Overview of Evidence Base to

Assess PTSD Petition

April 10, 2015 - Scientific Advisory Council Meeting
Ken Gershman, MD,MPH
Medical Marijuana Research Grant Program Manger

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Outline

Board of Health regulations

Status of existing treatments for PTSD

Summary of evidence submitted with petition

Summary of efficacy of MJ for PTSD - lit. review

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Board of Health Regulations: 5 CCR 1006-2

Department Denial of Petitions:
6(D)(2): The Department shall deny a petition to add a debilitating
medical condition in all of the following circumstances:
(a) If there are no peer-reviewed published studies of randomized controlled
studies nor well-designed observational studies showing efficacy in humans
(b) if there are studies that show harm and there are alternative,
conventional treatments available for the condition;
(c) If the petition seeks the addition of an underlying condition for which the
associated symptoms are already listed as debilitating medical conditions for
which the use of medical marijuana is allowed, such as severe pain, are the
reason for which medical marijuana is requested
(d) If a majority of the ad hoc medical advisory panel recommends denial of the
petition

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Board of Health Regulations: 5 CCR 1006-2

Scientific Advisory Council (SAC)

The SAC will review petitions to add debilitating medical

conditions if the conditions for denial set forth in paragraphs
(2)(A), (B) and (C) of this section are not met.

Todays Purpose

The SAC shall review the petition information presented to the

department and any further medical research related to the
condition requested, and make recommendations to the executive
director . regarding the petition.

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QUESTION:
How effective are existing treatments for PTSD ?
(i.e., are there alternative conventional treatments available ?)

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Posttraumatic Stress Disorder (PTSD)

Diagnostic criteria (DSM-5) include history of exposure to traumatic

event and symptoms from each of 4 symptom clusters (below),
persisting >1 month with functional significance:

Intrusion (re-experiencing)

Avoidance

of trauma-related thoughts or feelings, or of external reminders

Negative changes in cognitions & mood

traumatic nightmares, flashbacks, intrusive memories

feelings of fear, guilt, shame; or loss of interest in activities

Hyperarousal & hyper-reactivity

sleep disturbance, irritable, aggressive, hypervigilant, difficulty

concentrating, exaggerated startle response

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Treatment of PTSD IOM Report, 2007

Institute of Medicine. Treatment of Posttraumatic Stress Disorder: An
Assessment of the Evidence. 2007

Commissioned by the VA to assess scientific evidence on treatment

modalities for PTSD

Identified 89 RCTs for review

IOM was not asked to develop clinical practice recommendations

published between 1980 and June 2007 in English

The IOM committee found the evidence inadequate to determine

efficacy of most treatment modalities (i.e., pharmacotherapies &
psychotherapies)

ONLY Exposure Therapy was found to have sufficient evidence of efficacy

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IOM Report 2007, Contd

Other Important Conclusions & Issues:

Assessing the outcomes of treatment depends entirely upon the self-report of

those affected without objective measures such as laboratory tests or imaging.

The committee was also struck by the scant evidence exploring some of the
possibly unique aspects of PTSD in veterans. For the most part we cannot say
whether the treatment of PTSD in veterans should be the same as in civilians

the committee found problems in the design and performance of studies

Lack of assessor blinding or independence, small sample size, lack of f/u for dropouts
High dropout rates & weak handling of missing data

the evidence fails to address the effects of high rates of comorbidity among
veterans with PTSD, especially major depression, traumatic brain injury, and
substance abuse.

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Treatment of PTSD Recent Meta-Analysis (1)

Watts BV, et al. Meta-Analysis of the Efficacy of Treatments for Posttraumatic Stress
Disorder. J Clin Psychiatry 2013;74(6): e541-50

Authors searched for RCTs of any treatment for PTSD in adults published
between January 1980 and April 1, 2012 in English

Final sample consisted of 137 Rx comparisons drawn from 112 studies

Effective psychotherapies included: cognitive therapy; exposure therapy;

eye movement desensitization & reprocessing

Effective pharmacotherapies included:

SSRIs: paroxetine, sertraline, fluoxetine

Risperidone (SGA), topiramate (anti-convulsant), and venlafaxine (SSNRI)

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Recent Meta-Analysis (2)

Pharmacotherapy: prior patient Rx and response appears important

e.g. risperidones larger effect size as monotherapy in contrast to add-on Rx

Psychotherapy: possibility of publication bias in published literature

For both Rx types, studies w/ more women & fewer vets had larger effects

Not possible to identify single best treatment

Ultimately, other factors, such as access, acceptability, and patient

preference, should exert strong and appropriate influence over the
choice of treatment.

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Example of Effective Treatment in Real World

Eftekhari A, et al. Effectiveness of National Implementation of Prolonged Exposure
Therapy in Veterans Affairs Care. JAMA Psychiatry 2013;70:949-955

The effectiveness of prolonged exposure therapy (PE) in the routine care

of male and female veterans with PTSD has yet to be conclusively
established.

VA Mental Health Services launched a national initiative w/ competencybased training to disseminate PE throughout VA in 2007:

Largest PE training program in the nation (> 1500 providers trained by 3/1/2012)

Includes systematic program evaluation primarily re: clinician training

Outcome data provided unique opportunity to assess real-world effectiveness

Data collected from 804 clinician trainees & 1931 patients w/ PTSD

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Effectiveness:National Implementation of PE (2)

Recommended that patients receive 8-15 sessions of PE (>8 = completer)

Outcomes measured by two self-reported (validated) symptom measures:

PTSD Checklist (PCL)

Beck Depression Inventory (BDI)

Results PTSD: all patient subgroups showed statistically & clinically

significant mean improvement in symptoms

62.4% had clinically significant improvement

But - 46.2% still had positive screening PCL scores at end of treatment
AND 28% dropped out of treatment before completing 8 sessions (mean = 3.6)
AND no follow-up to assess if improvement was maintained

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Treatment of PTSD-Related Nightmares & Insomnia (1)

Nappi CM, et al. Treating nightmares and insomnia in posttraumatic stress
disorder: A review of current evidence. Neuropharmacol 2012;62: 576-585

Disrupted sleep (nightmares & insomnia) is core component of PTSD

Linked to PTSD development and maintenance

May compromise response to evidence-based treatments of PTSD

Associated with significant distress, functional impairment & poor health

there have been relatively few studies to directly examine the impact
of a given intervention on sleep problems in PTSD, and even fewer that
have used validated measures of sleep. Thus, currently our arsenal is
quite limited when it comes to managing sleep disturbances in PTSD.

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Treatment of PTSD-Related Nightmares & Insomnia (2)

Nappi CM, et al.

Behavioral interventions: there remain more questions than answers.

In contrast to nightmares, insomnia appears to continue after evidence-based

treatments

Pharmacologic interventions: Overall, this review argues currently

employed medications have clinically significant limitations, from an
effectiveness perspective

Prazosin (alpha-1 adrenoreceptor antagonist) is most promising of pharmacologic

interventions especially for nightmares

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Treatment of PTSD-Related Nightmares & Insomnia (3)

Raskind MA, et al. A trial of prazosin for combat trauma PTSD with
nightmares in active-duty soldiers returned from Iraq and Afghanistan.
Am J Psychiatry 2013;170:1003-1010

RCT x 15 weeks in 67 (young) active duty soldiers w/ recalled distressing combatrelated nightmares

Standardized tools for primary outcome measures: CAPS; PSQI; CGI

Prazosin significantly better than placebo on all 3 primary measures

[combat-related trauma nightmares; sleep quality; global status]

Despite clinically meaningful effects ., the majority of soldiers continued

to experience substantial PTSD symptoms.

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ANSWER:
(to: How effective are existing treatments for PTSD ?)

The Management of Post-Traumatic Stress Working Group. VA/DoD Clinical

Practice Guideline for Management of Post-traumatic Stress. 2010
http://www.healthquality.va.gov/guidelines/MH/ptsd/cpg_PTSD-FULL201011612.pdf

[p. 9] All current treatments have limitations not all patients

respond to them, patients drop out of treatment, or providers are
not comfortable using a particular intervention.

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EFFICACY of Marijuana for PTSD:

Clinical Trials and Observational Studies
(review of published literature)

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States with PTSD as MMJ Qualifying Condition

Arizona
Connecticut
Delaware
Maine
Michigan
Nevada
New Mexico
Oregon

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Summary of Evidence Submitted With Petition

Part 1: Research Papers Supporting MJ to Treat PTSD Symptoms
[see handout]:
13 journal articles & 1 unpublished presentation

Unpublished open label, uncontrolled clinical trial of MJ for PTSD (Israel)

Open label clinical trial of nabilone for PTSD nightmares *
Observational study of New Mexico PTSD medical marijuana program patients *
3 clinical studies of other (pain) or related (emotional processing) conditions
2 review articles
6 pre-clinical (animal model) studies of fear extinction, fear memory, or stress

Assessment:

Clinical trial* and Obs study* included in Depts review of evidence (next)
Otherwise, non-contributory to adequately demonstrating clinical efficacy in
humans for PTSD

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Summary of Evidence Submitted With Petition

Part 2: Research Papers Supporting Use of MJ as Harm Reduction
[see handout]:

6 journal articles & 2 other types of articles

association between PTSD and receipt of opioids, hi-risk use, adverse outcomes

movement disorders from long-term use of antipsychotic drugs

review of antipsychotic drug-related weight gain & obesity
reviews (2) of pharmacotherapy for PTSD

epidemiologic analysis of national data on use of atytpical antipsychotic drugs

Ecologic analysis of national suicide data by state medical marijuana laws
Opinion piece on benefits of enacting state medical marijuana laws

Assessment: Non-contributory to demonstrating clinical efficacy in

humans for PTSD
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QUALITY of Evidence
Based on GRADE methodology & definitions:

System developed for clinical guideline development

Widely accepted in guideline writing community (internationally)

High Quality Evidence:

Moderate Quality Evidence

Systematic reviews (of one or more high quality RCTs)

Single RCTs w/ important limitations

Exceptionally strong observational studies

Low Quality Evidence

Observational studies & RCTs w/ serious limitations

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RCT of Nabilone for PTSD-associated Nightmares (1)

Jetly R, et al. Psychoneuroendocrinology (2015) 51, 585-588

RCT w/ crossover design for 2 x 7 weeks

10 Canadian male military personnel w/ PTSD and current distressing

nightmares (CAPS) & difficulty falling or staying asleep (CAPS)

Nabilone (synthetic THC analogue) started @ 0.5 mg; up to 3.0 mg max.

Outcomes assessed by:

CAPS Recurrent and Distressing Dream Item (frequency & intensity)

CAPS Difficulty Falling or Staying Asleep Item
Clinical Global Impression of Change (CGI-C)
PTSD Dream Rating Scale
General Well Being Questionnaire (WBQ)

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RCT of Nabilone for PTSD-associated Nightmares (2)

RESULTS [nabilone vs placebo]:

Significant reduction in CAPS Recurring and Distressing Dream scores

Significant improvement in Clinical Global Impression of Change scores

Significant improvement in General Well Being Questionnaire scores

NO observed effect on sleep quality and quantity

Nabilone was well-tolerated; no drop-outs

LIMITATIONS

Small size

Primary focus limited to nightmares

Use of THC analogue rather than cannabis

Males only

MODERATE Quality Evidence

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Open Label Clinical Trial of Nabilone for PTSDassociated Nightmares (1)

Fraser GA. CNS Neuroscience & Therapeutics (2009) 15, 84-88

Open label, uncontrolled clinical trial variable duration (months)

47 patients w/ PTSD and treatment-resistant nightmares

27 females & 20 males

Mixed types of trauma

Nabilone (synthetic THC analogue) started @ 0.5 mg (range 0.2 4.0 mg)

Outcomes assessed by:

Nightly tracking of nightmare presence/intensity and sleep quantity/quality

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Open Label Clinical Trial of Nabilone for PTSDassociated Nightmares (2)

RESULTS:

34 (72%) reported response

28 (60%) total cessation of nightmares

6 (13%)) satisfactory reduction in severity

Some reported improvement in sleep time

13 (28%) experienced mild-moderate side effects and stopped Nabilone

LIMITATIONS
No placebo control
Primary focus on nightmares only
Use of THC analogue rather than cannabis
No standardized or validated outcome measures
No reporting of results by gender or type of trauma
LOW Quality Evidence
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Open Label Clinical Trial of Add-on Oral THC for PTSD(1)

Roitman P, et al. Clin Drug Investig (2014) 34, 587-591

Open label, uncontrolled clinical trial x 3 weeks

To assess tolerance, safety, & preliminary clinical effects
10 patients w/ chronic PTSD on stable psychotropic meds

3 females & 7 males

Mixed types of trauma

THC in olive oil sublingually - started @ 2.5 mg bid; titrated to 5.0 mg bid
Outcomes assessed by:

Clinical measures: heart rate, BP, weight, BMI

Clinical Global Impression scale(CGI) - severity of illness & global improvement
Pittsburgh Sleep Quality Index (PSQI)
Nightmare Frequency Questionnaire (NFQ)
Nightmare Effects Survey (NES)

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Open Label Clinical Trial of Add-on Oral THC for PTSD(2)

RESULTS:

Systolic BP decreased mildly in week 1

Significant decrease in PTSD symptom severity:

hyperarousal, sleep quality, nightmare frequency, nightmare effects

4 reported mild side effects; none stopped treatment

LIMITATIONS

No placebo control

Small size w/ mixed gender & type of trauma

Use of THC alone, rather than cannabis

Short duration

LOW Quality Evidence

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Observational Study of Nabilone in Correctional

Population for PTSD and Other Indications(1)
Cameron C, et al. J Clin Psychopharmacol (2014) 34, 559-564

Observational (retrospective chart review) study

To determine indications, dosing & efficacy of nabilone usage

Nabilone was being used off-label for previous 4-5 years

104 Canadian male inmates w/ serious mental illness prescribed nabilone

Mean of 4.1 DSM-IV Axis I disorders
Approx. 90% w/ PTSD & Similar

Nabilone - started @ mean of 1.4 mg qd; titrated to mean of 4.0 mg qd

Mean treatment duration of 11.2 weeks

Mean # indications = 3.5 [most common: insomnia, nightmares, chronic pain]

Outcomes assessed by:

Self reported hours slept & nightmares

Posttraumatic Checklist-Civilian (PCL-C)& Global Assessment of Functioning (GAF)

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Observational Study of Nabilone in Correctional

Population for PTSD and Other Indications(2)
RESULTS:

Significant increase in hours slept & reduction in nightmare frequency

Significant decrease in PCL-C scores & increase in GAF scores

31 (30%) reported adverse effects; 10 (10%) stopped treatment

LIMITATIONS

No placebo control

Retrospective/observational design

Population w/ serious mental health co-morbidity

Use of THC analogue, rather than cannabis

No standardized tools used to assess sleep & nightmares

LOW Quality Evidence

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Observational Study of Medical Marijuana for PTSD (1)

Greer GR, et al. J Psychoactive Drugs (2014) 46, 73-77

Observational (retrospective chart review) study

80 applicants to New Mexico MMJ Program seeking physician approval

Screened for reporting significant relief of several major PTSD symptoms

when using cannabis

Single screening interview to collect selected CAPS criteria scores

retrospectively with and without cannanbis use

Outcomes assessed by:

Clinician Administered Posttraumatic Scale (CAPS) Criteria B,C, D

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Observational Study of Medical Marijuana for PTSD (2)

RESULTS:

Significant reduction in CAPS scores

LIMITATIONS

No placebo control

Retrospective/observational design

Extreme selection bias

only patients who reported benefit from cannabis in reducing their PTSD
were studied

Recall bias

Observer bias (author reported)

VERY LOW Quality Evidence

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Summary Regarding Evidence of Efficacy

There is some evidence, based on one small RCT and several

supportive lower quality studies, that THC/analogues are
effective in treating PTSD nightmares and possibly other PTSD
symptoms and/or overall well-being.

There are no published adequate quality clinical studies of cannabis

as treatment for PTSD.
(note: such studies havent been very possible to date in US)

This amount of evidence could be considered no worse than that

for several existing qualifying conditions in Colorados MMJ
program (especially, epilepsy & non-neuropathic/non-cancer pain).

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DISCUSSION

* PHOTO *

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