Understanding How Cannabinoids Regulate Emotion and Anxiety in the Brain

Consider three very different people: a college student unwinding after a stressful exam week, a veteran with PTSD who turns to medical marijuana after conventional antidepressants like Zoloft and Paxil fell short, and a young adult trying an edible for the first time with little sense of how it might affect a brain that is still developing.

Cannabis use is now widespread, both legally and culturally, but the science has not fully kept pace with its popularity. Does it genuinely help with anxiety and mood, or could it make things worse for certain people? As a neuroscience student, I wanted to move past anecdote and look closely at what is actually happening in the brain.

What follows is a closer look at three studies, each examining a different cannabinoid — CBG, CBD, and THC — and what they reveal about the brain circuits underlying mood and anxiety.

A Quick Crash Course

Cannabis contains dozens of active compounds known as cannabinoids, but three receive the most attention:

• THC — the primary psychoactive compound, responsible for the "high"

• CBD — non-intoxicating, widely marketed as a calming, anti-anxiety compound

• CBG — a lesser-known, non-intoxicating relative that remains under-researched

All three interact with the endocannabinoid system (ECS), a network of receptors — mainly CB1 and CB2 — along with natural signaling molecules such as anandamide, sometimes called the "bliss molecule." The ECS plays a substantial role in regulating emotion, stress, and memory, among other functions.

THC binds strongly to CB1 receptors in brain regions such as the amygdala (fear and emotion), the hippocampus (memory), and the prefrontal cortex (executive function and decision-making). CBD, by contrast, has little direct effect on CB1 or CB2 receptors; instead, it acts on other systems, particularly serotonin and GABA, both of which are closely tied to mood and anxiety regulation.

With that foundation in place, here is what the research shows.

Study 1: CBG — A Quiet Reducer of Anxiety

Researchers from Washington State University and UCLA conducted a double-blind, placebo-controlled trial with 34 healthy adult cannabis users. Each participant attended two sessions, one week apart — one involving 20 mg of hemp-derived CBG and one involving a placebo — with anxiety, stress, mood, and cognitive and motor performance assessed at several points.

The results were notable:

• Anxiety dropped by roughly 26.5 percent compared to baseline

• Stress ratings also declined, particularly shortly after dosing and before a stress test was introduced

• No intoxication or impairment was observed, and none of the typical THC side effects, dry mouth, elevated heart rate appeared

• Participants performed somewhat better on verbal memory tasks, the opposite of what is typically seen with THC

Interestingly, CBG had little measurable effect on the more formal mood questionnaire used in the study (the STAI), possibly because participants were healthy, non-clinical adults who were not particularly anxious to begin with.

The leading theory is that CBG interacts with serotonin (5-HT1A) and GABA receptors, the same systems implicated in much of the existing anxiety research. It is early evidence, but a compelling first look at a cannabinoid that may reduce anxiety without many of the tradeoffs typically associated with cannabis use.

Study 2: CBD and the Brain's Capacity to Build New Connections

This next study was conducted in rodents, but it offers insight into mechanism in a way human studies often cannot. Sales and colleagues (2019) set out to determine whether CBD produces genuine antidepressant effects and, if so, how quickly and through what pathway.

The researchers tested CBD across several established models of depression in rats, including the forced swim test, learned helplessness, and a genetic model of depression. A single dose of CBD reduced depressive-like behavior across all three models, with effects emerging within 30 minutes and persisting for a week. Locomotion was unaffected, indicating that the results reflected a genuine antidepressant effect rather than simple changes in activity level.

At the cellular level, the findings were particularly striking. CBD rapidly increased levels of brain-derived neurotrophic factor (BDNF) — a protein that supports neuron growth, connectivity, and survival — in the prefrontal cortex and hippocampus. This was accompanied by increases in synaptic proteins and dendritic spines, the small structures where neurons connect. Some of these changes faded within a week, while others, including elevated synaptic protein levels, persisted.

When researchers blocked the BDNF receptor (TrkB) or the mTOR signaling pathway, both essential for forming new synaptic connections, CBD's antidepressant effects disappeared entirely. This suggests CBD may not simply be masking symptoms but could be helping the brain physically rebuild toward a healthier state.

Study 3: THC and CBD in Competition Within the Prefrontal Cortex

Szkudlarek and colleagues (2018) took a more direct approach, infusing THC and CBD into the prefrontal cortex of rats to observe how each compound shapes anxiety and cognition.

THC's effect was unambiguous: it increased anxiety-like behavior, evidenced by rats spending less time in the open arms of an elevated plus maze, a standard measure of anxiety. Notably, co-administering CBD, or blocking the CB1 receptor, eliminated THC's anxiety-inducing effect entirely.

CBD alone produced a more complicated picture. In healthy rats, it actually impaired cognitive flexibility and working memory. However, when researchers disrupted prefrontal cortex function using NMDA receptor blockers to simulate impairment, CBD reversed those deficits rather than worsening them.

In short, CBD's effect on cognition appears to depend on the underlying state of the brain. In a healthy brain, it may slightly interfere with function; in an impaired one, it may help restore it — a distinction easily lost in the popular narrative that CBD is simply beneficial across the board.

It is also worth noting that THC's effects operated primarily through CB1 receptors, while CBD's effects tracked more closely with serotonin (5-HT1A) receptors, reinforcing that these two compounds, despite originating from the same plant, act on the brain in fundamentally different ways.

What This Means

A few themes emerge consistently across all three studies:

The prefrontal cortex is a recurring focal point. Mood and anxiety regulation by cannabinoids appear to converge heavily on this region, along with the amygdala and hippocampus.

Serotonin (5-HT1A) and BDNF/mTOR signaling show up repeatedly as the underlying mechanisms behind cannabinoids' calming or antidepressant-like effects, suggesting the story extends well beyond THC's more widely discussed CB1 activity.

Context matters considerably. CBD's effects shift depending on whether the brain is healthy or impaired. THC can be either anxiety-provoking or calming depending on dose and the individual. Little of this fits a simple narrative of cannabis producing uniform relaxation.

CBG appears genuinely promising and likely deserves more research attention than it currently receives, particularly given early evidence suggesting it may avoid many of the downsides associated with both THC and CBD.

Limitations Worth Acknowledging

It would be poor science to omit the gaps in this research. Two of the three studies were conducted in rodents, which can only tell us so much about human emotion and cognition. The CBG study involved healthy adults rather than individuals with clinical anxiety, so its real-world relevance for those who might benefit most remains unclear. Additionally, none of this research fully accounts for individual differences — genetics, mental health history, age — that likely shape how a given person responds to cannabinoids.

Why This Matters Beyond the Lab

As neuroscience students, we find this area compelling because it remains an active, unresolved puzzle. But its relevance extends beyond academic interest — cannabis use is already widespread and often guided more by anecdote than evidence. Without a better public understanding of how these compounds actually work, there is a real risk of people self-medicating without adequate information, particularly teenagers and those with a family history of mental illness.

The full brain basis of cannabinoid effects on mood and anxiety has yet to be mapped. But between BDNF signaling, serotonin receptors, and region-specific effects in the prefrontal cortex, researchers are beginning to arrive at real mechanistic answers rather than relying on impression alone.

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References

• Cuttler, C., Stueber, A., Cooper, Z. D., & Russo, E. (2024). Acute effects of cannabigerol on anxiety, stress, and mood: A double-blind, placebo-controlled, crossover, field trial. Scientific Reports, 14(1), 16163.

• Sales, A. J., Fogaça, M. V., Sartim, A. G., Pereira, V. S., Wegener, G., Guimarães, F. S., & Joca, S. R. L. (2018). Cannabidiol induces rapid and sustained antidepressant-like effects through increased BDNF signaling and synaptogenesis in the prefrontal cortex. Molecular Neurobiology, 56(2), 1070–1081.

• Szkudlarek, H. J., Desai, S. J., Renard, J., Pereira, B., Norris, C., Jobson, C. E. L., Rajakumar, N., Allman, B. L., & Laviolette, S. R. (2018). Δ-9-tetrahydrocannabinol and cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors. Neuropsychopharmacology, 44(4), 817–825.

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