Lecture 23 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (firstname.lastname@example.org) at Willamette University. Includes epidemiology, pharmacokinetics, of pharmacodynamics of LSD, ketamine, PCP, and peyote.
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
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
Indocybin• Indo: Indolamine/Indian• Sandoz Pharmaceuticals tests utility as adjunct to psychotherapy Albert Hoffman 1906-2008
Altered States of ConsciousnessHasler et al. (2004). Psychopharmacology, 172,145-156.
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.
• Similarity/Difference with Schizophrenic Hallucinations• Importance of Set & SettingHasler et al. (2004). Psychopharmacology, 172,145-156.
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: ?
Epidemiology of LSDMonitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
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.
Hallucinogen Information• Erowid is a highly popular source of drug- information (55K/day)
Hallucinogen Persisting Perception Disorder• Online study to determine frequency of HPPDBaggott et al. (2011). Drug & Alcohol Dependence, 114, 61-67.
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.
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?
Dextromethorphan• Low doses decrease coughing.• High doses cause dissociative state (phases).• Sigma1 agonist, SERT antagonist 2D6 Dextromethorphan --------------> Dextrorphan
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)!
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.
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.
Ketamine• Synthesized in 1962, Ketalar• Short-half like (3 hours)• Used with other drugs for pain• Mechanism: NMDA antagonist and sigma agonist
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.
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.
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