Could antidepressants work in the same way as cannabis?
New research published in Neuroscience suggests that escitalopram, one of the UK’s most commonly prescribed antidepressants, might be exerting its effects, in part, through the endocannabinoid system.
Yes, the same system targeted by cannabis.
This study adds to a growing body of evidence that supports a deeper, more holistic understanding of mental health, and it may have implications for how we approach treatment moving forward.
In this post, we’ll break down the findings in plain English, explain what the endocannabinoid system is, and explore how this could inform safer, more effective, and more personalised strategies for managing mental health.
What’s the study about?
The research looked at adolescent male rats who had experienced early life stress in the form of maternal separation, a well-established animal model that mimics the psychological effects of childhood neglect.
The researchers wanted to know: could treatment with escitalopram help reverse the damage? And if so, how?
As it turns out, escitalopram did help. The rats displayed less anxiety and fewer signs of despair-like behaviour after treatment.
But here’s where it gets really interesting: these behavioural changes were associated with alterations in the endocannabinoid system, particularly in regions of the brain responsible for mood and stress regulation.
Why this matters
Depression and anxiety are on the rise, especially among young people. Antidepressants like SSRIs (selective serotonin reuptake inhibitors) are often the first line of treatment, but they come with limitations:
- They don’t work for everyone
- They often take weeks to show effects
- They can cause side effects such as sexual dysfunction, emotional blunting, or weight gain
- They do not address the root causes of mental health disorders, such as chronic stress, trauma, or metabolic dysfunction
At High & Polite, we believe in getting to the root of the problem, and supporting the body’s healing through lifestyle, nutrition, and natural therapies, including cannabis and functional mushrooms.
That’s why this study is so compelling. It shows that SSRIs might not just work through the serotonin system, as we’ve long believed.
They might also be impacting our internal cannabinoid system, a system that we can support through non-pharmaceutical means.
Meet your endocannabinoid system
If you’re new to the term, the endocannabinoid system (ECS) is a vast network of receptors, signalling molecules, and enzymes spread throughout your body and brain.
It plays a central role in regulating mood, stress, inflammation, sleep, appetite, pain perception, and more.
Key players include:
- CB1 receptors: Found primarily in the brain and nervous system. Involved in mood, memory, and motor control.
- Anandamide: Known as the “bliss molecule,” this endocannabinoid promotes feelings of calm and well-being.
- FAAH and NAPE-PLD: Enzymes that break down and synthesise anandamide, respectively.
What happens when the ECS is out of balance (due to chronic stress, trauma, toxin exposure, poor diet, or lack of sleep)?
It can contribute to emotional instability, inflammation, and poor stress resilience.
This is particularly important during adolescence, when the brain undergoes massive changes in connectivity and chemistry. Disruption to the ECS during this time may lead to long-term mental health issues.
What the study found
Researchers separated rat pups from their mothers for 6 hours daily from day 2 to day 15 – a time of intense brain development. As adolescents, these rats showed classic signs of anxiety and depression, including:
- Avoiding open spaces (elevated plus maze)
- Decreased exploration and grooming (open field test)
- Giving up quickly in water (forced swim test)
However, after being treated with escitalopram for 20 days, their behaviour changed significantly:
- They ventured into open arms of the maze more often
- They explored and groomed more normally
- They took longer to become immobile in the swim test
Most notably, researchers found changes in the expression of ECS-related genes, especially in the amygdala and hippocampus, two regions heavily involved in emotion and memory.
Escitalopram seemed to downregulate the genes for CB1 receptors and key enzymes involved in endocannabinoid metabolism.
So, escitalopram seems to:
- Reduce CB1 receptor levels (possibly to prevent overstimulation).
- Slow down endocannabinoid breakdown (so natural “feel-good” signals last longer).
It’s like turning down the volume on how loud the system shouts, while also letting each message echo a little longer. This creates a more balanced, less reactive emotional state.
How cannabis could do the same
In the context of the escitalopram + early-life stress study (where CB1 gene expression was downregulated and enzymes that metabolise endocannabinoids were also reduced) cannabis could theoretically mimic or modulate these effects.
But there are important caveats depending on the dose, duration, and cannabinoid content.
Hypothetical role of cannabis in mimicking the effects of escitalopram:
1. Reducing CB1 receptor levels
Chronic THC exposure can downregulate CB1 receptors through:
- Reduced gene expression (fewer CB1 mRNAs → fewer receptors made)
- Receptor internalisation (pulling receptors off the cell surface)
This could be protective if the ECS is overactive — such as in hyper-emotional states, anxiety, or trauma-linked dysregulation. However, if overdone, this may blunt ECS tone, worsen mood over time, and contribute to tolerance or withdrawal symptoms.
Low-dose THC or intermittent use may gently nudge this effect without full receptor burnout.
2. Slowing endocannabinoid breakdown
CBD, CBG, and low-dose THC have been shown to inhibit FAAH and MAGL, the main enzymes that break down endocannabinoids Anandamide (AEA) and 2-AG.
This inhibition leads to higher levels of natural endocannabinoids, enhancing ECS tone without overstimulation.
It’s like turning up the volume on the body’s own cannabis-like molecules, rather than flooding the system with THC.
So, in theory: A carefully dosed cannabis regimen (especially high in CBD, low-dose THC, and perhaps CBG) might:
- Downregulate CB1: Help calm an overstimulated, stress-wired ECS
- Inhibit breakdown enzymes: Let your natural anandamide stick around longer, improving emotional resilience and recovery
The Caveat: If used chronically or in high doses, especially with high-THC strains, cannabis may:
- Overcorrect, leading to too few CB1 receptors
- Flatten emotional responses, contribute to apathy, or worsen depression
- Cause withdrawal symptoms due to depleted ECS signalling
This balance – recalibrating an overactive ECS without shutting it down – is exactly what SSRIs may be doing in part via ECS modulation, and what thoughtful cannabis use might be able to replicate or support.
A natural path to supporting the ECS
This research opens the door to some important questions: If part of escitalopram’s antidepressant effect is due to its influence on the ECS, could we support that same system through other natural, low-risk interventions?
We believe the answer is a resounding yes.
Here are some proven ways to support your endocannabinoid system:
1. Exercise
- Physical activity, especially moderate aerobic exercise, increases anandamide levels and improves mood through the ECS.
2. Diet
- Omega-3 fatty acids (found in grass fed meat, hemp seeds, and oily fish) are building blocks of endocannabinoids.
- Minimising processed foods and seed oils reduces chronic inflammation that can dysregulate ECS signalling.
3. Light and Circadian Rhythm
- Daily light exposure (especially in the morning) supports hormonal and ECS balance.
- Poor sleep disrupts ECS tone and contributes to mood instability.
4. Stress Management
- Chronic stress depletes anandamide and blunts ECS function.
- Practices like breathwork, meditation, grounding, and spending time in nature help restore balance.
A more empowered future for mental health
This study reinforces something we’ve long believed: your body already has the tools to heal, it just needs the right support.
Antidepressants can be lifesaving for some, and no one should feel shamed for using them. But we must also explore other avenues, especially those that honour the body’s natural systems.
Supporting the ECS, through lifestyle, cannabis, or nutrition might offer a gentler, more holistic path for many people.
And in the case of young people affected by early life stress, who may be more vulnerable to the side effects of pharmaceuticals, this could make all the difference.
The more we understand the ECS and its relationship to mood, trauma, and recovery, the better we can tailor treatments that truly work, and do so with compassion, wisdom, and choice.
Final thoughts
The antidepressant effects of escitalopram may go beyond serotonin, and into the realm of the endocannabinoid system.
While more research is needed, this insight strengthens the case for integrating natural ECS-supportive strategies into mental health care.
At High & Polite, we’ll keep you up to date with this evolving research, and continue to champion the power of plants, lifestyle, and self-awareness in the journey to better health.
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