Essentials: Psychedelics for Treating Mental Disorders | Dr. Matthew Johnson

The conversation opens with a basic question: what qualifies a substance as a psychedelic? Johnson says nomenclature is "a real challenge" in this field. For a pharmacologist the word is "not very satisfying" because it spans several pharmacological classes. He calls it "more of a cultural term." It does relate to drug effects, but only "at a very high level." What unites these compounds, in his framing, is that they all can "profoundly alter one's sense of reality," and part of that is acutely altering the sense of self while someone is on the drug.

He then describes the classes. The first is the classic psychedelics. He notes that "hallucinogen" and "psychedelic" have traditionally been used as synonyms in the literature, with a period of avoiding "psychedelic" because of its baggage before a return to the term in recent years. His examples are LSD; psilocybin, which he says occurs in over 200 known mushroom species; DMT, found in "dozens and dozens of plants"; and mescaline, from peyote and other cacti such as San Pedro. Chemically the classic psychedelics split into tryptamine-based compounds (psilocybin, DMT) and phenethylamine-based compounds. Johnson says the receptor effects matter more than this chemistry: all classic psychedelics act as agonists or partial agonists at the serotonin 2A receptor.

Other classes Johnson says can be called psychedelic: - NMDA antagonists, including ketamine, PCP and dextromethorphan (which he has researched and links to "robo-tripping"). He says their subjective effects overlap heavily with those of the 2A-agonist classic psychedelics. - MDMA, which he says "really stands in a class by itself." It has been called an entactogen, meaning "touching within," because it can put someone in touch with their emotions, and an empathogen, because it can afford empathy.

The host sums this up as "an enormous cloud of partially overlapping compounds": some act more on serotonin, others more on dopamine, and all share the partial definition of profoundly altering the sense of self.

Johnson offers his own frame: psychedelics profoundly alter models. "We're prediction machines," he says. Much of that prediction is top-down, and psychedelics have a way of, "loosely speaking, dissolving those models."