Hallucinogens

1. Hallucinogens Slides by: Bruna Brands, PhD Centre for Addiction and Mental Health Department of Pharmacology University of Toronto Live Dramatic Interpretation by: Wende Wood, B.A., B.S.P., B.C.P.P. Drug Information and Drug Use Evaluation Pharmacist Centre for Addiction and Mental Health

2. Definition • group of substances that produce changes in thought, perception and/or mood • term hallucinogen derived from Latin alucinari - “to wander in the mind”

3. Classes • indolealkylamines (similar to 5-HT) • phenylethylamines (similar to nor-ep) • anticholinergics • miscellaneous category

4. Clinical Manual of Chemical DependenceStreet Names of Hallucinogens Note LSD = lysergic acid diethylamide DMT = N,N-dimethyltryptamine DET = N,N-diethyltryptamine DOM = 2,5-dimethoxy-4-methamphetamine MDA = methylenedioxyamphetamine MDMA = methylenedioxymethamphetamine DEA = 3,4-methylendioxyethamphetamine Edited by D.A. Ciraulo and R.I. Shader

5. Indolealkylamines • LSD (d-lysergic acid diethylamide,semi-synthetic substance derived from ergot) • LSA (d-lysergic acid amide, from morning glory seeds) • psilocybin and psilocin ( isolated from hallucinogenic mushroom genus Psilocybe) • DMT( N,N-dimethyltryptamine), found in trees of genus Virola

6. History of LSD • hallucinogenic and psychotomimetic effects of LSD discovered by Hofmann who accidentally ingested a minute quantity of ergot derivatives • ergot alkaloids are produced by rye-plant inhabiting fungus (Claviceps purpurea) • outbreaks of ergotism in Middle Ages

7. History of LSD cont’d • two types • gangrenous ergotism • gangrene of limbs, loosened before death • convulsive ergotism • erythema, diarrhea, vomiting, formication, burning sensation in limbs, convulsions, maniacal excitement, death

8. Tryptamine-Related Hallucinogens (Indolealkylamines) • naturally-occurring plant alkaloids (ex ergot alkaloids, Claviceps purpurea) • chemically synthesized derivatives (LSD)

9. Tryptamine-Related Hallucinogens-LSD-Neuropharmacology • acts primarily through 5-HT receptor subtypes • antagonist or partial agonist at 5-HT2 and 5-HT1c receptors, agonist at multiple 5-HT1receptors • cannot attribute hallucinogenic effects to one 5-HT receptor subtype

10. Tryptamine-Related Hallucinogens-Pharmacology • well-absorbed from GI tract • LSD most potent (20-25g produces marked sympathomimetic effects) • 5 morning glory seeds a high of 12 hours or longer • LSD longer acting (8-12h) and more potent than psilocybin or psilocin (4-12h) • 1-2 mushrooms hallucinosis for 4-12h • all compounds mainly cleared by liver; excreted in feces • LSD no active metabolites • psilocybin is hydrolyzed to psilocin (active hallucinogen)

11. Clinical Symptoms of LSD Intoxication • usual doses 30-400g (20g clinically detectable symptoms) • tolerance occurs over time • symptoms within 30 min • maximum effects at 1-4h, symptoms subside after 8-16h • lower doses autonomic nervous system changes and mood changes:HR and BP and body temp, appetite, nausea, vomiting etc • higher doses perceptual distortions and body image changes

12. Clinical Symptoms of LSD Intoxication (cont’d) • subjective experience depends on personality of user, expectations, setting • perception: visual distortions, blurred vision, perception of distance and depth • synesthesia, colours are visible • delusions of supernatural abilities, suicide • euphoria or frightening experience may occur • flashbacks • prolonged adverse reactions: psychosis, paranoid states, depression

13. Other Tryptamine related Hallucinogens • similar to LSD • intensity of effects related to dose • restlessness, nausea and autonomic hyperactivity • visual disturbances more common • Psilocybe mushrooms: ataxia, hyperkinesis, anticholinergic effects (symptoms within 15-30 min)

14. Phenylethylamine Hallucinogens • close structural resemblance to catecholamines, nor-ep and DA • mescaline naturally occurring substance found in peyote cactus • modification of mescaline molecule led to synthetic amphetamine derivatives with hallucinogenic action • one dried flower top (mescal button) contains 6-45mg of active compound • ingested fresh or as a powder

15. Mescaline-Pharmacokinetics • <potent than LSD (5mg vs 1g) • readily absorbed from GI tract • concentrated in liver, spleen, kidney • clinical symptoms similar to LSD • nausea and vomiting 30 min to 2h after ingestion • mydriasis, diaphoresis, hypertension, dizziness, chills • hallucinogenic effects peak at 5-6h • vivid colours, kaleidoscopic visions, synesthesias

16. Phenylalkylamine Hallucinogens-cont’d • substituted phenethylamines- “designer drugs” • structural similarities to amphetamine and mescaline • MDMA

17. Chemical Structure of MDMA(3-4 methylenedioxy-methamphetamine)

18. Clinical Toxicology of Hallucinogenic Amphetamine Derivatives • effective dose of MDMA 50-150mg • well absorbed • peak effect at 1-5h

19. Anticholinergics • plants: Solanum dulcamara, Atropa belladonna (belladonna alkaloids: atropine and scopolamine) • Jimsonweed (Datura stramonium), seeds contain4% anticholinergicalkaloids (scopolamine, hyoscyamine and atropine)

20. Anticholinergics cont’d • low doses of scopolamine- mild euphoria, sedation, drowsiness • much higher doses intense cns and pns effects: • clinical findings: muscarinic effects: dry mouth, decreased GI motility, urinary retention, tachycardia, dry mouth, hyperpyrexia with dry, flushed skin • CNS effects: visual, auditory and tactile hallucinations; disorientation and confusion, memory loss, dilation of pupils, seizures • entire episode may last for 24 to 48 hours

21. Belladonna Alkaloids • atropa belladonna (deadly nightshade) • berries used as poison (Atropa, after Atropos, one of Greek Fates who cut the thread of life and was responsible for death) • belladonna means beautiful woman – refers to putting a drop of the juice of the plant to dilate pupils • also used by witches in Middle Ages

22. Datura stramonium • Jimson weed (“locoweed”, thorn apple) • Solanaceae family • all parts of plant are poisonous • seeds contain 4% anticholinergic alkaloids (scopolamine, hyposcyamine and atropine) • leaves can be eaten raw, prepared as tea or smoked • as little as 4-5g of crude leaf may be lethal for children • adolescents smoke the dried leaves or consume dried seeds to induce toxic delirium • effects dose dependents

23. Miscellaneous Category • PCP and Ketamine • dissociative anesthetics • both drugs produce hallucinogenic effects at low levels • PCP can produce stimulant, depressant, analgesic, anesthetic, and hallucinogenic effects (dose-dependent)

24. Medical Uses • ketamine:anesthetic • atropinic alkaloid: to control smooth-muscle spasms, hyperirritability of the GI tract, excessive salivation and bronchial secretions etc • scopolamine for motion sickness • no medical uses for LSD, MDMA etc

25. Undesirable Effects • acute; usually mild and transient feelings of physical discomfort, anxiety, depression • sometimes intense anxiety, panic, paranoia; rarely toxic psychosis • “bad trips” not always related to dose • PCP and LSD are hallucinogens most frequently associated with serious and lethal accidents • atropine, scopolamine, hyoscyamine dangerous at high doses • PMA highly lethal

26. Undesirable Effects (Cont’d) • deaths associated with MDA, MDMA, PCP • flashbacks • brain damage • tolerance develops to psychoactive effects of many hallucinogens (ex LSD) • psychological dependence may develop to some • development of physical dependence not supported by literature

27. Salvia divinorum • mint family • main active ingredient is Salvinorin A • used in spiritual practices for its psychoactive properties by Mazatecs of Oazaca, Mexico • no actions on 5-HT2A serotonin receptors (principal molecular target for classical hallucinogens) • structurally distinct from DMT, psilocybin, mescaline and synthetic hallucinogens such as LSD and ketamines

28. Pharmacology • not active orally, usually smoked • most potent naturally occurring hallucinogen (as potent as LSD) • effective dose in humans 200-1000 μg range when smoked • intense hallucinatory experiences • duration of action: several minutes to 1hr or so • potent and selective κopioid receptor agonist • first non-alkaloid opioid receptor subtype selective drug

29. Potential Therapeutic Use • psychomimetic selective for κ opioid receptors, therefore κ opioid selective antagonists may be helpful to treat diseases which involve perceptive disorders (e.g., schizophrenia, dementia, and bipolar disorders)

30. Issues • most of these drugs are produced in illicit laboratories • purity varies, adulterants • misrepresentation on the street • street drugs and driving