A classic theory of addiction, opponent-process theory, holds that a drug's immediate rewarding effects are followed by an aversive aftereffect that drives continued use. This study tested whether a 5-HT2A agonist (4-AcO-DMT, a psychedelic) follows that pattern in male rats. In a standard place-preference test 24 hours after dosing—when the drug had cleared—the rats showed no preference for the drug-paired location, suggesting no rewarding aftereffect. However, when the test was modified to capture only the acute drug effect, the rats did show a place preference, indicating the drug itself was rewarding. In a separate test measuring only the 24-hour aftereffect, that aftereffect also produced a strong place preference.
Entheogens have emerged in clinical research as an alternative treatment for Treatment-Resistant Depression (TRD). They produce rapid and lasting antidepressant effects, are anxiolytic, and mitigate suicidal ideation. Additionally, they induce positive emotions and provoke mystical or spiritual experiences, attributes that may contribute to their therapeutic efficacy given the protective influence of mysticism and religiosity against depression. This narrative review discusses existing evidence on the use of entheogens for TRD, provides an updated understanding of the research landscape, and discusses mechanisms of action for compounds such as psilocybin, DMT, LSD, ketamine, esketamine, and cannabinoids. The efficacy of entheogens in managing depression has been consistently validated in clinical trials, though limited understanding of potential adverse effects, especially long-term, remains despite data supporting acute tolerability.