Phase II clinical trial safety and efficacy of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in subjects with chronic, treatment resistant posttraumatic stress disorder.

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Phase II clinical trial safety and efficacy of
3,4-methylenedioxymethamphetamine (MDMA)-assisted
psychotherapy in subjects with chronic, treatment
resistant posttraumatic stress disorder.

• Michael C. Mithoefer, MD, principal investigator
• Annie Mithoefer, BSN, Mark Wagner, PhD,
  co-investigators
• Charleston, South Carolina, USA
• Sponsor
• Multidisciplinary Association for Psychedelic
  Studies

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Time Line of Approvals

• Food and Drug Administration (FDA)
• November 2001
• Institutional Review Board (IRB)
• September 2003 (Ethics Committee)
• Drug Enforcement Administration (DEA)
• February 2004
• First Subject Enrolled March 2004

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Hypothesis

• MDMA-assisted psychotherapy
• can be safely administered to people with
  treatment-resistant PTSD
• It will produce improvement in PTSD symptoms
• - four days after each of two or three
  experimental intervention sessions
• - and at 3 month follow-up.

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PTSD (Post Traumatic Stress Disorder)

• Re-experiencing
• Flashbacks, intrusive memories, nightmares etc
• Avoidance
• External avoidance or internal numbing
• Hyperarousal
• Anxiety, sleep problems, increased startle etc
• Most people have some degree of dissociation
• For our study must have significant symptoms
  after therapy and medicine (SSRI) - A complex
  and challenging group of subjects

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Reasons for studying PTSD

• 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 help PTSD patients connect emotionally
  with affirming experiences and gain a realistic
  perspective about present safety

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• Study Design
• Therapeutic Approach
• Preliminary Results

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The Protocol

• Double blind, placebo controlled
• Treatment resistant - SSRI Therapy
• Crime or war related PTSD

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Exclusion Criteria

• Most subjects have other psychiatric diagnoses
  with PTSD - eg. depression or other anxiety
  disorders
• Active addiction and some psychiatric disorders
  excluded.
• Significant medical problems excluded -
  particularly cardiovascular disease because MDMA
  elevates BP and pulse.

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Study Design

• 20 subjects with treatment resistant PTSD, male
  and female, crime or war related
• 1 subject with war related PTSD (Iraq)
• who has not had prior treatment
• Stage I - Double Blind
• 60 receive MDMA on 2 or 3 occasions
• 40 receive placebo on 2 occasions

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Study Design

• Stage II - Open label
• placebo subjects from
• Stage I receive MDMA
• on 2 or 3 occasions

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Study design continued

• MDMA or placebo administered during 8 hour
  experimental session with male and female
  therapist present.
• Overnight stay after session with nurse present.
• Initial dose of 125 mg. followed in 2 hours by
  optional supplemental dose of 62.5 mg.
• 11-15 additional non-drug therapy sessions in
  Stage 1 9 - 13 additional in Stage 2
• Blood Pressure, Pulse, q 15 min, Temp. q hour

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Study design continued

• Screening and outcome measures by psychologist
  not involved in treatment phase

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Therapeutic Approach

• Based on LSD psychotherapy model
• Stanislav Grof, MD
• Non-directive, supporting emerging experience
• Reclining, headphones with music, eyeshades
• Alternating inner focus talking to therapists

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Therapeutic Approach

• Emphasis on experiencing emotions and somatic
  symptoms rather than avoiding or suppressing
• Attention to
• - set and setting
• - preparation for sessions - including partner
• - follow-up processing and integration

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Outcome Measures

• Clinician Administered PTSD Scale (CAPS)
• Impact of Event Scale (IES)
• Symptom Checklist 90-revised
• (SCL 90-R)

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Preliminary Data

• 21 Subjects have been enrolled
• 18 have completed the double blind protocol
• 16 have completed the protocol
• 2 have dropped out
• Not secondary to drug related adverse event
• Both were improving in PTSD symptoms
• 5 currently enrolled

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Mean CAPS Scores pre post
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IES Mean values - Stage 1
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SCL-90R Mean values - Stage 1
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CAPS post placebo / post MDMA
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Mean CAPS Stage 2open Label MDMA post placebo
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Mean IES Stage 2open Label MDMA post placebo
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Mean SCL-90-R Stage 2open Label MDMA post placebo
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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

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RBANS Mean scores pre and post
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Long Term Follow-up

• 12 - 36 months after completing protocol
• Questionnaire and repeat CAPS
• Early response to the questionnaire suggests much
  of the effect is lasting

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The nature of the therapeutic process in
MDMA-assisted psychotherapy

• Symptoms may increase temporarily as part of the
  healing process
• Important to anticipate this possibility and
  provide proper support and help with integration
• More about this later from Annie

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SUDS MDMA subject 1
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Speculation about mechanism of actionof
MDMA-assisted therapy in PTSD

• Prolonged exposure - tends to happen
  spontaneously
• Working within the optimal arousal zone or
  window of tolerance (Wilbarger and others in
  Ogden,Minton Pain, Trauma and the Body)
• Increased access to self leadership (IFS model,
  Schwartz)
• Decreased activity in amygdala, increased in MPC
• Sensory gating - ? Normalization of evoked
  potential suppression, Vollenweider preliminary
  unpublished data
• Oxytocin increase - effects on affiliation
  (McGregor)
• Prolactin increase (Passie)
• Effect on fear extinction? (Valentine,
  unpublished pre clincal pilot data)

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Annie Mithoefer, BSN

• I will say more about
• Challenges / Integration
• with quotes to illustrate
• Nature of deep healing process
• with quotes to illustrate

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Challenges in MDMA-assisted therapy

• Symptoms may increase temporarily as part of the
  healing process
• - often happens 1-3 days after session
• including after long placebo sessions
• Important to anticipate this possibility and
  provide proper support and help with integration
• - involve significant other in preparation if
  appropriate

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CHALLENGES

• The anger feels like a volcano, Im afraid of
  being a one man wrecking crew, I feel such
  sadness, loneliness, nausea.
• Since Ive realized how shut down I had been I
  dont ever want to go back to being that way, so
  Im having a hard time in business situations or
  with my father knowing when not to say everything
  Im feeling.

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Challenges in integration

• After all these years of not talking about it,
  was it really safe to reveal that I felt physical
  pleasure along with horror when I was abused?
• Now that the medicine has worn off I sometimes
  feel guilty for saying the things I did about my
  parents not being emotionally available. I know
  it wasnt about blame, but theres still that
  judging voice that says we dont talk about any
  of this.
• Im still awestruck by the deep realization last
  time that that Im not 7 years old.

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Results of working with challenges

• I have respect for my emotions now (rather than
  fear of them) Whats most comforting is knowing
  now I can handle difficult feelings without being
  overwhelmed. I realize feeling the fear and anger
  not nearly as big a deal as I thought it would
  be.
• 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.

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The degree of difficultywith integration is hard
to predict.

• Importance of flexibility about integration, not
  having too many assumptions

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Some quotes from subjects about their healing

• Our research subjects have all spoken eloquently
  about the nature and depth of their healing
  experiences with MDMA-assisted therapy

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Some quotes from subjects

• Now I have a map of the battlefield
• I felt deeply connected to painful feelings of
  the traumas as I saw them go by in spheres, but
  it didnt cause anxiety. I felt deep sadness in
  my heart, crying but also deep happiness that I
  was healing it and letting it go.

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More quotes - 2

• A whole deeper level of consciousness, calmer,
  peacefulness, I dont remember ever having this,
  my mind has never been at peace like this
• I had never before felt what I felt today in
  terms of loving connection. Im not sure I can
  reach it again without MDMA but Im not without
  hope that its possible. Maybe its like having
  an aerial map so now I know theres a trail.

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Quotes - 3

• I got a glimpse of more of what Im capable of
  growing intoIm motivated to keep practicing
  openness until it gets more developed
• I can feel my body without having to make
  reference to the attack. My body is more than a
  victim. My body is my own its not there for
  somebody else.

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Quotes - 4

• Last night I had a clear sense that I got where
  I needed to get. What was missing has been
  found. What I needed Ive gotten. I dont feel
  like I need to do it again. I think there are
  still other issues in my life that I can work on
  with less intense methods.
• I dont think I would have survived another
  year. Its like night and day for me compared to
  other methods of therapy. Without MDMA I didnt
  even know where I needed to go. Maybe one of the
  things the drug does is let your mind relax and
  get out of the way because the mind is so
  protective about the injury.
• It wasnt an easy experience but it was so worth
  it. It was a very spiritual experience, very
  expansive. I feel a sense of calm and stability
  now.

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Quotes - 5

• I have a sense of much greater connection with a
  wise inner voice, inner knowing. It used to
  happen occasionally over the years, but now since
  the MDMA sessions its very common. Some think
  its my inner wisdom, I think its God.
• Its like, every time I go inside I see flowers
  and I pick one, and thats the thing to work on
  next. And there are things that are hard to
  take, but each time I move through them it feels
  so much better.
• Its like there have been ropes tied around me
  and now theyre loosening.

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Quotes 6

• I feel like Im walking in a place Ive needed
  to go for so long and just didnt know how to get
  there. I feel like I know myself better than I
  ever have before. Now I know Im a normal
  person. Ive been through some bad stuff,
  butthose are things that happened to me, not who
  I am
• This is me, the medicine helps, but this is in
  me.

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Quotes (3 weeks after 2nd MDMA session )

• Without the study I dont 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.
• It has felt like growing up, I feel wiser, more
  emotionally mature

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Quotes - Images

• I see huge white doors with beautiful white
  glass, so huge and heavy, but a master has
  engineered them so you can open them with one
  hand. Its only without the fear that the doors
  are so light. How interesting! If I go up to
  them with all the fears it makes me weak. Im
  taking those fears out of different parts of my
  body, looking at them and saying its ok but Im
  leaving you here. The fear served me well at
  one time, but not now for going through these
  doors.
• Im a huge pile of fertilizer composting and
  turning into beautiful rich soil. Its a perfect
  time to have rain. Im a converter, Im the
  earth, I am. Leaves, rain, even acid rain hit
  me, and I have a powerful ecosystem, all can be
  absorbed. What were doing here is turning
  compost.