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Lecture 23 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. ([email protected]) at Willamette University. Includes epidemiology, pharmacokinetics, of pharmacodynamics of LSD, ketamine, PCP, and peyote.
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Drugs & Behavior:Hallucinogens
Brian J. Piper, Ph.D.1933-2006
Goals
• Mescaline (I)• LSD (I)• Psilocybin (I)• Dextromethorphan
(NA)• Ketamine (II)• PCP (II)
Epidemiology: Past Year
Monitoring the Future: http://monitoringthefuture.org/pubs/monographs/mtf-vol1_2009.pdf
Epidemiology: High School
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
College Plans
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
Region
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
Ethnicity
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
Availability
Mescaline• Found in peyote cactus• Entheogen for Native American Church• Visual hallucinogens/synesthesia
2:50 on, 0 to 0:30ish: http://www.youtube.com/watch?v=0kraijbaLDo
Psilocybin
• Religious experiences for Aztecs & Mayans• Gordon Wasson is taken on “magic mushroom” trip
by Shaman Maria Sabina• Liver converts psilocybin (Pro-drug) to psilocin
Psilocybe mexicana
http://www.imaginaria.org/wasson/life.htm
1894-1995
Indocybin
• Indo: Indolamine/Indian• Sandoz Pharmaceuticals tests utility as
adjunct to psychotherapy
1906-2008
Albert Hoffman
Hasler et al. (2004). Psychopharmacology, 172,145-156.
Altered States of Consciousness
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 & Setting
Hasler 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 LSD
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf
Adolescent Phase?
Serotonin Receptors: 1, 2, 3, 4, 6, and 7Key: 2A/2C
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 HPPD
Baggott et al. (2011). Drug & Alcohol Dependence, 114, 61-67.
Visual experiences (non-drug) may be more common than previously thought
A small subset (1.1%) seek treatment
Baggott et al. (2011). Drug & Alcohol Dependence, 114, 61-67.
Hallucinogens Compared• Dimethyltryptamine (DMT): ≈0.5 hours
– Degraded by MAO• Psilocybin: intermediate• Mescaline/LSD: 6+ hours
Tryptamine
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
Dextromethorphan --------------> Dextrorphan2D6
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
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.
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.
*
Hallucinogen Mechanism Schedule Comments
LSD 5-HT1 antagonist?,
5-HT2A/C agonistI 8 hour trips, early model of
schizophrenia, psychotherapy
Psilocybin 5-HT2A/C agonist I LSD-light, headaches
Belladona alkaloids
mACh antagonist NA Dreamy, optical
Dextromethorphan NMDA antagonist
NA Mild dissociative
Ketamine NMDA antagonistSigma agonist
II Veterinary
PCP NMDA antagonistSigma agonist, Increase dopamine
II Anesthetic, recent “schizophrenia” model