Beyond Fear: Research on the Effects of MDMA

1. Beyond Fear: The
Effects of MDMA in
Humans
Matthew Baggott, Ph.D.
University of Chicago
Photo by Simon Webster

2. About Me
Worked on the first
federally funded
MDMA dosing study in
1998
Helped MAPS get FDA
permission to give
MDMA to patients
Have studied, in
humans: MDMA,
MDA, LSD,
stimulants...

3. About this research
University of Chicago: Harriet de Wit, Matthew
Kirkpatrick, Megan Wardle
California Pacific Medical Center: John
Mendelson, Gantt Galloway, Jeremy Coyle,
Kathleen Garrison
UCSF: Reese Jones

4. About this research
University of Chicago: Harriet de Wit, Matthew
Kirkpatrick, Megan Wardle
California Pacific Medical Center: John
Mendelson, Gantt Galloway, Jeremy Coyle,
Kathleen Garrison
UCSF: Reese Jones
University of Basel: Cédric Hysek, Matthias
Liechti

6. Location of the
discovery of LSD
by Sandoz
Chemist Albert
Hofmann

7. Why Basel?
Location of the
discovery of LSD
by Sandoz
Chemist Albert
Hofmann

8. • 1856, Perkin discovers mauveine, the first
synthetic dye.
• 1863, Bayer company founded as a dye
maker in Wuppertal
• 1865, BASF (Baden Aniline and Soda
Factory) founded in Mannheim, with factory
on the Rhine river
• 1886, Sandoz founded in Basel
Before drugs there were dyes

9. • 1886, aniline dye derivative
acetanilide sold as analgesic /
antipyretic “Antifebrin”
• 1891, methylene blue used to
treat malaria
• 1935, “Prontosil”, a red dye,
sold as the first antibiotic
Many dyes have biological effects
(Wikipedia)

10. Patent law protected the process
not the resulting chemical

11. Use trade names
Patent law protected the process
not the resulting chemical

12. Use trade names
Patent law protected the process
not the resulting chemical
Patent many processes
(Freudenmann,Öxler,&Bernschneider-Reif2006)

13. In what ways
can drugs like
MDMA
function like
dyes?
MDMA
(„Ecstasy‟)

14. Overview

15. Overview
MDMA does something novel
•not a typical stimulant (drunken/sedated effects)
•not a typical hallucinogen (consistently positive)
How does it work?
•Neurochemistry: Serotonin, oxytocin,
norepinephrine
•Psychology: Prosocial effects, authenticity
•Reduced anxiety may not be the core effect
(Focus here is on acute (short term) effects)

16. How We Measure Drug Effects

17. How We Measure Drug Effects

18. How We Measure Drug Effects

19. How We Measure Drug Effects
38
35
8

20. MDMA is not a typical stimulant
(Sedative-like effects)

21. N = 29 (15 M)
Time (Hr)
VASScore(-pre)
-20
-10
0
10
20
30
Clear headed
0 1 2 3 4 5 6
Confused
0 1 2 3 4 5 6
Drunken
0 1 2 3 4 5 6
Condition
Placebo
MDMA
N = 29 (15 M)
MDMA is not a typical stimulant
(Sedative-like effects)

22. MDMA is not a typical hallucinogen
(Consistent positive social effects)

23. Time (Hr)
VASScore(-pre)
-5
0
5
10
15
20
25
Closeness to others
0 1 2 3 4 5 6
Kind
0 1 2 3 4 5 6
Loving
0 1 2 3 4 5 6
Condition
Placebo
MDMA
MDMA is not a typical hallucinogen
(Consistent positive social effects)
N = 29 (15 M)

24. How does it work? Neurochemistry

25. Serotonin transporter (SERT) is
important to MDMA effects

26. Serotonin transporter (SERT) is
important to MDMA effects
Time (hours)
ClosenesstoOthers(0-100)
10
20
30
40
50
60
70
0 1 2 3 4 5 6
condition
Placebo
MDMA

27. Serotonin transporter (SERT) is also
important to MDMA effectsClosenesstoOthers(0-100)
Time (hours)
10
20
30
40
50
60
70
0 1 2 3 4 5 6
condition
Placebo
MDMA
First Citalopram
Cital-MDMA

28. MDMA increases Oxytocin

29. 200
400
600
800
1000
Time (hours)
Oxytocin(pg/ml)
-1 1 2 3 4
Placebo
MDMA
200
400
600
800
1000
CmaxOxytocin(pg/ml)
Placebo
MDMA
AUCOxytocin(pg*hrs/ml)
0
500
1000
1500
2000
MDMA increases Oxytocin
* *
* *
(Baggott et al. submitted)
N=16 (8F, 8M)

30. Sociability = i1 + cDose + e1
Sociability = i2 + c’Dose + bOxytocin + e2
Oxytocin = i3 + aDose+ e3
Oxytocin partly mediates MDMA
effects on self-report sociability
(MacKinnon et al. 2007; Preacher and Hayes 2004)
MDMA
or
Placebo
Sociability, 2.5 Hr
Oxytocin,
2 Hra b
c
ab = 0.36 (95%CI 0.06 – 0.87)

31. Blood levels after MDA or MDMA
MDA
MDMA
MDA T1/2 : 9.7 3.2 h
MDMA T1/2 : 8.1 2.1 h

32. Tolerance Development

33. Tolerance Development

34. Tolerance Development

35. Tolerance Development

36. Tolerance Development

37. Tolerance Development

38. Tolerance Development

39. Tolerance Development

40. Tolerance Development
Hypothetical
Plot showing
No Tolerance

41. Tolerance: MDA < MDMA

42. Tolerance: MDA < MDMA

43. (Hyseketal.2011)
Reducing
Norepinephrine‟s
RoleinMDMA
Reducing
Serotonin‟s
RoleinMDMA
Physical Self-report

44. (Hyseketal.2011)
Reducing
Norepinephrine‟s
RoleinMDMA
Reducing
Serotonin‟s
RoleinMDMA
Physical Self-report

45. (Hyseketal.2011)
Reducing
Norepinephrine‟s
RoleinMDMA
Reducing
Serotonin‟s
RoleinMDMA
Physical Self-report

46. (Hyseketal.2011)
Reducing
Norepinephrine‟s
RoleinMDMA
Reducing
Serotonin‟s
RoleinMDMA
Physical Self-report

47. Reducing
Norepinephrine‟s
RoleinMDMA
Reducing
Serotonin‟s
RoleinMDMA
Physical Self-report
>
<

48. How does it work? Psychology

49. Hypothesized MDMA Effect Hypothesized Benefit
Improved mood Positive mood encourages changes
in cognitive models about the
world
Increased interpersonal
connection
Improved couples therapy;
facilitation of therapeutic alliance;
more rapid therapy with fewer
sessions required
Reduced fear response Allows difficult/negative emergent
material to be re-evaluated
Entactogenic (“touching within”) Deeper contact with true self;
recognition of positive aspects of
self
(adapted from Parrott 2007)
How does it work? Psychology

50. Hypothesized MDMA Effect Hypothesized Benefit
Improved mood Positive mood encourages changes
in cognitive models about the
world
Increased interpersonal
connection
Improved couples therapy;
facilitation of therapeutic alliance;
more rapid therapy with fewer
sessions required
Reduced fear response Allows difficult/negative emergent
material to be re-evaluated
Entactogenic (“touching within”) Deeper contact with true self;
recognition of positive aspects of
self
(adapted from Parrott 2007)
How does it work? Psychology

51. MDA
(n = 12)
MDMA
(n = 16)

52. Hypothesized MDMA Effect Hypothesized Benefit
Improved mood Positive mood encourages changes
in cognitive models about the
world
Increased interpersonal
connection
Improved couples therapy;
facilitation of therapeutic alliance;
more rapid therapy with fewer
sessions required
Reduced fear response Allows difficult/negative emergent
material to be re-evaluated
Entactogenic (“touching within”) Deeper contact with true self;
recognition of positive aspects of
self
(adapted from Parrott 2007)
How does it work? Psychology

53. Time (Hr)
VASScore(-pre)
-5
0
5
10
15
20
25
Closeness to others
0 1 2 3 4 5 6
Kind
0 1 2 3 4 5 6
Loving
0 1 2 3 4 5 6
Condition
Placebo
MDMA
Interpersonal feelings
N = 29 (15 M)

54. Interpersonal Perception

55. Trustworthiness
-3 SD

56. Trustworthiness
-1.5 SD

57. Trustworthiness
0 SD

58. Trustworthiness
1.5 SD

59. Trustworthiness
3 SD

60. Perceptions of Trustworthiness
Predicted Trustworthiness (SD units)
PercievedTrustworthiness(1-7Scale)
3
4
5
-3 -2 -1 0 1 2 3
Placebo
MDMA

61. Perceptions of Trustworthiness
Predicted Trustworthiness (SD units)
PercievedTrustworthiness(1-7Scale)
3
4
5
-3 -2 -1 0 1 2 3
Placebo
MDMA

62. Predicted Trustworthiness (SD units)
PercievedTrustworthiness(1-7Scale)
3
4
5
-3 -2 -1 0 1 2 3
Placebo
MDMA
Citalopram
Citalopram-MDMA
Perceptions of Trustworthiness

63. Hypothesized MDMA Effect Hypothesized Benefit
Improved mood Positive mood encourages changes
in cognitive models about the
world
Increased interpersonal
connection
Improved couples therapy;
facilitation of therapeutic alliance;
more rapid therapy with fewer
sessions required
Reduced fear response Allows difficult/negative emergent
material to be re-evaluated
Entactogenic (“touching within”) Deeper contact with true self;
recognition of positive aspects of
self
(adapted from Parrott 2007)
How does it work? Psychology

64. Does MDMA really reduce
fear/anxiety?

65. Does MDMA really reduce
fear/anxiety?
It significantly decreased anxiety in one
study but not in two others, using the
STAI-S(Liechti & Vollenweider 2000; Liechti et al. 1998; Hasler et
al. 2008)
It increased anxiety scores in females but
not males, using the EWL Apprehension-
anxiety(Liechti et al. 2001)
It increased anxiety, more in females than
males, using a VAS (Bedi and de Wit 2011)

66. MDMA increases anxiety in our
studies
N = 29 (15 M)
Time (hr)
VASScore(-pre)
-15
-10
-5
0
5
10
15
Anxious
0 1 2 3 4 5 6
Relaxed
0 1 2 3 4 5 6
Condition
Placebo
MDMA
N = 29 (15 M)

67. Anxious
N = 16 (8 M)Time (Hr)
VASScore(-pre)
-10
0
10
20
Anxious
0 1 2 3 4 5 6
Loving
0 1 2 3 4 5 6
Condition
Placebo
MDMA

68. Time (Hr)
VASScore(-pre)
-10
0
10
20
Anxious
0 1 2 3 4 5 6
Loving
0 1 2 3 4 5 6
Condition
Placebo
MDMA
Anxious and More Loving ?
N = 29 (15 M)

69. Anxious and More Loving ?
• One possibility: a „Tend-and-befriend‟
response to threat
• Science has traditionally focused on a
„fight-or-flight‟ response to stress, but
mammals often seek safety and comfort
with others.
(Taylor 2006)

70. Prediction: people should not be socially
anxious

71. N = 12
Prediction: people should not be socially
anxious
Time (Hr)
VASScore(-pre)
-20
-10
0
10
20
30
Anxious
0 1 2 3 4 5 6

72. N = 12
Time (Hr)
VASScore(-pre)
-20
-10
0
10
20
30
Anxious
0 1 2 3 4 5 6
Time (hrs)
SocialAnxiety
-0.8
-0.6
-0.4
-0.2
0.0
0 1.5 2 2.5 24
Placebo
MDMA

73. N = 12
Anxious but not anxious about people
Time (Hr)
VASScore(-pre)
-20
-10
0
10
20
30
Anxious
0 1 2 3 4 5 6
Time (hrs)
SocialAnxiety
-0.8
-0.6
-0.4
-0.2
0.0
0 1.5 2 2.5 24
Placebo
MDMA

74. Hypothesis: Anxiety may be greatest in
inexperienced people left alone

75. Hypothesis: Anxiety may be greatest in
inexperienced people left alone
Chicago
Basel
SF

76. Hypothesized MDMA Effect Hypothesized Benefit
Improved mood Positive mood encourages changes
in cognitive models about the
world
Increased interpersonal
connection
Improved couples therapy;
facilitation of therapeutic alliance;
more rapid therapy with fewer
sessions required
Reduced fear response Allows difficult/negative emergent
material to be re-evaluated
Entactogenic (“touching within”) Deeper contact with true self;
recognition of positive aspects of
self
(adapted from Parrott 2007)
How does it work? Psychology

77. How do you measure feelings
of deeper contact with one‟s
true self?

78. How do you measure feelings
of deeper contact with one‟s
true self? Authenticity:
The operation of one‟s true self without impediment
1. Awareness: knowing and trusting own motives, feelings, desires,
and self-relevant cognitions.
2. Unbiased Processing of self-relevant information: lack of
interpretive distortions in processing of self-relevant information
(e.g., not being defensive)
3. Behavior: acting in accordance with own values, preferences, and
needs; not acting „„falsely‟‟ for others or rewards.
4. Relational Orientation: acting with openness, sincerity, and truth
in relationships with close others.
(Goldman & Kernis, 2002; Sheldon, Ryan et al. 1997)

79. Feelings of Authenticity
are increased by MDMA
Self-reportAuthenticity
3.0
3.2
3.4
3.6
3.8
Placebo MDMA
6M
6F

80. Overview
MDMA does something novel
•not a typical stimulant (drunken/sedated effects)
•not a typical hallucinogen (consistently positive)
How does it work?
•Neurochemistry: Serotonin, oxytocin,
norepinephrine
•Psychology: Prosocial effects, authenticity
•Reduced anxiety may not be the core effect
(Focus here is on acute (short term) effects)

81. Drugs, like dyes, can serve
as tools to see things that are
difficult to see

82. (Methylene blue and Mycobacterium tuberculosis, Wikipedia)

83. (Acerbi, Lampos, Garnett, Bentley 2013)
Emotion Expression in 20th Century Books

85. Photo by Simon Webster
Thank You!
Slides at slideshare.net/
mattbagg/beyond-fear