Low-Dose THC Reduced Anxiety in Female Rats but Not Males — and CBD Blocked the Anxious Response at Higher Doses

This study revealed a striking sex difference that most cannabis research has missed by testing only males. Low-dose THC (0.075-0.1 mg/kg) produced clear anxiolytic effects in female rats on the elevated plus-maze. At higher doses (1.0 mg/kg), the effect flipped to anxiogenic. Male rats showed no anxiety changes across the same dose range.

CBD entered the picture as a modulator. Co-administering CBD (1.0 or 3.0 mg/kg) with the anxiogenic THC dose prevented the anxiety response. At the lower CBD dose, it actually enhanced the anxiolytic effect of low-dose THC — making a calming dose even calmer. CBD alone at 3.0 mg/kg was anxiolytic on its own.

The neurochemistry matched the behavior. The anxiogenic THC dose increased dopamine in the medial prefrontal cortex and nucleus accumbens — regions linked to anxiety and salience processing. The anxiolytic dose did not produce these dopamine increases. CBD appeared to work by preventing THC's dopamine-elevating effects in these regions.

Women report higher rates of anxiety disorders and are increasingly using cannabis to manage anxiety. Yet almost all preclinical cannabis-anxiety research has been done in male animals. This study showed the anxiety response to THC is fundamentally different in females — more sensitive at both ends. Low doses helped more, high doses hurt more, and CBD modulated the response.

For women using cannabis for anxiety, this suggests the dose-response window is narrower and the consequences of getting it wrong (too much THC → increased anxiety) are more pronounced. It also provides preclinical support for THC:CBD combinations as potentially superior to THC alone for anxiety management.