NONADDICTIVE DRUGS OF ABUSE
Some drugs of abuse do not lead to addiction. This is the case for substances that alter perception without causing sensations of reward and euphoria, such as the hallucinogens and the dissocia-tive anesthetics (Table 32–1). Unlike addictive drugs, which primarily target the mesolimbic dopamine system, these agents primarily target cortical and thalamic circuits. Lysergic acid diethylamide (LSD), for example, activates the serotonin 5-HT2A receptor in the prefrontal cortex, enhancing glutamatergic trans-mission onto pyramidal neurons. These excitatory afferents mainly come from the thalamus and carry sensory information of varied modalities, which may constitute a link to enhanced perception. Phencyclidine (PCP) and ketamine produce a feel-ing of separation of mind and body (which is why they are called dissociative anesthetics) and, at higher doses, stupor and coma. The principal mechanism of action is a use-dependent inhibi-tion of glutamate receptors of the N-methyl-D-aspartate (NMDA) type.
The classification of NMDA antagonists as nonaddictive drugs was based on early assessments, which, in the case of PCP, have recently been questioned. In fact, animal research shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents. Concurrent effects on both thal-amocortical and mesolimbic systems also exist for other addictive drugs. Psychosis-like symptoms can be observed with cannabi-noids, amphetamines, and cocaine, which may reflect their effects on thalamocortical structures. For example, cannabinoids, in addition to their documented effects on the mesolimbic dopamine system, also enhance excitation in cortical circuits through presyn-aptic inhibition of GABA release.
Hallucinogens and NMDA antagonists, even if they do not produce dependence or addiction, can still have long-term effects. Flashbacks of altered perception can occur years after LSD use. Moreover, chronic use of PCP may lead to an irreversible schizophrenia-like psychosis.