1

+ 3,4-Methylenedioxymethamphetamine-

assisted Psychotherapy for

Post-traumatic Stress Disorder

http://mentalfloss.com/article/27390/3eanuts-peanuts-comics-minus-last-panel Emily Czeck, PharmD

PGY-2 Psychiatric Pharmacy Resident

Central Texas Veterans Health Care System

September 27, 2013

Learning Objectives:

1) Explain the proposed pathophysiology of post-traumatic stress disorder (PTSD)

2) Apply the proposed mechanism of action for + 3,4-methylenedioxy-methamphetamine (MDMA) for improving PTSD psychotherapy outcomes

3) Compare the evidence for MDMA-assisted psychotherapy for PTSD 4) Conclude if MDMA-assisted psychotherapy is an appropriate treatment

option for PTSD in specific patient populations

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POST-TRAUMATIC STRESS DISORDER Introduction1

- First named as soldier’s heart or DaCosta’s syndrome in a civil war study published in 1871 o Used to describe war-induced extreme and enduring reaction to psychologic trauma

- Subsequent names included fright neurosis; traumatic, combat, or war neurosis; railway spine; concentration camp syndrome; rape-trauma syndrome; combat fatigue; post-Vietnam syndrome; and shell shock

DSM-IV-TR Criteria2

A. Exposure to a traumatic event in which both of the following were present: 1. Experiencing, witnessing, or being confronted with an event that involved actual or threatened death or

serious injury, or a threat to the physical integrity of self or others 2. Response to the event involved intense fear, helplessness, or horror

B. The trauma is persistently re-experienced by: 1. Recurrent and intrusive distressing recollection of the event, including images, thoughts, or perceptions 2. Recurrent distressing dreams of the event 3. Acting or feeling as if the traumatic event were recurring (e.g., flashbacks, illusions, hallucinations) 4. Intense psychological distress with exposure to internal or external cues of the trauma 5. Physiological reactivity on exposure to these internal or external cues

C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness, as indicated by > 3 of the following:

1. Avoid thoughts, feelings, or conversations about the trauma 2. Avoid activities, places, or people that cause recollection of the trauma 3. Inability to recall aspects of the trauma 4. Markedly decreased interest in activities 5. Feeling of detachment from others 6. Restricted range of affect (e.g., unable to have loving feelings)

D. Persistent symptoms of increased arousal, as indicated by two or more of the following: 1. Difficulty falling or staying asleep 2. Irritability or outbursts of anger 3. Difficulty concentrating 4. Hypervigilance 5. Exaggerated startle response

E. Duration > 1 month F. Disturbance causes significant impairment of functioning

DSM-V Criteria3

A. Exposure to actual or threatened death, serious injury, or sexual violence 1. Directly experiencing trauma 2. Witnessing, in person, an event that occurred to someone else 3. Learning that traumatic events occurred to a close family member or friend 4. Experiencing repeated or extreme exposure to aversive details of the traumatic event

B. Presence of one or more of the following intrusion symptoms associated with the trauma 1. Recurrent, involuntary, and intrusive distressing memories of the trauma 2. Recurrent distressing dreams that are related to the event 3. Dissociative reactions in which the individual feels or acts like the trauma were recurring 4. Intense or prolonged psychological distress upon exposure to cues of the trauma 5. Marked physiological reactions to cues related to the trauma

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C. Persistent avoidance of stimuli associated with the trauma 1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings associated with the trauma 2. Avoidance of or efforts to avoid external reminders that arouse distressing memories, thoughts, or

feelings associated with the trauma D. Negative alterations in cognition and mood associated with the trauma, as evidenced by > 2 of the following:

1. Inability to remember important aspects of the trauma 2. Persistent and exaggerated negative beliefs or expectations about oneself 3. Persistent, distorted cognitions about the cause or consequences of the trauma that lead the individual

to blame him/herself or others 4. Persistent negative emotional state 5. Markedly diminished interest or participation in activities 6. Feelings of detachment or estrangement from others 7. Persistent inability to experience positive emotions

E. Marked alterations in arousal and reactivity associated with the trauma, as evidenced by > 2 of the following: 1. Irritable behavior and angry outbursts 2. Reckless or self-destructive behavior 3. Hypervigilance 4. Exaggerated startle response 5. Problems with concentration 6. Sleep disturbance

F. Duration > 1 month G. Disturbance causes significant impairment of functioning H. Disturbance is not attributable to physiological effect of a substance or another medical condition

Differences between DSM-IV-TR and DSM-V Criteria:

- Criterion A: Trauma does not have to involve the person with PTSD. It can involve a close family member or friend or it can be repeated exposure to details of the event (e.g., first responders)

- Criterion B: No major changes. - Criterion C: In DSM-IV, Criterion C consisted of both persistent avoidance and negative alterations in cognition

and mood. In DSM-V, Criterion C focuses on persistent avoidance, and Criterion D is negative alterations in cognition and mood.

- Criterion D from DSM-IV corresponds with Criterion E from DSM-V. - Duration of disturbance is consistent, as well as, significant impairment of functioning - Criterion H added to DSM-V

Epidemiology: 4-8

- Approximately 50% of men and 60% of women are exposed to a life-threatening traumatic event o Of these exposed, 8% of men and 20% of women will develop PTSD

- Lifetime prevalence 6.8% among American adults - Prevalence in OIF/OEF veterans = 13.8% of OIF/OEF

o Sampled between 2007 & 2008 - Estimated lifetime prevalence 30.9% for men and 26.9% for women who are Vietnam veterans - Economic impact: indirect costs = $4-6 billion between 2007 and 2008

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Risk Factors:3 Table 1:

Time Frame Variables

Pre-traumatic Temperamental- childhood emotional problems, prior mental disorders

Environmental- lower socioeconomic status, lower education, exposure to prior trauma, lower intelligence, minority racial/ethnic status, family psychiatric history

Genetic and physiological- female gender and younger age at the time of trauma exposure, certain genotypes may either increase or decrease risk of developing PTSD

Peri-traumatic Environmental- severity or dose of the trauma, perceived life threat, personal injury, interpersonal violence, witnessing atrocities, dissociation that occurs during the trauma and persists afterwards

Post-traumatic Temperamental- negative appraisals, inappropriate coping strategies, development of acute distress disorder

Environmental- exposure to repeated upsetting reminders, subsequent adverse life events, financial or other trauma-related losses

Pathophysiology:1,8

- Amygdala: centerpiece of the central nervous system involved in the fear response o Enhances processing of fear-inducing information by increasing the emotional valence assigned to

memories making them easier to access in the future o Able to bypass the cortex and neocortex, thereby, evaluating the surroundings before interacting with o Can activate every system in the body to initiate fight or flight response o Stimulates hippocampus to help the brain learn and form new memories specific to danger

- Neuroendocrine Theory: o Hypersecretion of corticotropin-releasing factor with subnormal levels of cortisol

- Neurochemical Theory: o Serotonin, norepinephrine, and glutamate are associated with processing memories in the amygdala

Serotonin’s role in PTSD symptoms not understood Hyperactive autonomic nervous system that overreacts to stimuli NE releasedstimulates

sympathetic and parasympathetic nervous systems Glutamate signaling abnormalities may result in distortion of amygdala dependent emotional

processing under stress Dissociative and hypervigilant symptoms Abnormalities in GABA inhibition increased awareness or response to stress

Treatment guidelines:9

Table 2:

Psychotherapy Interventions for PTSD

SR Significant Benefit Some Benefit Unknown Benefit None

A Trauma focused or Stress inoculation

C Patient Education Imagery Rehearsal Therapy Psychodynamic Therapy Hypnosis Relaxation Techniques Group Therapy

I Family Therapy WEB-Based CBT Acceptance and Commitment Therapy Dialectical Behavioral Therapy

Key: SR = strength of recommendation (A = strong recommendation, C = no recommendation for or against, I = insufficient evidence to make a recommendation)

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Table 3:

Pharmacotherapy Interventions for Treatment of PTSD

SR Significant Benefit Some Benefit Unknown Benefit No Benefit

A SSRIs SNRIs

- - -

B

-

Mirtazapine Prazosin (sleep/nightmares) TCAs Nefazodone MAOIs (phenelzine)

- -

C - - Prazosin (for global PTSD) -

D

- - -

BenzodiazepinesHARM! Tiagabine Valproate Topiramate Risperidone

I

- -

Atypical antipsychotic (monotherapy) First generation antipsychotics Buspirone Non-benzodiazepine hypnotics Bupropion Trazodone (adjunct) Gabapentin Lamotrigine Propranolol Clonidine

-

Key: SR = strength of recommendation (A = strong recommendation, B = recommended to eligible patients, C = no recommendation for or against, D = recommendation made against routinely providing the intervention to asymptomatic patients, I = insufficient evidence to make a recommendation)

Table 4:

Symptom Improvement with Select Pharmacological Interventions for Treatment of PTSD

Oral Dose Global Improvement

Re-experiencing

Avoidance/ Numbing

Hyperarousal

SSRI Fluoxetine 20-60 mg/d X X X X

Sertraline* 50-200 mg/d X X X X

Paroxetine* 20-60 mg/d X X X X

SNRI Venlafaxine 150-375 mg/d X X X X

TCAs Amitriptyline 150-300 mg/d X X X

Imipramine 150-300 mg/d X X X

MAOIs Phenelzine 45-75 mg/d X X X

Sympatholytics

Prazosin Target 6-10 mg/d

X X X

Other Mirtazapine 30-60 mg/d X X X

Nefazodone 300-600 mg/d X X X

Key: *= FDA approved for PTSD

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MDMA Drug Facts:10-11

- First synthesized in 1914 by Merck; therefore, not patentable at this time - Drug class: empathogen

o Properties of the stimulant amphethamine and the hallucinogen mescaline - Not physically addictive, however, psychologically addictive

o Those with preexisting psychiatric disorders, such as anxiety and depression, are at greater risk of abusing

o Tolerance develops in time - Street dose = 75 – 150 mg - Most commonly available in tablet form

o Also available as powder and capsule Proposed Mechanism of Action in PTSD10,12

- MDMA postulated to support and enhance psychotherapy by: o Causing the release of serotonin, dopamine, and norepinephrine o Increasing levels of oxytocin, prolactin, and cortisol

- Serotonin release associated with the subjective effects of MDMA including mood and perception o Allows for positive cognitive-emotional state with reduced fear, facilitating the processing of traumatic

material o Processing of traumatic material should be done within “optimal arousal zone” to avoid eliciting

extreme emotions Use of MDMA may widen this zone

- Serotonin release also directly or indirectly leads to increase in oxytocin by stimulating 5HT1A receptors o Oxytocin shown to be involved in affiliation, trust, and accurate perception of emotion

This allows patients to form a therapeutic alliance that is considered crucial for PTSD recovery - Prolactin release following MDMA administration allows for relaxation and receptivity

Pharmacokinetics13

- Half-life = approx. 7 hours - Cmax = 1.5 – 3 hours after ingestion

o After oral administration, effect onset in 20-30 minutes and lasts 2-3 hours - Metabolism: hepatic

o Mainly CYP2D6 - Excretion: renal

Adverse Effects 11-14

- Common: loss of appetite, insomnia, bruxism, trismus, hyperthermia, tachycardia, hypertension, depression, confusion

- Serious: hyponatremia, hyperthermia, neurotoxicity, serotonin syndrome

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REVIEW OF LITERATURE MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress

disorder15

STUDY OBJECTIVE: Assess the safety of a single psychotherapy session using 1 of 5 ascending doses of MDMA in patients with chronic PTSD

STUDY DESIGN: Randomized, double-blind, inactive placebo-controlled, ascending-dose study

STUDY SUBJECTS:

Inclusion Criteria: Females living in Madrid, Spain with chronic, treatment-resistant PTSD secondary to sexual assault, who scored > 15 on the Severity of Symptoms Scale for Post-Traumatic Stress Disorder (SSSPTSD) and had scores > 5, 6, and 4 on the re-experiencing, avoidance, and increased arousal subscales respectively; patients also had to be free of medications for > 30 days before beginning study

Exclusion Criteria: Previous experience with MDMA, any major medical condition including current pregnancy, any other psychiatric disorder

OUTCOMES:

SSSPTSD: assess the principal symptoms of PTSD such as re-experiencing, avoidance, and increased arousal, as well as, somatic symptoms related to anxiety

State-Trait Anxiety Inventory, State Version (STAI-S): measures 2 independent concepts of anxiety, state and trait; only state used for this study

o State = transitory emotional state or condition of the human organism characterized by subjective feelings of tension and apprehension and by autonomic hyperactivity

Beck Depression Inventory (BDI): evaluate symptoms of depression, focuses on cognitive symptoms

Hamilton Rating Scale (HAM-D): evaluates symptoms of depression, focuses on behavioral and physiological symptoms

Modified Fear Scale (MFS III): assess fear related to issues specific to sexual assualt

Maladjustment Scale (MS): related to social and work-related adjustment

Rosenberg Self-Esteem Scale (SE/R): evaluates elements from self-acceptance to self-esteem

Hallucinogen Rating Scale (HRS): assesses somaesthesia, affect, volition, cogntion, perception , and intensity

Penn Helping Alliance Questionnaire (HAq): assess the patient’s experience of the helping alliance

UKU Scale of Secondary Effects: assess clinical side effects of psychoactive medications in therapeutic doses

METHODS:

Treatment-resistant PTSD was defined as failing to response to > 1 standard treatment

All subjects had 6 non-drug psychotherapy sessions with a male and a female therapist present o 3 before the experimental session to prepare subjects for MDMA experience o 3 after the experimental session for discussing the events and material from the MDMA session

1 session took place the day after the experimental session then the other 2 were at 5-7 day intervals thereafter

o Length of sessions: non-drug = 90 minutes, experimental = 6 hours with an additional 2 hours of rest After experimental session, subjects were accompanied home by a predetermined person

Patients completed questionnaires to assess their feelings on therapeutic alliance, subjective effects of experimental session, and side effects at 24 hours and again at 5-7 days after the experimental session

An independent, blinded evaluator conducted psychological tests at the beginning and end of treatment

Follow-up planned at 1, 3, 6, 9, and 12 months after treatment

STATISTICAL ANALYSES:

Due to limited sample size, statistical analysis between groups were not completed

Only descriptive analysis provided

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RESULTS:

Study population: original goal = 29 patients (MDMA = 21, placebo = 8) o Study stopped prematurely as a result of political pressure

Total study population: n = 6, MDMA = 4 (3 received 50 mg dose, 1 received 75 mg dose), inactive placebo = 2

Mean current age in years: MDMA 50 mg = 36.67, MDMA 75 mg = 38, placebo = 33

Table 5:

Efficacy Measures MDMA 50 mg (n=3) MDMA 75 mg (n=1) Placebo (n=2) Psychopathological Assessment Scale Scores Mean Values*

Pre-MDMA Session 37.3, 38.6, 25.6, 39, 115.6, 25.6, 24.6

48, 34, 25, 60, 132, 28, 24 44.5, 28.5, 20, 35.5, 119.5, 20, 27.5

Post-MDMA Session 28.3, 25.6, 15, 22, 103.6, 14.6, 27.3

32, 24, 1, 19, 78, 20, 33 40, 28, 23.5, 22.5, 110.5, 23, 30

1 month follow-up 25, 33, 16.6, 21.6, 102.6, 15.6, 23.6

31, 28, 21, 39, 96, 22, 22 -

2 month follow-up 17, 24, 1, 11, 86, 18, 30** 28, 27, 14, 43, 86, 24, 25 -

3 month follow-up 27, 23, 0, 15, 72, 18, 31** - -

Hallucinogen Rating Scale Scores Mean Values

Somaesthesia 0.82 2.54 0.345

Affect 1.17 2.06 0.145

Perception 0.723 1.88 0.09

Cognition 1.176 2.92 0.125

Volition 1.126 2.50 0.00

Intensity 0.916 2.75 0.00

Helping Alliance Questionnaire

Session 1 10 19 12.5

Session 2 17.6 - 13**

Session 3 15.3 30 21

***Session 4 21.3 24 20.5

Session 5 19.3 25 23

Session 6 20.3 26 27.5

Session 7 29.5**** 31 15.2 *Correspond to this order: SSSPTSD, STAI/S, BDI, HAM-D, MSF III, MS, SE/R; **n = 1; ***Experimental session; ****n = 2

Adverse effects: 2 subjects (1 from 50 mg group and 1 from 75 mg group) reported very mild side effects at the 24 hour assessment including:

o 50 mg: fatigue, sedation, inner unrest, tachycardia, photosensitivity, decreased libido, and headache

o 75 mg: difficulty concentrating, fatigue, sedation, failing memory, depression, inner unrest, emotional indifference, diarrhea, and headache

Physiological effects: no significant elevation in blood pressure, heart rate, and other somatic side effects o No dose-response curve distinguished with blood pressure or heart rate changes

Evaluation of blinding: o Subjects: 2/6 (33%) incorrectly guessed group assignment

1 patient thought she had placebo but received MDMA 50 mg, another patient who received placebo thought she received “medium” dose MDMA

o Therapists: Therapist 1 incorrectly guessed treatment for 2/6 (33%)patients

Therapist 2 incorrectly guessed treatment for 3/6 (50%) patients

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AUTHORS’ CONCLUSION: “Low doses of MDMA administered as an adjunct to psychotherapy were found to be safe for the 6 subjects with chronic PTSD treated in this clinical trial, and there were promising signs of efficacy and reduced PTSD symptomatology.” REVIEWER’S OPINION Table 6:

STRENGTHS LIMITATIONS

Study design Small sample size

Blinded, independent reviewer for assessments Lacks external validity

Validated scales and assessments utilized Not all doses used

Lack of follow-up

The safety and efficacy of MDMA-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic

stress disorder: the first randomized controlled pilot study10

STUDY OBJECTIVE: Assess the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant, chronic PTSD

STUDY DESIGN: Randomized, double-blind, inactive placebo-controlled, pilot, phase II study

STUDY SUBJECTS:

Inclusion Criteria: Adults age 21 - 70 years old, diagnosis of crime or war-related PTSD according to DSM-IV-R criteria, presence of treatment-resistant symptoms defined as CAPS > 50 after > 3 months of SSRI or SNRI in addition to > 6 months of psychotherapy

Exclusion Criteria: Any major medical condition, borderline personality disorder or any current Axis I disorder except anxiety disorders, affective disorders other than bipolar disorder type I, substance abuse or dependence in remission for > 60 days, and eating disorder without active purging

PRIMARY OUTCOME: Difference in global symptom severity and categorical ranking for diagnosis of PTSD according to change in CAPS score

SECONDARY OUTCOME(S):

Impact of Events Scale Revised (IES-R): response to stress

Symptom Checklist 90-Revised (SCL-90-R): self-reported symptoms

Repeatable Battery for the Assessment of Neuropsychological Status (RBANS): attention and processing speed, expressive language, visual-spatial and constructional abilities, and memories

Paced Auditory Serial Addition Task (PASAT): processing speed and mental flexibility

Rey-Osterrieth Complex Figure (RCFT): visuospatial memory associated with neurological conditions

Physiological changes in blood pressure, pulse, and temperature

METHODS:

Subjects randomized via computer-generated randomization list to MDMA or inactive placebo in conjunction with psychotherapy

o n =20, MDMA = 12, inactive placebo = 8

Patients required to taper and abstain from all psychoactive medications except as needed rescue medications o Sedative hypnotics and anxiolytics

Drop-outs were replaced to preserve group-assignment ratio and double-blinding o Two subjects dropped-out during study: 1 due to relapse of depression, 1 was unwilling to travel o One additional patient replaced because not categorized as treatment resistant

After screening and enrollment, subjects completed baseline psychological and neurocognitive measures listed in outcomes section above

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o Outcomes were repeated approximately 4 days after each of two 8-hour experimental sessions and 2 months after the second experimental session

Each subject had two 90-minute introductory sessions within 6 weeks before first experimental session to prepare for structure of sessions, approach to therapy, and possible effects of MDMA

Experimental sessions lasted 8-10 hours followed by an overnight stay at the clinic o Daily telephone contact was maintained during the week after the experimental sessions

Eight integration sessions were conducted with each subject to discuss experimental sessions, allow for additional emotional processing, and help incorporate any insights or new perspectives

o An integration session occurred the morning after each experimental session o Additional integration sessions were permitted as needed

Manual outlining psychotherapy technique written prior to study used for session structure

Patients given first dose of inactive placebo or MDMA 125 mg at 1000 on day of experimental session o Optional dose of 62.5 mg MDMA or placebo administered 2-2.5 hours after initial dose

Therapists stayed with the patients until at least 1700 or until effects of the session had subsided and the patient was judged to be at baseline mental status and medically stable

If necessary, patients were prescribed zolpidem or lorazepam for insomnia

During the integration session the day after the experimental session, the patients and investigators were asked to guess group assignment and the certainty of their guess

Stage 2: placebo subjects could enroll in open-label arm of study after outcomes measures were repeated at the visit 2 months after the second experimental session

Protocol amendment allowed patients to have 1 additional MDMA-assisted session and 3 additional non-drug sessions

STATISTICAL ANALYSES:

ANOVA with repeated measures for CAPS, IES-R, SCL-90-R to test difference between groups over time o Holms sequential Bonferroni correction for multiplicity used after significant ANOVA

t tests for group comparisons of vital signs

Minimum sample size of 8 per group with oversampling for the experimental group was “determined adequate”

RESULTS:

One-hundred and thirty-four patients assessed for eligibility o One-hundred and twelve excluded: 61 did not meet inclusion criteria at telephone screen, 46 declined

to participate, 5 did not meet criteria at full screen o Twenty-three patients randomized

Table 7:

Participant Characteristics MDMA (n=12) Placebo (n=8) Mean age (std) 40.2 (7.6) 40.8 (7.0)

Female 10 (83%) 7 (87%)

Caucasian 12 (100%) 8 (100%)

Hx alcohol abuse/dependency 1 (8%) 1 (13%)

Hx other substance abuse/dependency 0 (0%) 1 (12%)

Prior MDMA use 6 (46%) 3 (38%)

Lifetime MDMA use for prior users (# of times) 6 (1-5) 3 (1-2)

PTSD mean # months of duration (std) 232 (201) 273 (126)

Prior therapy mean # months of duration (std)* 40.6 (38.5) 85.3 (54.2)

Comorbid major depression 9 (75%) 7 (88%)

Comorbid anxiety disorder 2 (17%) 1 (13%)

Mean baseline CAPS score (std) 79.2 (23.6) 79.6 (22) *p = 0.04

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Table 7 Continued:

Participant Characteristics MDMA (n=12) Placebo (n=8) Index Trauma

Sexual assault or childhood sexual abuse 9 (75%) 7 (86%)

Physical neglect 2 (16%) 0 (0%)

Violence 1 (8%) 1 (13%)

Combat stress 1 (8%) 0 (0%)

Emotional 1 (8%) 0 (0%)

Table 8:

Clinical Efficacy MDMA Placebo CAPS mean scores (std)

Stage 1: n = 12 n = 8

T1 (< 4 weeks before first experimental session) 79.2 (6.6) 79.6 (8.1)

T2 (3-5 days after 1st

experimental session) 37.8 (8.4)* 74.1 (10.3)

T3 (3-5 days after 2nd

experimental session) 29.3 (6.5)* 66.8 (8.0)

T4 (2 months after 2nd

experimental session) 25.5 (7.7)* 59.1 (9.4)

Stage 2: n = 7 n = 0

T1c (pre-MDMA & > 2 months post placebo) 65.6 (24.2) --

T4c (4-6 weeks after 2nd

MDMA session) 33.9 (12.8)* --

IES-R mean scores (std) n = 12 n = 8

T1 44.9 (4.3) 45.1 (5.3)

T2 23.7 (5.3)* 46.0 (6.5)

T3 18.2 (4.1)* 38.28 (5.0)

T4 15.0 (5.0) 32.6 (6.1) *p <0.05

Clinical response was defined as > 30% reduction from baseline CAPS total severity score o Stage 1: 10/12 (83%) MDMA patients and 2/8 (25%) placebo patients achieved o Stage 2: 7/7 (100%) MDMA patients achieved

Physiologic: Table 9:

Maximum Change in Physiological Data: All experimental sessions

MDMA Mean (std)

Range Placebo Mean (std)

Range

Systolic BP 25.2 (13.7) 16 - 50 22.2 (15.3) -3 - 57

Diastolic BP 14.4 (6.5) 1 - 14 13.8 (7.5) 2 - 28

Pulse 28.8 (11.5) -7 - 52 22.2 (13.7) 3 - 57

Temperature 0.5 (0.4) -0.6 – 1.5 -0.7 (0.6) -0.06 – 1.9 There was a statistically greater increase in all physiologic measures from 15-min pre-session to highest recorded value during experimental sessions for the MDMA group than placebo (p < 0.05). All values returned to pre-session norms by 6 hours after session completion.

Adverse Effects o Most common in MDMA group on day of experimental session: jaw tightness, nausea, feeling cold,

dizziness, loss of appetite and impaired balance o Most common in placebo group on day of experimental session: anxiety, insomnia, headache and

fatigue o Week following experimental session most common reported side effects were similar between groups:

fatigue, anxiety, low mood, headache and nausea o All typically resolved over hours to days; some required treatment such as sedative hypnotics or NSAIDS

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Neurocognitive: No significant difference between groups on any cognitive measure at baseline or at 2-month follow-up

Additional integration sessions: 20 for MDMA group and 1 for placebo group

Supplemental doses: 4/12 (33%) patients took additional dose of MDMA o No difference in mean CAPS score change compared to patients who did not take additional dose

Rescue medications: o Zolpidem: administered after 31/51 (61%) MDMA sessions and 11/16 (69%) therapy only sessions (p=

0.77); administered to 17/20 (85%) total patients o Benzodiazepines: administered after 24/51 (47%) MDMA sessions and 6/16 (38%) therapy only sessions

(p = 0.57); administered to 14/20 (70%) total patients

Evaluation of blind: 19/20 (95%) of participants correctly guessed group assignment, therapists guessed correctly 100% of the time

AUTHORS’ CONCLUSION: “This pilot study demonstrates that MDMA-assisted psychotherapy with close follow-up monitoring and support can be used with acceptable and short-lived side effects in a carefully screened group of subjects with chronic, treatment resistant PTSD.” REVIEWER’S OPINION: Table 10:

STRENGTHS LIMITATIONS

Use of validated scales Small sample size

Selection of patient population Lacks external validity

Use of blinded independent rater Did not use intent-to-treat analysis

Drug screens required Transparency of blinding

Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after MDMA-assisted psychotherapy: a prospective long-term follow-up study16

STUDY OBJECTIVE: Assess the long-term effects of MDMA-assisted psychotherapy in patients with treatment-resistant, chronic PTSD

STUDY DESIGN: Long-term follow-up (LTFU) completed by the patients from the Mithoefer 2011 publication

STUDY SUBJECTS:

Same patients from previous study

All 20 patients from previous study completed LTFU questionnaire

PRIMARY OUTCOME: Difference in global symptom severity and categorical ranking for diagnosis of PTSD according to change in CAPS score

SECONDARY OUTCOME(S):

Impact of Events Scale Revised (IES-R): response to stress

LTFU questionnaire: patient perceived benefit or harm of MDMA-assisted psychotherapy and changes in any areas not addressed by CAPS or IES-R, such as changes in relationship or creativity

METHODS:

All 20 participants from previous trial were mailed informed consent form and a letter requesting their participation in LTFU study

All 20 patients agreed to participate and were asked to complete LTFU questionnaire, CAPS and IES-R o The questionnaire measured the degree and persistence of perceived benefits and/or harm of MDMA-

assisted psychotherapy using an ordinal scale

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Additional items were used to assess participant beliefs about the benefits of receiving an extra MDMA session, any additional psychiatric treatment after the study, and their use of illicit psychoactive substances since the study

Change in cognition was also assessed and a comment section was provided o LFTU questionnaire and IES-R were mailed to participants to complete and mail back o Participants were contacted to schedule CAPS administration either in person or via telephone

The same independent rater who administered the CAPS in the previous study was used

To assess long-term PTSD symptom improvement, post-treatment outcome scores at the 2-month follow-up were compared to LTFU scores obtained in present study

STATISTICAL ANALYSES:

t tests were used for the continuous global scores

Mann-Whitney U tests were used for ordinal outcomes

Descriptive statistics were used for questionnaire-based measurements

RESULTS:

LTFU ranged from 17-74 months o Mean (std) = 45.4 (17.3) months

Twenty completed LTFU questionnaire

Seventeen completed CAPS and IES-R o One patient excluded from data analysis because they did not receive MDMA in original trial o One patient lost to follow-up after LTFU questionnaire due to relocation o Two patients refused to complete

Table 11:

Outcomes Scores p

CAPS mean scores (std) n = 16

2-month 24.6 (18.6) 0.91

LTFU 23.7 (22.8)

IES-R mean scores (std) n = 16

2-month 19.8 (19.5) 0.72

LTFU 22.1 (21.8)

At LTFU, 2 patients had CAPS scores above 50 (13%), which indicates relapse with moderate-to-severe PTSD symptoms

Using an intent-to-treat analysis, the 3 patients who did not complete the CAPS were treated as negative outcomes, as were the 2 patients who relapsed, therefore, 5/19 (26%) patients had negative outcomes

If based on those patients who received MDMA and completed the CAPS, 2/16 (13%) had negative outcomes

One patient who had a strong sustained response was excluded from data analysis because they only ever received placebo-assisted psychotherapy

o CAPS: 2-month = 14, LTFU = 16 o IES-R: 2-month = 5, LTFU = 15

Subgroup analysis: completed for patients who were included in the protocol amendment and received a third MDMA-assisted psychotherapy session

o n = 8 o No statistical difference in outcomes compared to patients who had 2 MDMA-assisted sessions

Difference in CAPS: p = 0.83 Difference in IES-R: p = 0.48

o Therefore, LFTU scores were compared to the outcomes from the endpoint of the pre-amendment protocol

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Psychotherapy: participation at original study enrollment was 16/19 (84%); at LTFU it was 8/19 (42%) o Only 1 patient who had not been in psychotherapy at enrollment was attending at LTFU

Psychiatric medications: o Number of patients on psychiatric medications unchanged from baseline: 12/19 (58%) o Mean number of medicines taken decreased from 1.7 1.3

Illicit drug use: 1 patient took “ecstasy” in an attempt to re-create experimental session but found the effects “unsatisfactory”

o No other new onset illicit drug use based on participant report

Other outcomes: o There was not any perceived harm from the study based on participant questionnaire completion and all

subjects reported benefit from the study o All participants felt that additional MDMA-assisted sessions would have been beneficial o No reports of worsened or decreased cognition

AUTHORS’ CONCLUSION: “These results indicate that there was a favorable long-term risk/benefit ratio for PTSD treatment with just a few doses of pure MDMA administered in a supportive setting, in conjunction with psychotherapy.” REVIEWER’S OPINION: Table 12:

STRENGTHS LIMITATIONS

Length of follow-up Small sample size

Reported intent-to-treat analysis Use of questionnaire that was not validated

A randomized, controlled pilot study of MDMA-assisted psychotherapy for treatment resistant, chronic post-traumatic stress disorder (PTSD)17

STUDY OBJECTIVE: Examine the safety and efficacy of MDMA-assisted psychotherapy for treatment resistant PTSD in an outpatient setting

STUDY DESIGN: Randomized, double-blind, active-placebo, controlled study

STUDY SUBJECTS:

Inclusion Criteria: Diagnosis of PTSD according to DSM-IV-TR criteria, with treatment resistant symptoms defined as CAPS > 50 after > 3 months of SSRI or SNRI, in addition to, > 6 months of psychotherapy

Exclusion Criteria: Any significant medical condition, except hypothyroidism under hormonal replacement; history of psychotic illness, bipolar disorder type 1, borderline personality disorder, dissociative identity disorder, and substance abuse or dependence < 60 days of enrollment; MDMA use on > 5 occasions or < 6 months prior to enrollment

PRIMARY OUTCOME: Difference in PTSD symptoms according to a validated German version of the CAPS and the self-reported Posttraumatic Diagnostic Scale (PDS)

SECONDARY OUTCOME(S):

Safety assessed by recording physiological data such as blood pressure, heart rate, and temperature

Degree of psychological distress measured using a 1-item visual analog scale, the Subjective Units of Distress

METHODS:

Prospective participants screened for inclusion and exclusion criteria via telephone o If the patient met inclusion criteria, an informational meeting with the investigator, including

administration of the CAPS, was completed

Written informed consent of all participants was obtained

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Stage 1: 3 experimental sessions and 12 non-drug therapy sessions were conducted o Patients randomized to full dose MDMA received 125 mg followed 2.5 hours later by 62.5 mg o Patients randomized to active placebo received 25 mg followed 2.5 hours later by 12.5 mg MDMA

Stage 2: patients from active placebo group had option to enter open-label arm and complete 3 full dose MDMA sessions and 12 non-drug sessions

Stage 3: patients from full dose group had option to receive 2 additional high dose MDMA sessions and 7 non-drug sessions

o 150 mg followed 2.5 hours later by 75 mg MDMA o Open-label arm

Psychotherapy: followed MDMA-assisted psychotherapy manual from Mithoefer et al. o Two preparatory sessions to establish therapeutic alliance and prepare subjects for experience and

possible emotions were conducted before first MDMA session o Before all MDMA sessions, patients completed testing for drugs of abuse and pregnancy o One male and one female therapist were present for the entire session o MDMA sessions lasted approximately 8 hours o Patient stayed overnight in the clinic with a support person on the day of MDMA sessions o A non-drug session took place the morning after the MDMA session, followed by 2 sessions that were 1

week apart to help integrate the experiences from the MDMA session o For one week following each MDMA session, patients were contacted daily via telephone

Assessments: o CAPS completed at:

T0: < 4 weeks before MDMA session and after discontinuation of psychotropic medications T1: 3 weeks post MDMA session 2 T2: 3 weeks post MDMA session 3 T3: 2 months after MDMA session 3 T4: 6 months after MDMA session 3 T5: 12 months after MDMA session 3

o PDS completed at T0, T2, T3, T4, and T5 o Clinical response not clearly defined; however, insufficient clinical response defined as: investigator and

patient believed there was a lack of improvement, CAPS score changes at T3 < 15 points, and CAPS item #25 > 3 and overall score still > 50 points at T3

STATISTICAL ANALYSES:

CAPS and PDS scores were analyzed by ANOVA

Wilcoxon-Signed-Rank-Test for paired data was used to analyze whether a third MDMA session improved CAPS scores compared to only two MDMA sessions

Confidence interval of 95% used

Results were considered significant when p < 0.05

RESULTS:

Thirty patient were assessed for eligibility o Sixteen were excluded: 11 did not meet inclusion criteria, 5 declined to participate o Fourteen patients randomized

Nine patients randomized to full dose MDMA

Eight received allocated interventions, 1 patient withdrew after first MDMA session o Three elected to enter Stage 3 open-label arm

Seven completed follow-up analysis, 1 patient who passed away was lost to follow-up Five patients were randomized to active placebo

Four received allocated interventions, 1 patient withdrew after first MDMA session o Four elected to enter stage 2 open-label arm

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Table 13:

Participant Characteristics Full Dose MDMA (n=8) Active Placebo (n=4) Mean age (std) 42.1 (12.8) 40 (6.2)

Female 7 (87%) 3 (75%)

Hx alcohol abuse/dependency 1 (13%) 0 (0%)

Hx cannabis substance abuse/dependency 1 (13%) 1 (25%)

Prior MDMA use (# of subjects) 0 1 (3 occasions)

Mean # years duration of PTSD (std) 16.4 (10.9) 22.3 (12.1)

Mean # months of prior therapy (std) 39.9 (73.3) 123 (60.6)

Comorbid Disorder

Depressive Disorders 8 (100%) 3 (75%)

Anxiety Disorders 0 (0%) 1 (25%)

Feeding and Eating Disorders 1 (13%) 0 (0%)

Index Trauma

Sexual assault or childhood sexual abuse 5 (63%) 2 (50%)

Medical treatment or illness 2 (25%) 1 (25%)

Accident 1 (13%) 1 (25%)

Medication for PTSD at enrollment 4 (50%) 2 (50%)

Table 14:

Primary Outcomes Full Dose MDMA (n=8) Active Placebo (n=4) CAPS Mean Total Scores (std)

T0 66.4 (13.6) 63.4 (7.9)

T1 63.0 (17.8) 60.0 (6.8)

T2 50.8 (19.7) 66.5 (7.6)

PDS Mean Scores (std)

T0 30 (6.3) 23.5 (1.9)

T2 21.4 (11.9) 30.8 (6.2)

Clinical response: o Stage 1:

Full dose:

Four of eight patients met study criteria for a clinical response o These 4 patients still met PTSD criteria but showed a reduction in severity from

severe to moderate (CAPS 40-59, n=1) or mild (CAPS 20-39, n=3)

Three of eight considered non-responders and were enrolled in Stage 3 Active placebo: 0/4 patients had a clinical response

o Stage 2: 4/4 patients who were in the crossover group responded to treatment Two of four no longer met PTSD criteria Two of four improved to moderate PTSD

o Stage 3: no additional improvement observed in Stage 3

Long-term follow-up: o Full dose: CAPS scores had decreased by a mean of 24 points (35%) from baseline o Crossover group: CAPS scores had decreased by a mean of 35 points (52%) from baseline o Nine of twelve (75%) total patients met criteria for significant clinical improvement o Five of twelve (42%) total patients no longer met criteria for PTSD, 2/12 had mild PTSD, 4/12 had

moderate PTSD o One of twelve (8%) patients unavailable for analysis for reason not related to study

Quantity of MDMA sessions: 3 MDMA sessions were more effective than only 2 sessions (p = 0.016)

Physiologic: increases from baseline to the maximally-observed value for systolic and diastolic blood pressure, pulse, and temperature were not significantly higher in the full dose than the active placebo group

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Safety: no serious adverse reactions or events requiring medical intervention during or following MDMA sessions

o Commonly reported reactions: moderate insomnia, loss of appetite, and restlessness in full dose and headache, moderate insomnia, and loss of appetite in active placebo

All reactions were self-limiting

Rescue medications: o Zolpidem for insomnia used on 1 occasion o Lorazepam for anxiety administered to 6/9 (66%) patients in full or high dose groups after 10/56 (18%)

sessions; administered to 2/5 patients in active placebo group

Additional integration sessions: 21 sessions in 8/13 patients in full dose group, 4 sessions in 2/5 patients active placebo group

Evaluation of blinding: o Full dose: 24 total guesses, 16 correct (66%), and 8 incorrect (34%) o Active placebo: 13 total guesses, 6 correct (46%), and 7 incorrect (54%)

AUTHORS’ CONCLUSION: “MDMA-assisted psychotherapy was safely administered, with no drug-related serious adverse events, in a small sample of treatment resistant patients who were suffering from chronic PTSD; however, the approach did not produce significant symptom reductions. Further research into MDMA-assisted psychotherapy is warranted.”

REVIEWER’S OPINION Table 15:

STRENGTHS LIMITATIONS

Active placebo to ensure blinding Small sample size

Used same therapy manual as Mithoefer trial Lacks external validity

No other psychotropic medications permitted Interpretation of change in CAPS score

Summary MDMA Research in Progress17

Randomized, triple-blind study comparing 3 different doses of MDMA in conjunction with psychotherapy in 24 veterans with chronic PTSD o Seeking equal numbers of male and female participants o Three doses to assess if successful blind o Assess if appropriate for war-related PTSD

Use of 1 additional MDMA-assisted session after relapse from a previous study o Goal: participants free of PTSD diagnosis

Conclusion MDMA-assisted psychotherapy not recommended at this time due to:

o Limited evidence to support its use o Difficulty obtaining medication o Small and narrow patient population

Ideal Study o Diverse patient population o Compare to current recommended pharmacotherapy o Regular toxicology screens

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References: 1.) Vieweg WV, Julius DA, Fernandez A, Beatty-Brooks M, Hettema JM, Pandurangi AK. Posttraumatic stress

disorder: clinical features, pathophysiology, and treatment. Am J Med. 2006 May;119(5):383-390. 2.) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fourth edition. Text

Revision. Washington, DC: American Psychiatric Association, 2000. 3.) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth edition.

Washington, DC: American Psychiatric Publishing, 2013. 4.) Gradus, Jaimie. Epidemiology of PTSD. National Center for PTSD. United States Department of Veterans Affairs,

20 Dec 2011. Accessed 20 Aug 2013. <http://www.ptsd.va.gov/professional/pages/epidemiological-facts-ptsd.asp>.

5.) Tanielian T. & Jaycox L. Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery. Santa Monica, CA: RAND Corporation. 2008. http://www.rand.org/content/dam/rand/pubs/monographs/2008/RAND_MG720.pdf

6.) Kessler RC, Berglund P, Delmer O, Jin R, Merikangas KR, & Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Archives of General Psychiatry. 2005;62(6): 593-602.

7.) Kulka RA, Schlenger WA, Fairbanks JA, Hough RL, Jordan BK, Marmar CR, et al. Trauma and the Vietnam War generation: Report of findings from the National Vietnam Veterans Readjustment Study. New York: Brunner/Mazel. 1990.

8.) DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. Eighth edition. New York, NY:McGraw-Hill; 2011.

9.) The Management of Post-Traumatic Stress Working Group. VA/DoD Clinical Practice Guidelines for Management of Post-Traumatic Stress. Department of Veterans Affairs, Department of Defense. Oct 2010.

10.) Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of MDMA-assisted psychotherapy in subjects with chronic, treatment-resistant PTSD: the first randomized controlled pilot study. J Psychopharmacol. 2011;25(4):439-452.

11.) Ecstasy (MDMA). Dartmouth: Health Promotion. http://www.dartmouth.edu/~healthed/groups/dapa/otherdrugs/mdma.html. Updated Jan 1, 2009. Accessed Sept 15, 2013.

12.) Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA-assisted psychotherapy for treatment resistant, chronic PTSD. J Psychopharmaco .2013;27:40-52.

13.) DrugFacts: MDMA (Ecstacy or Molly). National Institute on Drug Abuse. http://www.drugabuse.gov/publications/drugfacts/mdma-ecstasy-or-molly. Updated Sept 2013. Accessed Sept 15, 2013.

14.) Drugs and Human Performance Fact Sheets: Methylenedioxymethamphetamine (MDMA, Ecstasy). National Highway Traffic Safety Administration. http://www.nhtsa.gov/people/injury/research/job185drugs/methylenedioxymethamphetamine.html. Accessed Sept 15, 2013.

15.) Bouso JC, Doblin E, Farre M, Alcazar MA, Gomez-Jarabo G. MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. J Psychoactive Drugs. 2008 Sep;40(3):225-36.

16.) Mithoefer MC, Wagner MT, Mithoefer AT, et al. Durability of improvement in PTSD symptoms and absence of harmful effects or drug dependency after MDMA: a prospective long-term follow-up study. J Psychopharmacol. 2013;27(1):28-39.

17.) Research: MDMA-Assisted Psychotherapy. Multidisciplinary Association for Psychedelic Studies (MAPS). http://www.maps.org/research/mdma/. Updated 2013. Accessed Sept 15, 2013.

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Appendix A: PTSD Guidelines Guideline First-line Second-line Third-line Other

American Psychiatric Association (2004) Guideline Watch (2009)*

-Psychotherapy -SSRI: fluoxetine, paroxetine, sertraline -SNRI: venlafaxine* -Adrenergic: prazosin* (combat-related PTSD)

-TCAs: imipramine, amitriptyline, desipramine -Nefazodone -Mirtazapine

-SGAs: risperidone, olanzapine -Tiagabine, divalproex, carbamazepine, lamotrigine

British Association for Psychopharmacology (2005)

-Trauma-focused CBT and EMDR -SSRIs: fluoxetine, paroxetine, sertraline -SNRI: venlafaxine

-TCAs: amitriptyline, imipramine

-Phenelzine -Mirtazapine, lamotrigine -Augmentation with SGA, combination of evidence-based treatments

Canadian Psychiatric Association (2006)

-SSRI: fluoxetine, paroxetine, sertraline -SNRI: venlafaxine XR

-Fluvoxamine, mirtazapine, phenelzine -Adjunctive: risperidone, olanzapine

-Amitriptyline, imipramine, escitalopram -Adjunctive: carbamazepine, gabapentin, lamotrigine, valproate, tiagabine, topiramate, quetiapine, clonidine, trazodone, buspirone, bupropion, prazosin

-Citalopram, fluphenazine, naltrexone

International Psychopharmacology Algorithm Project (IPAP) (2005)

-Psychosocial therapy -SSRI: fluoxetine, paroxetine, sertraline -SNRI: venlafaxine -Mirtazapine

-If SSRI/SNRI not available: imipramine or amitriptyline

-Augmentation with: prazosin, trazodone, nefazodone, imipramine, or amitriptyline

-Augmentation with anticonvulsants, clonidine, guanfacine, propranolol, SGA -Phenelzine

National Institute for Health and Clinical Excellence (2011)

-Trauma-focused psychotherapy

-Paroxetine or mirtazapine may be used in general practice

-Amitriptyline or phenelzine may be prescribed by mental health specialists

-Different class of antidepressant or adjunctive olanzapine

Veterans Association/ Department of Defense (2010)

-Trauma-focused therapy or stress management and/or pharmacotherapy with SSRI or SNRI

-Switch to different antidepressant class and/or psychotherapy if no reponse -Adjunctive prazosin, mirtazapine or add SGA

-TCA, nefazodone, phenelzine -Buspirone, trazodone, gabapentin, lamotrigine

World Federation of Societies of Biological Psychiatry – First Revision (2008)

-SSRI: fluoxetine, paroxetine, sertraline -SNRI: venlafaxine

-Amitriptyline, imipramine, mirtazapine, risperidone, lamotrigine

-Adjunctive olanzapine or risperidone

-Citalopram, escitalopram, fluvoxamine, quetiapine, phenytoin, carbamazepine, gabapentin, topiramate, memantine -Adjunctive T3 to an SSRI, imipramine + clonidine

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Appendix B: PTSD Rating Scales Name Purpose Clinician or Self Rated Values and Interpretations

Clinician Administered PTSD Scale (CAPS)

-Gold-standard -Diagnose -Can be used clinically or for research purposes

Clinician -30-item, structured interview that corresponds to the DSM-IV criteria -Assesses 17 PTSD symptoms as well as their impact on social and occupational functioning, improvement in symptoms, overall PTSD severity, and frequency and intensity of 5 associated symptoms (guilt over acts, survivor guilt, gaps in awareness, depersonalization, and derealization) -Scoring: symptom considered present if frequency > 1 and intensity > 2; diagnosis if > 1 “B” symptom, > 3 “C” symptoms, and > 2 “D” symptoms, as well as meeting other diagnostic criteria; severity scores calculated by summing frequency and intensity ratings for each symptom. -Response: Remission = 70% reduction in symptoms and maintained for 3 months; Adequate response = > 50% reduction in symptoms; Partial response = 25-50% reduction in symptoms; Non-response = < 25% reduction in symptoms

Impact of Event Scale – Revised (IES-R)

-Assess subjective distress caused by traumatic events -Evaluation of recovery and measure response to traumatic event

Self -22-items that relate directly to 14/17 DSM-IV PTSD symptoms, 7 extra items related to hyperarousal -Specific event is identified and patients respond how much that event has impacted them over that past 7 days for each “difficulty” listed -Scoring: items rated from 0 (not at all) to 4 (extremely); total scores from 0-88 possible; subscales can be calculated for intrusion, avoidance, and hyperarousal

Post-Traumatic Stress Diagnostic Scale (PDS)

-Diagnose and evaluate symptoms of PTSD -Determine level of impairment associated with PTSD

Self -49-items organized into 4 sections -Section 1: lists different types of trauma for responder to indicate which they have witnessed or experienced -Section 2: subject describes traumatic event that is most troubling to them -Section 3: assess the 17 PTSD symptoms and criteria outlined in DSM-IV -Section 4: rates the interference caused by the different symptoms in areas including work, relationships, and family -Scoring: assign items in Section 3 values from 0-3 based on how often each symptom has bothered them in past 7 days; total scores range from 0-51

PTSD Symptom Scale (PSS)

-Assess the presence and severity of PTSD symptoms

Either -17-item scale based on DSM-IV PTSD symptoms (5 items related to re-experiencing, 7 for avoidance, and 5 for increased arousal) related to a single identified traumatic event in individuals with a known trauma history -Scoring: items rated 0 (not at all) to 3 (5 or more times per week/very much) based on how often the symptoms have occurred in the last 2 weeks; total score possible 0-51 -Score > 13 indicates likely PTSD