Rhazya stricta leaves, which have both antidepressant and sedative properties in animal models, are widely used in folk medicine in the Arabian peninsula. In this study, the effects of oral administration of leaf extracts on rat brain tribulin levels [endogenous monoamine oxidase (MAO) A and B inhibitory activity], were determined. In an acute study, low doses brought about an increase in MAO A inhibitory activity, while intermediate doses caused a significant reduction. The highest doses had no significant effects on activity. There were no significant effects on MAO B inhibitory activity at any dose. Subchronic administration (21 days) caused a significant decrease in MAO A inhibitory activity, most prominent at low dosage, and an increase in MAO B inhibitory activity. Acute intramuscular administration also resulted in a similar pattern. Such paradoxical effects were at least partially explained when different extracts of the leaves were used; a weakly basic chloroform fraction caused an increase in MAO A inhibitory activity, whereas butanol extracts brought about a decrease. These fractions had no significant effects on MAO B inhibitory activity. The findings show that Rhazya stricta leaves contain at least two different components that affect MAO inhibitory activity in opposite directions. It may be that the antidepressant and sedative actions of the plant are explicable in terms of these different components.