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Cannabidiol in the Treatment of Post-Traumatic Stress Disorder: A Case Series

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Objectives: Cannabidiol (CBD) is a non-psychotomimetic cannabinoid compound that is found in plants of the genus Cannabis. Preclinical research has suggested that CBD may have a beneficial effect in rodent models of post-traumatic stress disorder (PTSD). This effect is believed to be due to the action of CBD on the endocannabinoid system. CBD has seen a recent surge in research regarding its potential value in a number of neuro-psychiatric conditions. This is the first study to date examining the clinical benefit of CBD for patients with PTSD. Methods: This retrospective case series examines the effect of oral CBD administration on symptoms of PTSD in a series of 11 adult patients at an outpatient psychiatry clinic. CBD was given on an open-label, flexible dosing regimen to patients diagnosed with PTSD by a mental health professional. Patients also received routine psychiatric care, including concurrent treatment with psychiatric medications and psychotherapy. The length of the study was 8 weeks. PTSD symptom severity was assessed every 4 weeks by patient-completed PTSD Checklist for the DSM-5 (PCL-5) questionnaires. Results: From the total sample of 11 patients, 91% (n = 10) experienced a decrease in PTSD symptom severity, as evidenced by a lower PCL-5 score at 8 weeks than at their initial baseline. The mean total PCL-5 score decreased 28%, from a mean baseline score of 51.82 down to 37.14, after eight consecutive weeks of treatment with CBD. CBD was generally well tolerated, and no patients discontinued treatment due to side effects. Conclusions: Administration of oral CBD in addition to routine psychiatric care was associated with PTSD symptom reduction in adults with PTSD. CBD also appeared to offer relief in a subset of patients who reported frequent nightmares as a symptom of their PTSD. Additional clinical investigation, including double-blind, placebo-controlled trials, would be necessary to further substantiate the response to CBD that was observed in this study.
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Cannabidiol in the Treatment
of Post-Traumatic Stress Disorder:
A Case Series
Lucas Elms, BS,
1
Scott Shannon, MD, FAACAP,
2
Shannon Hughes, PhD,
3
and Nicole Lewis, ND
4
Abstract
Objectives: Cannabidiol (CBD) is a non-psychotomimetic cannabinoid compound that is found in plants of the
genus Cannabis. Preclinical research has suggested that CBD may have a beneficial effect in rodent models of
post-traumatic stress disorder (PTSD). This effect is believed to be due to the action of CBD on the en-
docannabinoid system. CBD has seen a recent surge in research regarding its potential value in a number of neuro-
psychiatric conditions. This is the first study to date examining the clinical benefit of CBD for patients with PTSD.
Methods: This retrospective case series examines the effect of oral CBD administration on symptoms of
PTSD in a series of 11 adult patients at an outpatient psychiatry clinic. CBD was given on an open-label,
flexible dosing regimen to patients diagnosed with PTSD by a mental health professional. Patients also received
routine psychiatric care, including concurrent treatment with psychiatric medications and psychotherapy. The
length of the study was 8 weeks. PTSD symptom severity was assessed every 4 weeks by patient-completed
PTSD Checklist for the DSM-5 (PCL-5) questionnaires.
Results: From the total sample of 11 patients, 91% (n=10) experienced a decrease in PTSD symptom severity,
as evidenced by a lower PCL-5 score at 8 weeks than at their initial baseline. The mean total PCL-5 score
decreased 28%, from a mean baseline score of 51.82 down to 37.14, after eight consecutive weeks of treatment
with CBD. CBD was generally well tolerated, and no patients discontinued treatment due to side effects.
Conclusions: Administration of oral CBD in addition to routine psychiatric care was associated with PTSD
symptom reduction in adults with PTSD. CBD also appeared to offer relief in a subset of patients who reported
frequent nightmares as a symptom of their PTSD. Additional clinical investigation, including double-blind, placebo-
controlled trials, would be necessary to further substantiate the response to CBD that was observed in this study.
Keywords: cannabidiol, cannabis, post-traumatic stress disorder, PTSD, anxiety, nightmares
Introduction
Post-traumatic stress disorder (PTSD) is a relatively
common psychiatric condition with a lifetime prevalence of
6.1% in the United States.
1
PTSD often presents in clusters of
symptoms, including the re-experiencing of traumatic events
through intrusive memories and nightmares, avoidance of cer-
tain distressing factors, and alterations in mood, level of arousal,
and cognition. Psychotherapy is the established first-line treat-
ment for PTSD, and various psychiatric medications are also
1
Rocky Vista University, Osteopathic Medical Student IV, Parker, CO.
2
Department of Psychiatry, University of Colorado Denver, Denver, CO.
3
School of Social Work, Colorado State University College of Health and Human Sciences, Fort Collins, CO.
4
Department of Naturopathic Medicine, Wholeness Center, Fort Collins, CO.
ªLucas Elms et al, 2019; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the
Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution,
and reproduction in any medium, provided that the original work is properly cited.
THE JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE JACM
Volume 00, Number 00, 2018, pp. 1–6
Mary Ann Liebert, Inc.
DOI: 10.1089/acm.2018.0437
1
typically employed. The development of additional treatment
agents is important because current medications, including se-
lective serotonin reuptake inhibitors, serotonin/norepinephrine
reuptake inhibitors, antiadrenergic agents, and second-
generation antipsychotics, have questionable efficacy and
often carry significant undesirable side-effect profiles.
Although the pathophysiology of PTSD has not yet been
definitively described, a number of factors are suspected to
contribute to the development of this disorder. One hy-
pothesis relates PTSD to dysregulated memory retrieval
through the process of reconsolidation and impaired ex-
tinction of aversive memories.
2
The endogenous cannabi-
noid system has been shown to play an important role in the
process of aversive memory extinction through the activity
of central CB1 receptors.
3
Two cannabinoid receptors are
known to exist in the human body: CB1 and CB2 receptors.
CB1 receptors are located mainly in the brain and modulate
neurotransmitter release in a manner that prevents excessive
neuronal activity, thus calming and decreasing anxiety. CB1
receptors also have a role in reducing pain, inflammation,
regulating movement and posture control, and regulating
sensory perception, memory, and cognitive function.
Cannabidiol (CBD) is known to have multiple physio-
logic mechanisms of action, including 5-HT
1A
serotonergic
agonism, adenosine and opioid receptor modulation, acti-
vation of the endogenous endocannabinoid system, antago-
nism at GPR55 receptors, and activation of transient
receptor potential channels.
4,5
CBD’s activity at 5-HT
1A
receptors may drive its neuroprotective, antidepressive, and
anxiolytic benefits, although the mechanism of action by
which CBD decreases anxiety is still unclear.
6
CBD was
shown to be helpful for decreasing anxiety through a sim-
ulated public speaking test at doses of 300–600 mg in single-
dose studies.
7–9
Other studies suggest that lower doses of
10 mg/kg have a more anxiolytic effect than higher doses of
100 mg/kg in rats.
10
Of particular interest to this study is the effect of CBD on
the endogenous cannabinoid system. CBD has minimal af-
finity for CB1 and CB2 receptors,
11
but it does indirectly
cause activation of CB1 receptors by increasing the avail-
ability of endogenous endocannabinoids. Anandamide is an
endogenous cannabinoid that acts as a partial agonist at CB1
receptors. It is metabolically deactivated by the enzyme
fatty acid amide hydrolase (FAAH). CBD has been shown in
some studies to inhibit FAAH, thus increasing the avail-
ability of anandamide and causing activation of the en-
docannabinoid system.
12
Studies in rodent models have
shown that pharmacologic activation of the endocannabinoid
system through CB1-receptor agonist agents leads to de-
creased behavioral response to aversive memories in rodent
models through the inhibition of memory reconsolidation
and enhanced extinction.
13–15
This early research suggests
that agents such as CBD that cause indirect activation of
the endocannabinoid system may have utility in the treatment
of PTSD.
Current evidence regarding the use of CBD for PTSD in
humans is minimal. One case report showed that adminis-
tration of 12–37 mg of oral CBD daily was associated with a
reduction in anxiety symptoms and sleep disturbances in a
10-year-old patient with PTSD due to sexual trauma.
16
Another study showed that 32 mg of inhaled CBD resulted
in consolidation of aversive memory extinction and atten-
uation of explicit fearful responding in healthy human
subjects.
17
See Bittencourt and Takahashi
18
for a recent
comprehensive review of pre-clinical and clinical studies
regarding the relationship of CBD to PTSD. To date, no
clinical trial evaluating the effectiveness of CBD in reduc-
ing symptoms of PTSD in humans has been completed.
The hypothesis of this study was that patients with DSM-
5-diagnosed PTSD who were administered CBD along with
routine psychiatric care would show a decrease in PTSD-
specific symptomatology. This hypothesis was based on
prior rodent and limited human studies that suggest that (1)
CBD may cause decreased response to and increased ex-
tinction of aversive memories, and that (2) CBD may have
an anxiolytic effect, which, in turn, would have therapeutic
value in patients with PTSD. To this end, we conducted a
retrospective file review of adult patients with PTSD who
were treated with CBD as part of standard psychiatric care
in an outpatient clinic. The goal of this review was to ex-
amine the tolerability of CBD and its effectiveness in PTSD
symptom reduction.
Materials and Methods
Design and procedures
This article describes a retrospective chart review of adult
psychiatric patients with a diagnosis of PTSD who con-
sented to treatment with CBD as augmentation to routine
psychiatric treatment at an outpatient psychiatric clinic. All
current patients with a diagnosis of PTSD were considered
for treatment with CBD between February 2016 and May
2018. Patients were not excluded based on the presence
of other psychiatric comorbidities (aside from an active
thought disorder) or concurrent use of cannabis. The diag-
nosis of PTSD was established through clinical evaluation
by a mental health professional (psychiatrist, psychiatric
nurse practitioner, or physician assistant). Inclusion criteria
for the present analysis required a cut-off score of 33 on the
Post-Traumatic Stress Disorder Checklist for the DSM-5
(PCL-5)
19
and a minimum of two consecutive follow-up
appointments after the initial intake appointment. The final
sample consisted of 11 adult patients with a diagnosis of
PTSD and who met inclusion criteria.
After the initial baseline assessment, PCL-5 assessments
were completed by patients every 4 weeks to monitor
changes in the severity of PTSD symptoms. In addition to
CBD, patients also received routine treatment in the form of
psychiatric medications, various psychotherapy modalities,
and standard integrative treatments, as indicated for their
diagnoses of PTSD and other psychiatric comorbidities.
These integrative treatments often included dietary changes,
herbal supplementation, neurofeedback, and intravenous
infusions of vitamins and minerals.
Four patients received CBD as an oral capsule only. One
patient only received CBD in the form of an oral liquid
spray. Fifty-five percent (n=6) of patients received both
forms of CBD either concurrently or sequentially over the
course of the study. The form of CBD (capsule vs. liquid
spray) was determined by provider and patient preference.
The CBD products used in this study were supplied by CV
Sciences. Capsules were demonstrated by high-performance
liquid chromatography with ultraviolet detection (HPLC-
2 ELMS ET AL.
UV) to contain 22–28 mg of CBD per capsule. Patients were
instructed to take whole capsules, which were assumed to
contain 25 mg of CBD for dosing purposes. Patients were
instructed to take liquid CBD as a specified number of
sprays from a spray bottle. The liquid product used in this
article was demonstrated by HPLC-UV to contain between
425 and 575 mg of CBD in total per bottle, equating to about
1.5 mg of CBD per spray.
Patients were instructed to take CBD once or twice per
day based on severity of symptoms. The median starting
oral capsular dose was 25 mg per day (range: 25–100). The
median dose of liquid CBD given throughout the study was
9 mg per day (range: 1–16). The mean total starting dose of
CBD (liquid or capsular or both) was 33.18 mg (standard
deviation [SD] =23.34). The mean total dose of CBD pre-
scribed at the 8-week follow-up appointment at the con-
clusion of the study period was 48.64 mg (range: 2–100).
The dose of CBD was adjusted at each 4-week appointment
based on the patient’s presentation and experience. Most
patients received an increase in the dose of CBD because
treatment was provided to maximize PTSD symptom re-
duction, which seemed to be directly correlated with dose.
These doses are much lower than the doses used in the
previous clinical literature for multiple reasons. The first is
that lower doses appear to elicit an adequate clinical re-
sponse in our experience. Second, the current retail cost of
CBD would make the use of 600 mg per day cost-
prohibitive. Finally, doses for the liquid spray route of ad-
ministration are typically lower than that of capsules and are
usually measured as single milligrams of CBD per spray,
thus rendering higher doses impractical for patients relying
on liquid CBD.
Informed consent was obtained for each patient at their
intake appointment. Appointments every 4 weeks included
clinical evaluation and documentation of patients’ PTSD
symptomatology through PCL-5 questionnaires. Concurrent
psychiatric medications were held constant or changed ac-
cording to routine clinical practice, whereas CBD was often
intentionally used as a method of decreasing or avoiding the
use of psychiatric medications. CBD was added to care,
dropped from care, or refused as per individual patient and
practitioner preference. The Western Institutional Review
Board approved a retrospective analysis of the charts of
patients with a diagnosis of PTSD who received CBD as
part of their treatment program.
Setting
Wholeness Center is a large mental health clinic with a
focus on integrative medicine and psychiatry. Practitioners
from a range of disciplines (psychiatry, naturopathy, acu-
puncture, neurofeedback, yoga, etc.) work together in a
collaborative and cross-disciplinary environment. Based on
existing research and patient experience, CBD had been
widely incorporated into clinical care a few years before
this study.
Sample
Characteristics of the study sample are presented in
Table 1. The average age of the population in this study was
39.91 (range: 22–69, n=11). The majority (73%, n=8) of
patients were female. On average, patients were concurrently
taking three psychiatric medications, including antidepres-
sants, mood stabilizers, anxiolytics, and stimulants. One pa-
tient used cannabis daily throughout the study. Overall, 73%
(n=8) of patients were concurrently receiving psychotherapy
as part of their overall care. Patients had on average 1.8
comorbid psychiatric conditions in addition to their PTSD
diagnosis, including anxiety, mood, personality, and sleep
disorders.
Main outcome measures
Changes in PTSD symptoms were assessed by admin-
istering PCL-5 questionnaires before starting CBD and at
4-week intervals thereafter. The PCL-5 is a reliable and valid
test published in 2013 to provide an assessment of PTSD
symptoms that is consistent with changes to the criteria of
PTSD in the DSM-5.
20
Patients complete a 20-question self-
report form that rates their symptoms on a scale of 0–4, with
total scores ranging from 0 to 80. The PCL-5 is used only to
assess PTSD symptom severity and no particular numeric
score establishes a definitive diagnosis of PTSD, although
a provisional diagnosis of PTSD may be established based
on (1) individual scoring clusters in relation to the diagnostic
criteria of the DSM-5 or (2) a cumulative score of 33 or
greater. Side effects and tolerability were assessed through
spontaneous patient self-report and were documented in
case records accordingly. Any other spontaneous com-
ments or complaints of patients were also documented in
case records and included in this analysis.
Analysis
After patient information was de-identified, the main
outcome measure of total PCL-5 score was tracked and
descriptively analyzed based on mean score and percentage
change from the prior 4-week appointment. The endpoint
for statistical analysis of the study was set at 8 weeks after
initial evaluation. Data beyond this period were not ana-
lyzed because follow-up beyond this period dropped to
<50%. However, anecdotal data were still considered and
qualitatively presented in the Results sub-section.
Table 1. Characteristics of the Patient Population
and Concurrent Treatments Received
Characteristic Value
Age, mean (SD) 39.91 (17.39)
Gender, n(%)
Male 3 (27)
Female 8 (73)
Total psychiatric medications received,
mean (SD)
3 (1.84)
Relevant medication classes received by patients, n(%)
Anticonvulsant 6 (54.55)
Antidepressant 6 (54.55)
Antipsychotic 2 (18.18)
Anxiolytic/sedative 6 (54.55)
Beta-blocker 4 (36.36)
Number receiving psychotherapy, n(%) 8 (73)
Psychiatric comorbidities, mean (SD) 1.8 (1.54)
SD, standard deviation.
CANNABIDIOL IN THE TREATMENT OF PTSD 3
Results
Of the initial 21 patients who were prescribed CBD and
attended at least one follow-up appointment, 86% (n=18)
remained on CBD and completed PCL-5 questionnaires at 4
weeks of follow-up. This number dropped to 67% (n=14) at
8 weeks of follow-up. This is generally reflective of normal
attrition rates experienced in this clinic, and reasons for dis-
continuation of care were largely unknown. Of the 14 patients
who remained in the study at the endpoint of 8 weeks, 11 met
inclusion criteria for data analysis by attending both 4- and
8-week follow-up appointments. Attrition rates by week
are depicted in Table 2.
The baseline mean PCL-5 score for the statistical analysis
sample was 51.82 (SD =9.13). After 4 weeks of treatment,
91% (n=10) of patients from this group reported a decrease
in symptoms of PTSD. PCL-5 scores declined from 51.82 to
40.73 (SD =12.92), a decrease of 21%. One patient did,
however, experience an increase in PCL-5 score from 51 to
63. After 8 weeks of treatment with CBD, 73% (n=8) of
patients reported a further decrease in PTSD symptoms from
their follow-up appointment 4 weeks earlier, and the aver-
age PCL-5 score decreased 9% down to 37.14 (SD =14.38).
At 8 weeks, 27% (n=3) of patients had worsening of PTSD
symptoms from their prior 4-week appointment, with a
mean score increase of 8 (SD =6.08). Despite this increase
from the prior appointment experienced by some patients,
nearly all patients (n=10) reported a PCL-5 score that was
lower than their baseline at the beginning of the study, with
an average decrease of 28%. The results of the study are
depicted graphically in Figure 1.
Four patients from the initial sample continued to receive
CBD for 36 weeks or more. These patients had an initial
mean PCL-5 score of 57.75 (SD =6.20) and all experienced
long-term sustained decreases in PCL-5 scores, with a mean
score at 36 weeks of 29.25 (SD =9.88). An unexpected
finding revealed through the course of this analysis was a
possible effect of CBD on nightmares. Item number 2 on the
PCL-5 questionnaire assesses symptoms of ‘‘repeated, dis-
turbing dreams of the stressful experience.’’ Of the patients
who responded to item number 2 on the PCL-5 with a se-
verity rating of 3 (‘‘quite a bit’’) or higher, 50% (n=4)
reported a subjective improvement in their nightmares after
starting CBD. Of the total 21 patients in the original sample,
38% (n=8) also reported subjective improvement in the
quality of their sleep. Other reported benefits of CBD in-
cluded decreased anxiety (n=3), improved focus (n=1), and
improved mood (n=1).
CBD was well tolerated by the majority (76%, n=16) of
the total number of patients (n=21). Two patients reported
feeling fatigue after taking CBD. One patient experienced
daytime fogginess and impaired concentration the day after
a night-time CBD dose. Two patients reported gastrointes-
tinal bloating or pain. One of these patients had pre-existing
inflammatory bowel syndrome and anorexia. One patient
with a history of gastroesophageal reflux reported worsening
reflux symptoms.
Discussion
Patients taking daily oral CBD over an 8-week period
demonstrated an overall decrease in PTSD symptom se-
verity as measured by continual decreases in mean PCL-5
scores. CBD was well tolerated and no patients discontinued
it due to side effects, although a minority of patients did
report fatigue and gastrointestinal discomfort. It is unclear
whether the fatigue caused by CBD is due to a sedative
effect, and further information should be obtained about the
safety profile of CBD.
Doses of CBD used in this study were generally lower
than those used in prior preclinical and clinical research.
Patients did generally report greater improvement in symp-
toms with higher doses of CBD. Further investigation into
the optimal dosing of CBD for PTSD is warranted. Patients
also received liquid spray and oral capsular forms of CBD,
and it is unknown whether there is a difference in response
between the two routes of administration. CBD is commer-
cially available in many different forms, and further studies
should be done to determine the most effective form of CBD.
A surprising number of patients with significant symp-
tomatology related to PTSD nightmares reported subjective
improvement in these symptoms. It is unclear whether this is
due solely to the placebo effect or an effect of CBD based
on a previously unknown mechanism of action. Due to the
current paucity of medications approved for PTSD night-
mares, further investigations should examine whether CBD
Table 2. Number of Patients Who Presented
at the Corresponding Four-Week Interval
Appointment After Their Intake and Completed
a PCL-5Questionnaire
Weeks in study
Number of patients
(% of initial sample)
Intake 21 (100)
4 18 (86)
8 14 (67)
12 8 (38)
16 6 (29)
20 7 (33)
24 5 (24)
28 4 (19)
32 4 (19)
36 4 (19)
40 3 (14)
PCL-5, Post-Traumatic Stress Disorder Checklist for the DSM-5.
FIG. 1. Mean PCL-5 score of the sample over the course
of the study depicted as a function of time showing the
observed decrease. PCL-5, Post-Traumatic Stress Disorder
Checklist for the DSM-5.
4 ELMS ET AL.
has a clinical benefit for patients with PTSD-related night-
mares.
Although a qualitative examination of the results of this
study appears to show a sustained decrease in PCL-5 score
after extended periods, the early endpoint for statistical
analysis makes it difficult to definitively determine whether
continued use of CBD results in continued improvement of
symptoms. We have shown that the mean PCL-5 score de-
creased at every 4-week interval for the majority of patients
at the 4- and 8-week follow-ups, but further work should be
done to determine how long this effect continues and whe-
ther there is an eventual reversal and return to baseline.
Limitations
The results of this study should be interpreted carefully
as this was a retrospective, open-label chart review and, as
such, does not include a placebo or a control group. Con-
current psychiatric medications were frequently added,
removed, and changed through the course of the study. A
precise dosing system for CBD was not established, and
regimens varied between patients. Patients also received
liquid or oral capsular CBD without a definitive guideline,
and typical doses between the two routes of administra-
tion differed widely. Although the product was derived
from agricultural hemp, it may still contain trace amounts
of delta-9-tetrahydrocannabinol. The sample used in this
study was small in size, consisting of only 11 patients, and
was disproportionately female. Significant attrition was
observed and some patients could not be included based on
non-consecutive appointments, further reducing the sample
size and limiting the endpoint of the analysis to 8 weeks
after initial evaluation. The study was conducted at a clinic
with a focus on integrative medicine, and the patient popu-
lation may differ at baseline from the general psychiatric
population. There may also be a selection bias among this
patient population as patients at this clinic often seek to avoid
the use of psychiatric medications. The role of cannabis in
society and patients’ pre-existing beliefs may have played a
role in the way that patients experienced CBD and could
plausibly contribute to an increased placebo effect. Rando-
mized, controlled studies are clearly indicated to fully explore
the benefit of CBD for symptoms of PTSD that was observed
in this chart review.
Conclusions
This retrospective chart review represents the first case
series, to our knowledge, examining the effect of CBD on
symptoms of PTSD in humans. The results indicate that oral
CBD, when given in addition to routine outpatient psy-
chiatric care, may have a beneficial effect for patients
with PTSD.
About Cannabidiol
CBD is a phytocannabinoid compound found in plants of
the genus Cannabis. It is not responsible for the psychoto-
mimetic effect traditionally associated with cannabis use, as
this is attributed to another phytocannabinoid: delta-9-
tetrahydrocannabinol (delta-9-THC). Different varieties of
cannabis may have differing percentages of CBD and delta-
9-THC. Although CBD can be derived from cannabis plants
that are grown for recreational use, the CBD used in this
study was derived from agricultural hemp, a cannabis plant
that contains <0.3% delta-9-THC. The process of extracting
CBD oil yields not only a product containing almost entirely
CBD but also other cannabinoids in trace amounts, and it is
not completely free of delta-9-THC. CBD remains in a legal
gray area and there have recently been frequent changes to
policy. Although law varies from state to state, CBD re-
mains federally illegal and categorized by the Drug En-
forcement Administration as a Schedule I substance.
Acknowledgments
No financial support of any kind was provided to the
authors or clinic. CV Sciences provided CBD products for
the study. CV Sciences was not involved in the data col-
lection, data interpretation, the preparation of the article, or
the decision to submit for publication. The authors would
like to express their deep appreciation to the staff and cli-
nicians at Wholeness Center for their professionalism.
Author Disclosure Statement
S.S., MD has published four professional books in the
area of Integrative Mental Health. Dr. S.S. is a Principal
Investigator for a Phase III study of MDMA assisted
psychotherapy for severe PTSD and receives compensa-
tion for his clinical work from a nonprofit corporation,
the Multidisciplinary Association for Psychedelic Studies.
Dr. S.H., Dr. N.L., and Mr. L.E. report no competing fi-
nancial interests.
References
1. Goldstein RB, Smith SM, Chou SP, et al. The epidemiology
of DSM-5 posttraumatic stress disorder in the United
States: Results from the National Epidemiologic Survey on
alcohol and related conditions-III. Soc Psychiatry Psychiatr
Epidemiol 2016;51:1137–1148.
2. Parsons RG, Ressler KJ. Implications of memory modula-
tion for post-traumatic stress and fear disorders. Nat Neuro-
sci 2013;16:146–153.
3. Marsicano G, Wojtak CT, Azad SC, et al. The endogenous
cannabinoid system controls extinction of aversive memo-
ries. Nature 2002;418:530–534.
4. Campos AC, Moreira FA, Gomes FV, et al. Multiple
mechanisms involved in the large-spectrum therapeutic
potential of cannabidiol in psychiatric disorders. Philos
Trans R Soc Lond B Biol Sci 2012;367:3364–3378.
5. Ibeas Bih C, Chen T, Nunn AV, et al. Molecular targets of
cannabidiol in neurological disorders. Neurotherapeutics
2015;12:699–730.
6. Zanelati TV, Biojone C, Moreira FA, et al. Antidepressant-
like effects of cannabidiol in mice: Possible involvement of
5-HT1A receptors. Br J Pharmacol 2010;159:122–128.
7. Bergamaschi MM, Queiroz RH, Chagas MH, et al. Can-
nabidiol reduces the anxiety induced by simulated public
speaking in treatment-naı
¨ve social phobia patients. Neuro-
psychopharmacology. 2011;36:1219–1226.
8. Zuardi AW, Rodrigues NP, Silva AL, et al. Inverted U-shaped
dose-response curve of the anxiolytic effect of cannabidiol
during public speaking in real life. Front Pharmacol 2017;
11;8:259.
CANNABIDIOL IN THE TREATMENT OF PTSD 5
9. Zuardi AW, Cosme RA, Graeff FG, Guimara
˜es FS. Effects
of ipsapirone and cannabidiol on human experimental
anxiety. J Psychopharmacol 1993;7(1 Suppl):82–88.
10. Guimara
˜es FS, Chiaretti TM, Graeff FG, Zuardi AW. An-
tianxiety effect of cannabidiol in the elevated plus-maze.
Psychopharmacology (Berl) 1990;100:558–559.
11. Pertwee RG. The diverse CB1 and CB2 receptor pharma-
cology of three plant cannabinoids: D9-tetrahydrocannabinol,
cannabidiol and D9-tetrahydrocannabivarin. Br J Pharmacol
2008;153:199–215.
12. De Petrocellis L, Ligresti A, Moriello AS, et al. Effects of
cannabinoids and cannabinoid-enriched Cannabis extracts
on TRP channels and endocannabinoid metabolic enzymes.
Br J Pharmacol 2011;163:1479–1494.
13. Stern CA, Gazarini L, Takahashi RN, et al. On disruption
of fear memory by reconsolidation blockade: Evidence
from cannabidiol treatment. Neuropsychopharmacology 2012;
37:2132–2142.
14. Bitencourt RM, Pamplona FA, Takahashi RN. Facilitation
of contextual fear memory extinction and anti-anxiogenic
effects of AM404 and cannabidiol in conditioned rats. Eur
Neuropsychopharmacol 2008;18:849–859.
15. Chhatwal JP, Davis M, Maguschak KA, Ressler KJ. En-
hancing cannabinoid neurotransmission augments the ex-
tinction of conditioned fear. Neuropsychopharmacology
2005;30:516–524.
16. Shannon S, Oplia-Lehman J. Effectiveness of cannabidiol
oil for pediatric anxiety and insomnia as part of post-
traumatic stress disorder: A case report. Perm J 2016;20:
108–111.
17. Das RK, Kamboj SK, Ramadas M, et al. Cannabidiol en-
hances consolidation of explicit fear extinction in humans.
Psychopharmacology (Berl) 2013;226:781–792.
18. Bitencourt RM, Takahashi RN. Cannabidiol as a thera-
peutic alternative for post-traumatic stress disorder: From
bench research to confirmation in human trials. Front
Neurosci 2018;12:502.
19. Weather FW, Litz BT, Keane TM, et al. The PTSD
checklist for DSM-5 (PCL-5) [homepage on the Internet].
National Center for PTSD. Online document at: www.ptsd
.va.gov/professional/assessment/adult-sr/ptsd-checklist.asp,
accessed September 7, 2018.
20. Blevins CA, Weathers FW, Davis MT, et al. The post-
traumatic stress disorder checklist for DSM-5 (PCL-5):
Development and initial psychometric evaluation. J Trauma
Stress 2015;28:489–498.
Address correspondence to:
Scott Shannon, MD, FAACAP
2620 East Prospect Road, #190
Fort Collins, CO 80525
E-mail: scott@wholeness.com
6 ELMS ET AL.
... Open trials administering cannabinoids with no comparison group have found a 28% decrease in general PTSD symptoms [79] as well as decreases in hyperarousal symptoms [82] and frequency or intensity of nightmares (50-72% report improvement) [79,78]. These trials are characterized by small, predominately male, veteran samples, and considerable variation in type of cannabinoid administered, dose, and length of administration. ...
... Open trials administering cannabinoids with no comparison group have found a 28% decrease in general PTSD symptoms [79] as well as decreases in hyperarousal symptoms [82] and frequency or intensity of nightmares (50-72% report improvement) [79,78]. These trials are characterized by small, predominately male, veteran samples, and considerable variation in type of cannabinoid administered, dose, and length of administration. ...
... These trials are characterized by small, predominately male, veteran samples, and considerable variation in type of cannabinoid administered, dose, and length of administration. Most of the open trial studies administered a synthetic THC-based cannabinoid such as nabilone [79,80], with the study by Elms and colleagues [80] administering CBD. In addition, across studies the method for determining PTSD diagnosis was inconsistent. ...
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Purpose of Review Individuals with posttraumatic stress disorder (PTSD) may use cannabis to reduce symptoms yet are also at risk for developing problematic use. This review outlines theories, summarizes recent empirical studies, and discusses clinical implications of cannabis use and PTSD recovery. Recent Findings Although naturalistic studies and open trials find a relationship between cannabinoids and PTSD symptom reduction, methodological limitations preclude definitive conclusions. The only randomized controlled trial to date found cannabis had no greater effect on PTSD symptoms than placebo. Summary Rigorous studies of the long-term impact of cannabis use on PTSD recovery are needed. Clinicians and researchers must weigh the potential therapeutic effect against the costs and risks associated with long-term cannabis use. Clinicians should consider all available PTSD treatment options, along with client level factors such as the function of cannabis use, motivation to change use, and the potential impact of cannabis on treatment engagement when making clinical recommendations.
... CBD is a non-psychotomimetic cannabinoid. A retrospective case series of adults with PTSD (n = 11) examining CBD use at a dosage 2-100 mg/day over 8 weeks reported a 28% symptom reduction, particularly for nightmares, using the PTSD Checklist for DSM-5 (PCL-5) [119]. This study was limited by a small sample size and possible selection bias (e.g., disproportionate demographic representation) ( Table 1). ...
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Posttraumatic stress disorder (PTSD) can be a chronic and disabling condition. Post-traumatic nightmares (PTNs) form a core component of PTSD and are highly prevalent in this patient population. Nightmares in PTSD have been associated with significant distress, functional impairment, poor health outcomes, and decreased quality of life. Nightmares in PTSD are also an independent risk factor for suicide. Nightmare cessation can lead to improved quality of life, fewer hospital admissions, lower healthcare costs, and reduced all-cause mortality. Effective treatment of nightmares is critical and often leads to improvement of other PTSD symptomatology. However, approved pharmacological agents for the treatment of PTSD have modest effects on sleep and nightmares, and may cause adverse effects. No pharmacological agent has been approved specifically for the treatment of PTNs, but multiple agents have been studied. This current narrative review aimed to critically appraise proven as well as novel pharmacological agents used in the treatment of PTNs. Evidence of varying quality exists for the use of prazosin, doxazosin, clonidine, tricyclic antidepressants, trazodone, mirtazapine, atypical antipsychotics (especially risperidone, olanzapine and quetiapine), gabapentin, topiramate, and cyproheptadine. Evidence does not support the use of venlafaxine, β-blockers, benzodiazepines, or sedative hypnotics. Novel agents such as ramelteon, cannabinoids, ketamine, psychedelic agents, and trihexyphenidyl have shown promising results. Large randomized controlled trials (RCTs) are needed to evaluate the use of these novel agents. Future research directions are identified to optimize the treatment of nightmares in patients with PTSD.
... Of these studies, a treatment naïve patient group with SAD was given CBD and had also exhibited indications of reduced anxiety, both subjective and physiological (Bergamaschi et al., 2011). Clinical studies assessing the anxiolytic properties of cannabinoids in PTSD and chronic pain pathologies have also observed general improvements in patients having consumed whole cannabis products (Greer et al., 2014;Bonn-Miller et al., 2021) or CBD alone (Elms et al., 2019) as indicated by lowered scores in clinician administered posttraumatic stress scales and PTSD checklists which assess emotional response and cognitive Frontiers in Pharmacology | www.frontiersin.org April 2022 | Volume 13 | Article 881810 function. ...
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Cannabinoids, including those found in cannabis, have shown promise as potential therapeutics for numerous health issues, including pathological pain and diseases that produce an impact on neurological processing and function. Thus, cannabis use for medicinal purposes has become accepted by a growing majority. However, clinical trials yielding satisfactory endpoints and unequivocal proof that medicinal cannabis should be considered a frontline therapeutic for most examined central nervous system indications remains largely elusive. Although cannabis contains over 100 + compounds, most preclinical and clinical research with well-controlled dosing and delivery methods utilize the various formulations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most abundant compounds in cannabis. These controlled dosing and delivery methods are in stark contrast to most clinical studies using whole plant cannabis products, as few clinical studies using whole plant cannabis profile the exact composition, including percentages of all compounds present within the studied product. This review will examine both preclinical and clinical evidence that supports or refutes the therapeutic utility of medicinal cannabis for the treatment of pathological pain, neurodegeneration, substance use disorders, as well as anxiety-related disorders. We will predominately focus on purified THC and CBD, as well as other compounds isolated from cannabis for the aforementioned reasons but will also include discussion over those studies where whole plant cannabis has been used. In this review we also consider the current challenges associated with the advancement of medicinal cannabis and its derived potential therapeutics into clinical applications.
... Preclinical evidence shows the potential of CBD to reduce anxiety in PTSD, generalized anxiety disorder, panic disorder, obsessivecompulsive disorder, and seasonal affective disorder, with clinical trials finding 300-600 mg CBD effectively reduced anxiety (Blessing et al., 2015). A recent case series on anxiety found CBD doses ranging from 25-275 mg reduced daily anxiety scores for 79% of the patients, with most finding improvement at only 25 mg (Elms et al., 2019). ...
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Medical Cannabis is receiving renewed interest in clinical practice due to the gradual increase over the last few decades of cannabis legalization and high-quality research on the potential benefits of cannabis for treating a variety of conditions (NASEM, 2017; Nursing Care of the Patient, 2018). However, the pace of medical cannabis legalization and research are outpacing the training for medical providers, leaving gaps in their confidence and ability to safely guide patients using medical cannabis (NCSBN, 2018). Medical providers are increasingly fielding questions from patients regarding the use of medical cannabis for conditions commonly seen in clinical practice, but many are uncertain of if and how they should guide patients on this use. The aim of this research is two-fold: to assess current barriers to medical providers discussing medical cannabis with their patients; and to assess the impact a one-hour educational presentation can have on addressing these barriers and increasing the likelihood of providers engaging in discussions. Though the results of this research may be limited by the small sample size surveyed, they could highlight barriers present in clinical practice and indicate possible areas for future research in expanding cannabis education for medical providers.
... Anxiety scores decreased in 79.2%, 15.3% patients experienced worsening anxiety symptoms [243]. Other studies also reported CBD was efficient in reduction anxiety signs in different patient populations [244][245][246]. However, additional studies are required to verify longterm effectiveness and safety and establish appropriate dosing. ...
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Autism spectrum disorder (ASD) is a group of disabilities with impairments in physical, verbal, and behavior areas. Regardless the growing frequency of autism, no medicine has been formed for the management of the ASD primary symptoms. The most frequently prescribed drugs are off-label. Therefore, there is necessity for an advance tactic for the treatment of autism. The endocannabinoid system has a central role in ruling emotion and social behaviors. Dysfunctions of the system donate to the behavioral deficits in autism. Therefore, the endocannabinoid system represents a potential target for the development of a novel autism therapy. Cannabis and associated compounds have produced substantial research attention as a capable therapy in neurobehavioral and neurological syndromes. In this review we examine the potential benefits of medical cannabis and related compounds in the treatment of ASD and concurrent disorders
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Individuals diagnosed with post-traumatic stress disorder (PTSD) are often comorbid for substance use disorders. Cannabis is widely used by PSTD patients, and the literature is mixed on whether cannabis use ameliorates or exacerbates patient responses to stress-associated conditioned stimuli (stress-CS). We determined if cannabis use affects responsivity to stress-CS in rats receiving 2 h stress in the presence of an odor stress-CS. Three weeks after acute stress, rats self-administered cannabinoids (delta9-tetrahydrocannabinol + cannabidiol; THC + CBD) for 15 days, and the stressed males consumed more THC + CBD than sham males. We then used the stress-CS or a novel odor (stress-NS) to reinstate THC + CBD seeking. Surprisingly, the stress-NS reinstated THC + CBD seeking, an effect blocked by N-acetylcysteine. Moreover, the stress-CS inhibited THC + CBD-CS induced reinstatement. To determine if the unexpected effects of stress-NS and -CS resulted from THC + CBD altering conditioned stress, the effect of THC + CBD use on stress-NS/CS-induced coping behaviors and spine morphology was quantified. In THC + CBD-treated rats, stress-NS increased active coping (burying). Conversely, stress-CS reduced active coping and increased passive coping (immobility) and other behavioral parameters associated with stress responses, including self-grooming and defecation. Transient spine head expansion in nucleus accumbens core is necessary for cue-induced drug seeking, and THC + CBD self-administration prevented the increase in head diameter by stress-CS in control rats. These data show THC + CBD self-administration altered the salience of environmental cues, causing neutral cues to promote active behavior (drug seeking and burying) and stress-CS to switch from active to passive behavior (inhibiting drug seeking and immobilization). We hypothesize that cannabis may exacerbate conditioned stress responses.
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Purpose: To compare the effectiveness and tolerability of add-on treatment with nabiximols (NBX: delta-9-tetrahydrocannabinol: cannabidiol) oromucosal spray or oral dronabinol (DRO: synthetic tetrahydrocannabinol) in patients with severe neuropathic pain poorly responsive to established treatments. Methods: An analysis was conducted of anonymized, propensity score-matched real-world data from the German Pain e-Registry, using a sequential non-inferiority superiority approach, for adult outpatients with neuropathic pain who had initiated treatment with NBX or DRO between 10 March 2017 and 31 December 2019. The primary effectiveness variable was percent change from baseline in a 9-factor aggregated symptom relief (ASR-9) score, a composite index of nine distinct pain- and health-related parameters assessed using validated patient-reported instruments. Safety was assessed by the incidence of physician-confirmed treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation. Results: Propensity score-matched data were analyzed for 337 patients treated with NBX and 337 patients treated with DRO. Mean (standard deviation) THC dose over the 24-week evaluation period was 16.6 (6.5) mg for NBX and 17.2 (7.6) mg for DRO (p<0.001). Median (standard error) improvement relative to baseline in the ASR-9 composite score was 55.4% (0.5) for NBX and 40.5% (0.5) for DRO (least squares mean difference, 14.0 (0.7), 95% confidence interval 12.6-15.4; p<0.001), and incidences of TRAEs (21.1 vs 35%) and TRAE-related discontinuations (5.9 vs 14.8%) were significantly lower with NBX than DRO (p<0.001 for both), collectively indicating pre-specified non-inferiority and superiority of NBX. More NBX- than DRO-treated patients discontinued non-cannabinoid background pain medications and rescue analgesics, especially opioid analgesics (p<0.001 for both). Conclusion: Add-on treatment with cannabinoids is effective for treatment of severe neuropathic pain with inadequate response to established treatments. In daily practice, NBX had superior effectiveness and tolerability compared to DRO. The results emphasize the importance of combining CBD with THC in this patient population.
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Introduction Cannabis products, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are increasingly easy to procure and use across the United States. The 2018 National Survey on Drug Use and Health (NSDUH) reported a past-month cannabis use rate of 8.6% among adults 26 years of age or older in the U.S. general population. Cannabis use is commonly reported by U.S. Military Veterans with histories of mild traumatic brain injury (mTBI) receiving services at the Marcus Institute for Brain Health (MIBH), a specialty interdisciplinary clinic serving this population. The aims of this study are to describe the frequency and characteristics of cannabis product use among Veterans evaluated at MIBH and to compare the rate of cannabis use in this group to that in the general and Veteran populations reported in the 2018 NSDUH. Materials and Methods Study data were collected as part of MIBH clinical assessments between January 2018 and December 2019, which included the evaluation of the current use of cannabis products. Affirmative cannabis use responses were clarified with inquiries about the frequency of use, method of administration, product ingredients (i.e., THC and/or CBD), and reason(s) for use. Results Among 163 MIBH patients (92.6% male), 72 (44.2%) endorsed cannabis product use during the month preceding the clinical assessment. Cannabis users were significantly younger than nonusers. The frequency of past-month cannabis use was significantly greater than that reported in the comparably aged NSDUH survey general and Veteran populations (44.2% vs. 8.6% and 44.2% vs. 7.7%, respectively, both P < .00001). Among the 72 MIBH patients reporting cannabis use, 62 (86.1%) reported THC or combination product use, and 10 (13.9%) reported CBD product use. Concurrent medication use, including psychotropic medications use, did not differ significantly between cannabis users and nonusers. Conclusions Self-reported cannabis use is significantly higher in the MIBH population than in similarly aged individuals in the general population and significantly more frequent among younger than older members of this cohort. Self-reported reasons for cannabis use in this cohort included mTBI-associated neuropsychiatric symptoms, sleep disturbances, and pain for which standard treatments (both pharmacologic and nonpharmacologic) provided insufficient relief and/or produced treatment-limiting adverse events. However, cannabis use did not provide sufficient improvement in those symptoms to obviate the need for further evaluation and treatment of those problems at MIBH or to replace, in part or in whole, standard medications and other treatments for those problems. Further study of cannabis use, including standardized individual cannabinoid (i.e., THC and CBD) and whole-plant cannabis preparations, in this and similar cohorts is needed to more fully understand the drivers, benefits, risks, and safety of cannabis use in this and in similar Veteran populations, as well as the potential pharmacological and/or nonpharmacological therapeutic alternatives to cannabis use.
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The endocannabinoid system is known to be involved in mechanisms relevant to PTSD aetiology and maintenance, though this understanding is mostly based on animal models of the disorder. Here we review how human paradigms can successfully translate animal findings to human subjects, with the view that substantially increased insight into the effect of endocannabinoid signalling on stress responding, emotional and intrusive memories, and fear extinction can be gained using modern paradigms and methods for assessing the state of the endocannabinoid system in PTSD.
Technical Report
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Sleep is an important physiological function that represents about a third of our daily lives. This function can be altered by several sleep disorders with varying prevalence. Cannabis is often viewed as a hypnotic drug, based on user’s reports or objective measurements. The two main cannabinoids of the plant are THC and CBD. They both act differently on the endocannabinoid system, which is itself involved in regulating the sleep-wake cycle. In acute exposure, THC has sleep-promoting properties (decreasing sleep onset latency and wake after sleep onset ; increasing total sleep time and slow wave sleep). Data on CBD is inconsistent, it is sometimes presented as a wakepromoting drug. These effects of cannabinoids on sleep raise questions about the relevance of their use in the pharmacological treatment of certain sleep disorders. Among the seven medical situations for which there is literature, the best – yet weak – data relate to sleep apnea and PTSD-related nightmares. Further work should shed light on this field of research in the future. (text in French)
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Post-traumatic stress disorder (PTSD) is characterized by poor adaptation to a traumatic experience. This disorder affects approximately 10% of people at some point in life. Current pharmacological therapies for PTSD have been shown to be inefficient and produce considerable side effects. Since the discovery of the involvement of the endocannabinoid (eCB) system in emotional memory processing, pharmacological manipulation of eCB signaling has become a therapeutic possibility for the treatment of PTSD. Cannabidiol (CBD), a phytocannabinoid constituent of Cannabis sativa without the psychoactive effects of Δ9-tetrahydrocannabinol, has gained particular attention. Preclinical studies in different rodent behavioral models have shown that CBD can both facilitate the extinction of aversive memories and block their reconsolidation, possibly through potentialization of the eCB system. These results, combined with the currently available pharmacological treatments for PTSD being limited, necessitated testing CBD use with the same therapeutic purpose in humans as well. Indeed, as observed in rodents, recent studies have confirmed the ability of CBD to alter important aspects of aversive memories in humans and promote significant improvements in the symptomatology of PTSD. The goal of this review was to highlight the potential of CBD as a treatment for disorders related to inappropriate retention of aversive memories, by assessing evidence from preclinical to human experimental studies.
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The purpose of this study was to investigate whether the anxiolytic effect of cannabidiol (CBD) in humans follows the same pattern of an inverted U-shaped dose-effect curve observed in many animal studies. Sixty healthy subjects of both sexes aged between 18 and 35 years were randomly assigned to five groups that received placebo, clonazepam (1 mg), and CBD (100, 300, and 900 mg). The subjects were underwent a test of public speaking in a real situation (TPSRS) where each subject had to speak in front of a group formed by the remaining participants. Each subject completed the anxiety and sedation factors of the Visual Analog Mood Scale and had their blood pressure and heart rate recorded. These measures were obtained in five experimental sessions with 12 volunteers each. Each session had four steps at the following times (minutes) after administration of the drug/placebo, as time 0: -5 (baseline), 80 (pre-test), 153 (speech), and 216 (post-speech). Repeated-measures analyses of variance showed that the TPSRS increased the subjective measures of anxiety, heart rate, and blood pressure. Student-Newman-Keuls test comparisons among the groups in each phase showed significant attenuation in anxiety scores relative to the placebo group in the group treated with clonazepam during the speech phase, and in the clonazepam and CBD 300 mg groups in the post-speech phase. Clonazepam was more sedative than CBD 300 and 900 mg and induced a smaller increase in systolic and diastolic blood pressure than CBD 300 mg. The results confirmed that the acute administration of CBD induced anxiolytic effects with a dose-dependent inverted U-shaped curve in healthy subjects, since the subjective anxiety measures were reduced with CBD 300 mg, but not with CBD 100 and 900 mg, in the post-speech phase.
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Objectives: To present current, nationally representative US findings on the past-year and lifetime prevalences, sociodemographic correlates, psychiatric comorbidity, associated disability, and treatment of DSM-5 posttraumatic stress disorder (PTSD). Methods: Face-to-face interviews with 36,309 adults in the 2012-2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. PTSD, alcohol and drug use disorders, and selected mood, anxiety, and personality disorders were assessed using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-5. Results: Past-year and lifetime prevalences were 4.7 and 6.1 %, higher for female, white, Native American, younger, and previously married respondents, those with <high school education and lower incomes, and rural residents. PTSD was significantly associated with a broad range of substance use, mood, anxiety, and personality disorders, and past-month disability. Among respondents with lifetime PTSD, 59.4 % sought treatment; an average of 4.5 years elapsed from disorder onset to first treatment. Conclusions: DSM-5 PTSD is prevalent, highly comorbid, disabling, and associated with delayed help seeking. Additional research is needed to elucidate relationships identified herein, estimate PTSD-related costs, investigate hypotheses regarding etiology, course, and treatment, and support decisions about resource allocation to service delivery and research. Initiatives are needed to destigmatize PTSD, educate the public about its treatment, and encourage affected individuals to seek help.
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Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: 1) this cannabinoid being present in the most significant quantities in these preparations; and b) the proportion:potency relationship between tetrahydrocannabinol and other plant cannabinoids derived from cannabis. However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol (CBD), in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations. Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects. Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD. We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors, transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability. Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. In some cases, the targets identified had little or no established link to the diseases considered. In others, molecular targets of CBD were entirely consistent with those already actively exploited in relevant, clinically used, neurological treatments. Finally, CBD was found to act upon a number of targets that are linked to neurological therapeutics but that its actions were not consistent withmodulation of such targets that would derive a therapeutically beneficial outcome. Overall, we find that while >65 discrete molecular targets have been reported in the literature for CBD, a relatively limited number represent plausible targets for the drug's action in neurological disorders when judged by the criteria we set. We conclude that CBD is very unlikely to exert effects in neurological diseases through modulation of the endocannabinoid system. Moreover, a number of other molecular targets of CBD reported in the literature are unlikely to be of relevance owing to effects only being observed at supraphysiological concentrations. Of interest and after excluding unlikely and implausible targets, the remaining molecular targets of CBD with plausible evidence for involvement in therapeutic effects in neurological disorders (e.g., voltage-dependent anion channel 1, G protein-coupled receptor 55, CaV3.x, etc.) are associated with either the regulation of, or responses to changes in, intracellular calcium levels. While no causal proof yet exists for CBD's effects at these targets, they represent the most probable for such investigations and should be prioritized in further studies of CBD's therapeutic mechanism of action.
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Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of fear. Their development involves heredity, previous sensitizing experiences, association of aversive events with previous neutral stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding, treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic, including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed approaches to disorders of fear regulation.
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Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.
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The search for reconsolidation blockers may uncover clinically relevant drugs for disrupting memories of significant stressful life experiences, such as those underlying the posttraumatic stress disorder. Considering the safety of systemically administered cannabidiol (CBD), the major non-psychotomimetic component of Cannabis sativa, to animals and humans, the present study sought to investigate whether and how this phytocannabinoid (3-30 mg/kg intraperitoneally; i.p.) could mitigate an established memory, by blockade of its reconsolidation, evaluated in a contextual fear-conditioning paradigm in rats. We report that CBD is able to disrupt 1- and 7-days-old memories when administered immediately, but not 6 h, after their retrieval for 3 min, with the dose of 10 mg/kg being the most effective. This effect persists in either case for at least 1 week, but is prevented when memory reactivation was omitted, or when the cannabinoid type-1 receptors were antagonized selectively with AM251 (1.0 mg/kg). Pretreatment with the serotonin type-1A receptor antagonist WAY100635, however, failed to block CBD effects. These results highlight that recent and older fear memories are equally vulnerable to disruption induced by CBD through reconsolidation blockade, with a consequent long-lasting relief in contextual fear-induced freezing. Importantly, this CBD effect is dependent on memory reactivation, restricted to time window of <6 h, and is possibly dependent on cannabinoid type-1 receptor-mediated signaling mechanisms. We also observed that the fear memories disrupted by CBD treatment do not show reinstatement or spontaneous recovery over 22 days. These findings support the view that reconsolidation blockade, rather than facilitated extinction, accounts for the aforementioned CBD results in our experimental conditions.
Article
Introduction: Anxiety and sleep disorders are often the result of posttraumatic stress disorder and can contribute to an impaired ability to focus and to demonstration of oppositional behaviors. Case presentation: These symptoms were present in our patient, a ten-year-old girl who was sexually abused and had minimal parental supervision as a young child under the age of five. Pharmaceutical medications provided partial relief, but results were not long-lasting, and there were major side effects. A trial of cannabidiol oil resulted in a maintained decrease in anxiety and a steady improvement in the quality and quantity of the patient's sleep. Discussion: Cannabidiol oil, an increasingly popular treatment of anxiety and sleep issues, has been documented as being an effective alternative to pharmaceutical medications. This case study provides clinical data that support the use of cannabidiol oil as a safe treatment for reducing anxiety and improving sleep in a young girl with posttraumatic stress disorder.
Article
The Posttraumatic Stress Disorder Checklist (PCL) is a widely used DSM-correspondent self-report measure of PTSD symptoms. The PCL was recently revised to reflect DSM-5 changes to the PTSD criteria. In this article, the authors describe the development and initial psychometric evaluation of the PCL for DSM-5 (PCL-5). Psychometric properties of the PCL-5 were examined in 2 studies involving trauma-exposed college students. In Study 1 (N = 278), PCL-5 scores exhibited strong internal consistency (α = .94), test-retest reliability (r = .82), and convergent (rs = .74 to .85) and discriminant (rs = .31 to .60) validity. In addition, confirmatory factor analyses indicated adequate fit with the DSM-5 4-factor model, χ(2) (164) = 455.83, p < .001, standardized root mean square residual (SRMR) = .07, root mean squared error of approximation (RMSEA) = .08, comparative fit index (CFI) = .86, and Tucker-Lewis index (TLI) = .84, and superior fit with recently proposed 6-factor, χ(2) (164) = 318.37, p < .001, SRMR = .05, RMSEA = .06, CFI = .92, and TLI = .90, and 7-factor, χ(2) (164) = 291.32, p < .001, SRMR = .05, RMSEA = .06, CFI = .93, and TLI = .91, models. In Study 2 (N = 558), PCL-5 scores demonstrated similarly strong reliability and validity. Overall, results indicate that the PCL-5 is a psychometrically sound measure of PTSD symptoms. Implications for use of the PCL-5 in a variety of assessment contexts are discussed.
Article
Rationale Whilst Cannabidiol (CBD), a non-psychotomimetic cannabinoid, has been shown to enhance extinction learning in rats, its effects on fear memory in humans have not previously been studied. Objectives We employed a Pavlovian fear-conditioning paradigm in order to assess the effects of CBD on extinction and consolidation. Method Forty-eight participants were conditioned to a coloured box (CS) with electric shocks (UCS) in one context and were extinguished in a second context. Participants received 32 mg of CBD either following before or after extinction in a double-blind, placebo-controlled design. At recall, 48 h later, participants were exposed to CSs and conditioning contexts before (recall) and after (reinstatement) exposure to the UCS. Skin conductance and shock expectancy measures of conditioned responding were recorded throughout. Results Successful conditioning, extinction and recall were found in all three treatment groups. CBD given post-extinction enhanced consolidation of extinction learning as assessed by shock expectancy. CBD administered at either time produced trend level reduction in reinstatement of autonomic contextual responding. No acute effects of CBD were found on extinction. Conclusions These findings provide the first evidence that CBD can enhance consolidation of extinction learning in humans and suggest that CBD may have potential as an adjunct to extinction-based therapies for anxiety disorders.