Psychopharmacology

https://doi.org/10.1007/s00213-023-06517-1

REVIEW

5‑MeO‑DMT: An atypical psychedelic with unique pharmacology,

phenomenology & risk?
Haley Maria Dourron1 · Charles D. Nichols2 · Otto Simonsson3 · Melissa Bradley1 · Robin Carhart‑Harris4 ·
Peter S. Hendricks1,5

Received: 14 June 2023 / Accepted: 29 November 2023

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2023

Abstract
5-MeO-DMT is a tryptamine being developed as a potential antidepressant that may display a distinct therapeutic mecha-
nism due to its unique pharmacology and subjective effects compared to typical psychedelics. In this article, we parallel
the relatively distinct phenomenology and behavioral effects of the acute and post-acute effects of 5-MeO-DMT to those
induced by epileptiform activity, particularly in instances within epileptogenic zones of the temporal lobes. This is done by
reviewing aberrant 5-HT1A receptor functioning in epilepsy, noting that 5-MeO-DMT has notable 5-HT1A receptor agonist
properties—and then comparing the acute behavioral and subjective effects induced by 5-MeO-DMT to those that occur
in seizures. It might be that 5-MeO-DMT's therapeutic mechanism is partly mediated by evoking temporary epileptiform
activity, suggesting a similarity to electroconvulsive therapy. It is also noted that “reactivations,” the sudden re-experiencing
of drug effects common after 5-MeO-DMT but not after typical psychedelics, may suggest that 5-MeO-DMT produces
recurrent epileptiform activity. Overall, this review indicates that further evaluation of 5-MeO-DMT's unique mechanisms
in research settings and among naturalistic users are warranted.

Keywords 5-MeO-DMT · Psychedelics · 5-HT1A Receptors · Flashbacks · Seizures

Introduction Sonoran Desert toad) that is typically vaporized and inhaled

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is
a tryptamine found in a number of plant species as well
as in the defense secretions of the Incilius alvarius (Colo-
rado River toad; previously known as the Bufo alvarius or
This article belongs to a Special Issue on Psychedelics 2024.
* Haley Maria Dourron
hdourron@uab.edu
1
Drug Use & Behavior Lab, Department of Health
Behavior, School of Public Health, University of Alabama
at Birmingham, Birmingham, AL, USA
2
Pharmacology & Experimental Therapeutics, LSU Health
Sciences Center, New Orleans, LA, USA
3
Department of Clinical Neuroscience, Karolinska Institutet,
Solna, Sweden
4
Psychedelics Division, Neuroscape, University of CA — San
Francisco, San Francisco, CA, USA
5
Department of Psychiatry, School of Medicine, University
of Alabama at Birmingham, Birmingham, AL, USA
by humans for recreational and spiritual use (Ermakova et al.
2022). It is a derivative of N,N-dimethyltryptamine (DMT),
a non-selective ligand at multiple serotonin (e.g., 5-hydroxy-
tryptamine, 5-HT) receptors, including the G-protein cou-
pled receptors 5-HT1A and 5-HT2A (Nichols and Nichols
2008). Unlike most psychedelics (Nichols et al. 2022), it is
not clear whether the principal pharmacological action of
5-MeO-DMT is via 5-HT2A receptor agonism. 5-MeO-DMT
does, however, display some characteristic psychedelic-like
subjective effects (Ermakova et al. 2022). Therefore, we
propose defining this substance as an ‘atypical’ psychedelic
in the current manuscript given its low affinity for 5-HT2A
receptors (907 inhibitory constant in nanomolar, Ki nM) and
its higher affinity for 5-HT1A receptors (3.0 Ki nM)(Halber-
stadt et al. 2012).
Unlike DMT, which has been used in as an admixture
in ayahuasca by the indigenous peoples of South America
(Malcolm and Lee 2018), and has been studied in humans
in within scientific contexts since 1956 (Szára 1956), it is
unclear whether there is a long-term history of human use
of 5-MeO-DMT (Ortiz 2022). A South American snuff

13
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known as ‘yopo’, composed of beans from Anadenanthera
peregrina, contains trace amounts of 5-MeO-DMT, however,
these amounts are probably too low to produce appreciable
psychoactive effects (Ott 2001). Despite some recent mis-
taken claims of indigenous use of Incilius alvarius (Ortiz
2022; Ott 1993), the history of vaporized use of toad secre-
tions appears to date only as far back as the 1970s (Oroc
2009; Ortiz 2022). 5-MeO-DMT is relatively rarely used
recreationally today, with an estimated 0.003% of a repre-
sentative US sample assessed in 2019 reporting lifetime
use (Sexton et al. 2020). This is approximately 33 times
rarer than reported lifetime use of DMT and 2833 times
rarer than reported use of psilocybin-containing mushrooms
in the United States (Sexton et al. 2020). Still, interest in
the compound is notably increasing online (Al-Imam et al.
2023), and in recent years researchers have begun to exam-
ine the effects of naturalistic use of the compound (Davis
et al. 2019; Ortiz Bernal et al. 2022; Uthaug et al. 2019,
2020a, b). Naturalistic use is drug use that occurs outside of
controlled medical or scientific research settings. It includes
use within retreats, ceremonial settings, and individual use
outside sanctioned settings.
Much like typical psychedelics, research examining
naturalistic use of 5-MeO-DMT has suggested that it has
the potential to decrease anxiety and depressive symptoms
(Ermakova et al. 2022) and a recent open-label trial sug-
gests that it may reduce symptoms of treatment resistant
depression for at least one week (Reckweg et al. 2023).
Additionally, because inhaled 5-MeO-DMT has a duration
of action between 15 and 30 min (Ortiz Bernal et al. 2022;
Siebert 2022), it has been proposed to be a more scalable
therapeutic relative to typical psychedelics. Oral psilocybin,
for example, lasts approximately six hours, thus requiring
extended observations in clinical settings, making it poten-
tially less practical to use (Lowe et al. 2021). Due in part
to these findings, there is substantial interest in develop-
ing 5-MeO-DMT-assisted therapy for treatment-resistant
depression (Reckweg et al. 2022, 2023). However, any
advantage over the short acting typical psychedelic, DMT,
which displays potential antidepressant-like action in mouse
models (Cameron et al. 2018), is unclear. Still, it is plausible
that differences in pharmacokinetics, pharmacodynamics,
subjective effects, and/or longer-term effects on psychologi-
cal and brain functioning could suggest a unique niche for
5-MeO-DMT as a therapeutic. If this is the case, the need to
delineate 5-MeO-DMT’s plausible distinctions compared to
typical psychedelics is crucial.
Despite the putative therapeutic potential of 5-MeO-DMT
(Davis et al. 2019; Reckweg et al. 2022; Uthaug et al. 2019),
it displays several properties that call for increased aware-
ness of its unique mechanism of action and phenomenologi-
cal profile. We posit that the unique phenomenology of the
acute and post-acute experiences elicited by 5-MeO-DMT
13
Psychopharmacology
parallel those induced by epileptiform activity, particularly
within the temporal lobes. It might be that 5-MeO-DMT’s
therapeutic mechanism of action is mediated by evoking
temporary epileptiform activity, somewhat similar to elec-
troconvulsive therapy (Chen et al. 2021; Husain et al. 2004;
Trifu et al. 2021) or some forms of meditation that also can
evoke epileptiform activity (Dennison 2019).
Overall, this suggests that further evaluation of 5-MeO-
DMT’s unique mechanisms and additional safety monitoring
in research settings as well as among naturalistic users are
warranted. Importantly, the novel hypothesis offered here is
not conceptualized as an attempt to hinder the development
of 5-MeO-DMT or psychedelics as therapeutics. Rather,
it is a call for further research investigating the potential
mechanisms of action of this emerging drug and potential
risk of all psychedelics. Moreover, if the current hypoth-
esis is supported, epileptiform activity would not preclude
5-MeO-DMT in the treatment of mental health conditions,
just as generalized seizures do not preclude electroconvul-
sive therapy in the treatment of mood disorders (Espinoza
and Kellner 2022). Rather, confirmation of epileptiform
activity associated with 5-MeO-DMT use would allow for
optimizing best practice to maximize efficacy and safety.
Of course, ruling out the current hypothesis also represents
a worthwhile endeavor that could also assist in elucidating
5-MeO-DMT’s mechanism.
Unique mechanism of action: Primary 5‑HT1A
receptor agonism & behavioral research
5-MeO-DMT’s high selectivity for the 5-HT1A receptors
over 5-HT2A receptors suggest 5-MeO-DMT may be distinct
from typical psychedelics, whose psychoactive effects are
known to be largely a product of 5-HT2A receptor agonism,
as has been shown in human studies (Becker et al. 2022;
Holze et al. 2020; Madsen et al. 2019; Preller et al. 2018).
It should be noted that many typical psychedelics, such as
LSD, display somewhat higher affinity for 5-HT1A receptors
over 5-HT2A receptors; however, as noted in Table 1. The
selectivity ratio of 5-MeO-DMT to 5-HT1A is substantially
higher than for other psychedelics (Besnard et al. 2012;
Rickli et al. 2016). 5-MeO-DMT’s significant agonism at
5-HT1A receptors is crucial, as agonism at 5-HT1A receptors
is often antagonistic to 5-HT2A receptor agonism (Carli et al.
2006; Celada et al. 2013). For example, on pyramidal neu-
rons, agonism of 5-HT1A receptors elicits inhibitory effects
whereas agonism of 5-HT2A receptors produce excitatory
effects (Araneda and Andrade 1991). Additionally, 5-HT1A
receptor agonism has been documented to inhibit the effects
of typical psychedelics, including psilocybin (Pokorny et al.
2016) and DMT (Strassman 1995) in humans. This suggests
that 5-MeO-DMT may produce distinct neurobiological
Psychopharmacology
Table 1  Human cloned receptor affinity for 5-MeO-DMT & typical
psychedelics
Ligand 5-HT1A 5-HT2A Ratio
(5-HT1A/5-
HT2A)
5-HT 3.3 9.8 0.34
LSD 2.2 0.7 3.5
DMT 450 131 3.4
5-MeO-DMT 1.9 207 .0091
Psilocin 49 25 1.96
The typical psychedelics, LSD, DMT, and psilocin (the active metab-
olite of psilocybin) have roughly equivalent selectivity for the 5-H1A
to 5-HT2A. 5-MeO-DMT has over 108 times greater selectivity for
the 5-HT1A receptor compared to the 5-HT2A receptor. This likely
suggests that 5-MeO-DMT produces distinct neurobiological effects
compared to other psychedelics. These data are from the Psychoac-
tive Drug Screening Program and reported in nanomolar (nm) (Bes-
nard et al. 2012)
and subjective effects compared to psychedelics with more
5-HT2A agonism (Araneda and Andrade 1991; Carhart-Har-
ris and Nutt 2017).
5-MeO-DMT is also distinct from many other substances
with predominant 5-HT1A agonism that are also effective
antidepressants and anxiolytics (Celada et al. 2013). Cur-
rently available anxiolytic and antidepressant medications
that are full or partial agonists at 5-HT1A receptors include
buspirone, vilazodone, and vortioxetine (Celada et al. 2013).
However, these do not have acute salient subjective effects
and require ongoing activation of 5-HT1A receptors through
regular use to have therapeutic effects whereas 5-MeO-DMT
is associated with therapeutic effects with only a single dose,
or several doses within a day (Davis et al. 2019; Reckweg
et al. 2023). This may in part be due to functional selectivity,
which is the ability of different ligands to produce differ-
ent signaling cascades making it possible that agonists may
vary widely in their physiological and psychological effects
(Newman-Tancredi et al. 2022).
5-HT1A receptors are one of the most widely implicated
receptors in the etiology of seizure disorders, with 5-HT1A
receptor agonists capable of producing both anti- and pro-
convulsant properties, depending on the type of seizure
examined and the ligand’s effects on intracellular signaling
cascades (Bagdy et al. 2007; Gerber et al. 1998; Gharedaghi
et al. 2014; González-Trujano et al. 2022; Martínez-Agu-
irre et al. 2020; Sałaciak and Pytka 2021; Theodore 2003).
Previous studies in humans have used decreases in 5-HT1A
receptor expression in the temporal lobe to identify epileptic
loci (Cai et al. 2023; Didelot et al. 2008; Savic et al. 2004;
Toczek et al. 2003). In mice, those lacking 5-HT1A recep-
tors also display a lower seizure threshold within the tem-
poral lobe and adjacent regions (Bagdy et al. 2007; Sarnyai
et al. 2000). In contrast, some drugs with anticonvulsant
properties can display inverse agonism at this receptor,
such as cannabidiol (CBD), which at high concentrations
acts as an inverse agonist at 5-HT1A receptors and reduces
­Gi/o signaling (Martínez-Aguirre et al. 2020). Tabernaemon-
tana arborea extract, which contains psychoactive alkaloids
ibogaine and voacangine, produces paroxysmal activity
in mice that is blocked by the relatively selective 5-HT1A
antagonist, WAY-100635, suggesting that the pro-convulsant
properties of T. arborea extract could be at least partially
due to agonism at 5-HT1A receptors (González-Trujano et al.
2022). Even in the invertebrate Drosophila melanogaster,
5-HT1A receptors have been implicated in seizure activity
(Roy et al. 2020). Together, these studies suggest that altera-
tions in the 5-HT1A receptor system may be implicated in the
development of seizures, although the exact relationship is
uncertain.
Animal behavioral research indicates that 5-MeO-DMT
can have proconvulsant properties. Seizures or seizure-like
behaviors have been documented in mice, rats, Guinea pigs,
sheep, and non-human primates after the administration of
5-MeO-DMT within controlled laboratory settings (Ahl-
borg et al. 1968; Ermakova et al. 2022; Gessner and Page
1962; Gillin et al. 1976; Grahame-Smith 1971; Lucki et al.
1984; Nielsen 1998). Conversely, decreases in behavioral
correlates of myoclonic seizures in response to photically-
induced seizures in cats during the acute effects of 5-MeO-
DMT have been reported (Wada et al. 1992). Despite this,
the same study found trend level increases in spontaneous
paroxysmal (e.g., seizure-like) EEG activity. However, it is
difficult to discern what relevance such studies might have
for human clinical studies, as the doses used often have
unclear relevance to human use.
Additionally, licking an Incilius alvarius has been
reported to cause seizures in pets (Weil and Davis 1994)
and in one instance in human children (Hitt and Ettinger
1986). In such instances, 5-MeO-DMT could plausibly be
absorbed via the oral mucosa (Ott 2001). Although Incilius
alvarius secretions contain additional alkaloids apart from
5-MeO-DMT, such as bufotenine, these secretions are still
20–30% 5-MeO-DMT by weight (Sherwood et al. 2020).
This, along with the laboratory research implicating 5-MeO-
DMT in seizures, this suggests that 5-MeO-DMT could pos-
sibly contribute to seizures in cases of accidental Incilius
alvarius secretion ingestion.
Furthermore, 5-HT1A receptors display a distinct receptor
density expression profile compared with 5-HT2A receptors
(Beliveau et al. 2017), which may support the notion that
5-MeO-DMT produces distinct subjective and physiologi-
cal effects. 5-HT2A receptors are densely expressed within
cortical regions, particularly in pyramidal neurons in layer
V (Beliveau et al. 2017; Carhart-Harris and Nutt 2017). In
contrast, presynaptic 5-HT1A inhibitory autoreceptors are
most densely expressed in brain stem regions such as the
13

dorsal raphe nuclei, and postsynaptic 5-HT1A receptors are
most densely expressed within the medial temporal lobes
and receptor expression is overall more localized (Beliveau
et al. 2017; Lanfumey and Hamon 2000).
The most prevalent foci for partial complex seizures are
within the medial temporal lobes (Chowdhury et al. 2021;
Skidmore 2016) and occasionally the insular cortex (Picard
et al. 2021). It is plausible that 5-MeO-DMT’s agonism at
post-synaptic 5-HT1A receptors may affect medial temporal
lobe regions in such a way as to precipitate epileptiform
activity. However, it is unknown whether 5-MeO-DMT is a
full or partial agonist at both pre-synaptic and post-synaptic
5-HT1A receptors. If 5-MeO-DMT is a full agonist at post-
synaptic 5-HT1A receptors, this may explain how it might
produce distinct experiences and changes in brain activity
compared with other 5-HT1A receptor agonists such as bus-
pirone, which displays full agonism at pre-synaptic 5-HT1A
receptors (Blanco et al. 2014) and only partial agonism at
5-HT1A post-synaptic receptors (Loane and Politis 2012;
Peroutka 1988).
Some may take issue with 5-HT1A inhibitory receptors
being posited to provoke an excitatory event, such as a sei-
zure. It could be possible that 5-MeO-DMT acts at 5-HT1A
receptors to inhibit GABAergic post-synaptic neurons. Inhi-
bition of GABA interneurons would reduce GABA release
and thereby might lower seizure threshold. This, coupled
with promiscuous affinity at various other serotonin recep-
tors located throughout the cortex, including 5-HT2A, may
facilitate epileptiform activity in a distinct way from the
effects elicited by substances with lower affinity for 5-HT1A
receptors. It also may be that 5-MeO-DMT agonize 5-HT1A
receptors in a functionally selective manner that it could be
inducing distinct signaling cascades at the receptor from ser-
otonin, potentially contributing to it having effects other than
inhibitory action. Additional potential mechanisms include
agonism at other serotonin receptors, such as the excitatory
5-HT7 receptor (Gharedaghi et al. 2014). However, several
other psychedelics like psilocybin also display relatively
high affinity for this receptor (Nichols 2016).
In short, considering the role that 5-HT1A receptors play
in producing the effects of 5-MeO-DMT (Darmani et al.
1990; Halberstadt et al. 2011; Krebs-Thomson et al. 2006;
Leysen et al. 1985; Mckenna et al. 1990; Winter et al. 2000)
and 5-HT1A receptors distinct localization within the brain
compared to 5-HT2A (Beliveau et al. 2017), it seems likely
5-MeO-DMT would exert distinct subjective and psycho-
logical effects compared to typical psychedelics. The reports
of seizures or seizure-like behavior in laboratory research
with 5-MeO-DMT in animals (Grahame-Smith 1971; Lucki
et al. 1984; Nielsen 1998), cases of ingestion of the Incil-
ius alvarius toad secretions provoking seizures (Hitt and
Ettinger 1986; Weil and Davis 1994), and the documented
role 5-HT1A receptors play in temporal lobe epilepsy (Bagdy
13
Psychopharmacology
et al. 2007; Didelot et al. 2008; Gharedaghi et al. 2014; Roy
et al. 2020; Sarnyai et al. 2000; Savic et al. 2004; Theo-
dore 2003; Toczek et al. 2003), contribute to the notion that
epileptiform activity within the medial temporal lobes may
be precipitated by 5-MeO-DMT, although this hypothesis
requires empirical verification.
5‑MeO‑DMT acute effects: Distinct
phenomenology?
Others have previously remarked that the effects of 5-MeO-
DMT are distinct from the effects of other classic psych-
edelics, which often involve "rich sensory phenomenology"
(Millière et al. 2018). In contrast, 5-MeO-DMT often elicits
a sense of “nothingness," producing experiences sometimes
known as a "whiteout" (Gallimore 2022; Millière et al. 2018;
Shulgin and Shulgin 1997). Experiences with whiteouts have
been described as an experience "beyond ordinary human
comprehension" (Oroc 2009) and often involves the subjec-
tive impression of a void and/or amnesia of the experience
(Ball et al. 2022; Davis 2019; Millière et al. 2018; Oroc
2009; Shulgin and Shulgin 1997). Amnesia of the experi-
ence has also been documented within a controlled research
setting (Reckweg et al. 2021). Despite people having diffi-
culty remembering the experience, some people describe the
experience as orgasmic, ecstatic, and blissful, while others
describe it as one of terror or information overwhelm (Ball
et al. 2022; Davis 2019; Lancelotta and Davis 2021; Oroc
2009). Many people describe spiritual or religious expe-
riences, including near-death experiences (Michael et al.
2023), perhaps leading some to describe the drug as the
“God molecule” (Davis et al. 2018).
Some may wonder if distinctions in experience occa-
sioned by 5-MeO-DMT compared to typical psychedelics
might be due to a more rapid onset and frequently vapor-
ized methods of administration. However, the subjective
effects produced by 5-MeO-DMT appear at least partially
distinct from another frequently vaporized and short-acting
psychedelic, DMT (Lawrence et al. 2022). According to
the non-profit harm reduction organization Dancesafe, the
effects of 5-MeO-DMT, “cannot be directly compared to
any other drug, including DMT” (Clark 2022a, b). Erowid,
an educational organization that compiles many experiences
reports, or descriptions of the acute effects from naturalis-
tic users, also suggest that the subjective effects of 5-MeO-
DMT (Erowid 2015a) and DMT (Erowid 2015b) have over-
lapping but distinct effects. In Table 2, a list of subjective
effects according to recent research and harm reduction
organizations is provided. Although harm reduction guides
are anecdotal evidence, in the absence of comprehensive
phenomenological research, harm reduction guides provide
further insight into the acute subjective effects and at the
Psychopharmacology

Table 2  Acute effects of 5-MeO-DMT compared to DMT

5-MeO-DMT Both DMT

• Amnesia/lack of memory of experience
• White-out, sense of nothingness or a void
• More frequently described as erotic/sensual, or
as a “body high”
• Muscle jerking, twitching, abnormal vocaliza-
tions
• Unconsciousness/non-responsiveness lasting
5–20 min
• Possible mystical or spiritual experiences
• Overwhelming, profound experiences possible
• Altered self-experience
• Compared to near death experiences
• Receiving of “specific messages”
• Potentially positive post-acute psychological
effects
• Prominent visual pseudo-hallucination
• Encounters with Entities
• Sense of visiting other worlds
• Personal insights
• Information-rich subjective experience

This table compares the acute experiences reported from 5-MeO-DMT compared to DMT, another short-acting, often vaporized psychedelic.
Although both psychedelics have agonism at the 5-HT2A receptor, 5-MeO-DMT is about 373.6x more selective for the 5-HT1A receptor. This
may explain differences in experiences reported with 5-MeO-DMT, such as white-outs and dissociation. In contrast, during DMT experience,
people describe more "information-rich experiences," such as encounters with entities or a sense of visiting another world. Still, both 5-MeO-
DMT and DMT can produce spiritual experiences with altered self-experiences that are at times described as overwhelming and profound.
Although some of this information is from anecdotal harm reduction sources, it may prove valuable for conducting more exacting research into
the acute subjective effects of 5-MeO-DMT. Sources: DMT (Clark 2022a, b; Davis et al. 2020; Bradley; Dourron et al. 2022; Erowid 2015b;
Lawrence et al. 2022; Timmermann et al. 2018); 5-MeO-DMT (Ball et al. 2022; Clark 2022a, b; Erowid 2015a; Lancelotta and Davis 2021;
Metzner 2013; Michael et al. 2023; Millière et al. 2018; Oroc 2009; Reckweg et al. 2021)

very least suggest a more detailed examination of the phe-
nomenology is needed.
Despite some differences in subjective effects compared
to typical psychedelics, 5-MeO-DMT may still occasion a
mystical experience under some circumstances. Within the
context of a psychospiritual retreat setting with ibogaine
administered 48 h prior, inhaled bufotoxin, obtained from
the Incilius alvarius, containing 5-MeO-DMT, induces a
complete mystical experience with comparable frequency
to high-dose psilocybin administered to healthy volunteers
in a controlled research setting (Barsuglia et al. 2018). Still,
another study indicates that 5-MeO-DMT may be less likely
to induce mystical experiences than psilocybin (Reckweg
et al. 2022). In a safety dose-finding study in healthy volun-
teers (n = 22), only three individuals (13.6%) who received
5-MeO-DMT reported an experience that met the thresh-
old for a complete mystical experience, which is below the
approximate 60% of those who received high-dose psilocy-
bin (Barrett et al. 2015; Johnson et al. 2019; Reckweg et al.
2021). It seems likely that 5-MeO-DMT regularly produces
aspects of the mystical experience, without necessarily
eliciting “a complete mystical experience.” It may be that
contextual factors, such as being in an environment (e.g.,
psychospiritual retreat) that arouses psychedelic expectan-
cies may play a role in how an extreme shift in subjective
experience (e.g., the drug effects of 5-MeO-DMT) is inter-
preted. It is also important to consider that mystical experi-
ences are not specific to psychedelics and can occur with
other drugs, including ketamine (Dakwar et al. 2018; Ko
et al. 2022; Rothberg et al. 2021) and ibogaine (Brown et al.
2019) which have distinct pharmacological and subjective
effect profiles than typical psychedelics (Ona et al. 2022;
Rocha et al. 2023; Schep et al. 2023). Therefore, relying on
a drug’s ability to elicit mystical type experiences is a blunt
proxy for determining its phenomenological profile.
5-MeO-DMT does not produce the same responses on
some dimensions of the 5-Dimensional Altered States
of Consciousness Scale (5D-ASC) (Liechti et al. 2017;
Studerus et al. 2010) as typical psychedelics, including
LSD (Holze et al. 2022), psilocybin (Holze et al. 2022), and
DMT (Gouzoulis-Mayfrank et al. 2005). Still, despite these
lower scores on some measures of typical psychedelics
effects, a survey-based study of naturalistic use indicates
that 64% of people indicate that 5-MeO-DMT produces a
“more intense” experience compared to other psychedelics
(Davis et al. 2018). Peak experiences, as measured with
the Peak Experience Scale, which measures intensity, feel-
ings of loss of control, and profoundness of the experience,
have also been reported after 5-MeO-DMT, particularly
after repeated administration (Reckweg et al. 2021, 2023).
However, as this scale has only been used to measure the
acute effects of 5-MeO-DMT, it is difficult to discern if the
“peak experiences” induced by 5-MeO-DMT are distinct
from the effects of typical psychedelics (Reckweg et al.
2021, 2023). However, the scale was described better for
capturing the effects of 5-MeO-DMT by the study team
than the MEQ, Ego Dissolution Inventory, and 5D-ASC
scales (Reckweg et al. 2021). Taken together these find-
ings, indicate that the effects of 5-MeO-DMT may not be
adequately captured by measures designed to quantify the
effects of typical psychedelics, as has been previously sug-
gested (Reckweg et al. 2021).

13

5-MeO-DMT also seems unique in comparison to
typical psychedelics in that, for some, sensitization to
the effects might occur. In a macaque, behavioral sensi-
tization has been reported after repeated administration
of 5-MeO-DMT daily over a 12-day period (Schlemmer
et al. 1977). Sensitization also might explain how studies
using an “individualizing dosing regimen” report higher
levels of peak experiences using this method than when
participants are initially administered higher doses (Reck-
weg et al. 2021, 2023). In a recent study in patients with
TRD, 7 out of 8 participants reported a peak experience
and remission of depression at one-week follow-up after
successive vaporized doses of 6 mg and 12 mg 3 h later
(Reckweg et al. 2023). This is higher than the remission
rate achieved with a single administration of 18 mg or
12 mg (50% and 25%, respectively). This might suggest
sensitization could occur occurs with repeated use, at least
for some users. However, future studies should use the
same dose for repeated administrations to confirm this.
It might be possible that such sensitization could be due
to a kindling-like effect. If 5-MeO-DMT is in part producing
its psychoactive effects by medial temporal lobe epileptiform
activity, repeated use might introduce a “kindling” phenom-
enon, in which the induction of seizures can increase the
strength of subsequent seizures (Bertram 2007). Although
questions have been raised about the relevance of kindling to
human epilepsy, it is a relevant concern to consider, particu-
larly considering kindling is thought to be especially likely
with temporal lobe seizures (Bertram 2007). Regardless of
the etiology of a possible sensitization effect, the success
of an individualized dosing regimen (Reckweg et al. 2021,
2023) and report of behavioral sensitization in a primate
(Schlemmer et al. 1977) is a notable different from other
psychedelics, such as LSD and psilocybin, which have a
tolerance to effects (de la Fuente Revenga et al. 2022) and
DMT which does not produce a rapid tolerance but, does
not seem to prompt sensitization (dos Santos et al. 2012).
Clearly, there are some distinctions in subjective expe-
riences between 5-MeO-DMT and typical psychedelics.
In-depth phenomenological work is needed to document
the experiences occasioned by 5-MeO-DMT in the acute
effects in a systematic manner. Such a study may assist
with developing a questionnaire that more accurately cap-
tures the phenomenology of 5-MeO-DMT’s acute effects
and outcomes. It also may be that the optimal therapeutic
paradigm is distinct for 5-MeO-DMT, particularly given
that people often report less “information rich” experiences
than classic psychedelics, suggesting that different media-
tors of therapeutic response (e.g., loss of control as opposed
to mechanisms such as personal insight) might be at work
(Dourron et al. 2022; Millière et al. 2018; Peill et al. 2022).
Understanding such differences may pave the way to optimal
development of 5-MeO-DMT as therapeutic.
13
Psychopharmacology
Behavior during acute effects: Potential
parallels with temporal lobe seizures?
5-MeO-DMT also appears capable of producing rela-
tively unique behavioral and physiological responses.
5-MeO-DMT is more likely to cause odd behaviors, such
as “muscle jerking, twitching, abnormal vocalizations”
(Erowid 2015a) than other psychedelics (Erowid 2015b;
Lancelotta and Davis 2021). One facilitator guidebook
cautions that under the influence of 5-MeO-DMT, people
may display behaviors such as vomiting, screaming, and
taking off their clothes (Ball et al. 2022). Odd behaviors,
such as highly sensual and even hypersexual experiences,
such as spontaneous orgasms (Ball et al. 2022; de Greef
2022) and occasional self-injurious behavior (Skully 2001)
have also been documented antidotally amongst facilita-
tors and users. According to a survey study of naturalistic
use, 5-MeO-DMT might occasionally produce “physical
danger… due to involuntary/unaware bodily movements”
(Erowid 2015b; Lancelotta & Davis 2021). Others also
report observations of uncontrolled motor movement and
seizure-like behavior, which may occasionally provoke
seeking medical intervention (Ball et al. 2022; Shulgin
and Shulgin 1997; Skully 2001). Curiously, it seems that
users often lack awareness or memory of their behaviors
during the acute effects (Ball et al. 2022; Erowid 2015a;
Oroc 2009; Reckweg et al. 2021).
These behaviors parallel many symptoms often
observed with seizures. The apparent seizures reported by
some naturalistic users appear to be tonic–clonic or may
be cases of focal impaired awareness seizures (e.g., may
resemble a seizure to a layperson) (Devinsky et al. 2018.).
It is possible that the apparent tonic–clonic seizures may
be due to rapid changes in neural functioning within the
temporal lobes, where post-synaptic 5-HT1A receptors are
most densely localized, may propagate throughout the
cortex, plausibly provoking focal to bilateral tonic–clonic
seizures (Devinsky et al. 2018; Sinha et al. 2021). The
abnormal behavior sometimes noted during the acute
effects of 5-MeO-DMT have also been reported in cases
of focal impaired awareness seizures (Chowdhury et al.
2021; Kramer et al. 1997; Kumar and Sharma 2022), par-
ticularly of temporal lobe origins, including spontaneous
orgasms and “genital automatisms” (Dede et al. 2018;
Leutmezer et al. 1999; Remillard et al. 1983) and rarely
self-injurious behavior (Rathi et al. 2020; Shakya et al.
2010). It is also plausible that partial focal seizures with
less dramatic behavior changes may occur and could
impact memory (Chowdhury et al. 2021; Devinsky et al.
2018; Skidmore 2016).
Potentially dangerous physiological alterations can
also occur with temporal lobe seizures (Thijs et al. 2021).
Psychopharmacology
Ictal vomiting has been associated with epilepsy in medial
temporal or possibly insular origins but, is more rare in
seizures with other origins (Kumar and Sharma 2022;
Pietrafusa et al. 2015; Ryvlin and Nguyen 2021). More
concerningly, respiratory arrest and sudden unexpected
death is a well-known phenomenon in epilepsy (McLean
and Wimalaratna 2007; Vilella et al. 2019) that may
be especially prevalent with temporal lobe seizures
(Malatinsky et al. 1975; Nelson 1968; Page and Rugg-
Gunn 2018; Thijs et al. 2021). 5-MeO-DMT has been
implicating in causing vomiting during the acute effects,
and in some rare cases of an unknown frequency,
respiratory arrest/depression (Antibody 2016; Bateman
2014; Bowers 2015; Oroc 2009; Shulgin and Shulgin
1997). Instances of respiratory arrest and convulsions have
also been reported in animal studies (Ahlborg et al. 1968;
Ermakova et al. 2022). These physiological responses
suggest a plausible parallel between the effects of 5-MeO-
DMT and some forms of seizures. Still, it is important
to acknowledge that some instances of respiratory arrest
have also been reported with typical psychedelics, such
as ayahuasca (Heise and Brooks 2017), LSD, and more
rarely psilocybin-containing mushrooms (Leonard et al.
2018). The frequency of such events, relatively speaking
is unknown, but is worth monitoring in future studies,
including among naturalistic users.
Still, despite the risk of abnormal behavior and harm,
some people report that the subjective experiences induced
by 5-MeO-DMT are pleasurable and repeatedly use the sub-
stance despite prior experiences with undesirable effects
(Oroc 2009). Further empirical work is needed to better
understand the frequency of abnormal or adverse outcomes
in response to 5-MeO-DMT in both naturalistic users and
clinical settings. However, the combination of these data
with animal research documenting seizure behaviors with
5-MeO-DMT (Gessner and Page 1962; Grahame-Smith
1971; Lucki et al. 1984; Nielsen 1998) and the unique phar-
macology of this compound (Ermakova et al. 2022) sug-
gests that a potential explanation for 5-MeO-DMT-related
behavioral abnormalities may be seizures or seizure-like
brain activity. Regardless of distinctions in subjective and
behavioral effects being due to potential epileptiform activ-
ity, it seems likely that 5-MeO-DMT should be examined as
distinct from typical psychedelics.
Temporal and insular seizures: Experiential
parallels
Experiences elicited by 5-MeO-DMT seem to be subjectively
distinct from those evoked by typical psychedelics and yet
appear to have parallels with the experiences produced by
some forms of focal seizures. Focal seizures that involve
the temporal lobes and anterior insula occasionally induce
elements of mystical experience (Carhart-Harris 2007; Naito
and Matsui 1988; Picard et al. 2021; Picard and Craig 2009;
Picard and Kurth 2014), described by some as a sense of
“spiritual awakening” (Corneille and Luke 2021). So-called
“ecstatic” seizures can produce “a feeling of union with the
world,” an experience of “sensory overload,” a sense of
bliss, physical well-being, self-awareness, and altered time
perception (Gschwind and Picard 2016). There is also often a
highly pleasurable somatic component that some describe as
highly sensual or even erotic (Åsheim Hansen and Brodtkorb
2003). Near-death-like experiences have also been reported
in cases of temporal lobe epilepsy (Trimble and Freeman
2006). Additionally, these seizures are often described by
patients as some of the most intense experiences of their
lives (Åsheim Hansen and Brodtkorb 2003; Gschwind
and Picard 2016) and some patients describe a sense of an
encounter with God or a “divine power” (Åsheim Hansen
and Brodtkorb 2003).
Despite the intensity of the experience, some individu-
als report that they cannot fully remember the experience
(Åsheim Hansen and Brodtkorb 2003). Other times, some
individuals describe sensory alterations, including visual,
which can vary widely but which can include an experi-
ence of a bright white light or sense of blindness (Kasper
et al. 2010). Some people occasionally experience the sei-
zures as so pleasurable that they will attempt to induce them
intentionally (Åsheim Hansen and Brodtkorb 2003; Lindsay
2014). However, experiences with strong negative valence
are also possible, with intense fear during the “acute” (e.g.,
ictal phase) seizure occurring in up to one-third of patients
(Cao et al. 2022; Feichtinger et al. 2001; Sazgar et al. 2003;
Taylor and Lochery 1987).
There is also a long history of temporal lobe seizures
being implicated in highly religious experiences (Corneille
and Luke 2021). Some people have speculated that Fyodor
Dostoevsky, the Russian novelist (Baumann et al. 2005;
Morgan 1990), and several saints, including Catherine of
Siena and Teresa of Avila (Carrazana and Cheng 2011),
had temporal lobe epilepsy. Still, such speculation should
be considered with caution (Bone and Dein 2021). More
concretely, there are case reports of spontaneous religious
conversion and hyper-religiosity being associated with
temporal lobe epilepsy, with some even suggesting that
those with repeated temporal lobe seizures display a
particular personality syndrome marked largely by hyper-
religiosity (Persinger 1983; Picard et al. 2021). However,
some of these traits have also been found in high prevalence
in people with non-epileptic (e.g., psychogenic) seizures
(Tremont et al. 2012).
Additionally, bizarre behaviors, sometimes referred to as
automatisms, can occur during partial seizures (Chowdhury
et al. 2021; Vinti et al. 2021). People frequently move their
13

lips and jaws (e.g., chewing, lip smacking, swallowing),
and some may move around erratically or may attempt to
take their clothes off (Chowdhury et al. 2021; Devinsky
et al. 1991, 2018; Horvath et al. 2009; Kramer et al.
1997). Spontaneous laughing, screaming, crying, and
vocalizations can also occur (Hartl et al. 2018; Hogan and
Rao 2006; Horvath et al. 2009; Kovac et al. 2015; Kramer
et al. 1997; Luciano et al. 1993). Behavioral arrest, a total
cessation of body movements, may also be observed (Vinti
et al. 2021).
In short, aside from visible tonic–clonic seizure-like
behavior, focal seizures, particularly those with epilepto-
genic zones within the temporal lobes, appear to have over-
lap with some of the effects of 5-MeO-DMT. 5-MeO-DMT
appears capable of producing an experience "beyond ordi-
nary comprehension" marked by strong emotional salience,
though people also paradoxically report amnesia of the expe-
rience (e.g., a "white-out") (Ball et al. 2022; Ermakova et al.
2022; Oroc 2009). In addition, somatic components are very
prominent, erratic behavior can occur, and physiological dis-
turbances have also been reported (Ball et al. 2022; Bowers
2015; Clark 2022a; Lancelotta and Davis 2021).
Reports of focal seizures implicating temporal lobe
regions can also provoke intense experiences that can
partially overlap with mystical-type experiences (Åsheim
Hansen and Brodtkorb 2003; Carhart-Harris 2007; Cor-
neille and Luke 2021; Gschwind and Picard 2016; Pic-
ard et al. 2021). For some, focal seizures can involve an
"ecstatic” experience (Åsheim Hansen and Brodtkorb
2003; Gschwind and Picard 2016; Naito and Matsui 1988;
Picard et al. 2021; Picard and Craig 2009; Picard and Kurth
2014), whereas for others, they can provoke feelings of
panic (Cao et al. 2022; Hurley et al. 2006; Kirmani and
Mungall 2013; Mirsattari et al. 2011). Erratic behaviors
(Åsheim Hansen and Brodtkorb 2003; Chowdhury et al.
2021; Kramer et al. 1997; Vinti et al. 2021) and, in many
cases, lack of recollection of the seizure are reported
(Spiers 2021). Thus, it is apparent that some experiences
occasioned by focal seizures may have some parallels with
5-MeO-DMT-induced experiences.
5-MeO-DMT may be able to produce localized focal
seizures that provoke aspects of the mystical experience
that, in some instances, may appear to become a focal
to bilateral tonic–clonic seizure during the acute effects.
Tonic–clonic seizures would likely be described as
“seizures” by bystanders and might explain a lack of
recollection during acute effects. Subsequently, focal
seizures might occur within temporal lobe foci. This may
suggest that 5-MeO-DMT could elicit a “shockwave-
like” seizure cascade phenomenon. The possibility of
shockwave-like seizures occurring is highly relevant to the
discussion that follows on reactivations.
13
Psychopharmacology
Risk of reactivations or flashbacks
Phenomena in which one re-experiences drug effects after
acute drug action has subsided, commonly termed flash-
backs or reactivations, are well documented subsequent
to administration of 5-MeO-DMT. These occurrences are
described following both naturalistic and clinical use (Ball
et al. 2022; Clark 2022a, b; Davis 2019; Ortiz Bernal et al.
2022; Reckweg et al. 2021, 2023; Uthaug et al. 2020a, b).
Estimates of reactivation prevalence in naturalistic use of
5-MeO-DMT range from 27 to 73% (Ortiz Bernal et al.
2022; Uthaug et al. 2020a). Frequency estimates gleaned
from survey data are notably subject to some biases and
limitations. Regarding controlled research settings a
recent study in patients with treatment-resistant depres-
sion found flashbacks were reported in 25% of participants
and occurred in 25% of each dosing category/study stage
(e.g., 12 mg, 18 mg, and an individualized dosing regimen
arm) (Reckweg et al. 2023). In a safety dose-finding study,
5-MeO-DMT also led to reports of what the study team
deemed flashbacks, hallucinations, “confusional states,”
and abnormal dreams among some participants (Reckweg
et al. 2021). Their report is unclear on the distinctions
between these adverse events (e.g., flashbacks verses hal-
lucinations). Overall, it appears that both naturalistic and
clinical use of 5-MeO-DMT precipitate reactivations/
flashback-type phenomena at a higher regularity than
typical psychedelics, even those with rapid onset, such as
DMT (Vogt et al. 2023). Table 3 shows a summary of the
frequencies of reactivations or flashbacks reported in con-
temporary studies of 5-MeO-DMT and more commonly
used psychedelics (e.g., psilocybin, LSD, and DMT).
Hallucinogen Persisting Perception Disorder (HPPD) is
defined in the Diagnostic and Statistical Manual of Mental
Disorders (DSM-V) as "the reexperiencing of one or more
of the perceptual symptoms that were experienced while
intoxicated with the hallucinogen," particularly those that
are visual, after exposure to a hallucinogen, and must
include feelings of distress in order to meet DSM-V diag-
nostic criteria (American Psychiatric Association 2022).
The DSM-V suggests that HPPD has a prevalence rate
of 4.2%, although this has been disputed as an overesti-
mate at least with typical psychedelics (Müller et al. 2022;
Vis et al. 2021). There is also a low prevalence of “visual
alterations” (1.3%) in a representative sample of typical
psychedelic users from the general population (Simonsson
et al., in review).
Previous studies report an unclear distinction between
flashbacks and reactivations, even referring to "flash-
backs/reactivations" (Reckweg et al. 2022) or "flashback-
like reactivation phenomenon" (Ortiz Bernal et al. 2022).
The lack of visual phenomena generally reported during
Psychopharmacology

Table 3  Flashbacks & reactivations reported in clinical trials & studies of naturalistic use

5-MeO-DMT
Study
Reckweg et al. 2023
Reckweg et al. 2022
Ortiz Bernal et al. 2022
Uthaug et al. 2020a, b
Typical Psychedelics
Drug (Study)
DMT
(Vogt et al. 2023)
Psilocybin, LSD, and Psilo-
cybin + LSD Coadminis-
tration
(Müller et al. 2022)
Recurrence Terminology Details
Flashbacks Open-label study in patients with treatment resistant
No definition depression (n = 16)
• Flashbacks in 25% (n = 4); 1 = 12 mg, 1 = 18 mg,
2 = individualized dosing regimen (6 + 12 + 18 mg)
Flashbacks and Hallucinations Dose finding study (n = 22
No definition • 1 Flashback and 1 hallucination reported out of a total
of 4 participants who received 18 mg of 5-MeO-DMT
dose administrations
Reactivations Secondary data from a larger 5-MeO-DMT survey;
“Spontaneous re-experiencing/flashback or feeling as structured group subsample (n = 344) and unstructured
though experience is happening again” subsample (n = 169)
• 73% (n = 251) of structured setting users experienced
reactivations
• 27% (n = 46) of unstructured setting users reported
reactivations
Reactivations Survey data; vaporized vs. intramuscular injection (IM)
“Flashbacks/re-experiencing [parts of] the experience” administration
• 69% (n = 13) of the vaporized route group reported
reactivations
• 22% (n = 14) of the IM injection route group experi-
enced reactivations
Recurrence Terminology Details
Flashback Double-blind crossover randomized control trial (RCT)
of intravenous DMT (n = 27) with 4 doses
• 3.7% (n = 1) experienced multiple “moderate to strong”
flashbacks for several weeks after study completion
Flashback Review of 6 double-blind crossover psychedelic RCTs
“Reoccurring drug-like experiences” (pooled n = 146)
• 7.8% (n = 7) in LSD-only trials reported flashbacks
• 8.3% (n = 2) in psilocybin-only trials reported flash-
backs
• 14.3% (n = 4) in LSD and psilocybin trials reported
flashbacks

This table describes the prevalence of reactivations and flashbacks reported in studies within the context of experimental studies, including
DMT, LSD, psilocybin, and 5-MeO-DMT. Although the prevalence of re-experiencing events varies, it seems that, in general, people who use
5-MeO-DMT are more likely to do so. The term flashback was used in both studies of 5-MeO-DMT and typical psychedelics. However, the term
reactivation was only noted in studies of 5-MeO-DMT

the acute effects of 5-MeO-DMT (Erowid 2015a; Reck-
weg et al. 2021) may be why the term "reactivations" has
developed as a term for reexperiencing 5-MeO-DMT drug
effects. Descriptions of "reactivations" suggest people may
experience altered emotions (e.g., "bliss or terror"), bod-
ily sensations, and altered self-experiences (5-MeO-DMT
Information and Vital Education n.d.; Ball et al. 2022;
Davis 2019; The Conclave n.d.). Such experiences are
well within the DSM-V-defined scope of "flashbacks,"
(e.g., "the reexperiencing of one or more of the percep-
tual symptoms"), depending on how one defines percep-
tual symptoms. Others have also noted that occasionally
flashbacks, can include altered self-experience and a “mild
sense of strangeness” (Lerner et al. 2014). Still, such expe-
rience seems at least somewhat distinct from the primarily
visual "flashbacks" (e.g., visual pseudohallucinations and
intensified color perception) described in prior trials of
typical psychedelics (Müller et al. 2022).
The time course of 5-MeO-DMT reactivation duration
also seems different than HPPD with the majority of HPPD
patients experiencing symptoms for longer than one month
and many reporting symptoms for years (46.5%) (Vis et al.
2021). Reactivations are reported to occur most commonly
within one to two weeks after administration (Ortiz Bernal
et al. 2022; Uthaug et al. 2020a). As the half-life of 5-MeO-
DMT is in the order of minutes (Reckweg et al. 2022), it
is unlikely reactivations are due to residual amounts of the
drug itself.
5-MeO-DMT-associated reactivations have also been
observed to occasionally have specific triggers, including

13

falling asleep, meditation, and ingestion of other sub-
stances (Ortiz Bernal et al. 2022; Uthaug et al. 2020a). In
other instances, reactivations have also been documented
to occur without a clear trigger — with potentially danger-
ous implications. For instance, there is an anecdotal report
of “dissociative after-effects,” including brief amnesia and
uncontrolled movement occurring while driving the day
after 5-MeO-DMT use (Metzner 2013, p. 52).
For a minority of people, reactivations can be nega-
tively valanced with 4% of ceremonial users (n = 344)
and 7% of general naturalistic users (N = 169) negatively
valanced reactivations (Ortiz Bernal et al. 2022). This is
higher than the prevalence of distress (1.4%) from flash-
backs in people who participated in trials using LSD and
psilocybin (N = 142) (Müller et al. 2022). Albeit factors
such as support before or after the experience, and pre-
existing mental health conditions present potential con-
founds. Still, no flashbacks or reactivations, distressing
or not, have been reported in trials of psilocybin for treat-
ment-resistant depression (Goodwin et al. 2023; Carhart-
Harris 2007). There is also anecdotal evidence to suggest
that, for some, reactivation can be significantly distress-
ing, prompting seeking psychological help and pharma-
cological intervention, as has been previously mentioned
in academic discourse about 5-MeO-DMT (Davis 2019;
Ortiz Bernal et al. 2022). Still, some may contend that due
to the often positive or neutral valence of reactivations
(Ortiz Bernal et al. 2022), there occurrence is a benign
epiphenomenon of post-acute changes to the brain after
5-MeO-DMT. However, there are many instances where
the valence of a phenomenon (e.g., so-called “ecstatic”
seizures, mania, psychosis) does not necessarily indicate
long-term potential harm (Dourron et al. 2022; Picard and
Kurth 2014). Until a mechanism of reactivations and flash-
backs is known, it suggested they be examined from the
perspective of an adverse event to be watchful of for both
typical psychedelics and 5-MeO-DMT.
Unfortunately, a lack of systematic long-term follow-up
studies makes it impossible to determine the frequency,
intensity, duration, and impairment associated with reac-
tivations. Regardless, based on existing data, 5-MeO-DMT
appears to elicit reactivation or flashback phenomenon
with higher frequency than typical psychedelics in con-
trolled and naturalistic settings. Future studies of 5-MeO-
DMT reactivations should specify the symptomology of
reactivations or flashback phenomenon, as it seems likely
from anecdotal evidence that the subjective experience of
reactivations is at least somewhat distinct from flashbacks
occasioned by typical psychedelics. This will help under-
stand whether 5-MeO-DMT has a distinct post-acute risk
profile compared to typical psychedelics, which seems
probable based on preliminary studies.
13
Psychopharmacology
Reactivations: Comparison to seizure auras
The experiences evoked by some focal seizures share some
phenomenological overlap with reactivations elicited by
5-MeO-DMT. Focal aware seizures are not associated
with loss of consciousness, lack regional propagation,
and are often described as seizure auras (Devinsky et al.
2018; Janszky et al. 2004; Sperling et al. 1989; Taylor and
Lochery 1987). Focal seizures have been described as an
"over-consciousness" or a “dreamy state” at times and in
general have some overlapping phenomenological char-
acteristics and neurobiological effects of typical psych-
edelics (Carhart-Harris 2007; Hughlings-Jackson 1888).
During such seizures, many people report altered sensory
experiences, including somatosensory experiences (e.g.,
tingling) and visual alterations such as a "whitening" of
the visual field (Erickson et al. 2017), "bright lights," or a
sense of "looking down a tunnel" (Persinger 1983). Alter-
ations in self-experiences also may occur (Fried 1997).
Oftentimes, auras or simple partial seizures can feel like
a "strong reliving" of an experience, otherwise known as
déjà vu, particularly in cases of hippocampal involvement
(Picard et al. 2021). Descriptions include "early morning
highs occurring between 2 and 4 am," "vibration sensa-
tions before sleeping," and "waves of energy permeating
the body," along with a sense of peacefulness and unreal-
ity (Persinger 1983). The majority of people with medial
temporal lobe epilepsy experience auras independent of a
partial seizure (Janszky et al. 2004; Sperling et al. 1989;
Sperling and O’Connor 1990), meaning that it is possible
to have a "seizure aura" without a focal impaired aware-
ness or tonic–clonic seizure thereafter.
Many supposed triggers for 5-MeO-DMT reactivations
(Uthaug et al. 2020a) have also been identified as triggers
for focal seizures, such as substance use (Pinikahana and
Dono 2009) including caffeine (Chrościńska-Krawczyk
et al. 2011; Kaufman and Sachdeo 2003; van Koert et al.
2018), which may reduce the seizure threshold. In addi-
tion, meditation has also been shown to induce seizures in
some people with epilepsy (Jaseja 2005, 2010; Lansky and
Louis 2006; Lindsay 2014). However, triggers for seizures
are highly idiosyncratic, with everything from exercise to
heat to humidity to sleep deprivation (Garg et al. 2022;
Giorgi et al. 2013) reported as potential triggers (Pinika-
hana and Dono 2009).
Others have also suggested that psychedelic-related
flashbacks in general, at least in some cases, might have
epileptiform origins (Abraham 1983; Lerner et al. 2014;
Lettvin and Leary et al. 1967). Further, drugs that reduce
epileptiform activity including anticonvulsants, such as
lamotrigine, and benzodiazepines, show potential efficacy
in reducing HPPD symptoms in some instances (Lerner
Psychopharmacology
et al. 2014; Hermle et al. 2012; Thurlow and Girvin 1971).
In other cases, drugs that lower the seizure threshold, such
as some antipsychotics have also been documented to exac-
erbate flashbacks from LSD (Abraham 1983; Hermle et al.
2012). Still, flashbacks have a very heterogenous response
to medications, perhaps suggesting multiple distinct patho-
physiologies (Lerner et al. 2014; Hermle et al. 2012). It
also appears that in some instances, environmental triggers
for flashbacks can overlap with those of seizures (Abra-
ham 1983). It may be that both typical psychedelics and
5-MeO-DMT may produce epileptiform activity associated
with flashback or reactivations symptoms during the post-
acute effects, albeit perhaps via unique mechanisms, due
to their differences in pharmacological mechanisms, and
as suggested by distinction in prevalence of such occur-
rences (see Table 3).
Contributing factors: Dose, administration
method & predisposing characteristics
The hypotheses outlined here, that 5-MeO-DMT may exert
its psychological and therapeutic effects partially through
evoking epileptiform activity (e.g., somewhat like ECT),
and that reactivations are partial seizures, could possibly
be modified by a range of factors including, but not limited
to, dose, administration method, setting, and predisposing
biological and psychological characteristics. It is possible
that many of the effects described here may be most relevant
for methods of administration that have highly rapid onsets
of subjective effects. Indeed, a previous study of naturalistic
users found that reactivations were significantly more likely
to occur in those who vaporized the substance compared
to those who administered 5-MeO-DMT via intramuscular
injection, which has a slower onset of effects (Uthaug et al.
2020a). Vaporized use was also associated with greater
redosing, which could possibly contribute to a kindling-like
effect that might add to the development of reactivations.
Some may also suggest that adverse events may be
due to the presence of bufotenine in bufotoxin. However,
this seems unlikely as 5-MeO-DMT is metabolized by
cytochrome P450 2D6 (CYP2D6) to bufotenine (Shen et al.
2010), suggesting that differentiating use of toad secretions
(e.g., bufotoxin) from pure 5-MeO-DMT based on the pres-
ence of bufotenine is likely irrelevant. Moreover, some of
the studies documenting the highest risk of reactivations in
naturalistic users (73% of users, n = 344) have documented
use occurring with “laboratory-tested synthetic 5-MeO-
DMT” in a structured group (Ortiz Bernal et al. 2022). Still,
individual differences in cytochrome P450 alleles may also
play a role in the metabolism of 5-MeO-DMT and whether
bufotenine may build up to the degree where it could have
notable effects. Futhermore, differences in CYP2D6 alleles
have previously been reported to predict adverse responses
to various substances (Bertilsson et al. 2002).
It is also possible that many of the effects discussed here
are most relevant for naturalistic use and will be reported
less frequently within clinical research settings, particularly
in those that use administration methods with a slower onset
time. However, it must be emphasized that examining the
potential risk associated with psychedelic-assisted therapies
is generally an understudied topic (McNamee et al. 2023).
Understanding the cause of reactivations, regardless of their
mechanism, will help elucidate how 5-MeO-DMT produces
its neurological and psychological effects.
Typical psychedelics & seizures?
There is also a case for typical psychedelics potentially pro-
voking seizures. Calls to the national poison control center
involving LSD, ayahuasca, and psilocybin-containing mush-
rooms reporting instances of single seizures occur, albeit
rarely (2.4%, 2.2%, 0.6% of calls respectively (Heise and
Brooks 2017; Leonard et al. 2018). However, the poison
control center does not account for concomitant medica-
tions and cannot test the substances in question for verifica-
tion or adulteration. As such, assigning definite causality
to the substance reported may not be entirely accurate. In a
more recent study, drawing on the general US population,
it was reported that 1.5% of people reported experiencing a
seizure while using a typical psychedelic (Simonsson et al.
2022). Most of these individuals had a personal and/or fam-
ily history of epilepsy. Concurrent use of psychiatric medi-
cations, particularly lithium, also appears to also be a risk
factor for typical psychedelic-related seizures (Nayak et al.
2021; Picker et al. 1992; Simonsson et al. 2022). This may
be due to the combination provoking serotonin syndrome,
which can include convulsions, and can occur with lithium
in combination with other serotonergic substances (Netto
and Phutane 2012).
All reports seem to indicate that LSD is more often
implicated in apparent seizures than psilocybin-containing
mushrooms (Leonard et al. 2018; Nayak et al. 2021). Pos-
sible explanations include misrepresented substances sold as
“acid” to unwitting consumers (most recently N-methoxy-
benzyl phenethylamines (NBOMe’s) (Suzuki et al. 2015))
and LSD’s more promiscuous binding affinities (Nichols
2016), which suggest a range of interactions might contrib-
ute to the development of seizures, particularly at higher
doses. Still, there have been case reports of very large over-
doses of LSD with a range of dire systemic effects, but no
seizures reported (Klock et al. 1975). In instances where
ayahuasca has been implicated in a seizure, it is possible
that the β-carbolines within Banisteriopsis caapi with mono-
amine oxidase inhibitor activity in combination with DMT
13

may have contributed to development of serotonin syndrome
(Kawanishi et al. 1994). Potentially active uncharacterized
alkaloids in ayahuasca may also play a role.
Other psychedelics, such as those in the 25X-NBOMe
series, have significant preferential affinity for 5-HT2A over
5-HT1A and have been reported to more regularly provoke
seizures than non-selective partial 5-HT2A agonists (e.g.,
psilocin) (Rudin et al. 2021; Zawilska et al. 2020). Seizures
are reported in 40% of adverse reactions to NBOMes (Suzuki
et al. 2015). This might seem in contrast to the hypothesis
that 5-MeO-DMT’s selective affinity for 5-HT1A contrib-
utes to its putative convulsant properties However, NBOMe
series compounds also have a complex metabolism, and an
overall unusual toxicity associated with them compared to
5-HT2A agonists in general, suggesting metabolites may be
responsible for off-target adverse toxic effects (Leth-Petersen
et al. 2016).
It is also possible that typical psychedelics-induced sei-
zures may occur more frequently than reported. A cluster of
seizures (32) occurred in a patient with refractory temporal
lobe epilepsy after exposure to approximately 2.5 to 3 g of
psilocybin-containing mushrooms (Blond and Schindler
2023). The patient reported that during the acute effects,
he “felt high, and he described feeling symptoms similar to
when his seizures occur but with calmness instead of anxi-
ety.” However, he was unaware that he had had seizures dur-
ing the experience, and only became aware of the seizure
cluster when a physician was reviewing his responsive neu-
rostimulation system. This suggests that seizures occurring
during the acute effects of psychedelics could be mistaken
for drug effects and therefore not reported.
Despite some evidence suggesting typical psychedelics
can cause seizures, there is also evidence suggesting that
typical psychedelics can have anticonvulsant properties. For
example, baboons have been shown to be less sensitive (e.g.,
measured with cortical spikes and waves) to intermediate
light stimulation after administration of LSD, DMT, and
psilocybin, suggesting these substances have anticonvulsant
properties (Meldrum and Naquet 1970). Some more recent
work also suggests that the novel psychedelic, N, N-dipro-
pyltryptamine, might display anticonvulsant properties that
are not dependent on serotonergic functioning (Tyagi et al.
2023). An early study reported that both LSD and mescaline
provoked no convulsive effects (e.g., self-report and EEG)
in people with temporal lobe epilepsy with auras (Schwarz
et al. 1956). In short, it seems there is potential for psych-
edelics to both elicit and inhibit seizures. Still, given the
differences in 5-HT1A versus 5- H ­ T2A selectivity, subjec-
tive experiences reported, and frequency of reactivation or
flashback phenomenon, it might be that a distinct mechanism
might be at play for potentially provoking both therapeutic
and adverse effects (e.g., seizures) with typical psychedelics
and 5-MeO-DMT.
13
Psychopharmacology
Alternative hypotheses for reactivations
Some have suggested that 5-MeO-DMT reactivations are a
method of coping with an emotionally salient, potentially
psychologically traumatic experience (Davis 2019). This
may be the case, but to our knowledge, reactivations are
not regularly reported with the use of typical psychedelics
(Müller et al. 2022), even after challenging experiences
(Barrett et al. 2016; Carbonaro et al. 2016; Gashi et al.
2021), and flashbacks are rarely reported with MDMA in
the treatment of post-traumatic stress disorder (9%) despite
flashbacks being among the diagnostic criteria for this
mental health condition (Vizeli and Liechti 2017). Yet,
this would likely be the case if reactivations were due to
intensely negative emotional experiences alone. Moreover,
to reiterate, reactivations have been documented as often
being positive or neutral in valence (Davis 2019; Ortiz
Bernal et al. 2022).
Alternatively, 5-MeO-DMT reactivations may, in some
instances, share similarities to panic attacks. The devel-
opment of panic attacks after exposure to 5-MeO-DMT
in naturalistic settings has been discussed (Davis 2019).
5-MeO-DMT reactivations could, in negatively-valenced
cases, be classic panic attacks, or may resemble post-trau-
matic stress disorder symptoms (Ehlers et al. 2004; Samara
et al. 2019). Still, symptoms of panic disorder substantially
overlap with temporal lobe focal aware seizures (Hurley
et al. 2006). Indeed, there have been many instances of
misdiagnosis of panic disorder that were later found to be
ictal panic induced by partial seizures, particularly those
with medial temporal origins (Hurley et al. 2006; Kirmani
and Mungall 2013; Kulason et al. 2018; Mirsattari et al.
2011; Scalise et al. 2006; Thompson 2000; Young et al.
1995). In fact, temporal lobe epilepsy is the most common
condition to be misdiagnosed as panic disorder (Hurley
et al. 2006). Still, partial seizures can often be distin-
guished from panic attacks as they are typically of shorter
duration and may worsen with some standardized panic
disorder treatments. The sudden onset of panic attacks in
people over 45 years of age also suggests epileptic origin.
Others have recently suggested that reactivations may
be caused by a learned association with changes in alpha
oscillations during the immediate post-acute effects of
5-MeO-DMT (Ortiz Bernal et al. 2022). This is based
on the observation that alpha oscillation suppression
occurs during acute effects, followed by an alpha rebound
effect in some people as drug effects diminish (Acosta-
Urquidi 2015; Ortiz Bernal et al. 2022). Ortiz Bernal and
colleagues suppose that in the weeks following 5-MeO-
DMT use, when a shifting from high to low frequency
oscillations occurs in the course of routine activity (e.g.,
when falling asleep), this serves as a cue to remember
Psychopharmacology
“the transitions from the deep 5-MeO-DMT state back
to normal consciousness,” which is experienced as a
reactivation.
This is a hypothesis worthy of empirical test. However,
there are also some outstanding issues that should be noted.
The single study that reported an alpha rebound effect
with 5-MeO-DMT collected these data among people who
were administered either DMT or 5-MeO-DMT in a natu-
ralistic setting, but the study did not distinguish between
these groups in their analyses (Acosta-Urquidi 2015). It is
therefore unclear from the study the prevalence of the post-
acute alpha rebound effects for 5-MeO-DMT specifically as
compared to DMT. The lack of specificity for 5-MeO-DMT
may suggest that alpha rebound effects are not causal to the
experience of 5-MeO-DMT related reactivations. Further-
more, reactivations seem to parallel acute effects more than
immediate post-acute effects – and yet it is hypothesized
that the alpha-rebound, which occurs during the immediate
post-acute effects, is what serves as a cue to remember the
acute state (Ortiz Bernal et al. 2022).
Additionally, 5-MeO-DMT reactivations are often
described as a particularly vivid memory, or even a sense
of “reliving,” may further suggest that these experiences
share parallels with focal seizures (Ball et al. 2022; Davis
2019). A sense of déjà vu is particularly well documented to
occur in focal seizures involving the medial temporal lobes
(Adachi et al. 2010; Bancaud et al. 1994; Cleary et al. 2021;
Warren-Gash and Zeman 2014). While most people have
experienced déjà vu at some point in their lives (Adachi et al.
2003; Warren-Gash and Zeman 2014), people with temporal
lobe epilepsy often report additional associated symptoms
such as depersonalization during the experience of déjà vu
(Adachi et al. 2010; Bancaud et al. 1994; Cleary et al. 2021;
Warren-Gash and Zeman 2014). As people often describe
5-MeO-DMT reactivations as a reliving of acute effects,
where self-experience alterations are prominent (Ball et al.
2022; Ermakova et al. 2022; Oroc 2009), this may further
suggest that 5-MeO-DMT reactivations share some parallels
with focal seizures, since they both likely include a sense
of reliving and altered self-experience; however, further
research would be needed to confirm that alternations to
self-experience occur during reactivations.
Discussion
5-MeO-DMT is an atypical psychedelic that displays a phar-
macological and phenomenological profile that shows some
overlap, but also distinctions from typical psychedelics such
as psilocybin. It has substantial selectivity for the 5-HT1A
receptor compared to 5-HT2A receptor (Ermakova et al.
2022). It also may display sensitization due to repeated
administrations (Reckweg et al. 2021, 2023; Schlemmer
et al. 1977), in contrast to tolerance (de la Fuente Revenga
et al. 2022). Subjectively, the acute effects of 5-MeO-DMT
likely partially overlap with typical psychedelics but 5-MeO-
DMT also seems to have some acute subjective effects
that are not widely shared with typical psychedelics (see
Table 3). These include “white-out” experiences and cases
of loss of behavioral control (Lancelotta and Davis 2020),
perhaps suggesting automatism. Reactivations or flashback
phenomena are reported at a higher rate compared to typical
psychedelics (See Table 2). These distinctions in pharmacol-
ogy, combined with apparent differences in subjective effects
and potential for flashbacks phenomenon, suggest a distinct
mechanism and risk profile might be present for 5-MeO-
DMT compared to typical psychedelics.
Some of these distinctions suggest an epileptiform-like
mechanism might play a role in the unique effects and pos-
sibly therapeutic efficacy of 5-MeO-DMT. Additionally,
early behavioral research in animals (Ahlborg et al. 1968;
Ermakova et al. 2022; Gillin et al. 1976; Neuman and
Thompson 1989; Weil and Davis 1994) and case reports
and anecdotal accounts (Ball et al. 2022; Hitt and Ettinger
1986; Oroc 2009; Shulgin and Shulgin 1997) suggest that
5-MeO-DMT may precipitate seizure-like behaviors. Addi-
tionally, 5-MeO-DMT displays unique subjective effects
during the acute and post-acute periods that overlap with
focal seizures, particularly those implicating the temporal
lobes were 5-HT1A receptors are densely expressed (Beliv-
eau et al. 2017). Hypothetically, 5-MeO-DMT reactivations
could plausibly be focal seizures. The evidence presented
here supporting that notion highlights the need for further
basic research to elucidate 5-MeO-DMT’s mechanism of
action, as it appears to be distinct from typical psychedelics.
Still, despite the putative phenomenological overlap
between some manifestations of focal temporal lobe seizures
and 5-MeO-DMT-occasioned experiences and reactivations,
it is important to note that epileptic experiences do show
some distinctions from those induced by 5-MeO-DMT. For
instance, olfactory hallucinations have been reported to
occur in temporal lobe epilepsy, though they are relatively
uncommon (between < 1% and 7%) (Acharya et al. 1998;
Chen et al. 2003; Savage et al. 2017). To our knowledge,
olfactory hallucinations are not regularly discussed in anec-
dotal or scientific investigations of 5-MeO-DMT effects.
More crucially, mystical-type experiences are relatively rare
among people with epilepsy during a seizure, even those
involving the temporal lobes (Devinsky et al. 1991; Devin-
sky and Lai 2008). Although aspects of “ecstatic seizures”
overlap with mystical-type experiences (Åsheim Hansen
and Brodtkorb 2003; Gschwind and Picard 2016; Naito and
Matsui 1988; Picard et al. 2021; Picard and Craig 2009;
Picard and Kurth 2014), especially with regard to inef-
fability and timelessness/spacelessness, it is exceedingly
rare for a seizure to induce a complete mystical experience
13

(Greyson et al. 2015). This, then, suggests that mystical-
type phenomena associated with 5-MeO-DMT might not
be related to medial temporal lobe seizures. Still, the paral-
lels between generalized tonic–clonic seizures and visible
convulsions reported in cases of naturalistic use (Antibody
2016; Clark 2022a; Handsome 2009; Reverend 2002; Skully
2001) make the comparisons between focal seizures and the
5-MeO-DMT-ocassioned experience more plausible. It is
also possible that expectancy effects regarding the effects
of typical psychedelics may make individuals consuming
5-MeO-DMT in ceremonial or retreat settings more likely to
ascribe mystical-like effects to the altered state of conscious-
ness produced by 5-MeO-DMT. Indeed, within a setting that
elicited psychedelic-expectancies, even a placebo has been
shown to produce reported psychedelic-like effects in some
participants (Olson et al. 2020).
It is also possible that epileptiform activity produced by
5-MeO-DMT is distinct from typical temporal lobe seizures.
This may overlap with some work examining the neural cor-
relates of some meditation practices (Dennison 2019). Jhāna
meditation is an advanced form of meditation focused on
absorption (Burbea 2020). Some highly experienced jhāna
meditators are also able to evoke brief posterior spike-wave
bursts or even clonic seizure-like activity (Dennison 2019).
Behaviorally, an individual was also observed to display
clonic behavior during seizure activity while mediating.
Furthermore, advanced jhāna meditators often describe a
sense of entering “a void,” which may parallel the subjec-
tive experience induced by 5-MeO-DMT (Burbea 2020). But
unlike seizures, entering jhāna states appear to be voluntary
and controllable, even if they are associated with seizure-
like EEG activity (Dennison 2019). However, much like
5-MeO-DMT, the neural correlates of jhāna meditation are
just beginning to be investigated.
If 5-MeO-DMT is revealed to elicit epileptiform activity,
what does that mean for the future of the substance as a psy-
chiatric treatment? Our hypothesis that 5-MeO-DMT may
precipitate epileptiform activity mediated by 5-HT1A ago-
nism does not rule out its therapeutic use. Instead, we sug-
gest that a deeper understanding of its mechanism of action
will serve to facilitate the drug development process and
optimize its application. Currently, many widely prescribed
psychotropic medications are associated with lowering the
seizure threshold (Bhatti et al. 2017; Oh and Bainbridge
2012). Furthermore, electroconvulsive therapy (ECT), which
intentionally induces a seizure to treat severe mood and psy-
chotic disorders, displays rapid response and high chances
of remission of depression and is often more effective than
standard pharmaceutical treatment options (Dierckx et al.
2012; Husain et al. 2004; Pagnin et al. 2004). ECT, like
5-MeO-DMT (Lima da Cruz et al. 2018), also enhances
neuroplasticity and promotes neurogenesis (Ramnauth
et al. 2022; Sauvaget et al. 2022; Schurgers et al. 2022).
13
Psychopharmacology
Additionally, in some patients with epilepsy, a single sei-
zure can decrease depression symptoms (Hopp et al. 2022).
Simply put, therapeutic action and the induction of seizures
are not mutually exclusive. Indeed, ECT is still considered
one of the most robustly and reliably effective antidepres-
sant interventions (Dierckx et al. 2012; Husain et al. 2004;
Trifu et al. 2021).
Overall, we highlight here the uniqueness of 5-MeO-
DMT, arguing that its mechanism of action is distinct from
typical psychedelics. Epileptiform activity within the tem-
poral lobes is explored as a possible explanation for some
of 5-MeO-DMT’s distinctive properties, particularly its high
prevalence of reactivations or flashback phenomenon in the
post-acute effects. Still, it is important to recognize that typi-
cal psychedelics can also provoke flashbacks and seizures.
Despite this overlap, the distinctions in pharmacology and
subjective experience suggest that investigation of 5-MeO-
DMT as distinct from typical psychedelics is warranted and
may assist with capitalizing on its most efficacious thera-
peutic use. Subsequently, we offer several future research
directions ranging from pre-clinical to studies of natural-
istic use to examine the potential mechanism and risks of
5-MeO-DMT:
Recommended research
• We encourage further research to directly investigate the
subjective differences between 5-MeO-DMT and typical
psychedelics. This may be done through qualitative work
to derive a richer, yet systematic investigation of the sub-
jective effects of 5-MeO-DMT. Such research could also
aid with the development of questionnaires that might
be more sensitive to the effects of 5-MeO-DMT. Evalu-
ation of the potential risk of 5-MeO-DMT as compared
to other psychedelics should be conducted, including
evaluation of the frequency and severity of flashbacks
or reactivations. We also suggest that the any subjective
differences between flashbacks induced by typical psych-
edelics and 5-MeO-DMT be investigated.
• Systematic ecological assessment in the weeks following
5-MeO-DMT use in controlled and naturalistic settings to
garner a better understanding of the time course of reacti-
vations and potential triggers is recommended. Examina-
tion of the experience of reactivations and their poten-
tial impact on psychological outcomes is also suggested.
Further data is also needed to understand the frequency
of reactivations while doing activities such as driving
(Metzner 2013), which could have safety implications. It
has been estimated that most reactivations occur within
days to weeks following 5-MeO-DMT use (Ortiz Bernal
et al. 2022; Uthaug et al. 2020a). However, some report
more lasting reactivations that may continue for months.
Psychopharmacology
Therefore, it is recommended that follow-up occurs at
least a month after use and more if individuals report a
reactivation during this time.
• Animal studies should examine the ability of 5-MeO-
DMT to induce paroxysmal EEG activity and examine
whether 5-HT1A receptors mediate this activity during
the acute effects. In addition to acute effects, potential
post-acute changes in EEG should also be monitored.
As intracranial electrodes are a possibility with animal
studies, this would allow greater specificity into under-
standing which regions, if any, are likely to display epi-
leptiform activity after 5-MeO-DMT exposure.
• Further pre-clinical research is needed into how 5-MeO-
DMT affects 5-HT1A receptors and the brain at large.
This may help elucidate the mechanisms behind the abil-
ity of 5-MeO-DMT to produce distinct subjective expe-
riences compared to typical psychedelics. It is unclear
whether 5-MeO-DMT displays full or partial agonism at
the 5-HT1A autoreceptors and post-synaptic receptors.
Answering such basic questions may help illuminate the
mechanism behind 5-MeO-DMT’s distinct effects.
Conclusions
5-MeO-DMT has a distinct pharmacology and unique sub-
jective effects compared to typical psychedelics. More spe-
cifically, 5-MeO-DMT has high selectivity for the 5-HT1A
receptor and can produce experiences known as "whiteouts."
5-MeO-DMT may also be more likely to prompt reexpe-
riencing phenomena (e.g., flashbacks or reactivations) in
the post-acute effects than typical psychedelics. Still, early
clinical trials and studies of naturalistic use suggest it may
have promising potential as a therapeutic. However, little
research examining its mechanism of action has been con-
ducted. Overall, it is hoped that this manuscript galvanizes
further research into the likely unique mechanisms of action
of 5-MeO-DMT and fosters a balanced research agenda for
studying psychedelics more broadly.
Acknowledgements The authors acknowledge Richard C. Shelton, MD
and Kevin Murane, PhD for their insightful comments on an earlier
version of the manuscript. Camilla Strauss also provided some editing
on very early drafts.
Declarations
Conflicts of interest HMD and MS have no conflicts of interest. CDN
is a co-founder and board member of 2A Biosciences, and has a Spon-
sored Research Agreement with 2A Biosciences. CDN is an advisor to
Palo Santo. OS is a founder of Eudelics AB. RCH is a scientific advisor
to Usona Institute, Synthesis Institute, Mydecine, Maya Health, Os-
mind, Entheos Labs, Beckley Psychtech, TRYP therapeutics, Journey
Collab and Journey Space. PSH has been in paid advisory relation-
ships with the following organizations regarding the development of
psychedelics and related compounds: Bright Minds Biosciences Ltd.,
Eleusis Benefit Corporation, Journey Colab Corporation, Reset Phar-
maceuticals Inc., and Silo Pharma. PSH has received research funding
from the NIH and Heffter Research Institute.
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