Classic psychedelics vs other compounds
Before describing the effects of psychedelic drugs and how they may relate to their therapeutic potential, it is useful to define which compounds are considered “classic psychedelics.”
The classic psychedelics are substances that operate primarily through activation of the serotonin 5-hydroxytryptamine receptor 2A receptor (5-HT2A) (Table 17). Many psychedelic drugs are derived from natural sources, including plants, fungi, and animals. For example, N, N-dimethyltryptamine (DMT), which is one of the most potent psychedelic compounds, is found in various plant species and can be imbibed in a tea known as ayahuasca, most commonly in the context of spiritual ceremonies.
Other compounds. Some researchers continue to classify other compounds as “psychedelics,” although the mechanisms of action and effects of these compounds may vary greatly from those of the classic psychedelics. These include the dissociative anesthetics ketamine and phencyclidine (PCP), which exert their effects via N-methyl-d-aspartate (NMDA) receptor antagonism, and the empathogen 3,4-methylenedioxymethamphetamine (MDMA), which acts primarily through monoamine reuptake inhibition.
The DSM-58 does not differentiate between classic psychedelics and related compounds. In its chapter on Substance-Related and Addictive Disorders, the section Hallucinogen-Related Disorders provides criteria for the diagnoses of phencyclidine use disorder and other hallucinogen use disorder. Researchers generally have abandoned the term “hallucinogen” because psychedelics typically do not induce frank hallucinations. Furthermore, lumping psychedelics and compounds such as MDMA and ketamine into the category of “other hallucinogen” fails to address important distinctions between them, including diagnostically relevant issues. For example, psychedelics do not cause symptoms of physiologic dependence such as craving or a withdrawal syndrome, whereas MDMA can.9 The DSM-5 also contains a diagnosis called hallucinogen persisting perception disorder (HPPD), referring to residual distortions of visual perception that remain following psychedelic intoxication. Although the text notes the estimated prevalence of HPPD in individuals who use psychedelics is 4.2%, the condition is thought to occur infrequently in both therapeutic and recreational users.10
How psychedelics work
Psychedelics can induce a spectrum of effects that are not necessarily dose-dependent. Mild effects of intoxication include altered sensory perception in visual, auditory, proprioceptive, and somatosensory spheres, including synesthesia. Progressively more severe changes include a distorted or eliminated perception or awareness of space, time, body, and self, resulting in derealization and depersonalization. Some of the most extreme alterations of consciousness reported by users include mystical or transcendent experiences of birth, giving birth, death, exchanging bodies with a nonhuman species, and meeting otherworldly beings.11 In terms of neurophysiology, psychedelics cause altered cerebral blood flow and metabolism, increased connectivity between brain regions that do not typically communicate, and a reduction in the activity of a group of cortical structures called the default mode network (DMN).12
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