Psychedelics: History and What Neuroscience Shows

History

Traditional use. NIDA says some psychedelic drugs come from plants and fungi with a long history of use in many cultures. It reports that Aztec shamans used psilocybin in healing rituals, that some Native American tribes used peyote as long ago as 5,700 B.C. in religious ceremonies, and that ancient texts from India and Greece refer to psychedelic use. [1] A review of Mesoamerica describes peyote, psilocybin mushrooms (called teonanacatl) and the seeds of ololiuhqui in the ritual and healing life of the Olmec, Zapotec, Maya and Aztec peoples. It notes mushroom stones from about 3000 BC and that local healers still use these substances in ceremonies today. [2] Those traditions are living practices with their own rules and meanings, covered on the page about Indigenous traditions, ethics and conservation.

The 20th century in laboratories. Nichols' review explains that LSD and the brain chemical serotonin were discovered at nearly the same time, and that in the 1950s researchers explored whether LSD and similar substances acted through serotonin. [3] The word "psychedelic" was proposed by Humphry Osmond in 1956. [4] A later review says research on mescaline and other classic psychedelics became limited after the prohibition of psychoactive substances in the early 1970s. [5] Interest returned in recent decades; NIDA dates a new wave of laboratory research to the early 1990s, helped by brain imaging. [6]

Neuroscience: what is reasonably well supported

Evidence labels on this page: established means widely agreed in the research literature; insufficient evidence means the question is open.

Serotonin 5-HT2A receptors. NIDA says studies suggest classic psychedelics such as psilocybin, LSD and DMT mainly act on the 5-HT2A receptor, a target of serotonin. [1] Nichols' review in Pharmacological Reviews describes a consensus that psychedelics are agonists or partial agonists at these receptors, especially on certain cortical neurons. [3] Evidence label: established for this receptor role in how classic psychedelics work; the other groups (such as ibogaine and salvia) work through different systems. [1]

Brain networks. A systematic review of imaging studies of LSD, psilocybin and ayahuasca found consistent acute disruption of connectivity within the default mode network and more connectivity between other networks. [7] NIDA describes the default mode network as most active during self-reflection and suggests this may help explain why thoughts feel less self-centered. [1]

What is not settled

• Whether network changes explain benefit. The same systematic review says it is unclear how central the default mode network is to therapeutic potential. [7] Evidence label: insufficient evidence for any single explanation of benefit.
• Mechanisms for depression. A review of psilocybin's molecular effects says the mechanisms behind its psychedelic and antidepressant effects are currently unknown, though they are thought to involve serotonin signaling, especially 5-HT2A. [8]
• Brain imaging is not a clinical outcome. A change on a scan shows that something happened in the brain, not that a person got better.
• Heart effects. A review of cardiovascular safety says serotonin receptor activity raises questions about heart risks, that trial data in healthy volunteers point to relative safety, and that data in people with heart disease are lacking. [9]

Why mechanism matters for safety

Because psychedelics act on systems also used by many medicines, interactions are possible. NIDA says some researchers suspect psychedelics may interact with medicines that also raise serotonin, with serotonin toxicity that is usually mild but can be life-threatening in rare cases. [1] See drug interactions and toxicology and medication interactions.

How to read the science

Animal and cell findings are not human findings, and brain scan findings are not treatment results. See reading early-stage research and the overview of natural psychedelics. This page is education, not medical advice.