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Rationale: One of the most commonly cited reasons for chronic cannabis use is to cope with stress. Consistent with this, cannabis users have shown reduced emotional arousal and dampened stress reactivity in response to negative imagery. Objectives: To our knowledge, the present study represents the first to examine the effects of an acute stress manipulation on subjective stress and salivary cortisol in chronic cannabis users compared to non-users. Methods: Forty cannabis users and 42 non-users were randomly assigned to complete either the stress or no stress conditions of the Maastricht Acute Stress Test (MAST). The stress condition of the MAST manipulates both physiological (placing hand in ice bath) and psychosocial stress (performing math under conditions of social evaluation). Participants gave baseline subjective stress ratings before, during, and after the stress manipulation. Cortisol was measured from saliva samples obtained before and after the stress manipulation. Further, cannabis cravings and symptoms of withdrawal were measured. Results: Subjective stress ratings and cortisol levels were significantly higher in non-users in the stress condition relative to non-users in the no stress condition. In contrast, cannabis users demonstrated blunted stress reactivity; specifically, they showed no increase in cortisol and a significantly smaller increase in subjective stress ratings. The stress manipulation had no impact on cannabis users' self-reported cravings or withdrawal symptoms. Conclusion: Chronic cannabis use is associated with blunted stress reactivity. Future research is needed to determine whether this helps to confer resiliency or vulnerability to stress-related psychopathology as well as the mechanisms underlying this effect.
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ORIGINAL INVESTIGATION
Blunted stress reactivity in chronic cannabis users
Carrie Cuttler
1,2
&Alexander Spradlin
1
&Amy T. Nusbaum
1
&Paul Whitney
1
&
John M. Hinson
1
&Ryan J. McLaughlin
1,2,3
Received: 28 March 2017 /Accepted: 7 May 2017 /Published online: 31 May 2017
#Springer-Verlag Berlin Heidelberg 2017
Abstract
Rationale One of the most commonly cited reasons for chron-
ic cannabis use is to cope with stress. Consistent with this,
cannabis users have shown reduced emotional arousal and
dampened stress reactivity in response to negative imagery.
Objectives To our knowledge, the present study represents the
first to examine the effects of an acute stress manipulation on
subjective stress and salivary cortisol in chronic cannabis
users compared to non-users.
Methods Forty cannabis users and 42 non-users were random-
ly assigned to complete either the stress or no stress conditions
of the Maastricht Acute Stress Test (MAST). The stress con-
dition of the MAST manipulates both physiological (placing
hand in ice bath) and psychosocial stress (performing math
under conditions of social evaluation). Participants gave base-
line subjective stress ratings before, during, and after the stress
manipulation. Cortisol was measured from saliva samples ob-
tained before and after the stress manipulation. Further, can-
nabis cravings and symptoms of withdrawal were measured.
Results Subjective stress ratings and cortisol levels were sig-
nificantlyhigher in non-users in the stress condition relative to
non-users in the no stress condition. In contrast, cannabis
users demonstrated blunted stress reactivity; specifically, they
showed no increase in cortisol and a significantly smaller
increase in subjective stress ratings. The stress manipulation
had no impact on cannabis usersself-reported cravings or
withdrawal symptoms.
Conclusion Chronic cannabis use is associated with blunted
stress reactivity. Future research is needed to determine
whether this helps to confer resiliency or vulnerability to
stress-related psychopathology as well as the mechanisms un-
derlying this effect.
Keywords Cannabis .Marijuana .Stress .Cortisol .
Craving .Withdrawal
Introduction
Cannabis is the most widely used illicit substance worldwide
(United Nations Office on Drugs and Crime 2012). In the
USA, recent state legislative reform permitting the use of can-
nabis for medicinal and now recreational purposes has led to a
reduction in social stigma and perceived harms of chronic
cannabis use among both adolescents (Stolzenberg et al.
2016) and adults (Okaneku et al. 2015; Schuermeyer et al.
2014). This has coincided with a steady rise in the prevalence
of daily cannabis use (SAMHSA 2014), which is only expect-
ed to increase in coming years.
Perhaps the most commonly cited reason for continued
cannabis use in chronic users is to cope with elevated levels
of perceived stress (see Hyman and Sinha 2009,fora
comprehensive review of this literature). A recent meta-
analysis of cross-sectional studies shows a high prevalence
of cannabis use among individuals with stress and anxiety
disorders, and vice versa (Kedzior and Laeber 2014).
Although the direction of these relationships has yet to be
established, evidence indicates that the second most common
reason medical cannabis patients report using cannabis is to
*Carrie Cuttler
carrie.cuttler@wsu.edu
1
Department of Psychology, Washington State University, PO Box
644820, Pullman, WA 99164-4820, USA
2
Translational Addiction Research Center, Washington State
University, Pullman, WA, USA
3
Department of Integrative Physiology and Neuroscience,
Washington State University, Pullman, WA 99164-7620, USA
Psychopharmacology (2017) 234:22992309
DOI 10.1007/s00213-017-4648-z
treat anxiety (Sexton et al. 2016) and that cannabis consump-
tion reduces feelings of stress/anxiety in medical cannabis
patients (Webb and Webb 2014). Moreover, stress coping mo-
tives are largely unique to cannabis relative to other drugs of
abuse and are specific to chronic experienced users (Copeland
et al. 2001).
Double-blind, placebo-controlled studies have further cor-
roborated these self-report data, as acute cannabis or Δ-9-tet-
rahydrocannabinol (THC) administration dampens amygdala
responses to affective stimuli (Gruber et al. 2009). Research
by Childs et al. (2017) suggests that dose may be important to
consider, as a low dose of oral THC attenuated cannabis users
subjective stress ratings after an acute stressor, while a high
dose increased subjective stress ratings, and neither dose in-
fluenced cortisol or heart rate. It has also been shown that
THC administration reduces emotional arousal to threatening
faces (Phan et al. 2008; Cornelius et al. 2010). Notably, these
studies have further shown that acute cannabinoid administra-
tion reduces amygdala reactivity in response to social signals
of threat (Phan et al. 2008) and enhances connectivity between
the amygdala and prefrontocortical subregions (Gorka et al.
2015), which is critical for proper emotional regulation, stress
coping, and cortisol secretion (Phan et al. 2005;Urryetal.
2006).
These data suggest a mechanism by which acute cannabis
consumption may elicit stress-alleviating effects. However,
comparatively fewer studies have examined the effects of
chronic cannabis consumption on stress-related endpoints,
and the results of these studies have been equivocal. For in-
stance, while some have shown that chronic cannabis use is
associated with higher baseline cortisol concentrations (King
et al. 2011; Monteleone et al. 2014; Somaini et al. 2012),
others have reported no significant differences (Block et al.
1991). Furthermore, DSouza and colleagues have shown that
THC-induced increase in cortisol is blunted in frequent users
relative to naïve controls (Ranganathan et al. 2009). Chronic
cannabis users also exhibit impaired adrenocorticotropic hor-
mone and cortisol release as well as reduced emotional reac-
tivity in response to unpleasant pictures compared to non-
users (Somaini et al. 2012). Moreover, higher levels of canna-
bis use have been associated with lower levels of amygdala
reactivity in response to images of threatening faces
(Cornelius et al. 2010). These results may indicate that chronic
cannabis use is associated with hypothalamic-pituitary-
adrenal (HPA) axis dysfunction. Alternatively, they may indi-
cate that chronic cannabis use could provide beneficial effects
in individuals exhibiting abnormal emotional responses to
threatening stimuli.
Although these data suggest a relationship between canna-
bis consumption and stress responsivity, surprisingly, no stud-
ies have examined the impact of an acute stressor on subjec-
tive or physiological indices of stress in chronic cannabis users
compared to non-users. Thus, the objective of our study was
to determine the effects of an acute stressor on subjective
stress, as well as on basal and stress-induced salivary cortisol
concentrations in chronic heavy cannabis users compared to
non-users. Additionally, given that stress can precipitate
symptoms of withdrawal and craving in drug users (Cleck
and Blendy 2008), we further sought to examine whether
acute stress increases subjective reports of cannabis craving
and withdrawal in chronic cannabis users. Based on data de-
scribed above indicating blunted emotional reactivity and
amygdala activation in chronic users (Cornelius et al. 2010),
we hypothesized that chronic cannabis users would exhibit
dampened subjective and physiological stress responses com-
pared to non-users but that acute stress would nevertheless
exacerbate cravings and symptoms of withdrawal.
Methods
Design and procedure
A 2 × 2 factorial design was used, with stresscondition (stress,
no stress) as a manipulated between-subject factor and canna-
bis use status (cannabis users, non-users) as a non-
manipulated between-subject factor. The Washington State
UniversityInstitutional Review Board reviewed and approved
the study; thus, all procedures were performed in accordance
with the ethical standards described in the 1964 Declaration of
Helsinki.
Participants were recruited via ads posted in local recrea-
tional marijuana dispensaries, local retail locations, as well as
on Facebook and Craigslist. Prior to scheduling an appoint-
ment, each participant was screened to ensure that he/she was
eligible. To be eligible, participants had to report no current
diagnosed or treated psychiatric conditions, no diagnosed
chronic medical or neurological disorders, and no current
use of medications containing steroids. Participants also could
not be heavy users of alcohol (e.g., defined as use of alcohol
four or more days of the week) and could not have used any
illicit drugs in the past 6 months. Further, cannabis users were
required to use cannabis on a daily or near daily basis (defined
as using cannabis a minimum of 34 days per week) for at
least 1 year and to abstain from cannabis on the day of testing.
Non-users were required to have used cannabis fewer than 10
times in their lives and never in the past year.
Upon arrival, participants were asked to sit quietly and wait
outside the lab room for 10 min to allow for any increases in
cortisol due to traveling and attempting to locate the lab to
diminish. After providing written informed consent, partici-
pants completed a brief survey, provided a baseline subjective
stress rating, and gave their first saliva sample. Participants
then completed either the stress or no stress condition of the
Maastricht Acute Stress Test (MAST), providing another sub-
jective stress rating half-way through the MAST. Immediately
2300 Psychopharmacology (2017) 234:22992309
after the MAST, participants once again gave a subjective
stress rating and saliva sample. Participants then completed
measures of cannabis withdrawal symptoms and cravings.
Finally, participants provided a urine sample, were debriefed,
and compensated with $25. Experimenters were blind to par-
ticipantscannabis use status until the urine sample was tested
after participants left the laboratory.
Materials
Screening Participants were screened via brief open-ended
questions to ensure that they met the study eligibility require-
ments. Specifically, participants were asked when they had
last used cannabis, how frequently they use cannabis, for
how long they had been using cannabis at that frequency,
approximately how many times they had used cannabis in
their lifetime, whether they had used any illicit drugs in the
past 6 months, how often they drink alcohol, and how many
drinks they consume when they drink alcohol. They were also
asked whether they had a current diagnosed psychological
disorder or were being treated for a psychological disorder;
whether they had any diagnosed chronic medical or neurolog-
ical disorders; whether they were currently taking prednisone,
dexamethasone, or any other steroids; whether they had ever
had a head injury involving a loss of consciousness for more
than 2 min; and whether they had ever been diagnosed with a
learning disability or intellectual disability.
Survey A brief survey was administered to assess demograph-
ic characteristics, chronic stress (the 10-item Perceived Stress
Scale (PSS); Cohen and Williamson 1988), and cannabis use
patterns (the Daily Sessions, Frequency, Age of Onset, and
Quantity of Cannabis Use Inventory; Cuttler and Spradlin
2017). The measure of chronic stress was used to ensure that
there were no baseline differences in chronic stress across the
groups and to control for individual differences in chronic
stress, as it is known that chronic stress can impact responses
to acute stress (Herman 2013). The measure of cannabis use
patterns was administered to assess lifetime and current can-
nabis use and to confirm that participants met the eligibility
requirements of the study.
Subjective stress Subjective stress was measured by asking
participants to rate how much stress they were currently
experiencing using a scale ranging from 0 (indicating no
stress) to 10 (indicating extreme stress). Similar single-item
measures of subjective stress have demonstrated content, cri-
terion, and construct validity (Elo et al. 2003).
Salivary cortisol Saliva samples were collected using
salivettes (Sarstedt, Germany). Participants were required to
refrain from ingesting anything other than water for 30 min
prior to their testing session. To collect saliva samples,
participants were instructed to rinse their mouth for 1 min
and then to tip the swab into their mouth, chew on it for
1 min, and then place it carefully back in to the plastic tube
without touching it. Saliva samples were taken before, during,
and after exposure to the stressor and subsequently stored at
20 °C until analysis. Radioimmunoassays for salivary corti-
sol concentrations were performed according to methods pre-
viously described (Tu et al. 2006) using a cortisol enzyme
immunoassay kit (Salimetrics, State College, PA). The assays
detection limit was 0.01 μg/dL, and the intra-assay coefficient
of variance was 5.67%.
THC urine test THC pre-dosage urine tests from Kappa City
Biotech (Saint Victor, France) were used to confirm the pres-
ence or absence of THC in urine. This test was used to ensure
that cannabis users were indeed cannabis users (that they had
detectable levels of THC in their urine) and that the non-users
had no THC in their system.
Maastricht Acute Stress Test (Smeets et al. 2012)Stress
was manipulated using the MAST, a multidimensional stress
paradigm that combines elements of physical, psychosocial,
and unpredictable stress. Participants in the stress condition
were required to place their hand in cold water (36 °F) for
trials of various lengths (45, 60, 90 s), which participants were
told were randomly set by the computer. Between these trials,
participants were required to count backwards from 2043 by
17 and were given negative feedback and required to start
again each time they made an error. Participants were further
monitored on a webcam, which they were told would be later
evaluated and which was displayed directly in front of them so
they could view themselves. Participants in the no stress con-
trol condition were required to place their hand in lukewarm
water (92 °F) for trials of the same lengths as those used in the
stress condition. Between trials, they were required to count
from 1 to 25, but they received no feedback and were not
video monitored. The entire MAST procedure lasted approx-
imately 10 min. In previous studies, the MAST has produced
similar subjective stress increases and increased salivary cor-
tisol responses, compared to more traditional cold pressor
tasks and the Trier Social Stress Test (Smeets et al. 2012).
Further, the stress condition of the MAST has been shown to
produce significantly higher salivary cortisol responses com-
pared to the no stress condition of the MAST (Smeets et al.
2012).
Withdrawal symptoms and cravings The Marijuana
Withdrawal Checklist (Budney et al. 2003) is a 15-item inven-
tory that was used to measure withdrawal symptoms. Scores
were averaged such that they could range from 0 (none) to 3
(severe). The MWC shows good internal consistency
(α= 0.81) and sensitivity to effects associated with abstinence
(Budney et al. 1999,2003). Cronbachs alpha in the present
Psychopharmacology (2017) 234:22992309 2301
sample was 0.77. The Cravings Questionnaire-Short Form
(Heishman et al. 2001) is a 12-item inventory that was used
to measure cannabis cravings. Scores were averaged such that
they could range from 1 (strongly disagree to experiencing
cravings) to 7 (strongly agree to experiencing cravings).
Cronbachs alpha in the present sample was 0.86.
Participants
A total of 87 participants passed the initial screening and were
tested. However, fiveparticipants were subsequently excluded
because their self-reported cannabis use patterns on the day of
testing were discrepant from their responses at the time of
screening and no longer conformed to our eligibility require-
ments (e.g., they used cannabis on the day of testing, or in the
case of non-users, had used cannabis more than 10 times in
their life).
The remaining 82 participants ranged from 20 to 64 years
of age with a mean of 25.84 (SE =0.86) years. The majority
of participants identified as white (70.7%), but the sample was
well balanced with respect to sex (52.4% male). Complete
demographic characteristics broken down by group are pro-
vided in Table 1.
Approximately half of the final sample (n= 40) comprised
cannabis users. All of the cannabis users tested positive for
THC in urine; almost all (n= 38; 95%) reported last using
cannabis the day prior to testing; one participant (2.5%) re-
ported last using cannabis this week, and one participant
(2.5%) reported last using cannabis last week. Over half
(55%) of the cannabis users reported using cannabis more than
once a day, 32.5% reported using it once a day, 5% reported
using cannabis five to six times per week, and 7.5% reported
using it three to four times per week. All cannabis users re-
ported using cannabis on a daily or near daily basis (a mini-
mum of three to four times per week) for at least 1 year, with
the majority (65%) reporting the use of cannabis on a near
daily basis for 3+ years.
The remaining (n= 42) participants comprised non-users.
The majority of the non-users (76.2%) reported never having
used cannabis. The remaining 23.8% of non-users reported
that they last used cannabis over a year ago and that they
had used cannabis 10 or fewer times in their entire life. All
non-users tested negative for THC in urine.
Statistical analyses
An a priori power analysis indicated that a sample size of 82
would provide power of 0.80 to detect medium-sized effects
(η
p
2
= 0.09) using factorial ANCOVA with four groups and an
alpha of 0.05. To control for variability in cortisol levels due to
individual differences, potential differences in burden of trav-
el, and time of day, cortisol difference scores were created.
Specifically, baseline cortisol levels were subtracted from
post-stress manipulation cortisol levels. Similarly, to account
for individual differences in subjective stress ratings, baseline
subjective stress ratings were subtracted from subjective stress
ratings at time points 1 (during the stressor) and 2 (immedi-
ately after the stressor). Table 2shows the baseline levels of
cortisol, subjective stress, and chronic stress across the four
groups.
Results
Baseline differences
Approximately half of the cannabis users (n= 19) were ran-
domly assigned to the stress condition, and the other half
(n= 21) were randomly assigned to the no stress condition.
These two groups did not differ significantly with respect to
when they last used cannabis, t(38) = 1.44, p=0.16,d=0.45,
the frequency they reported using cannabis, t(38) = 0.94,
p=0.35,d= 0.30, or the number of years they reported using
cannabis, t(35) = 0.64, p=0.53,d=0.21.
Half of the non-users (n= 21) were randomly assigned to
the stress condition, and half (n= 21) were randomly assigned
to the no stress condition. These two groups were perfectly
matched with respect to whether they had ever used cannabis,
χ
2
(1) = 0.00, p=1,φ
c
= 0.00, and in ratings of the number of
times they had used cannabis in their entire life, χ
2
(2) = 0.00,
p=1,φ
c
=0.00.
As shown in Table 1, comparisons of the four groups re-
vealed significant differences in the percentage of white can-
nabis users in the no stress condition and white non-users in
the no stress condition, as well as in the percentage of
employed/student cannabis users in the stress condition and
employed/student non-users in the stress condition. As such,
these variables were entered in as covariates in the primary
analyses (i.e., 2 × 2 ANCOVAs).
As shown in Table 2, comparisons of the baseline stress
measures (cortisol, subjective stress ratings, chronic stress
scores) across the four groups revealed only a significant dif-
ference in the mean baseline subjective stress ratings of the
cannabis users in the stress condition and the mean baseline
subjective stress ratings of the non-users in the stress condi-
tion. Once again, differencescoreswerecomputedby
subtracting baseline subjective stress ratings from subjective
stress ratings during the MAST and after the MAST to statis-
tically control for this baseline difference.
Finally, there were no significant differences in the time of
day (coded into hours) that cannabis users in the stress and no
stress conditions were tested, t(38) = 1.67, p=0.10,d=0.53,
in the time of day that non-users in the stress and no stress
conditions were tested, t(40) = 0.78, p=0.44,d= 0.24, in the
time of day that cannabis users in the stress condition and non-
users in the stress condition were tested, t(38) = 0.21,
2302 Psychopharmacology (2017) 234:22992309
p=0.83,d= 0.07, or in the time of day that cannabis users in
the no stress condition and non-users in the no stress condition
were tested, t(40) = 1.23, p=0.22,d=0.38.
Stress response
Cortisol A 2 × 2 ANCOVA with cannabis use status (cannabis
user, non-user) and stress condition (stress, no stress) as
between-subject factors and sex, ethnicity, employment status,
and chronic stress as covariates was conducted to examine
putative effects of cannabis use and the stress manipulation
on cortisol difference scores. The results revealed a significant
main effect of stress, F(1, 74) = 14.20, p<0.001,η
p
2
=0.16,
and a cannabis × stress interaction, F(1, 74) = 8.28 p=0.003,
η
p
2
= 0.10. As depicted in Fig. 1, follow-up one-way
ANCOVAs revealed significantly higher cortisol difference
scores in the non-users under conditions of stress relative to
the non-users in the no stress condition, F(1, 36) = 19.65,
p<0.001,η
p
2
= 0.35. In contrast, the cortisol difference scores
of the cannabis users in the stress condition were not signifi-
cantly different than the cortisol difference scores of the can-
nabis users in the no stress condition, F(1, 34) = 0.80,
p=0.38,η
p
2
= 0.02. Thus, cannabis users show reduced cor-
tisol mobilization in response to acute stress.
Subjective stress ratings Aseriesof2×2ANCOVAswith
cannabis use status (cannabis user, non-user) and stress con-
dition (stress, no stress) as between-subject factors and sex,
ethnicity, employment status, and chronic stress as covariates
were conducted with subjective stress difference scores as the
dependent variables. The results of the analysis on subjective
stress difference scores at time point 1 (during the stressor)
revealed a significant main effect of stress, F(1, 60) = 41.56,
p<0.001,η
p
2
= 0.41, and a cannabis × stress interaction, F(1,
Tabl e 1 Demographic characteristics of cannabis users and non-users in the stress and no stress conditions
Cannabis users Non-users
Stress No stress Stress No stress
Age M= 26.05 (SE =1.44) M= 25.14 (SE = 1.86) M= 26.95 (SE =2.23) M=25.24(SE =1.19)
Gender (male) 63.2% 71.4% 33.3% 42.9%
Ethnicity (white) 84.2% 81.00% 66.7% 52.4%
Education (post-secondary degree) 47.6% 47.4% 71.4% 71.4%
Current employment (employed or student) 68.4% 80.9% 95.2% 95.2%
Income (<$20,000) 73.7% 85.7% 76.2% 80.0%
Relationship status (single) 73.7% 85.7% 85.7% 76.2%
For all seven variables, ttests and chi-squared tests were conducted to compare (i) cannabis users in the stress condition to cannabis users in the no stress
condition, (ii) non-users in the stress condition to non-users in the no stress condition, (iii) cannabis users in the stress condition to non-users inthestress
condition, and (iv) cannabis users in the no stress condition to non-users in the no stress condition. The only significant differences that were detected
were in the comparison of the percentage of white cannabis users in the no stress condition and white non-users in the no stress condition, χ(1) = 3.86,
p=0.05,φ
c
= 0.30, and in the comparison of the percentage of employed/student cannabis users in the stress condition and employed/student non-users
in the stress condition, χ(1) = 3.86, p=0.05,φ
c
= 0.35. Ital values denote significant difference
Mmean, SE standard error of the mean
Tabl e 2 Baseline stress in cannabis users and non-users in the stress and no stress conditions
Cannabis users Non-users
Stress No stress Stress No stress
Baseline cortisol M=0.22(SE = 0.04) M=0.17(SE =0.03) M=0.16(SE = 0.02) M=0.19(SE =0.04)
Baseline subjective stress rating M = 3.16 (SE = 0.47) M =2.29(SE = 0.50) M = 1.86 (SE = 0.40) M =2.29(SE = 0.46)
Baseline chronic stress M=18.89(SE = 1.03) M= 14.48 (SE = 1.20) M= 16.00 (SE =1.61) M=15.14(SE =1.17)
For all three variables, ttests were conducted to compare (i) cannabis users in the stress condition to cannabis users in the no stress condition, (ii) non-
users in the stress condition to non-users in the nostresscondition, (iii) cannabis users in the stress conditionto non-users in the stress condition, and (iv)
cannabis users in the no stress condition to non-users in the no stress condition. The only significant difference that was detected was in the comparison of
the mean baseline subjective stress ratings of the cannabis users in the stress condition and the non-users in the stress condition, t(38) = 2.13, p=0.04,
d= 0.67. Ital values denote significant difference
Mmean, SE standard error of the mean
Psychopharmacology (2017) 234:22992309 2303
60) = 4.79, p=0.03,η
2
= 0.07. Follow-up tests revealed a
significant effect of the stress manipulation on the subjective
stress difference scores of non-users, F(1, 28) = 30.03,
p< 0.001, η
p
2
= 0.52, as well as cannabis users, F(1,
281) = 13.30, p=0.001,η
p
2
= 0.32. As depicted in Fig. 2,
the interaction indicates that the effect of the stress manipula-
tion on subjective stress ratings during the stressor was signif-
icantly smaller in the cannabis users than the non-users, once
again providing evidence for a blunted stress response. At
time point 2 (immediately after the stressor), there was only
a significant main effect of stress, F(1, 74) = 20.82, p<0.001,
η
p
2
= 0.22, and no cannabis × stress interaction, F(1,
77) = 2.07, p=0.15,η
p
2
=0.03(Fig.3).
Relationships between cortisol and subjective stress
ratings
Pearson bivariate correlation analyses indicated that overall
cortisol difference scores were significantly positively corre-
lated with subjective stress ratings at time point 1 (during the
stressor), r(66) = 0.42, p<0.001,aswellasattimepoint2
(immediately after the stressor), r(80) = 0.27, p= 0.02.
Analyses broken down by group revealed that for non-users,
cortisol difference scores were significantly positively
correlated with subjective stress ratings at time point 1 (during
the stressor), r(32) = 0.59, p<0.001,aswellasattimepoint2
(immediately after the stressor), r(40) = 0.45, p=0.003.In
contrast, for the cannabis users, there were no significant cor-
relations between cortisol difference scores and subjective
stress ratings at time point 1 (during the stressor),
r(32) = 0.06, p= 0.75, or at time point 2 (immediately after
the stressor), r(38) = 0.08, p= 0.61. Tests of the difference
between these two sets of correlations confirmed that the cor-
relations detected in non-users are significant higher than
those found in cannabis users (p=0.02,p= 0.01, for time
points 1 and 2, respectively).
Withdrawal symptoms and cravings Two separate 2 × 2
ANCOVAs were conducted with cannabis use status
(cannabis user, non-user) and stress condition (stress, no
stress) as between-subject factors; sex, ethnicity, employment,
and chronic stress as covariates; and cannabis withdrawal
symptoms and cravings as the dependent variables. The re-
sults of the analyses of withdrawal symptoms showed only a
significant main effect of cannabis use status, F(1, 74) = 6.92,
p=0.01,η
p
2
= 0.09. The effect of the stress manipulation was
not statistically significant, F(1, 74) = 0.08, p=0.78,
η
p
2
= 0.001, and the interaction between cannabis use and
Fig. 1 Mean cortisol difference
scores in non-users and cannabis
users in the no stress and stress
conditions of the MAST with
standard error bars. *p<0.05
Fig. 2 Mean subjective stress
difference scores in non-users and
cannabis users during the no
stress and stress conditions of the
MAST with standard error bars.
*p<0.05
2304 Psychopharmacology (2017) 234:22992309
stress was not statistically significant, F(1, 74) = 0.09,
p=0.77,η
p
2
= 0.001 (see Fig. 4). Planned comparisons of
the cannabis users in the stress condition with cannabis users
in the no stress condition also revealed no significant effect of
the stress manipulation on cannabis usersself-reported with-
drawal symptoms, F(1, 34) = 1.81, p=0.19,η
p
2
=0.05.
Similarly, as shown in Fig. 5, the results of the analyses of
cravings showed only a significant main effect of cannabis use
status, F(1, 74) = 136.67, p<0.001,η
p
2
= 0.65. The effect of
the stress manipulation was not significant, F(1, 74) = 1.33,
p=0.25,η
p
2
= 0.02, and the interaction between cannabis use
and stress was not significant, F(1, 74) = 0.17, p=0.68,
η
p
2
= 0.002. Planned comparisons of the cannabis users in
the stress condition with cannabis users in the no stress con-
dition also revealed no significant effect of the stress manipu-
lation on cannabis usersself-reported withdrawal symptoms,
F(1, 34) = 1.42, p=0.24,η
p
2
=0.04.
Discussion
The present study was conducted to examine the extent to
which basal and stress-induced cortisol concentrations and
subjective stress ratings differed between chronic cannabis
users and non-users in response to a multidimensional acute
stress manipulation. Despite abstaining from cannabis use on
the day of testing, cannabis users exhibited no increase in
salivary cortisol concentration in response to the stress manip-
ulation compared to non-users. Moreover, cannabis users
showed a diminished increase in subjective stress ratings dur-
ing the acute stressor relative to non-users. These dampened
responses to stress occurred in the absence of increased self-
reported cravings and symptoms of withdrawal. Together,
these data indicate that chronic cannabis users display blunted
psychological and adrenal stress reactivity compared to non-
users.
This study is unique in that it is the first to compare indices
of subjective and physiological stress in chronic cannabis
users and non-users following an acute stress manipulation
with distinct psychological and physiological components.
The main findings of this study are consistent with a growing
body of literature indicating that chronic cannabis use is asso-
ciated with blunted amygdala activation and emotional reac-
tivity to images of threatening faces (Cornelius et al. 2010)
and dampened hormonal responses to unpleasant images
(Somaini et al. 2012). Thus, converging evidence indicates
that chronic cannabis consumption may render users less re-
active to stressful and negatively valent images, both at a
psychological and physiological level. However, it is also
possible that residual low levels of active cannabinoids and
Fig. 3 Mean subjective stress
difference scores in non-users and
cannabis users immediately
following the no stress and stress
conditions of the MAST with
standard error bars. *p<0.05
Fig. 4 Mean self-reported
withdrawal symptoms in cannabis
users and non-users following the
no stress and stress conditions of
the MAST with standard error
bars. *p<0.05
Psychopharmacology (2017) 234:22992309 2305
associated metabolites impacted stressreactivity, and it will be
important for future research to examine stress reactivity in
cannabis users after a longer period of abstinence.
These cannabis-related alterations in the stress response
could be particularly beneficial in conferring enhanced resil-
ience to stress, particularly in individuals exhibiting sensitized
HPA axis responses and heightened emotional reactivity to
stress. At the neurobiological level, excessive glucocorticoid
activity can lead to atrophy in brain areas responsible for HPA
axis negative feedback, such as the hippocampus, prefrontal
cortex, and amygdala, which can contribute to the emergence
of stress-related neuropsychiatric disorders involving hyper-
arousal as a symptom, such as melancholic depression (see
McEwen 1998;McEwenetal.2016 for reviews). Thus,
chronic cannabis use may protect against exaggerated gluco-
corticoid secretion in individuals at risk for developing mel-
ancholic depression or other disorders characterized by persis-
tent hyperarousal. In this respect, it is not particularly surpris-
ing that the most commonly cited reasons for medical canna-
bis use are to manage stress and alleviate symptoms of anxiety
(Sexton et al. 2016; Webb and Webb 2014).
While a dampened emotional and hormonal response to
stress can certainly be beneficial under certain circumstances,
it is important to note that acute cortisol release typically
serves an adaptive purpose, allowing individuals to mobilize
energy stores and respond appropriately to threats in the envi-
ronment (McEwen 1998). Thus, an inability to mount a proper
hormonal response to stress could also have detrimental ef-
fects that could subsequently increase vulnerability for devel-
oping other pathological states. For instance, an inability to
mount an effective cortisol response during a traumatic event
has been identified as a key determinant of post-traumatic
stress disorder susceptibility (see Yehuda 2009 for review).
Additionally, the atypical subtype of major depression has
been associated with reduced cortisol concentrations com-
pared to healthy controls (Gold and Chrousos 2002;Lamers
et al. 2013). Furthermore, in mice, high anxiety-like behavior
is associated with significantly reduced corticosterone secre-
tion to an acute stressor and a blunted response in the
dexamethasone suppression test compared to normal and
low anxiety mice (Sotnikov et al. 2014). These data indicate
that blunted HPA axis reactivity may actually perpetuate the
development of the very symptoms that individuals are using
cannabis to alleviate. Therefore, chronic cannabis use may
have either beneficial or detrimental consequences, which
are likely dependent on individual differences in the sensitiv-
ity of HPA axis activation prior to initiating chronic cannabis
use.
As expected, there was a strong positive correlation be-
tween levels of perceived stress and salivary cortisol concen-
tration in non-users. However, this correlation was conspicu-
ously absentin chronic cannabis users. Thus, despite reporting
increased subjective stress (albeit not to the extent of non-
users), chronic cannabis users did not show a corresponding
recruitment of cortisol during the stressor. This suggests that
there may be a discordance between subjective and physio-
logical stress measures in chronic cannabis users, which fur-
ther supports the idea that these individuals have general im-
pairments in cortisol mobilization.
The fact that we failed to observe a significant increase in
cortisol in chronic cannabis users following the stress condi-
tion is especially interesting because the MAST includes a
physiologically stressful component (holding hand in ice-
cold water) along with a psychosocialcomponent (performing
difficult math under conditions of social evaluation). Based on
previous findings that the hormonal response to emotionally
valent stimuli is blunted in chronic cannabis users (Somaini
et al. 2012), and that psychosocial and physiological stressors
each activate the HPA axis via distinct pathways (Herman
et al. 2016), one might predict that the stress dampening ef-
fects of chronic cannabis use would be specific to psychoso-
cial stress, with the physiological stress response remaining
intact. That cannabis users similarly failed to mount a proper
cortisol response to the physiological component of the stress-
or further underscores the notion that the blunted stress re-
sponse observed herein may be more detrimental than benefi-
cial. Nevertheless, there is evidence that the normal hormonal
response can recover following an extended period of
Fig. 5 Mean self-reported
cravings in cannabis users and
non-users following the no stress
and stress conditions of the
MAST with standard error bars.
*p<0.05
2306 Psychopharmacology (2017) 234:22992309
abstinence, even though the perceived unpleasantness of neg-
ative emotional images remains blunted (Somaini et al. 2012).
Future research should therefore examine whether a period of
abstinence would similarly lead to a recovery of the normal
response to an acute stressor such as the MAST.
There are multiple mechanisms by which chronic cannabis
use may be dampening physiological stress responsivity. For
instance, acute stress exposure is well known to recruit cate-
cholamines (i.e., noradrenaline and dopamine) to activate the
HPA axis (McEwen and Sapolsky 1995), while chronic can-
nabis use has been associated with impairments in dopamine
synthesis and release (see Sami et al. 2015 for review). Thus,
the blunted endocrine stress response observed herein could
be due to compromised recruitment of catecholamines in
heavy cannabis users. In support of this, Volkow et al.
(2014) have demonstrated that chronic cannabis users display
attenuated behavioral, cardiovascular, and brain dopamine re-
sponses to methylphenidate, which increases catecholamine
concentrations by blocking the dopamine and norepinephrine
transporters. However, a recent PET study has shown that the
striatal dopamine response to acute psychosocial stress is not
significantly altered in chronic cannabis users (Mizrahi et al.
2013), which argues against this being a central mechanism
underlying the observed effects.
Alternately, a more parsimonious explanation could be that
chronic cannabis use is dampening stress reactivity by inter-
fering with the normal actions of the endocannabinoid system,
the primary target for cannabis in the brain. Indeed, mounting
evidence has indicated a fundamental role for the
endocannabinoid system in constraining HPA axis activation,
promoting stress recovery, and dictating proper behavioraland
emotional responses to stressful stimuli (Hill and Tasker 2012;
McLaughlin et al. 2014). Endocannabinoid-mediated activa-
tion of the type 1 cannabinoid receptor is required for many
glucocorticoid effects, particularly negative feedback inhibi-
tion of HPA axis activation (Di et al. 2003; Malcher-Lopes
et al. 2006;Hilletal.2011), while chronic cannabinoid ad-
ministration causes alterations in endocannabinoid content in
both humans (Morgan et al. 2013) and rodents (Di Marzo et al.
2000; González et al. 2004). Thus, cannabis-induced alter-
ations in endocannabinoid signaling could contribute to the
attenuated hormonal response observed herein. Clearly, future
studies will be required to fully understand the precise mech-
anisms by which heavy cannabis use blunts stress reactivity.
Exposure to psychological and physiological stress is well
known to augment craving in regular drug users (see Cleck
and Blendy 2008 for review). Given the literature showing
that stress coping motives often underlie cannabis-seeking
behaviors in habitual users (Hyman and Sinha 2009), it is
surprising that our group of heavy cannabis users did not
report increased cravings in response to stress. Although this
could be due to several factors, our data indicating that can-
nabis users also reported a diminished increase in subjective
stress suggests that this acute manipulation in a controlled
laboratory setting may not have been sufficient to augment
cannabis craving. Alternatively, it could be that stress-
induced cannabis craving only occurs in distinct subpopula-
tions, such as those with social anxiety disorder. For instance,
individuals with social anxiety disorder have been found to
report greater cannabis craving during a public speaking task,
an effect that was absent in cannabis users without social
anxiety (Buckner et al. 2011). Similarly, cannabis users
assigned to a social anxiety induction task (but not a reading
task) reported increased cannabis craving, an effect that was
exacerbated in individuals with social anxiety disorder
(Buckner et al. 2013,2016). Thus, the lack of effect on can-
nabis craving in the current study may be because the cannabis
users were not sufficiently impacted bythe stressoror because
this phenomenon is unique to individuals experiencing path-
ological anxiety.
Less is known about the effects of acute stress on cannabis
userswithdrawal symptoms, and to our knowledge, the pres-
ent study represents the first attempt to examine this potential
impact. Consistent with the findings on cannabis cravings, the
results indicate that acute stress does not trigger cannabis
withdrawal symptoms. However, the lack of significant effect
may once again be a function of cannabis usersdampened
stress response. Moreover, given that most participants had
abstained from cannabis for less than 24 h and that cannabis
withdrawal symptoms peak after approximately 1 week of
abstinence (Hesse and Thylstrup 2013), it is possible that in-
troducing an acute stressor after a more prolonged period of
abstinence would exacerbate withdrawal symptoms, cannabis
cravings, and possibly stress reactivity.
There are several noteworthy limitations to acknowledge.
First, we did not obtain baseline measures of cannabis crav-
ings and withdrawal symptoms because we did not want to
illicit cravings or trigger withdrawal symptoms prior to the
stress manipulation due to concerns that this would impact
cannabis usersstress response. Nevertheless, future research
should obtain these baseline measures in order to examine
changes in cravings and withdrawal symptoms as a function
of acute stress. Second, given the short period of abstinence, it
is possible that residual levels of THC in the cannabis users
may have influenced their responses. Once again, future re-
search should attempt to replicate these findings after a more
prolonged period of abstinence. Third, while all participants
were screened for any illicit drug use in the past month, we did
not measure or statistically control for illicit drug use beyond
this period of time or for use of tobacco. Cigarette smokers
also elicit lower salivary cortisol levels in response to stress
(Ginty et al. 2014), and therefore, it will be important for
future research to replicate these results in non-cigarette
smokers or groups of cannabis users and non-users matched
on tobacco use. Future research should also seek to balance
the distribution of males and females across groups and
Psychopharmacology (2017) 234:22992309 2307
measure menstrual cycle phase in order to examine potential
sex differences and/or menstrual cycle phase effects on the
cannabis × stress interactions found in the present study.
In conclusion, the results of the current study indicate that
the subjective and physiological responses to an acute stressor
are significantly blunted in heavy cannabis users compared to
non-users. Additionally, a discordance between subjective and
physiological stress was observed in cannabis users that may
suggest general impairments in the recruitment of cortisol in
response to stress. Notably, these aberrations occurred in the
absence of increased self-reported craving and symptoms of
withdrawal. Future studies will be needed to identify both the
positive and negative implications of blunted stress reactivity
in chronic cannabis users, the mechanisms by which chronic
cannabis use impairs cortisol mobilization, and whether these
effects are reversible following a period of abstinence.
Acknowledgements Washington State Universitys Dedicated
Marijuana Account funded this study. We thank Anthony Berger for
running the cortisol assays.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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Psychopharmacology (2017) 234:22992309 2309
... For example, there is research suggesting long-term changes in the endocannabinoid system in response to chronic cannabis use (Fox et al. 2013), although research on long-term effects of cannabis use on hypothalamic-pituitary-adrenal (HPA) responses is scant. Limited research indicates effects of regular cannabis use on heart rate (Li et al. 2005), subjective, and cortisol responses to stress (Cuttler et al. 2017;Somaini et al. 2012). Although other studies have found cortisol responses in the opposite direction (Fox et al. 2013) or not at all (Mizrahi et al. 2013). ...
... Our study provides a partial replication and an extension of recent studies on cannabis use (Cuttler et al. 2017;De Angelis and al'Absi 2020) and of studies on nicotine use (al'Absi 2018;al'Absi et al. 2003;Ginty et al. 2014;Lovallo et al. 2019;Sorocco et al. 2006) by examining the effects of co-use of these substances on acute stress responses. Chronic nicotine use has been associated with alterations in physiological systems involved in stress responses, with nicotine users showing decreased cortisol and SBP responses to acute stress (Badrick et al. 2007;Ginty et al. 2014;Rohleder and Kirschbaum 2006). ...
... Although acute stress in the current study produced the expected increases in cardiovascular and cortisol measures, unlike a previous study (Cuttler et al., 2017), we did not observe blunted stress responses in cortisol among regular users of cannabis, nor did we observe significant effects of cannabis use on cardiovascular measures. It is possible that our study found different results for cortisol stress reactivity due to the acute stress tasks or due to the nature of our within-subject study design. ...
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Rationale Cannabis is one of the most prevalent substances used by tobacco smokers and, in light of the growing list of states and territories legalizing cannabis, it is expected that co-use of cannabis and nicotine will escalate significantly and will lead to continuing challenges with tobacco use. Objectives This study was conducted to examine the interactive effects of chronic cannabis and nicotine use on adrenocortical, cardiovascular, and psychological responses to stress and to explore sex differences in these effects. Methods Participants (N = 231) included cannabis-only users, nicotine-only users, co-users of both substances, and a non/light-user comparison group. After attending a medical screening session, participants completed a laboratory stress session during which they completed measures of subjective states, cardiovascular responses, and salivary cortisol during baseline (rest) and after exposure to acute stress challenges. Results Nicotine use, but not cannabis use, was associated with blunted cortisol and cardiovascular responses to stress across both men and women. Men exhibited larger cortisol responses to stress than women. Co-users had significantly larger stress-related increases in cannabis craving than cannabis-only users. Cannabis users reported smaller increases in anxiety during stress than cannabis non/light-users, and both male nicotine-only users and male cannabis-only users experienced significantly smaller increases in stress than their non/light-user control counterparts. Conclusions This study replicates and extends earlier research on the impacts of sex and nicotine use on stress responses, and it provides novel findings suggesting that when co-used with nicotine, cannabis use may not confer additional alterations to physiological nor subjective responses to stress. Co-use, however, was associated with enhanced stress-related craving for cannabis.
... The existing literature focused on the effects of cannabis use on hormone function focuses almost exclusively on adults and predominantly on fertility, sexual function, hunger hormones, thyroid function, and psychobiological aspects of stress. 11,[86][87][88][89][90][91][92][93] Some studies have shown that cannabis use may affect hormone levels involved in various important endocrine systems, including the hypothalamic-pituitary-adrenal (HPA) axis. 86,94 Although adolescent-focused research on this topic is scarce, increasing attention has been given to the possible effect of cannabis on pubertal timing and tempo in adolescents, informed by animal studies conducted in the 1980s and 1990s. ...
... 11,[86][87][88][89][90][91][92][93] Some studies have shown that cannabis use may affect hormone levels involved in various important endocrine systems, including the hypothalamic-pituitary-adrenal (HPA) axis. 86,94 Although adolescent-focused research on this topic is scarce, increasing attention has been given to the possible effect of cannabis on pubertal timing and tempo in adolescents, informed by animal studies conducted in the 1980s and 1990s. Specifically, animal data support that prepubertal exposure to cannabis is associated with pubertal delays in women and decreases in pubertal growth spurts in men. ...
... The HPA axis is responsible for the physiological response to stress, and dysfunction in the HPA axis can have negative consequences for physical and emotional health. 14,86,94,111 Few studies had samples of adolescents, and studies that had adolescent samples were either animal studies or clinical samples, such as adolescents who are at-risk for psychosis. 111,112 However, findings from a nonclinical cohort study of adolescents, the TRacking Adolescents' Individual Lives Survey (TRAILS) study, have yielded interesting results pertaining to stress reactivity and cannabis use. ...
Article
The current review highlights the available research related to cannabis and indicators of physical health in a variety of domains. Various studies have found associations between cannabis use with pulmonary, cardiovascular, gastrointestinal, and endocrine function as well as body mass index and sleep. At this time, more research is needed to understand the influence of cannabis use on physical health, particularly among adolescent samples.
... It might be that the Flanker Test induced a greater emotional arousal state (stress) in the older THC users, which might have resulted in poorer performance ( Table 2). Chronic cannabis use has also been related to the dysregulation of stress responsivity in humans [63], with studies indicating that chronic use was related to both blunted and hyperactive stress responses [64][65][66]. Cuttler, et al. [66] showed that controls had increased cortisol levels under a stress-provoking condition compared to baseline. They did not notice similar increases in active cannabis users. ...
... Chronic cannabis use has also been related to the dysregulation of stress responsivity in humans [63], with studies indicating that chronic use was related to both blunted and hyperactive stress responses [64][65][66]. Cuttler, et al. [66] showed that controls had increased cortisol levels under a stress-provoking condition compared to baseline. They did not notice similar increases in active cannabis users. ...
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Δ9-Tetrahydrocannabinol is the main psychoactive component of cannabis and cannabidiol is purportedly responsible for many of the medicinal benefits. The effects of Δ9-tetrahydrocannabinol and cannabidiol in younger populations have been well studied; however, motor function, cognitive function, and cerebral glucose metabolism in older adults have not been extensively researched. The purpose of this study was to assess differences in cognitive function, motor function, and cerebral glucose metabolism (assessed via [18F]-fluorodeoxyglucose positron emission tomography) in older adults chronically using Δ9-tetrahydrocannabinol, cannabidiol, and non-using controls. Eight Δ9-tetrahydrocannabinol users (59.3 ± 5.7 years), five cannabidiol users (54.6 ± 2.1 years), and 16 non-users (58.2 ± 16.9 years) participated. Subjects underwent resting scans and performed cognitive testing (reaction time, Flanker Inhibitory Control and Attention Test), motor testing (hand/arm function, gait), and balance testing. Δ9-tetrahydrocannabinol users performed worse than both cannabidiol users and non-users on the Flanker Test but were similar on all other cognitive and motor tasks. Δ9-tetrahydrocannabinol users also had lower global metabolism and relative hypermetabolism in the bilateral amygdala, cerebellum, and brainstem. Chronic use of Δ9-tetrahydrocannabinol in older adults might negatively influence inhibitory control and alter brain activity. Future longitudinal studies with larger sample sizes investigating multiple Δ9-tetrahydrocannabinol:cannabidiol ratios on functional outcomes and cerebral glucose metabolism in older adults are necessary.
... Our findings regarding stress may also be somewhat consistent with past research. Previous work has demonstrated for example that cannabis use may be associated with a blunted stress response [71]. Regarding anxiety, however, the evidence is less clear-cut. ...
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Background Some evidence suggests substance use affects clinical outcomes in people with posttraumatic stress disorder (PTSD). However, more work is required to examine links between mental health and cannabis use in PTSD during exposure to external stressors such as the COVID-19 pandemic. This study assessed mental health factors in individuals with self-reported PTSD to: (a) determine whether stress, anxiety, and depression symptoms were associated with changes in cannabis consumption across the pandemic, and (b) to contrast the degree to which clinically significant perceived symptom worsening was associated with changes in cannabis intake. Method Data were obtained as part of a larger web-based population survey from April 3rd to June 24th 2020 (i.e., first wave of the pandemic in Canada). Participants ( N = 462) with self-reported PTSD completed questionnaires to assess mental health symptoms and answered questions pertaining to their cannabis intake. Participants were categorized according to whether they were using cannabis or not, and if using, whether their use frequency increased, decreased, or remained unchanged during the pandemic. Results Findings indicated an overall perceived worsening of stress, anxiety, and depression symptoms across all groups. A higher-than-expected proportion of individuals who increased their cannabis consumption reached threshold for minimal clinically important worsening of depression, X ² (3) = 10.795, p = 0.013 (Cramer’s V = 0.166). Conclusion Overall, those who increased cannabis use during the pandemic were more prone to undergo meaningful perceived worsening of depression symptoms. Prospective investigations will be critical next steps to determine the directionality of the relationship between cannabis and depressive symptoms.
... Although these effects appear independent of any hormonal changes, other evidence suggests cannabis affects the hypothalamic-pituitary-adrenal axis, resulting in elevated cortisol levels in infrequent users and depressed adrenocorticotropic hormone and cortisol reactivity among frequent users (Cservenka et al., 2018;Cuttler et al., 2017). ...
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Substance abuse is an established risk factor for crime and violence, including sexual violence. Nevertheless, the link between cannabis use and sexual offenses remains poorly understood. Cannabis use has a broad effect on sexual functioning and can have both acute and lasting adverse effects on psychological functioning, which in turn can elevate the risk of sexual offending behavior. Yet there is a scarcity of studies that have examined the link between cannabis use and sexual offending. To help fill the gap, this perspective review investigates the link between substance use and crime with a particular emphasis on cannabis use and its effects on sexual and psychological functioning. It then explores how these mechanisms may contribute to sexual offenses and recidivism, with a final discussion on how cannabis use should be conceptualized as a risk factor for sexual violence.
Article
Background To advance our understanding of the health-related consequences of chronic cannabis use, this study examined hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) reactivity and regulation in response to a well-characterized, acute, social evaluative stress task among cannabis users and non-users. We also explored differences in HPA-SNS coordination across the stress task in cannabis users and non-users. Method Participants were 75 adults (53% female) who reported no use of tobacco/nicotine products. Cannabis use was measured using self-report and salivary/urinary THC levels. Participants were classified as cannabis users (n = 33) if they reported using cannabis at least twice per week in the prior year and had a positive salivary/urinary THC test or as non-users (n = 42) if they reported no use in the prior year and had a negative THC test. During a laboratory visit, participants completed the standard Trier Social Stress Test (TSST) and provided saliva samples before, and 5, 20, and 40 minutes after the task. Samples were assayed for salivary cortisol and alpha-amylase (sAA) as indices of HPA and SNS activity, respectively. Results Multilevel piecewise growth models revealed that, relative to non-users, cannabis users showed (a) blunted cortisol reactivity and recovery to the TSST, and (b) greater reductions in sAA concentrations following the TSST. Chronic cannabis users may exhibit blunted HPA axis responses and greater SNS recovery to acute psychosocial stress. Implications of individual differences in stress reactivity and regulation for the biobehavioral health of chronic cannabis users are discussed.
Chapter
Legalization of cannabis in the US and other countries highlight the need to understand the health consequences of this substance use. Research indicates that some cannabis ingredients may play beneficial role in treating various medical conditions while other ingredients may pose health risks. This review is focused on the brain and mental health effects of cannabis use. The rationale for examining cannabis use in behavioral and neural conditions is that these conditions are highly widespread in the US and account for high level of medical healthcare and associated cost. The purpose of this review is to provide an overview of the known medicinal benefits of selected cannabis cannabinoids in conditions like pediatric epilepsy, attention deficit hyperactivity disorder, autism spectrum disorder, and the known side effects or contraindications in conditions such as addiction, cognition, and psychosis. Several recommendations are made as to studies that will help further understanding the increasing role of cannabis in neuropsychiatric health and disease.
Chapter
Cannabinoid hyperemesis syndrome (CHS) was first described in 2004 as a cyclic vomiting illness in cannabis users. It is a puzzling condition because cannabis is a well characterized antiemetic. Cannabis acts through cannabinoid receptors of the endocannabinoid system, which is expressed throughout the body, including the gut-brain axis, where it influences neural, immune, and epithelial mechanisms involved in digestive and defensive functions of the gut. This chapter outlines the pathways of the gut-brain axis involved in nausea and emesis that are regulated by cannabinoid receptors and examines the cannabinoid receptor biology that is central to an understanding of the emetic and antiemetic actions of cannabis. In the final section, potential mechanisms for development of CHS are described based on preclinical literature, case studies, and clinical findings that constitute our understanding of this condition. Chronic cannabis consumption is the precipitating factor for CHS development in susceptible individuals. Many factors may contribute to mechanisms of CHS, including downregulation of cannabinoid-1 receptors, hypothalamic–pituitary–adrenal axis dysregulation, concomitant mood disorders, and altered endocannabinoid system genetics or epigenetics. Evidence for these potential mechanisms is limited. Future research aimed at understanding CHS pathophysiology is required to provide a better understanding of the biology and epidemiology of this debilitating condition.
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Several studies have found an association between salivary cortisol levels and dropping out of inpatient substance addiction treatment programs. The results are mixed due to variations in the study design and the lack of standardized routines for cortisol assessment. The aim of this study was to investigate whether there was (1) an association between salivary cortisol levels and dropping out from inpatient substance addiction treatments; (2) higher predictive validity for dropout in one of the cortisol indexes: Area Under the Curve with respect to ground (AUC G ) or Daily Cortisol Slope (DCS); (3) an interaction effect with time for each cortisol index; and (4) different dropout rates for sex and patients in short-term versus long-term treatment programs. This was a prospective, repeated-measures observational study. Patients (n = 173) were recruited from 2 inpatient facilities in the central region of Norway between 2018 and 2021. Salivary cortisol was measured 4 times during the treatment period, with 8 samples collected over 2 consecutive days at each time point. Cortisol levels were calculated using the cortisol indices AUC G and DCS. Dropout was used as the outcome measure at each time point. Associations were calculated using a logistic linear regression. The results suggest a main effect of AUC G , whereby higher levels reduce dropout risk (OR = 0.92, P = .047). An interaction with time in treatment also revealed a higher dropout risk (OR = 1.09, P = .044) during week 4 of the treatment, depending on the AUC G. These results support using AUC G as the recommended index when assessing cortisol, and that the relationship between cortisol levels and length of treatment should be further investigated.
Article
Objective: Given increasing rates of daily cannabis use and Cannabis Use Disorder (CUD) in the United States, it is imperative to understand CUD mechanisms in high-risk groups. Cannabis users with high distress intolerance (DI) are at elevated risk for severe and chronic CUD, but neural mechanisms linking CUD and DI are unknown. Cross-sectional data suggests that acute stress modulation of the cannabis and threat cue-elicited late positive potential (LPP), a neurophysiological marker of motivated attention, are possible mechanisms. However, longitudinal research is needed to clarify the roles of these elicited LPPs in CUD maintenance. Method: Sixty cannabis users with high DI were randomized a brief computerized intervention targeting DI or a control intervention. Elicited LPPs were measured before and after a stressor at baseline and postintervention. Intervention effects on stress modulation of the cannabis and threat LPPs, as well as their prospective associations with CUD, were assessed. Results: Elicited LPPs did not significantly change in either intervention group. Acute stress enhancement of the cannabis LPP predicted more severe CUD and greater chronicity at 4-month follow-up. Conclusions: Cannabis and threat LPPs were not altered by a brief DI intervention despite improvement in DI and cannabis use outcomes. Given that acute stress enhancement of the cannabis LPP predicted poorer CUD outcome, it may be a fruitful intervention target in distress intolerant cannabis users. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Objective We created the Daily Sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ-CU) because the current lack of psychometrically sound inventories for measuring these dimensions of cannabis use has impeded research on the effects of cannabis in humans. Method A sample of 2,062 cannabis users completed the DFAQ-CU and was used to assess the DFAQ-CU’s factor structure and reliability. To assess validity, a subsample of 645 participants completed additional measures of cannabis dependence and problems (Marijuana Smoking History Questionnaire [MSHQ], Timeline Followback [TLFB], Cannabis Abuse Screening Test [CAST], Cannabis Use Disorders Identification Test Revised [CUDIT-R], Cannabis Use Problems Identification Test [CUPIT], and Alcohol Use Disorder Identification Test [AUDIT]). Results A six-factor structure was revealed, with factors measuring: daily sessions, frequency, age of onset, marijuana quantity, cannabis concentrate quantity, and edibles quantity. The factors were reliable, with Cronbach’s alpha coefficients ranging from .69 (daily sessions) to .95 (frequency). Results further provided evidence for the factors’ convergent (MSHQ, TLFB), predictive (CAST, CUDIT-R, CUPIT), and discriminant validity (AUDIT). Conclusions The DFAQ-CU is the first psychometrically sound inventory for measuring frequency, age of onset, and quantity of cannabis use. It contains pictures of marijuana to facilitate the measurement of quantity of marijuana used, as well as questions to assess the use of different forms of cannabis (e.g., concentrates, edibles), methods of administering cannabis (e.g., joints, hand pipes, vaporizers), and typical THC levels. As such, the DFAQ-CU should help facilitate research on frequency, quantity, and age of onset of cannabis use.
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Background: The political climate around Cannabis as a medicine is rapidly changing. Legislators are adopting policies regarding appropriate medical applications, while the paucity of research may make policy decisions around conditions for which Cannabis is an effective medicine difficult. Methods: An anonymous online survey was developed to query medical Cannabis users about the conditions they use Cannabis to treat, their use patterns, perception of efficacy, and physical and mental health. Participants were recruited through social media and Cannabis dispensaries in Washington State. Results: A total of 1429 participants identified as medical Cannabis users. The most frequently reported conditions for which they used Cannabis were pain (61.2%), anxiety (58.1%), depression (50.3%), headache/migraine (35.5%), nausea (27.4%), and muscle spasticity (18.4%). On average, participants reported an 86% reduction in symptoms as a result of Cannabis use; 59.8% of medical users reported using Cannabis as an alternative to pharmaceutical prescriptions. Global health scores were on par with the general population for mental health and physical health. Conclusions: While patient-reported outcomes favor strong efficacy for a broad range of symptoms, many medical users are using Cannabis without physician supervision and for conditions for which there is no formal research to support the use of Cannabis (e.g., depression and anxiety). Future research and public policy should attempt to reduce the incongruence between approved and actual use.
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The hypothalamo-pituitary-adrenocortical (HPA) axis is required for stress adaptation. Activation of the HPA axis causes secretion of glucocorticoids, which act on multiple organ systems to redirect energy resources to meet real or anticipated demand. The HPA stress response is driven primarily by neural mechanisms, invoking corticotrophin releasing hormone (CRH) release from hypothalamic paraventricular nucleus (PVN) neurons. Pathways activating CRH release are stressor dependent: reactive responses to homeostatic disruption frequently involve direct noradrenergic or peptidergic drive of PVN neurons by sensory relays, whereas anticipatory responses use oligosynaptic pathways originating in upstream limbic structures. Anticipatory responses are driven largely by disinhibition, mediated by trans-synaptic silencing of tonic PVN inhibition via GABAergic neurons in the amygdala. Stress responses are inhibited by negative feedback mechanisms, whereby glucocorticoids act to diminish drive (brainstem) and promote transsynaptic inhibition by limbic structures (e.g., hippocampus). Glucocorticoids also act at the PVN to rapidly inhibit CRH neuronal activity via membrane glucocorticoid receptors. Chronic stress-induced activation of the HPA axis takes many forms (chronic basal hypersecretion, sensitized stress responses, and even adrenal exhaustion), with manifestation dependent upon factors such as stressor chronicity, intensity, frequency, and modality. Neural mechanisms driving chronic stress responses can be distinct from those controlling acute reactions, including recruitment of novel limbic, hypothalamic, and brainstem circuits. Importantly, an individual's response to acute or chronic stress is determined by numerous factors, including genetics, early life experience, environmental conditions, sex, and age. The context in which stressors occur will determine whether an individual's acute or chronic stress responses are adaptive or maladaptive (pathological).
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Sustained exposure to various psychological stressors can exacerbate neuropsychiatric disorders, including drug addiction. Addiction is a chronic brain disease in which individuals cannot control their need for drugs, despite negative health and social consequences. The brains of addicted individuals are altered and respond very differently to stress than those of individuals who are not addicted. In this Review, we highlight some of the common effects of stress and drugs of abuse throughout the addiction cycle. We also discuss both animal and human studies that suggest treating the stress-related aspects of drug addiction is likely to be an important contributing factor to a long-lasting recovery from this disorder.
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Social anxiety disorder appears to be a risk factor for cannabis-related problems. Although it is presumed that increases in cannabis craving during elevated social anxiety reflect an intent to cope with greater negative affectivity, it is unclear whether increases in physiological arousal during social stress are related to cannabis craving, especially among those with social anxiety disorder. Similarly, no studies have assessed motivational reasons for cannabis use during elevated social stress. Thus, the current study tested whether increases in state social anxiety (measured subjectively and via physiological arousal) were related to greater cannabis craving among 126 current cannabis users (88.9% with cannabis use disorder, 31.7% with social anxiety disorder, 54.0% non-Hispanic Caucasian) randomly assigned to either a social interaction or reading task. As predicted, cannabis users in the social interaction condition reported greater cannabis craving than those in the reading condition. This effect was particularly evident among those with social anxiety disorder. Although physiological arousal did not moderate the relationship between condition and craving, coping motives were the most common reasons cited for wanting to use cannabis and were reported more among those in the social interaction task. These experimental results uniquely add to a growing literature suggesting the importance of elevated state social anxiety (especially among those with social anxiety disorder) in cannabis use vulnerability processes.
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The hippocampus provided the gateway into much of what we have learned about stress and brain structural and functional plasticity, and this initial focus has expanded to other interconnected brain regions, such as the amygdala and prefrontal cortex. Starting with the discovery of adrenal steroid, and later, estrogen receptors in the hippocampal formation, and subsequent discovery of dendritic and spine synapse remodeling and neurogenesis in the dentate gyrus, mechanistic studies have revealed both genomic and rapid non-genomic actions of circulating steroid hormones in brain. Many of these actions occur epigenetically and result in ever-changing patterns of gene expression, in which there are important sex differences that need further exploration. Moreover, glucocorticoid and estrogen actions occur synergistically with an increasing number of cellular mediators that help determine the qualitative nature of the response. The hippocampus has also been a gateway to understanding lasting epigenetic effects of early life experiences. These findings in animal models have resulted in translation to the human brain and have helped change thinking about the nature of brain malfunction in psychiatric disorders and during aging, as well as the mechanisms of the effects of early life adversity on the brain and body.Neuropsychopharmacology accepted article preview online, 16 June 2015. doi:10.1038/npp.2015.171.