mdma-assisted psychotherapy for ptsd: an update: recent ... · an update: ! recent research &!...

MDMA-assisted !psychotherapy for PTSD: !

An update: !recent research &!

ongoing research with veterans!" "

Michael Mithoefer, MD, FAPA"

Clinical Assistant Professor of Psychiatry and Behavioral Sciences"

Medical University of South Carolina"

Research sponsored by Multidisciplinary Association for Psychedelic Studies"

Santa Cruz, CA""

"Mithoefer 2012 VA San Francisco"

References """Can be found in…."

•  (+/-)-3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) Investigator’s Brochure, "

•  Literature Review annual updates"

"!

Lisa Jerome Ph.D!

"

mdmaptsd.org"

Mithoefer 2012 VA San Francisco"

Outline"""

•  History of MDMA"

•  MDMA effects"

•  Why MDMA for PTSD"

•  Clinical trials - completed and in progress "

•  Current study with veterans"

Mithoefer 2012 VA San Francisco!

!""

•  Ring-substituted "

phenylisopropylamine "

derivative"

"

•  Patented in 1914 by Merck - now off-patent"

•  “Entactogens” - closeness to others, empathy, well being, and insightfulness, with little perceived loss of control"

"


MDMA"

!"

Complex pharmacological profile, dominated by" Monoamine release and reuptake inhibition "

•  Serotonin (5-HT),"

•  Norepinephrine (NE)"

•  Dopamine (DA)"

•  Greatest effects are on serotonin release"

 Some affinity for specific serotonin (5HT2), norepinephrine, acetylcholine and histamine receptors"

"


MDMA"

!""

MDMA elevates plasma concentrations of a number of hormones: "

 Oxytocin "

 Vasopressin"

  Cortisol"

 Prolactin"

 Dehydroepiandrosterone (DHEA) "

 Adrenocorticotropic hormone (ACTH)"Mithoefer 2012 VA San Francisco!

MDMA"

!"

"

 Classified as a controlled substance in 1985"

" " "“Schedule 1”""

 Before that MDMA was used as adjunct to psychotherapy "

by therapists in United States & Europe""

•  Shulgun AT, Nichols DE, Characterization of Three New Psychotomimetics, The Psychopharmacology of Hallucinogens, Stillman, R. C. Willette, R. E. (Eds). New York; Pergamon 1978"

•  Greer GR, Tolbert R. A method of conducting therapeutic sessions with MDMA. J Psychoactive Drugs. Oct-Dec 1998;30(4):371-379 "

•  Adamson R, Metzner, R, The Nature of the MDMA Experience and its Role in Healing, Psychotherapy and Spiritual Practice, ReVision 10(4) Spring 1988:59-72"

" Mithoefer 2012 VA San Francisco!

MDMA"

"

"

"

Many pre-clinical studies"

"

Phase 1 Trials"

•  United States"

•  " Spain"

•  " Switzerland""

"

""

"

"

"


Grob et al, In Preparation, Data presented to FDA; Grob et al. 1996; Vollenweider et al. 1998; 1999; Cami et al. 2000; de la Torre et al. 2000a; de la Torre et al. 2000b; Lester et al. 2000a Tancer et al. 2001, Harris et al. 2002; b; Liechti and Vollenweider2000a; b; Liechti et al,2001a: b; Mas et al. 1999; Pacifici et al. 2001; 2000;!

 Serious acute toxicity occurs in recreational users " "quite rare given millions of users"

 Changes in serotonin neurons in animal models"

 Mixed data about the possibility of memory changes in recreational users"

 Phase 1 & Phase 2 clinical trials, > 500 people "

""No drug-related serious adverse events in medical "research settings using pure MDMA"


MDMA Toxicity"

Need for additional treatments for PTSD"

existing recognized therapies:"•  Cognitive/Behavioral – prolonged exposure, CPT"

•  Eye movement desensitization and reprocessing (EMDR)"

•  Psychodynamic psychotherapy"

•  Pharmacotherapy (SSRIs only approved drugs, many others used)"

25 % - 50% of subjects don’t respond adequately to existing treatments"

2 – 4 million people in US alone in any year"

"18% (15%-35%) of returning vets"

"" < 10% screening + for PTSD get adequate treatment" Seal et al, UCSF/SF VA, 2011 Journal of Traumatic Stress, Vol. 23, No. 1, February 2010, pp. 5–16"


 "Obstacles to successful treatment of PTSD"

•  Fear"

•  Defensiveness / numbing"

•  Lack of trust"

 "MDMA has been reported to "

•  Decrease fear and defensiveness "

•  Increase trust and empathy "

 "Additional therapeutic effect"

•  Affirming experiences"

•  More realistic perspective about present circumstances/safety"


Why study MDMA for PTSD?"

"

•  a"Mithoefer 2012 VA San Francisco!

“Neurocircuitry model” of PTSD "•  deficit in extinction of fear conditioning"

• " mediated by the amygdala and the ventral/medial prefrontal cortex (vmPFC) "

•  reduced hippocampal activity and volume"

•  increased activity in the amygdala"

•  decreased activation of the medial prefrontal cortex1 "

Human Positron Emission Tomography (PET) 75 minutes following MDMA administration "

•  increases in cerebral blood flow in the ventromedial frontal and occipital cortex"

•  decreases in the left amygdala2"

"

""


1)  Rauch SL, Shin LM, Phelps EA (2006) Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research--past, present, and future. Biol Psychiatry 60: 376–382 !

2)  2)Gamma A, Buck A, Berthold T, Liechti ME, Vollenweider FX (2000) 3,4-Methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H(2)(15)O]-PET in healthy humans. Neuropsychopharmacology 23: 388–395 !

!

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 !


 FDA approval November 2001"

 IRB approval September 2003"

 DEA approval February 2004"

 First Subject Enrolled March 2004"

 Study completed September 2008"

 Results published 2010 – J. of Psychopharmacology"

"


Timeline"

•  Can be safely administered to people with "treatment-resistant PTSD"

• Will produce improvement in PTSD symptoms "

•  4 days after each of 2 or 3 experimental intervention "sessions"

•  At 2 month follow-up"


Hypothesis:"MDMA-assisted psychotherapy "

"


134 phone screening"

27 screened in person"

23"

randomized"21

completed

13 MDMA"" 8 placebo

7 crossover to MDMA

 Double blind, placebo controlled "

 Treatment resistant – 20 Subjects"

•  SSRI or SNRI + Psychotherapy"

 Crime or war related PTSD"


The Protocol"

"

•  60% receive MDMA on 2 or 3 occasions"

•  40% receive placebo on 2 occasions"


Stage I - Double Blind"

•  Placebo subjects from Stage I received MDMA"

"" " on 2 or 3 occasions "


Stage II – Open Label Crossover "

 MDMA or placebo administered during 8 hour “experimental session” "•  Male and female therapist present "

 Overnight stay after session "

 Initial dose 125 mg. "

•  Supplemental dose 62.5 mg. 2 hours later"

 Additional non-drug therapy sessions "

• " 11-15 in Stage 1 "

•  9 - 13 additional in Stage 2"

 Blood Pressure, Pulse, q 15 min, Temp. q hour"Mithoefer 2012 VA San Francisco!

"

"

Experimental Sessions!


"

 Non-directive, supporting emerging experience"

 Reclining, headphones with music, eyeshades"

 Alternating inner focus & talking to therapists"

"

We have now written a treatment manual and adherence measures used in current studies"


Therapeutic Approach"

"

“I don’t know why they call this ecstasy!”"


Screening and outcome measures by a psychologist not involved in

treatment phase""

Mark T. Wagner, Ph.D"

Director, Neuropsychology Section"

Professor of Neurology"

Medical University of South Carolina"

Charleston, SC"


"

 Clinician Administered PTSD Scale (CAPS)"

  Impact of Event Scale Revised (IES-R)"

 Symptom Checklist 90-revised (SCL 90-R)"

 NEO personality inventory"


Outcome Measures"

!!

Mithoefer © 2009" 27"

20!

30!

40!

50!

60!

70!

80!

90!

1! 2! 3! 4!

CA

PS

Sco

re!

Time of Measurement!

Placebo!

MDMA!

Mean CAPS scores by group "baseline → 2 months post"

" "" " "" " Time*Group interaction (p.= 0.015)"

"

Open label MDMA- assisted therapy for subjects who originally received placebo-assisted sessions"

  2 – 3 MDMA assisted sessions"

  integration non-drug therapy sessions "

" as in Stage "

  7 of 8 placebo subjects elected to participate"


Stage 2"

!!


65.6"

33.9"

0!

10!

20!

30!

40!

50!

60!

70!

Baseline Post placebo! 2 months post MDMA!

CA

PS

Sco

re!

Mean CAPS scores ! open label MDMA after placebo!" " " " " " "N = 7 " " " p< .05 !

"

"

"

Clinical Response (> 30% reduction in CAPS)"

"

Stage 1"

•  Placebo (psychotherapy only) = 25%"

•  MDMA = 83%"

Stage 2"

•  " placebo MDMA = 100%"


"

 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"


Neuropsychological Measures"

!!


0"

10"

20"

30"

40"

50"

60"

70"

80"

90"

100"

110"

120"

MDMA " Placebo"

RB

AN

S S

core

!

Baseline" Final"

RBANS – pre and post"

"" "> 1 year after study completion "

"""

 Repeat"

•  CAPS"

•  IES-R"

• NEO"

 Questionnaire"

"Mithoefer 2012 VA San Francisco!

Long-term Follow-up (LTFU)"

LTFU Mean Global CAPS Scores!17 - 74 months post final MDMA session !

(mean=45.4 months, SD=17.3) "

Mithoefer 2012 VA San Francisco!!

!

N=20 SD 7.3"

N=20 SD 18.6" N=16 SD 22.8"

Current Activities"

 6 day training program for research therapists"•  Based on manual"

•  Video from research sessions"

 MDMA-assisted session for researchers"•  Phase 1 trial – currently underway in Charleston"

 Relapse study"

•  1 additional MDMA-assisted session for relapse"

 Applying Manual Adherence Measures"

"" "- In all current and future studies"


Current Activities"

 Reproduce results in other locations"•  Switzerland – recently completed "

•  Israel – recently initiated"

•  Colorado – FDA approved, soon to be initiated"

•  Vancouver, – nearing final approvals"

•  Jordan, Australia– in application process with delays"

•  England, protocol design stages"

New US study - military veterans with PTSD"

•  Currently under way in Charleston"

•  "Dose-response design"

"Mithoefer 2012 VA San Francisco!

A Randomized, Triple-Blind, Phase 2 Pilot Study Comparing 3 Different Doses of MDMA in

Conjunction with Manualized Psychotherapy in 24 Veterans, Firefighters and Police Officers with Chronic Posttraumatic Stress Disorder (PTSD) "

Michael C. Mithoefer, MD, principal investigator"

Annie Mithoefer, BSN, Mark Wagner, PhD, Joy Wymer PhD"

co-investigators"

Charleston, South Carolina, USA"

Sponsor: "

Multidisciplinary Association for Psychedelic Studies !

"


Protocol Design Stage 1"•  24 veterans, firefighters, police officers"

"CAPS scores > 50 after medication and/or"psychotherapy"

•  Randomized to low, medium or full dose MDMA "(30mg + 15 mg, 75 mg + 37.5mg, 125 mg + 62.5 mg)"

-  Eight-hour MDMA-assisted sessions a month apart "with accompanying preparation and integration "sessions"

•  Outcome measures 1 month after 2nd session then blind broken before Stage 2"


Protocol Design Stage 2"

•  Full dose 3rd full-dose session"

•  Low or Medium dose 3 full dose sessions"

•  Followup: repeat outcome measures"

• " 2 months and 1 year"


Enrollment in Vet Study Thus Far"•  9 veterans enrolled "

- 5 completed all sessions"

- 2 dropouts"

•  1 medium dose with good results – completed follow-up"

•  1 low dose, decided not to continue"

- 1 in progress"

•  6 men & 1 woman with combat trauma (Iraq)"

2 women with military sexual trauma (MST)"

•  3 in screening process: 1 M vietnam, 1M Iraq, 1 F MST"

•  220 veterans have called to ask about participation"


Clinician Administered PTSD Scale (CAPS) !preliminary – first 6 participants"


Beck Depression Inventory (BDI-II) !preliminary – first 6 participants"


Global Assessment of Functioning (GAF) !preliminary – first 6 participants"


Posttraumatic Growth Inventory (PTGI) !preliminary – first 6 participants"


Future Plans""

Multicenter Phase 3 trial of "

MDMA-assisted psychotherapy for PTSD"

"

•  " " Several years in the future"

•  " " One or two in the US"

– hopefully with VA collaboration "

•  " " ? one in Europe, Canada or The Middle East"

" ""


mdma-assisted psychotherapy for ptsd: an update: recent ... · an update: ! recent research &!...

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