Methamphetamine (METH) abuse impairs verbal and nonverbal memory, recognition, attention, and decision-making. The exact neural mechanisms that underlie these mnemonic deficits are unknown. We have postulated that METH usurps hippocampal EEG and synaptic plasticity functions resulting in memory deficits. To test this, we utilize multidisciplinary methods and conduct experiments in awake and/or anaesthetized male guinea pigs. Our results show that repeated intraperitoneal injections for 7 days with 1.0 mg/kg METH (comparable to therapeutic doses) produces initial hyperactivity but levels return to baseline over the circadian cycle. By contrast, chronic 10.0 mg/kg METH (similar to abused doses) produce sustained hyperactivity and increases total distances moved in a day, indicating motor sensitization. These animals also exhibit a) impaired novel object recognition memory, and b) decrement in long-term potentiation (LTP) in vivo. They show significant reductions in delta wave (1-4 Hz) spectral power following tetanic stimulation to produce LTP; synaptic growth-associated protein-43 mRNA and protein are highly up-regulated in the hippocampus. In related experiments, we found that acute high METH increases baseline synaptic transmission but also decrease LTP in ex-vivo slices. Our results suggest a causal link between METH-induced changes in CAI network functions and memory deficits.