644 J.A. Ramos et al.
1
Introduction
Marijuana is the most commonly used illicit drug among women of reproductive
age. Its use during pregnancy in developed nations is estimated to be approxi-
mately 10% (Park et al. 2004). However, reports dealing with the effects of prenatal
exposure to this substance of abuse on the length of gestation, fetal growth, and
offspring behavior are still controversial (Park et al. 2004).
In animal models, the consumption of marijuana or otherCannabis sativa
derivatives during pregnancy and/or lactation affects the neurobehavioral devel-
opment of their litters. The cannabinoids present in these preparations modify
the maturation of neurotransmitter systems, including dopamine, serotonin, and
opioids and their related-behaviors (Fernández-Ruiz et al. 1999, 2000).
The principal agent responsible for these effects is∆^9 -tetrahydrocannabinol
(∆^9 -THC), the major psychoactive component ofCannabis sativa.∆^9 -THC can
interfere, not only with the activity of classical neurotransmitters but also with
the activity of the endogenous cannabinoid system itself. Different studies support
a role for this system in brain development and maturation, and several of its com-
ponents have been characterized (receptors, endogenous ligands, and metabolism
pathways). The effects of∆^9 -THC were caused by the activation of cannabinoid
receptors, which emerge early in the developing brain (Fernández-Ruiz et al. 1992,
1994, 1996, 1999, 2000).
With regard to the possible influence of cannabis use during human pregnancy,
CB 1 receptor immunoreactive labeling has been identified in most major cell types
throughout all layers of the human placenta, as well as in the placental villous
(Park et al. 2003). Thus, it is not surprising that increased cannabinoid levels may
interfere with the materno-fetal process.
Clinical research has been limited to epidemiologic and retrospective studies. In
some reports, cannabis use has been correlated with low birth weight, prematurity,
intrauterine growth retardation, presence of congenital abnormalities, perinatal
death and delayed time for the onset of respiration (for a review see Park et al.
2004).
In some studies, carried out in rats subjected to prenatal exposure to cannabi-
noids, specific congenital malformations were not produced, even by high doses.
However,otherstudieshavereportedanincreaseinembryotoxicityandfetaltox-
icity at pharmacologically relevant concentrations, resembling the adverse effects
of∆^9 -THC on human reproduction. Thus, in rhesus monkeys,∆^9 -THC expo-
sure during early pregnancy produced miscarriage (Asch and Smith 1986). In
mice cannabinoids impaired pregnancy and embryo development (Harbison and
Mantilla-Plata 1972; Yang et al. 1996).
More complex and less understood are the data concerning the possible long-
term consequences of in utero exposure to cannabis derivatives. Some data suggest
that prenatal exposure to marijuana could result in a certain impairment of human
fetal development (Fried and Smith 2001), albeit restricted to a few executive
functions. Thus, a longitudinal cohort study in Ottawa to examine the effects of
marijuana consumption during pregnancy upon offspring in the areas of growth,