Lesson 23 -- Hallucinogens/ Psychedelics

What are the main classes of classic psychedelic hallucinogens?

Indoleamines (serotonin-like) and Phenethylamines (NE/DA-like)

Indoleamines (serotonin-like) inlcude?

• LSD

• Psilocybin / Psilocin

• DMT, 5-MeO-DMT

• Bufotenin

Phenethylamines (NE/DA-like) inlcude?

• Mescaline

• DOM, DOx series

• High-dose MDMA has mild hallucinogenic effects

Which drugs fall under dissociative anesthetics?

• PCP (phencyclidine)

• Ketamine

• DXM (in cough syrup; at high doses)
  These do not activate 5-HT2A receptors — they block NMDA glutamate receptors.

Which common structural groups do most hallucinogens resemble?

Either phenethylamines (NE-like) or indoleamines (serotonin-like)

What is the primary receptor responsible for hallucinations caused by LSD, psilocybin, and mescaline?

The 5-HT2A receptor (a Gq-coupled serotonin receptor).
Activation increases cortical glutamate → sensory distortion, altered consciousness

How do psychedelics alter cortical signaling?

They activate 5-HT2A receptors on layer V pyramidal neurons, which:

• increase glutamate release

• disrupt cortical oscillations

• cause sensory cross-talk

• produce the “expanded consciousness” feeling

EEG shows disrupted rhythmic oscillations in cortex (NOT in amygdala or cerebellum)

What brain region shows altered rhythmic oscillations during psychedelic use?

The cerebral cortex → especially layer V pyramidal cells

Why do psychedelics cause perceptual distortions but little dopaminergic reinforcement?

They do not strongly activate the dopamine reward system → very low addiction potential

LSD potency and duration?

• Extremely potent: effective at 25–50 micrograms

• Duration: 8–12 hours

Psilocybin potency and duration?

• Moderately potent

• Duration: 4–6 hours

• Psilocybin is converted to psilocin, the active form

DMT potency and duration?

• Very potent, but extremely short-acting

• Smoked: 5–20 min

• Orally active only when taken with MAOI (Ayahuasca)

What are the 4 phases of an LSD trip?

• Onset (first 30–60 min):

  • Heightened awareness, sensory sharpening

• Plateau:

  • Distorted time sense

  • Altered colors

• Peak:

  • Intense visuals

  • Synesthesia (“hearing colors”)

  • Ego dissolution

• Come-down:

  • Gradual normalization

  • Fatigue, mild confusion

Why are “good” vs “bad” trips unpredictable?

Because outcomes are strongly influenced by set and setting:

• expectations

• mood

• personality

• environment

Drug itself is not unpredictable; context is

What is a “flashback”?

A sudden re-experiencing of perceptual distortions long after drug use.
Usually brief and harmless

What is HPPD?

Hallucinogen Persisting Perception Disorder — rare, chronic, distressing flashback-like visual disturbances

Are flashbacks common?

No — rare. They very rarely progress to HPPD

How do researchers detect hallucinogenic-like activity in animals if animals can’t report hallucinations?

Using drug discrimination and head-twitch response in rodents.
Rodents trained on LSD will respond similarly to other 5-HT2A agonists

What is the main mechanism of PCP and ketamine?

They are noncompetitive NMDA receptor antagonists.
They block the ion channel inside, not the glutamate binding site

What psychological effects do NMDA blockers produce?

• Dissociation

• Feeling detached from body/environment

• Analgesia

• Amnesia

• Hallucinogenic confusion

• “Dissociative anesthesia” (eyes open, unresponsive)

Why are PCP and ketamine thought to model features of schizophrenia?

Because NMDA hypofunction → abnormal glutamate signaling →

• cognitive deficits

• sensory disturbances

• dissociation
  similar to symptoms of schizophrenia

What is “dissociative anesthesia”?

A unique state seen with ketamine/PCP:

• Eyes open

• Reflexes preserved

• Patient appears awake but disconnected from environment

Not like typical sedative unconsciousness

What modern therapeutic uses are being investigated for classic psychedelics (psilocybin, LSD)?

• Treatment-resistant depression

• End-of-life anxiety

• OCD

• Addiction treatment (alcohol, tobacco)

What therapeutic use is ketamine approved for?

Treatment-resistant depression (as esketamine nasal spray).
Works via rapid increases in synaptic plasticity