Publisher Summary The chapter presents a study on the changes in gene expression and signal transduction following ibogaine treatment. Drug addiction may not be mediated by one neurochemical pathway and brain structure, but by a complex interaction of programs of gene expression with specific signal transduction pathways and environmental factors. The putative antiaddictive effect of ibogaine may result from the restoration of altered or disrupted programs of central and peripheral neuroadaptative processes involving programmed genes and their associated signaling mechanisms. One new hypothesis being explored is that both the peripheral and central actions of abused substances contribute to drug addiction. One new hypothesis being explored is that both the peripheral and central actions of abused substances contribute to drug addiction. Treatment with cocaine influences the regulation of certain genes in the brain, as indicated by the activation and inhibition of the expression sequence tags (ESTs) that have been isolated. The cAMP-responsive element binding protein (CREB), the first CRE-binding factor to be characterized ( 5 ), is a transcription factor of general importance in both neuronal and other cells. CREB phosphorylation on Ser-133 promotes the activation of genes with an upstream CRE element. If anxiety or stress is a factor in drug dependency, then the anti-addictive property of ibogaine in vivo may be associated with modifying the CNS neurotransmission that may be involved in anxiety.