MDMA-assisted Psychotherapy in Posttraumatic Stress Disorder

1. MDMA-assisted Psychotherapy in Posttraumatic Stress Disorder Study Design Therapeutic approach Preliminary Results

2. 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, Annie Mithoefer, BSN Charleston, SC, USA Sponsor: Multidisciplinary Association for Psychedelic Studies

3. Hypothesis MDMA-assisted psychotherapy: • can be safely administered to people with treatment-resistant 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.

4. 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.

5. The Protocol Double blind, placebo controlled pilot study of treatment resistant crime or war related PTSD

6. 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

7. 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

8. 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

9. 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

10. 17 visits after informed consent meeting • Medical and psychological screening Physical Exam, Labs EKG, SCID, CAPS • 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 • 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

11. Visits - continued • Follow-up psychotherapy the following morning Daily phone contact for 7 days following this • Repeat outcome measures 4 days after exp. session 8-10. Follow-up psychotherapy weekly • 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) • Termination visit Repeat outcome measures and neuropsych. testing Final psychotherapy visit

12. 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

13. 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

14. APA Guidelines & Treatment Resistant PTSD “Because there is a paucity of high-quality evidence-based 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”

15. Comparison: MDMA-assisted vs other approaches

16. Preliminary Data First 5 Subjects Completed Stage I Blind Broken 2 other subjects have completed all but final follow-up blind not broken several subjects in screening process

17. 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

18. MDMA Unipolar depression Panic disorder Unipolar depression Unipolar depression Placebo Unipolar depression Dysthymia Unipolar depression Dysthymia Eating D/O in remission Subs. abuse in remission Axis 1 Comorbidity

19. Physiological Response Vital sign measurements

23. Body Temperature - MDMA subjects

24. 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 - MDMA group

25. Anxiety Fatigue Headache Increased irritability Low mood Insomnia Side Effects within 7 days - Placebo group

26. 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

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

30. Clinican Administered PTSD Scale (CAPS)

31. CAPS - Baseline, 4 days post & 3 Month

32. Impact of Events Scale (IES)

33. Symptom Checklist 90-Revised (SVL 90-R)

34. Distress Levels during MDMA Sessions Subjective Units of Distress (SUD) Scale of 1 - 7 Beginning and hourly for 6 hours

37. SUDS MDMA subject 1

38. 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

39. 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.

40. 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

41. 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

42. 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.

43. 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

44. 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.

45. I guess I won’t have to go to Tibet