neuropharmacology: hallucinogens

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.

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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