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Earlier initiation of cannabis use is associated with poorer neuropsychological functioning across several domains. Given well-documented sex differences in neuromaturation during adolescence, initiation of cannabis use during this time may affect neuropsychological functioning differently for males and females. In the current study, we examined sex differences in the relationship between age of initiated cannabis use and neuropsychological performance after controlling for amount of lifetime cannabis use in 44 male and 25 female young adult cannabis users. We found that an earlier age of initiated use was related to poorer episodic memory, especially immediate recall, in females, but not in males. On the other hand, we found that, surprisingly, an earlier age of initiated use was associated with better decision making overall. However, exploratory analyses found sex-specific factors associated with decision making and age of initiated use, specifically that attention-deficit/hyperactivity disorder (ADHD) symptoms in females may drive the relationship between an earlier age of initiated use and better decision making. Further, an earlier age of initiated use was associated with less education, a lower IQ, and fewer years of mother's education for females, but more lifetime cannabis use for males. Taken together, our findings suggest there are sex differences in the associations between age of initiated cannabis use and neuropsychological functioning. The current study provides preliminary evidence that males and females may have different neuropsychological vulnerabilities that place them at risk for initiating cannabis use and continued cannabis use, highlighting the importance of examining the impact of cannabis on neuropsychological functioning separately for males and females.
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Neuropsychological Sex Differences Associated with Age of
Initiated Use Among Young Adult Cannabis Users
Natania A. Crane1,2, Randi Melissa Schuster3, Robin J. Mermelstein1,2, and Raul Gonzalez4
1Department of Psychology, University of Illinois at Chicago, 1007 West Harrison Street (M/C
285) Chicago, Illinois 60607
2Institute for Health Research and Policy, University of Illinois at Chicago, 1747 West Roosevelt
Road (M/C 275) Chicago, Illinois 60608
3Center for Addiction Medicine, Department of Psychiatry, Massachusetts General Hospital, 60
Staniford Street Boston, MA 02114
4Department of Psychology, Florida International University, 11200 S.W. 8th Street Miami, Florida
33199
Abstract
Introduction—Earlier initiation of cannabis use is associated with poorer neuropsychological
functioning across several domains. Given well-documented sex differences in neuromaturation
during adolescence, initiation of cannabis use during this time may affect neuropsychological
functioning differently for males and females.
Method—In the current study, we examined sex differences in the relationship between age of
initiated cannabis use and neuropsychological performance after controlling for amount of lifetime
cannabis use in 44 male and 25 female young adult cannabis users.
Results—We found that an earlier age of initiated use was related to poorer episodic memory,
especially immediate recall, in females, but not in males. On the other hand, we found that,
surprisingly, an earlier age of initiated use was associated with better decision-making overall.
However, exploratory analyses found sex-specific factors associated with decision-making and
age of initiated use, specifically that ADHD symptoms in females may drive the relationship
between an earlier age of initiated use and better decision-making. Further, an earlier age of
initiated use was associated with less education, a lower IQ, and fewer years of mother’s education
for females, but more lifetime cannabis use for males.
Conclusions—Taken together, our findings suggest there are sex-differences in the associations
between age of initiated cannabis use and neuropsychological functioning. The current study
provides preliminary evidence that males and females may have different neuropsychological
vulnerabilities that place them at risk for initiating cannabis use and continued cannabis use,
Address correspondence to: Raul Gonzalez, PhD, 11200 S.W. 8th Street Miami, Florida 33199; phone: (305) 348-4921; fax: (305)
348-6670; raul.gonzalezjr@fiu.edu.
The authors declare no conflicts of interest.
HHS Public Access
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J Clin Exp Neuropsychol. Author manuscript; available in PMC 2016 May 01.
Published in final edited form as:
J Clin Exp Neuropsychol. 2015 May ; 37(4): 389–401. doi:10.1080/13803395.2015.1020770.
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highlighting the importance of examining the impact of cannabis on neuropsychological
functioning separately for males and females.
Keywords
cannabis; cognition; marijuana; sex differences; THC
Introduction
As cannabis is legalized in more states and the perceived risk of cannabis use decreases, the
rates and frequency of adolescent and adult cannabis use is increasing (Johnston, O’Malley,
Miech, Bachman, & Schulenberg, 2014; SAMSHA, 2013). Over a period of six years, the
number of daily or almost daily cannabis users have nearly doubled. In 2012, an estimated
5.4 million individuals 12 years or older used cannabis daily or almost daily, while there
were about 3.1 million daily or almost daily cannabis users in 2006 (SAMSHA, 2013). This
use is particularly concerning, as regular cannabis use is associated with neuropsychological
deficits (Meier et al., 2012; Pope, Gruber, Hudson, Huestis, & Yurgelun-Todd, 2001;
Solowij et al., 2002), lower educational attainment (Horwood et al., 2010; Meier et al.,
2012), and poorer health outcomes (Kalant, 2004), especially if cannabis use is initiated
earlier in adolescence (Crane, Schuster, Fusar-Poli, & Gonzalez, 2013; Lisdahl, Gilbart,
Wright, & Shollenbarger, 2013). However, accumulating evidence suggests there may be
important sex differences on the effects of cannabis on the neuropsychological outcomes of
cannabis users (Crane, Schuster, Fusar-Poli, et al., 2013; Crane, Schuster, & Gonzalez,
2013; Lisdahl & Price, 2012), which is an important area that needs further research.
Furthermore, the age of onset of cannabis use has emerged as another important factor that
influences the effects of cannabis on neurocognition (Battisti et al., 2010; Ehrenreich et al.,
1999; Fontes et al., 2011; Gruber, Sagar, Dahlgren, Racine, & Lukas, 2012; Pope et al.,
2003; Solowij et al., 2011; Solowij et al., 2012). In the current study, we expanded upon our
previous findings (Crane, Schuster, & Gonzalez, 2013) of a sex-specific relationship
between amount of cannabis use and neuropsychological functioning, to examine how age
of initiated cannabis use may contribute to neuropsychological performance among male
and female cannabis users.
Initiation of cannabis use often occurs in adolescence, a critical period of neurodevelopment
when growth of the prefrontal cortex, structures in the limbic system, and myelination of
white matter associational, commissural, and projectional fibers takes place (Giedd et al.,
1999). Therefore, the adolescent brain may be especially vulnerable to any adverse effects of
cannabis use. This effect may be particularly salient due to the high density of CB1
receptors in the prefrontal cortex and limbic areas (Mackie, 2005; Piomelli, 2003).
Importantly, the endocannabinoid system plays a crucial role in neuromaturation and
synaptic pruning (Viveros et al., 2012). As such, initiation of cannabis use during this time
may disrupt normal neuromaturation (Bava & Tapert, 2010), and in turn, lead to
impairments in neuropsychological functioning.
Indeed, several studies have found an earlier age of initiated regular cannabis use is
associated with poorer cognitive functioning (Battisti et al., 2010; Ehrenreich et al., 1999;
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Fontes et al., 2011; Gruber, Sagar, Dahlgren, Racine, & Lukas, 2012; Pope et al., 2003;
Solowij et al., 2011; Solowij et al., 2012), including poorer episodic memory (Pope et al.,
2003; Solowij et al., 2012) and inhibitory control (Battisti et al., 2010; Gruber, Sagar,
Dahlgren, Racine, & Lukas, 2012; Solowij et al., 2012). Many of these studies have used a
median-split approach to stratify the sample by age of initiated use in order to examine
differences in neuropsychological functioning, which may diminish some of the effects, as it
is not clear if there is a uniform specific age (or critical period) during adolescence when
cannabis use transitions from being more to less harmful or if such a critical period is the
same for males and females. In addition, age of onset is often measured in different ways,
with some studies reporting age of onset to be the first time an individual uses cannabis and
other studies reporting age of onset to be the age of regular initiated use, which may also be
defined differently across studies. Although a few recent studies have looked at age of onset
continuously (Battisti et al., 2010; Hooper, Woolley, & De Bellis, 2014; Solowij et al., 2011;
Solowij et al., 2012), no studies have yet examined whether there are sex differences in the
relationship between age of intitated use and neuropsychological functioning and also what
may be the most sensitive measure of age of onset (i.e., median split or age as a continuous
variable). Further, few studies have controlled for amount of cannabis use when examining
age of inititiated use, making it difficult to understand the unique influence of age of
initiated use on neuropsychological functioning, as age of initiation is often confounded with
amount of use (i.e., users who started earlier have consumed more cannabis than those who
began later).
Recent evidence suggests endocannabinoid signaling also plays a crucial role in establishing
normal sex differences in the brain (Viveros et al., 2012) and disruption of this process may
also cause sex-specific cognitive deficits. Given these differences, cannabis may
differentially affect males and females, especially when taking into account the age of
initiation of use. Importantly, males and females have different neurodevelopmental
trajectories. Females’ total brain size peaks when they are about 10–11 years old, while
males’ total brain size peaks when they are about 14–15 years old (Lenroot et al., 2007).
Similarly, prefrontal cortex gray matter volume seems to peak 1–2 years earlier in females
than in males (Giedd et al., 1999). This evidence indicates the female brain may mature at an
earlier age than the male brain. Therefore, if cannabis use is initiated in adolescence, it may
affect males more than females, as males’ brains are undergoing more protracted
neurodevelopment during that time. This, coupled with the fact that males often initiate their
use earlier than females (Gfroerer & Epstein, 1999; Pope et al., 2003), may make cannabis’
negative impact on neurocognitive functioning even more pronounced among males. Indeed,
in a recently published study with data derived from the same sample, we found that that
more cannabis use was more consistently associated with poorer episodic memory
performance in females than in males, but more cannabis use was associated with poorer
decision-making performance for males, but not females (Crane, Schuster, & Gonzalez,
2013).
Given sex differences in neurodevelopment, the pharmacological effects of cannabis, and
neuropsychological functioning, it seems that cannabis use may differentially affect males
and females; however, few studies have examined the impact of this interaction on
neuropsychological functioning. It is important to identify potential sex differences in
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neuropsychological functioning among cannabis users to better understand how important
aspects of use, like age of initiation are associated with neuropsychological functioning in
male and female cannabis users. Our recent findings of cannabis use being more consistently
associated with poorer episodic memory for females than males, but poorer decision-making
for males only (Crane, Schuster, & Gonzalez, 2013), warrants further attention with respect
to the influence of age of initiation. Given that males initiate their cannabis use earlier and
also undergo protracted neurodevelopment compared to females, it is possible that their
poorer decision-making is due to an earlier age of initiated use disrupting prefrontal cortex
development and not just from a higher lifetime exposure to cannabis. On the other hand,
females’ poorer episodic memory may be due to the negative effects of exposure to cannabis
use on hippocampal functioning and not necessarily due to the negative effects of cannabis
on neurodevelopment. Of course, it is difficult to parse apart the individual effects of age of
initiated use, duration of use, and lifetime exposure to cannabis, as these variables are
generally highly correlated. However, controlling for cumulative amount of use helps us to
begin disentangling the age of initiation from amount of cannabis consumed. It may be that
more cannabis use leads to poorer neuropsychological functioning in females, while an
earlier age of initiated use predicts worse neuropsychological functioning in males.
However, to date, few studies have looked at how age of initiated use is related to
neuropsychological functioning in cannabis users after controlling for amount of use and, to
our knowledge, no studies have examined sex differences in these relationships or contrasted
findings between using a median split or continuous variable with regards to age of
initiation.
In this study, we wanted to extend our prior findings (Crane, Schuster, & Gonzalez, 2013) to
better understand if age of initiated use uniquely contributes to neuropsychological
performance over and above the influence of amount of cannabis use in male and female
cannabis users. Thus, we examined how different indices of age of initiated use (i.e., age of
first use and age of regular initiated use) were associated with episodic memory and
decision-making, two domains we found to be associated with amount of cannabis use
(Crane, Schuster, & Gonzalez, 2013), in the same sample after controlling for amount of
cannabis use. Based on behavioral and neurodevelopmental sex-differences, we
hypothesized that an earlier age of use will be associated with worse episodic memory and
decision-making in male and female cannabis users. However, after controlling for lifetime
cumulative amount of cannabis use, we hypothesized that an earlier age of use will no
longer be associated with episodic memory performance, as amount of cannabis use may be
more strongly related to episodic memory performance than age of initiated use, especially
among females. On the other hand, after controlling for lifetime cumulative amount of
cannabis use, and earlier age of use will be associated with poorer decision-making only
among males, as poorer decision-making in males may be more strongly related to an earlier
age of initiated use disrupting prefrontal cortex development than lifetime exposure to
cannabis. In addition, we wanted to examine whether age of first use or age of regular
initiated use was more strongly associated with neurocognitive performance. Further, we
wanted to examine if results using age of initiated use as a continuous variable differed from
results using a median split of age of initiated use.
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Methods
Participants
Participants were cannabis users from the Chicago-metropolitan area recruited through
word-of-mouth and informational fliers. All participants were 18–24 years old; had
education >8 years; had estimated full-scale IQ >75; had no diagnosis of a learning
disability, developmental delay, mental illness (including Attention Deficit Hyperactivity
Disorder; ADHD), or neurological condition; had no significant birth complications; had no
loss of consciousness >10 min; had no current use of psychotropic medication; demonstrated
English fluency; had no significant recent alcohol use (AlcoMate Prestige Model AL6000;
Palisades Park, NJ); had no illicit drug use other than cannabis in the past 30 days or >10×
in life for each drug class (other than cannabis, alcohol, nicotine, or hallucinogens); had no
recent illicit drug use other than cannabis (10-panel Drug Check Cup; Express Diagnostics,
Blue Earth, Minnesota); used cannabis: >200 in life, >4× per week during peak use, and at
least once in the past 45 days; reported no cannabis use on testing day; and identified
cannabis as their drug of choice. The Institutional Review Board at the University of Illinois
at Chicago approved the study and written informed consent was obtained. Additional
details regarding the larger study, methods, and participants have been previously reported
(Gonzalez et al., 2012).
Demographics, Potential Confounds, and Substance Use
Demographic information, including race/ethnicity, and family of origin information was
obtained through an examiner-led questionnaire. The Wechsler Test of Adult Reading
assessed premorbid full-scale IQ (Wechsler, 2001), while current and lifetime substance use
were diagnosed with the Structured Clinical Interview for DSM-IV (First, Spitzer, Gibbon,
& Williams, 2002). The Beck Depression Inventory-II (Beck, Brown, & Steer, 1996) and
Beck Anxiety Inventory (Beck & Steer, 1990) assessed depression and anxiety symptoms,
the Barratt Impulsiveness Scale-11 evaluated trait impulsivity (Patton, Stanford, & Barratt,
1995), the Marijuana Problem Scale measured negative consequences of cannabis use in the
past 90 days (Stephens, Roffman, & Curtin, 2000), and the Wender-Utah Rating Scale
(WURS) assessed ADHD symptoms (scores >46 indicates possible ADHD diagnosis; Ward,
Wender, & Reimherr, 1993). An examiner-led semi-structured interview collected
participants’ amount and frequency of alcohol, nicotine, and illicit substance use during their
lifetime, the past year and the past month (Gonzalez et al., 2012), this method has been used
in several previous studies (e.g., Gonzalez et al., 2004; Rippeth et al., 2004). Participants
were also asked to report their age of first cannabis use and alcohol use and the age that they
started using cannabis and the age that they started using alcohol at least once a week for
three straight months (age of regular initiated use).
Laboratory Measures of Neurocognitive Functioning
Verbal Episodic Memory—Verbal episodic memory was assessed using the Hopkins
Verbal Learning Test–Revised (HVLT-R; (Benedict, Schretlen, Groninger, & Brandt, 1998)
normative-based, age corrected z-scores for immediate recall (total words recalled over three
learning trials), delayed recall (total words recalled after a 20–25 minute delay), and
recognition discrimination (hits minus false positives).
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Decision-making—Decision-making was assessed using the Iowa Gambling Task (IGT)
total net normative-based T-score (choices from advantageous decks minus disadvantageous
decks; Bechara, Damasio, Damasio, & Anderson, 1994). Demographically corrected norms
controlling for age and education were use. In this task, T-scores with lower values indicate
poorer decision-making or a bias toward immediate versus long-term rewards (Bechara,
2007).
General Statistical Procedures
All analyses were carried out using SPSS 20.0 (IBM). Data were inspected for non-normal
distribution and outliers. Square-root transformations were used for amount of cannabis and
alcohol use and nonparametric procedures were used for analyses of participant
characteristics with data that violated assumptions of parametric procedures. Males and
females were compared on demographic, substance use, and mental health variables using t-
tests or chi-square tests as appropriate. In addition, males and females were compared on
general neuropsychological performance using separate analysis of variance. We conducted
moderated hierarchical multiple regression analyses with centered age of first cannabis use
and age of regular cannabis use entered as separate independent variables in the first block;
vectors for sex (i.e., male, female) as well as with centered amount of lifetime cannabis use
(in order to control for the effects of amount of use) in the second block; and their
interaction in the third block as predictors. We also controlled for amount of past month
alcohol use in the second block of the model, but this covariate was not significant in any
model and was therefore removed from final models. The Variance Inflation Factor (VIF)
for variables in each model ranged from 1.00–1.99, indicating that multicollinearity was not
a significant issue. Performance on neuropsychological measures served as the separate
dependent variables. Results were deemed statistically significant when p-values < .05.
Results
Demographics, Mental Health, Substance Use and Other Potential Confounds
Males and females reported minimal mental health complaints, and they did not differ on
potential confounds, with the exception that males had higher alcohol consumption during
the past 30 days than females (p<.04; see Table 1; also reported in Crane, Schuster, &
Gonzalez, 2013). Age of first use was significantly correlated with age of regular initiated
use (r= −.74, p< .01) and with cumulative lifetime amount of cannabis use (r= −.26, p< .05).
Age of regular initiated use was significantly correlated with cumulative lifetime amount of
cannabis use (r= −.33, p< .01).
Relationships between Age of Initiated Use and Neuropsychological Performance
Males and females did not differ on neuropsychological performance (Table 1; also reported
in Crane, Schuster, & Gonzalez, 2013). However, males and females had poorer
performance on immediate and delayed recall compared to the published normative samples
for the HVLT-R (Table 1), suggesting mild memory impairments in both groups. In
contrast, decision-making performance for males and females was comparable to that of
healthy controls based on published normative data for the IGT.
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Episodic Memory—The interaction between age of first use and sex was significant for
immediate and delayed recall, after controlling for amount of use (Table 2). Follow-up of
the simple slopes found a trend towards an earlier age of first use being more strongly
associated with poorer immediate recall for females (β = .21, p = .06) than for males (β = −.
20, p = .09). However, age of first use was not significantly associated with delayed recall
(females: β = .18, p = .11; males: β = −.17, p = .14).
The interaction between age of regular initiated use and sex, after controlling for amount of
use, was significant for immediate recall and trended towards significance for delayed recall
(Table 2). Follow-up of the simple slopes found that an earlier age of regular initiated use
was associated with poorer immediate recall for females (β = .28, p = .01), but not for males
(β = −.11, p = .35) and this effect trended towards significance for delayed recall (females: β
= .20, p = .08; males: β = −.06, p = .61) (Figure 1).
Decision-Making—The interaction between age of initiated use (first use or regular
initiated use) and sex, after controlling for amount of use, was not significant for decision-
making (Table 2), and an earlier age of initiated use (first use or regular initiated use) alone
was not associated with decision-making performance. Surprisingly, after controlling for
cumulative lifetime cannabis use, an earlier age of first use predicted better decision-
making, regardless of sex, and this effect trended towards significance for age of regular
initiated use (Table 2).
Exploratory Analyses
Age of Initiated Use and Decision-Making—To better understand our unexpected
findings suggesting that an earlier age of first use and age of regular initiated use was
associated with better decision-making, and the similar pattern for age of regular initiated
use that trended towards significance, we performed several exploratory analyses. To
understand if age of initiated use was related to decision-making in the same direction and
magnitude in males and in females, we performed follow-up analyses of the simple slopes
for sex differences in the relationship between age of initiated use and decision-making.
Follow-up analyses of the simple slopes for sex differences with earlier age of first cannabis
use did not significantly predict decision-making in females (β = −.19, p = .11) or in males
(β = −.18, p = .15) (Figure 2). However, follow-up analyses of the simple slopes found that
an earlier age of initiated regular cannabis use was associated with better decision-making in
females (β = −.28, p = .02), but not in males (β = −.05, p = .67) (Figure 2).
Bivariate correlations between several theoretically relevant measures and decision-making
performance for males and for females were also run to examine what variables may be
contributing to an earlier age of age of initiated use and better decision-making (Table 3).
Due to the fact that WURS scores had the strongest bivariate correlation with decision-
making performance for females, and the results of the simple slopes analyses suggested that
females may be in part driving the relationship between an earlier age of initiated use and
decision-making, we controlled for WURS scores to see if ADHD symptoms influenced
how age of first use related to decision-making in females. After controlling for WURS total
scores and cumulative lifetime cannabis use, an earlier age of first use (β = −.29, p = .15)
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and an earlier age of regular use (β = −.28, p = .18) were not associated with better decision-
making for females.
Analyzing Age of Regular Initiated Use using a Median-Split—In order to explore
if our main results would remain the same if we used a median-split analyses without
controlling for amount of cumulative amount of cannabis use, which has commonly been
done in several prior studies, we compared individuals who began their regular use of
cannabis before the age of 16 (early-onset) to those who began their regular use of cannabis
at age 16 and older (late-onset) without controlling for cumulative amount of cannabis use.
Early-onset users had poorer immediate recall that late-onset users (F(3,65) = 4.45, p = .04)
and the interaction between onset and sex trended toward significance (F(3,65) = 2.92, p = .
09), with early-onset females performing worse than late-onset females (F(1,23) = 4.99, p
= .04), while early- and late-onset males performed similarly, F(1,42) = 0.13, p = .72. A
trend also emerged for delayed recall, such that early-onset users performed more poorly
than late-onset users (F(3,65) = 2.93, p = .09), but there was no interaction between onset
and sex, F(3,65) = 2.30, p = .13. On the other hand, there were no differences between
individuals with an early-onset and those with a late-onset on decision-making performance
(F(3,65) = 0.29, p = .59), nor was there an interaction between onset and sex, F(3,65) =
2.09, p = .15.
Further, using ANOVA and chi-square analyses, early-onset users were compared to late-
onset on several theoretical variables. IQ, education, mother’s education, BDI total, BAI
total, WURS total, or past or current cannabis abuse or dependence did not differ between
groups (all p-value’s > .10). Early-onset users used more cannabis in their lifetime (F(1,67)
= 11.66, p = .001) and there was a trend that they had higher total scores on the BIS (F(1,67)
= 3.24, p = .08) and the Marijuana Problem Scale, F(1,54) = 3.69, p = .06), but they did not
differ from late-users on amount of cannabis used per year, F(1,67) = 1.18, p = .68. Of note,
when examining these relationships only among female cannabis users, early-onset female
users’ mothers had less years of education than late-onset female users’ mothers (F(1,21) =
4.38, p = .049), but no other significant relationships emerged, all p-value’s > .10. When
examining these relationships only among male cannabis users, early-onset male users had
more lifetime cannabis use (F(1,42) = 9.53, p = .004) and had higher total scores on the BIS
(F(1,42) = 4.18, p = .047) than late-onset male users, but no other significant relationships
emerged, all p-value’s > .10.
Discussion
In this study we examined relationships between different indices of age of initiated use and
neuropsychological functioning, namely episodic memory and decision-making, among a
non-treatment-seeking, community-dwelling sample of young adult regular cannabis users
who had minimal mental health problems or other drug use. We found preliminary evidence
of a dissociation in how age of initiated use is related to episodic memory performance in
male and female cannabis users. Specifically, we found that after controlling for amount of
cannabis use, an earlier age of regular initiated use was related to poorer episodic memory,
especially immediate recall, in females, but not in males. This effect trended toward
significance for age of first use, indicating that age of regular initiated use may be more
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important than age of first use in influencing episodic memory performance in female
cannabis users. On the other hand, we found that surprisingly, an earlier age of first use was
associated with better decision-making overall after controlling for amount of cannabis use
and a similar effect was found for age of initiated regular use that trended towards
significance. This warranted further exploration and a more complex pattern of results
emerged when we examined exploratory relationships among age of initiated use (first and
regular initiated use) and decision-making separately for males and females.
Although the interaction terms between sex and age of initiated use were not significant, to
help understand the surprising relationship between an earlier age of initiated use and better
decision-making, we performed exploratory analyses and found that while there were no sex
specific relationships between age of first use and decision-making, an earlier age of regular
use was associated with better decision-making in females, but not in males. This evidence
suggests that females may be driving this relationship. Indeed, we found sex-specific factors
associated with decision-making and age of initiated use. For females, better decision-
making was associated with more symptoms of ADHD, and after controlling for ADHD
symptoms, an earlier age of initiated cannabis use was no longer associated with better
decision-making in females. Therefore, ADHD symptoms may be more strongly related to
decision-making in females than age of initiated use. Although findings on executive
functioning deficits and decision-making impairment in ADHD is mixed (Castellanos,
Sonuga-Barke, Milham, & Tannock, 2006), some recent evidence suggests that adolescent
females with ADHD may have better decision-making than adolescent males with ADHD
and adolescent healthy control females (Skogli, Andersen, Hovik, & Oie, 2014), so it is
possible that we see a similar pattern in the current study: females who have higher
symptoms of ADHD perform better on decision-making. On the other hand, it is important
to note that other studies have found the opposite in young adults: young adult males with
ADHD have better decision-making than young adult females with ADHD (Hobson, Scott,
& Rubia, 2011; Toplak, Jain, & Tannock, 2005), which may reflect age or
neuromaturational differences or difference in measuring decision-making (i.e, hot versus
cold cognition; see (Skogli, Andersen, Hovik, & Oie, 2014). Importantly, in the current
study, participants were excluded if they had a formal ADHD diagnosis (indeed only 2
female participants were above the clinical cut-off on the WURS; see Table 1), but it is
possible that sub-threshold ADHD symptoms may still play an important role in decision-
making for females. It is also possible that since only age of first use was significantly
related to decision-making, females with better decision-making may be more likely to
experiment with cannabis, but may not go on to regularly use cannabis. Of note, the beta
weights in our analyses of the relationship between age of initiated use and decision-making
in females with and without controlling for ADHD symptoms remain relatively similar,
indicating that the non-significant relationship between age of initiated cannabis use and
decision-making when controlling for ADHD symptoms may be due to power and may not
reflect a true mediation effect. In addition, we also found that among females, an earlier age
of use was associated with less education, a lower IQ, and fewer years of education for their
mothers, so there may be other factors that were not measured in the current study that are
driving this relationship. On the other hand, for males better decision-making was
significantly associated with higher IQ, more education, less lifetime cannabis use, and less
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cannabis use per year of use, while an earlier age of use was associated with more lifetime
cannabis use along with somewhat more cannabis-related problems. Taken together, our
findings suggest there may be sex-differences in the reasons why males and females initiate
use and then continue to use cannabis, in line with other studies (Guxens, Nebot, & Ariza,
2007; Guxens, Nebot, Ariza, & Ochoa, 2007; Pedersen, Mastekaasa, & Wichstrom, 2001;
Schepis et al., 2011). For example, females with less education and females whose mothers
have fewer years of education may be more vulnerable to initiate cannabis use earlier, while
other factors that were not measured in the current study (e.g., behavioral dyscontrol) may
increase males’ risk to initiate cannabis use earlier.
Additional analyses were conducted to better understand how results may change when
using different methods for examining age of first use, as has been the case with prior
studies. Analyses using a median-split analysis, as has commonly been done in several prior
studies, replicated previous findings, showing that an earlier age of initiated use was
associated with poorer episodic memory (Pope et al., 2003; Solowij et al., 2012). Although
we found the same pattern of sex differences in episodic memory as in our analyses using a
continuous measure of age of initiated use, that is, early age of initiation was associated with
poorer episodic memory, especially immediate recall, in females; the interaction term
between sex and age of initiated use only trended toward significance in the median-split
analyses, suggesting that continuous analyses may be more sensitive to finding important
sex differences. We did not find that age of initiated use was associated with decision-
making performance using median-split analyses. Due to the fact that median-split analyses
may diminish the power to find sex-differences, it is important that future studies consider
this issue.
The current study expands upon our previous findings that there are important sex
differences in how important indices of cannabis use are related to neuropsychological
functioning. We previously found that more cannabis use is more consistently associated
with poorer episodic memory for females than males, but poorer decision-making for males
only (Crane, Schuster, & Gonzalez, 2013). Given that we controlled for amount of lifetime
cannabis use in our current analyses, our findings that an earlier age of initiated use is
associated with poorer episodic memory in females, adds to (but does not duplicate) our
previous findings that more cannabis use is more consistently associated with poorer
episodic memory for females than males. Taken together, our previous and current analyses
indicate that poorer episodic memory may either be a vulnerability that places females at a
higher risk for earlier initiation of cannabis use or it may be a domain that is adversely
affected by cannabis use and continued use of cannabis may further add to the negative
impact of an earlier age of initiated use on episodic memory in females. For example, it is
possible that cannabis use disrupts estrogen-related dendritic spine maturation in the
hippocampus, especially during neurodevelopment (Gillies & McArthur, 2010), which may
facilitate continued use among females, leading to poorer episodic memory as use continues.
It is also possible that estrogen-related learned associations with cannabis use may also
contribute to females’ progression to cannabis dependence, in turn leading to even poorer
episodic memory (Fattore et al., 2007). However, our current and previous analyses suggest
that there may be other mechanisms involved in males’ initiation of cannabis use and it is
only after continued cannabis use that poorer decision-making emerges in males. Of note,
Crane et al. Page 10
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sex differences are evident among healthy, non-using adults in these domains, such that
females perform better on measures of episodic memory (Kramer, Delis, & Daniel, 1988),
while males perform better on measures of decision-making (Bolla, Eldreth, Matochik, &
Cadet, 2004; Overman et al., 2004; Reavis & Overman, 2001). Thus, cannabis use may
blunt these normal sex differences, as we found that the domains in which healthy males or
females tend to have better performance are the domains most negatively impacted by
cannabis use indices (e.g., age of initiated use and amount of cannabis use).
Our current findings should be considered in the context of several important factors. First,
it is important to note that in general, male and female cannabis users in this study
demonstrated deficits in episodic memory, especially immediate and delayed recall, but not
in decision-making, compared to their non-using counterparts in the parent project
(Gonzalez et al., 2012). Further, there are limitations of the current study including a cross-
sectional design that requires replication in a larger sample, and the fact that family history
of substance use was not measured, a factor that may have influenced the results. The
participants also had a limited age range, however, this could also be interpreted as a
strength, as the sample is comprised of young adults who are still undergoing
neurodevelopment, an important period to study; especially since cannabis use during this
time may have more pronounced effects. Longitudinal designs will be used in ongoing and
future studies to better explore mechanisms for the observed patterns of results, including
the possible role of sex hormones.
In conclusion, our study expands on previously reported associations between age of
initiated cannabis use and episodic memory and decision-making, using a non-treatment-
seeking community sample of young adult current cannabis users with minimal mental
health problems and use of other substances. We found evidence of a dissociation in how
age of initiated use is related to episodic memory performance among males and females. In
addition, we found that several factors seem to be related to decision-making performance
and age of initiated use in a sex-specific manner, suggesting there may be sex-differences in
the reasons why males and females initiate use and then continue to use cannabis. The
current study provides preliminary evidence that males and females may have different
neuropsychological vulnerabilities or cannabis-related neuropsychological sequelae that
place them at risk for cannabis dependence and highlights the importance of examining the
impact of cannabis on neuropsychological functioning separately for males and females.
Acknowledgments
This publication was funded by the National Institute on Drug Abuse (NIDA) (K23DA023560, R01DA031176, and
R01DA033156, PI: RG) and (F31DA038388-01, PI: NAC); the National Institute of Mental Health (NIMH)
(T32MH067631, to NAC); and the National Cancer Institute (NCI) (P01CA098262, PI: RM). Its contents are solely
the responsibility of the authors and do not necessarily represent the official views of NIDA, NCI or the National
Institutes of Health. We thank Dr. Kathi Diviak and Dr. Mermelstein’s group for their assistance with identification
and recruitment of a subset of participants.
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Figure 1.
Interactions between Age of Regular Initiated Cannabis Use and Sex on Episodic Memory
Performance
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Figure 2.
Interactions between Age of Regular Initiated Cannabis Use and Sex on Decision-Making
Performance
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Table 1
Participant Characteristics
Male CU (n=44)
% or M ± SD (range) Female CU (n=25)
% or M ± SD (range) p-value
Demographics
Age 20.75 ± 1.89 (18 – 24) 20.72 ± 1.62 (18 – 24) .95
Estimated FSIQ 102.11 ± 10.24 (76 – 118) 102.80 ± 10.02 (82 – 120) .79
Years of Education 13.34 ± 1.67 (10 – 16) 13.64 ± 1.68 (11 – 18) .48
Ethnicity/Race .70
Caucasian 43% 36%
Black 34% 40%
Hispanic 7% 16%
Asian 7% 4%
Other 9% 4%
Annual Household Income in Thousands of 26 [9, 61] 33 [7, 94] .84
Dollars [Md, IQR]
Mother’s Education 14.23 ± 2.68 (7 – 18) 14.13 ± 3.00 (5 – 20) .89
Mental Health
BDI-II Total Score [Md, IQR] 5 [2.25, 7.75] 5 [1.50, 10] .81
BAI Total Score [Md, IQR] 4 [2, 9] 5 [3, 8] .21
WURS, % of scores >46 [IQR] 2% [15.25, 30] 8% [9.50, 18.50] .27
BIS-11 Total Score 59.48 ± 9.16 (41 – 82) 59.04 ± 10.58 (37 – 79) .86
Substance Use
Current (30 day) DSM-IV SUD
Alcohol Abuse 11% 0% .08
Alcohol Dependence 0% 0% 1.00
Cannabis Abuse 34% 28% .60
Cannabis Dependence 27% 28% .95
Lifetime DSM-IV SUD
Alcohol Abuse 25% 16% .38
Alcohol Dependence 2% 4% .68
Cannabis Abuse 41% 44% .80
Cannabis Dependence 34% 28% .60
Years of cannabis use 5.18 ± 2.44 (1 – 12) 4.68 ± 2.14 (1 – 9) .39
Age of 1st Cannabis Use 15.80 ± 2.12 (11 – 21) 16.29 ± 2.35 (11 – 20) .38
Age of Regular Cannabis Use 17.36 ± 1.98 (13 – 22) 17.96 ± 2.32 (13 – 23) .26
Days since last cannabis use 4.18 ± 4.05 (1 – 26) 5.52 ± 8.45 (1 – 45) .38
% THC+ 77% 76% .90
MPS Total Score 5.54 ± 3.63 (0–15) 4.43 ± 2.89 (0–9) .24
Age of 1st Alcohol Use 15.68 ± 2.07 (10 – 20) 15.80 ± 1.68 (13 – 19) .81
Age of Regular Alcohol Use 18.12 ± 1.49 (16 – 22) 19.10 ± 1.66 (16 – 21) .13
Lifetime [Md, IQR]
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Male CU (n=44)
% or M ± SD (range) Female CU (n=25)
% or M ± SD (range) p-value
Alcoholic drinks 569.50 [189.75, 1215] 288 [104.50, 1527.50] .40
Cigarettes 1512.50 [19.50, 7515] 574 [0, 3186] .37
Cannabis (grams) 625.15 [198.50, 2219.41] 482.40 [124.63, 1328.70] .47
Past Year [Md, IQR]
Alcoholic drinks 132 [33, 291] 80 [24, 210] .33
Cigarettes 72 [0.50, 1417.50] 48 [0, 540] .35
Cannabis (grams) 114 [55.65, 440.63] 90 [24, 383.40] .42
Past 30 days [Md, IQR]
Alcohol drinks 11.50 [2.25, 20.75] 3 [0.50, 15] .04*
Cigarettes 6 [0, 90] 7 [0, 50] .52
Cannabis (grams) 10.75 [5.15, 36.68] 12 [2.38, 33.55] .81
Neuropsychological Performance
Verbal Episodic Memory
HVLT Immediate Recall (z score) −0.81 ± 1.23 (−3.62 – 1.51) −0.77 ± 1.45 (−3.89 – 1.24) .90
HVLT Delayed Recall (z score) −0.83 ± 1.32 (−4.13 – 0.88) −0.90 ± 1.26 (−2.88 – 0.88) .83
HVLT Recognition Discrimination (z score) 0.01 ± 0.82 (−2.83 – 0.5) 0.03 ± 0.95 (−2.86 – 0.5) .95
Decision Making
IGT Net Total (T score) 45.59 ± 9.50 (26 – 63) 45.60 ± 10.26 (22 – 65) 1.00
Note: all values are means, standard deviations, or ranges, unless otherwise noted; CU, cannabis users; Md, Median; IQR, interquartile range;
FSIQ, Full Scale IQ; BDI-2, Beck Depression Inventory-2nd Edition; BAI, Beck Anxiety Inventory; WURS, Wender-Utah Rating Scale; BIS,
Barratt Impulsiveness Scale-11th version; DSM-IV SUD, Diagnostic and Statistical Manual IV substance use disorders; THC+, positive rapid urine
toxicology testing; MPS, Marijuana Problem Scale.
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Table 2
Hierarchical Moderated Regression Models for Predicting How Age of Initiated Cannabis Use and Sex Affect Neuropsychological Functioning
Variable Age of 1st Use Age of Regular Use
R2Bp R2βp
HVLT (Immediate Recall)
Block 1-Age of Onset 0.01 0.08 .53 0.05 0.22 .07
Block 2-Age of Onset 0.13 −0.02 .91 0.14 0.11 .36
Sex -- −0.03 .83 -- −0.03 .81
Amount of Lifetime Cannabis Use -- −0.37 .004 -- −0.32 .01
Block 3-Age of Onset x Sex 0.22 0.38 .01 0.22 0.38 .01
HVLT (Delayed Recall)
Block 1-Age of Onset 0.01 0.10 .43 0.05 0.23 .06
Block 2-Age of Onset 0.19 −0.01 .92 0.22 0.09 .44
Sex -- −0.05 .65 -- −0.08 .49
Amount of Lifetime Cannabis Use -- −0.44 .001 -- −0.44 .001
Block 3-Age of Onset x Sex 0.25 0.32 .03 0.26 0.25 .09
IGT (Net Total)
Block 1-Age of Onset 0.03 −0.16 .19 0.01 −0.10 .41
Block 2-Age of Onset 0.16 −0.26 .04 0.14 −0.23 .07
Sex -- −0.02 .88 -- 0.00 .99
Amount of Lifetime Cannabis Use -- −0.38 .002 -- −0.38 .003
Block 3-Age of Onset x Sex 0.16 −0.05 .76 0.17 −0.23 .14
Note. The sex variable was dummy coded, with males serving as the referent group; covariates were only included in models in which they were significant; HVLT, Hopkins Verbal Learning Task; IGT,
Iowa Gambling Task; n/a, non-applicable; bold and italicized p-values are significant or trending toward significance.
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Table 3
Bivariate correlations with Decision-Making Performance for Female and Male CU
1 2 3 4 5 6 7 8 9 10 11 12 13 14
1. IGT Net Total -- −0.26 −0.35+0.09 −0.15 0.16 0.31 0.30 0.36+0.23 0.44*−0.07 0.02 −0.01
2. Age of 1st Use −0.10 -- 0.75*0.36+0.51*0.54*−0.17 −0.12 −0.23 −0.21 0.06 0.27 −0.12 −0.19
3. Age of Regular Initiated Use 0.07 0.72*-- 0.44*0.54*0.42*−0.16 −0.09 −0.20 −0.24 −0.23 0.10 −0.26 −0.08
4. FSIQ 0.34*−0.08 0.07 -- 0.65*0.31 0.44*0.22 0.17 −0.24 −0.01 −0.20 −0.49*0.17
5. Education 0.34*0.17 0.29+0.21 -- 0.40+−0.04 0.10 0.04 −0.34+−0.10 −0.22 −0.2 0.01
6. Mother’s Education 0.09 −0.14 0.09 0.15 −0.03 -- 0.12 0.34 0.08 0.00 −0.18 0.16 −0.09 −0.31
7. Current Annual Household Income 0.03 −0.01 −0.04 0.03 0.11 0.05 -- 0.16 0.05 0.03 0.02 −0.20 −0.44*0.19
8. BDI Total −0.13 −0.14 −0.03 0.10 0.01 0.01 −0.34*-- 0.54*0.35+0.04 −0.11 −0.16 0.36
9. BAI Total 0.08 0.02 0.06 0.15 0.02 −0.15 −0.19 0.62*-- 0.25 0.36+−0.22 −0.2 0.21
10. BIS Total −0.23 −0.15 −0.25 0.03 −0.31*0.07 −0.18 0.27+0.25 -- 0.47*0.10 0.13 0.43+
11. WURS Total −0.16 −0.11 −0.12 0.17 −0.35*−0.13 −0.26 0.47*0.32 0.44*-- −0.11 0.02 0.23
12. Amount of Cannabis Use (sq) per Year of Use −0.31*0.13 −0.03 −0.04 −0.49*−0.12 0.04 −0.08 −0.03 0.34*0.37*-- 0.81 −0.03
13. Amount of Lifetime Cannabis Use (sq) −0.49*−0.32*−0.37*−0.30*−0.24 −0.13 0.14 0.07 0.01 0.44*0.27+0.49*-- −0.02
14. Marijuana Problems Scale Total −0.13 −0.32+−0.22 0.13 −0.17 −0.20 −0.20 0.57*0.54*0.33+0.64*0.35*0.42*--
Note. Females in shaded area above dotted line and males in non-shaded area below dotted line; IGT, Iowa Gambling Task; FSIQ, Full Scale IQ; BDI-II, Beck Depression Inventory-2nd Edition; BAI, Beck
Anxiety Inventory; WURS, Wender-Utah Rating Scale; and BIS, Barratt Impulsiveness Scale-11th version; sq, square root;
*indicates p < .05.;
+ indicates p < .10.
J Clin Exp Neuropsychol. Author manuscript; available in PMC 2016 May 01.
... In contrast, greater visuospatial memory deficits were observed in females (Pope, Jacobs, Mialet, Yurgelun-Todd, & Gruber, 1997), which may be associated with age of initiation of cannabis use (Noorbakhsh, Afzali, Boers, & Conrod, 2020). Additionally, a series of studies by Crane and colleagues demonstrated that cannabis use was more strongly associated with deficits in episodic memory in females compared to males, although more cannabis use was correlated with poor decision-making in males, but not females (Crane, Schuster, & Gonzalez, 2013;Crane, Schuster, Mermelstein, & Gonzalez, 2015). Crane et al. (2015) also observed that in women, but not men, earlier onset of cannabis use was associated with greater memory deficits. ...
... Additionally, a series of studies by Crane and colleagues demonstrated that cannabis use was more strongly associated with deficits in episodic memory in females compared to males, although more cannabis use was correlated with poor decision-making in males, but not females (Crane, Schuster, & Gonzalez, 2013;Crane, Schuster, Mermelstein, & Gonzalez, 2015). Crane et al. (2015) also observed that in women, but not men, earlier onset of cannabis use was associated with greater memory deficits. Additionally, in women, earlier onset of cannabis use was associated with lower estimated intelligence, although this was observed at the trend (p = .10) ...
... Additionally, in women, earlier onset of cannabis use was associated with lower estimated intelligence, although this was observed at the trend (p = .10) level (Crane et al., 2015). ...
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Objectives: Preclinical and clinical studies suggest that males and females may be differentially affected by cannabis use. This study evaluated the interaction of cannabis use and biological sex on cognition, and the association between observed cognitive deficits and features of cannabis use. Methods: Cognitive measures were assessed in those with regular, ongoing, cannabis use (N = 40; 22 female) and non-using peers (N = 40; 23 female). Intelligence, psychomotor speed, and verbal working memory were measured with the Wechsler Abbreviated Scale of Intelligence, Digit Symbol Test, and Digit Span and Hopkins Verbal Learning Test, respectively. Associations between cognitive measures and cannabis use features (e.g., lifetime cannabis use, age of initiation, time since last use of cannabis, recent high-concentration tetrahydrocannabinoid exposure) were also evaluated. Results: No main effects of group were observed across measures. Significant interactions between group and biological sex were observed on measures of intelligence, psychomotor speed, and verbal learning, with greatest group differences observed between males with and without regular cannabis use. Psychomotor performance was negatively correlated with lifetime cannabis exposure. Female and male cannabis use groups did not differ in features of cannabis use. Conclusions: Findings suggest that biological sex influences the relationship between cannabis and cognition, with males potentially being more vulnerable to the neurocognitive deficits related to cannabis use.
... Nonetheless, cognitive difficulties have been shown to improve with abstinence (Schuster et al., 2018;Wallace, Wade, & Lisdahl, 2020), supporting their association with continued use. In young adults, sex has been reported to moderate the association between cognitive dysfunction and the frequency (Lisdahl & Price, 2012) and amount of cannabis use, as well as the age of initiated use (Crane, Schuster, Mermelstein, & Gonzalez, 2015). Several studies have supported associations between earlier age of cannabis use onset and worse neuropsychological outcomes (e.g. ...
... We then explored potential interactions (separately) with age of initiated use, frequency of cannabis use in the past 90 days (number of days), amount of cannabis use in the past 90 days (grams consumed), and withdrawal symptoms to test if similar patterns of cognitive performance were also related to measures of use severity. As in previous studies (Crane, Schuster, Fusar-Poli, et al., 2013;Crane, et al., 2015), we conducted a moderated hierarchical multiple regression analysis with neuropsychological performance as the dependent variable and age of cannabis initiation, frequency of cannabis use, amount of cannabis use, and cannabis withdrawal subscales (intensity, negative impact of withdrawal) as predictors (separately) in Block (model) 1; vectors for sex (male, female) in Block 2; and their interaction in Block 3. We additionally controlled for the same covariates delineated above (entered in the first block) to better isolate any observed effects to the influence of sex. Interdependencies between covariates were examined using multicollinearity diagnostics. ...
... A reverse pattern of cognitive performance was partly found in our study, such that female cannabis users showed poorer attentional functions. Similar sex-specific patterns of reverse association have been previously reported in non-acute studies, with females showing poorer episodic memory and males showing poorer decision-making, suggesting that cannabis use may blunt those domains in which healthy males and females typically perform better (Crane, Schuster, Mermelstein, et al., 2015). ...
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Objective Adolescence into young adulthood represents a sensitive period in which brain development significantly diverges by sex. Regular cannabis use by young people is associated with neuropsychological vulnerabilities, but the potential impact of sex on these relationships is unclear. Method In a cross-sectional study, we examined sex differences in multi-domain neuropsychological functioning using the Cambridge Neuropsychological Test Automated Battery (CANTAB) and tested whether sex moderated the relationship between cognitive performance and age of initiation, frequency of cannabis use, amount of cannabis use, and withdrawal symptoms in at least weekly adolescent and young adult cannabis users ( n = 171; aged 13–25 years; 46.2% female). Results Male cannabis users had poorer visual recognition memory and female cannabis users showed worse attention and executive functions, with medium to large effect sizes. These sex effects persisted, when controlling for age, IQ, amount of alcohol and nicotine use, mood and anxiety symptoms, emotional stability and impulsive behavior. Earlier age of initiated use and more use were associated with worse attentional functions in females, but not males. More use was more strongly associated with worse episodic memory in males than in females. More use was associated with poorer learning in males only. Conclusions Domain-specific patterns of neuropsychological performance were found by sex, such that males showed poorer visual memory and females showed worse performance on measures of attention (sustained visual, multitasking) and executive functioning (spatial planning/working memory subdomains). Larger studies including healthy controls are needed to determine if the observed sex differences are more exaggerated relative to non-users.
... In addition, preclinical models have demonstrated sexual dimorphic CB1 diffusivity in the endocannabinoid system, with greater desensitization of these receptors shown in adolescent female rodents after THC administration compared to males (Burston, Wiley, Craig, Selley, & Sim-Selley, 2010;Rodriguez de Fonseca, Ramos, Bonnin, & Fernandez-Ruiz, 1993). Furthermore, investigations into effects of sex within humans have indicated differences between CAN-using males and females and their non-using same-sex counterparts within use patterns (Cuttler, Mischley, & Sexton, 2016;Khan et al., 2013) and neuropsychological performance (Crane, Schuster, Fusar-Poli, & Gonzalez, 2013;Crane, Schuster, Mermelstein, & Gonzalez, 2015). Specifically, male CAN users exhibit impairments on psychomotor and visuospatial performance (Crane et al., 2013) and age of regular CAN onset is associated with poorer episodic memory amongst female users (Crane et al., 2015). ...
... Furthermore, investigations into effects of sex within humans have indicated differences between CAN-using males and females and their non-using same-sex counterparts within use patterns (Cuttler, Mischley, & Sexton, 2016;Khan et al., 2013) and neuropsychological performance (Crane, Schuster, Fusar-Poli, & Gonzalez, 2013;Crane, Schuster, Mermelstein, & Gonzalez, 2015). Specifically, male CAN users exhibit impairments on psychomotor and visuospatial performance (Crane et al., 2013) and age of regular CAN onset is associated with poorer episodic memory amongst female users (Crane et al., 2015). Further, previous studies have demonstrated sex differences in the impact of CAN use on brain structure with female users exhibiting larger right amygdala volume (McQueeny et al., 2011), larger prefrontal volume (Medina et al., 2009), and larger cortical surface structure (Sullivan, Wallace, Wade, Swartz, & Lisdahl, 2020). ...
Article
Objectives Studies examining the impact of adolescent and young adult cannabis use on structural outcomes have been heterogeneous. One already-identified moderator is sex, while a novel potential moderator is extent of aerobic fitness. Here, we sought to investigate the associations of cannabis use, sex, and aerobic fitness levels on brain volume. Second, we explored brain–behavior relationships to interpret these findings. Methods Seventy-four adolescents and young adults (36 cannabis users and 38 controls) underwent 3 weeks of monitored cannabis abstinence, aerobic fitness testing, structural neuroimaging, and neuropsychological testing. Linear regressions examined cannabis use and its interaction with sex and aerobic fitness on whole-brain cortical volume and subcortical regions of interests. Results No main-effect differences between cannabis users and nonusers were observed; however, cannabis-by-sex interactions identified differences in frontal, temporal, and paracentral volumes. Female cannabis users generally exhibited greater volume while male users exhibited less volume compared to same-sex controls. Positive associations between aerobic fitness and frontal, parietal, cerebellum, and caudate volumes were observed. Cannabis-by-fitness interaction was linked with left superior temporal volume. Preliminary brain–behavior correlations revealed that abnormal volumes were not advantageous in either male or female cannabis users. Conclusions Aerobic fitness was linked with greater brain volume and sex moderated the effect of cannabis use on volume; preliminary brain–behavior correlations revealed that differences in cannabis users were not linked with advantageous cognitive performance. Implications of sex-specific subtleties and mechanisms of aerobic fitness require large-scale investigation. Furthermore, present findings and prior literature on aerobic exercise warrant examinations of aerobic fitness interventions that aimed at improving neurocognitive health in substance-using youth.
... In humans and animals, adolescence is characterized as a secondary phase of growth between childhood and adulthood that includes the onset of puberty and secondary sexual development (Spear, 2000;Sawyer et al., 2018). Importantly for human and animal research on the effects of cannabis exposure during adolescence, initiation of use is less likely to be tied to the onset of puberty or the development of secondary sex characteristics, and more likely to be tied to chronological age (Crane et al., 2015) providing a useful justification for using age of onset as a reliable point of comparison for drug effects. Neuronally, adolescence encompasses periods of synaptic reorganization and dynamic changes in connectivity (Uhlhaas and Singer, 2011). ...
... While a significant portion of the human studies considered here included both men and women, the majority of rodent work concerning adolescent cannabinoid exposure has been completed only in males. When females are included in these studies, the results often present interesting divergent results (Lee et al., 2014;Wiley and Burston, 2014;Crane et al., 2015Crane et al., , 2013Keeley et al., 2015;Silva et al., 2015). These differences and the potential for other factors to influence long-term outcomes deserve further scrutiny in future studies. ...
Article
Cannabis is the most widely used illicit substance among adolescents, and adolescent cannabis use is associated with various neurocognitive deficits that can extend into adulthood. A growing body of evidence supports the hypothesis that adolescence encompasses a vulnerable period of development where exposure to exogenous cannabinoids can alter the normative trajectory of brain maturation. In this review, we present an overview of studies of human and rodent models that examine lasting effects of adolescent exposure. We include evidence from meta-analyses, longitudinal, or cross-sectional studies in humans that consider age of onset as a factor that contributes to the behavioral dysregulation and altered structural or functional development in cannabis users. We also discuss evidence from preclinical rodent models utilizing well-characterized or innovative routes of exposure, investigating the effects of dose and timing to produce behavioral deficits or alterations on a neuronal and behavioral level. Multiple studies from both humans and animals provide contrasting results regarding the magnitude of residual effects. Combined evidence suggests that exposure to psychoactive cannabinoids during adolescence has the potential to produce subtle, but lasting, alterations in neurobiology and behavior.
... Female cannabis users were also underrepresented in the literature, particularly in neuroimaging studies. Several studies have found divergent associations between cannabis and neurocognitive functioning according to sex, potentially attributable to activational effects of gonadal hormones and sexual dimorphism in the endocannabinoid system (Craft et al., 2013;Crane et al., 2013Crane et al., , 2015. Future studies should therefore also take care to include female cannabis users. ...
Article
Background Adolescents may respond differently to cannabis than adults, yet no functional magnetic resonance imaging (fMRI) study has examined acute cannabis effects in this age-group. We investigated the neural correlates of reward anticipation after acute exposure to cannabis in adolescents and adults. Methods This was a double-blind, placebo-controlled, randomized, crossover experiment. Forty-seven adolescents (n=24, 12 females, 16-17 years) and adults (n=23, 11 females, 26-29 years), matched on cannabis use frequency (0.5-3 days/week), completed the Monetary Incentive Delay task during fMRI after inhaled cannabis with 0.107 mg/kg THC (‘THC’) (8 mg THC for a 75 kg person) or THC plus 0.320 mg/kg CBD (‘THC+CBD’) (24 mg CBD for a 75 kg person), or placebo cannabis (‘PLA’). We investigated reward anticipation activity with whole-brain analyses and region of interest (ROI) analyses in right and left ventral striatum, right and left anterior cingulate cortex, and right insula. Results THC reduced anticipation activity compared to placebo in the right (P=.005, d=0.49) and left (P=.003, d=0.50) ventral striatum, and right insula (P=.01, d=0.42). THC+CBD reduced activity compared to placebo in the right ventral striatum (P=.01, d=0.41) and right insula (P=.002, d=0.49). There were no differences between ‘THC’ and ‘THC+CBD’ and no significant Drug*Age-Group effect, supported by Bayesian analyses. There were no significant effects in the whole-brain analyses. Conclusions In weekly cannabis users, cannabis suppresses the brain’s anticipatory reward response to money and CBD does not moderate this effect. Furthermore, the adolescent reward circuitry is not differentially sensitive to acute effects of cannabis on reward anticipation.
... For example, though there was no significant difference in substance use by sex, females reported higher levels of substance use. As prior research suggests females may be more vulnerable to the neurocognitive impact of substances (Crane, Schuster, Fusar-Poli, & Gonzalez, 2013;Crane, Schuster, Mermelstein, & Gonzalez, 2015;Squeglia, Schweinsburg, Pulido, & Tapert, 2011), the present sample's substance use may be impacting aspects of cognitive functioning, though past-year use was low and was used as an exclusion factor. In addition, subtle differences in neurodevelopment and cognition due to stages of puberty and sex hormones have been found previously (Schulz & Sisk, 2016;Sullivan et al., 2016), but were not accounted for here. ...
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Objective Research suggests positive relationships between aerobic fitness and cognition in older adults; however, limited research has adequately investigated the relationship between objectively measured aerobic fitness and broad cognitive functioning in healthy adolescents and young adults without psychiatric or physical health disorders. Further, studies to date have disproportionately examined males and failed to examine sex differences. Here we examine the relationship between aerobic fitness and neuropsychological functioning in physically healthy youth and whether sex moderates these findings. Design Sixty-four healthy emerging adults (16-25 years-old; 32 female) underwent measurement of objective aerobic fitness (VO2 max) and neuropsychological assessment. Exclusion criteria included: left-handedness, prenatal medical issues or alcohol/illicit drug exposure, Axis-I psychiatric disorders, major medical disorders including metabolic conditions such as diabetes, hypertension, hyperlipidemia, major neurologic disorders, LOS greater than 2 min, intellectual disability or learning disability, regular substance use (e.g., greater than bi-weekly use of cannabis) or positive drug toxicology testing. Method Multiple regressions examined VO2 max, sex, sex*VO2interaction in relation to neurocognition, controlling for objectively measured body fat percentage. Results Prior to including body fat percentage, higher VO2 max related to improved working memory (Letter-Number Sequencing; p = .03) and selective attention (CPT-II hit response time standard error; p = .03). Aerobic fitness significantly interacted with sex, as higher-fit males had better performance on two sustained attention tasks while females did not demonstrate this pattern (CPT-II variability standard error, p = .047; Ruff 2&7 Total Speed, p = .02). Body fat percentage was positively slower cognitive flexibility (D-KEFS color-word switching/inhibition, p = .046). Conclusions VO2 independently predicted better working memory and selective attention. Increased aerobic fitness level related to increased performance on sustained attention tasks in males but not females. Therefore, aerobic fitness may be positively related to better cognitive functioning in physically healthy adolescents and emerging adults without metabolic conditions. Further research into factors (e.g., intensity or type of activity) that may relate to beneficial outcomes by sex are needed.
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Background: There is a growing interest in the use of cannabis (and its extracts), as well as CBD oil (hemp extracts containing cannabidiol), for therapeutic purposes. While there is reason to believe that cannabinoids may be efficacious for a number of different diseases and syndromes, there exist limited objective data supporting the use of crude materials (CBD oil, cannabis extracts, and/or cannabis itself). Summary: In the present review, we examined data for pure cannabinoid compounds (dronabinol, nabilone, and CBD), as well as partially purified medicinal cannabis extracts (nabiximols), to provide guidance on the potential therapeutic uses of high-THC cannabis and CBD oil. In general, data support a role for cannabis/cannabinoids in pain, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting. Given the biological activities of the cannabinoids, there may be utility in treatment of central nervous system disorders (such as neurodegenerative diseases, PTSD, and addiction) or for the treatment of cancer. However, those data are much less compelling. Key Message: On balance, there are reasons to support the potential use of medical cannabis and cannabis extract (Δ9-THC-dominant or CBD-dominant), but much more careful research is required.
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Objective: To evaluate the relationship between onset age of cannabis use and cannabis abuse testing the mediating role of the number of friends using cannabis with a sample of Portuguese cannabis users. Comparing men and women regarding these relationships. Method: A sample of 529 Portuguese cannabis users, composed of 276 men and 244 women, aged from 14 to 21 years, completed a sociodemographic questionnaire, the Cannabis Abuse Screening Test and four questions related to cannabis use. Data were analyzed using the PROCESS macro in SPSS version 26.0. Results: The onset age of cannabis use was negatively related to the number of friends using cannabis, while the number of friends using cannabis showed a positive relationship with cannabis abuse. As predicted, the number of friends using cannabis seems to have a mediating role in the relationship between the onset age of cannabis use and cannabis abuse since the indirect effect was found to be significant. The pattern of the relationships among the variables observed was found to be similar both for the male and women’ samples. However, males reported higher cannabis abuse than females. Conclusion: Results highlight the mediating role of the friends’ using cannabis in the relationship between the onset age of cannabis use and users' abuse. Results highlight the importance of early intervention to cannabis use. Particularly, the pattern of the relationships observed among the studied variables emphasized the need to monitor and peer training intervention or the promotion of social skills.
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Cannabis use has historically been thought to cause amotivation, but the relationship between cannabis and apathy, anhedonia, and reward processing remains poorly characterised. In this systematic review, we evaluated whether cannabis exposure acutely and/or non-acutely was associated with altered reward processing using questionnaire, behavioural, or functional neuroimaging measures. Questionnaire studies demonstrated greater anhedonia in adolescent cannabis users, and some indication of greater apathy in young adult cannabis users. Behavioural studies yielded some evidence of reduced reward learning in adolescent cannabis users, though there were too few studies in this category for reliable conclusions. Finally, longitudinal and acute functional neuroimaging studies showed an association between cannabis and blunted neural responses to reward, which did not emerge consistently in cross-sectional studies. The current results suggest that cannabis use is associated with specific impairments in reward and motivation. Future large-scale, longitudinal studies which use multiple behavioural and neuroimaging measures of reward processing may further clarify the impact of cannabis use on motivational and reward processes, and neural networks.
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Accumulating evidence suggests neuropsychological deficits from cannabis use, with a burgeoning area of preclinical research indicating possible sex-differences. However, few studies have examined how cannabis use may differentially impact neurocognition in male and female cannabis users. As such, we examined potential sex-differences in associations between amount of cannabis use (across several time frames) and neurocognitive performance among young adult regular cannabis users. Consistent with previous studies, more cannabis use was generally associated with poorer episodic memory and decision-making, but not other measures of inhibitory control. However, patterns of results suggested sex-specific dissociations. In particular, more cannabis use was more consistently associated with poorer episodic memory performance in females than males. Conversely, more cannabis use was associated with poorer decision-making performance for males, but not females. These results provide further evidence for residual cannabis-associated neurocognitive deficits and suggest the importance of examining the impact of cannabis on neurocognition separately for males and females. (JINS, 2013, 19, 1-7).
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Context Cognitive impairments are associated with long-term cannabis use, but the parameters of use that contribute to impairments and the nature and endurance of cognitive dysfunction remain uncertain.Objective To examine the effects of duration of cannabis use on specific areas of cognitive functioning among users seeking treatment for cannabis dependence.Design, Setting, and Participants Multisite retrospective cross-sectional neuropsychological study conducted in the United States (Seattle, Wash; Farmington, Conn; and Miami, Fla) between 1997 and 2000 among 102 near-daily cannabis users (51 long-term users: mean, 23.9 years of use; 51 shorter-term users: mean, 10.2 years of use) compared with 33 nonuser controls.Main Outcome Measures Measures from 9 standard neuropsychological tests that assessed attention, memory, and executive functioning, and were administered prior to entry to a treatment program and following a median 17-hour abstinence.Results Long-term cannabis users performed significantly less well than shorter-term users and controls on tests of memory and attention. On the Rey Auditory Verbal Learning Test, long-term users recalled significantly fewer words than either shorter-term users (P = .001) or controls (P = .005); there was no difference between shorter-term users and controls. Long-term users showed impaired learning (P = .007), retention (P = .003), and retrieval (P = .002) compared with controls. Both user groups performed poorly on a time estimation task (P<.001 vs controls). Performance measures often correlated significantly with the duration of cannabis use, being worse with increasing years of use, but were unrelated to withdrawal symptoms and persisted after controlling for recent cannabis use and other drug use.Conclusions These results confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication and worsen with increasing years of regular cannabis use.