Lecture 23 from a college level neuropharmacology course taught in the spring 2012 semester by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University. Includes epidemiology, pharmacokinetics, of pharmacodynamics of LSD, ketamine, PCP, and peyote.

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)

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

4. Epidemiology: High School
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

5. College Plans
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

6. Region
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

7. Ethnicity
Monitoring 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/synesthesia
2:50 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
1894-1995
http://www.imaginaria.org/wasson/life.htm

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

12. Altered States of Consciousness
Hasler et al. (2004). Psychopharmacology, 172,145-156.

13. 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.

14. • Similarity/Difference with Schizophrenic Hallucinations
• Importance of Set & Setting
Hasler 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: ?

16. Epidemiology of LSD
Monitoring the Future: http://www.monitoringthefuture.org/pubs/occpapers/occ63.pdf

17. Adolescent Phase?

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

19. 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.

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

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

22. 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.

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?

25. 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.

28. 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

30. 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. Schedule
Hallucinogen Mechanism Comments
5-HT1 antagonist?, 8 hour trips, early model of
LSD I schizophrenia,
5-HT2A/C agonist
psychotherapy
5-HT2A/C agonist LSD-light, headaches
Psilocybin I
Belladona mACh antagonist
NA Dreamy, optical
alkaloids
Dextromethorphan NMDA NA Mild dissociative
antagonist
NMDA antagonist
Ketamine Sigma agonist
II Veterinary
NMDA antagonist
PCP II Anesthetic, recent
Sigma agonist,
Increase dopamine “schizophrenia”
model