Adolescence involves major behavioral, neural, and hormonal changes and a heightened tendency for risk-taking and drug use. This review of human and preclinical studies on dissociatives (PCP, ketamine, DXM), classic psychedelics (LSD, psilocybin), and MDMA finds that very little is known about their effects in adolescents. Emerging evidence suggests dissociatives and MDMA produce both reinforcing and aversive effects, and the balance between these may differ between adolescents and adults, potentially affecting drug use and addiction. However, many studies have not directly compared age groups, preventing firm conclusions. Sex differences and long-term consequences of adolescent use remain largely unexplored. Addressing these gaps is crucial given widespread adolescent use and potential therapeutic applications.
Repeated administration of dextromethorphan (DXM) during adolescence produces greater acute locomotor stimulation and locomotor sensitization compared to adults, and only adolescent-treated rats show cross-sensitization to ketamine after abstinence. DXM also leads to increased perseverative errors in reversal learning exclusively in the adolescent group, indicating long-lasting cognitive flexibility deficits. These findings suggest that adolescent DXM use causes neuroadaptations that may contribute to addiction, though further work is needed to confirm the cognitive effects.
Repeated ketamine use during adolescence produces greater acute locomotor stimulation than in adulthood, but long-lasting behavioral sensitization—a marker of addiction-related neuroadaptation—persists only when exposure occurs in adults. In rats, 10 daily injections of 25 mg/kg ketamine caused immediate locomotor sensitization in both age groups, yet after 20 days of abstinence only adults retained this effect. No cross-sensitization to dextromethorphan was observed. Ketamine did not cause statistically significant cognitive deficits in spatial learning or object recognition in either age group, though adult-treated animals showed a trend toward spatial learning impairments. The findings suggest that adolescent and adult brains respond differently to repeated ketamine, with lasting neuroadaptations in adults that may contribute to addiction risk.
Adolescent rats are more sensitive than adults to the initial stimulant effects of the club drugs PCP and ketamine, but they show less development of drug sensitization—an increase in drug effect with repeated use linked to addiction—than adults do. Periadolescent rats (30 or 38 days old) and young adults (60 days old) received either PCP (6 mg/kg) or ketamine (20 mg/kg) every three days for five injections. Adolescents showed a much stronger response to the first injection than adults, but their activity remained similarly high after the fifth injection, while adults escalated their activity over time, indicating robust sensitization. These findings highlight age-related differences in acute and repeated drug effects.