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Transcript
MDMA-assisted Psychotherapy
in Posttraumatic Stress Disorder
•Study Design
•Therapeutic approach
•Preliminary Results
Phase II clinical trial
safety and efficacy of 3,4methylenedioxymethamphetamine
(MDMA)-assisted psychotherapy in
subjects with chronic, treatment resistant
posttraumatic stress disorder.
Michael C. Mithoefer, MD, Annie Mithoefer, BSN
Charleston, SC, USA
Sponsor:
Multidisciplinary Association for Psychedelic Studies
Hypothesis
MDMA-assisted psychotherapy:
• can be safely administered to people with treatmentresistant PTSD
•
It will produce improvement in PTSD signs and
symptoms
- four days after each of two experimental
intervention sessions
- and at 3 month follow-up.
Reasons for studying PTSD & MDMA
• Fear, defensiveness, lack of trust often obstacles to
successful treatment of PTSD
• MDMA has been reported to decrease fear and
defensiveness and to increase trust and empathy
• MDMA may catalyze emotional connection with
positive experiences and cognitive restructuring
regarding present reality.
The Protocol
Double blind, placebo controlled
pilot study of treatment resistant
crime or war related PTSD
Study Design
• 20 subjects with treatment resistant PTSD,
male and female, crime or war related
• Stage I
60% receive MDMA (125 mg) on 2 occasions
40% receive placebo on 2 occasions
• Stage II
Open label - placebo subjects from Stage I
receive MDMA (125 mg) on 2 occasions
Study design continued
• MDMA or placebo administered during 8
hour “experimental session” with male and
female therapist present
• 11 additional non-drug therapy sessions in
Stage 1. 9 additional in Stage 2
• Screening and outcome measures by
psychologist not involved in treatment
phase
Inclusion Criteria
• DSM-IV chronic PTSD, + SCID & Clinician
Administered PTSD Scale (CAPS) score 50 or greater
• May have comorbid mood or anxiety disorders
• Crime related PTSD (rape, assault, sexual abuse, terrorist
attack violent incident - eg. police or rescue personnel) or
war related PTSD of < 5 years duration
• Failed at least 3 months of SSRI
• Failed at least 6 months psychotherapy -approved kind
• Willing and able to taper off all psychotropic meds
• If currently in therapy may continue but not change
• Willing to sign informed consent - 19 pages with quiz
Exclusion Criteria
•
•
•
•
•
•
•
•
•
•
Pregnant or nursing or no birth control
Psychotic disorder - current or history of
Bipolar I
Dissociative identity disorder (they may have DDNOS)
Eating disorder with active purging
Borderline personality disorder
Hypertension or any significant medical problem
Prior “Ecstasy” use within 6 months or > 5 times lifetime
Substance abuse or dependence within 60 days
Risk of re-traumatization, suicide or hospitalization
17 visits after informed consent meeting
1.
Medical and psychological screening
Physical Exam, Labs EKG, SCID, CAPS
2.
3.
4.
Introductory psychotherapy - 90 minutes
Introductory psychotherapy - 90 minutes
Baseline measures
Outcome Measures
CAPS, SCL 90, Impact of events scale (IES)
Neuropsychological measures
RBANS, PASAT, Rey-Osterrieth, NEO
5.
First Experimental session - 8 hours
ER DR. and Nurse on duty in next room first 5 hours
Subject spends the night afterwards with RN on duty
Visits - continued
6.
Follow-up psychotherapy the following morning
Daily phone contact for 7 days following this
7. Repeat outcome measures 4 days after exp. session
8-10. Follow-up psychotherapy weekly
11. Second experimental session - 3-5 weeks after 1st.
Followed by same format as after 1st experimental
session, plus repeat medical exam and LFTs
(visits 12 - 16)
17. Termination visit
Repeat outcome measures and neuropsych. testing
Final psychotherapy visit
Therapeutic Approach
•
•
•
•
•
Stanislav Grof, MD, LSD psychotherapy
Non-directive, supporting emerging experience
Reclining, headphones with music, eyeshades
Alternating inner focus & talking to us
Emphasis on experiencing emotions and somatic
“symptoms” rather than avoiding or suppressing
• Attention to:
- “set and setting”
- preparation for sessions - including spouse
- follow-up processing and integration
Comparison to other therapies
• American Psychiatric Association (APA) Treatment
Guidelines for PTSD, November 2004:
• Three recognized forms of psychotherapy
– Cognitive and Behavioral Therapies
– Eye Movement Desentization and Reprocessing (EMDR)
– Psychodynamic Psychotherapy
Ursano et al, Supplement to Am.J of Psychiatry, v 161,# 11, November 2004
APA Guidelines & Treatment Resistant PTSD
“Because there is a paucity of high-quality evidencebased studies of interventions for patients with
treatment-resistant PTSD treatment nonresponse
cannot be addressed algorithmically. …In some cases
a different modality (may need to be) selected as in
…a patient who is too overwhelmed by anxiety to
tolerate exposure therapy…. There are limited data to
guide the clinician in the treatment of patients with
treatment resistant PTSD”
Comparison: MDMA-assisted vs other approaches
Cog/Beha
EMDR
Prolonged
exposure
Cognitive
restructur.
AMT/SIT
*
*
*
+ Exp.
*
*
*
*
*
Transferr.
*
*
Somatic
*
*
Psydyn
MDMA
*
*
*
*
*
*
*
*
*
Preliminary Data
First 5 Subjects
Completed Stage I
Blind Broken
2 other subjects have completed all but final followup blind not broken
several subjects in screening process
Demographics of Subjects Enrolled
5 women
2 men
Age: average 47, range 41 - 55
All have had PTSD since childhood or early
adulthood - rape or childhood sexual abuse
In Screening: victim gunshot wound & police
officer involved in 9/11, & younger subjects
Axis 1 Comorbidity
Placebo
MDMA
1. Unipolar depression
Panic disorder
2. Unipolar depression
3. Unipolar depression
1.
Unipolar depression
Dysthymia
2.
Unipolar depression
Dysthymia
Eating D/O in remission
Subs. abuse in remission
Physiological Response
Vital sign measurements
Systolic BP - MDMA
200
190
180
Systolic BP
170
SBP 1A
SBP 1B
SBP 2A
SBP 2B
SBP 3A
SBP 3B
160
150
140
130
120
110
100
90
80
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Time in hours after dose
5.5
6
6.5
Diastolic Blood Pressure - MDMA
120
Diastolic BP
110
S1
S1
S2
S2
S3
S3
100
90
80
70
60
50
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Time in hours after dose
5
5.5
6
6.5
A
B
A
B
A
B
Pulse - MDMA
120
110
Pulse
100
Pulse
Pulse
Pulse
Pulse
Pulse
Pulse
90
80
70
60
50
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
Time in hourse after dose
5
5.5
6
6.5
1A
1B
2A
2B
3A
3B
Body Temperature - MDMA subjects
100
99.5
Temperature degrees F.
99
98.5
MDMA
MDMA
MDMA
MDMA
MDMA
MDMA
98
97.5
97
96.5
96
95.5
95
0
1
2
3
4
Hours since dose
5
6
7
1 A
1B
2 A
2 B
3 A
3 B
Side Effects within 7 days - MDMA group
•
•
•
•
•
•
•
•
•
•
•
Anxiety
Fatigue
Headache
Heavy legs
Jaw tightness
Lack of appetite
Parasthesias
Neck and back tension
Low mood
Increased irritability
Nausea
•
•
•
•
•
•
•
•
•
•
•
Restlessness
Altered color perception
Increased worries
Insomnia
Thirst
Sensitivity to cold
Diarrhea
Impaired balance
Dizziness
Difficulty concentrating
Myoclonic jerks
Side Effects within 7 days - Placebo group
• Anxiety
• Fatigue
• Headache
• Increased
irritability
• Low mood
• Insomnia
Neuropsychological Measures
Repeatable Battery for Assessment of
Neuropsychological Status (RBANS)
Immediate memory, Delayed memory, Language
Visuospatial/constructional, Attention
Paced Auditory Serial Addition Task (PASAT)
Rey-Osterreith Complex Figure Test
Repeatable Battery for Assessment of Neuropsychological Status
(RBANS)
140
120
Total Score
100
80
Baseline
3 Month
60
40
20
0
MDMA 1
MDMA 2
MDMA 3
Placebo 1
Baseline and 3 month scores
Placebo 2
Paced Auditory Serial Addition Task (PASAT)
120
100
Total Score
80
Baseline
3 Month
60
40
20
0
MDMA 1
MDMA 2
MDMA 3
Placebo 1
Baseline and 3 month scores
Placebo 2
Outcome Measures
• Clinician Administered PTSD Scale (CAPS)
• Impact of Event Scale (IES)
•Symptom Checklist 90-revised (SCL 90-R)
Clinican Administered PTSD Scale (CAPS)
120
103
100
80
76
Score
66
60
Baseline
3 Months
59
57
54
40
32
20
15
6
0
0
MDMA 1
MDMA 2
MDMA 3
Subject
Placebo 1
Placebo 2
CAPS
- Baseline, 4 days post & 3 Month
110
103
100
90
80
76
CAPS Score
70
66
60
Baseline
4 days post
4 days post
3 Months
59
57
54
50
40
32
30
20
10
15
6
0
0
MDMA 1
MDMA 2
MDMA 3
Subject
Placebo 1
Placebo 2
Impact of Events Scale (IES)
70
61
60
50
Global Score
46
42
40
Baseline
4 days post
4 days post
3 months
37
30
30
24
20
10
7
6
6
0
0
MDMA 1
MDMA 2
MDMA 3
Subject
Placebo 1
Placebo 2
Symptom Checklist 90-Revised (SVL 90-R)
80
Global Severity Index (GSI)
70
60
50
Baseline
4 days post 1
4days post 2
3 months
40
30
20
10
0
MDMA 1
MDMA 2
MDMA 3
Subject
Placebi 1
Placebo 2
Distress Levels during MDMA
Sessions
•Subjective Units of Distress (SUD)
•Scale of 1 - 7
•Beginning and hourly for 6 hours
Subjective Units of Distress - MDMA
7
6
Score
5
MDMA
MDMA
MDMA
MDMA
MDMA
MDMA
4
3
2
1
0
1
2
3
Hours since dose
4
5
6
1
1
2
2
3
3
A
B
A
B
A
B
Subjective Units of Distress (SUD) - Placebo
7
6
Score
5
Placebo
Placebo
Placebo
Placebo
4
3
2
1
0
1
2
3
4
Time in hours since dose
5
6
1
1
2
2
A
B
A
B
SUDS MDMA subject 1
7
6
Score
5
MDMA 1 A
MDMA 1 B
4
3
2
1
0
1
2
3
4
Time in hours since dose
5
6
Increase in symptoms after MDMA/placebo sessions
• 3 days after second MDMA session
– Anger, anxiety, derealization, fear of “losing it”
Old defense of shutting down the anger by getting busy no
longer working. “I knew it would get worse before it gets
better, it said that in the informed consent.”
– Lorazepam to help her at work
– Additional therapy session, good result
• 1 Week after second MDMA session
- vivid memories of trauma in more detail than ever before.
accompanied by grief and lots of tears. She understood it as
healing process, good result
Some quotes from subjects
• Now I have a map of the battlefield
• Now I have a reference point. With childhood
abuse where the hell’s the reference point!
• In the first session I gave up hypervigilance and
self-blame, that paved the way for the second
session.
Some quotes from subjects - 2
• In the second session revisiting the trauma was not
chaotic like in the first. Image of going down a
ladder, more control
• I felt deeply connected to painful feelings of the
traumas as I saw them go by in spheres, but it
didn’t cause anxiety. I felt deep sadness in my
heart (crying) but also deep happiness that I was
healing it and letting it go.
• Blaming myself was a way of distracting from the
fear
More quotes
• I finally feel loved and protected
• Exhausted but in a good way, relieved, peaceful, at ease.
Clarity, deep appreciation (morning after)
• The anger feels like a volcano, afraid of being one man
wrecking crew, sadness, loneliness, nausea (dissipated
as stayed with it)
• Not so rigid and compulsive, a lot calmer and more
rational, feel wiser, life has a deeper level, loosening
reins, sharing responsibility with husband, stress level at
home way down
More quotes - 2
• Being able to feel again is indescribable, like a
blind person being able to see again. I used to
have a barrier between me and everyone else.
• What’s most comforting is knowing now I can
handle difficult feelings without being
overwhelmed. Realize feeling the fear and anger
not nearly as big a deal as I thought it would be.
More quotes (3 weeks after second MDMA session)
• After the second session it was difficult but I felt
supported and it subsided.
• I have respect for my emotions now (rather than fear
of them)
• More aware of other’s needs, nurturing part of me
coming back
• Like the old me, but a new old me
More quotes (3 weeks after 2nd MDMA session -2)
• A whole deeper level of consciousness, calmer,
peacefulness, I don’t remember ever having this, my mind
has never been at peace like this
• Feel more efficient grounded, at ease, whole
• It has felt like growing up, wiser, more emotionally
mature
• Without the study I don’t think I could have ever dug
down deep, I was so afraid of the fear. In the sessions
there was just no fear; that builds your confidence. When
I tried in therapy before it would send me into a tail spin.
I guess I won’t have to go
to Tibet