Lecture 17

Categories of Hallucinogens

  • Cholinergic: Agonists or antagonists acting within the cholinergic nervous system, primarily targeting muscarinic receptors.

  • Serotonergic: Chemically resemble serotonin (e.g., LSD, psilocybin, DMT) and act on serotonin receptors.

  • Noradrenergic / Methylated Amphetamines: Chemically resemble noradrenaline or represent modifications of amphetamine.

  • Miscellaneous: Hallucinogens and deliriants that do not fit into the other three neurochemical categories.

Cholinergic Hallucinogens

  • Agonist (Amanita muscaria / Fly Agaric Mushroom):

    • Origin and Application:

    • Widespread in temperate zones of the Northern Hemisphere; bright red cap with white speckles.

    • Historically used as a fly pesticide by leaching toxins into milk.

    • Ingested by Scandinavian Vikings ("berserkers") before raids to induce invincibility, visions, and agitated raving.

    • Active Substances:

    • Ibotenic acid converts to muscomol upon drying.

    • Muscomol acts as an agonist at muscarinic cholinergic and GABA receptors (driving dissociative/detachment effects).

    • Excretion and Recycling:

    • Active compounds are excreted unchanged in urine; recycled historically via communal or reindeer urine consumption.

    • Effects and Toxicity:

    • Low doses produce euphoria and good humor; higher doses cause detachment, unreality, increased secretions, pupil constriction, GI upset, and agitated raving.

    • Severe overactivation can be lethal (mechanism parallels sarin nerve gas).

  • Antagonists (Atropa Belladonna, Datura stramonium, Mandragora):

    • Active Alkaloids:

    • Atropine, scopolamine, and hyoscyamine competitively block muscarinic receptors.

    • Physiological and Psychological Effects:

    • Dry bodily secretions, dilated pupils, drowsiness, dreamlike states, weightlessness/flying sensations, severe neurotic hallucinations, profound amnesia, and loss of reality testing.

    • Specific Features and History:

    • Atropa Belladonna (Deadly Nightshade):

      • Named after Atropos (Greek Fate who cuts the thread of life); belladonna ("beautiful lady") refers to pupil-dilating eye drops.

      • Highly toxic (22 to 55 berries or a single leaf is lethal).

    • Datura stramonium (Jimson Weed / Devil's Trumpet):

      • Features white trumpet flowers and thorny seed pods; ingestion of seeds frequently causes emergency admissions.

      • Causes bronchodilation (historically smoked for asthma).

      • Linked to American colonial witch trials due to topical application inducing delirium and flying sensations.

    • Mandragora (Mandrake Plant):

      • Medieval folklore connected its root shape to semen from hanged men and claimed uprooting caused lethal screams.

      • Contains identical active alkaloids and effects as Atropa and Datura.

Serotonergic Hallucinogens: LSD

  • Background and Discovery:

    • Synthesized in 19381938 by Albert Hoffman from ergot fungus derivatives (LSA).

    • Hoffman accidentally absorbed LSD in 19431943, leading to the first intentional self-trial (250 μg250\,\mu\text{g}, remembered as "Bicycle Day").

  • Dosage and Pharmacokinetics:

    • Initial self-trial dose (250 μg250\,\mu\text{g}) was 55 times modern street doses (50 μg50\,\mu\text{g}).

    • Administered via liquid drops on paper ("blotter acid") or tablets; odorless, colorless, and tasteless.

    • Readily crosses blood-brain and placental barriers; peaks in 22 to 44 hours, lasting 66 to 1212 hours.

  • Physiological Effects:

    • Sympathetic nervous system activation causes pupil dilation (directly correlates with trip intensity).

    • Strong analgesic properties (unused clinically due to cognitive side effects).

    • Rapid tolerance develops within 33 to 44 days (cross-tolerant with psilocybin and mescaline); lacks physical dependence.

  • Perceptual and Subjective Effects:

    • Visual Distortions: Wave-like or pulsing motion in stationary objects.

    • Object Trails: Visual residue of moving objects resembling stop-action frames.

    • Form Constants: Recurring geometric patterns (cobwebs, lattices, spirals, funnels).

    • Synesthesia: Cross-modal sensory perception (e.g., seeing auditory stimuli).

    • Time Distortion: Subjective time expansion (minutes feel like hours).

    • Ego Disintegration: Loss of self-environment boundaries driven by Default Mode Network (DMN) desynchronization.

  • Adverse Reactions and Disorders:

    • Bad Trips: Panic reactions occurring in ~5%5\% of uses; managed best in low-stimulation environments.

    • HPPD 1: Flashbacks; short, benign, non-distressing visual recurrences.

    • HPPD 2: Persistent, distressing, long-lasting visual disturbances (~4%4\% prevalence).

  • Lethality:

    • Direct toxicity is extremely low (LD50≈14,000 μgLD_{50} \approx 14{,}000\,\mu\text{g}, ~300300 times a street dose); fatalities stem from accidental behavior during intoxication.

Other Serotonergic Hallucinogens

  • Neurochemical Mechanism:

    • Act primarily as agonists at 5-HT25\text{-HT}_2 receptors (specifically 5-HT2A5\text{-HT}_{2A}); effects are completely blocked by ketanserin.

  • Lysergic Acid Amide (LSA):

    • Found in ergot fungus, morning glory seeds, and Hawaiian baby woodrose seeds.

    • Ergot-contaminated grain causes Ergotism ("Holy Fire"), leading to severe vasoconstriction, burning pain, and gangrene.

  • Psilocybin:

    • Chemical structure: 4-phosphoryl-dimethyltryptamine4\text{-phosphoryl-dimethyltryptamine}.

    • Isolated from Mexican/Central American mushrooms (teonanácatl);

    • Converted in the body to active psilocin; duration lasts 22 to 66 hours.

  • Dimethyltryptamine (DMT):

    • Endogenous trace amine and plant entheogen.

    • Orally inactive alone due to MAO degradation; combined with MAO inhibitors to produce Ayahuasca.

  • Bufotenin:

    • Chemical structure: 5-hydroxy-dimethyltryptamine5\text{-hydroxy-dimethyltryptamine}.

    • Found in Caribbean plants, fish, and toad skin (Bufo alvarius); produces severe peripheral vasoconstriction resulting in cyanosis.

  • Ibogaine:

    • Weak 5-HT25\text{-HT}_2 agonist from Central African shrub Tabernanthe iboga.

    • Low doses stimulate; high doses hallucinate; investigated for opioid addiction treatment without conclusive clinical evidence.