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Psychedelics Activate Serotonin to Produce Antidepressant Effect
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**Summary:** A new study advanced our understanding of how psychedelic
drugs activate serotonin receptors to offer potential treatments for
neuropsychiatric disorders. The identifies the interaction of
psychedelics like LSD and psilocybin with the serotonin receptor
5-HT1A, which is pivotal in their therapeutic effects.
By synthesizing derivatives of 5-MeO-DMT, a compound found in the
Colorado River Toad, the team demonstrated that specific targeting of
5-HT1A could lead to antidepressant effects without hallucinations.
These findings pave the way for developing non-hallucinogenic
psychedelic-derived medications for conditions like depression and
anxiety.
**Key Facts:**
1. **Psychedelics' Molecular Targets Identified:** The study highli
2. **Potential for Non-Hallucinogenic Treatments:** A newly synthes
3. **Implications for Mental Health Treatment:** This research coul
**Source:** Mount Sinai Hospital
**Researchers at the Icahn School of Medicine at Mount Sinai have
shed valuable light on the complex mechanisms by which a class of
psychedelic drugs binds to and activates serotonin receptors to
produce potential therapeutic effects in patients with
neuropsychiatric disorders such as depression and anxiety.**
In a study published May 8 in _Nature_ , the team reported that
certain psychedelic drugs interact with an underappreciated member of
the serotonin receptor family in the brain known as 5-HT1A to produce
therapeutic benefits in animal models.
"Psychedelics like LSD and psilocybin have entered clinical trials
with promising early results, though we still don't understand how
they engage different molecular targets in the brain to trigger their
therapeutic effects," says first author Audrey Warren, a Ph.D.
candidate in the Graduate School of Biomedical Sciences at Icahn Mount
Sinai
"Our study highlights, for the first time, how serotonin receptors
like 5-HT1A likely modulate the subjective effects of the psychedelic
experience and also play a potentially pivotal role in their
clinically observed therapeutic outcome."
LSD and 5-MeO-DMT, a psychedelic found in the secretions of the
Colorado River Toad, are known to mediate their hallucinogenic effects
through the serotonin receptor 5-HT2A, though these drugs also
activate 5-HT1A, a validated therapeutic target for treating
depression and anxiety.
Working closely with co-author Dalibor Sames, Ph.D., Professor in the
Department of Chemistry at Columbia University, the team synthesized
and tested 5-MeO-DMT derivatives in cell signaling assays and cryo-
electron microscopy to identify the chemical components most likely to
cause a drug to activate 5-HT1A over 5-HT2A preferentially.
That exercise led to the discovery that a compound termed 4-F, 5-MeO-
PyrT was the most 5-HT1A-selective compound in this series. Lyonna
Parise, Ph.D., an instructor in the lab of Scott Russo, Ph.D.,
Director of the Center for Affective Neuroscience and the Brain and
Body Research Center at Icahn Mount Sinai then tested that lead
compound in a mouse model of depression and showed that 4-F, 5-MeO-
PyrT had antidepressant-like effects that are effectively mediated by
5-HT1A.
"We were able to fine-tune the 5-MeO-DMT/serotonin scaffold to obtain
the maximum activity at the 5-HT1A interface and minimal activity at
5-HT2A," explains senior author Daniel Wacker, Ph.D., Assistant
Professor of Pharmacological Sciences and Neuroscience at Icahn Mount
Sinai.
"Our findings suggest that receptors other than 5-HT2A not only
modulate behavioral effects stemming from psychedelics but may
substantially contribute to their therapeutic potential.
"In fact, we were pleasantly surprised by the strength of that
contribution to 5-MeO-DMT, which is currently being tested in several
clinical trials for depression. We believe our study will lead to a
better understanding of the complex pharmacology of psychedelics that
involve many receptor types."
Indeed, researchers are hopeful, based on their breakthrough findings,
that it may soon be possible to design novel psychedelic-derived
medications that don't possess the hallucinogenic properties of
current drugs.
Raising their expectations is the discovery that their lead
compound—the most 5-HT1A-selective analog to 5-MeO-DMT—showed
antidepressant effects without the 5-HT2A-related hallucinations.
Another near-term target for scientists is investigating the impact of
5-MeO-DMT in preclinical models of depression (given the research
restrictions around psychedelic drugs, studies involving a 5-MeO-DMT
derivative have been limited to animal models).
"We've demonstrated that psychedelics have complex physiological
effects that span many different receptor types," emphasizes first
author Warren, "and are now ready to build on that finding to develop
improved therapeutics for a range of mental health disorders."
## About this psychopharmacology and psychedelics research news
**Author:** Audrey Warren
**Source:** Mount Sinai Hospital
**Contact:** Audrey Warren - Mount Sinai Hospital
**Image:** The image is credited to Neuroscience News
**Original Research:** Closed access.
"Structural pharmacology and therapeutic potential of
5-methoxytryptamines" by Audrey Warren et al. _Nature_
* * *
**Abstract**
**Structural pharmacology and therapeutic potential of
5-methoxytryptamines**
Psychedelic substances such as lysergic acid diethylamide (LSD) and
psilocybin show potential for the treatment of various
neuropsychiatric disorders. These compounds are thought to mediate
their hallucinogenic and therapeutic effects through the serotonin
(5-hydroxytryptamine (5-HT)) receptor 5-HT2A (ref. ).
However, 5-HT1A also plays a part in the behavioural effects of
tryptamine hallucinogens, particularly 5-methoxy- _N,N_
-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of
Colorado River toads.
Although 5-HT1A is a validated therapeutic target, little is known
about how psychedelics engage 5-HT1A and which effects are mediated by
this receptor.
Here we map the molecular underpinnings of 5-MeO-DMT pharmacology
through five cryogenic electron microscopy (cryo-EM) structures of
5-HT1A, systematic medicinal chemistry, receptor mutagenesis and mouse
behaviour.
Structure-activity relationship analyses of 5-methoxytryptamines at
both 5-HT1A and 5-HT2A enable the characterization of molecular
determinants of 5-HT1A signalling potency, efficacy and selectivity.
Moreover, we contrast the structural interactions and in vitro
pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic
agonist LSD and clinically used 5-HT1A agonists.
We show that a 5-HT1A-selective 5-MeO-DMT analogue is devoid of
hallucinogenic-like effects while retaining anxiolytic-like and
antidepressant-like activity in socially defeated animals.
Our studies uncover molecular aspects of 5-HT1A-targeted psychedelics
and therapeutics, which may facilitate the future development of new
medications for neuropsychiatric disorders.
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