Sex differences in ibogaine antagonism of morphine-induced locomotor activity and in ibogaine brain levels and metabolism.

Ibogaine, a substance studied for antiaddictive properties, produces stronger behavioral effects in female rats than in males, correlating with higher ibogaine levels in their brains and plasma. Five hours after a 40 mg/kg dose, ibogaine antagonized morphine-induced locomotor activity only in females. At 19 hours after 10-60 mg/kg ibogaine or one hour after 5-40 mg/kg noribogaine (a metabolite), antagonism was greater in females. Brain and plasma levels of ibogaine and noribogaine were higher in females given the same dose. Levels were much lower at 19 hours than earlier, unlike a prior human study. Subcutaneous injection produced greater antagonism than intraperitoneal, consistent with higher brain levels. Sex differences likely stem from lower ibogaine bioavailability in males.

Study at a glance

Abstract

The present study demonstrates that the putative antiaddictive agent ibogaine produces more robust behavioral effects in female than in male rats and that these behavioral differences correlate with higher levels of ibogaine in the brain and plasma of female rats. There were no differences in basal locomotor activity between the sexes, and the response of rats to ibogaine differed between the sexes even in the absence of morphine. Five h after receiving ibogaine (40 mg/kg, i.p.). antagonism of morphine-induced locomotor activity was evident in female but not in male rats. Either 19 h after administration of ibogaine (10-60 mg/kg, i.p.), or one h after administration of noribogaine (5-40 mg/kg, i.p.), a suspected metabolite, antagonism of morphine was significantly greater in female than in male rats. Brain and plasma levels of ibogaine (1 h) and noribogaine (5 h), measured by gas chromatography-mass spectrometry, were greater in females as compared with males receiving the same dose of ibogaine. Levels of both ibogaine and noribogaine were substantially lower at 19 h than at earlier times after ibogaine administration, contrary to a previous study in humans. For both sexes, subcutaneous administration of ibogaine (40 mg/kg, i.p., 19 h) produced greater antagonism of morphine-induced locomotor activity than did a comparable intraperitoneal injection, consistent with previous studies from this laboratory demonstrating that the former route of administration produces higher levels of ibogaine in the brain. These data show that there are sex differences in the effects of ibogaine and that this may be due to decreased bioavailability of ibogaine in males as compared to females.