Berman et al., Sci. Adv. 12, eaeb3034 (2026) 1 April 2026

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P L A N T S C I E N C E S

Complete biosynthesis of psychedelic tryptamines from

three kingdoms in plants

Paula Berman1,2

*†, Janka Höfer 1

†, Herschel Mehlman1

, Efrat Almekias-Siegl1

, Olga Khersonsky 3

,

Younghui Dong 4

‡, Uwe Heinig4

, Liron Sulimani5

, Let Kho Hao1,2

, Shahar Cohen2

, Yoav Peleg4

,

Sagit Meir1

, Ilana Rogachev 1

, David Meiri5

, Sarel J. Fleishman3

, Asaph Aharoni1

*

Psychedelic indolethylamines with therapeutic potential are naturally produced in plants, fungi, and animals.

Here, we elucidated the complete N,N-dimethyltryptamine (DMT) biosynthetic pathway in hallucinogenic plant

species traditionally used in shamanic rituals for spiritual healing. Leveraging the similarities in their chemical

structures, we reconstructed in one plant assay the full biosynthetic pathways of five renowned natural psyche-

delics; psilocin and psilocybin found in mushrooms, DMT from plants, and bufotenin and 5-methoxy-DMT secret-

ed by the Sonoran Desert toad. We further engineered halogenated analogs of these molecules, which do not

naturally occur in plants and exhibit prospective therapeutic potential for psychiatric conditions. Blending cata-

lytic functions across the tree of life, coupled with metabolic engineering guided by rational protein design of

mutant enzymes, enabled substantially more efficient in planta production of the indolethylamine components.

This work establishes a versatile platform for concurrent biosynthesis and diversification of psychoactive indole-

thylamines, paving the way for their production in plants.

INTRODUCTION

For thousands of years, psychedelic substances have been used by

indigenous cultures as entheogens in rituals intended to induce al-

tered states of consciousness for spiritual and therapeutic purposes.

Psilocybin-containing mushrooms were central to ancient Aztec

ceremonies (1), while N,N-dimethyltryptamine (DMT), the pri-

mary psychoactive component of ayahuasca, has long been used

in traditional Amazonian rituals. This ceremonial brew combines

Psychotria viridis (a natural source of DMT) with Banisteriopsis caapi,

which provides β-carboline monoamine oxidase (MAO) inhibi-

tors that render DMT orally active (1, 2). Similarly, 5-methoxy-N,N-

dimethyltryptamine (5-MeO-DMT), found in the secretion of

the Sonoran Desert toad (Incilius alvarius) and in several plant spe-

cies, is thought to have been used ceremonially by indigenous

groups in northern Mexico (3). 5-MeO-DMT has been described

as the most potent DMT analog, being about 4- to 10-fold more po-

tent than DMT in humans and is known to induce psychedelic ex-

periences that are distinct from those of DMT (4). Knowledge of

the traditional use of these molecules has fueled contemporary

therapeutic interest in psychedelics as treatments for neuropsychiat-

ric conditions.

Recent studies have shown that classical indolethylamine psy-

chedelics promote neuroplasticity and modulate serotonergic cir-

cuits, primarily through 5-HT 2A receptor activation (5–7). These

compounds have demonstrated therapeutic potential for depression,

anxiety, posttraumatic stress disorder, and addiction (5–8), with psi-

locybin receiving Food and Drug Administration Breakthrough

Therapy designation for major depressive disorder in 2019 (6, 7).

Although widely considered hallucinogenic, psilocybin itself func-

tions as a prodrug, undergoing enzymatic dephosphorylation in the

digestive tract and liver to produce psilocin, the active compound

responsible for its psychoactive effects. DMT is produced by a broad

range of plant species and, in low abundance, by certain animals (2).

When administered via smoking or intravenous injection, it pro-

duces rapid and intense psychoactive effects that typically peak with-

in 5 min and subside within 30 min, due to rapid metabolism by

MAO enzymes in the liver. Coadministration with MAO inhibitors

can extend the half-life of DMT in vivo (2). The traditional use of

ayahuasca exemplifies how combining compounds from different

sources can enable oral activity; however, such combinations require

carefully balanced dosing to mitigate adverse effects associated with

MAO inhibition (9).

The expanding clinical interest in psychedelics as therapeutics

has sparked the need for scalable and versatile production platforms

and structural diversification (10, 11). Traditionally, the supply of

psychedelics relies on natural producers, mainly plants, fungi, and

the Sonoran Desert toad. Harvesting these organisms for their psy-

choactive compounds raises ecological and ethical concerns, being

increasingly threatened by habitat loss and overexploitation (12).

While synthetic routes for these compounds are available and, in

some cases, relatively straightforward, they still require compound-

specific reactants, can lead to unwanted intermediates and prod-

ucts, and require several processing steps (2, 13, 14). Biocatalys