1.
Drugs & Behavior: Hallucinogens Brian J. Piper, Ph.D. 1933-2006

2.
Goals• Mescaline (I)• LSD (I)• Psilocybin (I)• Dextromethorphan (NA)• Ketamine (II)• PCP (II)

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Epidemiology: Past YearMonitoring the Future: http://monitoringthefuture.org/pubs/monographs/mtf-vol1_2009.pdf

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Epidemiology: High SchoolMonitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

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College PlansMonitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

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RegionMonitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

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EthnicityMonitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

8.
Availability

9.
Mescaline• Found in peyote cactus• Entheogen for Native American Church• Visual hallucinogens/synesthesia2:50 on, 0 to 0:30ish: http://www.youtube.com/watch?v=0kraijbaLDo

10.
Psilocybin Psilocybe mexicana • Religious experiences for Aztecs & Mayans • Gordon Wasson is taken on “magic mushroom” trip by Shaman Maria Sabina • Liver converts psilocybin (Pro-drug) to psilocin 1894-1995http://www.imaginaria.org/wasson/life.htm

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Indocybin• Indo: Indolamine/Indian• Sandoz Pharmaceuticals tests utility as adjunct to psychotherapy Albert Hoffman 1906-2008

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Altered States of ConsciousnessHasler et al. (2004). Psychopharmacology, 172,145-156.

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Healthy adults received Placebo, Very Low Dose, Low, Medium, or High Dose(315 µg/kg) of Psilocybin and rated their subjective experiences.Hasler et al. (2004). Psychopharmacology, 172,145-156.

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• Similarity/Difference with Schizophrenic Hallucinations• Importance of Set & SettingHasler et al. (2004). Psychopharmacology, 172,145-156.

15.
History of LSD• 1938: lysergic acid diethylamide synthesized by Albert Hoffman (Delysid)• 1950’s: military tested for “truth drug”• 1961: Timothy Leary• Current: Schedule I• Recreational Dose: 20 -80 μg• Lethal Dose: ?

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Epidemiology of LSDMonitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

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Adolescent Phase?

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Serotonin Receptors: 1, 2, 3, 4, 6, and 7Key: 2A/2C

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Individual Differences in Response to LSD• Flies voluntarily ate LSD and their behavior rated:• A = Resistant (Wild type), B = Sensitive (w1118), C = Resistant (w1118 P [w+]), – 1= no effect – 2= sluggish – 3= no non-prompted movements – 4= uncoordinated movements – 5= immobile Nichols et al. (2002). Neuroscience, 115, 979-984.

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Hallucinogen Information• Erowid is a highly popular source of drug- information (55K/day)

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Hallucinogen Persisting Perception Disorder• Online study to determine frequency of HPPDBaggott et al. (2011). Drug & Alcohol Dependence, 114, 61-67.

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Visual experiences (non-drug) may be more common than previously thoughtA small subset (1.1%) seek treatmentBaggott et al. (2011). Drug & Alcohol Dependence, 114, 61-67.

23.
Hallucinogens Compared• Dimethyltryptamine (DMT): ≈0.5 hours – Degraded by MAO• Psilocybin: intermediate• Mescaline/LSD: 6+ hours Tryptamine

24.
Hypothetical?• What if an experienced organic chemist described the subjective effects of self-tests of hundreds of hallucinogenic substances?• What if they also made freely available synthesis instructions?

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Dextromethorphan• Low doses decrease coughing.• High doses cause dissociative state (phases).• Sigma1 agonist, SERT antagonist 2D6 Dextromethorphan --------------> Dextrorphan

26.
Phencyclidine (PCP)• Parke-Davis marketed as Sernyl in 1950’s• Decreases pain sensitivity and increases body temperature & blood pressure• Strong dissociative, euphoria, reduces inhibition• NMDA anatagonist• Long-acting (≈40 hour half-life)!

27.
PCP and Brain Structure• Adult rats received 5 mg/kg of PCP for 7 days.• Brain sections of the prefrontal cortex were examined with electron microscopy for synapses (arrowheads), b=boutons, d=dendritic shafts.• PCP decreased spine synapses 41%.Hajszan et al. (2006). Biological Psychiatry, 60(6), 639-644.

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PCP and Brain Structure (continued)• Prefrontal cortex tissue was also examined by light microscopy for one type of glia (astroglial).• PCP increased astroglia processes by 58.8%.Hajszan et al. (2006). Biological Psychiatry, 60(6), 639-644.

29.
Ketamine• Synthesized in 1962, Ketalar• Short-half like (3 hours)• Used with other drugs for pain• Mechanism: NMDA antagonist and sigma agonist

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John Olney Ketamine & Development• Rodent studies indicate that ketamine causes programmed cell death (apoptosis)• Rhesus monkeys received therapeutic doses of ketamine (5 mg/kg i.v.) during pregnancy or later Brambrink et al. (2012). Anesthesiology, 116(2), 372-384.

31.
Ketamine & Development• Rodent studies indicate that ketamine causes programmed cell death (apoptosis)• Rhesus monkeys received therapeutic doses of ketamine (5 mg/kg i.v.) during pregnancy or later * Brambrink et al. (2012). Anesthesiology, 116(2), 372-384.

32.
ScheduleHallucinogen Mechanism Comments 5-HT1 antagonist?, 8 hour trips, early model ofLSD I schizophrenia, 5-HT2A/C agonist psychotherapy 5-HT2A/C agonist LSD-light, headachesPsilocybin IBelladona mACh antagonist NA Dreamy, opticalalkaloidsDextromethorphan NMDA NA Mild dissociative antagonist NMDA antagonistKetamine Sigma agonist II Veterinary NMDA antagonistPCP II Anesthetic, recent Sigma agonist, Increase dopamine “schizophrenia” model