Neurosci. Bull. January, 2023, 39(1):170–172
cn
https://doi.org/10.1007/s12264-022-00933-7
RESEARCH HIGHLIGHT
Non‑hallucinogenic Psychedelic Analog Design: A Promising
Direction for Depression Treatment
Ya‑Nan Yin1 · Tian‑Ming Gao1   
Received: 22 April 2022 / Accepted: 9 June 2022 / Published online: 5 August 2022
© Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences 2022
Depression is the most common neuropsychiatric disorder,
affecting 350 million people worldwide; it has been a leading
cause of suicide, causing serious harm to family members
and consuming a large amount of social resources. The onset
time of traditional antidepressants is usually 3–4 weeks, and
there is no ameliorating effect in nearly one-third of patients
with depression. Therefore, the discovery of fast and effec-
tive antidepressants has become an international research
hotspot [1]. Currently, there are two pathways for developing
novel and more desirable antidepressants. First, the most
common strategy is to identify new therapeutic targets by
uncovering the underlying mechanisms of depression, resil-
ience to stress, and drugs with ideal anti-depressive but seri-
ous side-effects. Secondly, retrofitting existing substances
with antidepressant potential is also an important tactic. The
natural hallucinogen psilocybin extracted from mushrooms
has been reported to have a fast and lasting therapeutic effect
on treatment-resistant depression and major depressive dis-
order in clinical studies [2, 3]. Moreover, it has been sug-
gested that increased spine density at the cellular level and
improved brain network integration at the organismal level
may underlie the therapeutic effect [4, 5]. Based on this, psy-
chedelic drugs seem to have promise for healing depression.
However, their hallucinogenic effects mean that they act as
* Tian‑Ming Gao
tgao@smu.edu.cn
1 pocket (EBP), which can accommodate and bind to ligands.
State Key Laboratory of Organ Failure Research, Key
Laboratory of Mental Health of the Ministry of Education,
Guangdong‑Hong Kong‑Macao Greater Bay Area
Center for Brain Science and Brain‑Inspired Intelligence,
Guangdong Province Key Laboratory of Psychiatric
Disorders, Department of Neurobiology, School of Basic
Medical Sciences, Southern Medical University,
Guangzhou 510515, China
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a double-edged sword, which limits their wide application.
So, it would be a significant achievement if their hallucino-
genic effects could be eliminated while their anti-depressive
effects are maintained.
Classic hallucinogens, such as psilocybin and D-lysergic
acid diethylamide (LSD) mainly bind to the 5-hydroxy-
tryptamine 2A receptor (5-HT2AR) [6], a G protein coupled
receptor. Even with the 5-HT2AR structure in hand [7], and
two recent studies reporting non-hallucinogenic psyche-
delic analogs with antidepressant effects in rodents [6, 8], it
remains unclear how to reasonably design such compounds.
Besides, whether the hallucinogenic effect is necessary for
the anti-depressive effect needs further exploration. Grati-
fyingly, scientists from China recently explained the pos-
sible mechanisms through which hallucinogens generate
anti-depressive effects by structural biology, and designed
some small molecule drugs that retain antidepressant effects,
but without hallucinogenic effects (Fig. 1) [9]. First, the
researchers purified 5-HT2ARs, then added the hallucino-
genic drugs psilocin (the active metabolite of psilocybin)
and LSD, as well as the non-hallucinogenic psychedelic
analogs lisuride and serotonin separately. Subsequently,
relatively high-resolution density maps of different ligand-
receptor complexes were obtained through X-ray crystal-
lography. By comparing the conformations of four differ-
ent substance-bound 5-HT2AR complexes, the researchers
found two binding pockets inside the 5-HT2AR, named the
orthosteric binding pocket (OBP) and the extended binding
The hallucinogen LSD can occupy both pockets at the same
time, while the hallucinogen psilocin is smaller and can bind
to either OBP or EBP. For the two drugs that do not produce
hallucinations, although the binding modes of lisuride and
serotonin are similar to those of LSD and psilocybin, respec-
tively, both molecules bind EBP less strongly. Functional
Y.-N. Yin, T.-M. Gao: Non-hallucinogenic Psychedelic Analog Design 171

Fig. 1  Mechanisms of action
of hallucinogens and designed
compounds. 5-HT2AR is a G
protein coupled receptor, which
possesses seven transmembrane
helices. Inside the receptor,
an orthosteric binding pocket
(OBP) and an extended binding
pocket (EBP) have been identi-
fied (Pocket 1 refers to OBP
and Pocket 2 refers to EBP),
which binds with hallucinogenic
drugs psilocin and LSD, as
well as the non-hallucinogenic
psychedelic analogs lisuride and
serotonin. The binding to OBP
triggers Gq-mediated signaling
while binding to EBP induces
activation of the β-arrestin
pathway. The hallucinogens
LSD and psilocin bind to both
the OBP and the EBP, and
this leads to strong activation
of both the G-protein and the
β-arrestin pathway and produces
hallucinatory and anti-depres-
sive behaviors in mice. The
compounds designed based on
the structure of the EBP mainly
bind to EBPs and prefer to
activate the β-arrestin pathway.
Meanwhile, these compounds
show significant anti-depressive
effects, but do not cause hal-
lucinations [9].

study showed that the binding of OBP activates the G protein
signaling pathway whereas the binding of EBP activates the
β-arrestin pathway. The hallucinogenic effect of the drugs
may be achieved through the simultaneous strong activation
of both signaling pathways. The second binding mode that
serotonin and psilocin can be accommodated at the EBP of
5-HT2AR is newly discovered and non-classical. Therefore,
designing ligands that bypass the OBP and target the EBP
may identify 5-HT2AR ligands that specifically activate the
β-arrestin signaling pathway, and these EBP-targeting mol-
ecules may not have hallucinogenic effects.
Based on the structural characteristics of the EBP in
the 5-HT2AR, the researchers designed a molecule named
IHCH-7086 that mainly binds to the EBP and avoids bind-
ing to the OBP. By analyzing the crystal structure of the
IHCH-7086-bound 5-HT2AR complex, it was found that the
binding site of IHCH-7086 in the 5-HT2AR is consistent
with the assumption, and there is a significant preference
for β-arrestin signaling. Subsequently, with the help of a
magnetometer-based detection system, the researchers exam-
ined the effects of IHCH-7086 and IHCH-7079 (analogues
of IHCH-7086) on the head twitch response (HTR) in mice,
which aims to evaluate the hallucinogenic effects of the
designed small molecules, and found that even high doses
of IHCH-7086 and IHCH-7079 did not induce HTR in mice.
Finally, the researchers found that both IHCH-7086 and
IHCH-7079 significantly improve depression-like behavior
in mice subjected to acute restraint stress or corticosterone
injection, and an antagonist of 5-HT2ARs (MDL100907)
blocks this improvement. Overall, the specific and modest
5-HT2AR arrestin-biased activation may be sufficient for
antidepressant effects, but not for hallucinogenic action.
This work not only illuminates the molecular mechanisms
underlying the anti-depressive effects of hallucinogens in

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172
depth, but also provides important theoretical guidance into
the development of fast- and long-acting antidepressants.
However, there are some interesting issues worth discuss-
ing. First of all, chronic social defeat stress and chronic
mild stress are more classical and widely-used rodent mod-
els of depression [10, 11]. Beyond this, the forced swim
test alone, which is similar to the tail suspension test, is
gradually being recognized as a paradigm for evaluating the
stress-coping response, not depression-like behavior [12].
Therefore, drawing support from widely-used rodent models
of depression and evaluating multiple indicators of depres-
sion, such as anhedonia and social avoidance will make this
significant work more persuasive for the treatment of depres-
sion. Second, hallucinations in humans are often defined as
high-confidence false visual or auditory percepts, and visual
and auditory hallucinations have been reported in mice [13,
14], so if subsequent studies of designed psychedelic ana-
logs include the detection of sensory-related hallucinations,
they will increase the awareness of novel designed drugs.
Third, this study demonstrated that strong activation of both
the G protein signaling pathway and the β-arrestin pathway
have hallucinogenic and antidepressant effects, while mod-
est β-arrestin pathway activation only has an anti-depressive
effect. Therefore, is there a regulatory mechanism specific to
hallucinogenic effects? Also, the effect of activation of the
G protein pathway alone on hallucinogenic responses and
depressive-like behaviors in mice is worth exploring.
Recently, it has been suggested that this study provides a
roadmap for eliminating hallucinations in healing through a
mind-shift approach [15, 16]. Furthermore, this study pro-
vides a good example for the development of new medi-
cations for mental illness through a strategy to circumvent
side-effects. Ketamine, an NMDAR antagonist, has gained
much attention due to its rapid and long-acting antidepres-
sant effects. However, because of the abuse potential and
side-effects such as hallucinations [17], its widespread use is
limited, especially for the treatment of depression. Besides,
in a phase III trial, assisted therapy with 3,4-methylenedi-
oxymethamphetamine (MDMA) significantly improved the
symptoms of patients with severe post-traumatic stress dis-
order. Just like ketamine, MDMA is also an illegal drug due
to its strong hallucinogenic effects and other side-effects.
Therefore, analog molecules may be designed based on the
detailed structural features of the target sites, which confer
therapeutic properties without side-effects. Consequently,
structure-based non-hallucinogenic psychedelic analogs may
be promising medications for the treatment of neuropsychi-
atric diseases.
Acknowledgements  This Research Highlight was supported
by grants from the National Natural Science Foundation of China
(82090032 and 31830033), the Key Area Research and Develop-
ment Program of Guangdong Province (2018B030334001 and
2018B030340001), Guangdong Basic and Applied Basic Research
13
Neurosci. Bull. January, 2023, 39(1):170–172
Foundation (2020A1515110565), and the Science and Technology
Program of Guangzhou (202007030013).
Conflict of interest  The authors declare no conflicts of interest.
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