









































Psilocybin, Depression, and 
Synaptogenesis: Insights into the 
Field’s Past, Present, and Future 

Anna Douglas, Daniel Staas, Anna Hampton, Kylie Burns, Fenn 
Suter

Volume Three
Edition Two
Spring 2023

 
GEORGETOWN SCIENTIFIC
RESEARCH JOURNAL

19



Georgetown Scientific Research Journal 

 

Psilocybin, Depression, and Synaptogenesis: Insights into the 
Field’s Past, Present, and Future 
 
AAnnnnaa  DDoouuggllaass**,,  DDaanniieell  SSttaaaass**,,  AAnnnnaa  HHaammppttoonn**,,  KKyylliiee  BBuurrnnss**,,  FFeennnn  SSuutteerr**  

  
*Indicates equal contribution 
Department of Biology, Georgetown University, Washington, D.C., United States of America 
E-mail: acd102@georgetown.edu, djs314@georgetown.edu, aeh157@georgetown.edu, kcb86@georgetown.edu, 
fcs14@georgetown.edu 
hhttttppss::////ddooii..oorrgg//1100..4488009911//ggssrr..vv33ii22..6622  

AAbbssttrraacctt  

Depression remains one the most commonly diagnosed mental health disorders in the United States. The 
Food and Drug Administration granted psilocybin breakthrough therapy status four years ago as a possible 
solution to this pervasive disorder. Since then, psilocybin, and hallucinogens in general, have produced 
promising results as alternatives to classical antidepressants. As more research confirms psilocybin’s 
potential therapeutic effect, research surrounding the mechanistic action of these 5-HT2A receptor agonists 
has increased as well. Hallucinogens have different downstream effects compared to non-hallucinogenic 
5-HT2A receptor agonists, including the formation of a 5-HT2A receptor and metabotropic glutamate 
receptor complex. Psilocybin’s unique synaptogenic effect may play a role in its therapeutic effect for major 
depressive disorder; however, the underlying mechanism by which synaptogenesis is induced upon 
psilocybin administration has not been explored.  Psilocybin’s distinctive upregulation of transcription 
factors, such as egr-2, c-fos, and brain-derived neurotrophic factors, and its connection with the TrkB 
signaling pathway, may be the answer to this unexplained mechanism. 

Keywords: Psilocybin, Hallucinogens, Depression, Synaptogenesis, 5-HTR, mGLUR

11..  IInnttrroodduuccttiioonn  

While originally discovered in blood serum for 
its effects as a vasoconstrictor (tonic) and its effects 
in the gut, serotonin’s role as a neurotransmitter 
was not thoroughly confirmed for nearly another 
decade when the findings of experiments with 
lysergic acid diethylamide (LSD) on peripheral 
nervous systems (PNS) were synthesized with the 
early localization of serotonergic receptors in the 
midbrain. Serotonin (5-HT) and LSD were 
quickly recognized to have an intimate 
relationship, but the subtypes of 5-HT receptors in 
the brain were not categorized or localized until 
decades later. One receptor, 5-HT2AR, was found 
to be tightly linked to hallucinogenic activity. 
Though it is debated, 5-HT2ARs are largely 

localized in the claustrum, cerebral cortex, 
olfactory tubercle, striatum, and nucleus 
accumbens.1 This debate is due to the fact that 
radioligands are not entirely specific to individual 
subtypes of receptors, including 5-HTRs.2 
Thorough research returned no indications of any 
GFP-tagged 5-HT receptor studies looking at 
neuroanatomy, which may be explained by the 
multitude of differences in 5-HTR localization 
between model species and humans. 

The first use for drugs targeting these receptors 
was recreational, as most were discovered as 
psychedelics or hallucinogens, producing 
consciousness-altering effects. The most 
prominent of these was lysergic acid diethylamide, 
or LSD, discovered in the 1900s by Swiss chemist 

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Albert Hoffman.3 While not as similar structurally 
to 5-HT or Psilocybin, it still shares the indole and 
similarly positioned nitrogen that allows binding 
to the 5-HT2AR, contributing to its similarity in 
hallucinogenic effect and usefulness in analogous 
psilocybin research. 

 
FFiigguurree  11..  CCoommppaarriissoonn  ooff  SSttrruuccttuurreess  ooff  
SSeerroottoonniinn,,  PPssiillooccyybbiinn,,  PPssiilloocciinn,,  aanndd  LLSSDD..  
Adapted from Bauer et al., 2019.4 Molecular 
structure of Serotonin, Psilocybin, its metabolite 
Psilocin, and LSD.  

Psilocybin (and its active metabolite, psilocin), 
however, is almost identical to 5-HT, featuring the 
same indole and distant NH2 group, with the only 
changes being the 2 additional n-methyl groups 
and the electronegative hydroxyl group shifting 
over one carbon on the benzene ring. Research into 
psilocybin, like LSD and other hallucinogens, was 
hampered by its designation as a schedule 1 drug 
by the US government, tightening regulations, 
increasing stigmas, and overall decreasing interest 
in researching its potential therapeutic effects. 

However, after decades of mixed opinions 
from the scientific community, hallucinogens are 
now widely accepted as potential therapies for all 
kinds of disorders, including substance abuse, 
anxiety, and depression, as will be discussed later.5 
In 2018, the FDA granted psilocybin 
breakthrough therapy status through COMPASS 
Pathways’ ongoing work in phase 2 clinical trials to 
combat Treatment Resistant Depression.6,7 In the 
United States, treatment resistant depression 
creates an annual burden of $43.8 billion dollars, 
with an estimated 12-month prevalence of 2.8 
million in 2021. More recently, the FDA also 
granted breakthrough status to a therapy from the 
Usona Institute in phase 2 trials to treat Major 
Depressive Disorder (MDD), expanding patient 
scope by an estimated 3-10 times. Medication-

treated MDD has a 12-month prevalence in the 
United States of 8.9 million adults, costing $92.7 
billion annually.6,8 Finding higher quality and 
more cost-effective treatments for these disorders 
would help millions of Americans and potentially 
tens to hundreds of millions of people 
internationally, as well as alleviate tens of billions 
of dollars in medical burdens in the US alone. 

22..  RReelleevvaannccee  ttoo  DDeepprreessssiioonn  

Depressive symptoms have been linked to 
overactivity of the brain network responsible for 
introspection and self-referential thinking, called 
the default mode network, which is localized to the 
medial prefrontal cortex, bilateral angular gyri, and 
temporal poles. Depression is also found to involve 
an impairment of the executive network and 
salience network, which are associated with 
cognitive control and switching between internal 
and external attention.9 The binding site of 
psychedelics such as psilocybin, 5-HT2AR, has 
become an important focus in depression research 
as this receptor is found most densely in a “broad 
pattern of cortex that closely resembles a 
conjunction map of the default mode, executive 
and salience networks.”10  

In a clinical trial in which patients with 
treatment resistant depression were given an orally 
administered 10mg dose of psilocybin and then 
another 25mg dose a week later, depression 
symptoms as measured by Beck’s depression 
inventory (BDI) decreased significantly. Starting 
from a BDI score of 34.81± 7.38, the mean was 
reduced by 21 points after one week and remained 
14.19 points lower relative to the baseline at the 
six-month check in. This was a greater decrease 
than that observed among those who were given 
the selective serotonin reuptake inhibitor (SSRI) 
escitalopram daily for six weeks.10 Another study 
which used the Quick Inventory of Depressive 
Symptomatology -Self Report (QIDS SR 16)  
showed no significant difference between scores of 
participants given psilocybin versus escitalopram 
after six weeks.11 This discrepancy is most likely 
due to the difference in timing between the two 

21



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studies' assessments and possible differences 
between the two self-reporting scales for 
depression symptoms. 

 
FFiigguurree  22..  BBeecckk’’ss  DDeepprreessssiioonn  IInnddeexx  SSccoorreess  aafftteerr  
ttrreeaattmmeenntt  wwiitthh  ppssiillooccyybbiinn  aanndd  eesscciittaalloopprraamm. 
DB-RCT BDI scores from each study arm and 
time point. Adapted from Daws et al., 2022.10 

In addition to having an equal or greater effect 
on self-reported feelings of depression, as 
measured by BDI or QIDS SR 16, than treatment 
with the SSRI escitalopram, psilocybin also 
decreased brain modularity, a measure of how 
segregated brain networks are from one another. 
Lower modularity means more functional 
connectivity between networks and a reduction of 
within-network connectivity. After treatment with 
psilocybin, there was a significant decrease in the 
hyperconnectivity within the default mode 
network that characterizes depression. There was 
also a significant increase in connectivity between 
the default mode and executive networks as well as 
the default mode and the salience networks. The 
researchers hypothesized that this increase of 
integration among brain networks was responsible 
for the antidepressant effect of psilocybin, so they 
compared brain modulation, measured by fMRI, 
and BDI scores of each patient and found that they 
were significantly correlated at the six-month 
point.10 Similarly, it has recently been shown that 
LSD, a hallucinogenic with a similar mechanism 
of action to psilocybin, is associated with a decrease 
in functional connectivity within the default mode 

network and an increase of functional connectivity 
between the default mode network and the 
executive network.12  

33..  MMoolleeccuullaarr  MMeecchhaanniissmmss  ooff  HHaalllluucciinnooggeennss  

3.1 Interactions with the 5-HT2A Receptor 
The clinical application of psilocybin as a 

treatment for depression is promising and has 
spurred investigations into how similar drugs 
function on a molecular level. Primarily, psilocybin 
and other hallucinogenic compounds function 
through their interactions with the 5-HT2A 
receptor. Psilocybin acts as a 5-HT2A receptor 
agonist, and the activation of this receptor can lead 
to hallucinogenesis in humans and experimental 
animals.13 Although there are other 5-HT2A 

receptor agonists, many do not produce 
hallucinogenic effects (non-hallucinogenic 
compounds)  indicating that hallucinogenic effects 
are caused by a specific signaling pathway.13 Both 
hallucinogenic and non-hallucinogenic 
compounds activate phospholipase C-β, but 
research conducted by González-Maeso et al. 
indicates that the hallucinogenic pathway is unique 
due to co-activation of heterotrimeric Gq/11 and 
pertussis toxin-sensitive Gi/o proteins.13 
Furthermore, expression of c-fos, egr-2, and egr-1 
is elevated by hallucinogenic compounds while 
non-hallucinogenic compounds only show c-fos 
elevation, allowing erg-2 and erg-1 to be used as a 
marker unique to 5-HT2AR hallucinogens.14 

Using the characteristic gene responses of c-fos 
and egr-1/2, González-Maeso et al. investigated 
how this hallucinogenic pathway worked. They 
found that when phospholipase C-β was inhibited 
by U73122, a gene response was not obtained by 
LSD or R-Lisuride, a non-hallucinogenic closely 
related to LSD (Figure 3A). Similarly, inhibition 
of Gi/o protein with pertussis toxin and inhibition 
of Src attenuated the gene response to LSD 
(Figure 3B). This indicates the importance of 
specific regulation of Gi/o protein and Src in 
response to hallucinogenic compounds like LSD, 
emphasizing their role in hallucinogenesis as a 

22



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result of partial or complete agonism of the 5-
HT2A receptor. 

 
FFiigguurree  33..  LLSSDD--SSppeecciiffiicc  SSiiggnnaalliinngg  iinn  PPrriimmaarryy  
CCoorrttiiccaall  NNeeuurroonnss. A) Cortical neurons treated 
with U73122, a PLC-β inhibitor, results in 
inhibition of gene expression in response to LSD. 
B) Gene induction pattern in response to LSD is 
attenuated by inhibition of Gi/o protein with 
pertussis toxin and not affected by inhibition of PI-
3-K with LY294002. LSD and R-lisuride are 
identical in the absence of Src activity via 
inhibition with PP2. Adapted from González-
Maeso et al., 2007.13 

Based on their research, González-Maeso et al. 
proposed a model that elucidates the molecular 
mechanism that results in the hallucinogenic 
response seen in psychedelics including LSD, 
psilocybin, and DOI. Although hallucinogenic 
and non-hallucinogenic compounds both interact 
with the 5-HT2A receptor, the conformation 
stabilized by hallucinogens like LSD is unique and 
leads to a different pattern of cellular signaling. In 
this research, they also assessed how recovery of 
the 5-HT2A receptor in specific neuron 
populations recovered the hallucinogenic response. 
Using htr2A−/− mice, they discovered that signaling 
and behavioral responses to hallucinogenic 
compounds were established when 5-HT2A 

receptors were restored within the cortical 
neurons. They did not find that restoration in the 
thalamus or subcortical brain region were sufficient 
in re-establishing normal hallucinogenic 
responses, indicating that these areas are not 
required for hallucinogenic activity, but that the 
cortex is.13 Overall, this outlines the molecular 
interactions with the 5-HT2AR typical of 
hallucinogenic drugs like psilocybin, dependent on 
Gi/o proteins, Gq/11 proteins, and Src. 

3.2 5-HT2AR and mGluR2 Complex Formation  
Although 5-HT2AR activation is an essential 

part of classical hallucinogenic function, discussion 
of the psychedelic mechanism would be 
incomplete without mentioning metabotropic 
glutamate receptors. These serotonergic receptors, 
5-HT2AR, and mGluRs are co-localized 
throughout the brain, specifically 5-HT2AR and 
mGluR2.15 Moreno et al. found that mGluR2 was 
essential to the hallucinogenic effects caused by 5-
HT2AR agonists. In this study, they injected (±)1-
(2,5-dimethoxy-4-iodophenyl)-2-aminopropane 
(DOI) and lysergic acid diethylamide (LSD) (both 
of which are functionally similar to psilocybin in 
their hallucinogenic effects) into mGluR2 
knockout (KO) mice. They found that the KO 
mice had a significantly reduced head twitch 
response (a common behavioral assay indicating 
hallucinogenic response upon 5-HT2AR 
activation) in a 30 minute window compared to 
wild type mice as seen in Figure 4, indicating 
mGluR2 was necessary for  hallucinogenic specific 
response within the mice.16,17 In a more recent 
study by Benvenga et al., DOI administered to 
mGluR2 KO mice failed to produce a significant 
number of head twitches even at a dose tenfold 
higher than the normal, peak effective dose that 
produced head twitches in wild type or mGluR3 
KO mice supporting Moreno’s findings.18

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FFiigguurree  44..  BBeehhaavviioorraall  rreessppoonnssee  ttoo  hhaalllluucciinnooggeennss  
DDOOII  aanndd  LLSSDD.. Wild type and mGluR2-KO mice 
(n = 4–5 per treatment group) were injected with 
vehicle, DOI (2 mg/kg) or LSD (0.24 mg/kg), and 
the head-twitch response was scored 15 min after 
injection for 30 min. ***p < 0.001; Bonferroni's 
post hoc test of two-way ANOVA. Data are 
means ± S.E.M. Adapted from Moreno et al., 
2011.16 

These findings suggested that 5-HT2AR relies 
on mGluR2 for its downstream effects upon 
activation. Per multiple co-immunoprecipitation 
based studies, it has been found that the two 
receptors form a heterocomplex.19 More 
specifically, phosphorylation at serine 843, an 
event dependent on 5-HT2AR activation, is a key 
modulator in mGlur2’s functioning in Gi/o and 
Gq/11 protein activation and subsequent 
signaling.20,21  

Gq/11 activation leads to phosphatidylinositol 
4,5-biphosphate hydrolysis and calcium release 
that promotes excitatory transmitter release. For 
example, extracellular glutamate levels in the 
somatosensory cortex of rats increases upon 
intracortical administration of DOI without any 
effect on GABA or glycine levels, thus increasing 
excitatory neurotransmission and activating 
NMDA receptors and AMPA receptors 
downstream (Figure 5).22 However, this activation 
is not only linked to hallucinogenic “behavioral” 
effects (such as head twitching in rats and mice), 
but also, as mentioned earlier, to the release of the 
transcription factor c-fos and brain-derived 

neurotrophic factor (BDNF).16,23 Gi/o’s activation is 
linked to increased egr-2 expression, a 
transcription regulatory factor highly expressed in 
migrating neural crest cells, and is essential for 
normal differentiation and maintenance of 
myelinating Schwann cells, which have been found 
to remyelinate in the CNS under certain 
conditions.24,25 The increased expression upon 
heterocomplex formation may be what underlies 
the increased synaptogenesis seen upon psilocybin 
administration in rats.  

 
FFiigguurree  55.. The figure shows a model in which 
hallucinogens, such as psilocin, lysergic acid 
diethylamide (LSD) and dimethyltryptamine 
(DMT), increase extracellular glutamate levels in 
the prefrontal cortex through stimulation of 
postsynaptic 5-HT2A receptors that are located on 
large glutamatergic pyramidal cells in deep cortical 
layers (V and VI) projecting to layer V pyramidal 
neurons. This glutamate release leads to an 
activation of AMPA (α-amino-3-hydroxy-5-
methyl-4-isoxazole propionic acid) and NMDA 
(N-methyl-D-aspartate) receptors on cortical 
pyramidal neurons. In addition, hallucinogens 
directly activate 5-HT2A receptors located on 
cortical pyramidal neurons. This activation is 
thought to ultimately lead to increased expression 
of BDNF. Adapted from Vollenweider et al., 
2010.26 

  

  

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44..  SSyynnaappttooggeenneessiiss  aanndd  PPssiillooccyybbiinn  

4.1 Synaptogenesis in the Pre-Frontal Cortex 
upon Psilocybin Administration 

Depression is associated with synaptic atrophy 
of the pre-frontal cortex; however, psilocybin may 
provide a fix to such atrophy.27 Shao et al. 
investigated how a single dose of psilocybin can 
lead to rapid and persistent growth of dendritic 
spines in the frontal cortex of mice (Cg1/M2), 
possibly reversing the synaptic atrophy associated 
with depression.28 Dendritic spines are small 
protrusions from neuronal dendrites that receive 
input from an axon at the synapse. They are the 
primary site of glutamatergic and excitatory 
neurotransmission in the brain and serve to 
maximize contact between neurons.   

Researchers dosed mice with 1mg/kg of 
psilocybin and analyzed the turnover of dendritic 
spines. Interestingly, dendritic spine formation 
increased significantly in both males and females, 
but the spine formation of females increased by 
nearly double that of males’.28 Additionally, there 
was no significant change in the rate of spine 
elimination, suggesting a net-positive growth rate 
in both males and females. Due to the deficit of 
synapses in the pre-frontal cortex, spine formation 
could lead to new neural connections that may 
alleviate symptoms of depression. This is 
significant because if these results can be replicated 
in humans, it could provide a possible molecular 
explanation to the alleviation of depressive 
symptoms commonly associated with 
hallucinogenics. 

The highest rate of dendritic spine formation 
occurred a day after administration; however, spine 
formation increased up to 7 days after 
administration suggesting that psilocybin has an 
extended ability to increase spine formation post-
administration. To further investigate, researchers 
imaged the new spines that formed 34 days later 
and found approximately a third of psilocybin-
provoked new spines persisted in growth (34% ± 
10% for females and 37% ± 12% for males).28 
These findings are novel and significant, 

considering there has been no direct 
demonstration in the past of psilocybin-induced 
structural plasticity observed at the cellular level in 
mammalian brains. 

 
FFiigguurree  66..  DDeennddrriittiicc  SSppiinnee  FFoorrmmaattiioonn  RRaattee  
PPeerrssiissttss  FFoorr  UUpp  ttoo  77  DDaayyss  AAfftteerr  TTrreeaattmmeenntt  wwiitthh  
NNoo  SSiiggnniiffiiccaanntt  NNeett  CChhaannggee  iinn  SSppiinnee  
EElliimmiinnaattiioonn  RRaattee. Mice (Cg1/M2) were dosed 
with 1mg/kg of psilocybin. After 7 days spine 
formation rate was greater in dosed mice compared 
to control mice. Spine formation rate was nearly 
double in females compared to males. 
Additionally, spine elimination rate did not 
significantly change. Adapted from Shao et al., 
2021.28  

Then, researchers attempted to replicate the 
above findings in a separate cohort of mice 
(ThyG1 mouse) and found similar results. By 
integrating data from these two cohorts, 
researchers were able to conclude that a single dose 
of psilocybin initiated dendritic spine growth in 
the medial frontal cortex of the mouse.28 
 Given that synaptic atrophy is associated with 
depression, these results have potential to 
revolutionize psilocybin’s use as an antidepressant. 
However, many questions remain before 
psilocybin can become an approved treatment for 
depression. For example, female mice experienced 
a much higher spine formation than male mice in 
this experiment. Perhaps biological sex plays a role 
in the effectiveness of psilocybin on spine 
formation. Research on human models is essential 
to further understanding of how psilocybin affects 
depression at the molecular level and its potential 
effects as a depression treatment.  

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Georgetown Scientific Research Journal 
 

 

4.2 Hypothesis to Synaptogenesis Caused by 
Psilocybin 

As previously mentioned, major depressive 
disorder has been linked to synaptogenesis 
disruption including loss of neurotrophic factor 
support.29 Antidepressants have shown to increase 
synaptogenesis and plasticity; however, the 
underlying mechanisms by which this occurs has 
not been investigated, likely because it is a 
combination of complex and interconnected 
mechanisms. Psilocybin’s analogous effect to 
antidepressants provides a new avenue to 
investigate the mechanisms that underlie 
synaptogenesis and plasticity upon serotonin 
receptor activation. 
 One such factor that may be involved is egr-2, 
specifically in its relation to hallucinogen 
generated synaptogenesis and plasticity. Moreno 
et. al. showed that mGluR2 KO mice did not 
express egr-2, indicating that this transcription 
factor relies on mGluR2 complex formation.16 
Very little research has been done on egr-2 as more 
focus has been given to its other gene family 
members. These family members include egr-1 
which is implicated in synaptic homeostasis and 
plasticity and egr-4 which has been found to 
modulate BDNF induction of potassium chloride 
cotransporter.30,31 However, one group found that 
mutations in the egr-2 gene are associated with 
hereditary myelinopathies.32 Although egr-2 has 
been found to be involved in the onset of 
myelination, its expression and effect on disrupted 
or damaged synapses had not been investigated, 
especially in its connection with hallucinogens or 
depression. 

Along with egr-2 expression being increased 
upon mGluR2 complex activation, c-fos 
expression was also increased. An important early 
response gene highly expressed within the 
prefrontal cortex, c-fos has been implicated in 
multiple important functions. For example, c-fos 
is essential for cell proliferation and differentiation, 
it is an activator of phospholipid synthesis during 
events that require biogenesis, and it modulates 
BDNF. In rats, c-fos and BDNF expression was 

found to be upregulated when administered 
antidepressants. 

No one has investigated BDNF’s expression 
upon mGluR2 complex activation despite the fact 
BDNF has been shown to encourage development 
and growth of new and existing neurons.33 BDNF 
potently binds to TrkB, creating a BDNF-TrkB 
signaling pathway. The TrkB gene contains at 
least three different receptor subtypes: TK+, T1, 
and T2.34 TrkB-T1 overexpression induces has 
been shown to promote elongation and an increase 
in the branch number of distal dendrites of cortical 
pyramidal neurons in slices.35 Moreover, research 
has implicated the BDNF-TrkB pathway as 
playing a role in cell migration, outgrowth of 
neurites, synaptogenesis, cell survival and death, 
neuronal transmission, and synaptic plasticity in 
the CNS.36 Referring back to Shao et al., (see 
under “synaptogenesis in the PFC”) researchers 
observed “rapid and persistent growth” of dendritic 
spines in the frontal cortex of mice.28 Shao et al. 
reported these observations but did not propose a 
molecular mechanism as to why this occurs. Upon 
further examination of new research and the results 
from Shao et al., it seems to be possible that the 
rapid and persistent growth of dendritic spines, as 
seen in Shao et al., could be caused by a 
complicated molecular pathway involving 5-
HT2AR-mGluR2 complex formation, c-fos and 
BDNF upregulation upon activation of this 
complex, and a BDNF-TrkB signaling pathway.  

55..  CCoonncclluussiioonn  aanndd  TThhoouugghhttss  ffoorr  tthhee  FFuuttuurree  

Psilocybin and other psychedelics are 
increasingly being explored for therapeutic 
purposes. Initial experiments show promising 
results for psilocybin in treating clinical 
depression, particularly treatment-resistant 
depression. Psychedelic applications could 
revolutionize depression treatments as experiments 
suggest the therapeutic effects of psilocybin may be 
prevalent after only one or two dosages, as opposed 
to the daily dosages required for many 
antidepressants. Furthermore, many 
antidepressants have unwanted side effects, such as 
drowsiness, that psychedelic therapy could  avoid.  

26



Georgetown Scientific Research Journal 
 

 

 Psilocybin acts on the 5-HT2AR. 
Hallucinogens stabilize a specific response at this 
receptor that results in a hallucinogenic specific 
response. Also vital to the molecular mechanism of 
psilocybin is the formation of a  5-HT2AR and 
mGluR2 complex. Specifically, glutamate release 
activates downstream receptors, which in turn 
release transcription factor c-fos and BDNF. 
Furthermore, BDNF binds to Trk, resulting in the 
BDNF-TrkB signaling pathway which has a role 
in processes including synaptogenesis and synaptic 
plasticity. 
 Psilocybin has also been shown to increase 
synaptogenesis in the prefrontal cortex. This 
finding is particularly significant as synaptic 
atrophy in the prefrontal cortex is associated with 
depression. More experiments should be 
conducted to determine the precise connection 
between these findings, including how egr-2 may 
play a role, but existing research supports 
psilocybin’s potential as an antidepressant. 
 Combining the research indicating the 
upregulation of c-fos, egr-2, and BDNF as a result 
of 5-HT2AR activation by psilocybin and the 
synaptogenesis seen in the prefrontal cortex, we 
put forth a hypothesis to explain how these results 
may work in conjunction with each other. The 
upregulation of c-fos, egr-2, and BDNF 
(connecting with the BDNF-TrkB signaling 
pathway) may be the molecular mechanism 
underlying synaptogenesis. One way to elucidate 
this mechanism would be to administer psilocin 
and track c-fos, egr-2 and BDNF’s expression 
throughout the brain. A few questions appear from 
this line of investigation: Does expression of these 
growth and plasticity related factors appear more 
in the prefrontal cortex? Does this expression 
coincide with synaptic growth and Schwann Cell 
migration? How might these factors and growth be 
related to mGluR2 complex formation? Exploring 
questions like these are on the forefront of the 
emerging field of psychedelic medicine. In the 
future, psilocybin and other psychedelics like LSD 
and DOI may play a vital role in the treatment of 
depression, impacting the lives of many and 

spurring research into new therapeutic 
applications. 

AAcckknnoowwlleeddggeemmeennttss  

We would like to thank Professor Katherine 
Maguire-Zeiss for her wonderful direction on this 
project during our Synaptic Transmission class and 
the Department of Biology at Georgetown 
University. 

RReeffeerreenncceess  

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https://doi.org/10.1007/7854_2017_478 

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psychedelics/ 

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