





































Berkeley
Pharma Tech
Journal of Medicine

Correspondence: 
suhina.sharma@berkeley.edu

Keywords:
Major Depressive Disorder (MDD) 
Antidepressants
Ketamine
Psilocybin
Psychedelics
Glutamate
Serotonin

Submitted: August 12, 2022 

Accepted: October 31, 2022

Published: December 28, 2022

Full Open Access

Creative Commons Attribution 
License 4.0

Abstract
Depression is a complex neurological disorder that has many potential causes and 
treatment approaches. Though there are many conventional antidepressants available 
in the market, it is becoming increasingly difficult to rely on them as many patients 
may experience a lack of effectiveness or tolerance to these antidepressants. While 
current antidepressants increase serotonin and norepinephrine concentrations 
through reuptake inhibition, novel forms of antidepressants rely on the direct 
manipulation of receptors, thereby also improving neuroplasticity, which has emerged 
as a promising approach to treating depressive symptoms. In this literature review, 
various forms of novel antidepressants are analyzed. The mechanisms studied are 
Psilocybin’s long-term success, Ketamine’s rapid action, hormonal treatments’ direct 
targeted approach, and natural products’ reduction of neurotoxic side effects. 
Understanding how these powerful mechanisms work may allow for the research and 
creation of more effective antidepressants in the future.

Novel Therapeutic Strategies for Depression
By: Suhina Sharma, Matt Gostkowski, Jay Patel and Christina Yang



 

Berkeley Pharma Tech Journal of Medicine | 21 

1. Introduction 

Within the last few years, Major Depressive Disorder (MDD) has become 
one of the world’s leading health problems. Within the last year, there were 
over 45,000 deaths, about one death every 11 minutes, by suicide, making it 
one of the leading causes of death in the United States1. Since MDD causes 
significant impairment in daily life, effective antidepressant treatments are 
necessary. Many current antidepressants focus on increasing serotonin, 
norepinephrine, or dopamine in patients with moderate to severe depressive 
symptoms through reuptake inhibition2. However, these conventional 
forms of antidepressant therapies are often ineffective in patients because 
there are many types of depression, including stress-induced, anxious 
depression, and treatment-resistant depression3. This complexity makes it 
difficult to find therapies that work for each patient. Furthermore, there is a 
lot of uncertainty regarding the long-term effects of conventional 
antidepressants and the potentially toxic side effects. 
 
There have been recent attempts at implementing novel therapeutic 
strategies for depression that are more effective than conventional 
treatments. In this literature review, we will analyze Ketamine as a short-
term therapeutic option4, Psilocybin as a long-term therapeutic option5, 
other psychedelic-related drugs6, natural depression remedies7, as well as 
hormonal treatments for depression8. All these novel strategies target 
depression differently through inhibition and modulation of specific 
receptors, neurotransmitters, and other biomarkers to significantly reduce 
suicide ideation and depressive symptoms. These novel antidepressants are 
researched because of their promising clinical tests and diverse 
mechanisms. Because these antidepressants have different mechanisms of 
treating depression, it is important to analyze which mechanisms are the 
most powerful in contributing to the most successful antidepressant, as it 
can be the baseline for the research and creation of more effective 
antidepressants in the future. The success of these novel antidepressants is 
measured based on their ability to prolong the therapeutic effect, increase 
neuroplasticity, and reduce neural toxicity. 



 

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2. Pathophysiology of Depression 

Currently, many neurobiological theories exist for the pathophysiology of 
MDD. However, it has been difficult to choose one unified theory due to 
the clinical and etiological heterogeneity of the disorder9. For example, 
depressive pathophysiology can change significantly over the course of the 
illness, and all theories of depression are only relevant to some depressed 
patients in the population. As each patient is likely unique, it is critical to 
tailor treatment approaches specifically. This review will discuss a few of the 
current theories with the strongest empirical foundation, as each can be 
useful in developing novel therapies. 
 
The monoamine deficiency theory posits that the underlying 
pathophysiological basis of depression is a depletion of the 
neurotransmitters—serotonin, norepinephrine, or dopamine—in the 
central nervous system9. Depletion of these neurotransmitters happens when 
presynaptic cells take the neurotransmitters back up before it reaches the 
receptor or when too little of a specific neurotransmitter is produced. These 
neurotransmitters are part of the monoaminergic systems, which are 
involved in important brain functions such as mood regulation, reward 
processing, circadian rhythm, and attention. In clinical trials, almost every 
compound that inhibits monoamine reuptake has been an effective 
antidepressant. This observation is what led to the development of the 
monoamine deficiency theory. Although antidepressants that target the 
monoamine systems can be initially effective, full, and partial resistance to 
these drugs and delayed onset of action occurs. These limitations suggest that 
dysfunctions of monoaminergic neurotransmitter systems in MDD 
represent effects of other abnormalities9. The monoamine deficiency theory 
remains the clinically most relevant theory, and new findings on dopamine 
have shown further potential in producing novel therapeutic strategies for 
depression. 
 
The GABAergic hypothesis of MDD suggests that alterations in GABAergic 
transmission represent fundamentally important aspects of the etiological 
sequelae of MDD that are reversed by monoaminergic antidepressant drug 
action10. GABA is a neurotransmitter predominantly responsible for 
mediating neural inhibition in the brain. Magnetic resonance imaging 



 

Berkeley Pharma Tech Journal of Medicine | 23 

studies have shown that in acute depression, there are consistent reductions 
in total GABA concentrations in the prefrontal and occipital cortex. This 
observation may be due to acute stress effects or reduction in the density and 
size of GABAergic interneurons. However, there is also contradictory 
evidence of the GABA hypothesis9. 
 
Circadian abnormalities have been hypothesized to be etiologically 
associated with MDD. The circadian rhythm is part of the body clock that 
helps regulate body fatigue through day and night11. Disruptions to sleep and 
daytime fatigue is a criterion for depression, which suggests a subgroup of 
depression patients may have impaired circadian rhythms. In clinical studies, 
adjustments to the circadian cycle have been shown to have specific effects 
on subsequent mood and can even have antidepressant effects. Based on 
these findings, this hypothesis suggests that shortened REM latency, the 
association between phase advance of the sleep-wake cycle and phase 
advances in nocturnal cortisol secretion, and the effect of antidepressants on 
circadian rhythms are etiologically associated with MDD9. However, more 
research is required into the molecular explanation. 
  

3. Important Receptors Involved in Depressive 
Symptoms 

 
The serotonin hypothesis has dominated the field of depression research for 
decades. There are multiple receptors that have been implicated, but 
serotonin-1A (5-HT1A) and serotonin-1B (5-HT1B) are among the most 
important receptors as deemed by recent and ongoing research projects12. 

The 5-HT serotonin receptor group has been broadly linked to both anxiety 
and depression disorders13. The 5-HT receptor is found throughout the 
central and peripheral nervous systems in the form of either a G protein-
coupled receptor or a ligand-gated ion channel. It is acted upon by the 
chemical serotonin and then proceeds to promote either excitatory or 
inhibitory neurotransmission. After binding to serotonin presynaptically, 
the receptor modulates the release of neurotransmitters such as glutamate, 
GABA, and dopamine and hormones such as oxytocin, prolactin, and 
cortisol, leading to physiological changes affecting emotion and cognition14. 
Furthermore, a growing and diverse body of evidence support the 



 

Berkeley Pharma Tech Journal of Medicine | 24 

involvement of 5-HT1A, the main inhibitory serotonergic receptor, in both 
mental disorders. This important role of the serotonin receptor was initially 
discovered through studies of tryptophan depletion, as tryptophan is the 
molecular precursor to the 5-HT receptors15. Recent studies have focused on 
the direct role of 5-HT receptors. Studies have implicated dysregulation of 
5-HT neurotransmission as a primary defect in mood and anxiety 
disorders13,15. Complementary research findings suggested that 5-HT may 
play a role in recovery from mood disorders via selective serotonin reuptake 
inhibitors (SSRIs) and other serotonergic agents16. The role of 5-HT 
receptors in depression has additionally been shown through human studies, 
5-HT1A polymorphism research, preclinical pharmacological studies, and 
preclinical genetic approaches. 
 

Beyond the 5-HT receptor, other receptors affecting brain chemistry have 
been indicated to improve outcomes for patients with MDD. NMDA 
antagonists, such as ketamine, have been associated with antidepressant 
effects in patients suffering from MDD17. The NMDA receptor is typically 
activated by glutamate, which causes an influx of calcium ions and 
subsequent membrane depolarization for an action potential18. However, 
antagonists have been proposed to antagonize NMDA receptors on 
GABAergic interneurons and broadly increase levels of glutamate, the major 
excitatory neurotransmitter in the nervous system. AMPA receptor 
activation functions in a similar manner, except calcium ions, are substituted 
for sodium ions which allows for faster action potentials. In recent studies, 
compounds that augment signaling through AMPA receptors have been 
found to promote antidepressant-like behavioral effects in animal models19. 

 

4. Molecular Mechanisms of Antidepressants 
Most current antidepressant medications fall under the category of reuptake 
inhibitors, namely selective serotonin reuptake inhibitors (SSRIs) and 
serotonin and norepinephrine reuptake inhibitors (SNRIs)20. These 
medications function by preventing neurotransmitters (serotonin and 
norepinephrine) from being reabsorbed back into neurons in the brain after 
they are released. The mechanism of these drugs is based on the monoamine 
hypothesis, which states that depression is caused by a lack of available 
monoamines. By blocking reuptake and increasing the extracellular 



 

Berkeley Pharma Tech Journal of Medicine | 25 

concentration of monoamines, these drugs are thought to enhance and 
restore connections between neurons, ultimately resulting in an improved 
mood in patients21. 
 
Current research in antidepressants, however, is not based on the 
monoamine hypothesis and reuptake inhibition mechanism, largely due to 
the inconsistent results and efficacy of the current antidepressant 
medications. Reuptake inhibitors do not directly target the glutamatergic 
system, which plays a significant role in the brain and is thought to be a vital 
system regarding depressive symptoms20,21. Glutamate is an important 
neurotransmitter of the glutamatergic system and is released in response to 
increased 5-HT2A receptor activation22. While SSRIs and SNRIs indirectly 
interact with the 5-HT2A receptor by increasing neurotransmitter 
concentrations, they do not impact receptor activation or functionality22. 
Reuptake inhibitors have instead been found to cause postsynaptic receptor 
downregulation, which explains the delayed effects that patients often 
experience with current antidepressants23. SSRIs have also been shown to 
disrupt K+ channels that are necessary for glutamate reuptake by astrocytes, 
which are glutamate transporters. Blunted glutamate reuptake has recently 
been found to be associated with MDD23,24. 

 
 



 

Berkeley Pharma Tech Journal of Medicine | 26 

 
Figure 1: Mechanism of Selective Serotonin Reuptake Inhibitors (SSRIs). When 
serotonin is released from a presynaptic cell into the synapse it can then bind to 5-HT receptors 
on the postsynaptic cell. This pathway, as mentioned before, is involved with important brain 
functions such as mood regulation, sleep, reward processing, and cardiac rhythm. Synaptic 
serotonin can also be reabsorbed by the presynaptic cell through 5-HT transporters, causing a 
decrease of serotonin available to bind to the postsynaptic 5-HT receptors. As seen in the figure 
above, SSRIs block the 5-HT transporter from reabsorbing serotonin, therefore increasing the 
concentration of serotonin in the synapse that can bind to postsynaptic 5-HT receptors. 

  
Novel antidepressant therapies currently being researched, such as ketamine 
and psilocybin, largely function as receptor agonists and antagonists. 
Receptor agonists activate a receptor to produce a response, which results in 
increased receptor functionality/activation. Psilocybin is an example of a 
receptor agonist, specifically activating 5-HT2A receptors. Receptor 
antagonists are molecules that block receptors to prevent a response, which 
in turn can increase neurotransmitter concentrations in the synapses and 
increase the activity of different receptor-mediated pathways, as seen with 
ketamine and the NMDA receptor25,26. While treatments of this nature show 
promise in effectively treating depression both short- and long-term, much 
is still unknown regarding the long-term adverse effects and the overall 
efficacy of repeated exposure to these drugs. The specific concerns and 
research required for these drugs are discussed below. 



 

Berkeley Pharma Tech Journal of Medicine | 27 

 
Figure 2: Ketamine as a Receptor Antagonist. Ketamine functions as an NMDA 
receptor antagonist, blocking molecules, such as glutamate, from activating the receptor. When 
the NMDA receptor is activated on inhibitory GABA interneurons (left figure), it blocks the 
release of glutamate from nearby neurons and from activating AMPA receptors in 
postsynaptic neurons. Glutamate and the AMPA receptor are important components of the 
glutamatergic system, which is heavily linked with processes of mood regulation. When 
ketamine is present (right figure) it functions by blocking the NMDA receptor, therefore 
preventing the inhibitory effect of the GABA interneuron. This increases the amount of 
glutamate that is released into the synapse and preferentially activates the AMPA receptors, 
which causes a more rapid cascade reaction and antidepressant effect. 

 



 

Berkeley Pharma Tech Journal of Medicine | 28 

 
Figure 3: Basic Mechanism of Receptor Agonists. Receptor agonists are molecules that 
can function like neurotransmitters and activate certain receptors, causing a cascade of 
reactions that ultimately lead to activation of other receptors or expression of specific genes and 
proteins. Psilocybin is an example of a receptor agonist, which is displayed as the red diamond 
in the figure above. 

  

5. Treatments of Interest and their Efficacy in 
Treating the Different Forms of Treatment-
Resistant Depression 

 5.1. Ketamine as a Short-Term Therapeutic Option 

There has been a lot of recent research utilizing ketamine as a short-
term therapeutic option. Ketamine gained popularity with its efficacy for 
treatment-resistant depression. Due to its rapid onset and short duration of 
action, ketamine has a strong antidepressant effect. As mentioned earlier, 
ketamine is an NMDA receptor antagonist, therefore keeping glutamate 
levels higher. Ketamine affects glutamate levels, essentially targeting a 
neurotransmitter different from most common neurotransmitters targeted 
with conventional antidepressants27. Increased glutamate levels result in 



 

Berkeley Pharma Tech Journal of Medicine | 29 

lessened depressive effects as scientific research confirms the involvement of 
the glutamatergic system in the processes of mood regulation. In addition, 
the glutamatergic system is involved in neuroplasticity processes28, such as 
the formation of synapses and the regulation of memory. However, other 
NMDA receptor antagonists do not have the same fast-acting effects, which 
suggests something else makes ketamine successful– ketamine metabolites29, 
depending on its structure and chemistry. Ketamine also acts on the mTOR 
pathway30, AMPA receptors and even the opioid receptors in the brain. The 
mTOR pathway is involved in cell proliferation, mortality, survival, and 
protein synthesis, resulting in the growth of new neural connections, and 
increasing neuroplasticity. Clinical trials have been done that show 
ketamine’s rapid antidepressant effects. In one study, twenty-five males were 
given one dose of ketamine and its changing effects were measured over time, 
starting baseline at 1 h and 2 weeks after the last dose of ketamine, and 1 
month after the last dose31. The table between the three pairs are shown 
below. 

 

 

 

 

 

 

 

 

 

 

 



 

Berkeley Pharma Tech Journal of Medicine | 30 

Hamilton Rating Depression 
Scale 

Mean ± SD 

Pair 1:   

Depression Baseline 23.40  ± 5.38 

After 1 hr. of ketamine dose 21.20 ± 6.34 

Pair 2:   

Depression Baseline 23.40  ± 5.38 

After 2 weeks of ketamine dose 10.25 ±  6.40 

Pair 3:   

Depression Baseline 23.40  ± 5.38 

After 1 month of ketamine dose 10.45 +8.47 

Table 1: Effect of ketamine treatment over time: Changes in the Hamilton Rating 
Scale for depression scores. 

 

The Hamilton Depression Rating Scale is the most used administered 
depression scale, with a higher rating indicating higher depressive levels in a 
patient31. From the table, it is clear that the mean reduction of depression 
scores decreased, with the most notable change being at the two-week 
mark31. However, after one month of ketamine doses, the numbers do not 
drop– they stay roughly the same. This data indicates that ketamine’s effects, 
though powerful and promising, are relatively short-term31. 

 

5.2. Psilocybin as a long-term treatment option 

Psilocybin is a naturally occurring hallucinogen that has recently been 
identified as a potential long-term therapeutic option for depression. 
Psilocybin acts as a 5-HT2A receptor agonist, activating the receptor that is 
involved with mood, emotions, thoughts, perceptions, etc. 32. By 
stimulating 5-HT2A receptors on large glutamatergic pyramidal cells, 
psilocybin also increases the synaptic concentration of glutamate in the 
prefrontal cortex (PFC) 33. Rather than blocking the reuptake of 



 

Berkeley Pharma Tech Journal of Medicine | 31 

neurotransmitters to increase synaptic concentrations like current 
antidepressant medications, psilocybin directly interacts and activates the 5-
HT2A receptor to induce changes in mood and thoughts32. In December 
2016, a randomized, double-blind clinical trial involving psilocybin 
administration to patients with life-threatening cancer found that treatment 
with a high dose of psilocybin administered under supportive conditions 
reduced depressive symptoms in patients as quickly as 1 week, with effects 
lasting up to 3 months in 12 patients. There was also a decrease in depressed 
mood in some patients at a 6 month follow-up34. Numerous adverse effects 
were observed, but none were deemed life-threatening. No adverse effects 
were displayed in patients after the study was concluded34. The table below 
shows the results of this study, with numerous different outcome measures 
used to evaluate symptoms of depression, anxiety, and overall mood. Each of 
the outcome measures used is briefly explained in the table. This was a 9-
month study performed with 56 participants randomly assigned to two 
groups either receiving high doses or low doses of psilocybin; while the 
results of this study are promising, there is a need for a larger and more diverse 
patient population to fully examine the effects of psilocybin as an 
antidepressant. 
  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 



 

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Measure Group Baseline Post-session 1 Post-session 2 6 months 

GRID-HAMD-17 
(Depression)a 

Low-Dose 1st 22.32 14.80 6.50 6.95 

High-Dose 1st 22.84 6.64 6.52 6.23 

Beck Depression Inventory 
(BDI)b 

Low-Dose 1st 18.40 12.92 8.17 8.00 

High-Dose 1st 17.77 7.00 5.80 6.17 

HADS 
Depressionc 

Low-Dose 1st 9.48 6.04 4.57 4.64 

High-Dose 1st 9.81 3.92 4.28 3.46 

HAM-A 
(Anxiety)d 

Low-Dose 1st 25.68 16.64 8.92 7.95 

High-Dose 1st 25.73 8.48 7.52 7.04 

STAI-Trait 
Anxietye 

Low-Dose 1st 47.46 40.48 35.48 36.83 

High-Dose 1st 47.73 34.64 34.28 35.32 

POMS Total Low-Dose 1st 51.72 42.48 21.09 23.50 

Mood Disturbancef High-Dose 1st 56.93 18.96 17.14 12.52 

Brief Symptom 
Inventory (BSI)g 

Low-Dose 1st 41.76 33.74 26.08 23.50 

High-Dose 1st 40.19 18.08 16.48 14.35 

MQOL (Overall 
Quality of Life)h 

Low-Dose 1st 5.69 6.17 6.90 6.88 

High-Dose 1st 5.32 7.14 7.46 7.65 

MQOL 
(Meaningful 
Existence)i 

Low-Dose 1st 6.03 6.10 7.30 7.29 

High-Dose 1st 5.43 7.23 7.30 7.62 

LOT-R 
Optimismj 

Low-Dose 1st 13.56 13.60 15.96 16.68 

High-Dose 1st 14.15 17.23 17.16 17.43 

Table 2: Effects of Psilocybin. Changes in 10 different outcome measures/scales after session 1, 2, and at a 6-
month follow-up in two groups receiving different dosages of psilocybin. 
__________________ 
a   The GRID-HAMD-17 is a clinician-rated measure of depression, with lower scores correlating to fewer 

symptoms of depression34. 

 



 

Berkeley Pharma Tech Journal of Medicine | 33 

b,c   The BDI and HADS tests are self-rated measures of depression, with lower scores indicating fewer depressive 

symptoms34. 

d   The HAM-A is a clinician-rated measure of anxiety, with lower scores signifying less anxiety in patients34. 

e   The STAI test is a self-rated measure of anxiety, with lower scores signifying less anxiety34. 

f   The POMS test is a self-rated mood measure, with lower scores indicating an overall better mood34. 

g   The BSI score is a self-rated measure of psychiatric symptoms, with lower scores indicating fewer feelings of 

distress34. 

h, i   The MQOL test is a self-rated measure of the overall quality of life, with higher scores indicating a better 

quality of life34.                                                                                                                                                                                                   

j   The LOT-R test is a self-rated optimism measure, with higher scores correlating to more feelings of optimism34.

  

 

Psilocybin also differs from current antidepressants in that limited exposure 
or administration of the drug has the potential for longer-lasting effects. 
Recent studies also show signs of high transient neuroplasticity after a single 
dose of psilocybin, which is a possible source of the longer-lasting effects 
associated with psilocybin33,34. Psilocybin targets inflammatory and 
oxidative stress pathways that lead to an increase in brain plasticity and 
cognitive flexibility, both of which are important gauges of 
neuroplasticity33. A study published in November 2021 also found that 
psilocybin increases the expression of genes related to neuroplasticity (c-Fos, 
Junb, Dusp1)33,34. This study refers to a clinical trial involving mice in 
which it finds that mice treated with psilocybin experienced increased 
density and strength of neural connections by 10 percent33. The same study 
published in 2021 also finds that suicidal behaviors are associated with 
neuroplastic dysfunction and that those that die from suicide have low 
levels of brain-derived neurotrophic factor (BDNF) in certain regions of the 
brain33. Psilocybin’s ability to increase neuroplasticity in patients suggests 
that it could be used to treat patients at high risk of suicidal behaviors. 
However, more research is needed to fully evaluate its efficacy for these 
conditions. 
 
While psilocybin has shown promise as a novel therapeutic option to treat 
depressive symptoms due to its prolonged effects on neuroplasticity, there is 
still much unknown. Many studies and trials performed involved small 
sample sizes, so their findings cannot be applied to a larger population33. 
There is a need for a trial involving administration in a clinical setting, which 
is not as ideal and accessible. 
 
 



 

Berkeley Pharma Tech Journal of Medicine | 34 

 5.3. Psychedelic-related drugs 

We have already seen an example of a popular, effective psychedelic-related 
drug– Psilocybin. Other drugs of similar properties will be discussed in this 
section. Ayahuasca is a psychoactive drink shown to have medicinal potential 
in treating psychological disorders. In recent clinical trials, the drug has been 
proven to decrease activity in the precuneus and medial prefrontal cortex35. 
These regions have also been implicated in the default mode network - a brain 
pathway most active during periods of introspection. Unsurprisingly, 
overstimulation of the default mode network has been associated with higher 
rates of depression and anxiety36. 

 

Ayahuasca combats stress-induced depression and anxiety through its 
composition of DMT and B-carboline37. DMT activates the Sig-1R 
receptor, which blocks neurodegeneration and regulates the production of 
protective antioxidants. B-carboline, meanwhile, has been shown to increase 
BDNF38. The drug ultimately leads to anti-inflammatory, neuroprotective, 
and potentially memory-boosting effects because of its focus on promoting 
nerve cell survival. Ayahuasca has added utility compared to traditional 
antidepressants due to its multifaceted approach to mental disorders: the 
drug has been shown to combat depression, anxiety, PTSD, and drug 
dependence39,40. Additionally, the psychedelic is faster-acting and lasts longer 
than other antidepressants that also target serotonin receptors 37. 
 
A recent clinical trial focused on ayahuasca’s effects on treatment-resistant 
depression35. Twenty-nine patients with persistent, moderate-to-severe 
depressive symptoms received either a single dose of a placebo or ayahuasca. 
The results of the study indicated that when compared to the placebo, 
ayahuasca generated significant antidepressant effects. Statistical analyses 
proved that the effects were rapid, and the positive outcomes persisted for at 
least seven days. Although ayahuasca is especially promising as an 
antidepressant medicine due to its rapid effect in combating depressive 
symptoms, some other key features contribute to its potential. The drug has 
a rare capability of improving depression in patients resistant to traditional 
antidepressant therapies35. Additionally, ayahuasca’s focus on the default 
mode network provides a direct focus on reducing the source of depressive 



 

Berkeley Pharma Tech Journal of Medicine | 35 

thoughts and instead increases blood flow to areas that regulate emotions and 
memory. Despite these encouraging findings, more studies must be 
conducted to prove ayahuasca’s efficacy in other mood and behavioral 
disorders. 
 
Lysergic Acid Diethylamide (LSD) is a classical hallucinogen more 
specifically characterized as an entheogen. Some of its characteristic mental 
effects include distortion of the sense of time and identity, visual 
hallucinations, and states of euphoria or dysphoria. Beyond these short-term 
effects on the brain, LSD may play an overlooked role in neurogenesis and 
possible long-term nervous system health. A recent clinical study indicates 
that the drug may help the brain grow cells and construct novel connections 
in brain regions that typically exhibit cell death in mental health disorders 
such as anxiety and depression41. The drug acts on the brain by interacting 
with the serotonin 5-HT2A receptor in an agonist capacity42. Thus, the drug 
is analogous to serotonin chemically, which has been associated with 
numerous brain-boosting and physiologically regulating benefits. Studies 
have implicated serotonin receptors specifically in promoting promnesic 
effects and regulating emotional behaviors43. Compared to other traditional 
antidepressant drugs that focus on inhibiting serotonin reuptake, LSD is 
both faster-acting and longer-lasting in the human body44. 
 
One current research trial presents that LSD promotes social behavior 
through mTORC1, a protein complex activating the translation of other 
proteins- in excitatory neurotransmission45.LSD was shown to potential 
both AMPA and 5-HT2A synaptic responses in the mPFC (medial 
prefrontal cortex) and increase the phosphorylation of protein kinases Akt 
and mTOR in a rodent model. This effect on signaling in the mTOR 
pathway was hypothesized as the rationale behind the increase in prosocial 
behaviors like Ketamine. Another recent clinical trial utilized the 
administration of LSD and placebo to 20 healthy volunteers and 
subsequently measured the emotional behaviors of the participants 2 weeks 
after administration46. The results indicated that LSD was responsible for the 
heightened mood, optimism, and trait optimism of the participants. 
Another important ongoing clinical trial will measure the efficacy of LSD 
administration in patients suffering from MDD. 



 

Berkeley Pharma Tech Journal of Medicine | 36 

 
By targeting the 5-HT2A receptor, LSD functions as a serotonin-like 
chemical in an agonist role. This may be advantageous to other 
antidepressants due to its rapid and longer-lasting effects. LSD also affects 
the mTORC1 pathway, which has been implicated in increasing sociality. 
Although much research was conducted regarding LSD’s therapeutic effects 
in the 1970s, government restrictions on psychedelic research have curtailed 
efforts in the past few decades46. The increasing rate of clinical trials, 
including psychedelics and LSD in psychiatric disorders, must continue to 
gather evidence of reproducibility and validity. Because of the prevalence of 
“bad trips” and the tendency of the drug to sometimes exacerbate existing 
psychiatric predispositions, trials testing the drug, in combination with 
therapy or trials focusing on micro-dosing the drug, may be an optimal 
focus47. 
  
5.4. Natural Products 
 
Natural products encompass many possible treatment options, which all 
work to cure depression through different mechanisms. Most natural 
products act prophylactically and help to alleviate symptoms of depression 
while also benefiting internal organ functions7.  Current natural products 
investigated as potential depression treatments include traditional Chinese 
medicine formula, herbs or their parts, and natural products that are either 
extracts or isolated compounds7. There are different types of natural 
products available for different types of depression, such as stress-induced 
depression, post-stroke depression, comorbidity depression, and more. Some 
products work well in conjunction with a good diet to prevent depression 
because some food components, such as omega-3 fatty acids and vitamin L1, 
can improve mood. Traditional herbal medicine has been used with multi-
targets, multi-levels, and multi-ways48. 
 
Natural products differ from commonly prescribed antidepressants because 
they tend to originate from non-western medicine and focus on treating 
other mechanisms in the brain. For example, suppressing signaling pathways, 
treating internal heat depression, and protecting brain glial loss. Natural 
products also tend to be produced naturally, compared to most 



 

Berkeley Pharma Tech Journal of Medicine | 37 

antidepressants which are produced in a laboratory environment. Some 
natural products have fewer adverse effects compared to conventional 
depression medication and can also reduce medication load and undesirable 
side effects49. Natural products provide many compounds with 
antidepressant-like effects, and their therapeutic impacts have been 
highlighted for a long time. Apart from using as-is, natural products are also 
a great source for future antidepressant drug discovery. 
 
There are in vitro, in vivo, nonclinical, and clinical/translational studies 
looking at the effectiveness of natural products in depression treatment. The 
potential of Tetragonia tetragonioides (TTK) was examined through a trial 
involving the animal model brain of depression50. Glial cells have a protective 
role within the CNS and PNS by helping to maintain homeostasis. 
Essentially, glial cells help to hold nerve cells in place so nerve cells can 
produce their appropriate function. Glial cells play a role in depression 
because the loss of glial functions has been shown to contribute to the 
pathophysiology of depression50. TTK is commonly called the New Zealand 
spinach and other local names. TTK is edible, both raw and cooked, and 
looks like a leafy plant51. In the research article, the team was able to protect 
glial loss (and hence loss of glial function) in the prefrontal cortex of a mouse 
brain by using TKK52, demonstrating that TKK is a potential candidate for 
depression treatment. However, further research is necessary. 
 
Xiaoyaosan, a mixture of dried plants and herbs, was shown to improve 
depressive-like behavior in rats52. Xiaoyaosan works by inhibiting 
immunoinflammatory activation and reducing the levels of inflammatory 
cytokines in the colon by suppressing the activation of the TLR4/NLRP3 
inflammasome signaling pathway. Improvement in depression is likely due 
to the decrease in levels of various proteins, such as TLR4, TAK1, and 
IRAK1, which lead to a subsequent decrease in inflammatory cytokines, 
including IL-6, IL-1β, and TNF-α. Evidence shows that inflammatory 
cytokines contribute to the development of depression, and reducing the 
concentration of inflammatory cytokines alleviates depression 
symptoms52,53. 
 



 

Berkeley Pharma Tech Journal of Medicine | 38 

Several natural products are effective in treating depression by reducing the 
likelihood of depression development, alleviating depressive symptoms, or 
accompanying conventional Western medicine. However, natural products 
are generally grouped under “alternative treatment," a treatment option used 
when Western medicine proves inadequate54. For natural products to gain 
more potential as novel therapeutic strategies, it is important for well-
designed, more extensive clinical trials to be carried out. Only then more 
clinical trials using natural products can be carried out to prove the efficacy 
of natural products in depression treatment. Better integration of natural 
products in Western medicinal research is recommended. 

5.5. Hormonal Treatment 

Thyroid, gonadal, pineal gland, and adrenal axis hormones are the four 
hormonal groups that have garnered the most recent attention in depression 
research. Some hormones play a direct role in the nervous system by acting 
as neurotransmitters and affecting neuronal signaling8. Other hormones 
regulate the production of proteins that affect both brain cell structure and 
synaptic neurotransmission. Sex hormones have even been proven to 
stimulate neuroprotection. 
 
Thyrotropin-releasing hormone, associated with the thyroid hormonal 
group, has been proven to stimulate locomotor activity, amongst other 
behavioral effects55. Additionally, thyrotropin is a pituitary hormone that 
stimulates the thyroid gland, and T4 and T3 are hormones secreted from the 
thyroid gland. Research studies have indicated that deficiency of these 
hormones in the central nervous system can result in fatigue, weight gain, 
and lack of energy-all common symptoms of depression56. The gonadal 
steroids estrogen and progesterone, beyond their neuroprotective effects, 
have been shown to affect brain regions involved in mood and behavior 
regulation57. Furthermore, Melatonin, the “sleep hormone,” has been 
implicated in mediating the circadian rhythm. Given the common 
occurrence of sleep disturbance and irregular sleeping patterns in MDD, 
melatonin replacement therapies have been gaining popularity58. 
Additionally, a link between hypersecretion of corticotropin-releasing 
hormone (CRH) and depression has been established. Higher levels of this 



 

Berkeley Pharma Tech Journal of Medicine | 39 

hormone have been shown to reduce free cortisol levels and may be a 
therapeutic option for stress-induced depression59. 
 
Hormone therapy targets differ from traditional antidepressants as they 
focus on replacement therapies that increase levels of chemicals found 
naturally in the body8. Although hormone replacement therapies often have 
indirect effects on brain function and can thus result in unintended 
secondary effects, these therapies are much more targeted than novel drug 
treatments due to their natural prevalence in the human body. Furthermore, 
because such therapies often focus on the replacement of natural chemicals, 
they are much safer and likely to be approved for funding and distribution. 
In future research efforts, the three major endocrine systems—the 
hypothalamic-pituitary-adrenal (HPA) axis, the hypothalamic-pituitary-
thyroid (HPT) axis, and the hypothalamic-pituitary-gonadal axis—should 
be studied more to enable hormones as research targets in depression. 
 

 
 Table 3: Summary Table that displays all forms of antidepressants discussed– 
both conventional and novel. 



 

Berkeley Pharma Tech Journal of Medicine | 40 

6. Practical Considerations 

Ketamine and psilocybin are the most thoroughly researched and promising 
therapeutic options for treating depression. Before their widespread 
implementation, however, greater efforts must be undertaken to reduce 
stigmas and influence public perceptions surrounding psychedelic 
treatments. Governmental action is needed to ease medicinal restrictions on 
psychedelic, natural, and hormonal treatments for mental disorders60. 
Reputable scientific journals and agencies should continue to publish and 
advertise content displaying the efficacy of these novel treatments to change 
public perception. However, some concerns regarding these treatments are 
valid—as high doses of certain drugs may cause adverse side effects and set 
back research efforts60. Thus, researchers must continue to prove the 
reproducibility of their clinical trials and consider the implementation of 
natural products in conjunction with conventional drugs. Such a strategy 
may prove to make therapeutic options more accessible for patients and 
more likely to be approved for medicinal use. 

7. Future Directions 

Ketamine and Psilocybin have emerged as potential antidepressant 
therapeutic options through mechanisms that promote increased 
neuroplasticity. We have seen similar mechanisms in other psychedelic drugs, 
such as interaction with the 5-HT2A receptor and signaling on the mTOR 
pathway30,32. By better understanding what specifically contributes to 
Psilocybin’s long-term success, Ketamine’s rapid action, hormonal 
treatments’ direct targeted approach, and natural products’ reduction of 
neurotoxic side effects, researchers can not only guide the development of 
novel antidepressants with similar properties, but we can even perhaps go 
into how to personalize antidepressants to meet individual needs. We can 
also expand this study of Depression to other neurological disorders as well, 
such as Post-Traumatic Stress Disorder, which could benefit from similar 
novel antidepressant mechanisms. 
 
 
 



 

Berkeley Pharma Tech Journal of Medicine | 41 

8. Conclusion 

Research on antidepressant therapies has significantly advanced in recent 
years while taking on a new approach to treating depressive symptoms in 
patients. While current antidepressant medications increase concentrations 
of serotonin and norepinephrine through reuptake inhibition, new research 
focuses on the direct manipulation of receptors, specifically targeting and 
improving neuroplasticity, which has emerged as a promising approach to 
treating depressive symptoms. Ketamine has been shown to rapidly reduce 
depressive symptoms by targeting glutamate, promoting the formation of 
synapses and new neural connections. Psilocybin has also shown numerous 
signs of improving neuroplasticity in clinical trials, with the potential for 
longer-lasting effects. While ketamine and psilocybin are at the forefront of 
current antidepressant research, much information remains to be known 
about the impact of long-term and repeated exposure to these drugs, and 
larger clinical trials are necessary to evaluate their efficacy. 

Psychedelic-related drugs, such as ayahuasca and LSD, display the potential 
to treat depressive symptoms as well. Ayahuasca inhibits default mode 
network activity to reduce stress-induced depression and anxiety, while LSD 
functions similarly to psilocybin and promotes cell growth and connections 
to improve neuroplasticity. However, concerns over side effects and 
government restrictions have limited research on the psychedelic approach. 
Natural products have also been found to work well in conjunction with 
current antidepressant drugs and therapies due to reduced side effects and 
medication loads. While recent clinical trials show signs of antidepressant 
effects, there is still an overall lack of research surrounding these products 
and their potential to treat depression. Hormonal treatment, which has been 
used for years to treat a variety of disorders, has recently emerged as a 
potential antidepressant therapy. Replacement therapies involving thyroid, 
gonadal, pineal gland, and adrenal axis hormones specifically have shown 
signs of reducing depressive symptoms by adjusting the naturally occurring 
chemicals to their optimum levels. While hormonal treatment offers a 
targeted approach due to the knowledge surrounding hormones and their 
effect on the body, there are concerns about unintended secondary effects 
that can occur. Due to the relative inconsistency and inefficiency of current 



 

Berkeley Pharma Tech Journal of Medicine | 42 

antidepressants, many novel therapeutic strategies, and approaches to treat 
depression have emerged in recent years. Larger and more diverse clinical 
trials are needed for all the potential therapies discussed in this review to 
determine their efficacy in treating depression and whether they offer 
significant improvements compared to current reuptake inhibitors. 
 

Conflicts of Interest 

The authors declare that there is no conflict of interest regarding the 
publication of this paper. 



 

Berkeley Pharma Tech Journal of Medicine | 43 

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29. doi:10.1177/1179573520907397 

 

https://www.ncbi.nlm.nih.gov/books/NBK500006/
https://www.ncbi.nlm.nih.gov/books/NBK500006/
https://www.ncbi.nlm.nih.gov/books/NBK500006/

	FRONT PAGE - Sharma et al.
	Body Template_Sharma et al.
	2. Pathophysiology of Depression
	4. Molecular Mechanisms of Antidepressants
	5.1. Ketamine as a Short-Term Therapeutic Option
	5.2. Psilocybin as a long-term treatment option
	5.3. Psychedelic-related drugs
	We have already seen an example of a popular, effective psychedelic-related drug– Psilocybin. Other drugs of similar properties will be discussed in this section. Ayahuasca is a psychoactive drink shown to have medicinal potential in treating psycholo...
	5.5. Hormonal Treatment
	6. Practical Considerations
	7. Future Directions
	8. Conclusion


	References_Sharma et. al.



