms from the same batch — and you won’t know that until about an hour into the experience.
That’s not a good thing for any clinical trial researcher trying to demonstrate reproducible outcomes using this complex and variable compound.
There are also considerations regarding growing and harvesting psilocybin mushrooms with limited economic feasibility due to the slow production process and high product variability, according to another study.
All these reasons are why the current production of the psilocybin active pharmaceutical ingredient for clinical trials is achieved through chemical synthesis, which despite recent advancements still requires a complex, multistep synthesis process with low yield and high production costs.
Synthetic psilocybin is derived from benzene, a fossil fuel. It is also very environmentally hazardous, and the chemical synthesis methods generate toxic waste. But companies have already taken steps to find new, more sustainable methods.
For example, Octarine, a synthetic biology company developing cannabinoid and psychedelic therapeutics, found a way to synthesize psilocybin in brewer’s yeast. Other researchers have discovered a way to make synthetic psilocybin using a type of fermentation process.
Abraham Dreazen, CEO & founder of Nextage Therapeutics and Imio Life, noted that it has to be remembered that MDMA is not psilocybin, and psilocybin is not ibogaine, and ibogaine is not LSD.
“Some of them are lab made, some of them are plant made. What we’ve seen is there’s a separation now,” he said on a panel at last month’s Wonderland conference. “So if it’s plant-based, it’s one regulatory agency. If it’s synthetic made, it’s a different regulatory agency. And there’s a lot of back and forth of who needs to deal with that hot potato.”
What a synthesized psilocybin can really mean is greater and broader access. “My mother can take a pill, but she’ll never be convinced to take a psychedelic unless the doctor says take the psychedelic,” Doblin said during the same panel. “So most Westerners are used to going to a hospital or going to a doctor setting and taking a pill. And if you can get that (psychedelic) dosage correct and make it in a synthetic way, it makes it way more viable to a larger community.”
As the discussion rages on, there are outlier issues. For example, anyone can make their own synthetic psilocybin homebrew in biologically relevant quantities using a recombinant E. coli strain. In less than two days, one study reported, researchers successfully produced approximately 300 milligrams per liter of psilocybin under simple conditions with easily sourced equipment and supplies.
This form of synthetic psilocybin likely has made its way into the black market already – preceded by a cautionary tale of the damage done by synthetic cannabinoids introduced by black market makers in 2004.
Some companies are deciding to forego synthetics for now and forging ahead with natural psilocybin production for research. For example, Filament Health developed extraction, purification, standardization, and stabilization technologies to extract the psychoactive alkaloids from the magic mushroom and standardize them to a precisely known quantity. Filament announced that these natural psychedelics have already been approved for various clinical trials, including a Phase 2 microdose study for depression at the University of Toronto; a Phase 1 study for psilocin at the University of California San Francisco; and a Phase 1 study for chronic pain and depression with EntheoTech Bioscience.
Other issues remain to be settled.
But there are other concerns about the safety of a natural psilocybin mushroom. The consumption of whole mushrooms may affect people with fungal allergies, and there could be a variability in phenylethylalanines in mushrooms, which are structural relatives to amphetamines and may induce tachycardia, nausea, and anxiety.
For now, there are a handful of companies making progress by developing and using synthesized psilocybin. Among them are Compass Pathways, which is developing Comp360 for treatment-resistant depression, with recent clinical trial results published in the New England Journal of Medicine; and Psygen, which is doing large-scale synthesis of psychedelic compounds in a production area of 6,000 sq. ft. where they manufacture, sale, import, export, and analyze LSD, DMT, MDMA, psilocybin, and mescaline.
“I think it’s ‘and’ as opposed to ‘versus’ when it comes to natural and synthesized substances,” Dr. Amy Reichelt, the director of neuropharmacology at Cybin, said while on the Wonderland panel. “There are so many medicinal compounds going through phase one to phase four clinical trials have been derived from natural products. That’s across the board in terms of pharmacology and drug development.
“So, I think that we learn so much from nature and the powerful compounds that are contained in our plants and then bring them it into synthetic, where we are refining certain molecules and then being able to test these in a different state for a different indications.”