Study Finds THC Directly Activates Dopamine D2 Receptors, Revealing Previously Unknown Signaling Pathway

A new study published online ahead of its appearance in the December 2026 issue of the journal Biochemical Pharmacology has identified a previously unknown way THC may influence the brain’s dopamine system, finding that the cannabinoid can directly bind to and activate dopamine D2 receptors.

The study found that delta-9 tetrahydrocannabinol (THC) acts as a partial agonist at the dopamine D2 receptor, triggering a distinct signaling pathway separate from THC’s well-established activity at cannabinoid CB1 receptors.

Researchers from Chonnam National University in South Korea screened 14 structurally different cannabinoid compounds for their effects on dopamine receptor signaling. THC emerged as one of the compounds capable of activating D2 receptor-linked signaling, with subsequent experiments showing that THC directly binds to the receptor with submicromolar affinity.

The finding is notable because THC’s effects on dopamine have generally been understood as indirect. THC activates CB1 receptors, which can alter the activity of neurons that regulate dopamine release. Previous human research has also found that THC can increase dopamine release in parts of the brain.

The new study suggests THC may have a second route into the dopamine system: interacting with a dopamine receptor itself.

Researchers found that THC acts as what is known as a G protein-biased agonist at the D2 receptor. Rather than activating all of the receptor’s possible signaling pathways, THC preferentially stimulated Gi/o-dependent signaling without recruiting arrestin pathways.

That activity set off a molecular cascade involving Src, PI3K and PKC proteins and caused activation of the epidermal growth factor receptor (EGFR). EGFR activity then fed back into the pathway, sustaining signaling through extracellular signal-regulated kinase (ERK).

In other words, THC did not simply activate the dopamine receptor and produce a brief downstream response. Researchers identified a self-reinforcing signaling loop capable of prolonging cellular activity.

The mechanism also differed from the way dopamine itself activates the D2 receptor.

The researchers said the findings establish “a previously unrecognized mechanism of THC action at D2R” and demonstrate that THC can directly engage the receptor alongside its conventional effects through CB1 receptors.

Dopamine D2 receptors are widely expressed in the brain and play important roles in motivation, reward, movement and other neurological processes. They are also major targets of several classes of psychiatric medications.

The findings could help explain aspects of THC’s complex relationship with dopamine that have been difficult to account for solely through cannabinoid receptor signaling.

The researchers said the newly identified dual mechanism provides a revised framework for understanding THC pharmacology and how cannabis exposure can influence dopaminergic signaling.

The study was conducted through molecular and cellular experiments rather than a clinical trial, meaning the findings do not establish how strongly the newly discovered pathway contributes to THC’s effects in humans. They do, however, identify a direct receptor interaction that was previously unknown.