Datura Stramonium (DS) is a tropical shrub which is availableworldwide. It has various uses and is often used to increase the intoxicationof certain beverages. The seeds of this plant are very toxic but are commonlysmoked in like manner as tobacco. The present study investigated the potential harmful effects of DS onpyramidal cells and CREB protein in the hippocampus of Wistarrats in order to further elucidate the effects of DS seed extract on hippocampalstructure. The study was conducted on both male and female Wistar rats (200-250 g). They were first divided intothree batches, which were further sub-divided into fourgroups in each batch with eight animals per group. Ethanolic extract of driedseeds of DS was diluted in normal saline and given to the treatment groups. Thetreated groups received intraperitoneal administration (i.p.) of 750 mg kg-1 (Bania et al.,2004) of diluted DS seed extracts, once in batch 1, twice in batch 2 and thrice in batch 3 per day respectively for 4 weeks whilethe control groups received an equivalent of normal saline. The rats wereeuthanized and Western blot analysis used to evaluate the levels of CREBprotein in the rats’ hippocampi. Sections of eachhippocampus were histologically processed in all the groups and silverimpregnation stain for degenerating axons and neurons was used to elucidate theactions of DS on the pyramidal neurons of the hippocampus. The result of i.p. administration of DS extract (750 mg kg-1) given three times per day to the treated ratsshowed significant histological changes such as axonal atrophy, cytoplasmicvacuolation and neuronal necrosis of the pyramidal cells of the hippocampus, as well as an increase in CREB protein levels inboth male and female rats. Excessive ingestion of DS seeds, therefore, may leadto hippocampal pyramidal cell losses and an increase in CREB protein levels inthe hippocampus. This may be implicated in neurological disorders.