Josh Kaplan, PhD, is a neuroscientist and associate professor in the Behavioral Neuroscience program at Western Washington University, where his lab focuses on optimizing cannabidiol (CBD) based medicines for pediatric conditions. His work examines not only CBD’s therapeutic potential, but also its long-term developmental effects on the brain, an area of growing importance as cannabinoid therapies move deeper into clinical use.

Kaplan’s interest in CBD research began in 2015, when he was asked to evaluate Epidiolex in a mouse model of pediatric epilepsy. The treatment produced significant seizure reduction in cases where other medications had failed. The results were striking and sparked his interest in a deeper investigation of CBD and how it might work in other pediatric conditions.

While different medical conditions require different dosing, Kaplan’s lab is also exploring whether the same medication or formulation could be effective across a range of symptoms by adjusting the dose. “Can we improve CBD-based medicine by expanding that dose window so that, regardless of whether you are trying to treat epileptic seizures or improve social behaviors and communication deficits, a single formulation could be effective?” explained Kaplan.

The team evaluates CBD’s effects by modeling specific behaviors in mice, including anxiety, depression, and social interaction. By testing a wide range of doses, they can pinpoint where therapeutic effects emerge and where they fade.

Stress, Brain Development, and CBD

The lab also takes a bottom-up research approach, examining what is happening inside the brain at the cellular level. Many pediatric neurological conditions, including epilepsy and autism, are associated with altered protein expression and disrupted communication between neurons. Kaplan’s team applies CBD, sometimes in combination with terpenes such as beta-caryophyllene and linalool, to examine how these compounds affect molecular signaling and neuronal communication.

The lab uses live slices of mouse brain tissue outside the body and recreates the brain’s natural environment with oxygen, glucose, and essential ions. Researchers can keep neurons alive for hours and directly measure their electrical activity using electrodes. This technique allows the team to observe how CBD alters communication in specific brain regions tied to different conditions.

For example, the hippocampus, often implicated in seizures, can be studied to assess whether CBD dampens excessive neural excitation. Other regions, such as the amygdala and prefrontal cortex, are examined for changes related to anxiety, depression, and cognitive function.

“What is CBD doing there?” asks Kaplan. “We can zoom in on specific regions of the mouse brain and start manipulating them with CBD and other terpenes to see how it alters those communication patterns, which are known to change in characteristic ways across different neurological conditions.”

He explains that with epilepsy or autism, there is a shift in the brain’s balance toward excessive excitation and signaling that can lead to seizures, hypersensitivities, and certain repetitive behaviors characteristic of autism.

“We can see that actually playing out in the cellular communication patterns that we’re observing. Then we might explore what CBD is doing on those patterns. What is beta-caryophyllene doing? What happens when you put them together? That’s the approach we’re taking,” Kaplan said.

Proving the Entourage Effect

While anecdotal evidence around the entourage effect is widespread, there is little clinical validation, particularly for combinations of CBD and terpenes rather than THC-based formulations. Kaplan’s lab is beginning to generate early preclinical data indicating promising results for targeted, custom CBD and terpene formulations.

Previous research has shown that repeated stress or trauma during critical developmental periods can alter brain connectivity, leading to long-term behavioral and mental health challenges. In a recent, unpublished preclinical study, Kaplan’s team examined whether CBD could remedy early stress-related effects on brain development. Using an established animal model, the researchers induced early life stress and observed measurable changes in proteins involved in how brain cells connect and communicate.

Following stress exposure, the mice were treated with either CBD alone, beta-caryophyllene alone, or a combination of the two. Neither compound on its own produced meaningful changes in altered protein expression. However, when CBD and beta-caryophyllene were administered together, the combination effectively reversed the stress-induced molecular disruptions.

These findings suggest that cannabinoids and terpenes interact with distinct receptors and signaling proteins, influencing neuronal circuits and communication between brain regions. Kaplan emphasizes that cannabinoids do not “activate” one another; rather, their parallel actions converge to produce coordinated effects across neural networks. This framework helps explain the benefits of combined CBD and terpene treatments, highlighting how multi-target strategies can modulate brain function more effectively than single compounds alone. It is an early step toward understanding which compound combinations and dosing strategies are most effective for specific conditions.

Some studies suggest that removing the olfactory component—such as when terpenes are consumed in edibles—may diminish their effects. Could these benefits be mediated, at least in part, through olfactory processing, which is known to influence emotion and mood? “Why do people wear cologne or perfume? Why do we have scented candles? It makes us feel relaxed and comfortable,” said Kaplan. While earlier experiments demonstrated clear effects with oral ingestion, Kaplan believes that each method of consumption may have its own benefits.

Activating Endocannabinoid Expression

Another line of research in Kaplan’s lab examines how different cannabis components influence endocannabinoid expression. Anandamide, often referred to as the “bliss” molecule, is an endogenous cannabinoid that activates the brain’s cannabinoid receptors and plays an important role in mental health and well-being.

In autism, children often have lower levels of anandamide, and raising those levels may lead to improved social behaviors and communication, as well as other quality-of-life measures. Kaplan’s lab tested whether CBD alone would alter anandamide levels using a mouse model of autism spectrum disorder and measured outcomes using mass spectrometry.

They found that CBD and beta-caryophyllene increased anandamide levels on their own. “You put the two together and think you’ll get a massive effect,” Kaplan explained. “Actually, they contradicted one another and led to a reduction.”

He added, “The most exciting part about this field is the complex profile of how these different chemicals are working, and the targets they’re acting on in the brain and body. It creates a challenge, because it’s not as straightforward as we think.”

Are Some Terpenes More Effective Than Others?

Kaplan’s lab began its terpene investigations with beta-caryophyllene, which is widely considered the only terpene known to directly interact with the endocannabinoid system. It can activate CB2 receptors in a manner similar to endogenous cannabinoids such as anandamide and 2-AG, as well as THC.

While Kaplan’s team has observed therapeutic benefits from beta-caryophyllene, they are also examining other common terpenes, including linalool, myrcene, and others. Among these, linalool has emerged as a standout in preclinical testing, showing strong anxiolytic effects, particularly in behavioral models of anxiety.

Kaplan’s research has also revealed pronounced sex based differences in terpene response. In one published study, mice were exposed to vaporized linalool or myrcene for short periods. Female mice consistently showed reduced anxiety and actively sought out the terpene exposure. Male mice, by contrast, initially showed positive benefits from brief exposure, but displayed heightened anxiety under longer exposure conditions

When exposure time was reduced to a single brief dose, male mice exhibited the same anxiety-reducing benefits as females. The findings suggest that females may be less sensitive to terpene intensity or odor, while males may reach sensory saturation more quickly. These differences highlight dosing and exposure thresholds as critical variables in terpene-based formulations.

Kaplan’s lab is also exploring the biological mechanisms underlying these sex specific responses, with a particular focus on estrogen. Existing evidence indicates that estrogen modulates the endocannabinoid system, and Kaplan’s team has found that CBD increases anandamide levels in the brain more strongly during periods of elevated estrogen. This hormonal influence may help explain why cannabinoids and terpenes produce different effects across sexes and hormonal cycles.

What’s Next for Kaplan’s Lab?

With foundational studies now established, Kaplan is turning his attention to deeper molecular and physiological mechanisms to better understand what is happening beneath the surface and to help inform more reliable cannabinoid-based medicines.

One key area of investigation is the gut-brain axis. Kaplan’s team is exploring how CBD and related compounds influence the gut microbiome and immune signaling, both of which play a critical role in regulating brain inflammation and neurological health. To do this, the lab is collaborating with immunology and microbiome expert Annalise Snyder at Western Washington University to characterize how cannabinoid based therapies affect immune responses in the brain that may contribute to disease pathology.

The lab is also integrating computational neuroscience into its research strategy. In collaboration with computational neuroscientist Cam Harris, Kaplan’s team is using brain network modeling to simulate how different brain regions communicate and how cannabinoids and terpenes alter those signaling patterns. These models are designed to predict which compound combinations are most likely to be effective for specific conditions, such as epilepsy or autism, before moving into experimental testing.

Rather than testing an overwhelming number of possible cannabinoid and terpene combinations, the team can narrow the field to the most promising formulations using advanced predictive modeling, thereby providing a more precise approach for cannabinoid medicine.

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