lecture 9 from a college level introduction to psychology course taught Fall 2011 by Brian J. Piper, Ph.D. (psy391@gmail.com) at Willamette University, includes substituted amphetamines (methamphetamine and MDMA), epidemiology, pharmacokinetics, pharmacodynamics

1. Drugs & Behavior III:
Amphetamines
Brian J. Piper, Ph.D.

2. Amphetamines
_
_
Amphetamine Methamphetamine

3. Amphetamines
Amphetamine Methamphetamine
__
_
3,4-methylenedioxymethamphetamine

4. History of Methamphetamine
• 1893: Synthesized by Nagai Nagayoshi in Japan
• 1940s- : Popular with military
• 1960s- : used for short-term treatment of obesity, narcolepsy,
and, later, ADHD
• 1983- : federal and states laws attempt to reduce use by
decreasing availability of ephedrine and pseudoephedrine
• 2000s- : several aggressive advertising campaigns are aimed
at reducing demand

5. Montana Meth Project
• Businessman Thomas
Siebel supported
graphic advertising in
2005
• Goal was to reach each
teenager 3+
times/week (TV, radio,
print).
To View Ads:
http://www.montanameth.org/View_Ads/index.php

6. True of False: “the MMP results in
Montana have been more significant than
any other drug prevention program in
history”?
Youth Risk Behavior Survey
• High School students were
asked about lifetime
methamphetamine use
before and after the
Montana
Methamphetamine Project.
Anderson (2010) J Health Econ

7. True or False:
“the MMP results in Montana
have been more significant than any other
drug prevention program in history”?
Youth Risk Behavior Survey
• High School students were
asked about lifetime
methamphetamine use
before and after the
Montana
Methamphetamine Project.
Anderson (2010) J Health Econ

8. Other Faces of
Methamphetamine

9. Other Faces of Methamphetamine
Andre Agassi
Robert Downey, Jr.
Ted Arthur Haggard
Stacy Ann Ferguson “Fergie”

11. History of Ecstasy
Ecstasy is 3,4-methylenedioxymethamphetamine (MDMA)
• 1912: Synthesized by German pharmaceutical company Merck by Anton
Kollisch (1888-1916)
• 1950’s: U.S. Army conducted animals studies to determine the lethal dose.
• 1970’s: Mental health workers advocated using MDMA with psychotherapy.
There are ongoing studies to use MDMA with talk therapy for anxiety related
to post-traumatic stress disorder and among terminally ill cancer patients.
• 1985: Drug Enforcement Agency (DEA) classifies MDMA as Schedule I
• 1990’s- today: MDMA is popular recreational drug, especially among young-
adults.

12. Short-term effects of Ecstasy
• Psychological • Physiological
– Empathy – Increase in heart rate
– Increased energy – Increase in blood pressure
– Openness – Reduced appetite
– Increased sensitivity to – Bruxism: grinding teeth
sounds & touch – Trismus: jaw clenching

13. Example of tolerance
• Rats received ecstasy
(MDMA) on 6 days. Arrows
indicate times of
administration.
• Panel A shows that MDMA
altered core temperature
on the 1st day.
• Panel B shows that the
same dose had less effects
on the 3th day.
• Panel C shows almost no
effects by the 6th day.
Piper et al. (2005) Developmental Psychobiology, 47, 145-157.

14. Amphetamines
Amphetamine Methamphetamine
__
_
3,4-methylenedioxymethamphetamine

15. Chemistry
• Entactogen: touching within (Nichols)
MDMA (methylenedioxymethamphetamine)
MDA (methylenedioxyamphetamine)
Amphetamine

16. Ecstasy = MDMA?

17. Drug Levels in the Blood: Individual Differences
Following Oral Administration of MDMA
Plasma MDMA for each marmoset that
received 1 mg/kg.
80
70
60
M D M A (n g /m l)
Ng/ml
50 Lexi
40 Eric
Zale
30
Autumn
20
10
0
0 20 40 60
Time

18. Age Influences How Your
Body Responds to Drugs
Meyer, Piper,& Vancolli (2010) Annals of the New York Academy of Sciences.
MDMA -----> MDA

19. Brain Chemistry
• MDMA increases neurotransmitters
(serotonin, norepinephrine, dopamine) &
hormones (cortisol, prolactin)

20. Serotonin
• Serotonin is 5-hydroxytryptamine (5-HT)
• The brain uses the amino acid tryptophan
(found in bananas, milk, yogurt) to make 5-HT.
• 5-HT has been implicated in mood (anxiety,
depression & aggression), appetite, sexuality,
and cognition.
See also: http://en.wikipedia.org/wiki/Serotonin

21. Raphe nuclei
• 5-HT cell bodies (somas)
are found in the
brainstem in the raphe
nuclei.
• 5-HT axons descend
into spinal cord and
ascend to the
hippocampus and
cortex.

22. Serotonin Transporter (SERT)
• SERT is a protein found at the synapse and
along the axon that removes 5-HT from the
synaptic cleft.
• SERT (shown in pink) brings 5-HT from the
synaptic cleft back into the axon.
• Serotonin reuptake inhibitors (e.g. Prozac
or fluoxetine) prevent SERT from removing
5-HT.
• The density of SERT is used as a index of
the number of 5-HT axons and is altered by
MDMA.

23. Long-term effects of High Dose MDMA on 5-HT
neurons (animal data)
• Weeks after MDMA treatment to animals,
there is a reduction in 5-HT, 5-HT
metabolites, and SERT which suggests a 5-
HT axotomy (axons are cut).
• Months to years after MDMA in monkeys,
some brain areas still show a reduction in
SERT and 5-HT (hypoinnervation).
However, other areas show an abnormal
increase in SERT and 5-HT
(hyperinnervation).

24. Serotonin fibers in the caudate nucleus of a control squirrel
monkey (A), a monkey that received 5 mg/kg MDMA 2 weeks (B),
or 7 years (C) previously.
Hatzidimitriou, G. et al. J. Neurosci. 1999;19:5096-5107

25. What about brain function?
• Complex behaviors can be measured in non-
human animals like:
– Attention
– Learning
– Memory
– “Emotion”

26. Object-Recognition Memory
Task
Rats were exposed to two identical
objects in a 3-min sample phase.
There was a retention delay (15 min),
during which both objects were replaced:
one replacement object was identical to the
previous two, while the other was a novel
object.
Memory of the familiar object is
indicated by the animal spending more
time exploring the novel object during a
3-min choice phase.
Figure from A. Ennaceur.

27. Adolescent MDMA decreases memory.
Saline MDMA
Sample (A) 25.6 (3.1) 23.5 (1.4)
Test (A) 11.8 (2.0) 14.9 (1.4)
Test (B) 24.7 (3.5) 20.0 (3.1)
B/(A+B) 0.68 (0.03) 0.56 (0.04)*
Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731

28. Adolescent MDMA
reduces anxiety-like
behavior.
SALINE- MDMA- P VALUE
BEHAVIOR TREATED TREATED
Total arm entries 19.1 ± 3.0 27.4 ± 3.0 .074
Open-arm entries 3.1 ± 1.4 7.9 ± 1.8 .058
Open/Total (%) 12.8 ± 5.2 27.3 ± 5.3 .071
Open-arm duration 41.4 ± 18.7 108.9 ± 20.3 <.05
(sec)
Closed-arm 507.4 ± 30.5 400.5 ± 30.3 <.05
duration (sec)
Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731.

29. Piper & Meyer (2004) Pharm Biochem & Behav 79: 723-731.

30. Spatial Memory In Rodents
• Rodent research has found that early developmental
Methamphetamine treatments cause persistent impairments in
spatial memory.
Acevedo SF, de Esch IJ, Raber J (2007) Neuropsychopharmacology 32:665-672

31. MDMA Summary
• Short-Term Effects:
– Empathy
– hyperthermia,
– ↑5-HT & Dopamine
• Long-Term Effects: ↓5-HT

32. Amphetamine Comparison
MDMA Methamphetamine
History One-century One-century
Acute Subjective Effects Empathy Euphoria
Neurotoxicity Serotonin Dopamine
Schedule I III
Addiction No Yes

33. Hallucinogens
Hallucinogens are
psychedelic (mind-
manifesting) drugs that
distort perceptions and
evoke sensory images in
the absence of sensory
Ronald K. Siegel
input.

34. Hallucinogens
 LSD: (lysergic acid diethylamide) powerful
hallucinogenic drug that is also known as
acid.
 THC (delta-9-tetrahydrocannabinol): is the
major active ingredient in marijuana (hemp
plant) that triggers a variety of effects,
including mild hallucinations.
http://static.howstuffworks.com
Hemp Plant

35. Drugs
Summary