Early use of cannabis affects the working memory of adolescents, but its deleterious effect is more pronounced in girls, posing a risk to their academic success as well as to their memory when they reach adulthood.
These are the findings of a study conducted by Sima Noorbakhsh of the CHU Sainte-Justine Research Centre, under the direction of Professor Patricia Conrod of the Department of Psychiatry and Addictology of Université de Montréal.
This work is the subject of a scientific article published in early April in the journal Frontiers in Human Neuroscience.
Done in collaboration with the management and teaching staff of 31 high schools in the Greater Montreal area, the research project consisted of using surveys and various neuropsychological tests to evaluate the impact of cannabis and alcohol use on the memory and cognitive performance of 3,826 students.
“Their responses, obtained on an annual basis, were collected over a five-year period, allowing the researchers to follow a cohort of students from the beginning to the end of their high school studies,” Conrod said.
In addition to surveys to determine the evolution of drug use among young people, neuropsychological tests were used to measure their working memory, recall memory, perceptual reasoning and inhibitory control.
Young girls more greatly affected
Overall, the surveys showed a gradual increase in alcohol and marijuana use from Grades 1 to 5 among both boys and girls.
The neuropsychological tests showed that alcohol consumption is not associated with a significant reduction in cognitive and mnemonic performance, however this is not the case for cannabis use.
Indeed, the results revealed a decrease in performance in both boys and girls during the tests as well as a more damaging effect on working memory among those who used cannabis early, at the start of high school.
What accounts for this difference?
“Working memory, which involves the ability to process and store information over a short period of time, is related to the prefrontal cortex,” replied Conrod. “This is the last region of the brain to develop in adolescents, but this development occurs earlier in girls than in boys.”
“Several studies have shown that early marijuana use affects the maturation of the prefrontal cortex, and our results corroborate them: girls who report using cannabis in early adolescence show a deficit in working memory by the end of high school compared to girls who used later.”
Preventing early use
The study also reveals that there is a gender difference in the negative consequences of early cannabis use on brain development and, in particular, on the area related to working memory.
Data collected by Noorbakhsh and Conrod also show that by the time they reached Grade 5 – that is, before adulthood – “almost 80 percent of the participants reported having used cannabis,” the researchers write.
“More than 10 per cent of Canadian teenage girls aged 15 and older had used marijuana in the past year, according to Statistics Canada’s 2018 data, and we know that students who smoke cannabis are 2.3 times more likely to drop out of school than those who do not,” said Conrod.
As well, there is evidence that regular cannabis use has long-term effects on attention span and memory, as well as on academic performance, she added.
“Although the law prohibiting marijuana use before the ages of 18 to 21 in Quebec is a good thing, it does not change teenagers’ behaviour,” she said.
“We need to better prevent its early use through strategies that will engage parents, schools and public health departments, through interventions that will target and reach young people, because their long-term mental health is at stake.”
A typical case in the counselling situation in the German public health care system is a young adult who has been sent by the job centre and who needs support after he stopped his first education because he felt that this does not fit to him, and who failed during the second education because he was overwhelmed with the conditions and requirements asked for by the trainer.
The young adult seems unfocused, his memory is sketchy, in particular the short-term memory, and the affect is indifferent and a bit sappy. The intelligence is in the normal range. It is reported that he has a lack in daily structure.
A deeper exploration shows that he started to use cannabis, first as marijuana joints, later as dabs, with 15 years at school. With 17, he stopped school and started the education.
This is a very typical example seen today often in various counselling situations. Cannabis with its various preparations is frequently used by adolescents. In a cross-sectional study comprising all pupils in the 10th classes of an eastern German county, it was found that 25% of the pupils with a mean age of 16 years used cannabis .
Similar prevalence was reported by others: in Frankfurt, Germany, 35% of the pupils had experience with cannabis consumption , and in whole of Germany the 2016 report of the Bundesregierung shows 3.1% illegal drugs in the group of persons aged 18–20 years, and 23% cannabis .
In France 24% of the ninth grade pupils , 40.5% of the 15- to 16-year-old boys and girls in United Kingdom , 36% of boys and 38% of girls of the adolescents in Czech Republic, 28% of boys and 25% of girls of the adolescents in Slovakia, and 28% of boys and 20% of girls of the adolescents in Poland  consumed cannabis.
The most common way of administration is smoking. In this case, the maximum effect occurs after about 15 min and lasts for about 1 h. If administered orally, the absorption is slower and the effect starts with delay. Besides this, there is a growing field for use and evaluation of indications of cannabinoids in medicine (see ). This should be clearly separated from “abuse,” which is the topic of the present review on effects of cannabis abuse in adolescents and adults.
According to the current data, in mid-European countries about 1/4 or 1/3 of the adolescents consume cannabis.
The consume frequency is not exactly known. However, according to the data of the Drogenbeauftragte der Bundesregierung 2019, 1.2% of the adolescents (12–17 years) consume regularly, 3.1% consumed at least once in the last 30 days, and 8.0% consumed at least once in the last 12 months .
In 18- to 25-year-old young adults, 5.9% consume regularly, 9.2% in the last 30 days, and 22.0% in the last 12 months. The data for 18- to 59-year-old adults were 1.2, 3.4, and 8.3%, respectively . An important issue in this context is whether exposure to cannabis in adolescence may differ from the effects of exposure in adulthood.
In the German young adult population (18–25 years), the life prevalence of cannabis consume is about 33% . In the 18- to 59-year population of adults, this prevalence is 30.2% .
However, there is increasing evidence that cannabinoids affect the adult and adolescent brain in different ways: in younger people, cannabinoid use elicits long-lasting neuropsychological deficits  which is not or less pronounced in adults [10, 11].
In another investigation, authors concluded that duration of use (rather than frequency) may be the primary factor contributing to cognitive deficits , while others showed that early onset of cannabis use is associated with neuropsychological deficits . The focus of the present review is to discuss mechanisms which may underlie these effects and differences.
For that purpose, the literature from 1960 to 2019 (PubMed database) was investigated for the keywords “cannabis,” “marijuana,” “hashish,” “tetrahydrocannabinol,” “cannabidiol,” “endocannabinoids,” “adolescent,” and “adult.”
In addition, drug reports from Germany and the Netherlands were included. Moreover, the IUPHAR database was checked for “cannabinoid receptor,” “CB1,” “CB2,” and “endocannabinoids.”
Cannabinoids act typically at cannabis receptors (CB). The main cannabis receptors CB1 and CB2 belong to the group of G-protein-coupled receptors (GPCR) and can be activated by endogenous endocannabinoids, phytocannabinoids, or synthetic cannabinoids .
CB1, encoded by the CNR1 gene, is typically coupled to Gi/o-suppressing AC activity and cAMP formation but can switch to Gs or Gq . The CB1 subtype is expressed in the brain (highest expression in the olfactory bulb, hippocampus, basal ganglia, and cerebellum), peripheral nervous system (mostly expressed in sympathetic nerve terminals), and peripheral tissues such as the gut, heart, liver, reproductive system, immune system, and airways in a region-specific manner [15-18].
Unselective agonists at the CB1 are HU-210, CP55940, and WIN55212-2 , CB1-selective agonists are arachidonyl-2-chloroethyamide, arachidonylcyclopropylamide, O-1812, and R-(+)-ethanandamide [20-23], while tetrahydrocannabinol (THC) acts as a partial agonist [19, 20]. Rimonabant and AM6545 are used as antagonists at the CB1 [19, 24].
The second type of cannabis receptor, the CB2, encoded by theCNR2 gene, is also a GPCR and is typically coupled to Gi/o. Agonists at this receptor are HU-210, CP55940, and WIN55212-2  and antagonists are SR144528 and AM-630 [25, 26]. As at CB1, THC acts as a partial agonist at the CB2 .
The CB2 subtype is expressed in peripheral organs with immune function, such as the spleen, tonsils, thymus, as well as cells like macrophages and leukocytes. CB2 also is present in microglia and vascular structures. Moreover, CB2 is expressed in the lungs, testes, and central nervous system .
Besides the CB receptors CB1 and CB2, other receptor proteins have been identified as possible targets for the endocannabinoid system such as CPR55, GPR119, and transient receptor potential vanilloid 1 (TRPV1) .
While the receptors, their coupling, and possible agonists and antagonists have been characterized, the physiological or even pathophysiological function of the cannabinoid receptors is still a matter of debate.
Pharmacologically, cannabinoids are used because of their antinociception, anti-inflammation, anticonvulsant, and antiemetic (e.g., in cancer medicine) properties . The physiological mediators at CB1 and CB2 comprise N-arachidonoyl-ethanolamine (AEA, anandamide) and 2-arachidonoylgylcerol (2-AG), which are derivatives of arachidonic acid (see Fig. 1).
Physiologically, the endocannabinoid system plays a role in the brain in short- and long- term depression at both excitatory and inhibitory synapses by negative feedback mechanisms on neurotransmitter release [28, 29].
CB1-mediated self-inhibition has been described in neurons of the CA1 area in hippocampus and in neocortical interneurons and some pyramidal neurons (for review, see ). In the brain, endocannabinoid signalling has been considered to be involved in sleep regulation, reward reaction, anxiety control, appetite control, neuroprotection, and neural development.
In the cardiovascular system, negative inotropy and vasodilation have been associated with cannabinoids. In the gastrointestinal tract, motility and enteroendocrine functions seem to be influenced .
Moreover, endocannabinoids can act as immunomodulatory effectors . Thus, CB2 is the cannabinoid receptor which is predominantly expressed by immune cells and which upon stimulation seems to inhibit migratory activities of immune cells .
Pathophysiologically, it has been suggested that an overactive endocannabinoid system may contribute to the development of diabetes mellitus . An involvement of the endocannabinoid system in the pathogenesis of schizophrenia has also been suggested .
Moreover, dysfunction of the endocannabinoid system has been discussed to be involved in kidney disease  and liver fibrosis . CB1 activation by endocannabinoids has been suggested to be involved in proinflammatory cardiovascular processes and in atherosclerosis, while CB2 stimulation appeared to be protective . In addition, it has been shown that CB1 antagonists and CB2 agonists may protect against diabetic nephropathy .
Exogenous cannabinoids mainly origin from plant products made from Cannabis sativa like hashish and marijuana. Cannabis sativa contains several phytocannabinoids with THC and cannabidiol (CBD) being the most prominent (see Fig. 1).
Finally, it is pharmacologically important to discriminate endogenous and exogenous cannabinoids, since THC acts as a partial agonist [19, 20], which means that in presence of endogenous endocannabinoids (agonists) it may antagonize or attenuate the effects of the endocannabinoids, while in absence of endocannabinoid stimulation it rather works in an agonistic manner. Furthermore, this is affected by the receptor density. Thus, the resulting effect of THC may also depend on the context of endogenous stimulation of the cannabinoid system.
Composition and Composition Changes of Cannabis/Marijuana Preparations
Over the last 20–30 years, the composition of cannabis products has changed due to the fact that cannabis is grown in doors and that strains are cultivated with different THC and CBD contents and THC:CBD ratios [36, 37] (Table 1).
Thus, it was found in a large European study in samples from 28 EU countries and Norway and Turkey that from 2006 until 2016 the THC content in resin and in herbal cannabis increased from 8.14 to 17.22% and from 5.0 to 10.22%, respectively .
A similar development was found in samples from France over a 25-year period ranging from 1992 to 2015 . Comparable increases in THC content in the resin were found in Denmark from 2000 (mean: 8.3%) to 2017 (mean: 25.3%) with an increase in THC:CBD ratio from 1.4 in 2008 to 4.4 in 2017 .
Interestingly, in the Netherlands the THC content remained nearly unaltered (resin THC content: between 16 and 17% during the timespan from 2005 until 2015) . However, that means that in the Netherlands the THC resin content in 2005 was with 16% in the range, which was achieved in other European countries at 2016.
Depending on genetic selection, breeding conditions, outdoor or in door cultivation, etc., the content in certain cannabinoids in the herbs varies . This data shows that it is important to define the terms “cannabis,” “marijuana,” “hashish,” etc. in terms of THC content and CBD:THC ratio and to take the changes in this composition over the last decades into account [36-44] (see Table 1). Data from earlier studies may not be directly comparable to more recent studies due to the altered composition of the preparations.
Neuronal Effects of Cannabis Abuse and Special Effects in Adolescents
The brain is continually developing until the age of about 25 . New MRI technologies revealed that from birth to early adulthood, there are transformation processes regarding grey and white matter.
In principle, the process in adolescence can be described as a reduction of redundant grey matter and increase in white matter [46-48]. With birth and infancy, there is a huge formation of new synapses, in particular in the cortex.
Later on, a pruning process is observed with eliminating unused or redundant connections and improving those synapses that are used. This is from a histological point of view a part of the process of learning, aiming at improving the efficacy of the brain.
During this process, many neurons are lost, so that the adult has about 41% fewer neurons than the newborn . Increased loss of grey matter in the medial prefrontal cortex was found in drug users, in particular in those who used multiple drugs .
The brain, however, does not mature in all regions at the same time: more rudimentary regions, such as those enabling movement and somatosensory functions and general information processing, mature first (in childhood), while others being involved in impulse control, strategic planning, or social behaviour mature later in adolescence together with the maturation of the prefrontal cortex .
The total process may be considered as a highly complex “genetically patterned process of consolidating anatomical network hubs” . Finally, the process of increasing white matter connections and eliminating redundant grey matter leads to increased cognitive functioning [46, 48, 52].
Taken together, this means that the adolescent brain is a structure “under reconstruction” with complex neurophysiological processes of network formation. This may make the adolescent brain more prone to damages by substance abuse as compared to the adult brain and may lead to different impairment.
It has been shown that cannabis leads to lower circulating levels of brain-derived neurotrophic factor (BDNF) in physically active cannabis users . In another study, chronic cannabis use resulted in lower serum levels of nerve growth factor (NGF) , while BDNF was not altered in this group.
The connection between neurotrophic factors such as BDNF and NGF seems even more complex, if patients suffering from a psychosis such as schizophrenia are taken into account: in schizophrenic patients, chronic cannabis intake results in elevated NGF levels . Cannabis-using schizophrenic patients also exhibited elevated BDNF levels .
Interestingly, the same authors observed normalization of NGF levels after effective antipsychotic treatment . NGF has been found to be elevated in response to inflammatory brain diseases such as multiple sclerosis or systemic lupus erythematosus [58-60] and thus may be indicative for neuronal impairment.
On the other hand, NGF is not only a target of cannabinoid signalling, but also NGF can regulate the molecular machinery for the endocannabinoid 2-arachidonoyl glycerol signalling via tropomyosine kinase A receptors (NGF receptor) .
NGF has been demonstrated to sensitize transient receptor potential vanilloid 1 (TRPV1). CB1 receptor activation by the CB1 agonist arachidonyl-2′-chloroethyamide inhibited NGF-induced AKT phosphorylation and TRPV1 sensitization at least partially by attenuating NGF-induced PI2 signalling . It remains unclear at present how a partial agonist such as THC  would act in presence of endogenous agonistic endocannabinoids. This might be an interesting area of future research.
Thus, the endocannabinoid system is important for short-term and long-term synaptic plasticity in several brain regions including those involved in appetite control, learning, and action selection . One might speculate that a partial agonist may affect the endocannabinoid-regulated synapse plasticity. Taken together, there is a complex interplay between endogenous (agonistic) endocannabinoids, NGF, BDNF, and exogenous (partial agonistic) THC [19, 20] and cannabidiol .
Long-Term Effects of Cannabis Abuse in Adults and Adolescents
From the above considerations, one could imagine that early regular cannabis use in adolescence may have an impact on cerebral or cognitive functions. Indeed, it was found in 21 adolescent-onset cannabis users that verbal learning was slower in this group within 12 h after use of cannabis . In addition, a deregulation of the BDNF pathway was found to be the consequence of marijuana use in adolescence .
However, other researchers did not find an effect of adolescent cannabis use on structural brain characteristics in adulthood . On the other hand, the risk for the development of psychosis increases with the frequency of THC use .
Cannabis use in adolescence, in particular in the case of heavy users, is known to be related to impaired cognitive functioning , low educational attainment [69, 70], and educational problems  leading to socio-economic consequences.
Moreover, early cannabis use is associated with lower income and lower work commitment in early adulthood [72-74]. In a Swedish study on 42,240 young men, of which 8.8% (3,734) reported to have used cannabis at the age of 18, an increased relative risk was found for cannabis users to be unemployed later on or to receive social welfare assistance .
Although this was overshadowed by confounders such as parental separation, the association between early cannabis use and negative social outcome remained significant after adjustment for confounders. However, a possible explanation is also that both cannabis use and adverse life-course are caused by underlying social or genetic factors unknown yet. Thus, Daniel et al.  found weak evidence that childhood disadvantage is associated with later cannabis use.
The risk of becoming addicted to cannabis also is dependent on first use age. Thus, 9–10% of persons who start to use cannabis will develop addiction. If use is initiated in adolescence, this percentage is increased to 16–17%. Daily users exhibit addiction in 25–50% .
THC can act in certain systems as a CB1 antagonist [19, 20] and – paradoxically – in others as an agonist. This is attributable to its pharmacological characteristics as a partial agonist and, therefore, depends on the concomitant activation of the system by other endogenous cannabinoids, the receptor density, and possible limitations of the post-receptor signal pathway . Thus, THC is not simply mimicking or modulating the effects of endocannabinoids [19, 20] but rather evokes a complex interplay.
In long-term cannabis user, structural changes with reduced volumes have been detected by neuroimaging techniques in CB1-rich brain areas such as hippocampus, parahippocampus, and thalamus .
In adolescent chronic cannabis users also, structural changes were observed with loss of gray matter in the medial temporal cortex, parahippocampus, insula, and orbitofrontal cortex  and alterations in the amygdala and hippocampus [77, 80]. In particular, the functional connectivity among the neurons is predominantly impaired when users start in adolescence [81, 82].
Regarding abstinence, it was found that cessation of cannabis abuse did not lead to full recovery of cognitive deficits in adolescent-onset users. This indicates that early cannabis use (in adolescence) may result in greater loss of cognitive performance [83, 84]. However, this must be discussed with care because of possible confounding from socio-economic status .
Nevertheless, the study by Meier et al.  showed for a 1,037 person birth cohort study from birth (1972/1973) until the age of 38 years that persons who persistently used cannabis showed neuropsychological decline which was more prominent in those individuals who started cannabis use during adolescence.
Importantly, these authors also showed that cessation of cannabis use did not fully restore the deficits . Early use was associated in other studies with deficits in episodic memory, verbal fluency, and executive functioning [86-88].
Psychological problems such as sleep disorders, (hypo)manic symptoms, compulsive behaviour, depression, anxiety, hostility, or psychoticism have been observed to be more common if synthetic cannabinoids are used as compared to natural cannabinoids .
Moreover, Crane and co-workers [90, 91] reported on the background of earlier maturation of the female brain and gender-related differences in regional CB1 densities that the deficits in memory in rat studies were more pronounced in male rats. They assume that additionally ovarian hormones may enhance the association between cannabis use and cannabis-related stimuli. In humans, these authors found gender-related differences in the associations between age of onset of cannabis use and neuropsychological deficits .
Besides human studies, there are also animal experiments which support a negative effect of cannabis in adolescence on long-term development: in female rats, blockade of CB1 receptors from early to late adolescence seems to prevent the occurrence of pruning at glutamatergic synapses .
Other investigators found that adolescent exposure to THC in female rats resulted in impaired novel object recognition and reduced active social behaviour together with changes of selective histone modifications (H3K9me3) in the prefrontal cortex affecting the expression of genes involved in synaptic plasticity .
Interestingly, certain brain areas seem to react in a different manner to adolescent THC exposure: thus, in hippocampal postsynaptic fractions THC increased the expression of the NMDA receptor subunit GluN2B and of the AMPA subunits GluA1 and GluA2 and induced a persistent neuroinflammatory state with enhanced TNFa, iNOS, and COX2, while these alterations were not detectable in the prefrontal cortex .
In further support of these studies, chronic exposure to various cannabinoid agonists such as THC during adolescence, but not during adulthood, in rats of either gender was shown to induce long-term impairments in working memory [95-97]. THC exposure also impaired adolescent learning in male rats .
Other animal studies showed that THC exposure in adolescent rats altered in the prefrontal cortex those gene networks, which are related to cytoskeletal organization, cell morphogenesis, and dendritic development . In addition, THC caused premature pruning of dendritic spines in early adulthood .
In another rat study, however, THC during adolescence did not produce robust alterations in adult behaviour after a period of abstinence, so that the authors concluded that the adverse effects, which are associated with adolescent cannabis use, might be due to non-cannabinoid concomitants of cannabis use .
On the other hand, it was also shown in rats that adolescent exposure to THC reverses the normal correlations between the endocannabinoids anandamide and 2-arachidonoglycerol in the nucleus accumbens (negative) and in the prefrontal cortex (positive) . Taken together, most animal and clinical studies give evidence that adolescent exposure to THC leads to long-term changes with impairment of learning and social behaviour based on changes in the neurobiology of the prefrontal cortex, hippocampus, and nucleus accumbens.
- Dhein S, Schmelmer K, Guenther J, Salameh A. Aspects of methamphetamine abuse in adolescents and young adults in a Thuringian County. Eur Addict Res. 2018;24(2):98–105.External Resources
- Werse B, Müller O, Carsten Schell C, Morgenstern C. Drogentrends in Frankfurt am Main. Frankfurt: Centre for Drug Research, Goethe-Universität; 2010. Available from:.External Resources
- Die Drogenbeauftragte der Bundesregierung; Bundesministerium für Gesundheit: Drogen und Suchtbericht 2016. Available from: https://www.bundesregierung.de/Content/Infomaterial/BMG/_2902.html.
- Beck F, Guignard R, Richard JB. Epidemiological news in cannabis. Rev Prat. 2013 Dec;63(10):1420–4.
- Miller PM, Plant M. Drinking, smoking, and illicit drug use among 15 and 16 year olds in the United Kingdom. BMJ. 1996 Aug 17;313(7054):394–7.External Resources
- Čecho R, Baška T, Švihrová V, Hudečková H. Legislative norms to control cannabis use in the light of its prevalence in Czech Republic, Poland, Slovakia, and Hungary. Cent Eur J Public Health. 2017 Dec;25(4):261–5.
- Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch. Ärzteblatt Int. 2012;109(29–30):495–501.External Resources
- Die Drogenbeauftragte der Bundesregierung beim Bundesministerium für Gesundheit: Drogen und Suchtbericht 2019. Available from: https://www.drogenbeauftragte.de/fileadmin/dateien-dba/Drogenbeauftragte/4_Presse/1_Pressemitteilungen/2019/2019_IV.Q/DSB_2019_mj_barr.pdf.
- Grant JE, Chamberlain SR, Schreiber L, Odlaug BL. Neuropsychological deficits associated with cannabis use in young adults. Drug Alcohol Depend. 2012;121(1–2):159–62.External Resources
- Battisti RA, Roodenrys S, Johnstone SJ, Pesa N, Hermens DF, Solowij N. Chronic cannabis users show altered neurophysiological functioning on Stroop task conflict resolution. Psychopharmacology. 2010;212(4):613–24.External Resources
- McKetin R, Parasu P, Cherbuin N, Eramudugolla R, Anstey KJ. A longitudinal examination of the relationship between cannabis use and cognitive function in mid-life adults. Drug Alcohol Depend. 2016;169:134–40.External Resources
- Hirst RB, Watson J, S Rosen A, Quittner Z. Perceptions of the cognitive effects of cannabis use: a survey of neuropsychologists’ beliefs. J Clin Exp Neuropsychol. 2019;41(2):133–46.External Resources
- Skalski LM, Towe SL, Sikkema KJ, Meade CS. Memory impairment in HIV-infected individuals with early and late initiation of regular marijuana use. AIDS Behav. 2018;22(5):1596–605.External Resources
- Di Marzo V, Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics. 2015 Oct;12(4):692–8.External Resources
- Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018 Mar 13;19(3):E833.
- Bozkurt TE. Endocannabinoid system in the airways. Molecules. 2019 Dec 17;24(24):E4626.External Resources
- Oláh A, Szekanecz Z, Bíró T. Targeting cannabinoid signaling in the immune system: “high”-ly exciting questions, possibilities, and challenges. Front Immunol. 2017 Nov 10;8:1487.External Resources
- Chiurchiù V, Battistini L, Maccarrone M. Endocannabinoid signalling in innate and adaptive immunity. Immunology. 2015 Mar;144(3):352–64.External Resources
- Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995;48 (3):443–50.
- Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199–215.External Resources
- Khanolkar AD, Abadji V, Lin S, Hill WA, Taha G, Abouzid K, et al. Head group analogs of arachidonylethanolamide, the endogenous cannabinoid ligand. J Med Chem. 1996;39(22):4515–9.External Resources
- Hillard CJ, Manna S, Greenberg MJ, DiCamelli R, Ross RA, Stevenson LA, et al. Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB1). J Pharmacol Exp Ther. 1999;289(3):1427–33.
- Di Marzo V, Bisogno T, De Petrocellis L, Brandi I, Jefferson RG, Winckler RL, et al. Highly selective CB1 cannabinoid receptor ligands and novel CB1/VR1 vanilloid receptor “hybrid” ligands. Biochem Biophys Res Commun. 2001;281: 444–51.External Resources
- Bowles NP, Karatsoreos IN, Li X, Vemuri VK, Wood JA, Li Z, et al. A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc Natl Acad Sci U S A. 2015;112(1):285–90.External Resources
- Ross RA, Brockie HC, Stevenson LA, Murphy VL, Templeton F, Makriyannis A, et al. Agonist-inverse agonist characterization at CB1 and CB2 cannabinoid receptors of L759633, L759656 and AM630. Br J Pharmacol. 1999;126:665–72.External Resources
- Rinaldi-Carmona M, Barth F, Millan J, Derocq JM, Casellas P, Congy C, et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J Pharmacol Exp Ther. 1998;284(2):644–50.
- Howlett AC, Abood ME. CB(1) and CB(2) receptor pharmacology. Adv Pharmacol. 2017;80:169–206.External Resources
- Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009 Jan;89(1):309–80.External Resources
- Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012 Oct 4;76(1):70–81.External Resources
- Barrie N, Manolios N. The endocannabinoid system in pain and inflammation: its relevance to rheumatic disease. Eur J Rheumatol. 2017 Sep;4(3):210–8.External Resources
- Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015 May;36(5):277–96.External Resources
- Gruden G, Barutta F, Kunos G, Pacher P. Role of the endocannabinoid system in diabetes and diabetic complications. Br J Pharmacol. 2016 Apr;173(7):1116–27.External Resources
- Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016 Apr 1;79(7):516–25.External Resources
- Chua JT, Argueta DA, DiPatrizio NV, Kovesdy CP, Vaziri ND, Kalantar-Zadeh K, et al. Endocannabinoid system and the kidneys: from renal physiology to injury and disease. Cannabis Cannabinoid Res. 2019 Mar 13;4(1):10–20.External Resources
- Tam J, Liu J, Mukhopadhyay B, Cinar R, Godlewski G, Kunos G. Endocannabinoids in liver disease. Hepatology. 2011 Jan;53(1):346–55.External Resources
- Cascini F, Aiello C, Di Tanna G. Increasing delta-9-tetrahydrocannabinol (Δ-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Curr Drug Abuse Rev. 2012 Mar;5(1):32–40.
- McLaren J, Swift W, Dillon P, Allsop S. Cannabis potency and contamination: a review of the literature. Addiction. 2008 Jul;103(7):1100–9.External Resources
- Freeman TP, Groshkova T, Cunningham A, Sedefov R, Griffiths P, Lynskey MT. Increasing potency and price of cannabis in Europe, 2006–16. Addiction. 2019 Jun;114(6):1015–23.External Resources
- Dujourdy L, Besacier F. A study of cannabis potency in France over a 25 years period (1992–2016). Forensic Sci Int. 2017 Mar;272:72–80.External Resources
- Rømer Thomsen K, Lindholst C, Thylstrup B, Kvamme S, Reitzel LA, Worm-Leonhard M, et al. Changes in the composition of cannabis from 2000–2017 in Denmark: analysis of confiscated samples of cannabis resin. Exp Clin Psychopharmacol. 2019 Aug;27(4):402–11.
- Niesink RJ, Rigter S, Koeter MW, Brunt TM. Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005–15. Addiction. 2015 Dec;110(12):1941–50.External Resources
- Chandra S, Lata H, ElSohly MA, Walker LA, Potter D. Cannabis cultivation: methodological issues for obtaining medical-grade product. Epilepsy Behav. 2017 May;70(Pt B):302–12.External Resources
- ElSohly MA, Mehmedic Z, Foster S, Gon C, Chandra S, Church JC. Changes in cannabis potency over the last 2 decades (1995–2014): analysis of current data in the United States. Biol Psychiatry. 2016;79(7):613–9.External Resources
- Rigter S, Bossong M. THC-concentraties in wiet, nederwiet en hasj in Nederlandse coffeeshops (2018–2019). In: Drugs Informatie en Monitoring Systeem (DIMS), Programma Drug Monitoring and Policy. Utrecht: Trimbos-instituut; 2019. p. 2–76.
- Lebel C, Beaulieu C. Longitudinal development of human brain wiring continues from childhood into adulthood. J Neurosci. 2011 Jul 27;31(30):10937–47.External Resources
- Gogtay N, Giedd JN, Lusk L, Hayashi KM, Greenstein D, Vaituzis AC, et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci U S A. 2004 May 25;101(21):8174–9.External Resources
- Colver A, Longwell S. New understanding of adolescent brain development: relevance to transitional healthcare for young people with long term conditions. Arch Dis Child. 2013 Nov;98(11):902–7.External Resources
- Barnea-Goraly N, Menon V, Eckert M, Tamm L, Bammer R, Karchemskiy A, et al. White matter development during childhood and adolescence: a cross-sectional diffusion tensor imaging study. Cereb Cortex. 2005 Dec;15(12):1848–54.External Resources
- Abitz M, Nielsen RD, Jonesz EG, Lauren H, Pakkenberg NGB. Excess of neurons in the human newborn mediodorsal thalamus compared with that of the adult. Cereb Cortex. 2007;17: 2573–8.External Resources
- Kaag AM, Schulte MHJ, Jansen JM, van Wingen G, Homberg J, van den Brink W, et al. The relation between gray matter volume and the use of alcohol, tobacco, cocaine and cannabis in male polysubstance users. Drug Alcohol Depend. 2018 Jun 1;187:186–94.External Resources
- Whitaker KJ, Vértes PE, Romero-Garcia R, Váša F, Moutoussis M, Prabhu G, et al. Adolescence is associated with genomically patterned consolidation of the hubs of the human brain connectome. Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):9105–10.External Resources
- Giedd JN, Blumenthal J, Jeffries NO, Castellanos FX, Liu H, Zijdenbos A, et al. Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci. 1999 Oct;2(10):861–3.External Resources
- Lisano JK, Kisiolek JN, Smoak P, Phillips KT, Stewart LK. Chronic cannabis use and circulating biomarkers of neural health, stress, and inflammation in physically active individuals. Appl Physiol Nutr Metab. 2019 Jul 18;45(3):258–63.External Resources
- Angelucci F, Ricci V, Spalletta G, Pomponi M, Tonioni F, Caltagirone C, et al. Reduced serum concentrations of nerve growth factor, but not brain-derived neurotrophic factor, in chronic cannabis abusers. Eur Neuropsychopharmacol. 2008 Dec;18(12):882–7.External Resources
- Jockers-Scherübl MC, Matthies U, Danker-Hopfe H, Lang UE, Mahlberg R, Hellweg R. Chronic cannabis abuse raises nerve growth factor serum concentrations in drug-naive schizophrenic patients. J Psychopharmacol. 2003 Dec;17(4):439–45.External Resources
- Jockers-Scherübl MC, Danker-Hopfe H, Mahlberg R, Selig F, Rentzsch J, Schürer F, et al. Brain-derived neurotrophic factor serum concentrations are increased in drug-naive schizophrenic patients with chronic cannabis abuse and multiple substance abuse. Neurosci Lett. 2004 Nov 16;371(1):79–83.External Resources
- Jockers-Scherübl MC, Rentzsch J, Danker-Hopfe H, Radzei N, Schürer F, Bahri S, et al. Adequate antipsychotic treatment normalizes serum nerve growth factor concentrations in schizophrenia with and without cannabis or additional substance abuse. Neurosci Lett. 2006 Jun 12;400(3):262–6.External Resources
- Bracci-Laudiero L, Aloe L, Levi-Montalcini R, Buttinelli C, Schilter D, Gillessen S, et al. Multiple sclerosis patients express increased levels of b-nerve growth factor in cerebrospinal fluid. Neurosci Lett. 1992;147:9–12.External Resources
- Bracci-Laudiero L, Aloe L, Levi-Montalcini R, Galeazzi M, Schilter D, Scully JL, et al. Increased levels of NGF in sera of systemic lupus erythematosus patients. NeuroReport. 1993;4:563–5.External Resources
- Aalto K, Korhonen L, Lahdenne P, Pelkonen P, Lindholm D. Nerve growth factor in serum of children with systemic lupus erythematosus is correlated with disease activity. Cytokine. 2002;20:136–9.External Resources
- Keimpema E, Tortoriello G, Alpár A, Capsoni S, Arisi I, Calvigioni D, et al. Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons. Proc Natl Acad Sci U S A. 2013 Jan 29;110(5):1935–40.External Resources
- Wang ZY, McDowell T, Wang P, Alvarez R, Gomez T, Bjorling DE. Activation of CB1 inhibits NGF-induced sensitization of TRPV1 in adult mouse afferent neurons. Neuroscience. 2014 Sep 26;277:679–89.External Resources
- Augustin SM, Lovinger DM. Functional relevance of endocannabinoid-dependent synaptic plasticity in the central nervous system. ACS Chem Neurosci. 2018 Sep 19;9(9):2146–61.External Resources
- Blest-Hopley G, O’Neill A, Wilson R, Giampietro V, Bhattacharyya S. Disrupted parahippocampal and midbrain function underlie slower verbal learning in adolescent-onset regular cannabis use. Psychopharmacology. 2019 Dec 9. Online ahead of print.External Resources
- Miguez MJ, Chan W, Espinoza L, Tarter R, Perez C. Marijuana use among adolescents is associated with deleterious alterations in mature BDNF. AIMS Public Health. 2019 Jan 17;6(1):4–14.
- Meier MH, Schriber RA, Beardslee J, Hanson J, Pardini D. Associations between adolescent cannabis use frequency and adult brain structure: a prospective study of boys followed to adulthood. Drug Alcohol Depend. 2019 Sep 1;202:191–9.External Resources
- Di Forti M, Quattrone D, Freeman TP, Tripoli G, Gayer-Anderson C, Quigley H, et al. The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study. Lancet Psychiatry. 2019 May;6(5):427–36.
- Harvey MA, Sellman JD, Porter R, Frampton CM. The relationship between non‐acute use of cannabis and cognition. Drug Alcohol Rev. 2007;26:309–19.External Resources
- Legleye S, Obradovic I, Janssen E, Spilka S, Le Névzet O, Beck F. Influence of cannabis use trajectories, grade repetition and family background on the school-dropout rate at the age of 17 years in France. Eur J Public Health. 2010;20:157–63.External Resources
- Horwood JL, Fergusson DM, Hayatbakhsh MR, Najman JM, Coffey C, Patton GC, et al. Cannabis use and educational achievement: findings from three Australasian cohort studies. Drug Alcohol Depend. 2010;110:247–53.External Resources
- Degenhardt L, Coffey C, Carlin JB, Swift W, Moore E, Patton GC. Outcomes of occasional cannabis use in adolescence: 10‐year follow‐up study in Victoria, Australia. Br J Psychiatry. 2010;196:290–5.External Resources
- Fergusson DM, Horwood JL, Beautrais AL. Cannabis and educational achievement. Addiction. 2003;98:1681–92.External Resources
- Fergusson DM, Boden JM. Cannabis use and later life outcomes. Addiction. 2008;103:969–76.External Resources
- Hyggen C. Does smoking cannabis affect work commitment? Addiction. 2012;107:1309–15.External Resources
- Danielsson AK, Falkstedt D, Hemmingsson T, Allebeck P, Agardh E. Cannabis use among Swedish men in adolescence and the risk of adverse life course outcomes: results from a 20 year-follow-up study. Addiction. 2015 Nov;110(11):1794–802.External Resources
- Daniel JZ, Hickman M, Macleod J, Wiles N, Lingford-Hughes A, Farrell M, et al. Is socioeconomic status in early life associated with drug use? A systematic review of the evidence. Drug Alcohol Rev. 2009 Mar;28(2):142–53.External Resources
- Sachs J, McGlade E, Yurgelun-Todd D. Safety and toxicology of cannabinoids. Neurotherapeutics. 2015 Oct;12(4):735–46.External Resources
- Schoeler T, Bhattacharyya S. The effect of cannabis use on memory function: an update. Subst Abuse Rehabil. 2013 Jan 23;4:11–27.External Resources
- Benbadis SR, Sanchez-Ramos J, Bozorg A, Giarratano M, Kalidas K, Katzin L, et al. Medical marijuana in neurology. Expert Rev Neurother. 2014 Dec;14(12):1453–65.External Resources
- McCormick MA, Shekhar A. Review of marijuana use in the adolescent population and implications of its legalization in the United States. J Drug Metabol Toxicol. 2014;5:2.
- Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014 Jun 5;370(23):2219–27.External Resources
- Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, et al. Effect of long-term cannabis use on axonal fibre connectivity. Brain. 2012 Jul;135(Pt 7):2245–55.External Resources
- Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):E2657–64.External Resources
- James A, James C, Thwaites T. The brain effects of cannabis in healthy adolescents and in adolescents with schizophrenia: a systematic review. Psychiatry Res. 2013 Dec 30;214(3):181–9.External Resources
- Rogeberg O. Correlations between cannabis use and IQ change in the Dunedin cohort are consistent with confounding from socioeconomic status. Proc Natl Acad Sci U S A. 2013;110:4251–4.External Resources
- Pope HG Jr, Gruber AJ, Hudson JI, Cohane G, Huestis MA, Yurgelun-Todd D. Early-onset cannabis use and cognitive deficits: what is the nature of the association? Drug Alcohol Depend. 2003;69:303–10.External Resources
- Gruber SA, Sagar KA, Dahlgren MK, Racine M, Lukas SE. Age of onset of marijuana use and executive function. Psychol Addictive Behav. 2011;26(3):496–506.External Resources
- Ehrenreich H, Rinn T, Kunert HJ, Moeller MR, Poser W, Schilling L, et al. Specific attentional dysfunction in adults following early start of cannabis use. Psychopharmacol. 1999;142:295–301.External Resources
- Mensen VT, Vreeker A, Nordgren J, Atkinson A, de la Torre R, Farré M, et al. Psychopathological symptoms associated with synthetic cannabinoid use: a comparison with natural cannabis. Psychopharmacology. 2019 Sep;236(9):2677–85.External Resources
- Crane NA, Schuster RM, Fusar-Poli P, Gonzalez R. Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences and sex differences. Neuropsychol Rev. 2013;23:117–37.External Resources
- Crane NA, Schuster RM, Mermelstein RJ, Gonzalez R. Neuropsychological sex differences associated with age of initiated use among young adult cannabis users. J Clin Exp Neuropsychol. 2015;37:389–401.External Resources
- Rubino T, Prini P, Piscitelli F, Zamberletti E, Trusel M, Melis M, et al. Adolescent exposure to THC in female rats disrupts developmental changes in the prefrontal cortex. Neurobiol Dis. 2015 Jan;73:60–9.External Resources
- Prini P, Rusconi F, Zamberletti E, Gabaglio M, Penna F, Fasano M, et al. Adolescent THC exposure in female rats leads to cognitive deficits through a mechanism involving chromatin modifications in the prefrontal cortex. J Psychiatry Neurosci. 2018 Mar;43(2):87–101.External Resources
- Zamberletti E, Gabaglio M, Grilli M, Prini P, Catanese A, Pittaluga A, et al. Long-term hippocampal glutamate synapse and astrocyte dysfunctions underlying the altered phenotype induced by adolescent THC treatment in male rats. Pharmacol Res. 2016 Sep;111:459–70.External Resources
- Schneider M, Koch M. Chronic pubertal, but not adult chronic cannabinoid treatment impairs sensorimotor gating, recognition memory, and the performance in a progressive ratio task in adult rats. Neuropsychopharmacology. 2003;28(10):1760–89.External Resources
- Renard J, Krebs MO, Jay TM, Le Pen G. Long-term cognitive impairments induced by chronic cannabinoid exposure during adolescence in rats: a strain comparison. Psychopharmacology. 2013;225(4):781–90.External Resources
- Renard J, Rushlow WJ, Laviolette SR. What can rats tell us about adolescent cannabis exposure? Insights from preclinical research. Can J Psychiatry. 2016 Jun;61(6):328–34.External Resources
- Steel RW, Miller JH, Sim DA, Day DJ. Learning impairment by Δ(9)-tetrahydrocannabinol in adolescence is attributable to deficits in chunking. Behav Pharmacol. 2011 Dec;22(8):837–46.External Resources
- Miller ML, Chadwick B, Dickstein DL, Purushothaman I, Egervari G, Rahman T, et al. Adolescent exposure to Δ(9)-tetrahydrocannabinol alters the transcriptional trajectory and dendritic architecture of prefrontal pyramidal neurons. Mol Psychiatry. 2019 Apr;24(4):588–600.
- Bruijnzeel AW, Knight P, Panunzio S, Xue S, Bruner MM, Wall SC, et al. Effects in rats of adolescent exposure to cannabis smoke or THC on emotional behavior and cognitive function in adulthood. Psychopharmacology. 2019 Sep;236(9):2773–84.External Resources
- Ellgren M, Artmann A, Tkalych O, Gupta A, Hansen HS, Hansen SH, et al. Dynamic changes of the endogenous cannabinoid and opioid mesocorticolimbic systems during adolescence: THC effects. Eur Neuropsychopharmacol. 2008 Nov;18(11):826–34.External Resources
- Wilson J, Freeman TP, Mackie CJ. Effects of increasing cannabis potency on adolescent health. Lancet Child Adolesc Health. 2019 Feb;3(2):121–8.External Resources
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