Michael C. Mithoefer, MD, principal investigator Annie Mithoefer, BSN, Mark Wagner, PhD, co-investigators Charleston, S

1. 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

2. 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

3. 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.

4. 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

5. 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

6. Study Design • Therapeutic Approach • Preliminary Results

7. The Protocol Double blind, placebo controlled Treatment resistant - SSRI + Therapy Crime or war related PTSD

8. 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.

9. 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

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

11. 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

12. Study design continued • Screening and outcome measures by psychologist not involved in treatment phase

13. 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

14. 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

15. Outcome Measures Clinician Administered PTSD Scale (CAPS) Impact of Event Scale (IES) Symptom Checklist 90-revised (SCL 90-R)

16. 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

17. Mean CAPS Scores pre & post

18. IES Mean values - Stage 1

19. SCL-90R Mean values - Stage 1

20. CAPS post placebo / post MDMA

21. Mean CAPS Stage 2open Label MDMA post placebo

22. Mean IES Stage 2open Label MDMA post placebo

23. Mean SCL-90-R Stage 2open Label MDMA post placebo

24. 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

25. RBANS Mean scores pre and post

26. 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

27. 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

28. SUDS MDMA subject 1

29. 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)

30. Annie Mithoefer, BSN I will say more about: • Challenges / Integration with quotes to illustrate • Nature of deep healing process with quotes to illustrate

31. 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

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

33. 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 wasn’t about blame, but there’s still that judging voice that says we don’t talk about any of this.” • “I’m still awestruck by the deep realization last time that that I’m not 7 years old.”

34. Results of working with challenges • “I have respect for my emotions now (rather than fear of them) What’s 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.”

35. The degree of difficultywith integration is hard to predict. • Importance of flexibility about integration, not having too many assumptions

36. 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:

37. 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 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.”

38. More quotes - 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” • “I had never before felt what I felt today in terms of loving connection. I’m not sure I can reach it again without MDMA but I’m not without hope that it’s possible. Maybe it’s like having an aerial map so now I know there’s a trail.”

39. Quotes - 3 • “I got a glimpse of more of what I’m capable of growing into…I’m 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; it’s not there for somebody else.”

40. 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 I’ve gotten. I don’t 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 don’t think I would have survived another year. It’s like night and day for me compared to other methods of therapy. Without MDMA I didn’t 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 wasn’t 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.”

41. 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 it’s very common. Some think it’s my inner wisdom, I think it’s God.” • “It’s like, every time I go inside I see flowers and I pick one, and that’s 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.” • “It’s like there have been ropes tied around me and now they’re loosening.”

42. Quotes 6 • “I feel like I’m walking in a place I’ve needed to go for so long and just didn’t know how to get there. I feel like I know myself better than I ever have before. Now I know I’m a normal person. I’ve been through some bad stuff, but…those are things that happened to me, not who I am… This is me, the medicine helps, but this is in me.”

43. Quotes (3 weeks after 2nd MDMA session ) • “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.” • “It has felt like growing up, I feel wiser, more emotionally mature”

44. 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. It’s 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. I’m taking those fears out of different parts of my body, looking at them and saying ‘it’s ok but I’m leaving you here.’ The fear served me well at one time, but not now for going through these doors.” • “I’m a huge pile of fertilizer composting and turning into beautiful rich soil. It’s a perfect time to have rain. I’m a converter, I’m the earth, I am. Leaves, rain, even acid rain hit me, and I have a powerful ecosystem, all can be absorbed. What we’re doing here is turning compost.”