Drug abuse represents a significant health issue. The major substances abused include cannabis, opiates, cocaine, amphetamine, methamphetamine and 'ecstasy'. Alterations of intracellular messenger pathways, transcription factors and immediate early genes within the brain reward system seem to be fundamentally important for the development of addiction and chronic drug abuse. Genetic risk factors and changes in gene expression associated with drug abuse are still poorly understood. Besides cardiovascular complications, psychiatric and neurologic symptoms are the most common manifestations of drug toxicity. A broad spectrum of changes affecting the central nervous system is seen in drug abusers. The major findings result from the consequences of ischaemia and cerebrovascular diseases. Except for a few observations of vasculitis, the aetiology of these cerebrovascular accidents is not fully understood. The abuse of amphetamine, methamphetamine and MDMA has been related to neurotoxicity in human long-term abusers and to the risk of developing Parkinson's disease. However, whether such neurotoxicity occurs remain to be established. Systematic histological, immunohistochemical and morphometric investigations have shown profound morphological alterations in the brains of polydrug abusers. The major findings comprise neuronal loss, neurodegenerative alterations, a reduction of glial fibrillary acidic protein-immunopositive astrocytes, widespread axonal damage with concomitant microglial activation as well as reactive and degenerative changes of the cerebral microvasculature. These observations demonstrate that drugs of abuse initiate a cascade of interacting toxic, vascular and hypoxic factors, which finally result in widespread disturbances within the complex network of central nervous system cell-to-cell interactions.