3 Clinical psychopharmacology3.3 Pharmacodynamics

3.3.2.11 Hallucinogenics

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Written by Resident Doctor Committee · Published

Classic psychedelics

Lysergic acid diethylamide (LSD), psilocybin, mescaline and dimethyltryptamine (DMT) are classic serotonergic psychedelics.

  • Agonism at cortical 5-HT2A serotonin receptors produces their hallucinogenic effect.

  • 5-HT2A antagonists block the effect, but D2 dopamine antagonists do not.

  • 5-HT1A agonism does not produce the perceptual change.

  • Tolerance and cross-tolerance develop quickly, while dependence and physical withdrawal are uncommon.

Drug

Feature

Duration

LSD

Active at microgram doses

8 to 12 hours

Psilocybin

Prodrug, converted to psilocin

4 to 6 hours

DMT

Broken down by monoamine oxidase, so inactive by mouth

15 minutes smoked, hours with a monoamine oxidase inhibitor in ayahuasca

Dissociatives

Dissociatives act mainly by N-methyl-D-aspartate (NMDA) glutamate receptor antagonism.

Drug

Point to remember

Phencyclidine

Blocks the NMDA channel; does not act by 5-HT2A agonism, serotonin release, kappa-opioid agonism or CB1 cannabinoid agonism

Ketamine

Phencyclidine-related dissociative anaesthetic

Nitrous oxide

NMDA antagonist, not a GABA-B agonist like gamma-hydroxybutyrate (GHB)

  • Ketamine removes cortical awareness of pain without depressing the reticular activating system, unlike classic psychedelics.

  • Ketamine and phencyclidine can cause cognitive and negative-like symptoms, which supports glutamatergic models of schizophrenia.

  • Heavy ketamine use causes dependence, cognitive impairment and severe urinary tract injury.

Compare the two panels: when ketamine blocks NMDA channels on a GABA interneuron (B), the interneuron falls quiet and the disinhibited pyramidal neuron releases more glutamate, the NMDA receptor hypofunction model behind glutamatergic theories of schizophrenia. Drawn for MRCPsychiatrist

Harms

  • Acute effects include panic, paranoia, raised pulse and blood pressure, and dilated pupils.

  • Hallucinogens can precipitate psychosis or mania in susceptible people.

  • Material sold as LSD can contain more toxic NBOMe compounds.

  • Set (mood and expectation) and setting (environment and support) strongly shape the experience.

Revision material for the MRCPsych examinations. Not clinical guidance, and not for use in patient care.