The purpose of this paper is to provide an integrative review and offer novel insights
regarding human research with classic psychedelics (classic hallucinogens), which
are serotonin 2A receptor (5-HT2AR) agonists such as lysergic acid diethylamide (LSD),
mescaline, and psilocybin. Classic psychedelics have been administered as sacraments
since ancient times. They were of prominent interest within psychiatry and neuroscience
in the 1950s to 1960s, and during this time contributed to the emergence of the field
of molecular neuroscience. Promising results were reported for treatment of both end-of-life
psychological distress and addiction, and classic psychedelics served as tools for
studying the neurobiological bases of psychological disorders. Moreover, classic psychedelics
were shown to occasion mystical experiences, which are subjective experiences reported
throughout different cultures and religions involving a strong sense of unity, among
other characteristics. However, the recreational use of classic psychedelics and their
association with the counterculture prompted an end to human research with classic
psychedelics in the early 1970s. We provide the most comprehensive review of epidemiological
studies of classic psychedelics to date. Notable among these are a number of studies
that have suggested the possibility that nonmedical naturalistic (non-laboratory)
use of classic psychedelics is associated with positive mental health and prosocial
outcomes, although it is clear that some individuals are harmed by classic psychedelics
in non-supervised settings. We then review recent therapeutic studies suggesting efficacy
in treating psychological distress associated with life-threatening diseases, treating
depression, and treating nicotine and alcohol addictions. We also describe the construct
of mystical experience, and provide a comprehensive review of modern studies investigating
classic psychedelic-occasioned mystical experiences and their consequences. These
studies have shown classic psychedelics to fairly reliably occasion mystical experiences.
Moreover, classic-psychedelic-occasioned mystical experiences are associated with
improved psychological outcomes in both healthy volunteer and patient populations.
Finally, we review neuroimaging studies that suggest neurobiological mechanisms of
classic psychedelics. These studies have also broadened our understanding of the brain,
the serotonin system, and the neurobiological basis of consciousness. Overall, these
various lines of research suggest that classic psychedelics might hold strong potential
as therapeutics, and as tools for experimentally investigating mystical experiences
and behavioral-brain function more generally.