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Synthesis and Characterization of 5‑MeO-DMT Succinate for Clinical
Use
Alexander M. Sherwood,* Romain Claveau, Rafael Lancelotta, Kristi W. Kaylo, and Kelsey Lenoch
Cite This: ACS Omega 2020, 5, 32067−32075 Read Online
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ABSTRACT: To support clinical use, a multigram-scale process
has been developed to provide 5-MeO-DMT, a psychedelic natural
product found in the parotid gland secretions of the toad, Incilius
alvarius. Several synthetic routes were initially explored, and the
selected process featured an optimized Fischer indole reaction to 5-
MeO-DMT freebase in high-yield, from which the 1:1 succinate
salt was produced to provide 136 g of crystalline active
pharmaceutical ingredient (API) with 99.86% peak area by high-
performance liquid chromatography (HPLC) and a net yield of
49%. The report provides in-process monitoring, validated
analytical methods, impurity formation and removal, and solid-
state characterization of the API essential for subsequent clinical
development.
■ INTRODUCTION
Recently, interest has increased in understanding the clinical
include the intensity of mystical experience occasioned by the
psychedelic, the context in which the session was conducted
applications of psychedelic, entactogenic, and dissociative (known as set and setting), the dose at which the drug is
psychoactive drugs, such as psilocybin (1), DMT (2), LSD administered, psychological flexibility, connectedness, emo-
(3), MDMA (4), or ketamine (5) in combination with tional breakthrough, and increased neural entropy.1,7− 10
5-MeO-DMT (6) is a tryptamine natural product most
psychotherapeutic support to promote improved mental health
1,2 commonly identified as the primary psychoactive component
conditions (Figure 1). In particular, research has indicated
of the parotid gland secretions of Incilius alvarius, the Sonoran
favorable results in treating post-traumatic stress disorder
Desert toad (Figure 2).11 The alkaloid is also known to be
(PTSD), depression, end of life conditions, and anxiety-related
present in low concentrations in a variety of plants, shrubs, and
disorders.1,3− 6 This research shows that while the therapeutic
mechanisms are not fully understood, some factors have been
correlated with improvement in mental health. These factors
Figure 2. (Left) I. alvarius (image courtesy of Holger Krisp, Ulm,
Germany, 2011 under CC BY 3.0) with the parotid gland highlighted.
(Right) Structure of 5-MeO-DMT (6).
Received: October 19, 2020
Accepted: November 16, 2020
Published: December 2, 2020
Figure 1. Structures of clinically explored psychedelic, entactogenic,
and dissociative psychoactive drugs.
© 2020 American Chemical Society https://dx.doi.org/10.1021/acsomega.0c05099
32067 ACS Omega 2020, 5, 32067−32075
ACS Omega http://pubs.acs.org/journal/acsodf Article
seeds. Human consumption of this material for its psychoactive MeO-DMT appears to be pharmacodynamically unique
properties has been reported in the scientific literature for at compared to previous clinically studied psychedelics and
least 100 years.12− 15 Although it has been historically could provide a useful comparator in contemporary controlled
suggested that 5-MeO-DMT may have been used by clinical studies with psychedelics to better understand their
indigenous cultures,11 there is no known documentation to mode of action.
support this assertion. Due to the recent discovery of high Unlike psilocybin, psychedelic tryptamines such as DMT
concentrations of 5-MeO-DMT in I. alvarius secretions, there (2) and 5-MeO-DMT (6) are subject to rapid first-pass
has been a reported increase in its recreational and spiritual metabolism by monoamine oxidase and are therefore not orally
use.11,16,17 Recent evidence has indicated the presence of 5- active. When consumed parenterally, they produce a
MeO-DMT existing in concentrations between 20 and 30% of significantly shorter duration of action, typically less than 1
total dry weight or approximately 200−300 mg of 5-MeO- h, compared to the 5−8 h duration of e ects produced by
DMT per dried gram of toad secretion,17 concentrations much psilocybin. The shorter duration of action may help in
higher when compared to plant-derived sources of 5-MeO- reducing the amount of time a patient would spend in the
DMT. clinic. Additionally, compared to DMT, 5-MeO-DMT is
Anecdotally, and suggested by research over the last 5 years, known to be approximately 10− 20 times more potent in
