MDMA-assisted therapy for Post-Traumatic Stress Disorder ...sites.utexas.edu/.../04/MDMA-for-PTSD-Handout-Final...1. Discuss an overview of PTSD along with the theorized pathophysiology

MDMA-assisted therapy for Post-Traumatic Stress Disorder: Can we tame fear with ecstasy?

Image available at: https://thrivetreatment.com/

Shelby Ramion, PharmD

PGY2 Psychiatry Pharmacy Resident

South Texas Veterans Health Care System

University of Texas at Austin College of Pharmacy

UT Health Science Center San Antonio

May 1, 2020

Learning Objectives:

1. Discuss an overview of PTSD along with the theorized pathophysiology and etiology2. Compare the mechanism of action and side effect profile of MDMA to current treatment options for PTSD3. Assess the safety and efficacy of MDMA-assisted psychotherapy for PTSD according to recent literature

2

Background

Post-Traumatic Stress Disorder (PTSD)

I. Epidemiology1-3

• Lifetime prevalence – 4% (globally), 8% (US)

• Higher prevalence in women until age 40 to 50

• Prevalence highest in men and women among ages 18 to 24

• Most commonly reported traumatic events associated with PTSD:

o Physical or sexual assault (~45%)

o Death of family/close friend due to violence/accident/disaster (~30%)

o Natural disaster/accident/fire (~12%)

o Organized violence (e.g. combat exposure) (~11%)

II. Diagnostic Criteria and Presentation4,5

• Previously included under “Anxiety and Related Disorders” in the DSM-IV → now under “Trauma- and Stressor-Related Disorders” in the DSM-V (See Appendix 1)

• Characterized by presence of four symptom domains following exposure to a traumatic event

Figure 1. PTSD Symptom Domains

• Exposure may be directly experienced, witnessed, or through indirect discovery of the event

• One-third of patients will develop chronic unremitting symptoms

• Women less likely to recover

• Common comorbidities/conditions:

o Depression (80%)

o Alcohol or substance use disorders (50%)

o Suicide attempt (20%)

• Rating scales (See Appendix 2)

o Clinician Administered PTSD Scale (CAPS)

o PTSD Checklist (PCL)

III. Etiology5,6

• Cause unknown

• Potential genetic role (CRF stem gene and endocannabinoid system variations)

Intrusive Symptoms

Avoidance

Negative Alterations in

Mood or Cognition

Reactivity and Arousal

3

Figure 2. Risk factors for PTSD development

IV. Pathophysiology6-8

Table 1. Pathophysiological Changes in PTSD

Key Function Effect in PTSD Result

Brain Structures

Locus coeruleus • Attention to external stimuli (i.e. threat assessment)

• Response to stress and panic

Hyperactivity • Impaired fear appraisal (i.e. heightened sense of danger)

• Hyperarousal/Hyperreactivity

Prefrontal cortex • Execution and organization of complex behaviors and cognition (e.g. speech, working memory, emotional behavior, logical reasoning)

• Attention shifting and information filtering

• Fear extinction

• Interpretation of sensory perception

Decreased activity • Hyperarousal/Hypervigilance

• Negative mood, thoughts

• Avoidance behaviors

• Flashbacks

Limbic system (e.g. amygdala, hypothalamus)

• Fear center, fight-or-flight

• Associates emotion with memories

• Produces autonomic response to cues and memories

Hyperactivity • Impaired fear conditioning (i.e. neutral cues evoke fear response)

• Increased blood pressure/heart rate with memories/cues

Hippocampus • Formation and retrieval of memories

Reduced volume • Increased numbing symptoms

• Event amnesia

Hormones and Neurotransmitter Systems

Norepinephrine • CNS stimulation

• Fear and stress response

Increased • Impaired fear conditioning and appraisal

• Sleep disturbances

Serotonin • Involved in memory/learning, emotional processing, behavioral regulation (e.g. sex, sleep, feeding, aggression)

• Regulates GABA, NE, DA, ACh, glutamate

Decreased 5HT1A and 5HT1B binding

• Increased re-experiencing (e.g. flashbacks)

• Increased numbing

• Increased anxiety/fear response

• Sleep disturbances

HPA axis • Stress response Dysregulated (Increased stress → increased CRF → increased cortisol)

• Uncontrolled catecholamine release

• Exaggerated “fight or flight response”

• Decreased ability to cope with stress

Pre-traumatic

•Past diagnosis or family history of psychiatric disorder

•Drug/alcohol abuse

•Female

•Lower socioeconomic status

•Low education level

•Minority race

•Previous trauma

•Job (e.g. military, first-responer)

Peritraumatic

•Severity of trauma

•Perceived threat to life

•Emotional response

•Dissociation

Post-traumatic

•Perceived lack of social support

•Dysfunctional pattern of social interation

•Subsequent life stresses

4

Hormones and Neurotransmitter Systems (continued)

Opioid System • Expression of stress-induced behaviors

• Motivation to escape threats

Increased signaling • Depressive and anxious behaviors

Endocannabinoids • Involved in mood, stress, anxiety, learning, memory, and fear extinction

Decreased • Negative mood, increased anxiety

• Poor fear extinction

Figure 3. Pathophysiology of Stress Response

Image available at: https://psychscenehub.com/wp-content/uploads/2017/11/HPA-Axis-in-PTSD.jpg

V. Treatment9-15

Table 2. PTSD Treatment Guideline Recommendations

VA/DoD Guidelines (2017) BAP Guidelines (2014) APA Guidelines (2009)

First-line Trauma-focused psychotherapy or stress management

Trauma-focused CBT and EMDR

Fluoxetine, paroxetine*, sertraline*, venlafaxine

Psychotherapy

Fluoxetine, paroxetine*, sertraline*, venlafaxine, prazosin (combat-related)

Second-line

Non-trauma-focused psychotherapy

Paroxetine*, sertraline*, fluoxetine, venlafaxine XR

Amitriptyline, imipramine Amitriptyline, imipramine, desipramine, nefazodone, mirtazapine

Third-line Imipramine, nefazodone, phenelzine

Phenelzine Risperidone, olanzapine

*FDA approved agents; CBT = Cognitive behavioral therapy; EMDR = Eye movement desensitization and reprocessing

• Other SSRIs may also be beneficial but have insufficient evidence for first-line treatment

• Generally no treatment differences between combat and non-combat-related trauma

5

Figure 4. Forms of psychotherapy for PTSD

• Key features of non-pharmacological therapy involve emotional processing, stress management, and fear extinction, and are generally clinician-driven

• Trauma-focused therapy

o Larger effect sizes than all pharmacotherapy alone (0.96 vs 0.44)

o Can be particularly distressing for patients → high rates of dropout (30-50%)

• Treatment resistance to first-line options, including psychotherapy, may be as high as 50%

• Combination treatment (i.e. pharmacological and psychotherapy) has not consistently shown significant benefit over trauma-focused therapy alone

3,4-methylenedioxymethamphetamine (MDMA)

I. History16,17

1912 Late 1970’s Early 1980’s 1985 2017 Present

• MDMA synthesized by Merck as intermediate for a drug to stop bleeding

• First studied for psychoactive properties in humans

• Found to have “an easily controlled altered state of consciousness with emotional and sensual overtones”

• 150+ therapists were using as adjunct to sessions

• Became popular as the recreational drug “ecstasy”

• DEA emergency schedules MDMA as Schedule I

• MDMA granted “Breakthrough Therapy Designation” for treatment of PTSD based on two phase two studies

• FDA approved protocol for Phase 3 trials

• MDMA approved for “Expanded Access” program allowing use in PTSD therapy for treatment-resistant patients unable to do Phase 3 trials

•Usually 12 sessions, 60 minutes

•Taught to identify and alter maladaptive or dysfunctional cognitions

•Used alone or in combination with other psychotherapies or medications

Cognitive Behavioral Therapy (CBT)

•Six to 12 sessions, 60-90 minutes

•Eight-stage treatment during which therapists move finger or object rhythmically from side to side while patients recall physical and emotional sensations of disturbing then pleasant events

•Effective for both civilian and combat-related PTSD

Eye Movement Desensitization and Reprocessing (EMDR)

•Eight to 15 sessions, 60-120 minutes

•Involves exposure to distressing trauma cues in and out of therapy while practicing anxiety management techniques to lessen importance

Exposure Therapy

•Eight to 15 sessions

•Develops patients stress management skills with breathing exercises, progressive muscle relaxation, and stress inoculation training

Anxiety Management

6

II. MDMA Pharmacology17-20

• Chemistry

o Synthetic ring-substituted phenethylamine structurally similar to amphetamines and mescaline

o Exists as free base and salts

o Salts are soluble and may be administered orally, intranasally, or intravenously

o S(+) and R(-) enantiomers

Figure 5. MDMA Chemical Structure

• Mechanism of Action

o Inhibits serotonergic, adrenergic, and dopaminergic transporter proteins preventing reuptake in the mesolimbic and mesocortical systems

o Agonist at serotonergic, adrenergic, dopaminergic, and histaminergic receptors

o Reverses intracellular vesicular monoamine transporters (VMAT) preventing repackaging of free monoamines → increased intracellular monoamine concentrations → increased efflux into synapse

o Highest affinity for serotonergic transporters and receptors

o Stimulates neurohormonal control of oxytocin, cortisol, prolactin, and vasopressin

o Decreases amygdala activity

Figure 6. MDMA Mechanism of Action

Serotonin

Increased extracellular 5HT>NE> DA

5HT, NE, and DA reuptake

inhibition

5HT2, α2, β1+2, H1, D1+2

receptor binding

VMAT reversal

7

• Pharmacokinetics

Table 3. Pharmacokinetics of MDMA

Absorption • Rapidly absorbed from GI tract

Distribution • Onset: 30 minutes

• CMax: 1-3 hours

Metabolism • Liver: CYP2D6

• Active metabolite (MDA)

• T1/2: 7-8 hours (MDA = 16-30 hours)

• Saturable metabolism (nonlinear PK)

Excretion • Feces (80%), urine (20%)

III. Effects on User18-20

• Classified as “entactogen” or “empathogen” → promotes empathy and compassion for self and others

• Acts as stimulant and psychedelic

• Used recreationally in “rave culture” due to increased energy and enhanced sensory perception (e.g. of music)

• Proposed to be beneficial in PTSD due to ability to revisit traumatic events without extreme negative emotional reaction and by increasing therapeutic alliance with therapist

Figure 7. Positive and Negative Effects of MDMA

IV. MDMA-assisted psychotherapy (MDMA-AP) manual

• Manual adapted from research on psychedelics prior to Schedule 1 classification

• Developed to standardize series of MAPS-sponsored clinical trials for FDA approval

• MDMA-AP consists of three stages: preparatory, experimental, and integrative sessions

Positive/Desired Effects

•Enhanced mood

•Increased energy

•Increased emotions, empathy

•Increased social interactions

•Increased sensory perception

•Decreased adverse reaction to social rejection

•Positive response to physical touch

•Increased tolerance of distressing memories

Negative Effects

•Acute:

•Depersonalization, dissociation, anxiety

•Hypertension

•Hyperthermia

•Increased oxidative stress

•Post-acute:

•Transient deficits in recall, working memory, selective attention, and associative memory

•Fatigue

•Depression

•Sleep disturbances

8

Figure 8. MDMA-AP Manual Protocol

V. Background Literature21-23

Table 4. Foundational Studies for MDMA-AP

Greer and Tolbert (1998) Bouso, et al. (2008) Mithoefer, et al. (2011)

Design • First quantifiable data obtained on MDMA-AP

• Descriptive report of screening tools and subjective reports

• Double-blind, placebo-controlled, ascending dose study

• Study was stopped before completion due to “political pressures”

• First completed randomized, placebo-controlled trial for MDMA-AP

Participants • N = 80

• Men, women, and couples with depression, anxiety, and/or trauma

• N = 6

• Women with sexual trauma-related PTSD

• N = 20

• Men and women with PTSD of any cause

Intervention • 50-150mg MDMA with 1-3 hours “inward reflection” and 2-3 hours non-directed therapy

• Home and office visits

• Single MDMA dose of 50mg (n = 3), 75mg (n = 1), or placebo (n = 2) with 6 psychotherapy sessions

• MDMA 125mg (n = 12) or placebo (n = 8)

• Followed MDMA-AP manual (two preparatory sessions, two experimental sessions, and three integrative sessions) for all subjects; CAPS-IV reduction as primary outcome

• Placebo group crossed over after two months to receive active treatment intervention

Efficacy • 90% reported “personally significant and generally positive and useful experiences” at two weeks and one-year follow up

• Found most useful in subjects with traumatic experiences

• Modest improvement in Severity of Symptoms Scale for PTSD, BDI, and HAM-D in treatment group

• Subject with 75mg dose achieved larger reductions in PTSD and depression symptoms

• Clinical response in 83.3% (10/12) in MDMA group versus 25% (2/8) in placebo group before crossover and 100% (19/19) after crossover

Safety • No safety data published • No serious adverse events

• No notable increases in blood pressure nor heart rate observed during or after MDMA session

• No serious adverse events

• Transient increases in blood pressure and heart rate during peak

Preparatory Sessions

•Three 90-min sessions

•Establish trust and therapeutic alliance with therapists

•Review anticipated effects, safety measures, and goals of therapy

Experimental Sessions

•Two to three monthly 8-hour sessions with two therapists, non-directive

•Music and eyeshades provided, comfortable living-room-like environment

•Subjects stay overnight in medical facility

Integrative Sessions

•Three weekly 90-minute sessions starting morning after each experimental session

•Aim to integrate material from experimental session

9

Clinical Question

Literature Review

I. Oehen, et al. (2013)24

Study 1. Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). J of Psychopharmacol 2013;27(1):40–52.

Objective To test the safety and efficacy of MDMA-assisted psychotherapy in patients with treatment-resistant PTSD

Methods

Design Randomized, double-blind, active control, dose-response, phase 2 trial at an outpatient psychiatric clinic in Switzerland

Sample Inclusion Criteria:

• Chronic PTSD (6+ months)

• 18 or older

• CAPS-IV score ≥50

• Failure to respond to or inability to tolerate previous SSRI (3 months) and psychotherapy (6 months)

Exclusion Criteria:

• Significant medical conditions excluding hypothyroidism

• Comorbid psychotic illness, BD Type I, BPD, dissociative identity disorder, and substance abuse or dependence within 60 days of enrollment

• Anyone who had taken MDMA on more than five occasions or less than 6 months prior to enrollment

• Recruited participants through referrals by mental health professionals and internet advertisements

• Required to taper and abstain from psychotropics (except gabapentin for pain) for at least 5 half-lives before study initiation; required negative UDS before each active session

• Could continue current outside psychotherapy as long as frequency did not change

Intervention Stage 1

• 25 mg (active control) or 125 mg MDMA (1:2) in three blinded, client-directed 8-hour sessions spaced 3 weeks apart

• Supplemental dose after 2.5 hours (50% of initial dose)

• 2 preparatory therapy sessions, 3 MDMA-AP sessions, and 3 integrative sessions (Manualized Approach) Stage 2

• 125mg treatment group non-responders had 2 additional open-label MDMA-AP sessions at 150mg with 75mg supplemental dose

• 25mg treatment group crossed-over to receive 1 preparatory therapy session and 3 open-label MDMA-AP sessions at 125mg with 3 integrative sessions after each

• 12 month follow up of all groups

Outcomes Primary Endpoint: mean change in CAPS-IV total score and PDS from baseline to 3 weeks and 2, 6, and 12 months after third experimental session Safety: Adverse events, blood pressure, heart rate, body temperature, distress

Statistical Analysis

• ANOVA with α=0.05 for primary endpoints; compared Stage 1 to Stage 2 results due to insufficient number of Stage 2 patients for formal analysis

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

• Peak vital signs averaged in Stage 1 and 2 and analyzed by calculating a nonparametric 95% confidence interval covering the true median of the differences pre- to post-session

Should MDMA be considered as a safe and effective adjunct to psychotherapy in patients with PTSD?

10

Results

Participants • 30 screened; 14 met eligibility criteria; 25mg (n=5), 125mg (n=9); 12 completed Stage 1 treatments; 7 completed Stage 2 treatments; 11 completed 12-month follow up

o Mean age 41; 10 Women (83%) o Adult or childhood sexual assault (68%); comorbid depression (83%) o Mean CAPS-IV score 64 (moderate)

• 2 participants previously used psychedelics (1 MDMA, 1 psilocybin)

Safety • Reactions reported by ⩾40% in any group within 7 days of MDMA sessions: anxiety, impaired balance, insomnia, and jaw clenching

• No serious adverse events deemed related to MDMA

• No significant increase in any physiological parameters

• 6/9 high dose and 2/5 low dose subjects required lorazepam 1mg and 1 extra psychotherapy session following 2nd integrative session

Endpoints

• Stage 1: No response in active placebo group (0/4); 3/8 non-responders in full dose group

• Stage 2 crossover group: 4/4 responded (2/4 remission)

• Stage 2 full dose group: No further reduction in CAPS with 2 high-dose sessions (0/3)

• 12 month follow up: Mean change in CAPS from baseline -24 points (35%) in full-dose group and -35 points (52%) in crossover group; 5/12 subjects met remission; 4/4 subjects on disability returned to full time employment

Conclusions

Discussion Strengths

• Standardized psychotherapy protocol (per treatment manual), mirrored realistic implementation

• Low attrition

• Active control (improved blinding)

• No placebo response

• Discontinued other psychotropics

Limitations

• Very small sample sizes

• Internet advertisement recruitment

• Generalizable only to females with comorbid depression

• Uneven dosing between cross-over groups (supplemental dosing)

• Other therapies started within 12 month follow up

• CAPS-IV instead of CAPS-V measurement

• Psychotropic washout only 5 half-lives

Author’s 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, to verify the results of the Mithoefer (2011) study.”

• Therapeutic alliance contributed to treatment outcomes; minimization of additional psychotherapy in future studies is warranted

Reviewer’s Conclusion

• Results show a meaningful but not statistically significant therapeutic response in treatment-resistant PTSD

• Sample size was too small to draw any clinical conclusions but provided proof of concept for larger future trials

• Although hemodynamic parameters remained safe and adverse effects were transient, high rates of anxiety during experimental sessions may limit use or contribute to dropout in the general population

11

II. Ot’alora, et al. (2018)25

Study 2. Ot’alora G M, Grigsby J, Poulter B, et al. 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: A randomized phase 2 controlled trial. J Psychopharmacol. 2018;32(12):1295–1307.

Objective To evaluate the safety and efficacy of MDMA as an adjunct to psychotherapy in participants with chronic PTSD

Methods

Design Randomized, double-blind, active control, dose-response, phase 2 trial at an outpatient psychiatric clinic in the US


• Chronic PTSD (6+ months)

• 18 or older


• Failure to respond to or inability to tolerate previous pharmacotherapy or psychotherapy

Exclusion Criteria:

• Pregnant or lactating women

• Women not using effective contraception


• Required to taper and abstain from psychotropics for at least 5 half-lives before study initiation;


• 40 mg (active control), 100 mg, or 125 mg MDMA (1:1:2) in two blinded, client-directed 8-hour sessions spaced 4 weeks apart

• Optional supplemental dose after 90 minutes (50% of initial dose)

• 3 preparatory therapy sessions before MDMA-AP sessions and 3 integrative sessions after each (Manualized Approach)

Stage 2

• 125mg and 100mg treatment groups had third open-label MDMA-assisted session

• 40mg treatment group crossed-over to receive 1 preparatory therapy session and 3 open-label MDMA-assisted sessions at 100-125mg with 3 integrative sessions after each


Outcomes Primary Endpoint: mean change in CAPS-IV total score from baseline to 1 month after second experimental session Secondary Endpoints: mean change in CAPS-IV from baseline 12 months after last experimental session, depression symptoms (BDI-II); sleep quality (PSQI); symptoms of dissociation (DES-II) Safety: Adverse events, blood pressure, heart rate, body temperature, suicidality during and after treatment

Statistical Analysis • Power calculations based on prior MDMA-assisted psychotherapy study with similar design; powered to detect only large effect sizes

• ANOVA with α=0.05 for primary endpoint; preplanned t-tests compared dose groups; secondary measures (BDI-II,PSQI, DES-II) were analyzed with the same method.

• Cohen’s d independent-groups pretest-posttest design used for comparator-subtracted effect size estimates

• Descriptive statistics (participants not meeting PTSD criteria on CAPS-IV and those attaining a ⩾30% decrease in scores post-treatment)

• Open-label crossover: within-subjects t-tests compared scores on all measures at one-month after two open-label sessions and of two vs three sessions

• Peak vital signs averaged in Stage 1 and analyzed by a one-way ANOVA with t-tests to comparing groups

Results

Participants • 49 screened; 28 met eligibility criteria; 40mg (n=6), 100mg (n=9), 125mg (n=13); 28 completed primary treatments through 1 month; 25 completed 12-month follow up

o Mean age 42; 19 Women (68%); 26 White (93%) o Pre-study meds: antidepressant (71.4%), anxiolytic (53.6%), antipsychotic (21.4%), sleep aid

(17.9%)

• Mean CAPS-IV score 87 (severe)

Safety • Reactions reported by ⩾40% in any group on day of MDMA sessions: anxiety and jaw clenching, headache, muscle tension, dizziness, fatigue, and low mood

• Most common reactions in 7 days following MDMA sessions: insomnia, low mood, increased irritability, and ruminations

12

• No serious adverse events deemed related to MDMA

• Suicidal ideation in 3/28 (10.7%) reported on the C-SSRS during study; none at 12 month follow up

• Small to moderate dose-related increases in blood pressure and heart rate, none requiring intervention

Endpoints

Table 1. Primary Endpoints

40mg Group (n=6)

100mg Group (n=9)

125mg Group (n=12)

Mean Baseline CAPS-IV 84.8 94.4 93.5

1 month after 2 MDMA sessions

Mean CAPS-IV 73.3 70.0 64.3

Change -11.5 (N/A) -24.4 (p=0.36) -26.3 (p=0.27)

# who no longer met CAPS-IV PTSD diagnostic criteria

2 (33.3%) 4 (44.4%) 5 (41.6%)

# who had ≥30% decrease in CAPS-IV 1 (16.7%) 5 (55.6%) 6 (50%)

Table 2. Secondary Measures

Total (n=26)

Mean Baseline CAPS-IV 92.0

12 month follow up

Mean CAPS-IV 31.0

Change -61.0 (p<0.0001)

# who met CAPS-IV PTSD diagnostic criteria 6 (24%)

• Scores on all other secondary measures (BDI-II, PSQI, DES-II) at 12-month follow-up showed statistically significant improvement compared with baseline

Conclusions

Discussion Strengths


• Low attrition


• Discontinued other psychotropics

• Inclusion of psychiatric disorders

Limitations

• Small sample sizes


• Generalizable only to white females with fewer psychotropics

• Uneven dosing between cross-over groups (supplemental dosing)


• Psychotropic washout only 5 half-lives


• The promising efficacy and safety results from this dose response study, along with findings from five other phase 2 trials form the basis for expansion into multi-site phase 3 trials


• Protocol and demographic consistent with Study #1; moderate efficacy comparable to psychotherapy alone

• Again too small to draw robust clinical conclusion warrants larger phase 3 trials to assess efficacy in different populations

• Dose related increases in blood pressure, although transient, may limit safety to those without cardiac abnormalities or uncontrolled blood pressure

13

III. Mithoefer, et al. (2018)26

Study 3 Mithoefer MC, Mithoefer AT, Feduccia AA, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018 Jun;5(6):486-497.

Objective To assess the efficacy and safety of MDMA-AP for treating chronic PTSD in military personnel and first responders

Methods

Design Randomized, double-blind, active control, dose-response, phase 2 trial at an outpatient psychiatric clinic in the US


• Veteran, firefighter, or police officer with chronic PTSD (6+ months) resulting from traumatic experience during their service

• 18 or older


• Failure to respond to or inability to tolerate previous pharmacotherapy or psychotherapy

Exclusion Criteria:

• Major medical conditions except controlled hypertension or adequately treated hypothyroidism

• Pregnant or lactating women

• Women not using effective contraception

• “… an additional exclusion criterion that cannot be revealed publicly until a future phase 3 trial is complete”


• Required to taper and abstain from psychotropics except sedative hypnotics and as needed anxiolytics

• Allowed for anxiety disorders; affective disorders, except bipolar disorder type 1; substance abuse or dependence in remission for 60 days or more; and eating disorders without active purging


• 30 mg (active control), 75 mg, or 125 mg MDMA (1:1:2) in two blinded, client-directed 8-hour sessions spaced 3–5 weeks apart

• Optional supplemental dose after 2 hours (50% of initial dose)

• 3 preparatory therapy sessions before MDMA-AP sessions and 3 integrative sessions after each Stage 2

• 125mg treatment group had third open-label MDMA-AP session

• 30mg and 75mg treatment groups crossed-over to receive 1 preparatory therapy session and 3 open-label MDMA-assisted sessions at 100-125mg with 3 integrative sessions after each


Outcomes Primary Endpoint: mean change in CAPS-IV total score from baseline to 1 month after second experimental session Secondary Endpoints: mean change in CAPS-IV from baseline 12 months after last experimental session, depression symptoms (BDI-II); sleep quality (PSQI); perceived growth following trauma (PTGI); personality factors (NEO-PI-R); symptoms of dissociation (DES-II); and general psychological function (GAF) Safety: Adverse events, blood pressure, heart rate, body temperature, suicidality during and after treatment

Statistical Analysis

• ANOVA efficacy analysis with preplanned t-tests to compare CAPS-IV change between dose groups

• Effect sizes calculated with Cohen’s d independent-groups pretest–post-test design

• Within-subject t tests for cross-over data (scores from end of Stage 1 to end of Stage 2) and 12-month follow up data (baseline to 12 months)

• Not designed to meet power

Results

14

Participants • 26 service personnel met eligibility criteria; 30mg (n=7), 75mg (n=7), 125mg (n=12); 24 completed treatments through 1 month; 24 completed 12-month follow up

o Veterans (n=22), Firefighters (n=3), Police officer (n=1) o Mean age 37; 19 Men (73%); 22 White (85%) o Pre-study meds: antidepressant (96%), anxiolytic (88%), antipsychotic (38%), sleep aid (50%)

• Mean CAPS-IV score 90 (severe)

Safety Adverse Effects:

• 1 serious event (worsening of baseline premature ventricular contractions) – did not require intervention

• Most common during MDMA session: Anxiety (81%), headache (69%), fatigue (62%), muscle tension (62%), reduced appetite (58%), sensitivity to cold (54%), and jaw clenching (50%)

• 125mg and 75mg doses significantly increased blood pressure and heart rate compared to 30mg dose

• No treatment-emergent reports of suicidal behavior

Endpoints

Table 1. Primary Endpoint

30mg Group (n=7)

75mg Group (n=7)

125mg Group (n=12)

Mean Baseline CAPS-IV 87.4 82.4 89.7

1 month after 2 MDMA sessions

Mean CAPS-IV 76.0 24.1 45.3

Change -11.4 (N/A) -58.3 (p=0.0005) -44.3 (p=0.004)

# who no longer met CAPS-IV PTSD diagnostic criteria

2 (28%) 6 (85%) 7 (58%)

# who had ≥30% decrease in CAPS-IV 2 (29%) 7 (100%) 8 (67%)

• No significant changes in CAPS-IV scores between 2nd and 3rd sessions

Table 2. Secondary Measures

Total (n=26)

Mean Baseline CAPS-IV 87.1

12 month follow up

Mean CAPS-IV 38.8

Change -48.3 (p<0.0001)

# who met CAPS-IV PTSD diagnostic criteria 8 (33%)

• Pooled scores on all secondary measures at 12-month follow-up showed statistically significant improvement compared with baseline except the NEO personality trait of conscientiousness

• BDI-II, PTGI, DES-II, and NEO-PI-R personality traits analysis failed to reach significance in cross-over group by third session

Conclusion

Discussion

Strengths

• Results consistent with cross-over


• Low attrition


• Inclusion of psychiatric disorders

Limitations

• Small sample sizes


• Generalizable only to white male combat veterans

• Uneven dosing between cross-over groups


• Allowed for sedative hypnotics and as needed anxiolytics


• Adequate doses of MDMA are needed for therapeutic effects in psychotherapy and may vary among patients

• “This trial provides further evidence that MDMA-assisted psychotherapy can be used safely and effectively for treating patients with chronic PTSD. This novel approach to pharmacotherapy offers a means to accelerate substantially the therapeutic process…”

• Effects of MDMA-assisted psychotherapy are sustained long-term

15


• Results inconsistent with Study #1 and #2 despite almost identical protocol; potentially due to smaller active control doses, male majority, and/or more pre-study psychotropic medications

• MDMA-assisted psychotherapy may be effective for chronic, treatment-resistant combat or job-related PTSD in willing patients when performed in a controlled environment according to the MDMA treatment manual but feasibility is limited by long sessions and overnight stays

• Transient hemodynamic effects warrant further research and may limit the use in patients with cardiac comorbidities

• Adverse effects were prominent although transient, expected, and not reported in long-term follow up suggesting acceptable tolerability; however may be too uncomfortable for many in general population

Table 5. Safety and Efficacy Summary of Literature Review

Oehen, et al. (2013) Ot’alora, et al. (2018) Mithoefer, et al. (2018)

Efficacy

Mean High Dose CAPS-IV Reduction -15.6 -26.3 -44.3

Blinded CAPS-IV Response Rates 50% 52% 79%

Safety

Serious Adverse Events 0 0 1

Treatment-Emergent Suicidality 0 0 0

Mean Peak Increase in SBP/DBP of High Dose Group 25.8/12.7 22.4/11.3 26.9/10.2

Mean Peak Increase in HR of High Dose Group 18.8 31.9 31.4

Mean Increase in Temperature of High Dose Group 0.9°C (1.7°F) 0.9°C (1.7°F) 0.7°C (1.3°F)

IV. Other considerations27

• A 2019 meta-analysis pooled data from all six MAPS-sponsored Phase 2 trials (4 currently published)

Table 6. Pooled CAPS-IV Data from MAPS-sponsored trials

MDMA 75-125mg groups (Active) N=72

MDMA 0-40mg groups (Control) N=31

Mean change in CAPS-IV -37.8 -11.6

Cohen’s d effect size 1.5 0.6

Dropouts, n (%) 5 of 74 (6.8%) 3 of 31 (9.7%)

Table 7. Pooled MAPS Trial Data Compared to Sertraline and Paroxetine Sertraline Paroxetine MDMA

Placebo-subtracted CAPS reduction (Effect size)

6.8-9.8 (0.31-0.37)

6-14 (0.09-0.56)

26.2 (0.9)

Dropout Rates (% active group)

28-29% (28%) 33-39% (11.7%) 7.6% (6.8%)

Long term efficacy Not studied past 12 weeks

Not studied past 12 weeks

67.8% of n=90 did not meet diagnostic criteria at 12 months

Gender differences

Statistically significant in women only

No observed differences between men and women

No observed differences between men and women

16

• Diversion/Addiction potential

o Eight of 90 participants in MDMA trials reported taking “ecstasy” one to three times between

experimental sessions and 12-month follow up → Relatively low abuse potential

o Administration in controlled, monitored setting prevents diversion

Conclusions, Recommendations, and Future Directions

I. Conclusions

II. Recommendations

• Patients with severe PTSD who do not respond to at least two pharmacotherapy agents and one form of trauma-focused therapy should be considered for trials of MDMA-AP with doses of 100mg and two experimental sessions

• Patients with cardiovascular disease, uncontrolled blood pressure, or panic should not be considered for MDMA-AP

III. Future Directions

• Phase 3 trials (200-300 participants) began in late 2018, results not yet available

• Approval of Expanded Access Program indicates likely future approval

• Even with approval, wide-spread implementation unlikely due to many challenges including long duration of sessions, requirement of two opposite-sex therapists, and overnight stays in ACLS-capable facilities

• While overall response rates were only moderate when compared to trauma focused-therapy alone, they are clinically significant in the context of treatment-resistant PTSD

Efficacy

• High rates of anxiety and transient hemodynamic changes limit use in patients with panic and cardiovascular disease, respectfully

• No apparent increased risk of depression or suicide

Safety

• MDMA-AP is a relatively safe and effective option for severe, treatment resistant PTSD but poor tolerability and extensive session requirements may limit use

Overall

17

References:

1. Koenen KC, Ratanatharathorn A, Ng L, et al. Posttraumatic stress disorder in the World Mental Health Surveys. Psychol Med. 2017;47(13):2260–2274. doi:10.1017/S0033291717000708

2. Kessler RC, Rose S, Koenen KC, et al. How well can post-traumatic stress disorder be predicted from pre-trauma risk factors? An exploratory study in the WHO World Mental Health Surveys. World Psychiatry. 2014;13(3):265–274. doi:10.1002/wps.20150

3. Kilpatrick DG, Resnick HS, Milanak ME, Miller MW, Keyes KM, Friedman MJ. National estimates of exposure to traumatic events and PTSD prevalence using DSM-IV and DSM-5 criteria. J Trauma Stress. 2013;26(5):537–547. doi:10.1002/jts.21848

4. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 6. Abdallah CG, Southwick SM, Krystal JH. Neurobiology of posttraumatic stress disorder (PTSD): A path from novel pathophysiology to innovative

therapeutics. Neurosci Lett. 2017 May 10;649:130-132. doi: 10.1016/j.neulet.2017.04.046.

7. Dunlop BW, Wong A. The hypothalamic-pituitary-adrenal axis in PTSD: Pathophysiology and treatment interventions. Prog Neuropsychopharmacol Biol

Psychiatry. 2019 Mar 8;89:361-379. doi: 10.1016/j.pnpbp.2018.10.010.

8. Bailey CR, Cordell E, Sobin SM, Neumeister A. Recent progress in understanding the pathophysiology of post-traumatic stress disorder: implications for

targeted pharmacological treatment. CNS Drugs. 2013;27(3):221–232. doi:10.1007/s40263-013-0051-4

9. Veterans Health Administration, Department of Defense. VA/DoD clinical practice guideline for the management of post-traumatic stress. Washington

(DC): Veterans Health Administration, Departement of Defense, 2017. Available at:

https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal012418.pdf

10. Baldwin DS, Anderson IM, Nutt DJ, et al. Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-

compulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol. 2014;28(5):403-39. doi:

10.1177/0269881114525674.

11. American Psychiatric Association. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Arlington,

VA: American Psychiatric Association, 2009. Available at:

http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/acutestressdisorderptsd-

watch.pdfhttps://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/acutestressdisorderptsd-watch.pdf

12. Tsai, O. A literature review: the efficacy of MDMA-Assisted PTSD Psychotherapy. Simon Fraser Univ Sci Undergrad Res J. 2017;2:77–90.

13. Lee DJ, Schnitzlein CW, Wolf JP, Vythilingam M, Rasmusson AM, Hoge CW. Psychotherapy versus pharmacotherapy for posttraumatic stress disorder:

systemic review and meta-analyses to determine first-line treatments. Depress Anxiety. 2016; 33: 792–806.

14. Goetter EM, Bui E, Ojserkis RA, Zakarian RJ, Brendel RW, Simon NM. A systematic review of dropout from psychotherapy for posttraumatic stress disorder

among Iraq and Afghanistan combat veterans. J Trauma Stress. 2015; 28: 401–09.

15. Mott JM, Mondragon S, Hundt NE, Beason-Smith M, Grady RH, Teng EJ. Characteristics of US veterans who begin and complete prolonged exposure and

cognitive processing therapy for PTSD. J Trauma Stress. 2014; 27: 265–73.

16. Amoroso T. The Psychopharmacology of ±3,4 Methylenedioxymethamphetamine and its Role in the Treatment of Posttraumatic Stress Disorder. J

Psychoactive Drugs. 2015 Nov-Dec;47(5):337-44. doi: 10.1080/02791072.2015.1094156.

17. Schenk S, Newcombe D. Methylenedioxymethamphetamine (MDMA) in Psychiatry: Pros, Cons, and Suggestions. J of Clin Psychopharmacol. 2018;

38(6):632-638. doi: 10.1097/JCP.0000000000000962.

18. Mas M, Farré M, de la Torre R, Roset PN, Ortuño J, Segura J, Camí J. Cardiovascular and neuroendocrine effects and pharmacokinetics of 3, 4-

methylenedioxymethamphetamine in humans. J Pharmacol Exp Ther. 1999 Jul;290(1):136-45.

19. Mueller M, Peters FT, Maurer HH, McCann UD, Ricaurte GA. Nonlinear pharmacokinetics of (+/-)3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy")

and its major metabolites in squirrel monkeys at plasma concentrations of MDMA that develop after typical psychoactive doses. J Pharmacol Exp Ther.

2008 Oct;327(1):38-44. doi: 10.1124/jpet.108.141366.

20. Holze F, Vizeli P, Müller F, et al. Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects. Neuropsychopharmacol. 2020;45(3):462–

471. doi:10.1038/s41386-019-0569-3

21. Greer G, Tolbert, R. A method of conducting therapeutic sessions with MDMA. J Psychoactive Drugs 1998;30(4): 371-79.

22. Bouso JC, Doblin R, Farré M, Alcázar MA, Gómez-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.

23. Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted

psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J Psychopharmacol.

2011;25(4):439–452. doi:10.1177/0269881110378371.

24. Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA (±3,4-Methylenedioxymethamphetamine)-assisted

psychotherapy for treatment of resistant, chronic Post-Traumatic Stress Disorder (PTSD). J of Psychopharmacol. 2013;27(1):40–52.

25. Ot’alora G M, Grigsby J, Poulter B, et al. 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress

disorder: A randomized phase 2 controlled trial. J Psychopharmacol. 2018;32(12):1295–1307. Doi:10.1177/0269881118806297

26. Mithoefer MC, Mithoefer AT, Feduccia AA, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress

disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018

Jun;5(6):486-497. doi: 10.1016/S2215-0366(18)30135-4.

27. Feduccia AA, Jerome L, Yazar-Klosinski B, Emerson A, Mithoefer MC, Doblin R. Breakthrough for Trauma Treatment: Safety and Efficacy of MDMA-Assisted

Psychotherapy Compared to Paroxetine and Sertraline. Front Psychiatry. 2019;10:650. doi:10.3389/fpsyt.2019.00650

https://www.healthquality.va.gov/guidelines/MH/ptsd/VADoDPTSDCPGFinal012418.pdf

https://psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/acutestressdisorderptsd-watch.pdf

18

Appendix 1. DSM-V Diagnostic Criteria for PTSD

A. Exposure to actual or threatened death, serious injury, or sexual violence in one (or more) of the following ways: 1. Directly experiencing the traumatic event(s). 2. Witnessing, in person, the event(s) as it occurred to others. 3. Learning that the traumatic event(s) occurred to a close family member or close friend. In cases of actual or threatened

death of a family member or friend, the event(s) must have been violent or accidental. 4. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s) (e.g., first responders collecting

human remains; police officers repeatedly exposed to details of child abuse).

B. Presence of one (or more) of the following intrusion symptoms associated with the traumatic event(s), beginning after the traumatic event(s) occurred: 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s). 2. Recurrent distressing dreams in which the content and/or affect of the dream are related to the traumatic event(s). 3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event(s) were recurring. 4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect

of the traumatic event(s). 5. Marked physiological reactions to internal or external cues that symbolize or resemble an aspect of the traumatic

event(s).

C. Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the traumatic event(s) occurred, as evidenced by one or both of the following: 1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about or closely associated with the

traumatic event(s). 2. Avoidance of or efforts to avoid external reminders (people, places, conversations, activities, objects, situations) that

arouse distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s).

D. Negative alterations in cognitions and mood associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia and not to

other factors such as head injury, alcohol, or drugs). 2. Persistent and exaggerated negative beliefs or expectations about oneself, others, or the world (e.g., “I am bad,” “No

one can be trusted,” “The world is completely dangerous,” “My whole nervous system is permanently ruined”). 3. Persistent, distorted cognitions about the cause or consequences of the traumatic event(s) that lead the individual to

blame himself/herself or others. 4. Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame). 5. Markedly diminished interest or participation in significant activities. 6. Feelings of detachment or estrangement from others. 7. Persistent inability to experience positive emotions (e.g., inability to experience happiness, satisfaction, or loving

feelings).

E. Marked alterations in arousal and reactivity associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical aggression

toward people or objects. 2. Reckless or self-destructive behavior. 3. Hypervigilance. 4. Exaggerated startle response. 5. Problems with concentration. 6. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep).

F. Duration of the disturbance (Criteria B, C, D, and E) is more than 1 month. G. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of

functioning. H. The disturbance is not attributable to the physiological effects of a substance (e.g., medication, alcohol) or another medical

condition.

Specify whether “With dissociative symptoms”:

1. Depersonalization: Persistent or recurrent experiences of feeling detached from, and as if one were an outside observer of, one’s mental processes or body (e.g., feeling as though one were in a dream; feeling a sense of unreality of self or body or of time moving slowly).

2. Derealization: Persistent or recurrent experiences of unreality of surroundings (e.g., the world around the individual is experienced as unreal, dreamlike, distant, or distorted).

19

Appendix 2: CAPS-IV Rating Scale Description

General Gold standard for research

Questions correspond to DSM-IV criteria

Respondents endorse up to three traumatic events

Can be used to diagnose and assess impact on social and occupational functioning, symptom improvement, overall response, validity, severity, and frequency and intensity of symptoms

Items 30-item

Rater Clinician; requires training

Scoring Severity measured on 5-point scale for 22 items

Mild: 20-39

Moderate: 40-59

Severe: 60+

Remission: 70% reduction for 3 months

Adequate Response: ≥50% reduction

Partial Response: 25-50% reduction

Non-response: <25% reduction

Duration 45-60 minutes

Appendix 3. Abbreviations

5HT Serotonin

Ach Acetylcholine

BDI-II Beck Depression Inventory-II

CAPS Clinician administered PTSD scale

CRF Corticotropin Releasing Factor

DA Dopamine

DBP Diastolic Blood Pressure

DES-II Dissociative Experiences Scale II

DSM-IV/DSM-V Diagnostic and Statistical Manual of Mental Disorders (4th edition, 5th edition)

GABA Gamma aminobutyric acid

GAF Global Assessment of Functioning

HAM-D Hamilton Depression Scale

HPA (axis) Hypothalamic-Pituitary-Adrenal Axis

MAPS Multidisciplinary Association for Psychedelic Studies

MDA 3,4-methylenedioxyamphetamine

MDMA 3,4-methylenedioxymethamphetamine

MDMA-AP MDMA-assisted psychotherapy

NE Norepinephrine

NEO-PI-R Neuroticism-Extroversion-Openness-Personality Inventory-Revised

PDS PTSD Diagnostic Scale

PCL PTSD Checklist

PSQI Pittsburgh Sleep Quality Index

PTGI Post-Traumatic Growth Inventory

PTSD Post-traumatic Stress Disorder

SBP Systolic Blood Pressure

SSRI/SNRI Selective Serotonin/Norepinephrine Reuptake Inhibitor

Documents

MDMA-assisted therapy for Post-Traumatic Stress Disorder ...sites.utexas.edu/.../04/MDMA-for-PTSD-Handout-Final...1. Discuss an overview of PTSD along with the theorized pathophysiology