Lecture 16 Hallucinogens

What is the definition of a "hallucinogen"?

A broad category of drugs that alter sensory perception, thought processes, and mood without causing severe confusion, delirium, or gross intoxication.

What does the term "phantasticants" emphasize?

The capacity of these substances to stimulate vivid internal imagery, fantasy, and a sense of profound wonder, spiritual awe, or cosmic connectedness.

What is an "empathogen" and what is a classic example?

Drugs that specifically generate deep feelings of emotional openness, social bonding, and closeness to others[cite: 10, 75]. Example: MDMA (Ecstasy).

What does "psychotomimetic" mean in a clinical context?

Meaning "mimicking psychosis"; an older clinical perspective that these drugs simulate the core features of naturally occurring schizophrenia (such as hallucinations and thought disorganization)[cite: 89].

What is a "club drug"?

A sociological classification for a diverse group of synthetic drugs frequently used by teenagers and young adults at all-night dance parties, raves, or clubs (e.g., MDMA, GHB, Ketamine).

What are the primary pharmacological sites of action of LSD?

It acts as a high-affinity full agonist at the serotonin 5-HT2A receptor, which is critical for its psychedelic effects[cite: 12, 77, 89]. It also binds to 5-HT1A, 5-HT2C, and dopamine receptors.

Why is LSD referred to as an "indoleamine-like" drug?

Its core molecular structure contains an indole ring (a benzene ring fused to a pyrrole ring), making it structurally similar to the endogenous neurotransmitter serotonin.

List the typical positive, neutral, and negative psychological effects of LSD.

Positive: Heightened sensory awareness, euphoria, mystical experiences. Neutral: Visual distortions (synesthesia, trailing), altered time perception. Negative: Acute panic ("bad trips"), paranoia, cognitive fragmentation.

List the typical physiological effects of LSD.

Pupillary dilation, and modest elevations in blood pressure, heart rate, and body temperature.

Why do LSD and similar classical psychedelics have a low addictive potential and resist continuous use?

They lack direct, heavy stimulation of the mesolimbic dopamine pathway and trigger rapid, profound pharmacodynamic tolerance (tachyphylaxis) via immediate down-regulation of 5-HT2A receptors, making daily use ineffective.

What commonalities in site of action account for the similar psychedelic effects of LSD and psilocybin?

Both share an indoleamine core structure that mimics serotonin, and both achieve their primary psychedelic effects by acting as potent agonists at the 5-HT2A receptor.

Describe the dose-response function for indoleamine-like psychedelics like psilocybin.

Low doses cause mild somatic/emotional changes; medium doses show a steep linear phase of sensory/perceptual alterations; high doses flatten into a plateau of true hallucinations and ego dissolution, maintaining a very safe therapeutic index.

How do the psychotropic effects of DMT differ from LSD and psilocybin?

DMT produces an incredibly brief (15-30 mins), overwhelming, and highly intense "breakthrough" experience (feeling launched into another dimension), whereas LSD and psilocybin are much longer and more gradual.

What accounts for the marked high intensity of the DMT experience?

Rapid pharmacokinetics. When inhaled or injected, it crosses the blood-brain barrier almost instantaneously, causing a massive, simultaneous wave of cortical 5-HT2A receptor occupancy before rapid clearance by MAO.

What is the mechanism of action of DMT and 5-MeO-DMT?

They act as full agonists at serotonin 5-HT2A and 5-HT1A receptors.

What is the mechanism of action of DOM/STP, DOI, and DOB?

They are highly potent, selective full agonists at serotonin 5-HT2A and 5-HT2C receptors.

What is the mechanism of action of 2-CB?

It functions as a partial agonist at the serotonin 5-HT2A receptor[cite: 77].

Categorize DMT and 5-MeO-DMT based on structure.

Indoleamine-like (fused bicyclic indole ring structure that mimics serotonin).

Categorize DOM/STP, DOI, DOB, 2-CB, and mescaline based on structure.

Catecholamine-like (phenethylamine core structure containing a single flexible benzene ring that structurally resembles dopamine/NE).

Why are indoleamine-like psychedelics generally more potent than catecholamine-like hallucinogens?

Their rigid, fused bicyclic indole ring fits with much higher steric affinity and tighter binding alignment into the hydrophobic pocket of the 5-HT2A receptor, whereas flexible single-ring catecholamine structures bind less easily.

Describe the pharmacology of MDMA at the synapse.

It acts as an indirect monoamine agonist and substrate releaser; it enters terminals via transporters to block/reverse SERT, DAT, and NET while disrupting VMAT2 vesicles, dumping massive monoamines.

How does MDMA's synaptic mechanism relate to its subjective effects?

The massive surge of serotonin drives its unique empathogenic effects (emotional openness, bonding) [cite: 10, 75], while concurrent dopamine and norepinephrine elevations drive its psychomotor stimulant features (energy, alertness)[cite: 14, 79, 80].

Contrast the subjective effects of the MDMA "high" with the subjective experience of MDMA withdrawal.

The High: Intense euphoria, elevated mood, empathy, self-confidence. Withdrawal ("The Crash"): Profound depression, severe anhedonia, extreme fatigue, hyper-anxiety, and irritability[cite: 272].

Account for why the withdrawal from MDMA is so protracted.

1. MDMA undergoes self-limiting metabolic inhibition at liver enzyme CYP2D6, slowing its own clearance.\n2. It completely depletes vesicular serotonin stores, leaving the brain in a multi-day deficit state while synthesizing new stores.

What are the major reasons for MDMA-related death?

1. Lethal hyperthermia (disrupted hypothalamus + dancing causes core temp to spike, leading to organ failure).\n2. Hyponatremia (water intoxication caused by inappropriate ADH fluid retention + excess water drinking).\n3. Cardiovascular collapse.

How does the mechanism of action of Salvinorin A contrast with classical hallucinogens?

Classical hallucinogens act on the serotonin system (5-HT2A agonists)[cite: 12, 34, 36, 77, 89]. Salvinorin A completely avoids serotonin and is a highly selective Kappa (κ) Opioid Receptor Agonist containing no nitrogen atoms (non-alkaloid).

Contrast the time-course of smoked Salvinorin A with classical hallucinogens like LSD.

Smoked Salvinorin A has an incredibly brief timeline, peaking within 1-2 minutes and clearing within 15-30 minutes. LSD, psilocybin, and mescaline last anywhere from 4 to 12 hours.

Contrast the subjective effects of Salvinorin A with classical hallucinogens.

Salvinorin A produces a chaotic, intensely dissociative, and often terrifying detachment from reality (feeling pulled by geometric forces or turning into inanimate objects), completely lacking the warm euphoria of classical drugs.

Why do users of Salvinorin A tend not to repeat usage?

Because its selective activation of the Kappa (κ) opioid receptor directly induces a state of profound dysphoria, severe unease, and intense somatic discomfort rather than reward.