Psychedelics and Hallucinogens in Psychiatry – Mechanisms of Action and Clinical Application

Posted on:October 31, 2020
Last Updated: November 24, 2023
Time to read: 17–20 minutes

Psychedelics are any of the so-called mind-expanding drugs that are able to induce states of altered perception and thoughts, frequently with a heightened awareness of sensory input but with diminished control over what is being experienced. [Rucker J et al, 2018]

Hallucinogens were originally referred to as psychotomimetics after Isbell and colleagues described lysergic acid diethylamide (LSD) as “the most effective and safest agent for inducing an experimental, but reversible, psychosis in nonpsychotic subjects”. [Isbell et al. 1956]

However, in the 1940s and 1950s, LSD was actually also being trialled as a psychotherapeutic agent for treating depression and anxiety.

Today, hallucinogens are not classified as ‘psychosis inducers’ but instead are classified by their chemical structure, pharmacological mechanism of action, and clinical properties [Romeu et al. 2016]:

  • Classic psychedelics – These serotonergic hallucinogens are full or partial agonists of serotonergic 5-HT 2A receptors. They include LSD, psilocybin, and N, N-dimethyltryptamine (DMT), all of which induce a state of altered perception, thought, and feeling.

The feature that distinguishes the psychedelic agents from other classes of drugs is their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation. [Jaffe J., 1990]

Vargas et al. found that activation of intracellular 5-HT2A receptors is responsible for the plasticity-promoting and antidepressant-like properties of psychedelics, but serotonin may not be the natural ligand for those intracellular receptors. [Vargas et al, 2023]

  • Empathogens/entactogens – Mixed serotonin and dopamine reuptake inhibitors and releasers such as methamphetamine (MDMA) are known to cause emotional connectivity as well as increased sociability and affability.
  • Dissociative anaesthetics – Glutamatergic NMDA receptor antagonists such as ketamine, phencyclidine, and dextromethorphan (DXM) reduce excitation, causing sedation and perceptual distortion.

In this article, we cover:

  • Psilocybin
  • Lysergic Acid Diethylamide (LSD)
  • Mescaline
  • DMT
  • Ayahuasca
  • MDMA


Drug addiction and drug abuse, in Goodman and Gilman’s the Pharmacological Basis of Therapeutics

Jaffe JH. (1990) Drug addiction and drug abuse, in Goodman and Gilman’s the Pharmacological Basis of Therapeutics (Goodman AG, Rall TW, Nies AS, Taylor P. eds) 8th ed, pp 522–573, McGraw Hill, New York