Drug dependence, abuse, and addiction are complex phenomena that can precipitate various abnormal states. Physical dependence refers to a state of pharmacological adaptation to a drug. This adaptation often results in tolerance—a reduced response to the drug after repeated administrations. When the drug use is abruptly stopped, withdrawal symptoms occur due to the body's need to readjust from the pharmacologically induced imbalance. However, tolerance and withdrawal symptoms do not necessarily denote addiction. Addiction is a more severe condition characterized by compulsive, out-of-control drug use. It typically begins with the activation of brain reward circuits that motivate behavior. Tolerance can manifest through several mechanisms, including pharmacokinetic, pharmacodynamic, and learned tolerance. Misunderstanding tolerance can lead self-medicating opioid users to risk overdose by exceeding safe levels. Alarmingly, accidental overdoses have surpassed traffic accidents as a leading cause of mortality among young people in the US.

Addictive drugs elevate dopamine (DA) levels in the mesolimbic system, originating in the ventral tegmental area (VTA) and projecting to various brain regions, including the nucleus accumbens, amygdala, hippocampus, and prefrontal cortex. Drug-induced reinforcement is mediated via the firing of VTA dopamine neurons, leading to artificially increased concentrations of DA in reward sites - a phenomenon known as the Dopamine Hypothesis of Addiction. However, this hypothesis has been challenged by experiments showing that mice lacking the primary molecular target of cocaine can still self-administer the drug. Addictive drugs can be classified into three categories based on their molecular targets: G protein-coupled receptors, ionotropic receptors/ion channels, and biogenic amine transporters. Additionally, aversive stimuli activate subpopulations of DA neurons, suggesting parallels between reward and aversion-learning systems originating in the VTA. The development of drug misuse disorders is influenced by agent variables (such as drug reinforcement, rapidity of onset, and dopamine levels in the ventral striatum), host variables (including genes related to absorption, metabolism, excretion, inherent tolerance, and psychiatric disorders), and environmental variables (like societal norms and peer pressure). Physicians must understand the distinction between dependence and addiction when prescribing medications that produce tolerance and be vigilant for possible withdrawal symptoms if the dosage is reduced.