Psilocybin Production for Research and Therapy

By Dr Martin Williams

Psilocybin is rightly regarded as the prototypic “classic” psychedelic for several reasons. Notably, it is
a natural product found in Psilocybe species and in some other genera of mushroom; it has a close
chemical and pharmacological similarity to the neurotransmitter, serotonin, and has a benign
toxicology thanks to its metabolism and excretion via similar pathways; it is typically orally active in
small (milligram) doses; and, primarily through the action of psilocin at serotonin 5-HT 2A/2C receptors,
it reliably elicits an experiential response of therapeutically useful duration in a dose-dependent
manner. On this basis, psilocybin has attracted increasing attention for its potential therapeutic applications,
generally as an adjunct to psychotherapy. The mental health conditions most amenable to treatment
appear to be mood disorders including depression, anxiety, obsessive-compulsive disorder and
problematic substance use, and – as most of us are well aware – research has accelerated
dramatically in recent years.

Although psilocybin may be administered perfectly effectively in its natural form, through ingestion
of (usually dried and often powdered) mushroom material, there are several factors that complicate
the use of mushrooms in the clinical context. These factors include challenges in achieving consistent
psilocybin doses, the difficulty in ensuring mushrooms conform to globally accepted standards of
purity and quality control, the sensitivity of some people to other compounds commonly present in
mushrooms (including in Psilocybe species), and reluctance of some people to consume mushrooms
for cultural, personal or other reasons.

Consequently, research has been underway to optimise the production of pharmaceutical grade
psilocybin for clinical use, and thankfully the field already has a rich history that started with the full
synthesis of psilocybin by Dr Albert Hofmann – the Swiss creator of LSD – around 1958. Here is a brief
overview of psilocybin production methods for research purposes.

1. Synthetic Production: As was established by Albert Hofmann in the 1950s, psilocybin can be
produced in a laboratory setting by applying a sequence of well-established synthetic techniques to
a group of relatively simple – though not necessarily inexpensive – precursor compounds. This
approach allows for precise control over the purity and ultimately the dosage of the compound,
which is critical for scientific validity in research trials and is mandated in clinical practice. However,
this method can be costly and requires specialised expertise. Synthetic protocols have been refined
over the last two decades, initially by Professor David Nichols & colleagues and more recently by
chemists associated with Usona Institute and Compass Pathways, and although the achievement of
high synthetic yields remains challenging, chemical synthesis has been used to produce the majority
of psilocybin batches used in clinical research worldwide.

2. Mushroom Cultivation: Another method involves growing psilocybin-producing mushrooms in
controlled environments, drawing on wisdom in mushroom cultivation that has accumulated over
centuries and is widely applied in the production of many culinary and medicinal mushroom species.
This approach typically utilises species such as Psilocybe cubensis or P. semilanceata. Fungal
cultivation can be more cost-effective than synthetic production and may yield a more diverse array
of compounds present in the mushrooms. However, it requires careful attention to environmental
conditions and may be subject to variability in psilocybin content between batches. There are many

Psilocybe mushroom start-ups worldwide, including at least a couple in Australia, but unfortunately
both establishment and operating costs may present significant challenges to long-term viability.

3. Extraction from Mushrooms: Psilocybin can also be extracted from mushrooms, along with its
close biochemical analogues, baeocystin and norbaeocystin. This method involves grinding dried
mushrooms and extracting the target compounds using solvents such as ethanol or methanol. The
extract can then be purified to obtain psilocybin for research and clinical purposes. While extraction
of psilocybin with its analogues from mushrooms can be relatively straightforward, it may result in
lower yields compared to synthetic production or fungal cultivation. The extra step of purification,
should the aim be to generate pure psilocybin, represents a very significant further step in terms of
processing complexity, and hence infrastructure, time and cost.

4. Biotechnological Approaches: Some researchers are exploring biotechnological methods for
psilocybin production, such as microbial fermentation or genetic engineering of fungi to enhance
psilocybin biosynthesis. The breakthrough occurred around 2010 when Professor Dirk Hoffmeister
and colleagues in Germany elucidated the biosynthetic pathway, including the enzymes responsible
for the key biochemical steps of psilocybin synthesis in Psilocybe cubensis, and – crucially – the genes
coding for those proteins. They succeeded in producing significant quantities of psilocybin in a model
protein expression system using the fungus, Aspergillus nidulans. The approach was developed
further and adapted to generation of the biosynthetic enzymes in standard bacterial (Escherichia
coli) and bakers’ yeast (Saccharomyces cerevisiae) expression systems; the approach using yeast
offers the significant advantage of requiring glucose as a basic precursor of psilocybin, rather than
the 4-hydroxyindole required by other systems. These biotechnological approaches have the
potential to streamline production processes and increase yields with excellent economies of scale –
particularly as analogous approaches are already employed for the production of pharmaceutical
compounds worldwide – but are still in the early stages of development.

Overall, the choice of psilocybin production method for research and clinical applications depends
on factors such as cost, scalability, purity requirements, and the specific objectives of the study. Each
method has its advantages and limitations, and researchers, clinicians, and ultimately the
community, must carefully consider these factors when planning a medical future involving
psilocybin. Additionally, adherence to regulatory guidelines and ethical considerations is essential to
ensure the safe and responsible use of this psychedelic compound in research and therapeutic
settings.

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