Meta
Grant et al. Non-acute (residual)
neurocognitive effects of cannabis use: A
meta-analytic study
Rocchetti et al. 2013 Is cannabis neurotoxic
for the healthy brain?
A meta-analytical
review of structural brain alterations in
non-psychotic users
Meta-analysis + cannabis, marijuana, adolescent, cognitive
[ - psychosis, schizophrenia. no information about onset? ]
Adult human subjects.
With the exception of both the learning and forgetting domains, effect size confidence intervals for the
remaining 6 domains included zero, suggesting a lack of effect.
Original inclusion criteria for studies entering meta-analysis
1. Includes a group of “cannabis only” users
2. Includes an appropriate control group (i.e., non drug-using or
very limited cannabis use) 3. Provides sufficient information to calculate effect size
4. Outcome measures
include valid neuropsychological tests
5. Cannabis-using group is drug-free on day of neuropsychological
testing 6. Study addresses other potential substance use in cannabis group 7. Study addresses potential
history of neurological or psychiatric problems 8. Study reports length of abstinence from cannabis before
testing
The two exceptions were in the domains of learning and forgetting. Here when we averaged across the 11
studies that had the most rigorous inclusion0exclusion criteria and the best designs, the effect size for
learning was 2.21 99%CI (2.39, 2.022) indicating a very small but discernible negative effect. This effect was
slightly larger when all 15 studies were included [2.24 99%CI (2.41, 2.064)]. Similarly, in the domain of
forgetting (failure to recall or recognize) the average effect size was 2.27 99%CI (2.49, 2.044), again suggesting
a very small but measurable decrement.
The “real life” impact of such a small and selective effect is questionable.
limited and contrasting evidence supporting a cannabis-related alteration on the white and grey matter
structures of non-psychotic cannabis users. However, our meta-analysis showed a consistent smaller
hippocampus in users as compared to non- users. (cousijn, 2013)
362 non-psychotic cannabis users and 365 non-users (mean age of participants was respectively 25.1 and 23.7
years).
meta-analyses for the following regions: (i) ICV (Batalla et al., Schacht et al.,Cousijn et al., McQueeny et al.,
Mata et al.,Yucel et al., Medina et al., Block et al.; (ii) WBV (Zalesky et al.,Ashtari et al., Lopez- Larson et al.,
Mata et al., Yucel et al., Delisi et al., Tzilos et al. Block et al.); (iii) left amygdala (Schacht et al.,Ashtari et al.,
McQueeny et al. Yucel et al.); (iv) right amygdala (Schacht et al., Ashtari et al.,McQueeny et al., Yucel et al.);
(v) left hippocampus (authors)
brain volume, the amygdala and the hippo- campus
There is evidence indicating that, within the group of heavy cannabis users, grey matter volume in the
hippocampus is negatively correlated with the intensity of cannabis use and with the severity of dependence,
while no associations were related to onset age or duration of cannabis use.
chronic administration of cannabis may decrease hippocampal volume and this may be one of the reasons
why memory performance is affected. A number of parameters have a negative impact on the memory,
including the age of first use, the average frequency of use, the cumulative lifetime dose, the average dose
per occasion, and the duration of regular use
there is also evidence of a progressive change in the d-9-THC potency of street cannabis over more recent
years that should be carefully considered when interpreting our findings (see below).
a recent study suggests that some structural abnormalities could predate the onset of cannabis use.
Schreiner & Dunn 2012 Residual Effects of
Cannabis Use on Neurocognitive
Performance After Prolonged Abstinence: A
Meta-Analysis
small negative effect for global neurocognitive performance as well for most cognitive domains assessed.
Unfortunately, methodological limitations of these studies prevented the exclusion of withdrawal symptoms
as an explanation for observed effects. In the second meta-analysis, 13 of the original 33 studies met inclusion
criteria. Results indicated no significant effect of cannabis use on global neuro-cognitive performance or any
effect on the eight assessed domains. Overall, these meta-analyses demonstrate that any negative residual
effects on neurocognitive performance attributable to either cannabis residue or withdrawal symptoms are
limited to the first 25 days of abstinence.
There is also some evidence that an earlier age of onset for cannabis use may be related to poorer
neurocognitive performance (Pope et al., 2003). It may be that lasting residual effects of cannabis use are
dependent on onset of regular use occurring before a certain age or developmental stage.
As discussed by Grant et al., (2003), another important consideration is the lack of information regarding
users’ premorbid performance. It is difficult to interpret scores as notable changes resultant from their
cannabis use when their capabilities before onset are unknown.
Review
TITLE-ABS-KEY (cannabis, marijuana, adolescent, cognitive) AND DOCTYPE(re) (english, not about substance
use of mother, not about treatment)
Adolescents who use marijuana heavily tend to show disadvantaged attention, learning, and processing
speed; subtle abnormalities in brain structure; increased activation during cognitive tasks despite intact
performance; and compromised objective indicators of sleep quality. Some abnormalities appear to persist
beyond a month of abstinence, but may resolve within three months if cessation is maintained
Jacobus et al 2009 Functional
consequences of marijuana use in
adolescents
Pattij et al 2008 Cannabinoid modulation of
executive functions
Realini, Rubino, Parolaro. 2009.
Neurobiological alternations at adult age
Overall, findings of neuropsychological impairments in adolescent marijuana users are fairly consistent with
studies of adult users, suggesting significant but relatively subtle detrimental effects in the domains of
attention, memory, processing speed, and some executive functions (planning, perseveration, and fluency).
However, these cognitive disadvantages may be more likely to manifest, and to persist after a month of
abstinence, with adolescent as opposed to adult marijuana use
Adolescents who use marijuana heavily tend to show some disadvantages in attention, verbal learning and
memory, and processing speed that persist beyond one month of abstinence, but largely remit after three
months of sustained abstinence. Adolescent onset marijuana use has been linked to abnormalities in brain
structure,
Some abnormalities may predate the onset of adolescent substance use and relate to risk factors for early
drug involvement (e.g., inhibitory dysfunction), while some abnormalities may relate to indirect effects of
adolescent marijuana use (e.g., missing school or frequently being high, hence missing opportunities to
stimulate brain development), and other aberrancies may relate to excessive stimulation of cannabinoid
receptors during adolescent neuromaturation.
The magnitude of the abnormalities overall is relatively mild, with effect sizes appearing smaller than ins
similar studies focused on alcohol or other illicit drugs
In all, the majority of any marijuana- related abnormality appears to resolve within 3 months of abstinence.
However, the degree to which neural consequences of marijuana use would emerge or resolve may depend
on gender, genetic factors, premorbid cognitive reserves, psychiatric functioning, age of onset, intensity of
THC exposure, and other substance use.
consensus is still lacking regarding the long-term effects of adolescent cannabis exposure. While some studies
in adolescents or in adults that had started using cannabis during adolescence reported no lasting deficits in
cognitive abilities such as overall intelligence quotient, processing speed, working memory, and attention
(Fried et al., 2005; Jager et al., 2006), other studies found (subtle) long-lasting cognitive deficits following
cannabis use during adolescence (Jacobsen et al., 2004; Medina et al., 2007; Pope et al., 2003; Schwartz et al.,
1989).
a growing body of clinical and preclinical studies have suggested a particular vulnerability of the adolescent
brain. Thus, adolescent cannabis use may on the long run be associated with lasting changes in cognitive
functions
The literature here summarized, exploiting animal models of cannabis consumption, points to the presence of
subtle changes in the adult brain circuits after heavy cannabis consumption in adolescence. These alterations
triggered by adolescent exposure to
cannabinoids
.
.
.
lead to impaired emotional and cognitive perfor- mance, enhanced vulnerability for the use of more harmful
drugs of abuse, and may represent a risk factor for developing schizophrenia in adulthood. These pre-clinical
observations are strengthened by literature in humans where longitudinal studies often support the
experimental results
Adolescent exposure to increasing doses of the synthetic cannabi- noid agonist CP-55,940 for 21 days (PND
30–50) induced impaired working memory in adult female [46] and male rats [46–47] assayed by the object
recognition test. Schneider and Koch [44,63] using the same test showed a similar impairment in adult male
rats after a peripubertal chronic treatment (PND 40–65) with WIN 55,212–2, which was not delivered
regularly, to mimic the irreg- ular consumption practice in humans. Notably, WIN 55,212–2 did not lead to
long-lasting deficit when administered in adult rats [44].
cognitive impairments occur only when heavier proto- cols of treatment are applied. Indeed, Quinn et al. [64]
reported that after adolescent THC exposure adult male rats spent a decreased percentage of time relative to
controls investigating a novel object, suggesting working memory dysfunction.
Overall these findings suggest that cannabinoid exposure causes greater lasting memory deficits and
hippocampal alterations in adolescent than adult rats.
No alteration was found in aversive memory, but in the radial maze THC pre-treated animals exhibited a
worse performance than vehicles, suggesting a deficit in spatial working memory.
Human studies. suggests that the adoles- cent brain may be particularly vulnerable to the influence of heavy
marijuana use [69–72]. As a general comment, human studies are characterized by large variability both in
cannabis consumption and in the period of abstinence after consumption (form 1 week to 1 month or more)
that makes difficult to extrapolate data about the transient or long-lasting nature of the observed deficits.
Differences have been found in attention and executive func- tioning [73–74], memory [75,76], and
psychomotor speed and manual dexterity [77]. Most recent studies have examined work- ing memory and
verbal episodic memory and cumulatively, the evidence suggests impaired encoding, storage, manipulation
and retrieval mechanisms in long-term or heavy cannabis users [see 71 for review]. These impairments are
not dissimilar to those associ- ated with acute intoxication and have been related to the duration, frequency,
dose and age of onset of cannabis use.
[69] Pope Jr HG, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D. Neuropsy- chological performance in
long-term cannabis users. Arch Gen Psychiatry 2001;58:909–15.
[70] Jacobsen LK, Mencl WE, Westerveld M, Pugh KR. Impact of cannabis use on brain function in
adolescents. Ann NY Acad Sci 2004;1021:384–90.
[71] Solowij N, Battisti R. The chronic effects of cannabis on memory in humans: a review. Curr Drug Abuse
.
.
.
.
.
Rubino, Parolaro 2008 Long lasting
consequences of cannabis exposure in
adolescence
Rev 2008;1:81–98.
[72] SchweinsburgAD,BrownSA,TapertSF.Theinfluenceofmarijuanauseonneu- rocognitive functioning in
adolescents. Curr Drug Abuse Rev 2008;1:99–111.
[73] Bolla KI, Brown K, Eldreth D, Tate K, Cadet JL. Dose-related neurocognitive effects of marijuana use.
Neurology 2002;59:1337–43.
[74] PopeJrHG,Yurgelun-ToddD.Theresidualcognitiveeffectsofheavymarijuana use in college students. J Am
Med Assoc 1996;275:521–7.
[75] Pope Jr HG, Jacobs A, Mialet JP, Yurgelun-Todd D, Gruber S. Evidence for a sex-specific residual effect of
cannabis on visuo-spatial memory. Psychother Psychosomat 1997;66:179–84.
[76] Solowij N, Stephens RS, Roffman RA, Babor T, Kadden R, Miller M, et al. Cog- nitive functioning of longterm heavy cannabis users seeking treatment. JAMA 2002;287(9):1123–31.
heavy cannabis consumption in adolescence may induce subtle changes in the adult brain circuits ending in
altered emotional and cognitive performance
few human studies: some evidence that exposure during adolescence may lead to lasting deficits in working
memory (Schwartz et al., 1989).
Adolescent exposure to increasing doses of the synthetic cannabinoid agonist CP-55,940 for 21 days (PND 30–
50) induced impaired working memory in adult female (O’Shea et al., 2004) and male rats (O’Shea et al., 2006)
checked by the object recognition test. A similar impairment in object recognition memory was observed in
adult male rats after a peripubertal chronic treatment (PND 40–65) with another synthetic cannabinoid
agonist, WIN 55,212, which were not delivered regularly, to mimic the irregular consumption practice in
humans (Schneider and Koch, 2003, 2007). Notably, WIN- 55,212 did not lead to long-lasting deficit when
administered in adult rats (Schneider and Koch, 2003). When the natural agonist was employed, Cha et al.
(2006, 2007) reported no significant lasting effects on spatial learning tested with the Morris water maze in
adult male and female rats previously exposed to THC for 21 days (PND 30–50). However, the absence of an
effect of chronic THC exposure on subsequent water maze learning does not rule out the possibility that it
induced more subtle deficits that could be “unmasked” under certain conditions. It is important to recognize
that no behavioural technique can assess all aspects of learning. Therefore, THC could be expected to affect
performance on some indices and not others.
In fact, adolescent THC-pretreated rats spent a decreased percentage of time relative to controls investigating
a novel object, suggesting working memory dysfunction (Ennaceur and Delacour, 1988).
The intrinsic limitation of human epidemiological studies due to the great variability in the cultural, social, and
economic background, as well as in the education level of the subjects, makes difficult to establish causal links
between adolescent marijuana consumption and development of psychiatric illnesses, altered affective
outcomes and drug dependence in adulthood.
heavy cannabis consumption in adolescence may induce subtle changes in the adult brain circuits ending in
altered emotional and cognitive performance.
Schneider. 2008. Puberty as a highly
vulnerable developmental period for the
consequences of cannabis exposure.
Schweinsburg 2008 The influence of
Emerging evidence from human studies and animal research demonstrates that an early onset of cannabis
consumption might have lasting consequences on cognition. …. These findings suggest that young people
represent a highly vulnerable cannabis consumer group and that they run a higher risk than adult consumers
of suffering from adverse consequences from cannabinoid exposure.
controversy remains as to the residual long-term deleterious effects of cannabis exposure on cognitive
functioning. So far most studies seem to argue against this possibility (e.g. Lyketsos et al. 1999; Pope et al.
2001). … Studies that take the age of onset of cannabis consumption into consideration show a completely
differ- ent picture than those that do not differentiate between early- and late-onset consumers.
Ehrenreich 1999. Wilson 2000. Pope 2003.
limitations. First, they do not inform about the pattern of initial cannabis ingestion at young ages, whether
can- nabis was consumed regularly or just occasionally by the young users. Furthermore, there is a high
variation in abstinence periods before testing was done. … heterogeneity of consumption patterns (different
inhalation techniques, oral ingestion) and cannabis prod- ucts (marijuana, hashish, hashish oil), the final
bioavail- ability of THC differs extremely even between users showing a similar history of use. Taking these
limitations into account, animal research offers much better possibilities for a controlled investigation of the
direct association between can- nabinoid exposure during maturation and subsequent disturbances in
cognitive processing.
Animal: Schneider & Koch 2003, Schneider 2005, Schneider & Koch 2003, 2005. O’Shea 2006. Quinn 2008. no
residual alterations were seen in this study after chronic treatment from pd 30 to 50 (Cha et al. 2006).
However, treatment in these male rats started 10 days before puberty onset and ended about 10 days before
sexual maturity was reached and might therefore not have been sufficient to observe persistent effects.
Taken together, these findings from animal studies confirm the previous results from human studies and
indicate puberty/mid-adolescence as a highly susceptible time window for possible residual (and also acute)
effects on cognitive processing.
Animal research and studies of human adults support the conclusion that those who begin at an earlier age
marijuana use on neurocognitive
functioning in adolescents
Jager & Ramsey 2013 Long-term
consequences of adolescent cannabis
exposure on the development of cognition,
brain structure, and function: an overview
of animal and human research
Trezza 2008 Cannabis and the developing
brain: Insights from behavior
Quickfall Crockford 2006 Brain
neuroimaging in cannabis use: A review
show greater dysfunction than late-onset users. Importantly, no study demonstrated improved performance
among marijuana users, or among early-onset users relative to late-onset users, indicating a disruptive effect
of cannabinoids. In addition, lighter use was not always associated with neuro- cognitive decrements in
humans [36, 37] or animals [63], suggesting that impairments may be related to heavier use.
Lighter use, even if chronic, was often not associated with neurocognitive dys- function. Thus, it is unclear
whether only very heavy use is detrimental to brain functioning, or whether very heavy users differ from
lighter users on other factors that account for ab- normalities
Given that many marijuana users have experience with alcohol, nicotine, and other drugs [86], it is difficult to
disen- tangle the unique influence of marijuana.
even moderate alcohol use may impact neural functioning [88]. Yet the inclusion of marijuana users with
other substance use histories maintains representativeness in the sample, allowing for better generalization
to the popula- tion of adolescent marijuana users
Gender differences in the neural impact of marijuana use have rarely been explored, but provide an intriguing
line for future research.
Nine brain function in human adolescent marijuana users at increasing durations of abstinence studies.
Jacobsen = verbal working memory, others (Schweinsburg, Padula) are spatial. Fried 2005 and Schwartz 1989
is memory and processing speed.
Not available to me..
Fried, Pope, Ehrenreich.
Together, these findings suggest that the effects of cannabis on cognition might depend on the age of
initiation of cannabis use.
In a study30 of chronic cannabis users stratified by age of first use and gender, a significant correlation
between age of first use and decreased total brain volume was seen. Unfortunately, nonusing subjects were
not involved for comparison, so it is unclear if the findings represent differences from comparison subjects or
whether they relate to other nonspecific factors that predict earlier onset of substance use and being at
risk.17 Later MRI studies25,26 did not find correlations based on age of onset in secondary analyses of
imaging data.
The frontal lobes are thought to play a significant role in substance use dis- orders50 by their involvement in
cognitive functions, including executive control, working memory, novelty processing, attention and
awareness, and integration of multimodal sensory information.51
Hall & Degenhardt 2009 Adverse health
effects of non-medical cannabis use
In summary, functional neuroimaging studies have reported generally consistent frontal lobe differences.
Attenuated frontal lobe activity has been reported in recently abstinent heavy cannabis users compared to
healthy subjects in resting and task-based studies,
while increased frontal lobe activity has been generally reported with cannabis exposure in both heavy and
occasional users, correlating with subjective reports of intoxication. <- so intoxication gives better
performance?
Chronic effects
With no data for THC and other cannabinoids, chronic cannabis use has usually been defined as almost daily
use over a period of years. Epidemiological studies cited below have reported associations between this
pattern of cannabis use during adolescence and various adverse health outcomes. The major challenge in the
interpretation of these studies is to rule out alternative explanations of the associations. Cannabis use is
5
highly correlated with use of alcohol, tobacco, and other illicit drugs, all of which adversely affect health.
Regular cannabis users also differ from non-users before they use cannabis in ways that could affect their risk
5
of some outcomes, especially behavioural ones. Statistical control of confounding has been used to assess
36
these relations but some epidemiologists doubt the success of this strategy.
CNS effects
Poor cognitive functioning is a risk factor for regular cannabis use; however, whether chronic cannabis use
17
impairs cognitive performance is not clear. Studies that matched users and non-users on estimated
17
Block
intellectual function before cannabis use or on cognitive performance assessed before cannabis use
have
61
found subtle cognitive impairments in frequent and long-term cannabis users.
Deficits in verbal learning, memory, and attention are most consistently reported in heavy cannabis users, but
Solowij
these have been variously related to duration and frequency of use, and cumulative dose of THC.
Debate
continues about whether these deficits are caused by acute drug effects, residual drug effects, or the effects
62
of cumulative THC exposure. Whether cognitive function recovers after cessation of cannabis use is also
17
unclear. Solowij showed partial recovery after 2 years of abstinence but brain event-related potential
measures still showed impaired information processing that was correlated with years of use. Bolla and
63
colleagues found indications of persistent dose-related impairment in neurocognitive performance after 28
64
Weeda et al. Blijvende
neuropsychologische stoornissen en
structurele functionele hersenafwijkingen
na langdurig cannabisgebruik.
Hall & Degenhardt 2009 Adverse health
effects. What are they, and what are their
implications for policy?
Kalant 2004 Adverse affects of cannabis on
health: an update of the literature since
1996
Macleod et al 2004 Psychological and social
sequelae of cannabis and other illicit drug
use by young people: a systematic review
of longitudinal, general population studies
Moore 2007
Court 1998 Annotation. Cannabis and brain
function
days of abstinence in heavy young users (5 years of use) but Pope and colleagues reported recovery after 28
days’ abstinence.
Adolescent regular cannabis users are more likely to use other illicit drugs, although the explanation of this
association remains contested.
For cognitive performance, the size and reversibility of the impairment remain unclear. The focus of
epidemiological and clinical research should be on clarifying the causative role of cannabis for these adverse
health effects.
Op basis van zes onderzoeken kan geconcludeerd worden dat er vooralsnog onvoldoende bewijs is voor of
tegen het optreden van blijvende stoornissen door langdurig cannabisgebruik. Mogelijk heeft cannabisgebruik
in de vroege adolescentie blijvend effect op cognitief functioneren en de hersenstructuur. Aanwezigheid van
cognitieve en cerebrale afwijkingen voorafgaand aan cannabisgebruik en subacute effecten van cannabis
konden niet uitgesloten worden. Dutch
The one on politics
Not on adolescents
Not cognitive
Not cognitive
Regular use may have an adverse effect on learning, with possible mid- to long-term psychological and
cognitive impairment.
Article also explains acute, subacute (days or weeks after use), and long term effects (months after or
permanent).
Distinguish acute, sub-acute and long-term effects. Subaccute effect on attention and short term memory
(Pope et al., 2005). Deahl: short term memory deficits even after several weeks of abstinence.
Iversen 2005 Long term effects of exposure
to cannabis
McArdle 2007 – Long-term effects of
cannabis
Egerton Allison Brett Pratt 2006
Cannabinoids and prefrontal cortical
function: Insights from preclinical studies
Long-term: not clear whether there is irreversible damage. Solowij et al: short- and long-term cognitive
impairments, and impaired ability to focus attention. Solowij et al (other study) long term users had difficulty
focusing attention and filtering out information. Leon-Carrion: significant differences on formal assessment of
cognitive function.
Conclusion: “While intoxicated, users will probably exhibit some impairment of cognitive function and
reduced ability to carry out learning and other tasks. Cannabis may have residual effects lasting days or
weeks, and heavy, long-term users may suffer long-term impairment.
Too old
There is little evidence, however, that long-term cannabis use causes permanent cognitive impairment.
One confounding factor in human studies is that comparisons have to be made between groups of drug users
versus non-users; however, it is usually impossible to compare the baseline performance of these groups
before cannabis use to see if they are properly matched. Little on cognition, fuly covered
Only one reference on cognition: Fried 2005
Less relevant: focuses on acute effects
In future directions: To date, few studies have addressed the impact of chronic cannabinoid exposure on
cognitive function in rodents, and whether these impairments persist after periods of drug abstinence. This
question forms an important clinical concern, as several studies in humans indicate long-term or prolonged
effects of marijuana exposure on cognitive functioning (Bolla et al., 2002; Eldreth et al., 2004; Lundqvist,
2005; Pope et al., 2001; Schwartz et al., 1989; Solowij et al., 2002).
Details: age of onset, duration of use, frequency of use, dosage